qui peut tout aussi bien chlorure d'oxidede carbone, offre une composition si simple et si remarquable que, s'il

r\177alisait toutes les r\177actions que I'on a droit d'en esp\177rer,

\177tre consid\177r\177

L'acidechloroxicarbonique,
comme
un

on parviendrait reproduire, les plus curieuses de la chimie

\177
\177

Acad\177mie

desSciences on december 6 1 and

\177

son aide, les combinaisons organique... (Read to the french

\177

31, 833). 1

Die Chlorkohlens\177ure als das ChlorLir

besitzt

setzung, man die Recht davon erwarten gen

wL\177rde,

w (Phosgen), elche eben so gut des Kohlenoxyds betrachtet werden kann, eine so einfache und merkwLirdige Zusammendab wenn es allen Reaktionen entspr\177che, die

k6nnte, man damn gelandie merkwLidigsten Zusammensetzungen der organischen Chemiewieder hervorzubringen....(Translation published in Annalen der Chemie
\177

\177).

acid (phosgene)which can also be Chloroxycarbonic consideredas a carbon oxide chloride, offers a composition which is simple and yet remarkable. If it producesall the reactions we expectof it, we will be able to reproduce some of the most fascinating combinations in organic chemistry.

lean Baplisle
Dumas

Jean Baptiste Dumas

Canne, France), French chemist and politician. Tutor at the EcolePolytechnique (Paris one of the founders of the EcolePolytechnique (Paris ), one of the founders of the Ecole Centrale des Arts et Planufactures (Paris Professorof Chemistry at the facult\177 desSciences de Paris, at the facult\177 de Pl\177decine, Lecturer at the desSciences Coll\177ge de france, Member of the Acad\177mie electedat the Acad\177mie Fran(::aise (1875).)))

(b.1800 1821), 1821

Al\177s,

France

- d.1884

1829),

(1832),

Prefa(e

At the early beginnings, organic chemistry was taken by the scientific community as the chemistry of living matter. After the discovery of the synthesis of urea by W\177hler in organic chemistry was defined as the chemistry of carbon-containing compounds. Almost the entire amount of the carbon available on the earth surfaceexists in the form of carbonic acid (free or as calcium salts) and in fossil fuels obviously originated from living matter. It is well known that carbon dioxide is the necessaryingredient in the life cycle of animal and

1828,

as Therefore, rganic chemistry must be considered o relatedto the chemistry of carbon dioxide and its strongly
plants.

derivatives.
\177{

Carbonic acid dichloride called discovered by John Davy in still nowadays the only appears efficient simple activated form of carbon dioxide, and despite intensive researchdone to replace it with less noxious starting material, phosgeneremains a substitute for carbon dioxide, l\177oreover, becauseof the presenceof acid chloridefunctions, phosgeneexhibits a large range of other chemical reactionswhich make it a very useful multipurpose tool in organic chemistry. The first chemical studies on phosgenechemistry have been associatedwith the development of organic chemisIn the period e try during its classical ra
\177,

1812,

\177

(18201940).

after world war two,

a tremendous growth

phosgenechemistry has experienced and wide interest. Vast numbers)))

Preface
of scientific papers and patents have been published by several thousands of organic chemists working in academic
and industrial
By now,
I

Preface
wish to express y gratitude to all my Furthermore, m from SNPE group and from the US and French colleagues Universities who have participated along these last 25 in the development of news aspects of phosgene years chemistry.
Finally,
I

researchlaboratories. although phosgene chemistry

with well

as is established

books, chemistry and reviews, it seemsthat truly important monographs facets of new and unusual aspects are somewhat neglected. In this book, have tried to provide an essentially complete survey of the work done for a quarter century at
documented text
I

a fully-grown

would

particularly

like

to acknowledge Pro-

fessorRoy Olofson(The Pennsylvania

of phosgeneand related compounds, with specialemphasis on unusual, unexpected and new reactionsor applications. Phosgene is widely used in organic chemistry as a = building block providing the C O such as in carbamates, carbonates,isocyanates, reas, heterocycles tc., or as a e u reagent for chlorination, dehydration, alkylation, de-alkylaSNPE group
in the

chemistry

State University) for his unfailing enthusiastic support during our more than ten years collaboration on the development of new synthetic reagentsand preparative methods in phosgeneand related compounds chemistry. am deeply grateful to him for his
I

patience,wisdom and kidness scientist and a teacher.

and for being

a model as a

tion, protection Consequently,

and activation etc. have chosento divide this

I

book in

two Buthiers,

volumes :
Volume on physical

some considerations introduction, propertiesand chemical reactivity, and four

includes derivatives

Jean-Pierre SENET G. France Seine-ebMarne,

August
1997)))

chapters devoted to phosgeneand

as building

blocks.
Volume vatives

2 presentsapplicalEions of phosgeneand derias reagents and the general conclusion. Of course,selectionof topics to be included in these
I

two volumes is undoubtedly influenced by the author's interest. So would like to make here my apolopersonal who may found their own gies to any of my colleagues work discussed inadequately.

because nothing comes from nothing\177 in other becauseeverything has predecessors,is important it to note that if .John Davy discoveredphosgene,Jeanits chemistry and may be theBaptiste Dumas invented reforeconsideredas the true pioneerin the chemistry of T phosgene. o take stock of this question, have included in the first volume one sectiondedicatedto the history of phosgenechemistry.
Also\177

terms

\177

\177

Contents first volume

(ll\177pter Introduction

Section Section Section

Section1-4 Classification of phosgenereactions

(hapter

\177

o Characteristics f phosgene

Section2-1 Physical properties Section2-2 Chemical reactivity of phosgene

(hapter

\"\177

Phosgeneand derivatives as building blocks Section3-1 Reaction at a carbon center

Section3-2 Reactionsat an oxygen or sulfur center 3-2-1Highlights of some particular chloroformates

starting
from

3-2-2Reaction

of phosgene at oxygen center of unconventional substrates

of of of

3-2-2-1eaction R 3-2-2-2eaction R 3-2-2-3eaction R

3

................................ 1-1 ............ 1-2 10 .................... 1-3 .................. 11 ... 1 1 15 ........................ 15 ..................... 16 .......... ............. ................ 31 ........................ .................. ..................... ......................
7
History

of phosgenechemistry

Toxicity

of phosgene Breakdown of consumption

of

phosgenein

the industry

27

27

alcohols or phenols

34

phosgene with glycerol phosgene with epoxides phosgene with aldehydes

....................
and

48 48

224

ketones.novel c\177-chlorinated and related reagents

Vinylicchloroformates, carbamates

53 ...................................... carbonates 81 ............................................

and

chloroformates

Section3-3 : Reactions at a nitrogen center 3-3-1 Highlights of some reactions of phosgene

with amines, imines, oxazolines

3-3-2 Reaction

of 1-chloroalkyl chloroformates with amines, synthesis and useful applications of 1-chloroethyl carbamates 3-3-3 1-Chloroalkyl carbonates as acylating agents for the synthesis of carbamates

......... 105 105 .................. 115 .................... ..................

129)))

Contentsirst volume f
3-3-4 Reaction 3-3-5 Reaction
of phosgene and its derivatives ureas and amides

D
132

Introduction

with carbamates,

of phosgene with sulfonamides, preparation of sulfonyl isocyanates formation

Section3-4 : Ring 3-4-1Cyclisation

3+2

between two oxygen atoms Cyclisation between an oxygen and a nitrogen atoms

3-4-3Cyclisation 3-4-4Cyclisation
atoms

................. ................. .................. 143 ........... .............................................. 151 ......... ................................................................1)

141
reactions 143
between two nitrogen atoms between a nitrogen and a sulfur

167

173

lllslory of
\177hemislry

The story of phosgenediscovery (Ref.

phosgene
(\177ontents

second volume
Phosgeneand derivatives as reagents Section4-I Chlorination
(Acid chlorides, Imidoyl and Chloroiminium chlorides, Alkyl Chlorides, Chlorinated Phosphorous compounds chlorination of heterocycles, etc.)

In the early beginning of the 19th century, chlorine gas was still uniformly considered a combination of muriatic as acid (hydrochloric acid) and oxygen called oxymuriatic

Chapter4

acid

\177.

Davy, Sir Humphry Davy's the opinion that oxymuriatic younger brother, expressed acid was, as a matter of fact, an elementary substance. in

However,

Dr. 1810, John

Section4-2 Section4-3

Dehydration

This opinion was not at all acceptedand several scientists, in order to refute the arguments of Dr. Davy, tried therefore to remove oxygen content of oxymuriatic acid by treatment
with

(Nitriles and Isonitriles) Alkylation

charcoal at a

white

of phenols and amines

activation

monoxide
M
Muriat\177c

[Scheme
+

1].

heat or

with

carbon
MO

Section4-4 Protection and

functional

of

0
Oxygen

\177

groups (Amino acids protection and activation, protection of hydroxyl groups, activation of carboxylic acids, etc.)

acid

Oxymuriat\177c

acid

CO
Carbon monoxide

De-oxygenation
=.

M
Murlatlc

+
acid

CO2

Section4-5

N and

O- dealkylation
Scheme 1 This versy
\177

Expected

de- oxygenation opening

official

of oxymuriatic
\177

acid

(chlorine).

Chapter

Conclusion
Is any conceivable nontoxic option to overcome phosgene in its industrial applications ?

was the

between Dr. John

of the so called chlorine controDavy and Dr. Murray, fervent

supporter of the

theory. This

debate took

the form

7)))

Introduction
to Nicholson's Journal >), both from their own experiments. arguing In an experiment of fundamental importance, after a mixture of one volume of carbonic oxide having exposed and one volume of oxymuriatic acid to bright sunshine, Dr. Davy noticed that the color of the chlorine has entirely disappeared,and that the remaining gas occupiedthe of space one volume. After addition of ammonia, he found no tracesof carbonic oxide and observed effervescence an
<<

Introduction
contributed

of letters
authors

The infancy

of the phosgenechemistry

of

the ammoniacal salt formed with

nitric

acid. He also

spite of his neat discovery, Dr. Davy has not foreas prolific potentiality of phosgene an outstanding block and reagent in chemistry. However, while building with ammonia, he was very closeto anotreating phosgene ther discovery of extreme importance, that of the elucidation of the nature of urea. Dr. Davy noticed that phosgene dissolvesin alcohol,
In

seenthe

gas resulting from the evident action of oxymuriatic acid and carbonic oxide did not fume when thrown into atmosphereand that it had a most intolerable
suffocating

noticed that the new

but without
In

1833,

mentioning any reaction. French chemist Jean-Baptiste umas while D

odor and that water absorbedit very slowly. These results were however again contestedby Dr.

Murray who, to support his opinion that oxymuriatic acid and carbon monoxide do not react, quoted unsuccessful trials from French chemists Gay-Lussac Thenard : and
<<

alcohol in a flask containing phosgene, first synthetic derivative (Ref. He noticed a strong and instant heating, and after work-up and analysis, he identified the resulting compound as a new chloroxicarbonic ether (ethyl chloroformate). adding

absolute ethyl

discovered its

2).

muriatique
r\177 \177t\177

sec,et/egaz oxide de carbonepr\177paavecle fer et le carbonatede barite, quelque forte qu'ait la lumisre laquelle on les a exposes, enfin quelque
oxl\177n\177
\177 \177t\177 \177.

...mais

Dumas
<(

immediately

\177

quelque

dosequ'on

air

m\177l\177

le gaz acide

of phosgenechemistry
\177tre consid\177r\177

had an inkling of the with this prediction

importance

le contact, il n'y a point eu d'action long qu'ait At last, in an important and well-argued letter read to the Royal Society on February Dr. Davy refuted all the arguments of Dr. Murray and, on the basis of careful and indisputable experiments, proved the reality of the new gas [Scheme

6, 1812,

qui peut tout aussi bien comme un chlorure d'oxide carbone,offre de une composition si simple et si remarquable que, r)alisait routes les r\177actions que I'on adroit d'en esp)rer, on parviendrait son aide,les combinaisons reproduire,
\177 \177

L'acidechloroxicarbonique,

les plus curieusesde la chimie organique Translation Phosgeneexhibits such a simple

\177.
\177

and

2].

remarkable composition that, should

CI2
Chlorine
\"

+
(1 vol.)
acid
\"

CO
Carbon monoxide of phosgene.

Light

realizeall the reactions one is entitled to hopefor, one could reproduce,

it
\177

)
vol.)

COCI 2
Phosgene ( 1
vol)

thanks to it, the strangest combinations

in organic chemistry All investigations clearly fulfilled
\177.

(1

Oxymurlat\177c

Scheme 2

1-he discovery

the

since then have expectation of

To designateit, he suggesteda simple name,

that

of

Phosgene (or phosphene), , and to produce

light
)\177 \177

from

ancient Greek roots

Dumas who may be thereforeconsideredas the pioneerin the chemistry of phosgene.

Jean-Baptiste DUMAS (1800IB84) Pioneer in the Chemistry of Phosgene

\177.

9)))

Tntrod uction

uction Tntrod
highly

Phosgene is a

toxic gas which was

used as a

13
ol phosgene
\177nSlllnplion

chemical weapon during World War I.

At high concentration, it causessevere pulmonary irritation and can induce delayed pulmonary edema.It is the reasonwhy all personswho have been exposedto phosgene,even in very low concentration, must see a physician

Breakdown

in this field is generally Although information kept confidential, worldwide phosgeneproduction is estimated to range from 6 to 8 millions tons/year. The breakdown of phosgeneconsumption is the following

ihe industry

immediately.

concentrations in

Some relationships between phosgene

air and physiological

are summarized in table The table son betweensome toxic gases.

Perception of odor Recognition of odor
Irritation in

1-1.

effectson

1-2 gives

humans

compari-

-: -

Di and polyisocyanates (TDI, THDI) for polyurethanes Aromatic polycarbonates

Hanufacture

of fine chemicals

Beginning of lung damage Clinical pulmonary edema

L(CT)0 L(CT)50
lbble
(\177et

L(CT)100
I 1
\177).

.............................................. ............................................1.5 ......... ................................... ................................... ................................................................. ............................................................... .............................................................

eyes,nose,throat,
and bronchi

30 1.50 ~ 300 .500 ~ 1300

> > > > >

0.4 ppm
ppm ppm

The consumption of phosgenefor fine chemicals, about 300,000 T/year is roughly divided into : used as poly50% for perestersand percarbonates
merization initiators,

........................... ........................ .....................

85% 10%
and dyestuffs.

ppm-min ppm-min

25 % for agrochemicals, 25 % for pharmaceuticals

ppm-min ppm-min

ppm-min

Con\177enttatiot\177

effect

relattonshtps

of

phosqene exposure tn

hamcms

14
exp.

Gas
Phosgene
Chlorine

Odoridentification
ppm

min L(CT)0-30

ppm

Since the pioneering study by Dumas, phosgene devoted to fine chemicals, has grown chemistry, especially
and still remains in an active field of investitremendously gation with papersand patents published eachyear. can be diviAlmost all the chemical reactions phosgene of ded into two classes,epending on wether the structural d unit remains in the final product or not.

1.5
1
No

10
873 4 000 30 000

phosgene

real:lioll s

2500

Carbon monoxide
Ammonia

5
between some toxic gases,

Table 1-2 Comparison :

First

Due to these high toxicity properties, the presenceof on large quantities of phosgene a site must be strictly treated as major hazard. The regulatory requirements in transportation and safety know-how in the handling and storage of phosgene, have restricted its uses to specialized companies. Custom synthesis is a common practice in this field, because the transportation of raw materials to phosgene producers is preferredto the transportation of phosgeneitself.

introduce

as class: Reaction of phosgene a building block to Someexamples the structural unit carbonyl
\177

\177.

are given

in

table

1-3.

10

11)))

Tntroduction
Substrate Aromatic Product Ar-C-CI
Acid chloride

Tntroduction
class Second : Phosgeneand
Su bstrate
Carboxylic

derivatives

as reagents

: Ar-H

Product

O
Ar-C-Ar
Aromatic

II

ketone

acid

: R-COOH
(+

n-C-Cl

Acidchlorlde

O
Alcohol or

II

O
Chloroformate

II

phenol: R-OH

R-O-C-CI
II

R1OCOCI)

Esler R-C-O'Rlll

R-O-C- O-R
II

Carbonate

Alcohol : R-OH

R- CI

Alkyl

chloride

Primary amine

: RNH2

R-

=C= O

socyanate

N,N-Disubstituted

: R 1R2NCHO

R\177\\

Cl\"

formamide
RI\\

R2

N---CHCI

Vilsrneier

sail

Secondary or tertiary R 1 R 2 R3N (R

amine

:
R

\"

N-C-CI chlonde
II

Carbamoyl

Primary amide

: R-CONH 2 : R-OCOH

R-C\177N

Nitrile

O
1

3- = H or alkyl)

RI\\ R 2\"

N-C-N

/R 2
Urea

Alkyl

formate

R- O-CHCl2

t ,1-D\177chloromethyl

elher

II

\\R

Phenol

: At-OH : H2N-CHR-COOH

At- OMe

Aryl

methyl

ether

O
cz-Amino acids H2N-CHR-COOH
R\177N..
\177

Amino acid
N-Carboxy

RO-

C-NH-CH-COOH
II I

N-

Protected

amino acid

Anhydride

(NCA)

Tertiary
CI
I

amine:

R 1R2R3N

RI\\ R

3= (R alkyl)
c\177

2z

NH

N-Dealkylated

amine

Aldehydes

: RCHO

R- CH-O-C-CI
II

-Chloro

alkyl

Chloroformate

Aryl methyl ether

: Ar-O-He
(+ PhCOCI
+ catalyst)

Ar-O-\177

\177-\177 Phenol

Aryl

benzoate

Sulfonamide

: FLSO2NH

RSO2-

N----

C=O

At-OH

Sulfonyl

Isocyanate Table

Table I-3

I-4

,\"

Examples

of phosgene and derivatives

as reagents,

Examples

of phosgene reactions to introduce

the group

>C=O.

12
13)))

of Characteristics phosgene

Physical

properlies

At ambient temperature and pressure,phosgeneis a colorlessgas which exhibits an irritating and suffocating odonAt low concentrations, it has a characteristic odor like moldy hay. However, the odor threshold of phosgeneis higher than its toxic limit and one must remember that the senseof smell fails to detect small concentrations in air. Somephysical properties phosgeneare presentedin of

table

2-1.

CAS number Molecular weight Structure

98.92 +

75-44 - 5
= : C-O = C-Cl
nm 0.128 nm 0.168

Planar molecule Inter atomic distances

Melting point Boiling point

130\302\260C

8.2\302\260C

Vapor pressure Vapor density

Liquid density

1.6 atm.
3.42
I

(20\302\260C)

3.99 atm.
(50\302\260C)

(50\302\260C)

1.43
ppm

(O\302\260C)

1.275

Conversion factor

= 4.043 3 m\177/m
of moldy hay

Odor
Table 2-1 Principal

Reminiscent

physical

properties of phosgene,

15)))

Characteristics phosgene of
Chemi(al
rea(\177i\177i\177y

Characteristics phosgene of
be accounted
T gene reactions. wo

of

A large part of phosgenereactivity may for on the basisof two main mechanisms :

phosgene
a)
Nucleophilic attack on carbonyl function

nucleophilicity

-phosgene
substrate
;

catalytic by

paths

are obviously possible

of the

activation

means of an increasing of its

<<

character,, of chloride

activation by improvement anion.

leaving

Concerning phosgene reactions with active hydrogen strates [Scheme.5]

sub-

+Ci\"

Nu--H Scheme 3.

COCI 2

Catalyst
\177

Nu--C--CI o
II

+ HCl

Scheme 5.

b) Electrophilic

related reactions COCl 2

+ MCl Lewis acid

Friedel & Crafts reactions,especially

mechanistic
University in

studies performed with France (Ref. 4) resulted

the help of Nantes in the revelation of

activation based on nucleophilicity of chloride anion in the case of Q+ CI- type catalyst (quaternary ammonium chloride for example).The mechanism of nucleosubstrate

O
+
\\\\

of as an philic assistance these catalysts can be understood increaseof the nucleophilicity of the substrate by proton abstraction followed by the condensation the promoted of anion on the electrophilephosgene) [Scheme6] : (
1/2

Scheme 4.

Becausesome important aspectsof the mechanism of the nucleophilic reactionswith phosgeneseemed somewhat neglectedor unknown in the previous art, SNPE teams have focused their efforts in terms of basic and applied research on the catalysis of such reactions.The
main

Nu--H

Gcr

Nu

..... ......
1/2-

CI

o
+
Q\321\207

goal of

improve industrial

the range of substrates able to reactwith phosgene. As a consequence,his investigation succeeded devet in and lopment of many improved processes the discovery of several previously unknown reactions which are discussed
in this

this active and long investigation was to a phosgenation processesnd to extend

CI-

+ HCI

Cl,\177Nu

Scheme 5. This mechanism has been confirmed by reacting a series of onium chloridesalts with phenol using 3sCI NI\"IR determination as physical probe as shown in table

book.

the 16

The principal obstacleto progress this field has been in difficulty of establishing the catalytic mechanism of phos-

2-2.

17)))

of Characteristics phosgene
Range of

of Characterislics phosgene Line width

Q + CI
(a)
TMCA (b)

1/2
Q+

phosgenation
efficiency HIGH

(Hz) (c)

240

Tetra hexyl ammonium chloride

Benzyl tributyl
MEDIUM

220.5 145.5
141
58
o The success f this
new synthetic route

ammonium

chloride
Tetrabutyl ammonium

to

o\321\236-chodnated

chloride
LOW Benzyl trimethyl ammonium

chloroformates which are very useful intermediates (seechapter 3,section3-2) is strongly dependenton the nucleophilic power of the chloride anion as shown in table

chloride
Catalyst

2-3:
%)

(a)

Phosgenation

of phenol

into phenyl chloroformate

chloride

or

carboxylic GI

acids into
Me

Nucleophilicity

lIChloro ethyl chloroformate

Yield %

acid chlorides

(5 mol.

(Hz)

(b) Tetramethyl

chloroformamidinium

Me N\177
Me\"
I

Me

GI

Benzyl tributyl ammonium

chloride

145.5

95

(c)

Line width of the chloride (solvent

anion

resonance

;n the system onium

chloride
Benzyl trimethyl ammonium

salt/phenol

: CH3CN)
efficiency

Table 2-2.'General correlation between catalyst chloride anion. Study by35CI NMR.

and nucleophilidty

of

58

0
(No reaction)
and

chloride

out that the C-nucleophilicity of chloride anion is also acting. In the courseof our researchrelated with carbonyl compounds, we to the reaction of phosgene

We pointed

between nucleophilicity determined by 35CI NMR Table 2-3 Correlation results obtained in phosgenation of acetaldehyde.

The role of the

nucleophilicity

of the

chloride anion is

chloroformates when treated with phosgenein the presence of a Q+ Cl- catalyst (Ref. 5). The assumed mechanism involves the nucleophilic attack of the chloride of anion on the aldehyde followed by the acylation the intermediate chloroalkoxideanion by phosgene
roalkyl

KCI/18crown 6 as catalysts for the phosgenation of

aldehydes. Tracesof HCl (moisture) inhibit the reaction because than Cl-. HCl 2- anion exhibits much less nucleophilicity such as little toluene Including hydrochloric acid scavenger diisocyanate in the mixture generally solvesthe problem.

[Scheme7]
18

19)))

of arac;eris;icsphosgene
The nucleophilicity of the chloride anion is of coursea of the nature of the counterion To increase the nucleophilicity, one can either or both increase the bulkiness and the dispersal of the positive charge of the counterion. We discoveredthat hexaalkyl guanidinium chlorides are very efficient and powerful phosgenation
function
(\177+.

of Charac;eris;icsphosgene
R

NH

COCI2

/ \177 / N--C--N
R\\ R

COCI 2

II

\\ R R

CIR\\ +

catalysts
R R

[Scheme8]

/CI

2 R2NH
\177-

R \\
NIl

-/ CI+ R
I

R/N\177'N__ R

R,\\

+ R,,,NH

/ R

N/C\177N/
I

R
N
\177-

COCI2 4\1771

+
N

CI-.HCI

X X-

= CI or HCI2 = Me '
HBGCI\"
\"

90oc
Scheme 9

R \\
N

II /C\177

Fi

P%\"

/ N-C-CI
O

-torr) (0.2

' HCl

R/N\177R
Scheme 8
.\"

R=n Bu :
R
chlorides.

HMGCI\"
.\"

R
Preparation

R chlorides

Hexaalkyl

guanidinium

of hexa

alkyl guanidinium

This industrial

these guanidinium salts in a 198_5 on the conversion of carboxylic acids to patent (Ref. 6) acid chlorides with phosgene.In this process,nly o mol. % of HBGCl was required, two orders of magnitude less than the quantities of other catalysts typically used. reactions Many new other applications including phosgene with phenols, thiols, aldehydes, epoxides O-demethylaor
We introduced
tion methods have in this book.

0.02

chloride hydrochloride (HBGCI.HCl)which, as above mentioned, failed as a catalyst in the reaction requiring high C-nucleophilicity of chloride anion. Pure HBGCl may be

leads to process

hexabutylguanidinium

obtained

a solution of HBGCI.HCl with excess The dried (HgSO4)rganic layer is concen10% NaOH. o
by shaking

trated and then nitrogen.

treated at

100\302\260C

under vacuum

for 24 h. The off-white

powder obtained is stored under

been developed later

and

arediscussed

Moreover, these new catalysts may be considered themselves as phosgene derivatives becausethey are made from phosgene and secondary amines by the scheme

depictedbelow [Schemec)]

of The decomposition methyl chloroformate is a very convenient method to establish a nucleophilicity power scale of the chloride anion in onium chlorides, allowing thus to easily comparea priori the catalytic efficiency of different I candidates.t is known that the decarboxylation of methyl Cl- type compounds chloroformate is catalyzed by thus producing only methyl chloride and carbon dioxide accordingto a pure SN 2 reaction (Ref. 7) [Scheme :
(\177+

10]

Q+ Cl\"

CH3--O--C--

\177

CH3Cl

CO2+

Cl\"

Scheme 10 Decomposition of methyl

O
chloroformate
21)))

II

20

of Characlerisli(sphosgene
We used this specific reaction on IR analysis as kinet chemical probe (Ref. 8). Among the various oniuf chlorides commonly encountered,hexabutyl guanidiniuf chloride (HI3GCl) exhibits the highest activity as shown table 2-4
.-

of Chara(terisli(s phosgene

Catalyst HBGCI HHGCI Tetrahexyl ammonium

Relative rate constant

100
47
chloride chloride chloride

42
27

Benzyl tributyl

ammonium

Trioctyl methyl ammonium

Table formate

14
chlo\177

Relative rate constant values of SN 2 decomposition of methyl at in the presencef onium chloride catalysts o For HBGEI, the k value is 12.52in. m 8).
70\302\260E
\1771

24

Scheme 11 Molecular model of hexabutyl Although

guanidinium

chloride

(1%).

(Re\320\210

As
nium

expectedconsidering table 2-4, hexabutyl

chloride
displays higher
catalytic activity

chloride (HMGCI) is hexamethyl guanidinium i its hexabutyl congener,t is very useful in several industrial applications, becauseof its good water solubility, and alsobecauseits hydrochloride is often inso-

lessactive than

guanid than it

analogue. However, HMGCl offers sore becauseof its solubility in water which make advantages easier elimination by aqueous washings and because precipitates in several phosgenation media after removal c phosgeneexcess.
hexamethyl
\177

allow easy luble in organic mediums. Thesetwo properties removal of the catalyst after reaction. of octane thiol proceeds For example, phosgenation to give octyl of in presence HMGCI, even at rapidly thiochloroformate [Scheme

: 12]
n

30\302\260C

HMGOI n

To sum

up, hexabutyl

guanidinium

chloride

exhibit

Oct-S-H + OOOI 2
30\302\260O

\177

Oct-$--O--OI

\321\207

HMGOI.HOI

some particularities

due to its extraordinary bulkiness an, the hydrophobicity of the the n-butyl substituent: the dispersal f the positive charge is somewha o However, counterbalancedy the out of plane distortion of the bulk b
substituents as suggestedby molecular modeling calcul\177 tions on HBGCl using the CSC Chem 3D program (Ref. Due to this kind of geometry and for reasonsof symmetr\177 it is assumed that the chloride anion will be locatedalon the central axis and will interact weakly with the positiv

Scheme 12 Synthesis of n octyl

o
II

thiochloroformate

in presence of HMGCI.

After completion

9'

H gene excess, MGCI.HCIwhich

center[Scheme

: 11]

filtrated thus Another insoluble in all media and thereforeeasily removable by filc S reusable. uch heterogeneous atatration and indefinitely offersmany advantages, particularly in the caseof prolyst ducts difficult to purify by distillation becauseof thermal instability

of the reaction and removal of phosprecipitates completely is giving very pure product (Ref. approach is to have a catalytic system strictly

10).

or too high

boiling point.
23)))

22

Characteristics phosgene of
reported the preparation of silicasupported guanidinium salts, especially pentabutyl propylchloride grafted on silica beads,and their uses guanidinium as phosgenation heterogeneouscatalysts (Ref. For example, starting from macroporous silica glass beads
We have recently

Characteristics phosgene of
t /

11).

having

- diameter :1 characteristics: - specificsurface: 78 m2/g - porous : 0.9cm3/g - OH content :4.8 mol./m 2

the following

salts was supported guanidinium alsowell established reactions sensitive to reversal while in that treatment of aldehydes heating. Thus, we discovered with oxalyl chloride in the presence a naked of catalyst (e.g., BGCI)produces 1-chloroalkyl oxalyl chloridesin H 60-97%yields (Ref. 12)[Scheme
utility

The

of

silica

{{

\177

mm

: 14]
R

O
R...jk.H
+

O
CI\177L.\177CI

volume

FI

we obtained at pilot scalea catalytic of meq./g active sites.

system bearing

0.085
Scheme 14 Reaction
.\"

\177-

HBGCI

.......
\"CI-\" CI

O.\177 O
56-58\302\260C/20mm

= CH : bp 3

The synthesisroute we developedis depictedon scheme13

97% yield

ofexcessxalyl o
with

chloride with aldehydes.

Bu

CI\\ +
I \\

(MeO)3-Si-(CH2)3-NHBu+

N=C--=N
CI
Bu

Bu

(MeO)3Si(CH2) 3

Bu

However,
Bu

aromatic aldehydes or

Bu/

--\177
\177

Bu

/1\"4.
Bu

CA)

(A)

Silica

beads

/
\\

\177 i\177+
N

1\"4\177

heating resulted

in the in

presenceof the catalyst reversion to the aldehyde

fatty

chloral, during distillation and attempts to

with

cr

entirely remove the trituration

HBGCI catalyst, for example by

\\Bu

OH

Final treatment OH with Me3SiCI

\177

OSiMe 3
Si(CH2) 3 r,l.
Bu/\"
\177,,'+

Silica

beads

Bu
\177N

\\Bu

CI-

to the partial solubility of pentane this salt in the non-polar medium. This problem was overcome utilizing the supported by In catalyst above described. a typical example, distilled 1,2,2,2-tetrachloroethyl oxalyl chloride was thus obtained from chloral in 95% yield after 4 h reaction.
failed due

Bu/N\\Bu Scheme 13 Synthesis route to silica-supported

.\"

guanidinium

chloride catalyst.

Sincethis supported catalyst

diameter,
it

is

stable, insoluble

and

can be easily recovered by filtration and be and activity of silica supported stability salts, along with the ability to reusethe solid guanidinium catalyst were demonstrated on repetitive batch phosgenations of carboxylic acids.

composedof mechanically strong particles of 1 reused. he high T

mm

24

25)))

and derivatives as buildin blocks

Phos[lene

,i{eactions
,I (\177rl)on
(\177lll\177r

In the course of several studies, we demonstrated that with aromatics reaction of phosgene the Friedel-Crafts dependscritically on the purity of catalyst, the presenceof water and on the ratio catalyst/substrate. of with aromatics in Generally, condensation phosgene presence of Lewis acids affords benzophenonesas the main products, unless a specialmean is employed to remove : the intermediate complex [Scheme

15]
R

AICI

+ COCI 2

3
\177
\342\200\242

AICI3

O
R R
AICI

\342\200\242

\177

Scheme 15:Friede\177Craftsreacdon

ofphosgene with aromatics.

that the adduct ketone/AlCl stablethan the adduct acid chlofide/AlCl

Note

3 is

much

more

3.

an w developed improved processhich leadsto a very pure product with low content of xanthone [Scheme16]

ether with For example, condensation of diphenyl phosgeneunder Friedel-Crafts conditions gives 4,4'-dipheWe as noxy benzophenone the major product (Ref.

13).

27)))

a as b Phosgenend derivalives building locks

O \177\177 COCl
+

as b a Phosgenend derivalives building locks

Me
AICI

CICH2CH2CI
\177.

Me, 3
\177

Me Me

AlCl 3

2 O

[\177Me

COCI 2

Me

o Xylene

\177\177_ \177O\177
Yield

:85%
143\302\260C

M.P.:
Yield

> 80% Purity > 99.9%

of high
purity

Traces
( < O.1%)
Oxidation
==

O
BTDA

Scheme 15: Preparation

4,4;diphenoxy

benzophenone,

j\177\177\177
dianhydride

High purity ring material

i 4,4'-diphenoxy benzophenones a key star-

Scheme 18.'Synthesis of benzophenone tetracarboxylic

ether-etherketones(PEEK) scheme17

for the production of high molecular weight with terephtaloyl polymers. Thus, its polycondensation chloride in presence of FriedeI-Crafts catalyst gives poly-

Friedel-Crafts reaction of phosgenewith heterocyclic aromatic compounds is also difficult to stop at the acid
chloride

with the structure

depictedon

stage.However,

under chloride

selectedconditions, hetero[Scheme19]
\177,-

aromatics such as thiophene

give thiophenecarbonyl

can be

directly

acylated to (Ref. 1.5)

\1770\177 \1770
Scheme 17, Structural unit of thermoplastic
poly ether ether

'\177\"

Ol /n

COCI 2

CH2CI2
+ AICI 3 +

\177
\177S

ketones

Addition of thiophene at -20c'C the mixture in Phosgene + AICI 3 chloride

S\177 O
Yield
No

CI

: 96%

ether ether ketonesare usedas high performance engineering thermoplastics which offer an unique range of
Poly

Scheme 19

3-isomer

Preparation

of 2-thiophenecarbonyl

propertiesamong
continuous

them

working temperature ; high chemical resistance

of

250\302\260C

hours at temperature

-hydrolysis resistance on service of thousands of in excess f o in steam under

250\302\260C

pressure;
easily processible. Another example is the Friedel-Crafts

chloride is used as intermediate of many pharmaceuticals. For example, its condensation with protected L-4-hydroxyproline followed gives a product claimed as antiinflammaby deprotection tory and antidystrophic agent (Ref. 2-Thiophenecarbonyl
in the synthesis

16).

phosgene reaction

in o.xylene giving 3,3',4,4'-tetramethylbenzophenone and free of isomers(Ref. 14). his substituted T is t benzophenone easily oxidized into benzophenoneetraacid dianhydride (BTDA) widely used for the carboxylic manufacture of polyimides [Scheme with high yield

Nucleophilic addition efficient synthetic route

of vinyl ethers to phosgeneis an to valuable 3-alkoxy and 3-phe-

W noxy acryloyl chlorides. e studied an improved process under specialcatalytic based on literature data (Ref.
conditions

: 18]

[Scherne20]

17)

28

29)))

a a Phosgenend derivatives s building

blo\321\236ks

as a Phosgenendderivatives building
RO

blo\321\236ks

+ RO
Cl Cl

----\"
R.T.
LRO\" \"Cl

c,

HCl

Scheme 20 Phosgenation of vinyl ethers to give

Cl

o \"\177:= CI

Et-O-C-NHSiMe3 -\177-\177.

RO\177
\"\177

O
of Ethyl

II

Me3SiCI

HN o\177OEt

( E- configuration)

3 alkoxyacryloyl

chlorides

Scheme 23 . Preparation

N-alkoxyacryloyl

carbamate

E-3-alkoxyacryloyl chlorides are high potential intermefor organic synthesis, especially the preparation of various heterocycles, such as coumarins [Scheme

diates in

: 21]

OH

offer an interesting option carbamates N-alkoxyacryloyl to avoid the use of toxic and expensive alkoxyacryloyl isocyanates in the synthesis of uracil derivatives with antiviral activity [Scheme24] : HO. O
NH2

Et-O-CH\177CH-C-CI

\177
Yield

O
Scheme 21 P/epu/ulion of Ayapin

II

o
M.p. : 223-4{'C

0 MeON\177= o
HO

: 60%
(R\177L

uMng

3 ethoxyauyloyl :

chloHd\177

18) 1) Cyclisation

O MeOH
\177,

HO
NH

OMe

or quinolines [Scheme
NH

22]

',-.2HO\177N\177O
HO

2) 12 / HNO 3
2

0
II

87%

Scheme 24.'Preparation

of uracil derivatives

as antivirals

(ReL

20)

H2SO4

90%

F\177
O

POCl 3 87.5%

Scheme 22 Synthesis of quinoline of herbicides paration 19)

(Re\320\210

F\177,-\177 Cl
intermediates for the pre

Reactions
an

derivatives,

valuable

or sulfur center

oxyp\177en

Another valuable application of 3-alkoxyacryloyl chlorides is the preparation of N-alkoxyacryloyl carbamates to an original process eveloped SNPE Group at according d

[Scheme23]

mona or poly with aliphatic compounds at room temperature or below to afford corresponding aliphatic chloroformates in good yields. In contrast, phenols are quite inert toward phosgeReaction of ne, even at temperatures as high as s phosgenewith phenols requires an acid scavengeruch as tertiary amine or a mineral base (room temperature or below) or a catalyst (seesection2-2) such as HBGCI.HCl

Phosgenereacts easily

hydroxy

150\302\260C.

(temperature higher than

90\302\260C)

[Scheme25].

30

31)))

a as b Phosgenend derivalives building locks

R1-OH R-OH +
COC\177 \177

blocks a as Phosgenend derivalives building

1 R-O-C-O-R

\177\177 R-O-C-Cl
- HCI O
II

HCI

II

...

B.P. Structure R.N.

\302\260C/mm

chloroformate

Applications

\177Scavenger
Ar-OH
\177\"

Chloromethyl

\177.or catalyst

no reaction
R-OH Ar-OH +

R-O-C- -Ar O o R-O-C-O-Ar

II
\177\"

22128-62-7 106/760 CI-CH20-C-CI O

II

Pharmaceuticals Agrochemicals Photo resists

Trichloromethyl

CI3C-O-C-CI503-38-8 125/748 o
II
\"

Phosgene{{

diphosgene(als\302\260 calledSUbstitute,,)

COC! 2 scavenger,
or catalyst,

Ar-O-C-CI

o
II T<20\302\260C
90\302\260C

\177Scavenger

1-Chloroethyl

CI
OH3-C HIO

^.1 nu'\177 Ar -OH

'\177r

catalyst
II

T>

Ar-O-C- -At O o
1,2,2,2-Tetrachloro ethyl

50893-53-3 117/760 Antibiotics (pro N-dealkylation (+) 95597t. amines 56-1

drugs)

of

0
CI

\177I'CI

Pharmaceuticals

Scheme 25 Reactions of phosgene with alcohols and

98015-53-3

80/14

Peptide

chemistry,

phenols

pharmaceuticals

Cl3C-CHIO-C-CI

0
Aliphatic and aromatic chloroformates can reac further, easily with aliphatic hydroxy compounds to yiel of bases o carbonate diesters and only in
Vinyl

II

CH2=CH-O-C-CI 5130-24-5

89

presence

O
Isopropenyl H3

II

760

90/

Polymers

Contact lenses
Pharmaceuticals
N-dealkylation

catalysts with

chemistry of chloroformates has been alread reviewed in depth (Ref. ) and this section3-2 is limite to unusual or unexpectedproducts or reactions,mostl in developed SNPE Group.Table gives someexample

phenols.

The

57933-83-2

94.5/
747

Pharmaceuticals Peptide chemistry

21

CH2=C-O-C-CI

O
2.2-Dichloro
vinyl

It

3-1

of non

conventional

chloroformates.

CI2C=CH_O_C_CI

113421-96-8

O
2,2,2-Fluorodinitro ethyl
I

II

82-85/ 120 58/2

Polymers

(optical

fibers) Agrochemicals

?
\177

\302\2602

31841-79-9

Explosives Propellants

F__C_CH2_O_C.CI

NO

O
24608-52-4

II

t-Butyl

(CH3)3C-O-C-CI

3-4/0.9- Peptide
1.7
Dec.
\177s

chemistry

O
2-Oxo-1 3-dioxolan 4-yl methyl /\177/
CH

II

(this chloroformate very unstable)

20-C-Cl 23385-72-0

Dec.

UV

curable

acrylic

resins Hydro Blowing

plastic

gels foams

0
Table

agents for

Foods additives

3-1

:Some

unusual aliphatic chloroformates.

32

33)))

as b a Phosgenend derivatives building locks

the course of previous studiesdevoted to new substituted chloroformates,we were interested in the chloroformates. synthesis of nitro and aminoalkyl a in explosives and propellants, Thus, for application of 2,2,2-fluorodinitroethyl for safe process the preparation chloroformate was developedstarting from fiuorodinitrotable ethanol (Ref. 22).See The case of aminoalkyl chloroformates is more complicated becauseof the instability of chloroformates in presence of amines. It is well known (Ref. 21)that aliphatic
In

b as a Phosgenendderivatives building locks

cardiovascular agents for the acylation of
zinone

some parli(ular (hloroformales and (arbonales

of

Highlighls

(Ref. 24) [Scheme27] : OMe

quinolylthiadia-

S\177/Me

\177
o
Et

slarlingfrom al(oholsor phenols

3-1.

OI\177__N,

Scheme

27

chloroformatesdecompose by scheme 26:

(a)
\177

Et
agent.

New cardiovascular

two

paths

depicted in
of aromatic chloroformates bearing electrons withdrawing groups is posing a problem. For example, the phosgenation of p-nitrophenol in presenceof a catalyst to afford p-nitrophenyl chloroformate is equilibrated.The balanceis easily tipped towards starting mateAs excess. a consequence, rials by elimination of phosgene attempts of purification by distillation give rise to the forcarbonateand, more hazarmation of 4,4'-dinitrodiphenyl dous, phosgeneaccording to the mechanism depictedon The
manufacture

H--C--C--CI 2 + CO
I I I I

H--C--C--O-C-CI
I I

o
II

\177

(b)
Scheme 26: Decomposition paths of aliphatic

\177
chloroformates

+ HCl +

CO 2

scheme28

Temperature of decomposition varies widely depending : on the structure of the aliphatic radical ; on the presenceand nature of other compounds, espeammonium salts (SNi or SN2 cially amines or quaternary mechanisms).

Catalyst

o
O2N
O,

Therefore,the preparation of aminoalkyl chloroformates conditions (Ref. 23) requires carefully selected Low temperatures (below+ ; solutions ; into phosgene Addition of amino alcohols to have a completeprecipiselectedin order -Solvents tation of the hydrochlorides ; carried out away from any trace of moisture. Filtration Amino chloroformates are generally isolatedas their hydrochlorides and stored under dry nitrogen at low They are interesting potent intertemperature (< mediates for pharmaceuticals. Thus, 2-(N,N-dieth\177/lamino) ethyl chloroformateis used in the preparation of new

\177

O2N\177-O
p-nitrophenyl

Q+ +

COCI 2

10\302\260C)

Q+

c,O
Q+

chloroformate
\177)2N\177-'\177OI

O2 N

--\177--

CO + O+CI2

Scheme 28: The problem

of p-nitrophenyl

chloroformate

synthesis.

+5\302\260C).

elimiby Again, this difficulty was overcome complete nation of the catalyst from the mixture before distillation thus giving a pure and stablechloroformate.

34

35)))

b a a Phosgenend derivatives s building locks

p-Nitrophenyl chemistry, substitute

b a a Phosgenend derivatives s building locks

of
hexabutylguanidinium

chloroformate is widely
agent

of urethanes. For example, a new amine photogenerator was preparedfrom p-nitrophenyl chloroformate (Ref. 2,5)accordingto the scheme
in the synthesis
NO2 NO

especiallyas a protecting

usedin industrial or as a phosgene

chloride

hydrochloride

(HBGCl.

29.

to 3,5-dichloro-2-pyridinyl HCl) beads quantitatively On further heating, in presence chloroformate (Ref. 28). this slowly of HBGCI.HCl, new chloroformate decomposes to afford starting material and phosgenealmost quantitatively

). (reversereaction, seescheme31

p.Nitrophenyl chloroformate CH2-OH

\177

MeO

MeO

\177_
=\177

O MeO\177-\177k
MeO
NO

O==\177o\177N02
Me

2,6-dimethyl piperidine

MeO

- p. Nitrophenol

MeO

\177O
O==\177
\177N.\177.

]
T

COCI2
CAT. : HBGCI.HCl

80\302\260C

5\177herne

29

.'

Preparation

of

a new

amine photogenerator.

1
II II
\177

110\302\260C

another example, p-nitrophenyl chloroformate was required to introduce a sophisticated carbamate function in a multi-steps synthesis of retroviral protease inhibiting The structure of the intermediate compounds (Ref.
In

carbonateis given
p.Nitroph
chlor\302\260formate
\177

26).
in

scheme30. /F-S

enyl

STRUCTURAL

\177 N'Y
.\"

/f--S

PROOF
NO2

'OH

yield

: 78%
of

N\177 O
intermediate

i-PrOH
Et3N

_\1770\177 O
for the synthesis

Scheme 30 Preparation protease inhibitors.

a key

of retroviral

H +

ClAq.

with certain The final result of the reaction of phosgene hydroxy compounds may dependdrastically on the catalyst used. For example, the phosgenation of 3,5-dichloro-2in toluene, in presence of DMF, gives hydroxy pyridine in good yields. This compound is a 2,3,5-trichloropyridine valuable intermediate for producing herbicides (.Ref. 27). in presence Surprisingly, we found that the phosgenation

NH3

CI

\177
\177

CI

87%
OVERALL
YIELD 3,5-dichloro-2-pyridone.

\"N

\"CI

Scheme 31.'Unusual reaction of phosgene with

36

37)))

as a Phosgenend derivalives buildinblocks

reactswith Phosgenein excess
catalyst
trial

as a Phosgenend derivalives buildinblocks

The propertiesof chloromethyl chloroformate which been made alsoby phosgenation of monomeric formalfurther in section dehyde (Ref. 29),are discussed Someinteresting relationships between Diphosgene phosgene(Ref. 30)and the dismutation of phosgeneinto carbon tetrachloride and carbon dioxide (Ref. 31) are
has
{{

thiols in

presenceof a
in indus-

to

afford
it

disulfides and thiocarbonates. side products, especially in As already discussed section 2-2, use of HMGCI.HCI
catalyst,

processes,

thiochloroformates. However, is often difficult to avoid formation

of

3-2-2.

soluble during the reaction, insoluble

affcer

completion

and removed by simple filtration, gives high quality products. useful intermediate For example, n-octyl thiochloroformate, scheme is obtaifor the manufacture of herbicides ned in quantitative yield, without any tracesof sideproducts. the filtered catalyst is indefinitely reusable. Moreover,

depictedin scheme34
Charcoal
+

Lewis acid

[See

32]

Pressure
\"

2 COCl 2

\177

Cl3C-O-C-Cl
Q+ Cl

0
II

,,\177-- CCl4
Lewis acid + pressure

(FeCI3)

CO 2

type catalyst
CI--,,,\177N, N

Scheme 34.'Reverse dismutation of phosgene.

Foliar active herbicide

n-Oct-Scheme

\177,SyI

I1\177
PYRIDATE

Trade

introduced by Chemie-Linz AG mark Lentagran

\"

32.

from n Octyl thiochloroformate.

Chlorination

of methyl chloroformate

bonate affords
chloroformate
\177

also [11] [I], trichloromethyl carbonate called Diphosgene and bis(trichloromethyl) scheme33] known as Triphosgene [see [111]
chloroformate
\177 \177 \177

substitutes useful phosgene

and dimethyl carchloromethyl

The reversibility of the decomposition of carbon tetrachloride and carbon dioxide is still a controversial topic. However, the production of phosgene and carbon dioxide by reaction of carbon tetrachloride Lewis acidswas recently claimed in over catalysts such as The reaction is assumed to proRussian patents (Ref. 32). ceedthrough the formation of trichloromethyl chloroforcarbonate. mate or bis(trichloromethyl) At the presenttime, one crucial question still remains : what is the industrial value of Diphosgene and Triphosinto
\177 \177 \177

CH3-O-C-CI -

0
II

\177
Cl 2 , hv
HC\177

Cl2,hv

CICH2-O-C-CI -

[I] bp. 106oC

h C[2,v

II

HCI

CI2CH-O-C-CI

II

\177-

CI3C-O-C'CI ] [ II
O
II

\"Diphosgene\"

HC\177

bp. :
Vapor

128\302\260C

10mm

pressure/
/
20\302\260C

\342\200\242

gene as liquid and solid substitutes for phosgene? Are ? the two reagentsreally saferthan phosgene Both reagentshave proved to be useful substitutes for phosgenein all its main applications.Indeed,they are sold commercially as the efficient equivalents of 2 and 3 phosy gene moleculesrespectively in processesielding chloroformates, carbonates,carbamates,ureas and isocyanates, as well as in chlorinations, carboxylations and dehydrations use in organic syn(For a recentreview of Triphosgene
\177

{{

\177

O CH3- _C.O_CH 3

Cl 2

o
II

20\302\260C,

28 h\" - 6 HCI
from

thesis, seeRef. 33).

Accurate amounts

3 Cl3C_O.C.O--CCl

can be easily

weighed,

limiting

II

r [111

blems due to
80\302\260C

excesseagent.It is possiblealsoto increase r

industrial

pro-

\"Triphosgene\"

: bp. :
rnp.

206\302\260(\177

(dec.)

with phosgene itself. reagent concentrations compared However, there is little prospectthat either reagent will

Scheme 33: hlorination C

products

methyl chloroformate

and dimethyl carbonate.

be utilized

in significant

processes.
39)))

38

b a a Phosgenend derivatives s building locks

Both reagents decomposeto phosgene on heating, in preslowly when pure, very rapidly and quantitatively senceof a nucleophile such as a naked ,, chloride anion
\177

a a b Phosgenend derivatives s building locks

Table 3-2 gives a
Catalyst

cornparison

betweensome catalysts
Time for 100% conversion

Temperature

[Scheme35]:

HBGCI.HCl
HMGCI.HCI

160175 160170
guanidinium guanidinium

\302\260C

165 170

7.75H

\302\260C

IHIDAZOLE

\302\260C

5.25 H 2.50 H

\177,

2 COCI 2

HBGCI.HCI

+ Cl

HP1GCI.HCI

= Hexa n-butyl = Hexarnethyl

chloride hydrochloride. chloride hydrochloride.

lbble

3-2

c\177

cI

/0
\177,\177

F c*0

dlphenyl
c\177

Comparison of the efficiency of some catalysts in the synthesis of carbonate in bulk (3% Mol. Catalyst/phenol)
.'

CI3C-cI
O--\177:---CI

3 COCl 2
+

O+C;I

2
,\177

ClTriphosgene

carboAmong the numerous applications of diphenyl nate, the preparation and chemistry of dichlorodiphenoxy methane appears somewhat neglected.This phosgene derivative can be preparedin good yield by treatment of
diphenyl

Scheme 35 .'Decomposition of ,, Diphosgene ,, and

carbonatewith

phosphorus

pentachloride at

As noted by 5. Damle (Ref.34), the toxicity of both and triphosgene is exactly the same of phosdiphosgene on gene sinceboth decompose heating and upon reaction with any nucleophile. Even a trace of moisture leadsto formation of phosgene. or handling accident,both Thus, in any transportation compounds are phosgene. The manufacture of symmetrical or mixed carbonates or by reaction of chloroformates with alcohols phenols is I well documented. n the courseof different studies devoted to the manufacture of aromatic carbonates,we have designeda one-stepprocedurethat affords diphenyl carbonatein excellentield and purity using simple equipment y and no solvent [Scheme36]

temperature (Ref. 35)according to PCl5

scheme37

high

180-

CI
200'\177c

- POCI 3
bp

cI
: 183-187 / 12mm \"C mp : 42-44 80% yield
\302\260C

\177

heine

37

Preparation

of dichlorodiphenoxy
key starting

methane.

Besideseing a b
tion

material for the

of polyorthocarbonates, methane dichlorodiphenoxy is a versatile synthon for the construction of heterocyclic systems of medicinal interest (Ref. 36).Its condensation with cyanamide affords diphenyl cyanocarbonimidate in high yield (Ref. 35)as shown in scheme

prepara-

38:

OH

Neat

CI
\177

2
mp

+ COCI 2
bp

O--\177-O

+2H

: :

41\302\260C

Catalyst (1-5% tool.)

O\177 -O__\177
\177

+ NH2CN

\177
80\302\260C

AcOet

-CN

Cl

\177__
mp:

...[\177.

_\177
diphe41)))

182\302\260C

mp
bp

79.5\302\260C
315\302\260C

Scheme 36

91%yield
156-8\302\260C

Improved

diphenyl

carbonate synthesis.

\177cheme

38

.\"

Preparation

of diphenyl

cyanocarbonimidate

from dichloro

noxy methane.

4o

b a a Phosgenend derivatives s building locks

provides cyanocarbonimidate to N-cyanoguanidines a simple, low cost, high yield access which are active as histamine H2 antagonists. Kline &,'French For example, researchersfrom Smith a new facile synthesis has described (Ref.

b a a Phosgenend derivatives s building locks

of aromatic carbonatessubstituted by electronwithdrawing groups is an efficient method to get substituted diphenyl ethers.We found that pentaalare superior catalysts for the synthesis of kyl guanidines ether from 4,4'-dinitro diphenyl carbo4,4'-dinitrodiphenyl The generally acceptedmechanism involves nate (Ref. 37). nucleophilic attack by the substituted guanidine at the carbonyl of the carbonateto form an acylated guanidinium phenoxide salt. In a second step, the p.nitro phenoxide anion attacks the aromatic ring of the a\177lated guanidinium cation (SNAr reaction) to leadto the expectedether after lossof CO [Scheme 2 The decarboxylation

The availability of diphenyl

Laboratories
of the

36)
(\177{

scheme39: f--S
NH

anti-ulcer drug, Cimetidine

Tagamet

\177)

depictedon

Me
HN
x,\177,

\177 /\177 ' \177 \177

OPh
Me'NH2

N'CN

Room temp.
Yield

> 90%
NHMe H

Me
'k/_\177,'

f--S

\177
H

-Ue\177

41].

S\177__\177

N-CN

Yield

>90%
from diphenyl
cyanocarbonim\177da\177

N-CN

Scheme 39

Preparation

of Cimetidine

in

heterocydic chemistry (Ref. 3.5).

i-PrOH

Scheme40 shows someother examplesof applications

N
\177-

H2

[I

\"'-\177

/
/J

Ar

OAr + CO 2

R
N N

R AF=

/REFLUX lh
NH

'

MP.

278\302\260C

Scheme 41 Mechanism of the

decarboxylation

of 4,4'-dinitrodiphenyl

carbonate

catalyzed by pentaalkyl guanidines

i-PrOH, RT,

1h

74%

'

MP. : 175\"C

of the guanidine must be, carefully Nucleophilicity controlled,to avoid arylation of the catalyst ' itself. This could be easily accomplished through a proper choiceof Note also that delocalization of charge the substituents. over the three nitrogens in the assumed intermediate guathe nucleophilicity of its counter nidinium cation enhances
the p.nitro phenoxide anion. anion, With 2-methyl-l,l,3,3-tetrabutyl guanidine as catalyst, at temperature lower than the decarboxylation proceeds those described with conventional base catalysts. The result
lamina

N/CN
i-PrOH

'
,

e.g.

RT, 2h

HN

\177

\177

NH2NH2
H

N
\177-\177/NH2

15min
-2\177C MP. : 190

MP.

86% :

160-1\302\260C

is even better comparedwith

pyridine

using 4-N,N-dimethy-

Scheme 40

Examples

of diphenyl

cyanocarbonimidate

(I) applicatio, ns.

(DfIAP) as shown

in

scheme42.

43)))

42

a as Phosgenend derivatives buildin\177 blocks

ether can be easily hydrogenated 4,4'-Dinitro diphenyl suitable for the to 4,4'-diamino ether especially diphenyl manufacture of polymers such as polyimides.
through The required pentaalkyl guanidines were easily prepared of the appropriate urea to give the phosgenation salt which reactswith corresponding chloroformamidinium an excessf amine to yield the expected o guanidine (Ref.

a a Phosgenend derivatives s buildin\177 blocks

The course of the decomposition the mixed anhyof drides [Scheme which leadsto the formation of expec44] ted esters(path A) or to a mixture of symmetrical carbonates and anhydrides (path B) strongly depends on the structures of the chloroformate and the carboxylic acid but also on the choiceof the catalyst.. Becauseselectiveproduction of estersif of great interest, we have studied the thermal instability of the mixed anhydrides and developed a new efficient and selectiveesterification reaction with chloroformates using a silica supportedguanidinium in catalyst (Ref. 39).This method will be discussed vol. 2

37).

160\"C
\177

section4-4.
+ 002 O2N\177--O--\177--NO2

R\177O-C-R

\177

4,5H
Catayst

DMAP

: :
H2

77% yield 88% yield

O
2 R10-C-O-C-R O O 2
\177

(5 Mol. %)
Bu2N\177NMe Bu2N

1/2

R\177O-C-OR

Pressure Scheme 42
diphenyl

Scheme 44 Decomposition paths

ether and 4-4'-diamino

O
o\177

mixed carboxfliocarbonic

Improved

synthesis of 4,4'-dinitro diphenyl

ether

lhe use of the

also a
\177owerful

mixed

carboxglic-carboaic anhgdrides
for

One of the most convenient esterification methods developedearlier was based on the decarboxylation of unstable mixed carboxylic-carbonicnhydrides preparedby a reaction of chloroformates with carboxylic acids(Ref. 38) according to scheme43.
+ R]O-C-Cl O
II

the formation

method of carboxglic acidsactivatioa of amide bounds in \177e\177tide chemistrg

with

vol.

2, section4-4). 8eaction of chloroformates

(see

sodium

alkgl

carbo-

through reactioaof carbon dioxide with sodium alkoxides, affords dicarbonatesalso called \177grocarbonates as shown ia scheme

nates, easilg available

45.

2 CH2CI

R2-C-Cl O
II

\177

Etsa
O\177C

2 R]O-C-O-C-R O O
II II

Examples

Et-O-C-O-C-CH 3

Et-O--C-O-C\177-\177NO

1 R-O-C-CI R]-O-C-O-Na + R-O-C-O-C-O-R - NaCl O O O O Scheme 45: Preparation of dicarbonates from chloroformates.
II II II II

\177

0 o
Scheme 43 44

o 0
/

bp

64-7\302\260C

20mm

mp

56-7\302\260C

Preparation

of mixed

carboxylic-carbonic

anhydrides.

45)))

ne

a_nd

derivatives s buildinblocks a
Pyrocarbonatesfind

a as Phosgenend derivatives buildinblocks

several
reagents, Z20 and (AIIoc)20, conveniently supthe known chloroformates for the protection of amines. plement Cyanoformate esters may be prepared through reaction of alkyl chloroformates with cyanides salts by procedures
using phase-transfer ternary

fields, such as

useful

applications

in

These two

Preservatives for wines, soft drinks, fruit juices, specially e -- 1 = Ethyl. in the case of diethyl pyrocarbonate R R

Blowing

agents

for

plastics,
methyl,

Freon

\177'

substitutes. For
=

polyurethane example, t.butyl

Rt

foams as
methyl

pyrocarbonate

to achieve a cellular structure by liberation of carbon dioxide (Ref. 40). Protection of amino groups.Di-t.butyl dicarbonate called (Boc)20(which is not made from the very unstable t.butyl chloroformate) is well known as the most popular
reagent for the preparation

(R as a foaming agent

= t.

butyl)was

claimed

catalysis with 18-crown-6 43)or qua(Ref. ammonium salts (Ref.44) according to scheme

46.

of added during processing polymers

R-O-C-CI + or O
II

NaCN KCN

\177'

Phase transfer
catalysis

R-O-C-CN+ or O
II

NaCI KCI

Sideproduct :
Scheme

46:

RO-C-OR O
II

Preparation

of cyanofom\177ate

esters from

chloroformates.

of t.Bocprotectedamines,

especiallyt.Boc-amino acidsin peptide chemistry. We reported the synthesis (data on table 3-3)and some applications of dibenzyl dicarbonate (Ref. 41) and diallyl dicarbonate (Ref. 42).
Dicarbonate
Dibenzyl dicarbonate
Diallyl

Although convenient tities of cyanoformate

for the preparation

of small

quan-

esterssuch as ethyl

cyanoformate,

Yield

mp or bp

79 %

mp. 28

\302\260C

dicarbonate

82 % (60 %
distilled)
useful

bp. 65

\302\260C/0.05

Torr

Table3-3 Synthesis of new

Dibenzyl

dicarbonates.

we found the method to be unsatisfactory for the production on a larger scalebecauseof the formation of carbonate estersreducing the yield. In the courseof our studies devoted to the scaling up of ethyl cyanoformate preparation, we noticed that the sidereaction is strongly related to the nucleophilicity of the o cyanide anion which depends n the structure of the counter cation of the catalyst. Ouite goodresults can be achieved of by a proper choice the catalyst as depicted in scheme47.
CH2CI / H20 2

preparation red to the

preparation is easily achieved under standard pH-stat conditions if the pH is carefully regulated. was used for the allyloxycarbonyl Diallyl dicarbonate amino compounds including amino acids, protection of Except for the reaction with amino sugars and nucleosides. does not require an additional amino acids,the reagent and the only by-products, allyl alcohol and carbon

dicarbonate offers some advantages in the of N-benzyloxycarbonyl amino-acids, compawidely used benzyl chloroformate. For example, of dipeptide-free -benzyloxycarbonyl glycine N

EtO-C-CI+ O
II

NaCN

EtO--C-CN

+ NaCI

T:<

Catalyst:
20\302\260C

HM='CIG

Side

reactio\177n

:
NaCN

bp. : Yield

II

35\302\260C

/ 30 mm 83-6% distilled

Q+CI+
EtO--C-CN
+

Q+CN- +

NaCI
\321\207

Q+CN-

\177.__

O + EtOQ

EtO-C-CN

\177
: with
HMGCI

For example, N-allyloxycarbonyl dioxide are both volatile. obtained analytically was pure by simple glucosamine
evaporation

base,

O
Diethyl carbonate formed

II

NC-C-CN + EtO-Q O EtO-C-OEt+ Q+CNO

II

of the reaction

mixture.

Scheme 47

with HBGCI
preparation

: < 1% : 10%
47)))

Improved

of ethyl

cyanoformate.

46

a a b Phosgenend derivatives s building locks

Ethyl

a a Phosgenend derivatives s buildin\177 blocks

under-

cyanoformate is an effective dipolarophile

can be easily obtained through

glycerol and diethyl

transesterification

between

a going 1,3-dipolarddition

to azides, or examplewith ethyl f azidoacetate to afford tetrazoleaceticacid derivatives acid (Ref. 45).Tetrazoleacetic is a key starting material for the preparation of pharmaceuticals such as the antibiotic
<<

carbonateunder basicconditions. OCOCI

Cefazolin

>>

The chemistry of cyanoformate esters has been the subject of a recent review (Ref. 46).

[Scheme48].

OH

OH

OH

Excess COCi \177\" CICOO OCOCI 2 OCOCI

/\177/-(i)
Quantitative yield

EtO-C-CN EtO-CCH2N3 + 98% O O

II II

\177
110\302\260c

COOEt
N\177
I<1.-

,N-CH2COOEt

- 2 EtOH Basiccatalyst
\177-

Et2CO3

OH

OyO O
160\302\260C

/\177-0 0 (11)

1 N

HCI
\177

N\177
N..I

65%

-CH2COOH a
,N-CH2-C-NH
\177

Scheme 49
glycerol,

y O

bp.

/ 0.8mm
through phosgenation

Preparation

of chloroformate-carbonate

of

N\177
\177.--

S
\177

\"Cefazolin\"

\"\177[\177..,,,

N
I\1771

O/j- \177CH2S
COOH
Scheme 48 Preparation
.'

\177\"

\177oa3

and use of tetrazoleacetic acid starting

The chloroformate (I) and the corresponding alcohol (11) are very interesting intermediates for numerous applications Blowing agents adapted to the production of cellulated or expandedpolymers (Ref. 47),for example by reaction

from ethyl

cyanoformate.

of (11)with maleic

anhydride

[Scheme.50]. O-C

o,;,,
3-\177-\177

Reactionof

OyU
O
Scheme 50

\177
O
of a foaming

'--<\302\260\302\260\302\260\"

OyO O

mp.

Dec.' 150<'C (pure)

112'\177C

112-4\302\260C

al phosgene
oxygen \177enter
of uncon

1%aazco3)
agent for expanded polymers.

(with

Preparation

substrates
The

ventional

- Leavening systems for preparing baked goodsto (Ref. 48). - carbon metals. for
supply Extractants dioxide required

Reaction of phosgene
with
\177lycerol

doesnot

reaction of large excessphosgenewith glycerol afford the corresponding trischloroformate but a

five

For example, compounds obtained through reaction of chloroformate (I) with trimethylol propaneand with polyethylene

monochloroformate bearing a
nate function

membered

cyclic

carbo-

methyl (2-oxo-l,3-dioxolan-4-yl

(I) as shown on

T scheme49. he corresponding alcohol (11)

chloroformate

table
from

glycol are highly in hydro-metallurgy

aqueoussolutions

effective chelating agents suito recovervaluable metals ions (Ref. 49) [Scheme

51].

48

49)))

a a b Phosgenend derivatives s building locks

a as Phosgenend derivatives buildin\177 blocks

The study of light-induced polymerization of the new CL demonstrated the outcompounds, especially of acrylic monomers containing five standing reactivity membered cyclic carbonatefunction (Ref. _52). Photopo-

\302\260

ococI
EtC(CH2OH)3

1042,

/\177--

Pyridine

o
Et
\177_.\177

o
o--LL-

oyO(I) O

Acetone
88% Yield
mp,

O
o-\177

\320\205

\"j\"

120\302\260C

0%
83% yield
Mn

even occurswithout any added photoinitiator. These new monomers combine high reactivity and intensive cure to give hard but still flexiblematerials. CL 1042as used in _50% amount as reactive diluent in w
lymerization
with

formulation

HO(CH2CH20)n-H

+2

polyurethane oligomers bearing pendant was also employed to acrylate groups (Ref. _53). CL with synthesize cyclic carbonate copolymers pendant

1042

CH2Cl2 o.,.[r-

= 900
from

ox[i/O

groups.Their chemical modification

by

ring

opening

Soluble in toluene

Scheme 51 solutions.

reaction provided a convenient method for preparing functional polymers (Ref. 54), as shown on scheme_53 :

Cyclic

carbonates suitable for the extraction of metals

aqueous

--CH2-ca

-o
60\302\260C

-- -CH2CH

-- Paint
duct

of methacryloyl

-Ultraviolet-curable acrylic resins.

powders for automotive, for example the reaction prochloride and the alcohol (11) Ref. _50). (

The reaction of chloroformate (I) with acrylic acid followed by the decarboxylation of the unstable mixed carboxylic-carbonic anhydride

formed, gives the

2-oxo-l,3Scheme 53 Chemical bonate functions.

dioxolan-4-yl methyl acrylate in good yield (Ref. _51 ). The reaction of (I) with 2-hydroxyethyl acrylate in the presence of a baseaffords a new acrylic monomer, SNPE code num-

ber CL

in 1042, excellentield y

(Ref. 51 [Scheme )

52].

modification

of copolfmers containing pendant cfclic car-

00001
O,\177]/O

//
\177
of

\302\260 \302\260

72 Ojo

Yield

_Et3\"o

Pyridine

Reaction of
0,.\1770

0
93 %
42\302\2600

with phosgene

0
II

CL1042
Yield
chloroformote-

epoxides

The reaction of phosgenewith an epoxidecatalyzed by to afford \177-chloro chloroformates is well known pyridine U (Ref. 5.5). nfortunately, this reaction often leadsto non ring regio-specific opening of the epoxidesand produces bis-\177-chlorocarbonates as side products in yield up to

Scheme 52 carbonate.

Preparotion

UV-curable

mp, monomers from glycerol

20-30% [Scheme54].

50

51)))

a a Phosgenend derivatives s buildinblocks

Pyridine R
CI

a a Phosgenend derivatives s buildinblocks t /

In

Cl o..r_ O

+o
Cl

chloroformate was easily

(A)

(B)

+ [:\177-chloro

carbonate., Scheme 54 General react/on of epoxides with phosgene.

.\"

another example, 1-chloromethyl-2-chloroethyl preparedby catalyzed addition of This to epichlorhydrin using the sameprocedure. phosgene chloroformate is an useful intermediate for a simple carbamates route to new fluoroisopropenyl preparative in scheme_56 (Ref. 57) depicted

reactionsof monoalkyl epoxideswith phosw gene were conducted, ithin 2-6 h, using HBGCI or silicachloride as catalyst, neat or in supported guanidinium toluene solution, the results are strikingly different. The
When the
ring opening reaction gave single products with C-CI bond formation at the carbon that lacks the substituent. I'loreover, the reaction did not produceany of the symmetrical T carbonate. he \177}-chloro chloroformate (A) (seescheme_54) are thus isolated in nearly quantitative yields (Ref. _56). For example, the phosgenation of n-butylglycidyl ether in toluene, in presenceof 0._5 tool.% HBGCI, at within 2 h, gave the corresponding 1-chloromethyl-2n.butoxy ethyl chloroformate in 96% yield. This chloroformate is the key starting material for the preparation of an intermediate carbamateused in the Febarbamate
30\302\260C ((
\177

CI k_7,.,/'--

CI

COCI 2

\177

Cat. : HBGCI

/ Ci.--

\"--k.)_O-C-el 95% Yield

II

distilled

bp.
R1

93\302\260C

20 mm

C'---xkr__

c\177
THF

O-C-Cl4

R\\
NH

II

R 2\"

Base \177
R1

C,\177_._ Cl

O-C IIN\177/R2 O

Bu4N,

3e q.
\177_

F\177_

O\177I.N/R2

65\"C,8 h
\177ctyenye

72% yield with : 2 1 R = Pr ; R = cyclohexyl

i

56: New isopropenyl

carbamates

from

phosgene and

epichlorhydrine,

manufacture
n.BuO

as shown 00012

in

scheme5_5. Reaclion of
\177'

--/ O
NH

Toluene

2H n.BuO--\177

Cat. : HBGCI
50\302\260C

n.BuO\177_

CI--'96%Yield
( hexane )

OCOCI

3 / H20
\177

Cl\177/0
II I

)__O.C_NH

90%Yield
rap,
35.3\302\260C

aldehydesand ketones : novel chlorinated

\177\321\236

w phosgene ith

of alkyl chloroformates, generally Photochlorination limited to the case of methyl chloroformate and ethyl chloroformate, was the only method for the preparation of 1-chloroalkyl chloroformates before the work done at
SNPE

[Scheme57].
CI2, UV CI
\177

chloroformates
and

OCONH 2
'\"\"'\"\"-- Oin. Bu

related

RCH2- O-C-CI

reagents
Et2CO
\177

II

- HO
UV
\177-

RCH- O-C-CI

\"

eL...4
E

\"

NH

Febarbamate

\"

CI2, - HO

CI

O O
II

II

+ large amounts of

other (poly)chlorinated compounds

CH3CH-O--C-OEt
chloroformates

( Tranquilizer )

Scheme 57 Photochlorination
.\"

of alkyl useful

and diethyl carbonate.

Scheme 55
facture.

Preparation

of intermediate carbamate

for

a pharmaceutical

This method
manu-

synthesis

chloromethyl gives poor yields and bad quality

for

chloroformate
in

the

caseof
53)))

52

a as b Phosgenend derivalives building locks

1-chloroethyl chloroformate, and completely fails with higher chloroformates, becauseof the lack of selectivity of the radical chlorination. Eighteen attempts to dine,

as b a Phosgenendderivalives building locks

reactor already
that containing the catalyst reacts immediately, formaldehyde and phosgene,so thus avoiding its However, in this last case, we

years ago,

in

the

course of

unsuccessful

repolymerisation (Ref. found the procedure difficult technical that the

preparevinyl chloroformate by phosgenation of aldehydes in presenceof tertiary amines, especiallyyrip

we discovered a
new

route to

formate (Ref. 58)as presentedin

scheme58
H2C\177

e\177-chloroalkyl

chloro-CI

to scale up, becauseof problems of formaldehyde polymerization. Note reaction doesnot work with the polymeric forms of formaldehyde, either trioxane or paraformaldehyde. .Some results are gathered in table 3-4 (Ref. 5, 58, 60).
Catalyst Yield % Boiling point
\302\260C/mm

60).

CH3CHO+ OOOI+ 2

Pyridine

\177
CHoClo

/7\177

CH-O--\177

(mol. %/aldehyde) CI
I

( Catalytic amount)

\177
\"\177

Scheme 58 The origin of the route.

CH3-CH-O-C-CI 63% O
II

Me Me
Et

discovery

of the new u-chlorinated

chloroformates

CI3C
i-Pr

The value of this new route immediately was recognized because1-chloroethyl ethyl carbonatewhich could be obtained from 1-chloroethyl chloroformate and ethanol already was on the market as an alkylating agent to prepare coworkersat aldehydes are readiconverted to 1-chloroalkyl chloroformates when treated ly with phosgenein the presenceof a naked Cl\" catalyst The reaction has been found to proceedcleanly in (Ref. 5). good to excellentyields and to be quite general with almost all aldehydes, but not with most ketones (Ref. 59). On a laboratory scale,one of the favored catalyst is the benzyl tri-n-butyl ammonium chloride (BTBAC). The most
Penn the orally active antibiotic Bacampicillin Not long after, together with OIofson and
{{ \177.

CH2 = CH
Cyclohexyl

(1.8) (3.0) 18-Crown-6(5.7) KCI (35.2) BTBAC(9.0) BTBAC(10.7) BTBAC(12.5) Pyridine (10) Pyridine (10)
BTBAC BTBAC BTAC

42 (a) 96
78

106/760 77/180 117/760

62-3/52

89 65
87

75-9/19 58-9/28

54
87 87

38/10 90-3/10 81-3/1

70/0.4

(10.3) (10)

State University, we found

that

Phenyl

Pyridine

68

(a) With respect to the phosgene used CI

R-CHO + Catalyst

\177{

\177

COCI 2

R-CH-O-C-CI O
II

Table3-4

Preparation

of some

l-chloroalkyl

chloroformates.

important

reagent, (z-chloroethyl chloroformate

(\177

ACE-Cl

\177),

is isolatedin 96% yield by stirring acetaldehyde typically with phosgene eq.)neat for an hour in the presence of 3 mol. % BTBAC.Even chloromethyl chloroformate can be prepared using this process,but it is essential to

(1.1

introduce 54

the monomeric

gaseousformaldehyde

into the

The yields and recoveriespresentedin this table are those for isolatedmaterials (purity > 99%). Phosgenecan be replacedwith either diphosgeneor triphosgene in the same conditions to give the correspon). ding 1-alkyl chloroformates in very good yields (Ref.

61

55)))

and derivalives building locks as b

b as a Phosgenend derivalives building locks

mate previously prepared through chlorination of chloroformate in direct sunlight (Ref. 62). The addition of 1-chloroalkyl chloroformates to hols or phenols is a quite general method and gives

Phosgene

For safety

the reaction between suspected,we thoroughly

reasons,because a possiblereversibility of phosgeneand aldehydes was

studied the thermal
stability

I I
ethyl

of

are much more stable than the aralkyl compounds which at begin to decompose 60 C or below.It is important to note that the only products of thermal decompositionre a the derived 1,1-dichlorides and carbon dioxide [Scheme
\302\260

This stability greatly depends 1-chloroalkyl chloroformates. on the structure of the R radical. Simple alkyl compounds

alcogood

are to excellent ields. 5ome examples given y

R R1

in

table

3-5.

Method

Yield

bp.

\302\260C/mm

Ref.

(%)
H Et Pyridine

mp.

\302\260C

contrast, the chloroformate from chloral reverts to the aldehyde and phosgenewhen heated. This easily is decomposition catalyzed by naked Cl- and particular must be taken in the handling of tetrahaloethyl precaution
In
\177
\177

59].

76

bp. 53/14 bp. 67/22

bp.

63 64 64
5NPE

Me

Et Et
i-Pr

Pyridine Heating
(70\302\260C)

chloroformates, and more generally

roalkyl

in the

case of 1-chlo-

containing strong electron withdrawing groups (with regard to the mechanism of the see decomposition, farther on in this section).

chloroformates

He He He He He He

80
62
77

97

Pyridine Pyridine Heating Pyridine

t-Bu Cyclohexyl Benzyl

o\177CH2

90
94

160/760 5 bp. 57-9/10 65

bp. bp. 77/1 bp.

88/20

100/0.564
64 64 66
67

CI
I

Pyridine Pyridine

88
94

bp. 95/0.2
bp. rap. mp. rap.

Heating
-\177 II

CH3CH-O-C-CI O

T >>

CH3CHCI 2

CO 2

Me Me

Phenyl
Me

117/0.564
98-100 68-70
108\302\260C

100\302\260C

\177
I

\177\177 CH-O-C-CI CI

Heating
\177-

Cl3C

\1770
Me

Pyridine Pyridine

98
87

t-Bu

0
II II

>\177

60\302\260C

\177

CHCI 2

\321\207

CO 2

o Cl3C
\177,_

Triethylamine

83

CI
I

Heating
Q\321\207

CI3C-CH-O-C-CI or O
Schema 59
.\"

cr

\177

+ CI3C-CHO COOl 2
chloroformates. Table

CI
I

Base (pyridine) or heating

+ R1-OH

CI
I

R-CH-O-(\177-CI

Thermal

stability of l-chloroalkyl

- HCI

\177-

R-CH-O-(\177-

1 O-R

3-5

Preparation

of l-chloroMkyl
trialkyl

carbonates.

conventional chloro1-Chloroalkyl formates react easily with alcohols, ither in the presence e of or simply by heating to give the chloralkyl carbonates.1-Chloroalkylchloroformates reactalsowith phenols, but only in presenceof a base to afford 1-chloroalkyl aryl carbonates.

chloroformates like

The use of a

1-

base

amine, for example triethyl

amine,

expected

because1-chloroalkyl i as a scavengers not recommended

chloroformates react very easily with tertiary alkyl amines to afford N,N-disubsituted carbamates (Ref. 68)as discus-

sed in section3-3.
in the

1-Chloroethyl
by
M\177iller

ethyl

carbonateitself was first prepared

with

by heating

ethanol

1-chloroethyl

chlorofor-

Although pyridine process using

appearsas one of the bestscavengers must be avoided base,any excess

57)))

56

Phosgene /

s
,\177ecause

buildinblocks
scheme60:
formation

a as Phosgenend derivalives buildinblocks

salt
\177)--OH

of the

of a

quaternary

ammonium

on as depicted

x
+
1 R-CHO-C-OR
I

Base
R
I

O.

OEt

o
II

= CI Br, A.I. = Active ingredient

X
\342\200\242

(\177\177
functions (from carboxylic

O-CH-O'C-OR\177

\302\251o Scheme 60 Ouaternary ammonium salt carbonate.

.\"

from pyridine

and 1-choroethyl ethyl the development ton lots of 1-chlo-

Scheme 62 .' Modification of-OH using (z-chloroalkyl carbonates. This kind Bacampicillin,
H2 H
N N

II

acids or phenols)

In

the

courseof our

work

t processo manufacture roethyI ethyl carbonate,we studied the main side reaction which is the transesterification of the desiredproduct with ethanol [Scheme
industrial

of an

devoted to

of application was a prodrug from

initially

Ampicillin

to developed produce [Scheme63].

Me

61].

\177O\177 o
Scheme

\177-\177'Me

O O
Et

O
Me\177--

+ El-OH
CH3-CH-O-\177-O-EI

\177.\177. EI2CO3

CH3CHO+

HCI

2 CH3CHO

Aldo sation, dehydration

63 Semi-synthetic antibiotic l-iodoethyl ethyl carbonate.

Current
penicillins

Bocampicillin

from Ampicilhn

and

\177-

H20
\177.

O CH3ICH\177CH.CH
_

\177_

H20
n

CH3-(CH\177CH-)n-CHO
Scheme

61

max absorption
preparation

increasesith w

Main

side reactions in the

of

l-chloroethyl

ethyl carbonate.

or cephalosporins clinically used for suitable for oral administration becauseof their low absorption from the gastro-intestinal tract. The prodrug approach by chemical modification into bio-labile derivatives with improved physicochemical properties lipophiliciinjection

are not

Experimentally, the rate of formation of diethyl carbonate was found to be proportional to the concentration of both 1-chloroethyl ethyl carbonateand ethanol, so that the reaction rate in may be expressed term of following equation with an assumedfirst order with respectto both

ty) that

better transport enables

(i.e.

a powerful mean for improving such approach requires a latentiating group stable in both gastric acidic and basicintestinal conditions, and easily removable
by enzymatic hydrolysis. The modification of carboxylic acid function or phenolic function by the alkyloxycarbonyloxyalkyl estergroup is especially suitable as shown in scheme

through biological barriers, is o drug delivery. The successf

reactants
d At

carbonatesto mask acid or hydroxy functions 1-haloalkyl of certain types of active compounds such as parmaceuticalsor pesticides ccording to the scheme62. a
58

cations

[EtOH]/dt = k [EtOH][MeCHCIOCOOEt] the k value was determined at 7.2 x -`5 10 tool. -1.i.min-1. heat of activation was calculated at 25 The kcal. mol.-1. In the past 2_5 years,there have been numerous publi75\302\260C,

64.

R
I

Chemical
modification
1
\177

R 1 Drug--C-O-CH-O-C-OR O O
II II I

Drug--C-OH+

and

patents

0
II

X-CH-O-C-OR - HX O
II

claiming

applications

of

Drug delivery

Esterase Scheme 54.' The prodrug

Drug--C-OH+ O
II

R-CHO +

F\177-OH

CO 2
function.

concept apphed to drug with

a carboxyh'c

59)))

a as Phosgenend derivalives buildin\177 blocks

Tomeet all requirements needed,t is possible select i to radicals R and R for example : R = H or methyl R 1 = Et, isopropyl, even derivatives

a as Phosgenend derivalives buildin\177 blocks

N,OMeH
I

the

1,

S/\"\177NNr--\177S\"h

\177N\177s\\
\177J\"

N=\177

Nxx/N\177x

Me

cyclohe\320\247yl,

sugar

(seefarther Besides mpicillin, A

on in this

section).
Me

0 0
\177j\177

\"\1771\"

Me
CEFOTIAM

\177\"

Me HEXETIL

1-chloroalkyl alkyl carbonatesand particularly 1-chloroethyl ethyl carbonate(CEEC),1-chloroethyl isopropyl carbonate (CEIC), 1-chloroethyl cycloand chloromethyl ethyl carbonate hexyl carbonate(CECC) (CEMC), have been proposed to modify numerous com-

0 0 0
\177

\177j\177j

CEFPODOXIME

PROXETIL

(CS-807}

( SCE-2174)

/\177

.S,

Me
H

pounds.

which

Among the many types of prodrugs patented of require this method, there are examples : Antibiotics such as Cefpodoximeroxetil from Sankyo P

0
Me,\177O O0\1771\177

N,\177

F
O\177M\177)_..

Et
DIFLUNISAL

0\177._

(\177Et

of (Ref. 73) example Chem. (Ref. 74) - Herbicides(Ref. 75).

derivative
Diflunisal

Co.,Ltd.(Ref.69),Cefotiam Hexetil from Takeda Chem. Indust., Ltd (Ref. TO,71) Antiflammatories and analgesics such as Ampiroxicam from Pfizer and Toyama Chem. Co. (Ref. 65,72)or a
TCV

AMPIRQXlCAM

Der\177vatwe

for Antihypertensives, Indust., Ltd

116 from

Takeda
Scheme 65
,\"

Examples

of Prodrugs

from

1-chloroalkyl

alkyl

carbonates.

given in

Some structures of these pro-active scheme65.

ingredients

are

of insecticides F (Ref. 76). or example, Carbosulfan active systemic herbicide derived from Carbovery furan and much lesstoxic for mammalians than its parent compound. In order to improve transport through biological barriers of the plants, we thought that the chemical modification of known pesticides with 1-chloroalkyl alkyl carbonates containing sugar or glycerol moiety should be of some interest. For this purpose\177 we synthesized at laboracarbonates(Ref. 77). tory scaleseveral new o\177-chlorinated The products preparedand results obtained are depicted
field
\177 \177

Chemical modification of agrochemicals, to improve their pesticidal properties and to reduce toxicity toward nontarget organisms, has been the object of intensive researchin both academiaand industry, especially the in
\177

is a

\177

on

scheme66.

60
61)))

a a b Phosgenend derivatives s building locks

and b Phosgene derivatives building locks

as\177
1

O-C-CI

II

CH2CI , Pyridine 2 93%

bp

O : Dec. O

OyO

Diacetone-D-Glucose
Cl
\177_

0,)
\177--\177

CH2012,Pydine ri

pO

\1770\177

O\177\177o
O\177\"

Scheme 55 Some new 1-chloroolkyl alkyl carbonates, for the preporotion of prodrugs end propesticides.

99.7% useful

\177

starting moteriols

The 1-Chloroalkyl carbonate(11),obtained through the of 1-chloroalkyl chloroformate with glycerol carbonate was used for the preparation of a proherbicide derived from Acifluorfen scheme67]. (Ref. 77) [See
reaction

\177

acid or phenolic functions. However, these o(-iodocarbonates exhibit severeinstability (Ref. 78) and are generally preparedin-situ or just beforeuse (Ref. 79,80, ). Thus, researchefforts in different industrial laboratories have been directedtoward the preparation of 1-bromoalkyl alkyl carbonatesassumed to be more stable than the 1-iododerivatives, and more reactive than the parent chloro compounds.For example, 1-bromoethyl ethyl carbonate was made by the halide exchange of 1-chloroethyl ethyl carbonatewith LiBr or NaBr, or by a radical type bromination of diethyl carbonate(Ref. 82).However, in the caseof halide exchange,he conversion is low and a mixt ture results. Even with a large excess f bromide o salt, this problem remains. Radical bromination was found to give results for the same reasonsthan the chlounsatisfactory rination, and failed in the case of unsymmetrical dialkyl carbonatesbecauseof its non-regioselectivity. We reported a new method consisting of using a volatile bromine containing reagent (E- Br), especially HBr, and a catalyst to accomplish the exchange(Ref. 84).The equilibrium is driven to the desiredproduct by removal of the more volatile E-Cl formed as shown in table This table gathers some results thus obtained.

Sincein terms of leaving group ability in SN 2 reactions > Br > Cl, oeiodoalkyl alkyl carbonatesare the reagents of choicefor the chemical modification of either carboxylic
I

81

83, 3-6.
\302\260C/0.4

CI

1)DMF / Nail
F3C

O __\177

\177

NO 2

\177,.

COOH 2)(11)
CI

,\177:Nal

F3C--\177 O-\177NO20
920/0 Scheme 57 62
Proherbic/de from Acifluorfen.

phenyl carbonate (bp.72-7 ram) preparedin 91% yield from THS-Brand 1-chloroethyl phenyl carbonateusing this technic. It should be noted that 1-bromoalkyl carbonatescan be alsoeasily obtained through HBr addition to the double bond of vinyl alkyl or vinyl aryl carbonates (Ref. 8.5)This will process be describedin section3-2-2-4 devoted to

1-Bromoethyl

was

vinylic
f\"\"

chloroformates and derivatives.

/\177--0, >q o

0
\302\260

.\"

63)))

a and Phosgene derivatives s buildin\177 blocks

R1 Catalyst

a as Phosgenend derivatives buildin\177 blocks

bp.

Temp.
\302\260C

Eq. Me
Pie Et

Time Hours

Besides the

Yield %

synthesis

of

method is general enough to

1-chloroalkyl carbonates,this be used for the preparation

\302\260C/mm

none HgBr2

80 65 85 85

of 1-fluoroalkyl, 1-bromoalkyl or 1-iodoalkylcarbonates as shown in table 3-7. However, the method gives poor results or even failed when the haloformate is too unstable
in

Et

0.038 0.014 0.019

24 6
7

80 82 69
gas into the

' 0210/18

presence of the

catalyst

Me
n-Bu

iipr

TBAB(a)

B0-3/18

He
added

BTBAC(b)

60-2/2
R
medium

example, attempts to prepare1-chloroethyl ethyl carbonate dichloroethane at with (CEEC)itself in equ. almost total decomposition of ethyl chloropyridine, gave formate.

For (see section 3-2-1).

60\302\260C

1,2

0.05

R1

HBr was

(a)TBAB : (b) BTBAC : benzyl CI

I

continuously by bubbling the anhydrous tetra n-butyl ammonium bromide tri-n-butyl ammonium

Catalyst

Temp.
\302\260C

Time Hours

Yield

bp

\302\260C/Torr

mp

[\302\260C]

chloride

CH3 CH3
1

Ph

CI CI CI Br
I

Pyridine Pyridine Pyridine Pyridine Pyridine

80
60

1 + HBr

RCH-O-(\177-O-R

\177 \177

Br
I

CHCI-CH3 CH=CCI2
Ph Ph

5 4

HCI

RCH-O-(\177-O-R

CH3 CH3 CH3

80 83
70

1.5
1

Table

36

Preparation

of some l-bromoalkyl

1.5
5 4 24 2 20 20

alkyl carbonates.

67-8/0.15 67-72/9 83 44-5/0.1 82 74-9/0.03 80 93-7/0.45

71

49

[.59-61 ]
CCI3 CH2CI
CHCI-CCI3 CI CI Pyridine Pyridine

In order to complement the usual 1-chloroalkyl carbonates synthesis, we decidedto find a new route to a broader classof these compounds.More particularly, we tried to open accesso carbonatesin which the alcohol(R1-OH) t doesn'texist and to the previously unknown 1-fluoro-alkyl

CCI3 CCI3
H

80 80
82 65 65 83

76

60-1/11
82-6/0.03 82-5/2.5
77-8/5

88 90-5/0.05
32
76 72 67

Ph

DHAP KF/

(CH2)7CH3
Et

18-C-6
ICCI3
Ph
Table

carbonates. in Our efforts succeeded the discovery of a different based on the reaction of an aldemethod of preparation hyde with a halogenoformate in presence of a catalyst 8 (Ref. 86, 7), as depictedin scheme68.
Catalyst X
I
\177\"

KF/

18-C-6
C(CH3)=CH2
CI Pyridine

92-6/0.2

3-7

Preparation

of 1-haloalkyl of

carbonates.

None

R-CHO

R1-O-C-X

0
II

6o- 10ooc 32- 90%

salts,

the catalysts N,N-dimethylamino

tested : quaternary
pyridine

ammonium
imi-

1 R-CH-O-C-OR

(DHAP), 1-methyl

0
II

x =

F,

Cl, Br,

Scheme 68 New route to

l-haloalkyl

carbonates.

dazole, tertiary amines, Michler's ketone, quinoline etc. performed as well as pyridine. For the preparation of system found 1-fluoroalkyl carbonate, the best catalytic was the KF/18-crown-6omplex. o avoid side reactions, T c only aldehydes without hydrogen at 02should be used in
this

case.

64

65)))

a as Phosgenendderivatives buildin\177 blocks

Fluoroformates

a as Phosgenend derivatives buildin\177 blocks

attacked
ways
by

(Ref.

(Ref. 89)usedhere were preparedaccordingto literature procedure (see also farther on in this section). The preparation of isopropenyl chloroformate,as well as chloroformate will be presented in 2,2-dichlorovinyl section 3-2-2-4. At the beginning of our work devotedto new potential applications of 1-chloroalkyl chloroformates and 1-chloroalkyl carbonates,available literature data as well as our
preliminary

88) and

phenyl

iodoformate

as shown

nucleophiles following three in schemeTO

different

path-

Nu-C-Z
II

R-CliO + C[

A1

A\177

O
\177

R--CH-O--C--Z

R-CH-O-C-Z Cl+
I

Nu

O
II

Scheme69

products

strong variations in the distribution resulting from nucleophilic attacks. gives some examplesdemonstrating that the the nature
derivatives.

experiments indicated

R-CH-O-C-Nu
I

+z

types of obtained products strongly dependon of reactant.

Scheme 70 Possible types of nucleophilic attacks to

Cl
1-chloroalkyl-oxycarbonyl

EtO-C-F
3
EtO-\177-O-CH-CH

o
II I I II

Ethyl

fluoroformate

EtO--C-O-CH-CH 3 O 1-Iodoethyl ethyl

CI

carbonate

RO-C-N

,R

RO-C-O-CH-CH Base 3 _

R1R\177 O
II

'R

20
1 O-C-R
II

RO

-C-O-CH-CH 3

Cl

o
\177

o
II

CH3-CH-O-C-CI O CI
I II

CH3-CHCI2

1-chlo-

Research our laboratories the last fifteen years in over has beendirectedto understanding the mechanisms which are operative in nucleophilic attacks of 1-chloroalkyloxycarbonyl compounds, in order to be able to further predict new potential reactionsas well as to improve existing methods. The reactionsfactors assumed to affect the products distribution and the kinetics of the reactions are the : following Strength of nucleophilicity of the nucleophile. Strength of electrophilicity of centerA and B. Nucleofugacities of 1-chloroalkoxide anions and Z anions.
Solvent and temperature

effects.
in the framework

Stericeffects. Our approachwas

outlined

CI3C-CH-O-C-Cl
Scheme 69
roalkyl Examples chloroformates

+
C\177\177,

Hard-Soft Acid-Basetheory (HSAB,

+ 2 CI3C-CHO COCl

of variations of nucleophilic attacks pathways to and carbonates.

1-chloroalkyl chloroformates and derivatives very interesting mechanistic problem, since they present two reactive electrophilic centers which may be
In fact,

pose a
66

react with hard electrophilesnd a philes prefer to react with soft electrophiles. There are two electrophiliccentersin the 1-chloroalkyA Ioxycarbonyl derivatives (designated and B in scheme 70).Center B is a carbon sp3 hybridized and is softer than the carbonyl group, centerA. The factors that influence the degreeof hardness work

definition, prefer to

the HSAB theory

Ref. states that hard

90). In

of the a short nucleophiles soft nucleo-

67)))

a as Phosgenend derivalives buildin\177 blocks

for both centersA and B in the same way. That is electron withdrawing groups (in R or Z) increasethe hardness of
both
-\177

as a Phosgenendderivalives buildin\177 blocks

One of the first representative reaction with hard was the reaction of 1-chloroalnucleophileswe developed
with fluorides anion. This reaction proceeds kyl carbonates through A1 attack mechanism, which is in accordto the HSAB theory, thus converting 1-chloroalkyl carbonatesto fluoroformates in good yields (Ref. In the preferredliterature, most fluoroformates are prepared from their analogous chloroformates through KF using excess activated by a little halogen exchange

centers

In

term of the

R group

The following orderof hardness is proposedfor centers B > R = CCI3 Aryl > Alkyl > H Note that is also the same order for nudeofugacity (leaving group capability) in a A1,2type reaction In term of the Z group Electron withdrawing groups in the R radical will make centersA and B both harder. The orderchosenin our work was based on the Infra-Red carbonyl stretch. Assuming that electronwithdrawing Z groups will give a higher C=O the order of decreasing hardness stretch, we established
A and

91 ).

18-

\177

Crown-6. owever, H

this method proved

to be impractical

presentedin table 3-8.

OAr

for tertiary alkyl fluoroformates and/or benzyl fluoroformates, either because the corresponding chloroformates are not stable or because of the lack of selectivity of the alcoholswith fluoride attack. Acylation of the respective COF or COFClequires complexequipment not accessible r 2 to standard laboratories and/or multipurpose plants.
the easily available 1-chloroethyl ;R (RCHCI-OCO2R1= CH3)are heated,neat When

carbonates
or in
solution

O
-NI
\177

R
N'

\177

OR 1

SAr

II

-P(OR1)2

'R

C=O
stretch

1840 1780 1780 1775 O R-CH-O-C-Z

I II

1765 1745

1740 1729

presenceof to aldehydes and fluoro18-Crown-6, fragment they formates in good to excellent ields (Ref. 92)as shown in y table
with KF in

(benzonitrile or diglyme)

the

3-9.
Catalyst

Cl

R1 R

Solvent

Temp/press
\302\260C/mm

Time h

Yield

bp
\302\260C/ram

= Alkyl
t- Butyl t.
Amyl 1-Adamantyl Benzyl Cholesteryl Phenyl

(18-06)
mole/%

[rap.
None

\302\260C]

Table3-8 Decreasing hardness order of centers A and B asa function

of Z group.

The nucleophiles we three categories

studied

can be placedin one of

- Soft
-\177
\177 \177

Hard nucleophiles F-, Borderline nucleophiles

\177 \177 \177

nucleophiles

CN-. (RO)3P, The reaction.s of

amines,

: R-COOH, R 1R2NH, -OCN. ROH, : ArO-, ArNH2, Imidazole, Br-, CI-. :I-, -SCN,RS-, ArS-, (R10)R2p(=x)s-,
this

6 5 4 5 9 5
.Cl

None None None

Ph-CN

30 34 36 120/1.2
70/37

84
83
76

70/14

55/1.2
40/3 75/20

4 31

60 82
70

None

1.5

40-2/175 35-6/36 [30-2] 44-6/1 [114-7] 60-3/20

as well as ducts are not dicussed here in for section3-3.

68

1-chloroalkyl chloroformates with further reactionsof the resulting pro-

CH

KF 3-CH-'O=\177-OR\177+/...

\177
R1-O-\177-F

CH3\"CHO+

KCI

sectionand are reserved

Table

3-9.'Fluoroformates

prepared

from

1-chloroethyl

carbonates.

69)))

a a Phosgenend derivatives s buildin\177 blocks

be noted that this new methodology exempliunusual conversion of an ester to an acid halide. Because radical R = CCl3 inductively increasesthe the hardness of the electropholicenterA and makes c
It should

as a Phosgenendderivatives buildin\177 blocks

as reactants.While chloroformates react explosively with DM50(Pummerer reaction) and exothermically with DMF (Vilsmeier-Haack reaction), Olofson and coworkers (Ref. 9:5) have found that fluoroformates are stable in this solvents below 100
carboalkoxylating

Fluoroformates offer alsosomedecisive advantages

fies an

reagentsfor

polar

tetrachloroethoxideanion a better

1,2,2,2than

leaving

group

carbonate is a more reactive acylating agent than the analogous carbonatefrom acetaldehyde = CH3)and (R doesn'trequire a catalyst. Thus, heating 1,2,2,2tetrachlocarbonateat for 8 h with KF in the roethyl tert-butyl polar solvent DMF under vacuum of 20 mm, with a simultaneous treatment of the distillate with ethylene glycol, pure t.butyl fluoroformate (BOC-F)was isolated in 75-79%yield [.Scheme 1]. 7
50\302\260C

1-chloroethoxide, 1,2,2,2-tetrachloroethyl tert-butyl

\302\260C.

.Severalimportant ning compounds

classesof
only

and amino-contaihydroxyl soluble in polar solvents such as and efficiently carboalkoxy-

DP150and

DP1F

can be easily

lated with fluoroformates. For example,percarboethoxylation of glucosewas readily achieved in good yield with
ethyl OH

fluoroformate

in

DP150as shown

in

scheme72.

.
OH OH

OCO2Et

20mm press. t.Bu-O-O-O-OH-OCI 3 + KF t.Bu-O--O-F CI30-OHO + 1.5 eq. DMF O ca80% yield Scheme 71 Economics for commercial synthesis of 800-F NO
II I
\177

O CI

50\302\2600

ETOCO2
\177

H
I\177-D-GLUCOSE

DMSO KF,1 Oh, 60\"C

In

CO2Et EtOCO2---\177-\177
\177 \177O.

UL'U21:[

II

Scheme 72

89% yield mp : 100

Efficient

synthesis of penta-O-(ethoxycarbonyl)-D-glucose.

CATALYS\177

since t. butyl fluoroformate (BOC- ) has been highly recommendedy F b $chnabel (Ref. 93) and Carpino (94) as a substitute for the expensive di-tert.butyl dicarbonatecalled (BOC)20. Indeed,BOC F is an extremely cleanand efficient reagent
particular interest

These results are of

Under tions

selectedconditions,
with

fluoroformates

included

react easily BOC-F

to
afford result proved

products containing

aromatic

carbonates in

phenolic funchigh yields. This

for the amino

protection of amino-acids into BOC-AA. However, the reagent is not stableenough to be shipmore ped safely becauseit decomposes or lessrapidly into

isobutene, carbon dioxide and HF, thus developing autogenous pressurein containers.This has led SNPE and its to and react BOC-F on subsidiary I.SOCHEH manufacture thus offering low cost protectedamino compounds. site, we succeeded the preparation of in Furthermore, FI\"IOC-F (c)-fluorenylmethyl fluoroformate) as a crystalline solid (mp. 41 This reagent exhibits the samestability as FI\"IOC-ONSu and can be easily shipped.Compared with FHOC-F FHOC-ONSu, gives similar to superior results in the protection of amines in peptidessynthesis.
\302\260C).

to be suitable for the production of valuable monomers used in resist materials for microelectronic. Recentprogresshas been made in microelectronic devicefabrication, particularly in microlithography used to the high-resolution circuit elementsof intemanufacture based grated circuit (Ref. 96).Deep-UVphotolithography on chemically amplified resist is likely to be the first technology that met the severe performance criteria required. The best known chemically amplified resist is basedon poly styrene) or copolymers(Ref. c)7). (4-t-butoxycarbonyloxy As shown in scheme 73, irradiation of the resist of results in the decomposition an added photoactive acid thus liberating a Br6nsted's acid, generator(Crivello's salt) of which upon heating leadsto cleavage the t-BOC protecting group. The irradiated regions are soluble in basicwater
71)))

70

a as Phosgenend derivatives buildin\177 blocks

and insoluble in organic solvents. Image development can be achieved either with aqueousbaseaffording a positivetone image or with an organic solvent to give negative-tone

a as Phosgenend derivatives buildin\177 blocks

O- -CH3 O
BOC-F

\177,

O-K +
BOC-oxystyrene

t-BuOK

image.

Ph3S+ SbF6 Photoactive acid generator

av
\177

Ph2S

H+SbF6

RN : 87188-51-0 80%overall yield

distilled

bp.
NaOH H
+

90-3 0.06mm /
95% yield after workup

Diglyme

\"\177n
OH
Mn

BOC-F
in

\177,

excess

25\177'C

'\177n

= 1100-1500

O
Scheme 73 .'Photocatalyzed
oxystyrene). removal

Scheme 74 of the BOC protecting group ofpoly

0
of 4-t-butoxycarbonyloxy
styrene and its polymer using

Preparation

(80C-

BOE F.

Similar the

to

The required monomer, 4-t-butoxycarbonyloxystyrene, is widely described the literature. Because in 4-hydroxy styrene is difficult to isolatedue to its rapid polymerization, BOC-oxystyrene is generally prepared by treatment of 4with strong basethus giving the corresponacetoxystyrene followed by addition of ding phenoxide, immediately in THF solution (Ref. 98). (BOC)20 At SNPE Group, we developed s processesuitable for the manufacture of either BOC-oxystyrenefrom 4-aceor toxystyrene and BOC-F directly poly (BOC-oxystyrene) reaction of BOC-Fwith poly (4-vinyl phenol), through
I'dARUKA Lyncur in
I'd

soft nates is
reaction

nucleophile
in

case of fluoride attack, the reaction of iodideanion with 1-chloroalkyl carbogood accordancewith the HSAB theory. The
the

proceedselectively through B mechanism to give s

carbonates[Scheme75].

1-iodoalkyl

The poor stability of such compounds has been already mentioned in this section.Caubereand coworkers (Ref. 78) reportedthat when 1-iodoethylalkyl carbonateswere heated in toluene at 75-105 they decomposerapidely to form the corresponding alkyl iodides.
\302\260C,

from

I'dARUZEN

Petro-chemical

Co.

+ R-CH-O-C-O-R
\177

scheme 74, these processes re quite a simple and afford good yields (Ref. c29). Researchersfrom Nippon Telegraph and Telephone with Corp. disclosedpositive-working resists developable alkali aqueoussolutions, consisting of a novolak resin, an
Ltd. As shown acid-generating

\177
II

Na+l

Acetone
\177

1 + R-CH-O-C-O-R

II

NaCI

Toluene

CI

O
Nal R
1

+ R-CH-O-C-CI R1-OH+

\177
\177

R 1-1

agent

and

In our laboratories, the latter phenyl] propane(Ref. was readily prepared in good yield through reaction of bisphenol A with BOC-F, using usual procedure.

100).

2,2-[p-(t-butoxycarbonyloxy)

- OH = n-C12H25-OH

81%
\177

Isolated
yields

Scheme 75 New

= 1-Adamantyl -\177 = Ph-CH2CH2-OH \177

preparation

76 %

I 81%

of alkyl iodides.
73)))

72

a Phosgenend derivatives s building locks a b

Becauseduring the reaction the
transient authors

a Phosgenend derivatives building locks as b

discovered in acetone,in the that absenceof alkali thiocyanate, thiocyanates (I) were readily isomerized under mild conditions to the correspondingisothiocyanates as (11)
However, the authors

back formation

R1-OH,hey t formed one-potfrom

and Nal, thus

of the correspondingfree alcohol demonstrated that the reaction can be

1-chloroethyl chloroformate, discovering a new preparation
in

observedthe

pep

presenceof Bu4PBr
table

but in the

iodidesas shown

scheme7.5.

alcohol of alkyl
R

shown in

3-11.
72

of the reaction was thoroughly studied in order to understand the origin of the N-bounded compounds (Ref. Someexamples f the reaction are o given in table

corresponding1-thiocyanoand/or1-isothiocyano ethyl carbonatesin good yields (Ref.101 ). Because the interest of compounds of containing both carbonateand isothiocyano groups in chemistry, the mechanism phytosanitary

Another example of soft nucleophile attack according to the HSAB theory was given by the reaction of thiocyanate salts with 1-chloroethylcarbonates affording the

Time hours

Yield, isolated

(II)

Et t-Bu

n-C8H17
Ph-CH2 SCN
I

13 26 48
Acetone
\177--

81 81 56 82
N=C=S
CH3-CH
(11)
O-li\177-OR

102). 3-10.
Solvent
I\"leOH I\"leO H

CH3-CH
(I) Table

O-li\177-OR

Bu4PBr

56 C

3-11Isomen\177ation
.\"

carbon ates.
R Et
,'

of 1-thiocyanoethyl carbonates to

1-[\177othiocyanoethyl

H
K

Time h.

(I)+(II)
%

(I) +

(I)/
(11)

(II)/ (I)+ (11)

23
76

58
78
76

, Et
Et
\177'

NH4
K

HCONH2 HCONH2 HCONH2

PleOH

, Et
t-Bu
,'

NH4 NH4
K

4.75

, n-CSH17
\177

17
73 72
SCN

86 89
70 51

Ph

NH4

0.93
1
CH3-C

0.85 0.15 0.79 0.21

0.07
0
N=C=S
.\"

0.83 0.17

1 1

0 0

The authors proposedthe mechanism 76 (Ref. 101).

SCN
I

given

in

scheme

Bu4PBr

SH3-CH-O-C-OR

I
L
+

II

\177 CH3-CH-O-C-OR
O
carbonate
\177omerization.
II

N:C=S

--\177,-ICH3-CH-O--\177-OF
Bu\177PSCN

Scheme 76 Proposed mechanism

It could

HCONH2

of 1-thiocyanoethyl

L I I I I

CI
I

' CH3-CHO-F-OR+
,
Table

4MSCN

\177 R.T.

Solvent

CH3_CHO_\177.OR+

(I)

HO-\177.OR (II)

0
at

3-10: Reaction

give a more marked cationic like transition state.Therefore according to the HSAB theory, the substrate would be attacked by the harder side of thiocyanate anion. t predicted,he soft nucleophile cyanide 1-chloroalkyl carbonates to afford carbonates in good yields as shown with depictedin scheme77. As
with

be suggestedthat

the bromine

atom would

of

1-

chloroethyl

carbonates

with

MSCN

\177

protic solvent

anion

20\302\260C

reacts

-N=C=S harder nudeophile than is

thiocyanate anion

From this study, the authors concluded that most isothiocyanates (11)must be due to a N-condensation of the thiocyanate anion rather than an isomerization. Because

1-cyanoalkyl the example

to

decomposition.
74

\"SCN, attack of the isothe carbonyl will explain the observed

O
\"

KCN,

18-C-6
\177

O
,I

CICH2-O-C-O
Scheme 77

_\177
of

Me

Et20
25\177'C,

4 days
carbonate

N\177-C-CH2-O-C-O

90 %
preparation.

Me _\177

Example

1-cyanoalkyl

75)))

and derivatives buildin\177 blocks as

Scheme78 gives
the preparation dialkyldithiophosphate two examples[reactiona and c] of of insecticidal phosphoric acid estersfrom

tPhos\177ene

a as Phosgenend derivalives buildin\177 blocks

1

bonate claimed

in

a
II

anions and 1-chloroethyl patent (Ref.

S
(EtO)2-P-SNH4*
\177-

103).

ethyl

car-

a
CI
/\177\"

CH3CN,70\302\260C,

7h

\177

74%

reaction with triethyl phosphite appearsto be a violation of the HSAB theory. As already developedin the start of this section,the reaction of carboxylate anions with 1-chloroethyl carbonates is widely used for the preparation of commercial prodrugs. The hard nucleophile RlCOO attacks selectively the soft center B, that is apparently contrary to the HSAB theory. favour

The last

O-C-OEt
O
II

S
S(EtO)2-p. NH4 +
\177

2 s.P(OEt)

(a_)

However, the required

use of added

Nal

O-C-OEt

\\

Nal, THF, reflux,

PrS\177
\177.O
_

3h
N+

II

78% (b )

cation-like transition state, the cationic intermediate having thereforetwo hard electrophilic centersand B attack would not be in violation of the rule [Scheme

may

80].

H2Me2 c\177. EtO/P'-.S H20 , DMF,

70\302\260C,

% /SPr

Cl

O O-C-OR+
II I-

7h

\177-

\177

s.P\\ OEt
II

85%

\177
DMF

[t /\"O-C-OR\177
I-

O
II

R\177COO

1 \177-C-R

Scheme

78

Reaction

of dialkyldithiophosphate

-O-C-OEt O
carbonate.

\177

B
Scheme 80:Assumed mechanism carbonates. 1-chloroethyl

//\"'O-C-OR O
II

of the

reaction

of carboxylate

anion with

anions

with l <hloroethyl

Reaction b in

tories.In

reaction

scheme78 was performed in our laborac, the thiophosphate anion is an ambident

estersfor subsequentpeptidecoupling
the tetrachloroethyl

N-protected amino acidshave been converted to active

by treatment with

are gathered in scheme79 (Ref. 104). O

II

nudeophile and can attack with either the oxygen or the sulfur. As found, attack with sulfur is in accord with the HSAB theory. Some other examples attack of of chloroethyl ethyl carbonatewith soft nucleophile phosphorous compounds

1-

(EtO)2--P- Na+
THF,0\302\260C,1

O\177p(OEt)2

/\177O-C-OEt

77%

O
\"\177

O-C-OEt

Bu3P
\177\"

+PBu3
\"\177O-C-OEt

67%

R-C-O-C-O-Act + CI3C-CHO

0
II

o o
\" \"

J
A1
.\"

The reaction proceedsy initial attack of the carboxyb late on the carbonyl and releaseof either chloral and chloride anion (A1 mechanism) or N-oxysuccinimide
RCOO-

carbonate of N-hydroxysuccinimide, 2,4,5-trichloro penol,pentafluoro phenol, etc. (Ref. 67).

noxide) anion (A2 mechanism)

O-Act Cl3C-CH- O-;-C-\177'Cll

(or pheas depictedon scheme81.

\177

\177IO1\177

ActO-

\177 % O--C-R-C-O--CH-CCI
3

\177A2

( \177to)ap
\177-

00
h
eth\177l

Scheme

79

(\177tO)\177-P-C-O\177t

5g% phosphorous Scheme

R-C-O-Act

Cl- +

\17750\302\260C,

\1778

Cl3C-CHO
using

fxamples

of reactions of

compounds.

1-chloroeth.gl

carbonate

with

O 81
tetrachloroethyl

II

76

Assumed mechanism carbonates.

of active esters synthesis

1,2,2,277)))

as a Phosgenend derivatives buildin\177 blocks

l\"]ixed aryl and oximido tetrachloroethyl

as a Phosgenendderivatives buildin\177 blocks

carbonate. The method section4-4.
Again,
will

crystalline tion of tetrachloroethyl

and

carbonatesare stable compounds easily obtained by reacchloroformate imides as shown in

with

be developedin

volume

2,

phenols or N-hydroxy
Yield %

table 3-12.
Crystn solv.

substituted

Act-

mp bp

the HSAB theory, secondaryand 1-chloroalkyl carbonatesas hard through A 1 attack mechanism to afford carnucleophiles bamatesin high yields.This reaction has been shown to be primary amines

according to

reactwith

(\302\260C)

very

(\302\260C/mm)

general under different reaction conditions utilizing differents types of amines including amino acids(Ref. 64, Scheme below displays the gene-

66,105, 106,107). 82
ral picture

83 66
2

108 121-122
150-5/0.02

Pet. ether
CI
I

of the reaction.
R2

K2CO3/THF/H20
20\302\260C \177

O2N

\177'-\177
NO

Pet. ether

R-CH-O-C-OR +HN\" 'R 3 O

1
II

50 - 95 %

'2 R10-C-N
R

+ R-CHO

II

'R3

Cl

Cl--\177 Cl F\177-F F
(31

92 91 98 85

= H, CH , CCI 3 3 1 R = alkyl, aryl

R

Scheme 82 : ma tes.

1-Chloroalkyl

carbonates

as reagents

for the synthesis

of carba-

80/0.05 120
145-147
CI
Pyridine
I

In

terms of the rate of the reaction and the yield, the

following trends
Ethyl

are observed
CI
I

:
II

\177
OI
\177

acetate

CI
I

O
II

(31

NNN

O
CI
i I

Dichloromethane

O
II

O
II

+ Act-OH CI3C-CH-O-C-CI

--\177- I3C-CH-O-C-O-Act C or
triethylamine

L
Table

3-12Preparation

1 -O-C-ORt Cl3C-CH-O-C-OR 1\177 CH3-CH-O-C-OR CICH2 The releaseof an aldehyde can be a severelimitation in the use of this reaction since the aldehyde formed can react with the starting amine to lead to a considerable o decreasef the yield of the expectedcarbamate.However, this difficulty can be simply overcome depending on the and the structure of the carbonate choiceof the respective

>

II

ofsome aryl

and oximido

tetrachloroethyl

carbonates.

The easy preparation protectedamino acid active ester derivatives using cheap reagents, in a reaction where the by product is water
new method provides an N-

of

soluble and easily eliminated from the reaction mixture. The processs illustrated by the isolation of the N-succini imidyl ester of BOC-Alanine in 94 % yield from activation of BOC-Ala with 1,2,2-2-tetrachloro-ethyl N-succinimidyl
78

have been proposed Therefore, 1-chloroalkyl carbonates to as new acylating agents and thus are valuable precursors ureas as thiocarbamates and unsymmetrical carbamates, outlined in section3-3, this volume. carbonate(BOC-OTCE) 1,2,2,2-Tetrachloroethyl-t.butyl as was especiallydevelopped a crystalline, nontoxic reagent for the N-BOC protection of amino acids (Ref. 66) [see section3-3].
79)))

amine, and on the reaction conditions (Ref. 64).

as blocks Phosgeneand derivalives buildin

In

a as Phosgenendderivalives buildinblocks
In

related chemistry,

the Arbusov

1-chloroethyl chloroformate and easily converted into amino alkyl

reaction products of trialkyl phosphites were

another

case,we
of

have

observed and
chloroformate

studied

the

rearrangement

ted cI

in

scheme83(Ref. 108).

phosphonatesas depicCI

chloroformate (Ref. 110) chloro-l-propenyl [Scheme8.5].

1-chloroallyl

to E,Z-3-

Neat
ZnCI
90\302\260C,

CIH2C\177 2h
bp :
82-41\302\260C

cI O
II

e 2 , 0.012q.

+ CH3-CH-O-C-CI

@NH
CH2CI 2
,0\302\260C,

(i.PrO)3P-\177 CH3-CH-O-C-P(Oi.Pr)2 100% OO OO

II II
\177

93%
(i'PrO)2P-C-Nx.\177/\177

Scheme 85 Rearrangement

81%yield
of 1-chloroallyl
While studying the mechanism, of the rearrangement in

E/Z=3.1/1
chloroformate.

32mm

Scheme 83.'Acylation

ofphosphonate

compound.

reversibility

we demonstrated the presenceof TiCI4.

Some interesting miscellaneous reactionshave been also explored.For example, 1,2,2,2-tetrachloroethyl chloroformate reacts with carboxylic acids at without solvent to afford acid chlorides cyclic anhydrides in high or
110\302\260C

3-Z-Z 4

Vinylic

The
interest

yields

Since the reaction doesn'trequire any catalyst, such result cannot be explained by the decomposition of the chloroformate to phosgene and chloral. The assumed mechanism is given in scheme84.
CI
I

(Ref.

109).

\177:hloroformales,

rarbonatesand
(arbama\177es
\\

have been areas of major research species [Scheme86]

in

synthesis

and chemistry

of

1-alkenyloxycarbonyl

academiclaboratoriesas well

especiallyat

in the industry, the early beginnings for polymers applications.

/
1-Alkenyloxycarbonyl group
C\177O_C

?\177

R-COOH +

CI3C-CH-O-C-CI O
II

\177 '2
Neat
110\302\260C

O
+

II

R-COCI

80- 90% distilled

+ 2 CI3C-CHO CO + HCI

CH-O-C-CVinyl chloroformate CH2=

I

= Ph,

etc. cyclohexyl, 017H35,CH3-CH=CH,

\177,

CH3
I

O
chloroformate

II

OH2=C-O-C-CI Isopropenyl
90%

HOOC\177-\177COOH
Proposed mechanism:

\177 O
\177

O
CI2CzCH_O-C_CI 2,2-Dichlorovinyl
chloroformate

II

O
R-COCI CH2\177_CH-O-C.O-R Vinyl carbonate

II

R-COOH-\177
Scheme 84
.\"

Preparation

1,2,2,2-tetrachloroethyl

chloroformate

of acid chlorides or anhydrides through reaction of with carboxylic acids.

O4
Scheme 86

O O
E

II

- Butadienyl

carbonate

fxamples

of vinylic

oxycarbonyl

species.
81)))

8O

a a b Phosgenend derivatives s building locks

Huch of the early work describedin the literature was centered around vinyl chloroformate classically made by the gas phase pyrolysis of ethylene glycol bis-chloroforma-

a as b Phosgenendderivatives building locks

te at

However, this route (Ref. to be industrially and economically impracticable proved and because of low yields (11-44%) formation of large amount of chlorinated side products and tars. Scheme87 presents the decomposition pathways of ethylene glycol bis-chloroformate.
460-480\302\260C

111,112,113).

CI_C_O.CH_CH2_O_C.CI

0
Scheme 88

0
CI
.\"

bp : 104-6 arm. pressure

\302\260C

Pyrolysis

of the

bis-chloroformate

of propylene

glycol.

In

an

114),
viously king

Hatuszak

obscure short paper published in 1934 (Ref. reported the first preparation of the preisopropenyl

unknown

chloroformate. While

wor-

- CO 2

co 2
HCI

as a physical chemist at the US Bureau of Hines, he isolatedthis compound by microfractionation from a reaction mixture of 70 ml of acetoneand 7 ml of liquid phosgene after half an hour at room temperature. Several chemists teams in the world, as well as researchersin our laboratories this exciattempted to reproduce whatever ting simple and cheap process. nfortunately, U the conditions and catalysts used, all the carried out trials
failed and the only products isolated were mesityl oxide and various chlorinated compounds.The conclusion of

o
- CO 2

cI

- CO 2
__\177,c\177

cI

most investigators was that Platuszak did not isolate isopropenyl chloroformate but a mixture of chlorinated products. However, as shown in table the properties Matuszak closelycorrespond those of the isoto given by

3-13,

propenyl chloroformate made farther on in this section).

glycol at
450-480\302\260C

by

the mercury

processsee (
index

Scheme 87

.\"

Pyrolysis

of the

bis-chloroformate

of ethylene

Isopropenyl chloroformate

Boiling point
\302\260C/mm

Density

Refractive
\302\260C

20

\302\260C/20

20\302\260C

Besides severedifficulties encounteredin the scathe was stymied by tile impossibility of this process ling up,
generalization 1-alkenyl chloroformates.For the same conditions, pyrolysis of the bischloroexample in formate of propylene glycol affords selectively the 1-propenyl chloroformate instead of the desired isopropenyl chloroformate as shown in scheme (Ref.

Phosgenation of

to other

acetone
Phosgenation of chloro-mercuri

93/746
94.5/747

1.103 1.121
made by the mercury

1.4138
by Matuszak

88

111).

acetone
Table

3-13 Comparison

properties of the 82

of properties of the product obtained

chlororoformate

and

isopropenyl

process.
83)))

a a Phosgenend derivatives s building locks b

spite of numerous failures to preparevinyl chloroformate and isopropenyl chloroformate by direct phosgenation of either acetaldehyde acetone,we or the chalIn

a as b Phosgenend derivatives building locks

The

zable aldehydes could react with chloroformates to

vinyl

r lenge to find economical outes to vinylic chloroformates and their derivatives, vinylic carbonatesand carbamates. We have shown in investigations that easily enoli-

accepted

of enol silanes was studied in a phosgenation secondstageof our investigations. Severalilyl enol ethers s from acetaldehyde, cetone, cyclohexanone were prepaa red accordingto general procedures given in the literature.

197.5

carbonatesin goodyields as illustrated

O

in

scheme89.

afford

However, again, all the attempts failed, the only products isolated resulted from C-acylation of the enols.For example, phosgenation of the enol silane of acetonein presenceof amount of mercury (11)chloride afforded 2,4,6catalytic
heptanetrione

O
(EtO)2P-CH2-CHO +

as the
Et3N

major product

as depictedin scheme

91.

RO-C-Cl
O
II

\177 (EtO)2PCH=CH.O.C_OR
II

Scheme

89 Reaction

O R=Me bp : 128-9/1.5 63% mm; R=Et bp:138/1.5mm ; 70%

with diethyl (2-oxoethy/phosphonate).

y
O \177

+ Me3SiCI

Et3N

. HCI

OSiMe3

of alkyl

chloroformates

+00012

Olofsonand coworkers (Ref. 115) found that reaction of ketoneswith LiTHP producedenolateswhich were spewith chloroformates when cifically O-acylated hexamethyl phosphorotriamide (HP1PT) was added in the reaction mixture thus giving alkenyl carbonatesin 49-90% yield. Therefore,our first idea was to O-acylateimple enolates s with phosgene.n a first courseof I attempts, we investigated the reaction of phosgene with alkaline metals enolates. For example we preparedlithium enolateof acetaldehyde through cleavageof tetrahydrofuran by n- butyllithium and (Ref. 116) reactedwith phosgeneunder various conditions. Unfortunately, no trace of vinyl chloroformate was found in all experiments performed [Scheme 90].
+ n-BuLi O\177

\177
from
20\302\260C)

O-C-CI

0 0 0
=\177/

Scheme 91 Phosgenation of the enol silane

OSiMe 3

acetone.

led The phosgenation of the tributyltin enolateof acetone the same results although some trials performed at low showed the possibility to obtain temperature (below small amounts of isopropenyl chloroformate. It is noteworthy to
new synthesis of retinal A aldehyde), Bienaym& from Rh6ne-Poulenc (Ref. (Vitamin in low yield obtained isopropen-l-yl chloroformate of the reaction product of tributyltin through phosgenation that, in

a recent work devoted to a

117),

methoxide with

92. as 1-acetoxy isoprene depictedin scheme

0\302\260

--.-\177H2C\177CH_
II

O- Li +

+ n-C4Hlo + CH2=CH 2

COCI 2

\177
COCl2

OAc

+ Bu3SnOMe

H2C=CH-O-C-CI o
Scheme

\177

90.'Reaction

of phosgene with the

lithium

enolate of acetaldehyde.

CH2CI / Toluene 2

\177 \177 \177

C
CH2Cl2

OSnBu3

+ AcOMe

OiC-CI

+ Bu3SnCl

28% yield
Scheme 92.'Prepara
rio

o
te.
85)))

II

unstable product n of isopren- 1-yl chloroforma

84

a as b Phosgenend derivatives building locks

,\177t

b a as Phosgenend derivatives building locks

precautions and efficient cleaning up methods used. To circumvent the difficulty, we attempted to start from keto compounds. hus, we prepared other c\177-C-metallated T the reaction of disodium by acetonyltetracarbonylferrate tetracarbonylferrate (Caution : pyrophoric !)with chloroacetone in THF according to literature data (Ref. chloroformate in situ afforded isopropenyl Phosgenation
safety but in very variable and non-reproducible yields not % as depictedin scheme94 (Ref. ding

this point

of our

investigations,

we thought

that the

work,

were later to provide the basis for a long collaboration in new areasof chloroformate chemistry between SNPE and Penn State University. In the first step of the SNPE process, chloromercury
contact\177

good way to synthesize enol chloroformates may be the reaction of phosgenewith c\177-C-metallated aldehydes and ketones.With this new courseof action, we were able for the first time to obtain the desiredcompounds by treating with chloromercury acetaldehydeor chloromercury acetone phosgenein polar solvent. about the same time, Olofson and coworkers turned a similar conceptnto a practicable laboratory route to enol chloi roformates (Ref. 118). When we became acquainted with this
,\177t

121).

excee-

50

122).

were initiated

which

Na2Fe(CO)

4+
ClCH2-\177I-CH

THF

20o\177CH3-\177I-CH2Fe(CO)4-Na+
-NaCI

cOQ2
\177'

CH3
I

a acetaldehydend chloromercury red by reaction in water of vinyl

acetate respectively
oxide and
In

mercury

a mixture of (11)chloride (Ref.

with
80\302\260C

1:1

acetoneare easily prepaacetate and isopropenyl

< 50%
Scheme 94

H2C\177C-O-C-CI

NaCI

\"

Fe3(CO)12\"

O
Isopropenyl chloroformate

II

through phosgenation

of acetonyltetra-

second step, the dried chloromercurials comin nitrobenzepounds are treated with phosgeneat ne as the key solvent (Ref.120). chloroformate and Vinyl isopropenyl chloroformate are isolated by simple distillation in 75-85 yield rseescheme93]. %
the

119).

mercury

(ll)

carbonylferrate.

The studies
However,
it

in this

area were

not further

pursued.

possibilities still remain untapped. To give lust one example, the phosgenation of the reaction product of zirconium tetrachloride with acetone CI3ZrCH2COCH by 3 described Joseph and

seemsthat several high-potential

J 1/2 HgCI 2 H2C\177CO-CCH3+ 1/2 HgO

I

II

\177
H20
\177,

CIHgCH2--C-R + CH3COOH

mp:134\302\260C,97%yield R = Me, mp 105\302\260C, 90% yield

R=H,

0
:
R
I

II

should yield, under selectedconditions, isopropenyl chloroformate. In the course of other studies related to dehalogenation methods through electrosynthesis with sacrificial Blumenthal

(Ref.

123),

Nitro

benzene
\302\260c

CIHgCH2-C-R + COCI 2

0
Scheme 93 process.

II

80

H2C\177C-O-C-CI

of 1,2-dihathought that the dehalogenation chloroformates should provide with an interesting Ioalkyl route to vinylic chloroformates.ln orderto checkthe feasiw bility of such process, e carried out a set of exploratory

anode, we

75-85%
R R

0
= H ; bp :89-90 = CH3 ; bp : 94.5
chloroformates
\302\260C/760 \302\260C/747

II

mm mm

experiments under aprotic conditions using 1,2-dibromoechloroformathyl chloroformate and 1,2-dibromoisopropyl t te as starting materials (Ref. 124),hese materials having
bromination of vinyl and isopropenyl chlowas performed in an roformates. The electroreduction undivided cell equippedwith a stainless steelcathodeand a consumable zinc anode using acetonitrile as the solvent and Bu4N+BF4 as the electolytic salt.The promising resulLs

Preparation

of vinyl

and

isopropenyl

by the mercury

been made by

The system was designed recycle HgCI 2 in nitro to the benzenewithout removal from the reactor.However, the w process as severely handicapped by of
86 mercury

compounds

whatever

the bad reputation the strictly controlled

obtained

are given

in

schemec)5.

87)))

a as b Phosgenend derivatives building locks

R
Br B/\177\"r

a as Phosgenend derivatives buildinblocks

high

O
O/jL'CI

e
CH3CN , Bu4N+BF4
\177-

Zn

anode

C\302\260nstantcurrent(l'lA/dm2)

Temperature Scheme 95
dibromoalkyl

2.1Faraday

:30'-C
mole
chloroformates

O o/JL'cI R=H; 54% yield

R
/'\177\"

commercial interest of vinylic chloroformates derivatives

(seefarther
efforts nates

on
by

on in this the synthesis

which

section), we decidedto focus our of alkenyl carbamates and carbo-

methods

do

not require

vinylic

chlorofor-

R= Me ; 76% yield
by electroreduction

mates.
of 1,2-

Preparation chlo rofo rma

of vinylic tes.

made

1-Chloroalkyl carbonates and carbamatesare easily from reaction of 1-chloroalkyl chloroformates with

Thesepretty good results prompted us to find a practical route to 1,2-dihaloalkyl chloroformates.

1,2-Dichloroethylchloroformate is a known product made by classicalhlorination of vinyl chloroformate with c a 2. We have developed new, easily practicable route by treatment of 4-chloroethylene carbonate with PCI5 at which gives a mixture of the desiredchloroformate and the dichloro isomer in a 95 : 5 ratio as depictedin scheme Careful fractional distillation afforded the dichloroethyl chloroformate in 65% pure yield (Ref.

alcohols amines through standard processes secand tion 3-2-2-3,this volume) or original methods developed teams (section If a simple method by SNPE research

(see

for the

]\177-elimination

could be devised, the

3-3).

ready availabili-

and carbonates would seem ty of 1-chloroalkyl carbamates to make these compounds attractive precursors vinylic to

carbamatesand carbonates. Olofsonand coworkersdiscovered a

o process f thermal
chloroethyl high yields carbonyl)
refluxing

110\302\260C

relatively

simple

elimination
In

of hydrochloric acid from example, N-(vinyloxyin

1-

96.

1,2125).
o

carbamatesto produce vinyl carbamates in

(Ref.

126). a typical
[see

%o__.%o__.
O
CCI4

\177

CI2 , hv

PCI

CI

110

\"C

CI

% yield just by piperidine for 3 h in N-(1-chloroethyloxycarbonyl) o.dichlorobenzene containing eq. recyclable2,4,6-collidine as an acid scavenger scheme

piperidine

was obtained

89

1.2

97].

CI

58% dist.
107\302\260C/10

Distill.

mm

91-2\302\260C

90mm

CI

O--\177

95:5

CI

cI
H
3C_C\177

o.Dichlorobenzene\177, H.O.\177I.

CI

N\177_/\177

Collidine,
Reflux,

3h

1.2 eq_

H2C

Scheme

9\177

Scheme 97 of
1,2-dichloroethy! chloroformate.

O 89% distilled bp. 123-8 / 47 mm

\"C

=CH-O-\177-

N\177__\177

Preparation

of VOC-piperidine

from ACE-piperidine.

Novel preparation

The starting material, was preparedby standard

ethylene Unfortunately,

4-chloroethylene carbonate of the cheap photo-chlorination carbonateas describedin the literature.

the

the dechlorination of 1,2-dichloroethyl the electroreduction method afforded by only very bad yields of vinyl chloroformate, whatever the conditions selected. Moreover, all the attempts to prepare the 1,2-dibromoethyl chloroformate failed.

Without collidine, the reaction has been proved to work but is much slower. When the methyl of the 1-chloroethyloxycarbonyl group is substituted by alkyls, the elimination is easier,probably due to inductive stabilization of the carbocation intermediate.

chloroformate

At this point
88

of our

investigations,

and on

accountof the

The effectsof various conditions such as added mineral or organic salts (to catalyse the EI elimination), temperature and solvents were carefully studied by Wooden (Ref. 127). Some representative examples of the method are gathered in table

3-14.

89)))

a a b Phosgenend derivatives s building locks

RI

b a a Phosgenend derivatives s building locks

bp.

R2

-NR3R4

Base

Solvent

Yield

cI
H3C-CH-OoC-N

(%)
H H H Pie

(\302\260C/mm)

--N\177

Collidine Collidine

o.DCB
Tetrachloro
ethylene

82 134-6/49 84 86-90/0.5
78

II

\177

o. DCB
\177,

\177
H2C\177---CH-O-C-N

150\321\236C,

vacuum

Catalyst

Catalyst

:0.055 eq. : - TBAB,9 h.

non isolated,

il

\177

-N\177

20% decomposition. - CHBG.HCI, h, 100%completion 7

Scheme 98
bonyl)

100%completion 80 % by NMR

--'\177'\177
N

Collidine

/
Collidine

Bromo benzene Bromo benzene 1,2-Dichloro

ethane

81-5/0.2

100%yield of two
E1

NMR,

85 % isolated.

Comparison

promoters in the synthesis of N-(vinyloxy-car-

morpholine.

R'

\177
Zo-V
Me +

86 125-7/0.6
97
Light

tion red

Pie

l\"le

c[
3

_N(CH2)aNMe

None

gum

the carbamate chemistry, thermal eliminahydrochloric acid from 1-chloroalkyl carbonates much higher temperature and is accompanied by requires major yield destructive sidereactions.The key to an economiIn

contrast

to

of

CI
R\177\\

3 4

R R

CH-CH-O-C-N'

'R3
CH_O_C_
II

\\C\177

O
of

II

'R

'R 4

Table

3-14 Preparation

and w to vinylic carbonates as discoveredby Olofson o This discovery was the consequencef coworkers (Ref. a beautiful observation made by Dang, Olofson'student, on s the formation of neopentyl fluoroformate and, unexpectably
cal route

129).

1-alkenyl

carbamates

from

1-chloroalkyl

carbamates.

of

extra functionnalities are t\177lera\177edl Somemoieties even catalyze the elimination by last example in the table). increasing salt concentration The value of hexabutylguanidinium chloride or

As illustrated

in

table 3-14,many

(see

heating 1-chloroethyl neopentyl carbonate with KF in benzonitrile (Ref. Treatment of enolizablealdehydes with fluoroformates and KF in DP1SO for 15-24 afforded 1-alkenyl h) (55-100\302\260C stu% yield. According to Olofson's carbonatesin
vinyl

neopentyl

carbonatewhile

130).

72-92

acylation catalyst has been already outlined in section2-2 of this volume. In a later study devoted to the evaluation of potential facilitation of E elimination 1 in sensitive systems by including HBGCI, Kreutzberger (Ref. proposed a modification of the Wooden method basedof the use of a salt promoter

as HBGCI.HCI) an

(HBGCI

dies,the
nares the

activated

fluoride anion acting

as a basedeproto-

aldehyde to yield an enolatewhich reacts rapidto give the desiredvinylic carboly with the fluoroformate Excess neutraKF nate as shown in scheme99 (Ref.

131 ).

128)

lisesthe o
nl\\

HF which

is liberated
RI\\
\342\200\242

in the

reaction as KHF 2.
+ KHF 2

\177

\177.

of comparisons experiments without collidine in o.dichlorobenzeneunder vacuum demonstrated a decisive advantage of HBGCI.HCIover TBAB as shown in scheme98.
allows to avoid the use of collidine combined with its thermal stability at tempera,fores exceeding 200\302\260C made this salt a prime candidate as salt promoter in this process.
\177 \177

with collidine tetrachloroethylene as the acid scavenger,the guanidinium salts are superior to ammonium bromide (TBAB). Moreover, the tetrabutyl
\302\260C),

In refluxing

(121

CH-CH

II

DMSO + KF

C=C-O

R 2/
RI\\

R 2/ DMSO

RO-C-F / R2 O Scheme 99 Mechanism of the

C\177-C-O-

\177

R\177\\

C=C-O-C-OR F +
O
fluoroformates
II

II

n 2/

The efficiency of HBGCIwhich

presence of KF in

reaction of

with aldehydes

in

DMSO.

Note that the reaction tonitrile

if

also can be carried out in aceis 18-crown-6 used as a catalyst. In this latter
9|)))

9o

a b Phosgenend derivatives building locks as

case, chloroformates
mates if
method
n may

a as b Phosgenend derivatives building locks

in a work carried out to assess the kinetics of radical polymerization of somevinyl alkyl carbonates, bdon and coworE kers showed that contrary to the conclusions of the previous

be

substituted

for fluoroforin the

two equivalents

of KF are included

medium.

Some results obtained using the fluoroformates are presentedin table 3-15.
R RI

R2

Temp., Time, h

\302\260C

Yield

bp.
\302\260C/mm

studies, the compounds can be polymerized readily polymers of high molecular weight with conventional initiators such as benzoyl peroxide(Ref.

to

give

radical

Hg

1 Et H 1 C6HS-CH2H 1 i-Pr H - CH2CH2CH22 H 2 CH2CH2-O-CH2CH2 H 1 Et Ple 1 CF3-CH2H

H H H H H Pie H

55/20 70/15
80/5 80/24

73 87

43-5/45

112-5/4

90/8
90/24

86 44-6/33 92 130-2/O.5 80 123-30/O.7

74

45-7/16
43-4/2..5

80/20 /n

81

R1XC=CH_O_C_O/R R2'
\177

Table

3 15.reparation P
KF

The chemical modification of poly (vinyl chloroformate) and its copolymers has been also studied. Treatment of such polymers with amines, alcohols and phenols affords the corresponding poly (vinyl urethanes) and poly (vinyl carbonates) (Ref. Poly (mixed anhydrides) have been also preparedby chemical modification of poly (vinyl chloroformate) by carboxylic acids under various conditions (Ref. The materials obtained from polymerization of vinyl carbonates and carbamates hard (but not brittle) cleartherare with high decomposition temperatures, excellent moplastics chemical resistanceand varying glasstransition temperatures.

137).

138, 39). 1

140, 142). 141,

of

1-alkenyl

carbonates

flora aldehydes,

fluoroformale\177

and

in

DMSO.

is notable, because the 2,2,2-trifluoroethyl vinyl carbonate has beenproposed useful monomer in optical fibers as applications (Ref. 1-Alkenyl chloroformates, especially vinyl and isopropenyl

3-15

The good yield

obtained

in the last experiment

of table

that the heretoforenot accessible at cost diethyleneglycol bis-vinyl carbonatecalled acceptable CVD [see scheme100] made in 80% yield using the is fluoroformate as depictedin table 3-15. process
It is noteworthy
\177 \177

o
,CH2CH2-O'C-O-CH\177CH

o
2

132).

o,
CH2C H2-O-C'O'CH\177CH2

=CH ,CH2CH2-O-C-O-CH2-CH 2
CH2CH
2-O-\1771

a chloroformates, as well as vinylic carbonatesnd carbamates have found number of valuable applications in various fields.

o
II

-O\" CH2\"CH

\177

CH2

considerableotential of these p vinylic compounds in organic syntheses, selectedtypes of applications are presentedin the following pages. The use of vinyl chloroformate and its derivatives as
In

orderto illustrate

the

CVD

CR

o-

Scheme 100 Compared structures of two calplastic lenses. CVD is known

39
for the fabrication

monomers

of opti-

to

monomers

in the manufacture

of thermoplastic

or crosslin-

polymerize

an

order of

magnitude

ked polymers is the oldestapplication developed. of vinyl chloroforPolymerization and copolymerization mate (Ref. carbonatesand carbavinyl

more easily (Ref. 143)than the analogous bis-allyl nate marketed under the designation CR-39which
leading material

carbois the

133, 34, 35), 1 1 mates (135, using standard 136)

yield high oxydicarbonates) and random copolymers is well

for

radical initiators

to

p (e.g. er-

molecular weight polymers documented. More recently,

crosslinked homopolymer of CVD exhibits similar propertiesbut with the advantages of much better scratch resistance and higher hardness and modulus.
Hethacryloxyethyl vinyl

decades. he T

casting

prescription

eyewear since

carbonateprepared from

hydro93)))

92

and derivatives s building locks a b

a a Phosgenend derivatives s building

enolates generatedin
the

hosgene

blocks

and vinyl chloroformate [Scheme ] was claimed as an UV curable crosslinking agent useful in the formulation of hydrogels for contact lenses manufacture (Ref.
xyethyl

101

methacrylate

144).

of presence N,N,N',N'-tetramethydiamine (TP1EDA) as depicted in scheme 103. lethylene In our continuing trials to extent the scopeof the vinylic carbonatessynthesis through the fluoroformate process,
vinyl menthyl

o\177Ok__/O
paration

+ \177
0--\177

0
CI

--'\177\" 0--/< =\177\177 0

O\\

0 '

carbonate was
menthyl

(80%)from

obtained in excellent yield fluoroformate. The polymer of vinyl men-

thyl carbonate was

Scheme 101 Synthesis of methacryloyloxyethyl

of biomedical

0%

vinyl

carbonate used in the pre-

as alsoproposed menthol-release agent. It is noteworthy that this polymer can be easily prepared by reaction of menthyl fluoroformate with poly(vinyl alcohol) in DP1SO.
1)Nail (

articles,

1.1 eq.)
reflux of

Aromatic product

bis-vinylcarbonates,

for example the

with

reaction

bisphenoI-A [Scheme are recommended the preparation of highly senfor sitive, high-contrast positive working resists (Ref.

102],
o
\177

of vinyl chloroformate

Y
O

r\177
+ L'v\177
--

TMEDA

THF,

( 1 eq.)
enol\177t

145).

\177

o.-JC- 2) Addition ci
formate

solution to chloro-

\177 i
\177

O..J[\177

O.\177

(-)-Menthyl

chloroformate

; THF,

0\302\260C

79 % yield

Me

Scheme 103 Effident synthesis of isopropenyl facture of polymeric menthol-release agents.

menthyl carbonate for the manu-

Scheme 102 Aromatic mance photoresists,

o
his-vinyl

Vinylic
for the manufacture

carbonate

of high

not limited
perfor-

the New N-vinyloxycarbonyl leucine alkyl estershave been synthesized from vinyl chloroformate and polymerized to
yield polymers and copolymers optically and physiologically active with liquid crystals properties(Ref.

chloroformates, as well as their derivatives are to rolesas monomers. Initial Olofson'spublications outlined (Ref. use of vinyl chloroformate (VOC-Cl) as a reagent for

150, 151)

in especially peptide synthesis, via the electrophile-labilecarbamate.Amino acidsare converted

amine protection,

to

carbonatesand carbamatescontaining chromophore groups have been prepared and claimed as useful polymerisablephotoinitiators for photoreticulable polymers (Ref. 147). and carPolymers and copolymersof vinylic carbonates bamates may find interesting applications as aroma and flayours releasing agents. For example, isopropenyl menthyl carbonate has beenpatented (Ref. 148) s an useful monomer a for the manufacture of a smoking composition comprising an admixture of tobaccoand a menthol-release agent. Recently, Harwood et al (Ref. 149) have published a new preparation of enol carbonates including especially isopropenyl menthyl carbonate by selective O-acylation of ketones sodium
Vinyl

146).

cedure.The most significant advantage of the VOC-group is associated with its removal which is facilited by the high of the C=C bound toward electrophiles. cidA reactivity induced hydrolysis with HCI or HBr in Ac-OHor with HCI gas through
wed by

their N-vinyloxycarbonyl derivatives by standard acylation with VOC-CI, for example by Schnabel's pH-stat pro-

an inert solvent containing the peptidefollowarming the hydrohalide adduct in ethanol affords the deblocked peptidesalt in excellent yield. The value of the methodology was underscored an efficient process in for the construction of the heptapeptide sequence, H-Ser-

(all L) (Ref. ). chloroformate (IPCF) has no value in amine protection but appears to be the most versatile chloroformate for acid activation. Thus, IPCF was proved
Phe-Leu-Pro-VaI-Asn-Leu-OH Isopropenyl
95)))

151

94

a a b Phosgenend derivatives s building locks

a as b Phosgenend derivatives building locks

in
(z-Amino

\"r
H2

to be an excellent eagent for the amino acid activation r

esters

Yields

peptideamide bound formation via the mixed anhydride intermediate as depictedin scheme104 (Ref. 152).

(%)

mp

(\302\260C)

[(z]D, Cl, i\"leOH

.o
+

Z-Ala-OCH2-pNO2C6H4 Boc-Phe-OBzl

78

N\"T\"'COOMe R2
I\177\"

w
Boc..\177

R2
N.\177J,,.COOMe

Scheme 104 Amino acid activation

propenyl chloroformate.

\177H R
1

CO + 2

y
O
formation

.]
by

Cl2C6H3 Boc-VaI-OCH2-o,p Fm ooTrp-O-[2.3-O-(isopro pylidene glyceryl]

Boc-VaI-O(+) Z-Phe-O-t.Bu Z-Pro-O-t.Bu Z-Trp-O-t.Bu Table Bornyl

92 85 65 60

99-100 64-5 110-1 61-2

54-7 B1-2

- 16.3 - 6.3 - 10.5 - 12 - 75 - 9.9 - 51 - 5.2

(z-amino

88
90 60

70-1
of N-protected

3- 16 cz-Amino
It

for

peptide amide bound

iso-

esters by

IPCF activation

acids.

by isosecondaryand terin as tiary alcohols presenceof 4-dimethylamino pyridine catalyst affords the corresponding estersin good yield as shown in scheme105 (Ref. 153).

Reaction

of N-protected amino acidsactivated

with

propenyl

chloroformate

primary,

coworkers (Ref. 154) made from recently proposedallyl isopropenyl dicarbonate isopropenyl chloroformate and sodium allyl carbonateas a convenient reagent for the preparation of allyl estersof
that Takeda and carboxylic acids.Allyl isopropenyl dicarbonatereacts with carboxylic acidsin the presenceof DP1AP under mild neutral conditions to give allyl esters in high yields. Allyl esters
which

is noteworthy

could

p --N.\177COOH
H DMAP
RI\"oH
\177

===\177/

Et3N

-oo2 /P-NH Acetone

L

Scheme

105 IPCF activation

. :
/

O-C-CI O
II

especiallyuseful in the caseof unstable compounds under acid or basic conditions, for example O-glycopeptides,
penicillin

be deprotected by

palladium

catalysts

are

derivatives,

etc.

/L.
\";1\"

.DMAP + ' R10

\177
in

p_N

O-R1

O
for

-J'\177 H

The condensationof a chiral N-protected amino acid with Pleldrum's acid in the presence isopropenyl chloroof formate and DI\"IAP is the key for a stereospecific synthesis of N-protected Statine (Ref. The novel route to
Statine is

depictedin scheme106.

155).

one-pot esterification

of N-protected

amino

adds.

Someexamples are given

table

3-10.
Boc__N\177COOH H

\177\"

BocNH
O.\177
\177

O\177:
IPCF
DMAP

AcOEt

OH
BOC--

(I)

O\177O

_\177 - Acetone
NHBoc
\177

O
88% from (I)

H2

Adam's catalyst\177

\177UH Boo--N: J

\177 \177 \177

\177,

\177cheme

\17705

2) HQ

\177 \177COOH 1)aaoH

I \177H

Acetone

N-Boc-Statine

\177tereospecific

synthesis of \177t\177tine

#ore

IPEE

96

97)))

a as b Phosgenend derivatives building locks

strategy was utilized acylation of Pleldrum's In this work, isopropenyl ester chloroformate was found to give the best results of several mixed carbonic anhydrides derived from the required starting carboxylic acid when used in the presenceof 5 molar equivalents of

a as b Phosgenend derivatives building locks

reactive than the commonly

Plore recently, a similar to prepare the Dolastatin

15via

synthetic

used reagents.
Me,.

(150).

o Me.,s,.O
\177.\177O..\177Ci

Me,.s,O. O ]
1

.CO 2

DI\177IAP.

Dolastatin

proved to

exhibit promising

remarkable

Scheme 108 Pummerer rearrangement With penicillin

._o
the

\177-

./..L..__CI

with vinyl chloroformate.

anticancer properties.

J]-sulfoxide, VOC-CIinduces a novel

Olofsonand coworkers alsointroduced vinyl chloroformate as a reagent for the N-dealkylation of tertiary amines 1 159). (Ref. 157, 58, Comparedwith commonly utilized reain N-dealkylation procedures, the use of VOC.-CI eads l gents
to significantly improved yields under milder conditions combined with greater discrimination between alkyl groups in is unsymmetrical amines. The procedure illustrated by the selective N-deethylation of N-ethyl piperidine to afford piperidine.HCI in 90% yield (Ref. 159) depictedin scheme 107. as The N-dealkylation selectivities follow the order : benzyl; allyl; t.butyl >> s.alkyl n.alkyl >> piperidine scission. The methodolo\177 was subsequently applied to the pre_>

rearrangement

depictedin
H

involving cleavageof scheme109,

ZNH_

C-5-C bound as

O 56%

S. /
O\177 O

Scheme
formate.

109

CO2Me
Novel rearrangement

from penicilfin

l\177-sulfoxide

and

vinyl chloro-

Alkenyl kyl

carbonatesreadily add HBr to give 1-bromoalcarbonateswhich are better alkylating agents for the
of carboxylic acid functions
in

modification

than 1-chloroalkyl

paration of the potent analgesic Nalbuphine and the potent narcotic antagonists Naloxone and Naltrexone (Ref.

100).

carbonates as already mentioned

(Ref.
nate
yield

example, 1-bromoethyl tisopropyl (BEIC) was preparedat pilot scale in 92 %

by bubbling

85). For

section 3-2-2-3 carbo

distilled

_/N 1

1,2-DCE
\177

Et VOC-CI
0\302\260C

'Et
L

CI-

-\177
90%

O
N--\177

HBr through

vinyl isopropyl

neat,
O\177,

at

20-25\302\260C

as depictedin scheme
Br

) HCI

2) EtOH

100%
Scheme 107

\177\"

1.1 eq. 20-25oc

HBr,
Neat

\177NH.HCI
tion of N-ethyl pipefidine with vinyl chloroformate.

7h

/-4 /-04-0
O
92%

110.

carbonate,

(98% pure)
mm

N-Deethyla

bp:
Scheme 110 Preparation

78\302\260C/100

However, vinyl chloroformate largely has been replaced for N-dealkylation by 1-chloroethyl chloroformate which shows similar dealkylation selectivities and equally easyreplacement of N-alkyl by the carbamate group (seesection3-3).
in Vinyl chloroformate might find interesting applications Pummerer related rearrangements. Thus, VOC-CI reacts

d of
1-bromoethyl isopropyl

2\302\260

: 1.34
(BEIE).

carbonate

mates,

with

me
98

108 161 (Ref. ).

sulfoxides

to

yield
In

o\177-chlorosulfides

as shown

in

sche-

this type

of reaction, VOC-CIis more

Besidesthe synthesis of vinylic carbonatesand carbaOlofson coworkers reported a simple synthesis of and and carbamates 1-(1,3butadienyl)carbonates (Ref. 162). and its congeners are easily and often Crotonaldehyde converted to trans-butadienyl carbonates stereospecifically and carbamates treatment with potassium tert.butoxide by
99)))

a blo(ks a Phosgenend derivatives s building

followed chloride
given Y in with

a as b Phosgenend derivatives building lo(ks

to reospecifically form
(IV) which, after LAH reduction and (+) - Hernandulcin (V) as depicted in

addition

of a chloroformate or

table 3-17.

as depictedin scheme
THF
KOt.Bu

111. examplesare Some

0
Et\177
Y,N/__\177O

carbamoyl

scheme112, o
N\177L-

oxidation

affords

0
+

HsC/_\177H
H

Z-C-el

0
II

- 78 oc

,
H

--/k/z

O
H +

o
II

Y = H, Me, CI 2 Z = OR or NF\177R

(I)
I\177,\177 Me

k
OH

Me

TiC'4
-\177

(Et)2N-C\177 v
Me\"

Me

\177MgBr
(111)

Scheme 111 Alkyl dienyl carbonates and carbamates dehydes with KOt.Bu and acyl chlorides.
Y H H H Z

(ll)

from reaction

of crotonal-

o
II

OH

Yield

(%)

bp

(\302\260C/mrn)

2) Pyridinium
M\177v)V

Me\"

O-Et
O-Allyl

O-CH2CCI3
O-Et O-Et N(Et)2

He
CI

83 58 68 78 32
75

48-51/0.6 .5 58-61/I
74-84/I
carbamates and carbonates.

55/0.8 99/0.7

42/3

Scheme 112 Novel

In

.\177
preparation

chlorochromate

v.\177

(V)

of the sweet sesquiterpene Hernandulcin,

Table 3-17 Preparation

of trans-

1-(1,3-butadienyl)

course of several investigations devotedto the of new halogen substituted carbamates and phosphonato esters for agricultural screening, we were interested in the compounds containing the 2,2-dichlorovithe synthesis
nyloxycarbonyl

unit.

The alkyldienyl carbamates were utilized both at Pennstate University and at 5NPE in parallel studies to - Hernandulcin developa stereospecific synthesis of (_+) and congeners (Ref. The intensely sweet sesquiterpene, ernandulcin, was H isolated from a plant known to the Aztecs as Tzonpelic Xihuilt or sweet herb (Lippia dulcis). Hernandulcin which could be considered the prototype of a new classof times sweedietary sucrosesubstitutes is said over ter than sucrose. owever to a human panel at SNPE, H while tasting synthetic Hernandulcin made by the new some aftertaste and a slight bitterness was methodology, perceived 50% of the persons. by

163).

in the world continue to take advantage of the toxicity to insects of particular patterns of halogens in the molecule. be more accepTo

Various

insecticides sed extensively u

table than
gically

many

sensitive

other agricultural agents in today's ecolosociety, they must contain functionalities

c\177

1000

guaranteeing ready degradation by environmental agents. A report published thirty years ago (Ref. outlined the potential insecticidal activity of 2,2-dichlorovinyl carbamates and carbonates.However, progressin this area has been stifled because 2,2-dihalovinyl chloroformates were unknown. For the preparation of the phosphonato

164)

In our method, the N,N-diethyl butadienyl carbamates reacts both regio and stereospecifically methyl vinyl to (I) ketone to give the cyclohexene in 89% yield, which in (11) turn adds the Grignard's reagent (111), gain and stea
re\177io

ester (A) assumedto exhibit interesting insecticidal properties as compared to the well known insecticide unknown 2,2-dichloDichlorvos, we neededthe heretofore scheme rovinyl chloroformate [see

113].

100

101)))

a as Phosgenend derivatives buildin\177 blocks o

CI2C =CH-O-P(OMe)2
Dichlorvos
from
II

a as Phosgenend derivatives buildin\177 blocks

avoid any uncontrollable exotherm. No induction period found in the same reaction from 1-chloro-2,2,2-tribromoethyl chloroformate but the yield of 2,2-dibromovinyl

o
CI2C \177CH-O-C-P(OMe)2
(A)

was

Arbuzov reaction of

chloroformate was only

dichlorovinyl chloroformate Scheme 113 Comparedstructures ofthe insecticide Dichlorvos and a parent comunit. pound containing the 2,2-dichlorovinyloxycarbonyl

33% [Scheme115]. o
Br2C\177CH-O.C-CI

CI2C---CH-O-C-CI
Yield

75 %

33%

describedin section 3-2-2-3. thought that if this We chloroformate could be induced to undergo a Boord elimination of chlorine, the desired2,2-dichlorovinyl chloroformate would be easily available as shown in scheme114.
dy

chlopreparation of 1,2,2,2-tetrachloroethyl roformate by treatment of chloral with phosgenein the of n presence a reusable, aked CI-, catalyst has beenalrea-

The facile

82-5 / 120mm bp. Scheme 115 2,2-dihalovinyl chloroformates.

\302\260C

68-3

\302\260C/12

mm

Both chloroformates are stable for at least several months at room temperature if all tracesof the byproducts zinc salts are carefully removed by distillation. Even more surprising, we discoveredthat 2,2-dichloroviis isolated in 50% distilled yield when nyl chloroformate and zinc dust in methyl acechloral is treated with phosgene tate (Ref. Efforts were made to generalize this process and o\177-bromo by extending the reaction to other oechloro

CI
I

O
II

O
Dechlorination
\177,

II

CI3C-CH-O-C-CI

CI2C__--CH-O-C-CI
chloroformate.

167).

Scheme 114 Expected route to 2,2-dichlorovinyl .'

However, several precedents in the literature would seem to negate a favourable outcomefor such a scheme. For example, the treatment of 2,2,2-trichloroethyl acetate with zinc leads to 1,1-dichloroethylene a dramatically in exothermic process. Sincechloroformate anion is a better than acetate,it should compete with chloride leaving group for that role. Chloroformate ion also should be lost in an anticipated subsequentzinc-mediated elimination to yield the explosive chloroacetylene. Horeover,the well-known of chloroformate in presenceof zinc salts decomposition

(Ref. 167). aldehydes and ketones as shown in table When Z is hydrogen, alkyl or aryl, the chloroformate is obtained only when A and B are halogen or alkyl but not hydrogen.
A
CI

3-18

B
CI

Yield

(%)

bp.

(\302\260C/mm)

Ph Ph
CN

Me

Me
I\"1e

66 54
67

86-8/0.4
57-74/0.5

He He
CI

80-3/10

He He

P(O)(OHe)2
H H

provides another

problem.

-(CH2)5He O
+ x-C--C-Z COCI 2
,A
II

Despitethese strong omensof failure, the reaction was successfully performed (Ref. 165, 66). 1 When zinc dust was added in small portions to a solution of 1,2,2,2-tetrachloroethyl
dichlorovinyl yield. Initiation

-(CH2)4Zn
\177-

83 56 59 68
\"CA/k-\177-('O-/k/'

68-71/52 48-50/0.7 80-2/8

O
I

chloroformate in THF at room temperature, chloroformate was isolatedin 75% distilled

reaction after addition of the first portion of zinc is variable in time and no more zinc should be added until the first portion has been consumed to

of the

Table nyl

3 18.'Preparation

of substituted

vinylic chloroformates

from u-halo

carbo-

cpds.

102

103)))

b a a Phosgenend derivatives s building locks

that the reaction applied to 2,2-dichlodione leadsto the previously unknown ro-l,3-cyclohexane through a clean decomposition dichlorocyclohexenone of the intermediate enol chloroformate as depictedin scheIt

a as b Phosgenend derivatives building locks

Entry

is noteworthy

IHonomer

bp.

(\302\260C/ram)

ND20

Density

20

me

116.

I 2 3
Table

CI2C=CH-OC(O)OC6F5 CI2C=CH-OC(O)OCD3 56/15 C12 2CC13 142/760 C=CH-OC(O)OCH

115/151.4663 1.658
1.4590 1.420 1.5005 1.604
fibers

0 CI

FO
00012Zn

CI

3-19 New vinylic

.\"

carbonates

as monomers for

optical

applications,

\177)
.\"

IYW__0
I

- 002

CI

Their polymerization

and copolymerization

with

vinyl

Scheme 115Preparation

of 2,3-dicbloro-2-cyclobexen-1-one.

carbonate was also studied. vinyl methyl Whatever the radical initiator used (AIBN, benzoyl peroxit de,dicyclohexyl percarbonate)he monomers are too hinderedto self-polymerize. phosphoMonomer

acetate or

The value of being able to

nato groups among allowed

include cyano and

is of particular interest. Severalmodel experiments were carried out to guarantee the efficiency of these enol chloroformates as
Z substituents acylating

(I) and (2)polymerize

give alternating tail structure and

1:1 copolymers
Tg
95\302\260C

with

vinyl

acetate to
head to

with

an unusual

and

75-90\302\260C

respectively.

agents. Thus,

many

carbonates, carbamates,
new chloroformates with

phosphonato

estershave been obtained in good to excelreaction of the

alcohols phenols, amines, trialkyl phosphites (Ref. 168). or carbonates and carba1,2-dichlorovinyl Significantly, mates may have an interesting future as specialty monomers, for example as core materials in all-plastic optical fibers.
known that the optical absorption which is the drawback of the classical lastic materials such as major p PMMA, is dominated by the higher harmonics of the carbon-hydrogen stretching vibrations. The value of polymers
It

lent yields from

is

3-3Reactions
at a nitrogen

center

from

chloroformates derivatives has to 2,2-dichlorovinyl to their lower optical absorption as compared standard plastics in the visible and near-infrared regions of the Some new 1,2-dichlorovinyl carto l\177m). spectrum i % yield bonatespreparedby standard proceduresn

I i

do with

(0.6 1.5

I\177ighlights

of

for that

purpose are gathered

in

table

3-19 169). (Ref.

90-95

ome reactions
with

o|phosgene

amines, imines, oxazolines

ted

tertiary amines at low temperaunstable crystalline I or phosgeneamine adducts. In the case of tertiary alkylamines, these comp.lexes decomposewith elimination of alkyl chlorides to give carbamoyl chlorides and then isocyanates s depica tures

Phosgenereacts with
to
afford

:I 1:2

in

scheme117.

104

105)))

Phosg\177_ne

in ex\177ces\177s

R3 N

COCI 2

- 60to + 20\"C

R-N-C-CI
I

,R+

Cl-

1
T>20\302\260C
F\177NH

0\302\260C

+ OOOI 2

2) Reflux

Toluene
R2NH'HCI

R',N-

C-Cl
Ioi

00 RCI

N-O-N
R'
R

,R

Scheme 119 Preparation

COCI2

Reflux

\177 \177 \177

/N--% O

of carbamoyl

chlorides from secondary amines.

Amine in

excess
COCI 2

R3N

- 60to+20'C

CI-+

+ Cl

R3N-\177-NR3

Scheme

117: Reaction

of phosgene with tertiary

alkyl amines.

structure (11)for the phosproposed1:2 was deducedby analogy to the comgene-pyridine salt (I) as shown in scheme pyridinium monly observed as a conclusionof a study of low temperaHowever, ture 130 NMR and solid-state130 CP/MAS spectra,King

The originally

adduct

118.
and

1:1

mutagenic Low molecular weight and carcinogenicsuspectedagents. dimeproducts exhibit high toxicity levels.For example, chloride is a powerful lachrymator and a thylcarbamoyl confirmed carcinogen and mutagen. Extreme care should be taken to avoid inhalation or skin contact. In orderto developvarious new applications of carbamoyl Caution chlorides,

!several carbamoyl

chlorides are

Jr.

coworkers (Ref. 170)assigned a to structure (111) the pyridinium (2-DHPP)

ol

dihydropyridine-

salt. 1:2 ol-

in the synthesis of compounds such as ether oxidesof tertiary containing functional groups amines. Thus, we studied and scaled an improved process up for the production of N-chlorocarbonyl morpholine basedon [Scheme a modification of literature data (Ref. valuable N-chlorocarbonyl morpholine has found some amino acids to N-morpholinocarapplications to convert

we were interested

172)

120].

o,+

bonyl \177/=\177

amino

COCI 2

/=\177_//o

o (,)

phenylalanine
inhibiting

acids,for example N-morpholinocarbonyl-(L)for [Scheme120] the preparation of renin-

peptides.
Toluene
I

% 92.4 yield
m\177.

84-7\177'C

6ec.

z/\177

Scheme 118 Structure of the Note that the

\177
adduct.

. +

cr

/---N
I

COCl 2
Reflux

_---

(I)

O,k___./NHIHC

1:2 phosgene-pyridine

c\177N\177 > 95 % distilled yield / 73 mm bp. :

153\302\260C

which can be stored at least adduct (111) one year at room temperature and which reverts easily to its components in solution was proposedas a convenient (safe ?) storage system for phosgene under the term in phosgene- - can (Ref. 170). The reaction of phosgenewith secondaryamines or their hydrochlorides is a well known useful route to carba(Ref. 171. ) moyl chlorides as shown in scheme

/ H2O
(I)

+ H-Phe-OH
NaOHTH

\177'-

\177
morpholine

/---%N \177O
N

a-

))

80 % yield mp. :
134\302\260C

-\177
coOH
107

Scheme 120 Preparation

L-phenylalanine.

of N-chlorocarbonyl

and condensation with

119

]06)))

a a b Phosgenend derivatives s building locks

Such modified peptideswere proposedfor the treatment of hypertension, in a patent from Squibb originally and then in numerous patents from other companies. (Ref. In another example, N-chlorocarbonylmorpholine is used

a as b Phosgenend derivatives building locks

in our laboratories was also devoted to the preparation of process carbamoyl chlorides as N-chlorofunctions,such containing tertiary alkylamine This carbacarbonyl, N'-methyl piperazine hydrochloride. chloride is for example used in the synthesis of the moyl sedative and hypnotic pharmaceutical Zopiclone as shown

Some work

173)

improve

s (besideseveral other phosgenederivatives)

synthesis from Fujisawa

of FK-906,an
in

antihypertensive
in

in a multi-step renin inhibitor

121 174). (Ref.

CI

phase II

Japan, as depictedin scheme

in

scheme122 (Ref.1T5).

O/---\177N\177

\177

H3C,

N\177 H
\177--N,

Et3N
\177-

,OH3

Me

\177
N
\\\177

Aproticsolvent
+

./

NH

COCl2
0\302\260C,

2-3h

\177-

MeN

\177 N-C-CI. HCI \177

Oii

t.BOC
H3Q
CF3COOH
\177.__

97% yield

H3C,
N

\177N._\177

\177 O

O -\":/\177

II
o
H2

N,CH3

't.aoc

\177

O/\177'kN

\177

__\177N

-'\177. N,C
\"\177)

H3
\177

N\177J\177

O O

el H2N\177
\177

N--

\177N\177

:/\177__
\177\177

\177N

\177/

O'/'hf\177

H3C

\177
uction
Red_

O
N
\177,[\177 \177.\177Z\177N

2) BASE

\177
q
\177

\177L\177/

#
\177.

//

Cl

\177 MeN N-C-CI. HCI X ./

II

OH

Pd/C

N% \177 O\177 \177 H3C

\177

\177

,N\177 \177R

,P

\177OH

O\177

C-N

\177
H3C

o\177

\177)

(coco\177

.30
H3C

\177

CH3

Scheme 122 5ynthesis of carbamoyl \177hloride its use in the prepe\177tion of Zopidone.

//

\177

N-Me

derived #ore N-methyl piperezine end

Scheme 121
renin inhibitor

\177
morpholine

CH3

While studying the reactivity of carbamoyl chlorides, we found that they react easily with aldehydes in the presence of a Lewis acid as the catalyst to afford 1-chloroalkyl carbamates in goodyield as shown in scheme The (Ref.

\177
in the preperetion

chemical properties of 1-chloroalkyl carbamates which can

be obtained

by other

123 176). in routes are discussed section 3-3-2.

109)))

N-Chlorocerbonyl FK-905.

of the

hypertensive

108

a a b Phosgenend derivatives s building locks

CI
RI\\

a as b Phosgenend derivatives building locks

AWithout Two
RNH

R2

N-C-Cl

+ R-CHO

ZnCl2
\17760\302\260C

acid scavenger

R\177

O
R 1\\ R2

II

-5h

R2

N-C-O-CH-R
O
90% yield
II

stepsprocess
2 +

N-- =

\177

N--

COCI 2

\177 T<
20\302\260C

RNH-C-CI +

RNH

2.HCI

O
2 RNCO+4HCI
100\302\260C

II

Scheme 123 Reaction of carbamoyl

chlorides with aldehydes.

RNH--C-CI + RNH 2.HCI

0
chloride made by phosN-MethyI-N-methoxycarbamoyl of methoxy methyl amine hydrochloride is a very genation useful intermediate for the synthesis of N-methoxy ureas A 2 One step process

II

\177 T>
OOOI 2
\177,

Chlorobenzene
RNH

to be unsatisfor the production on a large scale, because of factory rather low yields and also of technical difficulties. To overcome these problems, we developeda new procedure based on the reaction of phosgenewith methoxy methyl amine sulfate as depictedin scheme Sulfuric acidformed is easily removed by decantation (Ref. 177).
the method

herbicides. owever, we found H

2.HCI

COCI 2

RNCO

+3

HCI

T = 100-140\"C

124.

- With acid scavenqer

B1 Anhydrous
Example

medium
Toluene
N,N-Dimethyl

:
aniline

MeO\\

Me

NHJ

/
'\177
.\"

\342\200\242

H2SO4 +

2 OOOI 2

Toluene
\177-

95\302\260C,

5h

2MeO\\ N-C-CI +

HCI

Me/ O
[I

t2

H2SO4

80% dist. yield / 36 mBar bp.

60-7\302\260C

\177__NH

COCI 2

( 1 eq. )
+
5\302\260C

-NCO
87%

Scheme 124 Preparation of methyl methoxy ric acid salt of methoxy methyl amine.

bp

60\302\260C

/ 8 mm

carbamoyl

chloride from the sulfu-

B2 Biphasic
Example
NH

process
o. Dichlorobenzene
COCl 2

methods available for the Among the more than preparation of isocyanates, phosgenation of primary amines or their hydrochlorides still remains the most popular. The method is employed on a large scalefor the industrial production of mono and polyisocyantes. Four phosgenation proceduresare used.The procedures without any acid scavengerare the methods commonly employed for the production of almost all commercial

30

:
2 +
\177,

\177

NaOH +

/ H20
5\302\260C

---NCO
73 %
bp.
yield
84-5\302\260C

isocyanates.
111)))

110

blocks a and Phos\177ene derivatives s buildin\177

as a Phosgenend derivatives
This dimer

buildi\177n\177

blocks
/

devoted to the synIn the course of several studies an we developed improved theses of unusual isocyanates, of the already known ethylprocessfor the preparation hexanoate by phogenation of L-Lysine

2,6-diisocyanato in scheme125 (Ref. 178). ethyl ester as depicted

COCI 2
NH2\"HCI

HCI.H2N\177 COOEt
Scheme

.----

OCN\177
50% dist. yield / 0.01mm bp.
101\302\260C

NCO

of reacts as two molecules free 5- alkyliamines or with alcowith soxazolyl-3-isocyanate secondary carbamatesuseful hols to give the corresponding ureas or intermediates. For as agrochemicals or fine chemicals is isoxazole a key intermeexample, 3-amino-5-tert-butyl urea (comdiate for 3-(5-tert-butylisoxazolyl)-1,1-dimethyl as a herbicide for which is useful mon name [Scheme127]. cane and other crops(Ref. 180) sugar

Isouro______O_n)

CHCI3/NaOH

COOEt H

Me

N-Me

125 Phosgenation
.'

of L-Lysine ethyl ester to the

corresponding

isocyanate.

useful in the preparation This diisocyanate is especially of biocompatible polyurethanes or polyureas. that the In another example, surprisingly, we found substituted isoxazolamine hydrochloride phosgenation of a but free isocyanate a peculiar the expected doesn't afford to the mechanism depicted on scheme

Scheme 127

.\"

Isouron.

by

dehydrochloridation affords N-substituted

dimer according

126 179). (Ref.

NH

carbamoyl chlorides in good carbamoyl chloride was yields. For example, N-methyl-N-vinyl of ethyin 67%distilled yield through phosgenation
vinyl

imines followed with CH-acid The reaction of phosgene of triethylamine in the presence

prepared

2.HCI
+

TOLUENE
35\"60\302\260C

NH-C-CI
II

IsOxazOlamlne

). (Ref. lidene methyl amine as depicted in scheme available on the p-carbon, If there is no hydrogen atom of tert-butyl in the case of the Schiff's base for chloamine and formaldehyde, N-(1-chloralkyl) carbamoyl
ride

128 181

example

\177

COCl2

\"-

O R
\177o\177N

- HCl

are obtained

in

excellent ields [Scheme128]. y

CH3N:C .CH3\177
H

COCl 2

\302\260'k\177-

Cl

IMe--N

0.10o0
3h

CI)---Me\177

Toluene
N\177CH2

COCl2
20\302\260C

\"\"

\177_

1.5h

| |
Et3N

1\177
Reflux

Toluene

\177X
,N--\177

Cl

Me
63\302\260C

67% yield / 23mm bp.

CH2Cl

\177._N,

\177-Cl

90% yield
117\302\260C/25
17\302\260C

bp.
mp.

mm

' Scheme 126 A peculiar isocyanate dimer

zolamines.

from phosgenation

of substituted

isoxa-

Scheme 128 Reaction

.\"

ofphosgene with

Schif

t\177s

bases.
113)))

112

a a Phosgenend derivatives s buildin\177 blocks

It is noteworhy

a as Phosgenend derivatives buildin\177 blocks \177 H20

175\302\260C

that

starting materials for the synthesis of W pesticides. e have carried out some trials based on literature data (Ref. in order to synthesize N-phenyI-N-

rides are valuable

N-(1-chloroalkyl) carbamoylchloEt
\177
\177--

182)

H-CH3
CH2OH 96.5%

100\302\260C

98%

chloromethyl

carbamoyl

chloride to

by

1,3,5-triphenylhexahydro-s-triazine However, all the efforts

12c).

as

of phosgenation shown in scheme

improve the

OOOI 2 NaOH / H20

\177-

appreciably

described yield (24 %) failed, around 50%.

Ph-N\177N.Ph +
L\177N/I
I\177h

the

best yield obtained being

10to

\177 /CH2CH2-NCO

18\302\260C

\1770\177
I.E.I\177I.

88 %
bp.
211\302\260C

Scheme 131 .'Industrial process for the

preparation

of I.E.M.

30OCI 2

\1773\177
X.\177__\177

\1770H2Cl

< 50%
.'

tC
I

Scheme 129 Attempt to prepare good yield.

an interesting monomer which combines to in on molecule. functionalities Unfortunately, I.E.M.exhibits a very high level of toxicity. It is recommended that the averageeight-hour working environment not well-known
chlonde in

I.E.M.is

N-pheny-N-chloromethyl

carbamoyl

exceed0.025 ppm.

Phosgenereacts also readily with substituted oxazoto afford depending lines, for example 2-phenyloxazoline, on the conditions either N-(2-chloroethyI-N-chlorocarbonyl

me

amides or isocyanato ethyl estersas depictedon sche(Ref.

130
(a)

183, 184).
\177

-3-2 Rea(liens
ioroformales
ith

l-chloroelhyl

//

Toluene

COC[ 2
1
oo\302\260c

O.\177,N -CH2CH2-Cl

0\177

O
47 %
bp.
132-4\302\260C

amines:

synlhesis
/ 0.7mm

cI

COCI2 (b)\177 NaOH / H20

\177_

0\302\260C

\177c \177

and useful o pplicalions f

l-(hloroallql
carbamales

\177O-CH2CH2-NCO
97 %
bp.
mm 109-16/0.1
oxazoline.

Scheme

130 The two pathways

.\"

for the phosgenation

ofphenyl

The process illustrated in the conversion of piperidiis ne to N(1-chloroethyloxycarbonyl) piperidine. Piperidine eq.)in ether was addedto a cooledsolution of 1-chloroethyl chloroformate in ether.The piperidine hydrochloride was filtered off and the expectedcarbamate was isolated from the filtrate in 77% yield (Ref. 127). Someexamples f representative carbamates o obtained by this method are gathered in table

chloroformates react easily with primary amines under the same standard conditions secondary used with classical hloroformates (Ref. 21 c ).
1-Chloroalkyl and

(2.3

3-20.

Process(b) in scheme130 applied to the was depictedin scheme131 185). (Ref.

preparation

industrial

of

isocyanatoethyl

methacrylate

a (I.E.M.)s

114
115)))

a a b Phosgenend derivatives s building locks

R
R1

a as Phosgenend derivatives buildin\177 blocks

Ref.

R2

Yield

bp.
(\302\260C/mm)

(%)
H H H OH Ple

68
76 77

83/3
rap.

186
187 127 127

3-CLC0H4

55-7

\177N

-et
(I)

---.DCE

ACE-Cl //\177x

/\\

Me
Et
i-Pr

(CH2)5 CH2CH2-O-CH2CH2
Me
N

Cyclohexyl

84 92
73

70-2/0.4 95-7/0.9

O
II

L--et
of N-ethyl

,C-O-CH'CH31 .., c,- /

+
(11)

CI
I

127 111-13/0.6

N-C-OCHCH3 \177 Warm

(111)

\177
Me-OH

\177,

99\302\260/\177

/NH.HCI (IV)

+ CH3CH(OMe)2 +

Pie GI

--N,,\177

80/0.5
CI
I

188
1

Scheme 132

CO 2

N-Deethylation

piperidine

via N-(1-chloroethyl-car

+ R-CH-O-C-CI

HN,R 2
1-chloroalkyl

--\177
_

Base
HCI

O
II

/R

2 R-CH-O-C-N\\R
by reaction

Table

3-20 Preparation
We

of

chloroformates

with primary

carbamates and secondary amines.

of

1-chloroalkyl

decarboxylaof the chloroformate. Phenyl chloroformate itself prefor N-dealkylation (Ref. 190)afforviously recommended
tion

Thus, only trace yields of alkylcarbamates and the tertiary amine primarily catalyzes the

are obtained

ded PhOC(=O)-piperidineonly 34% yield. in

The
high-yield

discoveredthat 1-chloroethyl chloroformate is undoubtedly the best reagent for the selective N-dealkylaof tertiary amines (Ref. Thus, in the initial test system (N-deethylation of Nthe use of oechloroethyl chloroformate ethylpiperidine), (acronym ACE-C surpassedthe yield obtained with vinyl 0 chloroformate : (I) -> (IV), 99% vs 90% as shown in scheme (Ref. Besidests interest for the synthesis of 1-chloroethyl i carbamatesfrom tertiary amines and the N-dealkylation of tertiary amines, this result is also quite unexpected. With most chloroformates other than vinyl chloroformate (VOC-Cl), for example EtOCOCl, l3CH2OCOCl , PhC the cationic intermediate analogous to (11) CH2OCOCl, fragments to alkyl chloride, carbon dioxide and (I).
tion

189).

dealkylation with ACE-Cl is therefore very surprising. Presumably, the -CHCl-CH unit is too hin3 deredto undergo competitive SN 2 attack by Cl- and the chloroethyl cation generated by an alternative SN 1 (El) must be too unstable. Because the cleavage substituent is

1-

electron withdrawing,
tiary

ACE-Cl is

132

189).

Olofsonand
of

amines than simple alkyl Hartz have thoroughly

more reactive toward terchloroformates.

studied the

orderas those of VOC-Cl : benzyl; allyl; t.butyl >> s.alkyl > I n. alkyl >> piperidine ring scission.n its reactivity, ACE-Cl
parallels VOC-Cl with the advantage that the conditions required for ACE removal are much milder thus expanding the functionalities allowed in the amine to be dealkylated.
with

191)

the new N-dealkylation process with ACE-Cl (Ref. 68that the selectivities follow the same and shown

scope

Even N-dealkylation of aromatic amines occurscleanly ACE-Cl as it is illustrated in a strigent test by the

conversion
N-phenyl

of N,N-diethyl

aniline

to

1-chloroethyl

N-methyl-

carbamatein 87 % yield (R.ef. 68).Caub\177re and Bachelet sed this methodology while operating without a u solvent for the demethylations as well as for the deethylations
of dialkylamino
benzofurans
in

good yields (Ref.

192).

116

117)))

a Phosgenend derivatives s building a blocks

Olofsonand
of
ACE-CI Plartz have

a as b Phosgenend derivatives building locks

F

to the N-dealkylation of significant tertiary amines, especially in the field of analgesics and narcotic antagonists alkaloids, for example in a brilliant synthesis of in % overall yield (Ref. Nalbuphine from Oxycodone The scope limitations of ACEoCI as a new reagent and ). for the selective,high-yield of tertiary N-dealkylation amines will be examined in section4-.5of vol.

developednumerous

applications

Tertiary amine

Carbamate

yield

(%)

191

69

H
OX___/N-

Me

O,x__/N-

O C-O CH2CI

96 99 96

2.

Me-N

N-Me

193). For example, N-methylpiperidine 1..5q.of chloromethyl chloroformate e thane (DCE)for 30 min.. After vacuum
(Ref.
volatiles, the distilled

Chloromethyl chloroformate reacts also selectively with tertiary alkyl amines to afford O-chloromethyl carbamatesin yields ranging from N,N-dialkyl to %

O CICH20C-N O
Me, CH2CI ,N- C-O
II

O N-C-O CH2CI

83 99

Me,

N-Et
Me'

Et
Me,
\177

was
in

refluxed with

0
II

(a)

(a): (b)

1,2-dichlorome0 C'OMe
N\177
Me

N- C-O CH2CI
Me
(b)

8:1

ted ter

in

97 %

of the O-chloromethyl carbamate was isolaevaporation

Totest
antitussive

yield. the scope the of Dextromethorphan

in

the morphinan

87

% yield

as depictedin scheme133.
Me

reaction, the over-the-counwas N-demethylated to

\177C'OMe
N

83

o.C.o CH2C
I

Et,
Et3N

\177
Scheme 133
mate.

CICH2.0_C.CI
\177'

o N-C-O CH-CH 3
II I

96

Et

'\177 \177
ReflDuCx\177

'1
r\"le

[\177N-Me

,5h
by chloromethyl chlorofor-

Me OX__/NO,x__/N-

0 CI C-O CH-CH 3
by reaction

84
of R-CHCI-

N-Demethylation

of Dextromethorphan

Table

3-21

.\"

Preparation

of

1-chloroalkyl

carbamates

with OC(=O)CI

tertiary amines.

Some examplesof
through N-dealkylation

table 3-21 (Ref. 127,

193).

1-chloroalkyl carbamatesobtained of tertiary amines are gathered in

carbamatespresenttwo
attacked
shown in
by

The value of 1-chloroethylcarbamatesstarting mateas rials for the synthesis of vinyl carbamates has been already pointed out in section3-2-2-4of this volume. As already discussedin section 3-2-2-3,1-chloroalkyl

scheme134.

which may electrophilic centers differents pathways nucleophiles following

be as

Similar to he caseof reaction with 1-chloroalkyl nates studied in section3-2-2-3,carboxylatesanions

with

carboreact
119)))

1-chloroalkyl

carbamatesto give

alkylation

derivatives

118

a as Phosgenend derivalives buildin\177 blocks

through

a as b Phosgenend derivalives building locks

THF

used in

numerous

a B attack mechanism. This reaction was widely patents on prodrugs.

R Nu 1

25\302\260C

C-N

+ R-CHO + \\R2

A1
A\177

cr

\\

A1

O
\177

II

O
-O\177

O\177

F
\177

Me
+

\177o

\\\177

0.1eq.:80O/o,18h : 97 % 3 h
1

No catalyst Nal

: 60%, 8h 1 '

eq. Nal

CH

0
Nu

C--N
2 A1,
\177

R-CH-O Nu

C-N, O
II

CI

B \177\"\177

Scheme 136 Reaction of N

,\"

(1-chloroethyloxycarbonyl)

piperidine

with sodium

4-

phenoxyphenoxide.

A2\177 \177,

R1 + HN
R2

R-CH-O

C-Nu

Scheme 134 Possible types of nucleophilic attacks to

cI
1-chloroalkyl

Someresults obtained in our laboratoriesfor pesticides screening purposesare gathered in table

3-22.
Time

carbamates.
R
-NR

1R2

Ar-O

Yield

For example this

conceptwas applied to

of novel

(acyloxyalkoxy) carbonyl amines functions in drugs as primary as well as secondary illustrated with the caseof a prodrug from the antibacterial Norfloxacin
in

the synthesis bioreversible moietiesfor

(h)

(%)

scheme135 (Ref. 194). o

He He He He CH2=CH
Cl

-NHe2

Ph-O-Ph-O p.CF3-Ph-O-Ph-O
Ph-O-Ph-O pmCF3-Ph-O-Ph-O

-NHe2
Plorpholino Morpholino -NEt2

o
O
\"\177\"

Ph-OPh-O
THF + Ar-ONa
\177

4 4 4 3 1

90
76

90 83 82
,R1

N
\"\177'\"1

Et

CH3COO

\"

1. 4..] N
mp.
215-7\302\260C

Et
I

0
II

ArO
I

R-CH-O-C-N

R1

0
II

F\177'\177\"COOH O
From reachon
with 1-chloroethyl of Nodloxac\177n chloroformate

\177 O Me

R
g\177\"-\177\"\177/\177'

Nal,

COOH

25 Table 3-22 Reaction of

,\"

eq.

R-CH-O-C-N

\302\260C

1-chloroalkyl

carbamates with sodium phenoxides.

Scheme

135: Preparation

of a prodrug

derived from Norfloxacin.

Sincethe -NR 1R2 group makes center A and B both much lessharder than doesthe ORgroup, we expectsome differences etween the reactivities of 1-chloroalkyl carbab mates and 1-chloroalkyl carbonates.For example the reaction the hard-soft borderline nucleophiles phenoxide protype anions with 1-chloroalkyI-N,N-dilakyl carbamates ceedsselectively through B mechanism to give exclusively instead of acylation as shown in scheme alkylation

scheme137.
CI

opposition to the preceding case,the reaction of phenoxides anions with 1-chloroalkyI-N-monoalkyl carbamates leadsto acylation instead of alkylation as shown in
In

O
II

Ph-O.-Ph-ONa
\177.,

of

CH3-CH-O C-NHCH3

O 65%

\177

O-C-NHCH

136.

Scheme 137 Reaction of sodium

carbamate.

THF, Nal 25\"C, 12h

phenoxy

phenoxide with 1-chloroethyI-N-methyl

121)))

120

a a Phosgenend derivatives s buildinblocks

However,

a as Phosgenendderivatives buildinblocks
More than twenty

carbarnate is

as depictedin scheme138, it

is not certain whether the the acylating agent in such

it

isocyanate or the reaction.In fact, is possible that this reaction

the transient through the group

could proceedthrough a mechanism involving formation of methyl isocyanaterather than normal addition (A1) directly to the carbonyl wed by lossof acetaldehyde. cI

some interest in the design of new prodrugs. The same kind of reactionsoccurswith thiols phenols as shown in scheme140.

has been preparedby

1-alkoxyethyI-N,N-dialkyl this methodology which

carbamates
should have and thio-

follo-

(
./
car5cheme

CI

2
\177

THF +
50\302\260C

S
70 %

O\177N\177.

, 2h

Ar-O

C-NHCH 3

CI

O
\177

THF
Et

Scheme 138 Possible mechanism of the reaction of bamate with phenols.

o
1-chloroethyI-N-methyl

II

+ PhSNa

,
Et

25\"C, 2 h
O\177

o
N

79 %
Et

The study of the reaction of 1-chloroethyI-N-methyl carbamate with phenols was undertaken in the hope that it in might replacethe noxious methyl isocyanate (M.l.C) the preparation of insecticidal N-methyl carbamates. Surprisingly, we found that the reaction of an alcohol can proceed with 1-chloroethyI-N,N-dialkylcarbamates through B mechanism to give alkylation rather than acylation (Ref. This result appearsto be a violation of the HSAB theory. In a typical example, N-(1-chloroethyloxycarbonyl) piperidine was added to a stirred mixture of sodium hydrocarbonate and methanol at The reaction was instantaneous. Solidswere removed by filtration, excess lcoholwas then distilled off and the resulting proa duct was isolated by flash chromatography in 96% yield

Et

140 Reaction
\342\200\242

of thiols with

1-chloroethyI-N,N-dialkyl

carbamates.

According

to

the HSAB theory,

195).

amines react as hard nucleophiles through A 1 attack mechanism with 1-chloroalkyl carbamates affords ureas. to However, the reaction is slower and lesseasy than the reaction of amines with 1-chloroalkyl carbonates and strong nucleophilic amines are generally required to reach

secondaryand

primary

goodyields.
Thus, the reaction has some value for the synthesis known ureas derived from methoxymethyl amine such the herbicide Linuron scheme (Ref.

25\302\260C.

of

as

[see
\177OMe

141] 196).

[Scheme139].

HN..

CI
I

Excess Me-OH O
.\"

O-Me
I

Me
\177

CI---\177.l-\177-O-CH2CI
O
Scheme 141
phenyl) piperidine. Preparation carbamate.
.\"

CI \177-N\177H
\177/\177

93%
Linuron

\177

N'MeOMe

NaHCO 3

25

96%

of the herbicide

from chloromethyI-N(4-chloro-

\302\260C

Scheme 139 Synthesis of N-(1-methoxyethyloxycarbonyl)

122

123)))

a as Phosgenend derivalives buildin\177 blocks I

The
reaction

a as Phosgenend derivalives buildin\177 blocks

chloroformate just 1,2,2,2-tetrachloroethyl THF or dioxane without any acid scavenby refluxing ger.Thereaction mixture is easily freed from hydrochloric
in

of secondaryamines

with

imidazole demonstrates the powerful thyloxycarbonyl) nucleofugacity (leaving group efficiency) of the chloroethoxide anion as shown in scheme (Ref.

1-(1-chloroe-

red amine

and

142
Et\"

197).
Ol

acid

by

heating

and evaporation

of

the solvent

generally

gives (I) as pure crystals. Table 3-23 gives some examples of carbamatesobtained by this method. Cl

-\177

CI N\177
[

\177I....\177N-C-O-CH-CH II

2 HN\\

/Et
Et \177\\

C-O-CH-CH 3 O
II

0
+ R'NH 2
CI

THF
Et
\"

CI3C\177O\177CI

Reflux,

.-\177 2
Dioxane
h

CI
\177'\177

O O
\177\" N\"

R1

72-99%
N204 / NaOAc
\177

OI30

(I)

mp.

50\302\260C

78 %

-J
\302\260C

/ bp. : 106 0.2mm

Scheme

II

Et

O
\177. N\"

142 Reaction
In the

mp.: 41
of
1 (1-chloroethyloxycarbonyl)

( Lit.

38-43\302\260C)

CCI4'

C, 0r CI3
\177

R1 NO

R2NH2
\177,\177

O
R2..N.I\177.N.R1H

0\302\260C

(11)

imidazole

with diethylamine.

K2CO3/ H20 THF,

20\302\260C

72-95 %
from (I)

1'40

(111)

courseof our studies dedicatedto the reactivity of 1-chloroalkyl carbamatestoward primary and secondathat the easyto prepare1,2,2,2ry amines, we discovered carbamatesare valuable versatile intermetetrachloroethyl diatesfor the synthesis of N-nitrosoureas (Ref. 198). ureas are an active classof N-(2-Chloroethyl)-N-nitroso antitumor agents, which are usually obtained by nitrosation of the previously prepared urea. Because difficulof ties in achieving regioselectiveitrosation, several authors n
have su\177ested alternatives processes. the Unfortunately, starting materials proposedare either unstable such as carbamoyl azides (Ref. lC)9)or extremely toxic such as the 2-

Scheme 143 Novel

preparation

of N-nitrosoureas.

Entry

R1

Yield

(%)

or mp. bp (\302\260C/mbar)
(\302\260C)

1 2 3

Cl-CH2CH2-

96
72
9c\177

81-2

F-CH2CH2C 2C (L)-HO2-CH H(COOH)-

11.5-20/7

131-3

Table 3-23 1,2,2,2-tetrachloroethylcarbamates (I) prepared.

isocyanate (Ref. Although we have noticed that 1,2,2,2-tetrachloroethyl carbamates (I) do react with amines to give ureas in modest yield, we thought that when the carbamates are (I) nitrosated to (11),the reactivity of the carbonyl should be greatly enhanced and good yiels of N-nitrosoureas (111)
chloroethyl

200).

be obtained.As depictedin scheme143, results the are quite good,the only drawback being that some minor impurities may arisefrom the reaction of the amino compounds with the releasechloral (Ref. 201). The carbamates(I) are easily preparedfrom the requiwould

The 1,2,2,2-tetrachloroethyl carbamates(I) are then with nitrogen tetroxide by a known procedure. The intermediates nitrosocarbamates are obtained as (11) oils and used as are in the next step to afford the expected N-nitrosoureas (111).For example, the antitumor drug Lomustine was preparedin 87 % yield from the carbamate 5ome results obtained by this [(I),entry 1of table method are gathered in table 3-24.
nitrosated

3-23].

124

125)))

a blocks as Phosgenend derivalives building

Entry R1 R2 Yield from
(\177o)

a as b Phosgenend derivalives building locks

mp.
(\302\260C)

(I)

1 2

3
4 5
.\"

Cl-CH2CH2F-CH2CH2CI-CH2CH2Cl-CH2CH2ClCH2CH2(111)

c-C6H11c-C6H11C6H5HOCH2CH2Et-OOC-CH2-'
prepared

87 72 75

87-8 44-5 78-80

oil oil

9.5 88

of our studies on the synthesis and of 1-chloroalkyl carbamates,and because our group was involved in the chemistry of 1,1-dimethyl hydrazine (UDMH), we have examined the reactionsof 1-chloroalkyl chloroformates with unsymmetrical dialkyl hydrazines.During this work, we discovered unexpectedly a new efficient generatorof the heretoforedifficult to prepare
In

continuation

reactivity

N,N-dimethylamino

Table 3-24 N-Nitrosoureas

(seescheme 143), miscellaneous chemistry of

Some

other

interesting

chloroalkyl carbamateshas been also explored.Thus, as already mentioned, acrolein add its congenersH2C=CRClioare easily converted to the chloroformates H2C= which CRCH(Cl)OC(=O)Cl rearrange in the presence of ZnCl 2 to the allylic isomer ClCH2-CR=CHOC(=O)Cl. We preparedsome carbamatesderived from these chloroformates for testing as agrochemicals. One example using 2-chloroacrolein as starting material is
given in easily

scheme144(Ref. 202).ndustrially, I
in up to
by

2-chloroacrolein is

In a preferredexample, when UDMH in anhydrous THF was added to a solution of 1-chloroethyl chloroformate in THF at the intermediate carbazate(a) was formed. After filtration to remove the UDMH hydrochloride, we accomplished cyclisation to (b)just by refluxing the a THF solution for 1 h..The resulting hygroscopic salt (b)
10-20\302\260C,

carbalkoxy aminimides were prepared from UDMH and 1-chloroalkyl chloroformates in three steps [Scheme Upon heating, these aminimides give high This yields of Me2N-N=C=O. unusual isocyanate dimerizes or can be trapped in the presenceof a nucleophile.

bered ring

isocyanate Thus, (Ref.203).

five

men-

145].

made

97%yield

by adding chlorine

to aqueous

acrolein followed

steam

distillation

of the

resulting mixture.

CI

0
+

COCI 2

\177
BTBAC

overall yield. In solid form, precipited immediately in is stable undefinitely at room temperature. The cyclic (b) aminimide (c) was then easily preparedfrom (b) by treatment with a resin supported base in high yield. The three stepsof the synthesis are depictedin scheme

71%

145.
/N

..OCCI
CI
ZnCI

eq. 2 , 0.01
5h
Me

Me, Me
U

91%distilled / bp 71-82 20 mm
(31

100\302\260C,

NH

2 +

DM H

0 Me 0 ACE-Cl
\177/\177

CI

----\177.CI
10-20\302\260C

THF

Me,
N

NH

Me,
NH2.HCI

Me/

\177/

(a)
Me

0
.\177

\177-0

Me

CI

o
Cl

Me,
N

0
NH

THE
O'\177NH Reflux,

\177--\177OCCl

/ bp, 94-7 22 mm Z:E

H 63 % distilled

Me Me
N

mp.

103\302\260C

Me

\1770
Me\177/
\177 Me\177e,\177,

CIMe

Amberlite IRA-4OO(OH

0
0/.\177. N-

0
Me
N
m\177.
5\177 \177C

\177

lh

Me/\177N'

15:1
.\"

(b)

Me +

Me Me Me +

\177

0
for testing.

Scheme 144 Example of 3\177hloroalkenyl carbamate synthesis

Scheme 145 New cyclic aminimide

71%from (a) dec. mp :

145-50\302\260C

(c)
91%from (b) mp.
170-2\302\260C

from UDMH and ACE-CI,

126

127)))

a b a Phosgenend derivatives s building locks

the
little attention in Carbalkoxy aminimides have received literature and to our knowledge, cyclic carbalkoxy ami-

a as b Phosgenend derivatives building locks

Entry

:Nu-

beforebeen synthesized. a Dialkylamino isocyanates re known transient intermediates and, in the absence of other reagents,have been shown to dimerize. When the cyclic aminimide (c)was heated at under vacuum (0.3 ram) for 3 h, (d) was obtained in 89% yield. At higher temperature (d) was formed but rearranged to (e)as depictedin scheme146. The chemistry of aminimides has been reviewed elsewhere (Ref. 204, 205)and the chemistry of dimethyl amino isocyanate, repared in the form of dimer (d) through a p
nimides have never
130\302\260C

Nu-COINH-NMe 2 Yield (%)

1 2

Et-O-

87

Ph-CH2-N(He)-

89 95

O S-Me = Me2N-C-C N-OII I

4 5

.,\177\"--.\177

s Me -N
N/\177--

74 76
carbal-

\177]\177...

EtO2C-CH2-NH-

phosphoramide synthesis,

studied

(206).

Table Preparation koxy aminimide (c) with

3-25

a nucleophile

of UDMH derivatives through reaction of cyclic

:Nu-H.

o
Me\177

N=C=O

+ CH3CHO

Me Me +
(\321\236)

130\302\260C/003mm

Me'

or refluxing
in acetonitrile

....

+ Me ,

Me\177

Me
N N

o\177-.\177o 190o\"c,o\177.\177o ' 5 min 89%or 100% (e)

(d)
MeZ
N

\"

Me

N-

carbonates as
acylatin\177

/ Chloroalkyl

333

Me

Scheme 146 Thermal decomposition of the cyclic

N,N-dimethyl

Me 92% ; bp,

\177N

Me

agents for the synthesisof

(c) to give

The reaction of secondaryand primary amines with carbonatesto afford carbamatesin high yield has been already tackled in term of mechanism in section 3-2-2-3(Ref. 64, 107).
chloroalkyl

1-

66,105, 106,

100\302\260C

/ 0,06mm
amin/de

carbamates
and

carbalkoxy

amino isocyanate.

liocarbamates

At the beginning, while studying the synthetic potential of 1-chloroethyl ethyl carbonate,we found that it readily reactswith amines at the carbonyl function to give the corresponding ethyl carbamatesin good to excellent yields. We thought therefore that 1,2,2,2-tetrachloroethyl tertbutyl

Our method representsa simple, rapid and high yield This isocyanate. interespreparation of N,N-dimethylamino intermediate has been the subject of several publicating
tions and the synthesis of a wide variety a carbazates, nd other moleculesontaining c heterocycles,

valuable

carbonate (I) (codenumber CN 916)should be a o reagent for the Boc-protectionf amino acids 66, 07). [Scheme147] (Ref. 2 (I) was easily preparedin goodyield from 1,2,2,2-tetrachloroformate
In

is useful for

of a

hydrazine group. We have preparedseveral carbazatesand semicarbazides by heating the cyclic carbalkoxyaminimide (c) and just the nucleophile (:Null) for 1 h in refluxing 1,2-dichloroe-

thane. Some examples are given 128

in

table

3-25.

and tert-butanol by a simple a typical example, pyridine (1 eq.)was slowprocedure. solution of t.butyl alcohol and ly added to a cooled chloroformate (1 eq. of each). 1,2,2,2-tetrachloroethyl After stirring for 4 h at washing with water and evaof the solvent and recrystallization from hexane, poration (I) was obtained in 87% yield (mp. chloroethyl
(0\302\260C) 20\302\260C, 70\302\260C). 129)))

a b as Phosgenend derivalives building locks

We
amino
with

a as Phosgenend derivalives building locks b

t

discovered (I) satisfactorily reactswith various that acidsin standard conditions.The reaction mixture is
and byproducts crystallisation
by extraction

freed from excess reagent

ether and
conventional extraction

the Boc-amino and

acidsare readily obtained by

pr-ocedu,e\177

according to scheme147. O
II

CI
I

R
I

O-C-OCH-CCI H2N CH-COOH20oc 3 +

0)
78

Dioxane

/ H20 / Et3N
.-\177

o
- 91%Yield --t

O-C-NH-CH-COOH + CI3C-CHO of amino acids by 1,2,2,2-tetrachloroethyl

Entry

The crystalline 1,2,2,2-tetrachloroethyl fluorenyl methyl carbonateobtained in 98% yield (mp. from 1,2,2,2-tetraethyl chloroformate and fluorene methanol proved to be suitable for the preparation of Fmocamlnu acids good to excellent yields (Ref, The reaction was also performed with various types of amines using different kinds of 1-chloroalkyl carbonates (Ref. 64) and was proved to be quite general exceptwith weakly nucleophilic amines. Someexamplesof carbamates obtained by the reaction of 1-chloroethyl carbonateswith primary and secondaryamines are given in table 3-27.
98-100\302\260C)
iI\177 \302\2514).

Scheme 147 tert-Butoxycarbonylation - tert-butyl carbonate

R1

Yield

mp

(\302\260C)

(1).

(%)
1

bp.

(\302\260C/ram)

useful in the case of Reagent (I) proved to be especially amino acids as examplified by the hydroxy unprotected and table synthesis of Boc-L-Serine Boc-L-Tyrosine [.See The 1-chloroethyl congenerof (I), the 1-chloroethyltert-butyl

Ph-CH Ph-CH

3-26].

3 4 5

carbonate(11)which is a
mm), was
found

medium

boiling liquid

to give unsatisfactory (bp. becauseit is much lessreactive than (I), and also results, becauseof the formation of acetaldehyde its conseand quent reaction with the starting amino compound. Some examples of preparation of N-Boc-amino acids with (I) are shown in table
88\302\260C/20

Ph-CH

/
Et

-(CH2)5H H
Ph-CH2-

88
84
74

bp
bp bp

95/18

22-

HO-CH2CH2He

\177O\177

79

175/0.1 170/0.5 rap. 62-3 mp. 148

-(CH2)2-O-(CH2)2-

84 0

bp. 140/1 mp. 49.5

CI

O /
HN, R

3-26.
(\302\260C)

1 CH3-CH-O-C-O-R +

--\177,.

R\177-O-C--N,

R3

Table 3-27 Carbamates prepared

.\"

from

1-chloroethyl

carbonates.

Amino acid

Yield

of

P1elting point

[cz]20D
Imidazole
butyl

N-Boc-AA (%)
Gly
L-AIa L-Phe

86 90
79

L-Pro
L-Tyr

L-Asp L-Ser
Table butyl

91 82 60 78
.\"

85-8 80-I 85-87 132-3 206 (DCHA salt)

alsoreactswith 1,2,2,2-tetrachloroethyl-tertcarbonate(I) or with 1-chloroethyl-tert-butyl carboscheme148.

derivative
in _50

117-9
139-40
acids using

-24,c 2.1AcOH EtOH +28,c 1.5 AcOH -60,c 2.0 MeOH +32,c 1.8 c 1.0eOH H -5,
+8, c

nate (II) to give its tert-butyloxycarbonyl and % yield respectively as shown in

86

O-C-O-CH-R
t

CIi

HN/\177N

2.8 HeOH

(I)

3-26 Preparation
carbonate (I).

(11) R

of N-Boc-amino

1,2,2,2-tetrochloroethyl-tert-

Scheme 148

::
= CCl 3
CH3

0'
With:
(11)

O\177

N,,\177N

K2CO3/H20
5\"10\302\260C

rap.

47\302\260C

(I) 50%

86%

Preparation

of 8oc-imidazole.
131)))

130

a Phosgenend derivatives s buildinblocks a

The application of the above method to the syntheses of insecticidescarbamates Carbofuran (entry 4, table 3-2T) and Aldicarbe was briefly studied.Thus, Carbofuran was readily obtained in 79% yield from 1-chloroethyl benzofuranyl carbonate which was itself obtained in 89% yield from the corresponding hydroxy benzofuran. The method was also successfully applied to the reaction of 1-chloroethyl-S-ethyl thiocarbonate to give thiocarbamates,for example the herbicide Molinate as depictedin

a as Phosgenend derivatives buildinblocks

/\177

H2
\177

Cl\177/
CI

,,-\"\177

NO 2

\177 C' \177 '/\177NHOH

\1777 CI

CH3NCO
\342\200\242

\177,-

Pt/C

poisoned

O
C,
CI

O
COCI2
},-

CI\177/\177/

N\177'\177NMe

\177N-C-NHMe OH
\"
.\"

or MeOCOCI

CI

\177
M\177th\177zol\177

scheme149.
CI

Scheme 150 Classical synthesis of the herbicide Methazole.

O
Et-SH
-\177

CI
80% bp :

O
78\302\260C

CH3-CH-O C-CI +
/
HN\\
\177

CH3-CH-O C-S-Et

/ 20mm

\177

r/\177

\\ tl

C-S-Et
/'\177

70%

bp.

141\"C/13 mm

Scheme 149 New

preparation

of the herbicide

Molinate.

laboratories,the reaction of phosgene with carbamateby an improvement of the procedure described in the literature (Ref. 208) afforded methyl carbamate (I) in high N-chlorocarbonyI-N-methyl of yield. The one-potcondensation the intermediate (I) led to Methazole in excellentield as depictedin scheme y For safety reasons,we thoroughly studied the thermal of the intermediate (I). e found that it decomW stability posesto methyl isocyanateon heating, very slowly when in presence of a pure, more rapidly and quantitatively to the mechanism depicted scheme in nucleophile, according
In

our

methyl

N-methyl

151.

152.

o
II

o
COCl 2

Selected solvent
\177\"

\177--

CI

4 Reaction of phosgene and its deriva rives with

\177 \177

As part alternatives
methyl

(arbamates, ureasand amides

lopment derivatives
In

of our program concerning the study of safe to the handle of the extremely hazardous isocyanate (MIC), we were interested in the deveof new routes to 3,5-dioxo-l,2,3-oxadiazolidine
which

MeNH-C OMe +

Me

Pyridine
60\302\260C,

2h 93 %

(I)
bp.

)/OMe
/ 13mm

85\302\260C

are

valuable

as pharmaceuticals

and

(I)

agrochemicals.
example, we developeda new synthetic strategy that doesnot use MIC for the preparation of the herbicide Methazole.Methazole was classically made the reaction of MIC with through 3,4-dichlorophenyl followed by treatment with methyl chlorohydroxylamine
typical

CI\177NH-OH 2)Heating\" IC'\177?-C'I\177 / OH Me

\"C-OMe\177

Ci

(\")

\177

\177

CI

.J

formate and cyclisation

as shown

in

scheme1.50.

Scheme 151 Preparation

of Methozole \177ithout

methyl isocyonote.

132
133)))

a a Phosgenend derivatives s buildin\177 blocks

a as b Phossene nd derivatives buildin8 locks

Me

O\177CICI

/\177

--\177,-Me-N=C=O+ MeCI + CO 2
of methyI-N{hlorocarbonyI-N-methyl
carbemate

Heat

,\177

SiMe3
O...\177/N-

2 -\177
\"

SCI

\177
O\177

\177N-s_cI
\177F\"

Me3SiCI

O O
II

O \177-O --\177\"\177 Me /-CH2CI2 ,

\177le\177

(IV)

(v)
-',

O-C-N
II

Pyridine

Scheme

152 Thermal

instability

(I).

O
MeO-CC-NHMe
II

o Me

\"S

N,

Horeover,I) exhibits a high level of toxidty. In orderto ( these problems, we investigated other routes and a novel and safer route to Hethazole, tars from the interesting intermediate ting (111)as shown in scheme
over\321\236ome dis\321\236overed

Me sQ2 \177 MeO-CC--N-S-CI

0
Me
O-C-NH

O
II

(VI)

153.

CH3

COCI
I

MeN
(\177)

C-OMe

MeOH

0
Me - N

Scheme 154 Syntheses

O
of new sulfenyl

II

N O-C-N--S C-C-OMe Me Me O O
tt

Carbofurans.

0
C-OMe

.C-OMe 'C-OMe
(111)

MeNH

....
NaH

---

-- T
_

O
(111)

II

MeOCOCI

//

The reaction of phosgenewith

known.
in high
mm

Low

15 CI\177NHOH h , CI
Scheme 153

-Cat. H+
\177 60\302\260C

bp, 86

mp. stable solid

\302\260C/8

Phosgenereacts with

substituted tetrasubstituted

ureas is well ureas as a

LD5o(Rat)

:2850mg / kg
92 %

Methazole

Novel

and safe preparation

of Methazole.

be modified by other acylating chloroformates. In the courseof our attempts dedicated to the search of new pesticides,we were interested in the design of proinsecticides, especially procarbamateswhich are less toxic to mammalians than the parent carbamates. N-Acylor N-sulfenyI-N-methyl carbamatesderived from N-methyl Carbofuran or Aldicarbe are quite effective insecticides and are often equal to superior to their parent compound against insects.
collaboration with SIPCAM (Italia) we studied the o synthesis and activity as insecticides f two new types of Carbofuran derivatives (V) et (VI) depictedin scheme
In

Also, carbamatescan agents than phosgeneand

chlorides agent to afford chloroformamidinium This topic will be discussed volume in yields. In the caseof ureas,phosgeneis attacked N,N'-dialkyl both oxygen and nitrogen atoms to give a mixture of by chloroformamidinium chlorides (A) (O-acylation of the and allophanoyl chlorides (B) (N-acylation) as ureas) shown in scheme (Ref. ). chlorinating

2.

155

211
\177-

CA)

+
I

CI4-

O
RNH-C-NHR
+

O-Acylation

RNH--=C--=NHR

CO 2

COCI 2
.\177 N-Acylation (B)
Q'XC-CI
\177

R-N'

+ HCI

Scheme 155 Phosgenation pathways of N,N'-dialkyl

\177,C-NHR

ureas.

(Ref. 134

209, 210).

154

The distribution of O-acylation and N-acylation can be controlled by the reaction conditions, but structural features of the N,N'-dialkyl ureas seemto be the dominant
slightly

factors.
135)))

a as Phosgenend derivalives buildinblocks

Acylation reaction which affords chloroformamidinium chloride is of great interest for the commercial synthesis of carbodiimides, especially dicyclohexylcarbodiimide (seevolu-

a as Phosgenend derivalives buildinblocks

o
II

MeNH--C-NHMe
let?orlOn

\177
200-250\302\260C

2MeN=C=O

me

2).
In

+
5\177henle

2 Ph-OH
w\177th

the

case of

separation of
the insolubility stituted

low molecular weight subtituents, the and (B) is very easy becauseof products (A)

158

Pmparc/tson

of MIC through

Of

dlpl'lenyl

ca/bonate

156 presentstwo
ureas.

of the

salt (A) in organic solvents. Scheme of examples phosgenation of N,N'-disub-

COCI=
II

O\\xc_
\177

CI

MeNH-C-NHMe

DCE
1

Me--N

+ CI+ MeNH--=C--=NHMe
CI

h, 20\"C 71%

-NHMe

O
mp.
36\302\260C

insoluble in ether

\177
HN

DCE
+

y O

NH

COCI 2

\177
\177

l h
80\"C

Y (C) O

HN

N
\177[\177

CI

86%
mp.
155-7\302\260C

Scheme 156
.\"

Examples

of phosgenation

of N,N'-disubstituted

ureas.

that in this process,one mole of pheis releasedfor one mole of HIC produced. We studied at a laboratory scale a similar route of synthesis starting from phenyl chloroformate instead of carbonate(Ref. The new process resents diphenyl p the advantage that only half a mole of phenol is formed per mole of MIC. Thus, phenyl chloroformate was reactedwith dimethyl urea in toluene at reflux to give methyl N-phenoxycarbonylN-methyl urea (D)in 95 % yield. No addedbasewas required. The intermediate (D) decomposedon heating at in presenceof a selected basic catalyst to afford
It is noteworthy

nol

213).

180\302\260C

HIC in quantitative
N-Chlorocarbonyl-2-imidazolidone (C) is for instance used in the preparation of pharmaceuticals such as the antibiotic Azlocillin

yield

[Scheme159].

[Scheme157].

ococl
+

o
II

Toluene
\177

\177
N

Phenylglycine
\177I...CI

MeNH-C-NHMe
Reflux

Me-

NO\177_

0__\177
NH

(C)

HNy O O

O O

COOH

0 \177 Ph
Me:B
Catalyst
\177_

),-0

Me

(D)

95%
mp.
98\"C

2 Me-N=C=O + PhOH

Coupling
H2N

agent
\177,,

S COOH

H\177/NA

N\177

N\177IC 0
Scheme 159 Novel
.\"

180\302\260C

preparation

of MIC

from phenyl

chloroformate.

COOH
of the antibiotic Azlocillin,
It is well known

Scheme 157

Preparation

that oxalyl

chloride

reacts with

non-

order to produce methyl isocyanate in good safety's an conditions, Bayer A.-G.has developed industrial process based the reaction of diphenyl carbonate with N,N'-climethyl on
In

urea at high temperature

according

to scheme

158 212). (Ref.

amides to afford acyl isocyanatesn high yields i (Ref. 214).In contrast, phosgeneacts as a dehydrating This interagent to give nitriles as shown in scheme esting reaction, its mechanism and applications will be
substituted

160.

discussed volume in

2.

136

137)))

a as Phosgenend derivalives buildinblocks 0 cl-c-c-cl

II II

a as Phosgenend derivalives buildinblocks

F
Et3N

o
II

o
R_C_NH

\177

R--C-N=C=O +

CO +

HCI

\177-'\177C.NH 2 + Me3SiCI
\177---\177

\177
Reflux

\177

O
F

II

F
\177-'\177C
\"\177-\177

- 'SiMe3
N

IOI

SiMe3
mm

65 % dist.
bp. 68\302\260C/0.15

CI--C-CI \177
O
Scheme \1770
.\"

R--C\177_\177N

CO 2

2 HCI
omides.

Neat
\177,

II

-N=C=O
F

+ Me3SiCI ( 100% recovery)

\177eoctions

of oxalyl chloride and phosgene with

primor\177

COCI 2 78\302\260C

O
100\302\260C

trichloro acetyl Acyl isocyanates, specially e (TAI),

isocyanate

Scheme 161 Novel

lyl)-2,6-difluoro

2,6-difluoro benzoyl isocyanate (DFBI)andmethacryloyl isocyanate (HAl) are very valuable intermediates and for pharmaceuticals, agrochemicals, plastics,adhesives The structures, physical data and types of applicoatings. cations of these three major acyl isocyanates re given in a
table
Name

benzamide.

54% dist. ; bp. mm / 0.25 of DFBI by phosgenation of N,N-bis(trimethylsipreparation

DFBI

3-28.

Structure

Data

Applications Pharmaceuticals antibiotics Cefuroxime

chlorideswith sodium cyanates.We found that special catalysts and solvants must be used for receiving satisfactory yields as depictedin scheme162 (Ref. 216, 217).
: prep. of
F F

It is noteworthy that, in the course of our studies on the preparation of acylisocyanates, put some we improvements to the known procedureby condensation of aroyl

CI3C_C_NCO TAI

bp : 80\302\260C/27 mm

O
CH3
I

II

> LDso 20OOmg

such as sodium

-CI
F

+ NaOCN

\177,

HAl

bp. 122 H2C=C-C-NCO (Atm. press.)

\302\260C

resins Vinyl functionalized for adhesives, coatings, fibers, electronic, medical materials

SRCI4
180\302\260C,

0.05 eq.
2h
F

-N=C=O

O
F

II

etc.

Scheme 162

70% dist. bp.

83-8\302\260C

/ 10mm

Preparation

of DfBI

from

2,6-difluoro benzoyl

chloride.

Synthesis of difluoro

bp. 80\302\260C/0.3

mm

-benzoylureas (numerous

as insecticides
patents)

\177-\177-NCO
Table

3-28 Valuable

sented in volume 2 in the chapter dedicatedto mistry of acid chlorides.

The scopeand

limitations

of

this

w process ill be pre-

the

che-

industrial acyl isocyanates.

The demonstrated utility of these high-reactive isocyanates prompted us to search for a phosgenation process more economicalthan the oxalyl chloride route. Our in attempts succeeded the development at a laboratory scaleof a method basedon the reaction of phosgenewith N,N-disilyl amides as depictedin scheme (Ref. 21_5).

insecticides effective against larvae, especially from lepiThe doptera (Ref. 218). synthesis is depictedin scheme

collaboration with Ishihara During our continuous Kaisha Ltd, we prepared 2-chloronicotinoyl Sangyo isocyanate and patented the synthesis of interesting new

161

163.

138

139)))

a a blocks Phosgenend derivatives s building

CI \177/='\177--C-NCO

a as Phosgenend derivatives building

blocks]
CI

+ H2N

CF3

('\177'00
Scheme 163 Preparation
In

Ci

N'\321\236'\177

c
\177, 68\302\260/\302\260

3-3-5
R,a\321\236tion

of
with

i p. Toluene sulfonyl isocyanate (PTSI)s an

hlos\177ene

Yield

fmamides : preparation

el sulfonyl

for -

which highly-reactive isocyanate such as applications

interesting has found several valuable

iso\177yanates

agent for mastic and filler resins, especially trade ; building chemical intermediate for the synthesis of hypoglycemic pharmaceuticals, for example Tolbutamide or Gliclazide :
dehydrating

of a new

N-pyridylcarbonyI-N\177p\177enyl

urea

as insecticide

0
key starting

the

generally

a\177ts

reactionswith N-substituded amides, phosgene as a \177hlorinating agent yo give Vilsmeier

\177ase

material

for the

preparation

of resinsfor nail

salts (see volume 2).As in the of primary amides, the use of N-silyl amides is often required to observeN-a\177ylation in reasonable yields. The preparation of 4-ethyl-2,3-dioxo-l-piperazine\177arbonyl provides with a good illustration of a commerdal pro\177ess through a silylation (Ref. We studied
\320\210hloride

lacquers,to replaceconventional arylsulfonamido formalformol (Ref. 220). dehyde resins which releasecarcinogenic The synthesis of p. toluene sulfonyl isocyanate by phosgenation of p.toluenesulfonamide in presenceof an alkyl i isocyanate as the catalyst, generally n-butyl isocyanate,s well described several patents and publications in [Scheme

in s\177heme thoroughly the pro\177ess depi\320\210ted brought some improvements. This \177arbamoyl \320\210hloride is used for the preparation of antibiotics as Piperadllin
su\320\210h

219). 164, and

165].

Chlorobenzene

Me---\177SO2NH
Scheme

2 +

COcI 2
BUNCO

\177,

Me--\177SO2NCO
rap. bp.

or Cefoperazone.
Et--N

PT$1

2\302\260C

270\302\260C

Dioxane

\177
NH

+ Me3SiCI

Et3N

165 Preparation
In

Et--N

SiMe 3

of p.toluene sulfonyl isocyanate (PTSI).

o
COCI 2

and

to

orderto economically improve the industrial process avoid side reaction such as the formation of tosyl
the mechanism that contrary

+ Me3SiCI

we thoroughly studied phosgenation. We demonstrated

chloride,

of to

the the

to be recycled

Piperacillin

Et_N\177N\177O\177

in the literature, the sulfonyl urea (11)is true intermediate in the reaction [Scheme only Our trials showedthat the phosgenation proceeds in a first stagethrough the readily and quantitative formation of the insoluble symmetrical sulfonyl urea (I) which reacts

impressions given
not

the

100].

Scheme 164 Phosgenation

bio tic Piperacillin.

COOH

of dioxo piperazine

and structure of the derived

anti-

with butyl isocyanateto afford sulfonyl urea (11)and PTSI. The intermediate (11) reacts then, more slowly, with phosgeneto give PTSI and regeneratesbutyl isocyanate. The assumedmechanism is depictedin scheme106 (Ref.

221).

140
141)))

a a Phosgenend derivatives s buildin\177 blocks

The formation of tosyl chloride was shown to of PTSIitself, thus affording through phosgenation which polymerizes. carbonyl isocyanate 1)
2 Me---\177SO2NH
+

a Phosgenend derivatives building locks as b

34

proceed chloro-

formation reactions

Rin\177

COCI 2

\177
H-\177I

This chapter usesan organization based the nature on of the two hetero atoms involved in the closing of the ring by the carbonyl group : O<->O O<->N N<->N ; N<->S. ; ;

Me---\177SO2N
2) (I) + Bu-NCO
\177

Me o HSO2-\177 O)
-N

34 /
Cyclisation

between two oxygen atoms

(II)

Although ethylene carbonate can be easily made by phosgenation of ethylene glycol, the only industrial process is the carbonatation of ethylene oxide [Scheme

167].

PTSI PTSI +
+

HO-CH2CH2-OH +

COcI 2
- 2HCl

3)

(11)

OOOi 2

\177
+

Bu-NCO

2 HCI
\177--70

002

\177
Catalyst

/\177

oyo O

Sidereaction :

Scheme 167

Pressure of ethylene carbonate.

Preparation

Me---\177--SO2NCO

COCI 2

\177 Me---\177--SO2-CI
+

value in
in

CI-C-NCO

o
II

section3-2-2-I the
which

However, the phosgenation processhas much more lesssimple products.We previously have treated
affords reaction of excess phosgenewith a monochloroformate containing a

glycerol
five

Scheme 166 Mechanism

.\"

fo the catalysed

synthesis of PT51.

membered cyclic carbonatefunction. The phosgenation of catechols of high interest, becaui se the resulting o-phenylene carbonateis the key starting material for the preparation of the insecticide Propoxur as
shown in
OH + OH

scheme168.
Toluene

/ H20
\177-

COCI2

0-

NaOH
5\302\260C

\177==
85%
mp.
120\302\260C \177

O
Me

\177
MeNH 2

\177,\177,,\177O-C-NH

\177,\177O-C-NHMe \177
\"OH

\1771\"\1770---// insecticide Propoxur.

Scheme 168

Preparation

of the

142
143)))

a a Phosgenend derivatives s buildin\177 blocks

of 2,3-butanediol presentsa high potenpharmaceutical field. The cyclic carbonate chlorinated to give a thus obtained can be photochemically in carbonate (I) as depicted scheme vinylene (Ref. 222).
Phosgenation
tial value in the

a as Phosgenend derivatives buildin\177 blocks

DCE
+ OX\177O H

COCl 2
N,N,-Dimethyl aniline

169

HO

W
hv

DCE
+

COCI 2
20\302\260C

W
O,,,\177O

6%
bp.
120\302\260C

/ 12mm

\"\177/
\177

OH

O...,/O
.\"

II O

72% mp.

79-80\302\260C

\177 63%
\177 \177

Scheme 171 Phosgenation

ofacetoin.

0\1770
Scheme 169

- HCI

160\302\260C

(\177)

%0 o
from

bp.

130\302\260C/

6 mm
diol.

Preparation

of vinylene

carbonate derived

2,3-butane

The substituted the

vinylene

carbonate(I) can be used for

King Jr reporteda facile synthesis of chlorinated dioxolanonesby a simple, one-pot,direct addition of phosgene to 1,2-diones 225). the reaction of 2,3-butane Thus, (Ref. dione with phosgenein the presenceof pyridine affords in trans-4,5-dichloro-4,5-dimethyl-l,3-dioxolane-2-one

preparation through chlorination and dehydrochlorination of the intermediate (11) which is the key reagent for the production of Lenampicillin [.Scheme

170].

82% yield as shown

in

scheme172.

CH2CI2
CICH2x\177CH3
(\177l)

COcI 2
CI

iPyridine in catalytic am.

\177
OyO
O

%0 o
HCI

Me

\177

0\177.--

NH

/\177'

k\177 S,k\177

\\
carbonate

Lenampicillin (Antibiotic)

\177

Meb'.\177 /CI
O..\177O

82 %
mp.
88\302\260C

Scheme 172 Phosgenation Scheme 170 Substituted

of2,3-butane

dione. formation of unusual ther-

vinylene

for the modification

of antibiotics.
mal

In

an

bromomethyl

me 169 be obtained by phosgenation can depictedin scheme171 (Ref.224).

a synthesis of Cefcanel, new cephalosporin from Kyoto Yakuhin and Astra (Ref. It is noteworthy that the vinylene carbonate in sche(I)
(11) is

also used in the

obscurepaper, Pews reportedthe ethylene carbonate through an

223).

of acetoinas

shown in

rearrangement of 2,3-dibromopropyl ethyl carbonate We studied the scopeand limitations of this (Ref. reaction and defined the best conditions of the process s a

226).

scheme173.

144

145)))

blocks a a Phosgenend derivatives s building

a)
Br or
\177

a as Phosgenend derivatives buildinglocks b

2 CI2 , hv -2
HCl
(111)

200\302\260C,

without
Br

catalyst

\177
\177

CI
\177_\177,.c

cI
/__\177CI

O
B:

b)

150\302\260C

presence a selectedatalyst c
of

in the

v\177

/ Et
\177.

O-----\177

%0 o
O
O.\177O

%0+ O

(\177v)

%o O
0

Decomposition
Q\321\207

of (IV)

Br

---\177
- EtBr
Scheme 173.'Unusual
O,.\177O

a) 88%

b) 95%

Cl

O route access

to substituted ethylene carbonate.

\177

derivatives of ethylene carbonateitself very interesting and valuable compounds. When ethylene carbonate is monochlorinated, Chlorinated

are
the

Scheme 175

CICH2-C-CI + CO 2
of pure dichloro ethylene carbonate
key
(111).

Preparation

was claimed as the (111)

for the

carbonate thus obtained is the starting chloroethylene material for the synthesis of vinylene carbonatewhich is
to yield high-molecular polymerization or and copolymers in Diels-Alder cycloadweight polymers ditions [Scheme174] (Ref. used
in

a explosives s shown
Cl

in

scheme176 (Ref. 228).

02N\"
\177

synthesis

of

novel

radical

,\177/Cl
(111)

227).

oyO O

, H2C

.NHNO 2 NHNO2

N/\177 N

-NO2

\177

CI \177 CI2 , hv

%O O

\177 ----\177HCI

Ether
Et3N
\177

\177 5h

Scheme 176
Vinylene

oyO O
ethylene carbonate.

Novel explosive

from dichlora

Scheme 174

%O O

Reflux,

%O O

carbonate mp. bp. 162

22\302\260C

\302\260C

Preparation

of vinylene carbonate.

When ethylene carbonateis partly chlorinated, the two dichlorinated products (111)and (IV) formed cannot be : mixture of (111) (IV) separatedby distillation and an

85:15

only

is available commercially.
We
\177

of ethylene carbonate carbonate (V) in high yield treated with a trace of a nucleo(Ref. 229). to oxalyl chloride and phosphile, it cleaves quantitatively gene[Scheme177] (Ref. 230). This decomposition today's standard is f processor the manufacture of oxalyl chloride.
affords tetrachloroethylene When (V) is

Photochemical perchlorination

to that discovered (IV) cleanly decomposes chloraThis chloride anion cetyl chloride in presenceof naked method which destroys preferentially (IV) allows to recover fractional distillation (111)in 92 % yield by subsequent 1 [.Scheme 75].
\177.

146

147)))

b a a Phosgenend derivatives s building locks

a as Phosgenend derivatives buildinblocks

CI CI
mm Neat
\177.

o
/\177k

4 CI2

hv

CI_
m

-4

\177
i i --u'Y\302\260

CI CI

_Ci

mp.bp. : d25:1.71
17\302\260C

78-80\302\260C/35

2 R-COOH +CI.\177]\177oCI
O\177
100-150\302\260C

0
Scheme 179

4-CO 002+ 2 4-

2 RCOCI

HCI

No catalyst

CI CI
Cl-\177_\177CI
O'-,]i/\302\260

Catalyst
\"

95-100%
ofacid chlorides
using tetrachloreethylene

Preparation

carbonate.

cr\"
\177-

+ COCl 2
CI

O
carbonate and its decomposition

Scheme 177 Preparation of tetrachloroethylene to oxalyl chloride and phosgene. While studying the

Oxalyl chloride

of catalyzed decomposition tetraonium salts, we observed chloroethylene carbonate(V) by chloride. Since(V) the formation of a little trichloroacetyl centers : the carbonyl present three reactive electrophilic linked with two chlorine group and the two carbon both atoms, it can be attacked following two different pathways

The main issue under discussion is how this reaction can work without any catalyst. In contrast to oxalyl chloride, phosgenerequires a catalyst to convert carboxylic acid to acid chloride.Thus, the above reaction would give acid chloride in no more than 50% yield. we studied the describeddechlorination Furthermore, of tetrachloroethylene carbonate(V) to dichlorovinylene
with zinc (Ref. (Vl) is an interesting intermediate which as a cyclophile permits simultaneous introduction of masked o,-hydroxy keto and o,-diketo functions respectively into the cycloadducts (Ref. One

carbonate(Vl)

229).

as diagrammed

in

scheme178.
Cl

example is given

in

scheme180.

232).

O O
I

O.3.O
\177)

CI

CI

Cl'd/\177 OyO
O

CI

Ether Zn(Cu)(DMF)
\177-

85%dist.
Cl,\177=.\177CI

\"\177-\C,-")

C,\177
,\\ \",

If

attack to the

Reflux,

10h
(Vl)

O O
YO
H20

mp. bp.

19.5\302\260C
147\302\260C

C012

CI

=
Scheme 178 Possible types of nucleophific
nate by

CO2
\177H2

Acetone

CI.

O
attacks to tetrachloroethylene carbo-

CH2

+ (Vl) hv

=
Room temp.

O \177 \177 [\177OOH

\177O\177%O

80%

OH

Scheme 180 Synthesis and example

.\"

of use of dichlorovinylene

carbonate.

We thought that if a catalyst for directing cleanly the reaction either to the formation of oxalyl chloride or to trichloroacetyl chloride could be devised,the ready availability of (V) would seemto make this compound a very attactive intermediate. This work is currently under investigation. carbonate Also, we discoveredthat tetrachloroethylene can be used as a highly effective chlorinating agent for acid 179 in ). chlorides preparation as depicted scheme (Ref.

Phosgenation of hydroxamic acidsaffords nitrile carbonates which has been suugested as isocyanates recursors p

(Ref.

231

One demonstrative exampleapplied to the synthesis of is isopropenyl isocyanate given in scheme181 (Ref. 234). Note that the use of a catalyst such as ferric salts permits to lower the required decomposition temperature.
]49)))

233).

148

Phosgene

blocks as and derivatives building

a as Phosgenend derivatives building locks b

reactseasily with amines containing a hydroxyl Phosgene in 2 or-3 position to afford oxazolidones (cyclic five membered carbamates) oxazinones or (cyclic six membered carbamates)respectively. The preparation of 3-H-benzoxazol-2-one o-amifrom nophenol and urea is well known but the reaction is accompanied by the formation of tars and other side reactions. In contrast, phosgenereacts cleanly with o-aminophenol. We have deviseda simple process without any acid scain venger which affords pure benzoxazolone excellentield y as depictedin scheme183 (Ref. 236).
function Chlorobenzene
H
\177-

+ ==k

NH2OH.\1772SO\177

coOMe
CH2C\1772

\177\177
H2
NaOH

NHOH

Cydisation between
oxygen and nitrogen atoms

\177
H20 /
COC\1772

=\177
'\177N\177

85 % yield
bp. rap.
38-40\302\260C
34\302\260C

dist.
/

0.1mm

O,..,/O
O

NaOH
pH

: 4-6

\177

\177
:
of isopropenyl phosgenation

N=C=O

O
scheme

181 Preparation

isocyanate.

\177'\177NH2 \177

COCI2
100\302\260C

-OH

,4h

[\177 O \177=
96% yield
rap.
139\302\260C

of

o\177-hydroxy

carboxy\177ic-carbonic

vated form of
afford

anhydrides reaction acid function in

by

acidsaffords cyclic actiused as which can be

with

mixed

- 2 HCI
Scheme 183

amines to
in

me

182
OOH

amides as i\177ustrated (Ref.

the

example given

sche-

Improved

phosgenation process to benzoxazolone. valuable

235).
COC\1772

Benzoxazolones a i

compound for several

\177
NaHCO3

applications, for example as a key starting material for the manufacture of Phosalone,an insecticide used mainly on cotton [Scheme

184].

_\177oCH

Mandelic acid

0
Me k

--\177
CI

0
S
II

H2N,\177S,\177

COOH

I
CI

s
,CH2CI
II

(eto)2P-SNa
\177

,CH2_S.P_(OEt)2

\177\177=

O
of Phosalone.

O
CI

Cefamandole
(Antibiotic)

Scheme 184 Synthesis

GOOH
scheme

182 Preparation
.\"

of Cefamandole.

Someother interesting substituted benzoxazolones are also used as pharmaceuticals, for example the muscle relaxant Chlorzoxazone[Scheme185] (Ref. 237).)))

b a a Phosgenend derivatives s building locks

outlines the utility of the NCA's. This brief presentation But this is only part of the picture. Added to this are urethane N-carbo\320\247y anhydrides calledUNCA's we developed UNCA's which I of under license Bioresearchnc. (Ref. both protectedand activated form of amino acidsare are

a Phosgenend derivatives building locks as b

improved phosgenation
and purity
w processhich leadsto higher yield as demonstrated in scheme200 (Ref. 251 ).

249).

1)H20/ HCI 2) COCI . T< 2

50\302\260C

highly

effective coupling agents for

in

tides

as illustrated

scheme198.

the synthesis

of pep-

j
]\177.COOH

95%pure O

R +

Z-O- -N

H2N,,,,,v,.,,\177

\177

0
NH2

\177O

Z-O-C-NHCH-C-NH-,\177,',v\177w

\177N
Chlorobenzene,
20\302\260C,

.,,\177

CO2

N-protected peptide agents in peptides synthesis. the and

Scheme 198 Principle of use of UNCA's

then

COCI 2
mp.

105\302\260C

(Vl)
252\302\260C

as coupling

are crystalline solids which are stable in They absenceof water and nucleophiles. react readily
UNCA's
with cleanly

96.5 yield % 99.9% pure

Scheme 200..Comparison
anhydride.

between described (a) and SNPE

(b) routes to isatoic

amino functions without

which

dioxide is the only by-product tion and isolation.

racemization. Carbon allows facile purificais given in

199.
Fmoc-CI +

One example of synthesis of UNCA's

scheme
O

Isatoic anhydride (Vl) is an extremely versatile combecauseof the ease of its reactionswith nucleophiles or electrophiles s outlined in a rewiew a (Ref. For example it is claimed as a starting material in the synthesis of the analgesic Glafenine as shown in scheme (Ref.
pound

252).

201
O

253).

50-70%

Fmoc--N\177oo

mp.
c\177

106-7\302\260C

: + 28.7
\302\260

Scheme 199

Example

of preparation

of UNCA's.

(Vl)

CI
o\321\236-amino

O
'-L,,,.\177% N
\177-

t Let us now considero what extent the previous reaction acid can be applied to p-amino with of phosgene carbamates. acidsto yield six membered cyclic O-acyl known as isatoic 2H-3,1-Benzoxazine-2,4(1H)-dione six memberedcyclic anhydride (VI) is the most popular of isatoic anhydride by O-acyicarbamate.The synthesis acid with phosgene is well ring closure of anthranilic However, we have developedan described(Ref.

CI
Deprotection Scheme 201

OH H

CI'\177
of Glafenine.
159)))

Preparation

250).

158

b as a Phosgenendderivatives building locks

a as Phosgenend derivatives building locks b

according

+ COCi 2
\177

OI4

:
mp.
relaxant).

to the

in process epicted scheme188 240). d (Ref. Neat

O 191
\302\260C

O O

\177

Scheme 185

Preparation

of Chlorzoxazone(muscle

Y O

HN

,CH2CH2-OH

Catalyst
\177

O
(IV)

/--k

\177C\"2CH2-O\"

115\"45\302\260C

3-4mbar
oxazolidone.

now such as the novel analgesic(111) Oxazolopyridines, a medicinal classof hetebeing in clinical trials, constitute of 2-amino-3-hydroxy rocyclic compounds.Phosgenation and as scavenger solof pyridine in the presence pyridine y (I) in excellent ield as vent leads to the oxazolopyridine shown in scheme (Ref.

- HOCH2CH20 H
Scheme 188
.\"

Y O

--\177'--- OH

100%

Preparation

of N-(2-hydroxyethyl)

186

238).
\177--

The substituted oxazolidone is especially useful as (IV) building block for acrylic monomers syntheses for pharor

maceuticals.

Pyridine

\177OH NH2 \177>

COCl 2

(I)

\177== H
1\177)

Thus, the esterification of (IV) by acrylic acid affords a new acrylic monomer, SNPE code number CL in good yield as shown in scheme

189.

959,

95.5%
mp.
210\302\260C

/---k 0 N

Toluene
+

o
\177\177
N/---\177N

Y O

\177---OH Ov)

H2C=CH-COOH
H2SO4
75\302\260C/300

\177

mm

Novel analgesic

\177
O....../N--\177

Scheme 185 Preparation

\\\\0
\"--u

CL959
bp.
155\302\260C/2

and

u\177e

of an

oxazolopyridine.

_./\177
\",,

mm

is 3-amino-2-pyridone less easy to prepare. via Guillaumet and coworkers eportedthe synthesis of (11) r The reaca one-stepprocesssin\177 diphos\177ene (Ref. 239). u mixture in presenceof tion was carried out in CH2CI2/THF
available
triethyl

\177e re\177ioisomeric

system (11)derived from the readily

0
II

Low viscosity

Scheme 189 Preparation oxazolidone.

.\"

of new

UV-curable

monomer from N-(2-hydroxy-ethyl)

Acticryl

CL

amine

at-78\302\260C,

and

the

fied by flash chromatography

[Scheme187].
H
(\177)

product

isolated and

puri-

c.3cococ,
\177.\177H2
H

;--

THF / CH2CI , 2

78\302\260C,

6h

L\177
(1H)-one.

=0
rap.

78%
252\302\260C

- classical for - adhesives,pressure wood,paper, plastics, adhesives ; - fibers ; - electronics,photo-resists.

coatings

in fast drying coatings (Ref. useful in various industrial sectorsfor :

as reactive diluent

959 widespreadapplications,mainly has

241).It
is
metals ; sensitive

optical

Scheme 187

N-(2-Hydroxyethyl) valuable intermediate

oxazolidone (IV)

should

be also a
of pharma-

Preparation

ofoxazolo[5,4-b] pyridin-2

zines which are widely

the serie, we have developed synthesis of oxazolidoneIV) at an industrial scale, ( N-(2-hydroxyethyl)

In

aliphatic

ceuticals such as the neuroleptic Fluanisone. Squibb reported an interesting example at the 207 th ACS National l'leeting depictedin scheme190 (Ref. 242).
153)))

for the synthesis of used in the preparation

N-arylpipera-

152

b a a Phosgenend derivatives s building locks

\177
N
O\"'\177\"

a as Phosgenend derivatives building locks b

NH3
\177.-

Ts-CI

\177
\177

ArNH

2 I\177H\177NHCH2COOE t

\177 OH
0v)

OH

Base

OY N\177- O'Ts
O
/\177k
HN

I\177
'CH2NHCH2-\177I-NH

HBr
N --\177__
O'-,\177\"

30%/ AcOH
\177

N-Ar

COCI2
=, \"\177

O
2

Caroxazone

N H_Ar

Heat of N-arylpiperazines.

Scheme 190 Novel

40-91%
the

NaHCO3 H20/ CH2CI2 Scheme 192 Preparation

\177,\177 NV\177NH

preparation

of the antidepressant Caroxazone.

c Oxazolidonesan be also preparedfrom of

reaction

primary amines with 2-haloalkyl chloroformates. This method has found widespread applications in various sectors of the chemical industry. The industrial preparation

The intermediary synthesis of oxazinonesderivatives is the key for the N-hydroxypropylation of substituted anilines used as componentsin hair dyes 245,

of process the systemic

illustration

[Scheme191] 243). (Ref.

CICH2CH2\"O-C-CI
Me

fungicide

Oxadixyl

is

a good first

One example is given

NH

in

scheme193.

(Ref.

246).

O CI-(CH2)3-O-C-CI
NaOH

Me
--NH-NH2

0
Me H

HO

K2CO3 Me

Me

O
Me
HO

O
II

Me

Me-O-CH2-C-CI

HY

CI
NaOH

O
=.
Me
HO

CI

NH-(CH2)3-OH

Scheme
hair dyes.
,N

193.'Hydroxypropylation

of substituted anilines

for the preparation

of

\177,O
\302\260xadixyL

\177/\177----kO

and

M\177

5theme

191 Industrial scale preparation

reactswith cz and \177amino acidsto yield Phosgene six memberedO-acylcarbamates respectively. Thus, phosgenehas proven to be very effective in
of N-carboxy
anhydrides

five

of the

fungicide Oxadixyl.

preparation

The reaction of phosgenewith amines containing an -OH function in 3-position readily affords oxazinones as
already mentioned.

acids.Thesecompounds 2,5-dioxo-1,3-oxazolidines (V), also calledLeuch'sanhydrides have widespreadapplications especially not only in peptides but synthesis [Scheme

the from cz-amino (NCA)

depictedin scheme192
(Ref. 244). 154

The

preparation

of

the antidepressant Caroxazone illustrates the value of the method

194].

155)))

a a b Phosgenend derivatives s building locks

COOH
R--\177 NH2
NH-\177-CI

a Phosgenend derivatives s building locks a b

cooMe\\--/
NH3\321\207

coc, (large excess)

\177,

i
L

OOH
R

CoCI , excess 2 3.5h,

\177 30\302\260C

O
Me --\177N<
H
/\177-r\177

95 % O
unisolated

O
C-CI

L-Alanine

o
2
R
__\177N\177,

HCI

1)
\177-\177N\177COOKH
\177,

=
H

Ala-Pro\177

R---\177

(V)

- CO 2

NH2'HCI

2) H

\321\207

H2N
.\"

Me\177N\177cooH 90% O
Ala-NCA.

--. --.
NCA

Scheme 195 Preparation

Enalapril

of Ala-Pro through (structure

in

COCI 2

C-CI
II

C-CI
N=C=O
and
%

scheme196)is an
O C, OH

angiotensin-

converting

R----\177

NH-C-Cl

- HCI

R----\177

tension.

enzyme (ACE) inhibitor for the control of hyper-

O
Scheme 194 5eneral picture reactions.
.\"

COOEt Me
anhydrides preparation
further

of N-carboxy

--N /,)--CH2CH2--C --C--C--N\177

Although

generally and sold in large quantities. The scopeand limitations of their chemistry, as well as their.applications are not discus-

to

sensitive to traces of moisture and more nucleophilic attacks, NCA are now produced

Scheme 196 Enalapril.

In

sedin
tion

details here in this section and are reserved secfor 4-4 in vol. 2 dedicated the protection and activation to

of functional groups.
However,
tions

(Ref. 248).
MeNHCH2_COOH

another example, Sarcocine-NCA prepared by of sarcosine,followed by cyclisation in the presenceof triethyl amine is used for the preparation of lipopeptide-basedranched polymers forming thermotrob pic and lyotropic liquid crystals as shown in scheme 197
phosgenation THF
\177-

are given

some representative examplesof applicain the presentsection.

coupling

O
Me_N,/\177

Sar-NCA

The NCA

method is conceptually

simple and

1)COCI 2
2) Et3N Boc-F

elegant.This method is now used in efficient large scale f production of peptides, or example for the preparation of dipeptides Enalapril and Lisinopril (Ref. semi-synthetic

O
\177

yO

H2N(CH2) 2-NH2 1

247).The synthesis of
block to synthesize

Ala-Pro which

195.

Enalapril

key building is diagrammed in scheme

is the

O
II

Boc--HN-(CH2)12-NH 2

H2C-----CH-C-C
I
\342\200\242

THF, Et3N

H2C\177---CH-C--HN-(CH2)12.NH.Bo

O
H2C\177CH-C-HN-(CH2)\1772-NH-(Sar)6-Sar_H

II

1)Sar-NCA
2) Deprotection
.\"

Scheme 197 Preparation mers for lipopeptides.

O
of Sarcosine.NCA
and use in the preparation

II

ofoligo157)))

156

a as b Phosgenend derivalives building locks

Phosgenereacts with
hydrazides to afford

a as Phosgenend derivalives building locks b

Compound (VII) can

1,3,4-oxa-

diazolinones.One well known example is the synthesis of the selectiveherbicide Oxadiazonfrom Rh6ne-Poulenc [Scheme (Ref. 254).

be further

transformed

Iones,useful

building

blocks for pharmaceuticals

202]

cl
CI NH-NH

-cl
--I--\1771

o
\177'

c\177

CI
NH-NH-\177:

iPr-O

iPr-O

Etoperidone or Nefazodone (seecyclisation nitrogen atoms, next section).In the case of Etoperidone, this transfomation avoids the use of toxic ethyl isocyanate to get the required intermediate as shown in scheme 3,5-Dioxo-l,2,4-Oxadiazolidines been found as a have moiety of the natural excitatory amino acid Quisqualic acid and their synthesis by numerous methods has been extensively studied by Zinner

to triazosuch as betweentwo

203.

COCI 2
Oxadiazon
iPr-O
=

Scheme 202

O
Oxadiazon.

scheme204 (Ref. 2.57).

O\177_

and co-workers (Ref. Reaction methyI-N-chlorocarbonyI-N-methyl carbamate, (VIII), (preparation given in section 3-3-4, this volume) with affords 3,5-dioxo-4-methyl-l,2,4-oxadiahydroxylamine zolidine (Acronym i as shown in P1ODD)n good

of

256).

yield

Preparation

of the herbicide

O cI
+ HCINH2OH
Me--N\">,-1

) NaOH / H20
\177\"

We have studied the preparation

diazolinone
(VII)

,/\177

of 5-ethyl-1,3,4-oxaof
propionyl hydrazide

NH
(\177

as depictedin scheme203 (Ref. 255).

Et

by phosgenation

O_Me//
(VIII)

2)) HCl

Me-Ny 90% O
mp.

101 \"c

(CHCl3)
Toluene Et-C-NHNH2
+

Scheme 204.'Improved

preparation

of MODD.

COCI2
60\302\260C,

\177'

O
Toluene
(VII)

II

5h

100%
+ EtNH 2
50-70\302\260C,
\177

II O
O
II

NH

(VII)

While exploring new alternatives to the handle of lower w alkyl isocyanates, e thought that the nitrosated MODD could be a good candidate for a new synthesis of methyl ding isocyanate through a t\177vo-components safe processaccorto the mechanism depicted scheme in

4h

Et-C-NH-NH-C-NHEt

97 %
Et-C-NH-NH 2 + Et-NCO

II

205(Ref. 258).

O
\177

O
I
\177,,

O
Scheme 203.'Preparation and use of 5-ethyl 1,3,4-oxadiazolinone.

II

N-Me

HN_/
O

\177 +
a

CO 2

ON/\177
of methyl
\177ocyanate by

+ N20
two-components

Scheme 205.' Expected generation safe process.

160
161)))

b a a Phosgenend derivatives s building locks

Sometrials applied to a model reaction by trapping the carbamatewere very methyl isocyanate as butyl N-methyl in scheme206. promising as demonstrated O
n-Bu-OH
z\177NH

a Phosgenend derivatives building locks as b

MODDreadily reacts with hydroxy compounds to afford 2-alkoxycarbonyI-MODD. These intermediates do not need to be isolatedand are reacted with an excess f o amine to give the corresponding carbamate in

n-Bu-OH t-Bu-ONO
50\302\260C,

\177,

Bu-O-C-NHMe

+ t-BuOH

Me-Ny\177

2h

O
85 % as methyl
isocyanate precursor.

II

good yield as depictedin scheme208 (Ref. 260).For example, the insecticide Aldicarbe was obtained in 85% yield without use of the noxious methyl isocyanate. O
COMODD
R2-NH2

Scheme 205 Use ofMODD/t-butyl nitrite

while

+ R'-OH

\177.

Furthermore, studying the potential applications HODD as a building block for the synthesis of 2-acylof that we 3,5-dioxo-l,2,4-oxadiazolidines,discovered it is a This led us to the design of the very good leaving group. unknown symmetrical 2,2'-carbonyl-bis(3,5dioxo-4-methyl-l,2,4-dioxazolidine), (acronym COHODD), previously

- 1 MODD
R,O.Io\177_N,o\177..\177-\177e

-1

\177-

MODD

R\177O-C-NHR2

85-90%
without MeNCO

\177
It

O
of AIdicarbe

II

: Synthesis
I

as a
ry

new coupling mates from hydroxy

reagent for the preparation of carbacompounds and primary or seconda-

Me2-C-CH=N_O_C.NHMe
Scheme 208..COMODD

85% overall
mp.

amines (Ref.

was COHHOD readily obtained in goodyield by simple in of HODD refluxing toluene in presenceof phosgenation
hexamethylguanidinium

259).

SMe as an useful

O
tool
for

II

99-100oc

yield

carbamates synthesis.

chloride hydrochloride

(HHGCI.HCl)

as the

catalyst

[Scheme207].
Toluene HMGCI.HCI,0.5mol %

O
O,k\177
N\177J\177

O
N..\177

\177-NH

COCI2
Reflux,

\177-

Me-Ny
O
Scheme 207

\177)

3h

\177)

\"MODD\"

82 % O
mp.
204\302\260C

MeNy

(\177NMe

\"COMODD\"

Preparation

of EOMODD.

is COHODD Comparedwith 1,1'-carbonyldiimidazole, a crystalline, stable and non-hygroscoDic compound. HODD releasedafter use of COHODDas coupling reagent is Horewater soluble and thereforecan be easily recycled. over, in contrast to imidazole, HODDis acidic (pKa meaThis characteristic can be very useful sured at in the caseof substrates sensitive to basicconditions.
20\302\260C

:3.6).

mainly senof 2-alkoxycarbonyI-P1ODD toward hydrolysis. However, Z-amino acids were obtained in medium yields and were found to be free of dipeptides impurities. We discoveredalso that COMODD reacts with carboxylic acids to give the unstable mixed anhydrides (IX) which are rapidly to decarboxylated the 2-acyI-P1ODD (X). As above mentioned, (X) are not isolated but are reacted in situ with an amine to afford the corresponding amides as shown in scheme209 (Ref. 260). This reaction has been successfully applied to the coupling of amino acids. Yields are generally good and the dipeptides are easily freed of by-products by washes.The HODDreleasedor its sodium salt are simple readily soluble in water and thus are easily separated from the fully protecteddipeptide. sitivity

is possibleto prepare BOC- Z-amino or acids from isolated 2-BOC- r 2-Z- HODDbut the method was o found of little synthetic interest becauseof the
the

162
163)))

b a a Phosgenend derivatives s building locks

a as b Phosgenend derivatives building locks

The reaction was
efficient
with

both

COMODD

R1-COOH

\177

alcohols. o secondary Providing that an excess f the alcohol is added,tertiary alcohols are esterified in medium but still
satisfactory yields. The reaction is catalyzed with DHAP, but no basewas necessary the alcohol already contained if a pyridine function. We assumethat the reaction proceeds through the mixed anhydride (IX) as depicted in scheme
\177-.

primary

and

-1

MODD

O
.\177

210. 1

- CO 2

\"\177_

N,o\177.\177\302\260\177)e

R2-NH2

-1 as an

R\177-C-NHR

2
COMODD +
R\177-COOH
\177_

MODD

II

(X)

R\177_C.O_C_N

\"\177N-Me

Scheme 209

COMODD

useful

tool for amides synthesis.

-1

MODD

o o
Ii II

'o---& /

procedure,one equivalent of COHODD a solution of the protected amino acid and is added to N-methylmorpholine (2 eq.)in acetonitrile or dichloromeIn

(\177x)

typical

thane and stirred at room temperature for I h. The amino acid esteror its hydrochloride is then addedand the reaction mixture is stirred for an additionnal hour. After conventional

--'\177\"R'L
-CO\177

NMe2, Me

\177RLC-OR2
\177

MOOD

O
acids.

II

the organic phase, the dipeptide is crystallized several from a suitable solvent. As shown in table dipeptides werepreparedand no deviations werefound in

washesof

Scheme210 COMODD

asa reagent

for the direct estefification

ofcarboxylic

3-29,

their optical rotations. Dipeptide

BOC-Phe-GIy-OEt
Z-VaI-GIy-OEt

Yield

(%)

mp.

\302\260

(\302\260C)

[c\177]D

80 06
74

80-8 80-81 90-98

105-16627 (c I EtOH)

-4 (c I

EtOH)

Z-Leu-Phe-OHe
Z-Ala-Phe-OP1e Z-Phe-Ala-OP1e Bz-Leu-Gly-OEt BOC-Tyr(OBzl)-GIy-OEt

88 83 78 79

10 127-129-22(c 1.25 EtOH) 137-139 - 4 (c 3.1 EtOH)

+ 117-119 2 (c 0.5EtOH)
COMODD

- 20 (c 2 HeOH) - (c I EtOH)

Table 3-29 Preparation

In

ofdipeptides using
the

asa coupfing

agent.

ester in 89% yield (rap. No sign of racemization the syntheses amino esters examined. of AcyI-I\"IODD (X) provided by activation of N-protected0\177-amino acids and O-protected-0\177-hydroxy acids with COHODD been proved to be suitable for the synthesis have of ]3-keto ester as depictedin scheme211 (Ref. 262).
95-96\302\260C).

In a typical procedure, COHODD(I eq.) and the appropriate alcohol eq.)are addedwithin 5 rain. to a solution of the acid (I eq.),triethylamine eq.) and DI\"IAP in dichloromethane and the reaction mixeq.) ture is stirred at room temperature for 2 h. Conventional acidicand basicwashesafford the corresponding ester in good yield. For example esterification of Z-AIa-OH with pnitrobenzylic alcoholusing this method gave the expected

(1.1

(0.1

(1,1

was detectedin

second publication, we reported the use of

one-potesterification of carboxylic acids, acids,under mild conditions (Ref. 261).
165)))

for COHODD

especiallyamino 164

a as b Phosgenendderivalives building locks

O
\177O\177

a as b Phosgenend derivalives building locks

diamine type compounds is a for the preparation of 2-imidazolidones (cyclic five membered ureas). The utility of this method is illustrated by the synthesis of a valuable intermediate (I) for D-biotine manufacture. We have developed an improved interracial process hich affords w (I) in good yield and high purity as shown in scheme Phosgenation
well

COMODD
R \177-COOH

\177

R2

.io\302\260

>
75\177C

CHR3
{\177yclisalion be\177veen

of ethylene

80-98% O
II

Et3N, 0cC

yNMe
(X)

established method

lwo

75-95%

nitrogen

a\177oms

R3
I

R\177-C-CHCOOR
.\"

213.

Scheme 211 Use of COMODD in the synthesis

of

\177-keto

esters.

of

This activation was successfully used in the preparation unusual \177amino-[3-hydroxy esterssuch as the protected

\177_

H
N

\177
N

\177

\177

1) KOH / H20 / Hydrophobic

COCl2 2) H20: HCI

solvent
\177,

derivative shown in

of (354R55)-Isostatine scheme (Ref. 1)

M
COMODD98%

212 202).

from

D-allo-isoleucine as

HOOC

Me...y/Et
Z-N/\"\177COOH H

e...y/Et
H

2)

Li

O
\177CH2

EtO

82%
Me...y/Et

O
Anti

.
.\"

H.\177\\H \"e
\177COOH

O
mp.
172.5\302\260C

o.
H H

(0

D-Biotine
(Vitamin H)

NaBH4
\177\"

-OH

Z-N/'\"r''\177COOEt ( de < 96 %)
H
\177H

(GH2)4GOOH

Scheme 213 Preparation

COMODD.

of the

Scheme 212 Preparation

.\"

key intermediate

of (354R55) Isostatine with

for the synthesis of Biotine.

of the key intermediate for the by the preparation production of the soil-applied nematocide Isazofos(Ref. of 1-cyano-l-isopropyl Thus, phosgenation hydrazine in THF gives a transient N-chlorocarbonyl compound (11) which is cyclized to (111). This salt, insoluble in THF is recovetrated

r Phosgeneeactswith cyanohydrazines to yield 3-hydroxyThe 5-chloro-l,2,4-triazoles. utility of the processis demons-

263).

red

by filtration by

and the

goodyield

simple acidification

desiredproduct (IV) is isolated in as depicted scheme214. in

166
167)))

a a b Phosgenend derivatives s building locks

CI-CN THF
.\177/
\177\"

a as b Phosgenend derivatives building locks

Note also that reaction of
methyl carbamate(preparation through in section 3-3-zLthis is

/H

COCl 2

,,\177N_NH2

,N-NH2 CN

preparation of numerous urazoles..Some examplesare presentedin table 3-30 265). (Ref.

\177, N-N
k/\177\"

methyI-N-chlorocarbonyI-Nphogenation given very suitable for the volume)

Cl\"

--NH .\177N
\177,\177*\177
N

Anhydrous NH3

O
\177
N-N
Cl\177,\177
k/\177-

\"

R O-NH+
(Ill)

Yield

(%)

mp.

(\302\260C)

CI.\177Z\177

Cl

[II)

\177

H Pie

56

HCl

/ H20
\177

81.4
89.5
+

(IV)

Ph

Scheme 214 Describedprocess for the m an ufacture of Isazofos.

OH 92% yield ofa intermediate

used for the
RNH--NH2

238-9 122-3 222-3

R.N_NH

preparation

O'\177cI
Me-N\177__

1) I-bO / NaOH
\177

OMe

2)

HCl

/H20

\321\236=:Z,

\"\177O

chloride.The new synthesis of (IV) is diagrammed scheme21.5 264). (Ref.

Acet\302\260ne

While exploring the synthesis and chemistry of urazoles, an alternative processtarting from carbazate s which avoids the handling of the extremely noxious cyanogen

AcOEt extract. carbamate

Me
for the

we studied

tion

Table 3130 Use of rnethyI-N-chlorocarbonyI-N-rnethyl ofurazoles.

prepara-

in

MeO-C-NH-NH 2

\177

NINH\177=:=
\1771

-OMe

Pt/H2 ---\177

O
MeOH

II

O
/ H2SO 4
\177

-N-NHICIOMe
H

WN-NHIC-OMe
O\177
NH

85%
rnp.

II

KOCN

,20\302\260C

O
.\177
N-N
Cl\177'\177
k/\177\"

II

161

\302\260C

The biological activities of condensedpyrimidine systems as diuretics, antitumor agents or as antagonists of constituents of nucleic acid and of folic-folinic acid family of vitamins prompted differents authors to study the synthesis of cyclic six membered acylureas such as pyrido[2,3-d] yrimidinones (Ref. p Reaction of phosgenewith 1-amino nicotinic acid affordedthe 3-azaisatoic anhydride (V). Treatment of (V)

266).

H20 / KOH
\177

oiDichlorobenzene
\177/\177

N-N
O\177=/\"N/\177--\"

POCI3

propargylamine yielded the 1-aminonicotinamide (VI). Phosgenation of (VI) in pyridine under reflux gave the expected product (VII) as depicted in scheme

in DMF with

100%

216.

Catalyst
160\302\260C

OH

78%

(IV)

26%
mp.
105.5\302\260C

Scheme 215 Synthesis and use of l-isopropyl

mp.

186\302\260C

urazole.

168

169)))

a as b Phosgenend derivatives building locks

O
COCi 2
\177,

a as b Phosgenend derivatives building locks

In

HC--CCH2NH2

lone

[\177COOH NH

O \177N.\177
(V)

DMF , 50 C
57\302\260'\302\260

O
NHC H2

O --C--CH2
Pyridine,
137-8\302\260C

done as depictedin scheme219 255,268). (Ref. Nefazodone.HCI launched in 1994 the US and was in in Canada by BristoI-Meyers Squibb as Serzone for the treatment of depression (Ref. 269).
\177

another study, we devised new route to the triazoa intermediate (X) useful for the synthesis of Nefazo-

(v0
mp.

63%

reflux,

6h
mp.
240-2\302\260C

O
H
(VII)

OH

\177
a

Et
O\177

Scheme 216 Example of preparation double phosgenation process.

\177

\177 175
Neat
\302\260C

II

of cyclic six membered acytureas through

0h
glycol
\177-

OCH2CH2NH-C-Et (A)

H20

/ 4h
bp.
99-102\302\260C/7

5-Ethyl-l,3,4-oxadiazolinone prepared by phos(VIII), genation of propionyl hydrazide as already describedin section3-4-2,is a key building block for the synthesis for the synthesis of 1,2,4-triazol-3-ones type antidepressants
(Ref

\177

ethylene

(A)

+ NaOH
145\302\260C,

OCH2CH2NH 2

(B)
dist. yield
mm

Steps1 + 2 : 86%overall
Et
\"\177N,

we obtained the triazolone (IX) in 7_3 % overall without the need of the yield according to scheme 217 toxic ethyl isocyanate.IX) is suitable for the manuhighly ( facture of Etoperidone [Stucture given in scheme (Ref.
Thus,

255).

Toluene
NH
80-85\302\260C

St_e#33

(B)

O
(VIII)

4h

O
II

O
II

267).
Toluene Et-CNH-NH2
+

218]
4h

Et.C.NH_NH_C_NHC

Et

COCI2
60\302\260c,

\"\177-\177 \177'

N.

2 Toluene
50-70\302\260C,

Et-NH

II

5h

(vm)
H20 / NaOH Et-C-NH-NH-C-NH-Et

y o

NH

) KO H / H20

\177

2 h reflux

(C)
2) HCI

Et\177NAN
loo\302\260c,

H73% mp. 125-7.5\302\260C of Etoperidone.

/ H20

.
useful

H2CH20_@
O
__N.
_\177H

O\177OCHCH2
Recryst.
138\302\260C

\177.\177N

(X)

Et from MEK

Steps3 + 4 : 80%yield
mp.

O
97%
Scheme

II

0
II

h
(IX}

Et!
\177--\177

from propiohydrazide

217 Preparation ofthe key intermediate

CI

for the manufacture

0
Et-- NAN
Et

,
:

\"\177-1\177

(CH2)\177--

Et

N/--XN-\177 CI
(anti\177lepressant).

Scheme 219 New synthesis

Nefazodone (Anti-depressant)
intermediate
(X) for Nefazodone.

of an

Scheme 218 Etopefidone

170

171)))

a a b Phosgenend derivatives s building locks

carbamatesare valuable products, especially N-Hethyl as pesticides, or example the insecticide Carbofuran, as f well as numerous pharmaceuticals. Industrially, the reaction far

a as b Phosgenend derivatives building locks

Without catalyst

/[J\177

isocyanate with hydroxy compounds is by one of the most widely utilized proceduresfor the production of numerous N-methyl carbamates. The Bhopal incident (India, 1984) dramatically outhas lined the high toxicity level of methyl isocyanate and moreover its very exothermic self-polymerization which requires extreme care during its production and storage (Ref. 270). In this volume, we have already examined some alternatives to the synthesis in situ and/orto the use of methyl
methyl

of

N- Me
(Xll)

2 Me-NCO
BusP

Me-N,\177/O

Scheme

221 Use of (XII) as methyl

0.5h ,

90\302\260C

isocyanate generator.

isocyanate.We

dione (XlI) which can releasemethyl isomethyl isocyanate precursor in safe conditions. This dimer was preparedfrom cyanate urea (XI) obtained by N-chlorocarbonyI-N-methyl N'-methyl of N,N'-dimethyl urea as previously described phosgenation in scheme section 1.56, 3-3-4. yclization of (X]) in a suitable C solvent and in presence a base such as DABCO afforded of
the

1,3-dimethyl diazetidine (methyl isocyanate dimer) should be a suitable

thought

that

3 4-4 lion C.vclisa belween a nilro\177en atom and a sulfur atom

L-2-Oxothiazolidine-4-carboxylate (OTC)

/COOH

S\177NH

dimer expected
Solvent

in (X]I) as depicted

scheme220.
(XlI)

Me-N

O'k\177

CI

DABCO
\177
\177,

Me-N N-Me Cas: 36909-44-1

\177/

o\177--N.

Me

1 h, 83%

30\302\260C

(Xl)

mp.
Preparation

98\302\260C

Recryst. hexane

Scheme

220:
wing

of methyl isocyanate and IR analytical

dimer.

a non-toxic precursorof cysteine proposedas a prodrug capableof penetrating into living cells.Therefore,ts i orally or parenterally administering to humans provides a method of restoring the glutathione level of numerous tissueswhere 5-oxoprolinase present, especially the liver is in I (Ref. 271).n HIV-seropositive patients, it was proved to increasethe levelsof gluthatione, the lack of which is suspectedto be a factor of their immunodeficiency (Ref. 272). OTCis available by several methods, among them the reactions phosgene(Ref. 273) more of or recently triphosgene(Ref. 274), with L-Cysteine or L-Cysteine methyl ester appearthe more convenient. We developed a laboratory scalea biphasic phosat
is genation

The NHR

data of (XlI) are the

follo-

led pH as depictedin scheme

f processrom

L-Cysteine hydrochloride

222 275). (Ref.

at control-

1H NHR (CDCI3) 2.87 8 ppm

IR

cm 1780 1.

This dimer

was

t decomposedo

221.
172

100% methyl

thermically (170\302\260C) or catalytically isocyante as shown in scheme

173)))

b a a Phosgenend derivatives s building locks

Toluene KOH/H20
/__\177,COOH

a as Phosgenend derivatives building locks b

This is the end of volume 1 mainly dedicated the use to of phosgeneand its direct derivatives as blocks building providing the carbonyl group in organic molecules. Obviously, several major topicsrelated to this type of applications are inadequately discussed even purely and or simply forgotten. Pleaseforgive me for these inadequacies which are not at all intentional. Also, the reader wiil understand that some sensitive

HS

/_\177COOH
NH2.HC
I

1)COCI 2, T:
10\302\260C

2) 3) Solvent
HCI

S.\177NH

extraction

0
0

OTC

70%

Cas: 19771-63-2
mp.
[c\177]\177 168\302\260C

:-61
\302\260

Scheme 222.' Preparation

of OTCby

phosgenation.

It

is noteworthy

that

OTC have other types of pharcan

maceutical applications than the delivery of cystein into the human body. For example, nitrated derivatives of OTC were recently patented as valuable coronary vasodilators
which

subjectshave been deliberately omitted for confidentiality reasons. It is obvious that substantial work remains to be done and it is the author's secret hope that this first volume will serveas a catalyst to open the way to new researchon the chemistry of phosgene.

replace nitroglycerin without having its disadvanAn tages (Ref. 276). example of synthesis of these new interesting pharmaceuticals is given in scheme223.
Et3N

/_.\177/COOH
NH

(EtO)2P(O)CN
+

HNO3.H2N-CH2CH2ONO2

in

THF

\177

OTC

O
N
S\177,[\177,

mp.

130-1\302\260C

( AcOEt )

Scheme 223
.\"

Preparation

ofa nitrated derivative of OTCasa vasodilator.

174

175)))

Relerences

L.Ann. 5cL,1945, 270-87 5, C Dumas, J.-B. R.Acad. 5ci., T.LIV, 225 3 Hathur, B.B.; Krishna, G. Chem. Waft. Agents, 237 4 Gauvreau, J.-R. ; Hartin, G. ; Halfroot, T. ; 5enet J.-R J. Chem. 5oc.,Perkin. Trans. 2, 1984, 1971-4 5 Cagnon, G. ; Piteau, ; 5enet,J.-R ; Olofson, R.A. ;
Dobbin,

1 2

1833,

1992,

J.T.(SNPE)
Gauthier,

EP

40153 1980
Pr. Pr.

II.

12,

l\177lartz,

6
7

21376; U5 4 806 286 9

Hegarty, New-York, Gauthier,

P. ; 5enet, J.-R ;

11alfroot, T. ; Wolf, R (SNPE) EP

850723

A.F. ; Comprehensive Organic Chemistry

Vol. 1972, 2 p. 1075

; Wiley,

8 9

Chim.,

1993, p. 554. 130,

Le Perchec,P.

P. ; Gros, P. ; LePerchec, . ; 5enet, J.-P. ull. 5oc. P B

; 5enet,

Gros, R;

10 Gauthier,
Pr.

59, pp. 4925-30

J.-R J. Org. Chem.,

Ft.

1994,

13 Horner,
145NPE,

545 774, Pr. 911129 12 Kreutzberger, C.B. Olofson, ; 703 046, Pr. 93 3 26
Pr. 178184, 841011
unpublished

11 Gauthier,

861017

P. ; Halfroot, T.; 5enet,J.-P. (5NPE)

2 605 317,

P. ; Gros,

R ; LePerchec, ; 5enet,J.-R R (SNPE) EP

R.A.

; 5enet, J.-R (SNPE)

Fr

RJ. ; Jansons,

V.

; Gors,

H.C.(Raychem Corp.) EP

results

15 Jones,5.5.Ogston, C.B.Webb, R.C.(Smithkline Corp.) U5 ; ; 4 321 399, Pr. 780621

177)))

rences
16 Rainoldi,
17 Paul,
R.

rences
A. (Pulitzer
Italiana

18 Crosby,

; Tchelitcheff,

Pr. 900530 WO 5.r.I.) 9118896 5. (Rh6ne-Poulenc) U5 2 768 174- 1956

R.V.\177

39 Gros,

P. ; Le Perchec, P. ; Gauthier, P. ; 5enet, J.-P. 5ynth. ; Commun., pp. 1835-42

1993, 23(13),

D.G.

\177

Berthold,

J. Org. Chem., 1962,

Nissan 19 Chemical

pp. 3083-5

Industries, Ltd. JP 55143 970 ; Pr. 790427 20 Borthwick, A.D. et al. ; J.Med. Chem.,1990, pp. 179-86. 33, 21 Matzner, M. ; Kurkjy, R.P. ; Cotter, R.J. ; Chem Rev., 1964, 64, pp. 645-687 22 Senet,J.-P. Ucciani, C. (SNPE) Ft. 2 327 228, Pr. 751010 ; 23 Senet,J.-P.SNPE) Ft. 2 230 60.5Pr. 730.524 ( 24 Jonas, R. ; Lues, I. ; Beier, N. ; Minck, K.O. (Merck Patent ; Gmbh) EP 7219.50Pr. 950111 25 Mochizuki, A.; Teranishi, T. ; Ueda, M. ; Macromolecules, 199.5, pp.365-9 28(I), 26 Norbeck, D.W. ; Sham, H.L.; Kempf, D.J.; hao, C. (Abbott Z Pr. Laboratories) WO 94 19332930225 27 H. ; Grieder, A. ; (Ciba-Geigy Corp.)US 4 287347 Pr.
F\177h,

40 Lecolier, S. ; Dionne, M.-C.; Ylansuy, D. ; (SNPE) Fr. 2 220 564 Pr. 730306 41 Sennyey, G. ; Barcelo, G. ; Senet, J.-P. Tetrahedron LetL, ; 1986, pp.5375-6 27, 42 Sennyey, G. ; Barcelo, G. ; Senet, J.-P.; Tetrahedron Left., 28, 1987, pp.5809-I0 43 Childs, M.E.;Weber, W.P. ; d. Org. Chem.,1976, pp. 3486 41, 44 Nii, Y. ; Okano, K. ; Kobayashi, S. ; Ohno, M.. Tetrahedron Left., 1979, pp. 2517-20 27, 45 Katner, A.S. ; (Lilly, Eli and Co.)DE 2 340409 Pr. 740228 46 Mander, N.M. ; Encyclopedia of Reagents for Organic
Synthesis, Paquette,
England, Vol. 1995, 5, pp. 3466-9

L.A. Editor, John Wiley &

Sons Inc.,

800512

47 D'Alelio, G.E (ScottPaper Co.) 3 225 063 Pr. 620521 US 48 Craig, T.W. ; Borochoff, E.H. (General Mills Inc.) US 3 554 762 Pr. 680117

28 Saboureau, C. ; Senet, J.-P.;

10 Pr. 29 Olofson, R.A. ; Martz, J.T.;SNPE) EP 8091381 11 ( 30 Malfroot, T.; Wolf, P. ; Senet,J.-P.(SNPE) Unpublished results 31 Donges, E. ; Kohlaas, N.R. ; 5chlegel, A. ; Langhans, G.
Cheme-lng. Techn.,

1992

(SNPE) Unpublished

results,

49 Burgard,

18259 790413 Pr.

M. ; Rollat, A. ; Piteau, M. ;

Senet,J.-P.SNPE) (

EP

1966, pp. 38(I)

32 Konstantinov, I.I.; Kormusshechkina,

a Pr. 2042618nd 2042619, 921007

A.I. ; Melenteva,

T.T. U R

33 Cotarga, L. ; Delogu, P. ; Nardelli, A. ; Sunjic, V. ; 1996, 553-76 pp. 71 4 34 Damle, S.; Chem. Eng. News, 1993,(16), 35 Webb, R.L. ; Labaw, C.S. J.Heterocyclic Chem, 1982, 19, ; pp. 1205-6 36 Webb, R.L. ; Eggleton, D.S.;abaw, C.S. Lewis, J.J. Wert, ; ; L K. ; 3. Heterocyclic. Chem., 1987', 24, pp. 275-8 37 Barcelo, G.; Grenouillat, D.; Senet, J.-P.; Sennyey, G. ; Tetrahedron, 1990, 1839-48 pp. 38 Stanley, D.S.Leister, N.A. ; J. Org.Chem., 1958, ; 23(8),pp.

50 (Dainippon Ink & Chem. Inc.) JP 04 1614 65 CA 117 235963 51 Brosse,J.-C.; Couvret, D. ; Chevalier, S. ; Senet, J.-P.; P/akromoL Chem., Rapid Commun., 1990, pp. 123-8 52 Decker, C.; Moussa, K.; Makromol. Chem., Rapid Commun., 1990, pp.159-67 53 Couvret, D. ; Brosse,J.-C. Chevalier, S. ; Senet,J.-P.; Eur. ; 27, Polym. J.,1991, pp. 193-7 $4 Couvret, D. ; Brosse,J.-C.; Chevalier, S. ; Senet, J.-P.;

11,

11,

P/akromol. Chem.,

55 Jones,J.J. d. Chem.5oc.,1957, 2735 ; pp. $6 Gros, P. ; Le Perchec,P. ; Senet,J.-P. d. Org. Chem., 1994, ; pp. 59(17), 4925-30 57 Shimizu, H. ; Tanaka, E. ; Yoshioka, M. ; d. Chem.5oc.,Chem. Commun., 1987, 136-7 pp. 58 Cagnon, G. ; Piteau, M. ; Senet,J.-P.SNPE) Ft. 2 482 587 (
Pr.

1990, pp. 1311-19 191,

1149-55

800514)))

178

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59 Olofson, 60 Olofson,
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& AppL

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1988, ), pp. 1715-24 60(11

DE

R.A. ; l'lartz,

J.T.; (SNPE)

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830826 62 HOller, H. ; Liebig's Annalen der Chemie, 1890, pp. S0-6 257, 63 B6hme, H. ; Budde, J.; Synthesis, 1971, 588-9 pp. 64 Barcelo, G. ; Senet,J.-P. Sennyey, G. ; Bensoam, J.; Loffet, ; A. Synthesis, 1986, 627-32 pp. 65 Harfat, A. (Pfizer Inc.) US 4 551452 Pr. 840502 66 Barcelo, G. ; Senet,J.-P. Sennyey, G. ; ./.Org.Chem., 1985, ; SO,pp. 3951-3
67 Jaouadi, H. ; Hartinez, J.; Castro, B.;Barcelo, G. ; Sennyey, G. ; Senet,J.-P. J.Org.Chem., 1987, pp. 2364-7 ; 52, 68 Olofson, R.A. ; Hartz, J.T.; Senet,J.-P. Piteau, H. ; Halfroot, ; T. ; J.Org.Chem., 49, pp. 2081-2 69 Drugs of the Future, ), pp. 16-8 70 Nishimura,T. et al. ; J.Antibiot., 1987, ), pp. 81-90 40(1 71 Drugs of the Future, pp. 13(3), 231-3 72 Drugs of the Future, p. 20(6), 73 Dorn, C.P. (Plerck & Co.,Inc.) EP 82 404 Pr. ; 74 Drugs of the Future, pp. 19(7), 707-8 75 Wada, N.; Yoshida, R. ; (Kumiai Chem. Indust. Co.; Ihara JP Chem. Indust. Co.) 06 565-Pr.910821

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84 Wooden, G.R ; Sennyey, G. ; Senet, J.-P.; ($NPE)

815 Pr. 860711
Pr.

EP

252

85 Plalfroot, T. ; Piteau,

841123

I%

; Senet,J.-R ; ($NPE)

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