Application of an ortho-Formylation

Reaction in One-pot Procedures and

Natural Product Syntheses
Dissertation for the degree of Ph.D.
Hany Fakhry Anwar
Department of Pharmaceutical Chemistry
School of Pharmacy
Faculty of Mathematics and Natural Sciences
University of Oslo
2009






















Hany Fakhry Anwar, 2009


Series of dissertations submitted to the
Faculty of Mathematics and Natural Sciences, University of Oslo
Nr. 864

ISSN 1501-7710


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iii
Acknowledgements
My doctoral studies were carried out at School of Pharmacy, Department of Pharmaceutical
Chemistry, University of Oslo under the supervision of Associate Professor Trond Vidar
Hansen. Financial support from Quota Programme and The Research Council of Norway is
gratefully acknowledged.
It is a pleasure to thank all of you who made this thesis possible.
Firstly, I sincerely thank my supervisor, Associate Professor Trond Vidar Hansen for giving me
the opportunity to start on this interesting project, and for his help, availability, advice, and
guidance during my stay in his research group.
I would like to thank Professor Lars Skattebl for his useful advice, guidance, helpful
discussions, and proof-reading my manuscripts throughout these years.
Also I would like to thank Professor Arne Jrgen Aasen for sharing his knowledge and proof-
reading my thesis.
I am grateful to all members of Trond Vidar Hansens group, the Department of Pharmaceutical
Chemistry, my colleagues, and especially Alexandra Gade and yvind Jacobsen, and also of the
technical staff for social and scientific contribution.
Lastly, I would like to thank my wife, Sylvia Antoun, for her love, encouragement and patience
over these years.
Hany F. Anwar
Oslo, May 2009
iv
Table of Contents
Abstract ........................................................................................................................................... vi
Graphical Abstract ......................................................................................................................... vii
Abbreviations .................................................................................................................................. ix
List of Publications ........................................................................................................................... x
1. INTRODUCTION ............................................................................................................ 1
1.1. Synthesis of Salicylaldehydes ................................................................................................... 1
1.2. Alternative Formylation Methods of Phenols ........................................................................... 8
1.3. Applications of the MgCl
2
-Et
3
N ortho-Formylation Method ................................................. 12
1.4. Other Applications of the MgCl
2
-Et
3
N Base System .............................................................. 14
1.5. Aim of the Study ..................................................................................................................... 15
References ...................................................................................................................................... 16
2. RESULTS AND DISCUSSION ..................................................................................... 19
2.1. Application of the ortho-Formylation Method........................................................................ 19
2.1.1. Synthesis of ortho-Hydroxycinnamate Esters ...................................................................... 19
2.1.2. Synthesis of Substituted Salicylamines ................................................................................ 22
2.1.3. One-pot Synthesis of Substituted Dihydro-2H-1,3-benzoxazines ....................................... 28
2.1.4. Synthesis of Substituted Salicylnitriles ................................................................................ 29
v
2.2. Applications of the ortho-Formylation Method in Natural Product Synthesis ....................... 33
2.2.1. First Total Synthesis of ()-Powelline ................................................................................. 33
2.2.2. First Total Synthesis of a Polyunsaturated Chromone ......................................................... 40
3. SUMMARY ..................................................................................................................... 46
References and Notes ..................................................................................................................... 47
4. APPENDIX ...................................................................................................................... 51
Experimental .................................................................................................................................. 52
List of Errata for Submitted Publications ....................................................................................... 57
Paper I
Paper II
Paper III
Paper IV, Supporting Information
Paper V, Supporting Information
vi
Abstract
This thesis has focused on the Casnati-Skattebl ortho-formylation method by which phenols are
converted to salicylaldehydes using a combination of paraformaldehyde and MgCl
2
-Et
3
N in THF,
and the development of one-pot methods via salicylaldehydes for the synthesis of useful starting
materials: i.e. ortho-hydroxycinnamate esters, salicylamines, and salicylnitriles. The same
method was applied for the synthesis of dihydro-2H-1,3-benzoxazines in a one-pot procedure.
In order to broaden the scope of the MgCl
2
-Et
3
N base system in organic synthesis, phenols were
converted to their magnesium salts with the MgCl
2
-Et
3
N base system and subsequently reacted
with Eschenmosers salt (N,N-dimethylmethylene iminium iodide), affording N,N-dimethyl
substituted benzylamines in 66-98% yields.
The first total synthesis of ()-powelline was reported in 10% overall yield over eight steps. The
key reactions were an ortho-formylation reaction of 2,3-(methylenedioxy)-phenol and an
intramolecular oxidative phenolic coupling reaction.
Finally, the first total synthesis of the marine natural product all-(Z)-5,7-dihydroxy-2-
(4,7,10,13,16-nonadecapentaenyl)chromone has been achieved in six steps and in 14% overall
yield, starting from the ethyl ester of eicosapentaenoic acid.
Additional experimental work, not presented in any of the Papers (I-V), is included as an
Appendix.
vii
Graphical Abstract
Introduction: Synthesis of Salicylaldehydes
One-pot Synthesis of Substituted Ortho-hydroxycinnamate Esters, Salicylamines, Dihydro-
2H-1,3-benzoxazines, and Salicylnitriles
viii
Synthesis of Substituted Salicylamines by the Mannich Reaction
R
OH
R
OH
N
Me
Me
MgCl
2
, Et
3
N
N
Me
Me

First Total Synthesis of ()-Powelline

First Total Synthesis of a Polyunsaturated Chromone Metabolite Isolated from the Brown
Algae Zonaria tournefortii
ix
Abbreviations
aq. aqueous
Boc tert-butoxycarbonyl
decomp. decomposition
DCM dichloromethane
DEPT distortionless enhancement by polarization transfer
DIBALH diisobutylaluminum hydride
DMAP 4-(dimethylamino)pyridine
DMP Dess-Martin periodinane (1,1,1-Tris(acetyloxy)-1,1-dihydro-
1,2-benziodoxol-3-(1H)-one)
dr diastereomeric ratio
equiv. equivalent(s)
HMPA hexamethylphosphoric acid triamide
HMT hexamethylenetetramine
IBX 2-iodoxybenzoic acid
SIBX Stabilized IBX: 2-Iodoxybenzoic acid contains 45 wt. %
benzoic acid and isophthalic acid as stabilizer.
LDA lithium diisopropylamide
MOM methoxymethyl
MVK methyl vinyl ketone
NOE nuclear Overhauser effect
NOESY nuclear Overhauser effect spectroscopy
PIFA [bis(trifluoroacetoxy)iodo]-benzene
ppm parts per million
temp. temperature
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
TMEDA N,N,N`,N`-tetramethyl-1,2-ethylenediamine
TMSOTf trimethylsilyl trifluoromethanesulfonate

reflux/heat
x
List of Publications
This thesis is based on the following papers:
Paper I
One-pot Synthesis of ortho-Hydroxycinnamate Esters. Anwar, H. F.; Skattebl, L.; Skramstad,
J.; Hansen, T. V. Tetrahedron Lett. 2005, 46, 5285-5287.
Paper II
Synthesis of Substituted Salicylamines and Dihydro-2H-1,3-benzoxazines. Anwar, H. F.;
Skattebl, L.; Hansen, T. V. Tetrahedron 2007, 63, 9997-10002.
Paper III
A One-pot Synthesis of Substituted Salicylnitriles. Anwar, H. F.; Hansen, T. V. Tetrahedron
Lett. 2008, 49, 4443-4445.
Paper IV
First Total Synthesis of ()-Powelline. Anwar, H. F.; Hansen, T. V. Synlett 2008, 2681-2683.
Paper V
First Total Synthesis of a Polyunsaturated Chromone Metabolite Isolated from fhe Brown
Algae Zonaria tournefortii. Anwar, H. F.; Hansen, T. V. Org. Lett. 2009, 11, 587-588.
1
1. INTRODUCTION
1.1 Synthesis of Salicylaldehydes
Salicylaldehydes are excellent precursors for the preparation of important classes of organic
compounds such as oxygen-containing heterocyclic compounds,
1,2
cinnamic acid
derivatives,
3
salen derivatives,
4
and useful industrial metal extractants.
5
Formylation of aromatic compounds for the synthesis of salicylaldehydes is an important
classical reaction in organic chemistry, and numerous methods are available.
6,7
Salicylaldehydes are accessible from the corresponding phenols by several of these classical
formylation reactions (Figure 1.1). However, for many of these reactions, the yields of
salicylaldehydes are often only moderate and the lack of regioselectivity is problematic.
8
Moreover, the reaction conditions are quite harsh, involve safety problems at a large scale,
and employ environmentally harmful reagents.

Over the years, many of the formylation methods depicted in Figure 1.1 have been
improved. For instance, the Gattermann-Koch reaction has been improved by using
CO/HF/BF
3
to give para-selectivity.
9,10
The Reimer-Tiemann reaction has also been
2
modified to give ortho-selective formylations of phenols by using H
2
O:EtOH (9:1) as a
solvent.
11
Highly selective para-hydroxybenzaldehydes were obtained with the same
reaction by using -cyclodextrin derivatives.
12
In the Reimer-Tiemann reaction,
trichloroacetaldehyde (chloral)
13
and trichloroacetic acid
14
have replaced chloroform.
The Duff reaction
15
is a formylation method for electron-rich phenols using
hexamethylenetetramine (HMT, 2) as the formylating agent in the presence of glycerol and
boric acid. The reaction is followed by an aqueous workup to give salicylaldehydes usually
in low yields (Scheme 1.1).
16
Suzuki and Takahashi modified the Duff reaction by using strong acids, such as
methanesulfonic-, trifluoroacetic-, or polyphosphoric acid as solvent. This modification has
successfully formylated many electron-deficient phenols which were unreactive under the
classical Duff conditions (Scheme 1.2).
17

Another adaptation of the Duff reaction has been applied for the preparation of 3,5-
difluorosalicylaldehyde and 5-bromo-3-fluorosalicylaldehyde under mild conditions when
using trifluoroacetic acid as solvent. The phenols were converted to imine products by HMT
and trifluoroacetic acid. Then the imine products were hydrolyzed to aldehydes in 79% and
3
78% yields,
18
respectively. This reaction was also applied in the preparation of 3,5-di-tert-
butyl-4-hydroxybenzaldehyde from 2,6-di-tert-butylphenol in 60% yield.
19
Phenol can be ortho-formylated by formaldehyde in the presence of one of several metal
salt catalysts (e.g. Ti, Zr, Al, Cr, and Fe), but these reactions require high pressure and are
unattractive for industrial processes.
20
Another method that employs paraformaldehyde as the formylating reagent is the
combination of tin tetrachloride and tributylamine which produce salicylaldehydes with
high selectivity.
21
This reaction has also been carried out in the presence of 2,6-
dimethylpyridine instead of tributylamine (Scheme 1.3).
22

A widely used industrial process for the production of salicylaldehydes was the base-
catalyzed reaction of formaldehyde with phenol (1a) affording a mixture of the
hydroxybenzyl alcohols 6 and 7. The alcohols were subsequently oxidized by an oxidizing
agent, in the presence of metal catalyst, e.g. palladium, silver, or platinum, to produce the
hydroxybenzaldehydes 3a and 8a (Scheme 1.4).
23
Selective ortho-formylation of para-substituted phenols 4 has been achieved with the
sulfonium salt 9, which was formed by the reaction of N-chlorosuccinimide and dithiane. In
4
the presence of triethylamine at -70
o
C, dithiane 13 was obtained. After hydrolysis,
salicylaldehydes 5 were obtained in 20-35% yield over the two steps (Scheme 1.5).
24
Reaction of phenol 1d with oxalyl chloride and 4-(N,N-dimethylamino)-pyridine as a
catalyst gave the phenoxyoxalyl chloride, which by ring closure with aluminium chloride
afforded 2,3-dioxo-benzofurans 14. Reduction with lithium aluminium hydride yielded 2-
(1`,2`-dihydroxyethyl)-phenol 15, that was finally oxidized with potassium metaperiodate to
afford the ortho-hydroxybenzaldehyde derivative 3d. The overall yield of the three step
synthesis was 54% (Scheme 1.6).
25
Unfortunately, all these reactions are hampered by one or more of the following
disadvantages: the use of large amounts of Lewis acids, hazardous reagents, difficult
separations of isomers, and multistage synthesis. Today, there is a general need for more
environmentally friendly synthetic methods.
26
5
In 1965 Casnati et al. used phenoxymagnesium bromide 16 and excess triethyl orthoformate
as a formylation agent to obtain the corresponding salicylaldehyde 3b without any detection
of the para-isomer (Scheme 1.7).
27
Some years later, Casnati and co-workers reported that the reaction of paraformaldehyde
and magnesium phenoxides 16, formed from the respective phenol and ethyl magnesium
bromide solvated in benzene and in the presence of stoichiometric amounts of
hexamethylphosphoric acid triamide (HMPA), resulted in monoformylation exclusively at
the ortho position in 23-90% yields. However, by-products such as methylenediphenol and
2,6-bis(o-hydroxybenzyl)phenol were formed in most of the reactions (Scheme 1.8).
28,29
No
formylation was observed by the Casnati method using phenols substituted with electron
withdrawing groups like NO
2
, COMe, and CO
2
Me.
27,28
A modification of the original Casnati ortho-formylation method was reported in 1994
when triethylamine was used instead of the carcinogenic metal complexing agent HMPA.
Salicylaldehydes 3 were obtained in good yields (Scheme 1.9).
30
6
Aldred et al. reported in 1994 a modification of the Casnati method.
31
First, they reacted
phenol with magnesium dimethoxide to obtain bis(phenoxide) intermediates 17 using
methanol as a cosolvent instead of HMPA. The free methanol was removed by distillation
with the addition of toluene. The ortho-formylation proceeded by the addition of
paraformaldehyde which afforded salicylaldehyde magnesium salts 18. The
salicylaldehydes 3 were obtained from their magnesium salts by acidic work-up (Scheme
1.10).
Salicylaldehydes 5 were prepared with high selectivity by the reaction of phenols 4 with
Grignard reagent EtMgX (X = Cl, Br) and paraformaldehyde in the presence of
triphenylphosphine oxide with yields ranging from 51-78% (Scheme 1.11).
32
Triphenylphosphine oxide was also replaced with either DMSO or N-methylpiperidine.
33
7
In 1999 Hofslkken and Skattebl used a combination of MgCl
2
-Et
3
N as a base and
acetonitrile or tetrahydrofuran (THF) as a solvent in order to improve Casnatis method.
This base system gives higher yields, fewer by-products, and the use of HMPA becomes
superfluous.
34
This reaction was later optimized by Hansen and Skattebl by reducing the
number of equivalents of magnesium dichloride, triethylamine, and paraformaldehyde to 2,
2, and 3, respectively. Salicylaldehydes 3 are easily obtained in good to excellent yields (70-
99%, Scheme 1.12). This method also works well with methyl-4-hydroxybenzoate (88%
yield), but unfortunately only poor yields were obtained using phenols substituted with
electron withdrawing groups (CN and NO
2
).
35
A plausible mechanism for the ortho-formylation of phenols 1, via phenoxymagnesium
chloride 19, obtained from the reaction of the phenol with magnesium dichloride and
triethylamine is proposed below (Figure 1.2). The intermediate A reacts with
paraformaldehyde through the cyclohexadienone structure B to give the magnesium salt of
salicyl alcohol C. This intermediate subsequently reacts with another equivalent of
formaldehyde, forming salicylaldehydes 3 and methanol.
34
8
1.2 Alternative Formylation Methods of Phenols
Condensation of phenol 1 (R = OMe) with glyoxylic acid in basic media gave substituted
mandelic acid 20, which on oxidative decarboxylation yielded the corresponding para-
hydroxyaldehyde 8 (vanillin) as major product together with ortho-hydroxy and di-
hydroxyaldehyde as by-products.
36
This method was applied to prepare ethyl vanillin (R =
OEt) in 100% yield by using NaOH and CuSO
4
followed by hydrolysis H
2
SO
4
-H
2
O
(Scheme 1.13).
37
Methyl formate can be used as the formylating agent of phenols in the presence of a mixture
of hydrogen fluoride and boron trifluoride to convert the phenols to the corresponding
aldehydes.
38
However, this method mostly leads to product mixtures and requires a large
excess of boron trifluoride.
9
The formylation of phenols with 1,1-dichloromethoxymethane (MeOCHCl
2
) and aluminum
trichloride or titanium tetrachloride proceeded with poor yields of aldehydes and also with
low selectivity.
39
Salicylaldehydes 3 were prepared via the ortho-lithio derivatives of methoxymethyl-
protected phenols 21 in a three-step protocol. First by the preparation of the phenyl ether 21,
second by a combined ortho-lithiation and formylation step, and finally by the cleavage of
the ether linkage of compounds 23. Overall yields ranged from 53-68% (Scheme 1.14).
40
Alternatively, a two-step protocol for the ortho-specific formylation of phenols exists via
directed ortho-lithiation of ortho-aryl N-isopropylcarbamates 24, which are obtained from
the corresponding phenols and isopropyl isocyanate. After a DMF quench of the
intermediate aryllithium 25 and basic work-up, the corresponding salicylaldehydes 3 were
obtained in 85-93% yields. However, no yields were reported for the protection step
(Scheme 1.15).
41
10
Hydroxymethylation of the borate ester 27 with paraformaldehyde followed by hydrolysis
with NaOH yielded 2-hydroxybenzyl alcohol (6). Oxidization by oxygen with 10%
platinum on carbon catalyst (or palladium) in aqueous NaOH yielded 60.5% of
salicylaldehyde 3a (Scheme 1.16).
42,43
5-Fluorosalicylaldehyde (5c) has been prepared from 4-fluorophenol (4c) in four steps in
order to make 5-fluorosalicylic acid, an important derivative that has anti-inflammatory and
other biological activity.
44
The procedure started with reductive amination of 4c using
HCHO-Me
2
NH to give the amino derivative 28a and bis-diamino derivative 28b as a 6:1
mixture, which was converted with excess Ac
2
O to the corresponding acetates 29a and 29b
as by-product. The major component was isolated and deacetylated with aqueous KOH in
ethanol, followed by KMnO
4
oxidation of the resulting hydroxybenzyl alcohol 30, to give
the salicylaldehyde 5c (Scheme 1.17).
45
Recently, Sartori and co-workers
46
synthesised substituted salicylaldehydes in good yields
(60-63%) and excellent selectivity (89-92%) from alkyl substituted phenols and
formaldehyde using montmorillonite KSF-Et
3
N as a heterogeneous catalyst (Scheme 1.18).
Unfortunately, recycling of the montmorillonite was problematic, as one additional cycle
11
yielded only 36% of the product. Moreover, four equivalents of formaldehyde were
employed.
Salicylaldehydes 33a-c can be obtained by the Fries reaction, in which aryl formates 32a-c
are rearranged in the presence of a Lewis acid to give hydroxyaromatic aldehydes.
47
The
yields in this reaction depend on the reaction conditions, e.g. temperature, solvent, the
Lewis acid catalyst used, and the position of the substituent. Aryl formates 32a-c were
prepared by the formylation of hydroxyarenes 31a-c with N,N-diformylacetamide or N,N-
diformylformamide in good yields (Scheme 1.19).
Fries rearrangement of the formyl group can also be induced by trifluoromethanesulfonic
acid, but in this case a mixture of regioisomeric aldehydes 33a, 34 and the deformylated
product 31a was formed in a 1: 1: 2 ratio, respectively (Scheme 1.19).
48

The Fries reaction can also be performed photochemically and the rearrangement of a
formyl group under such conditions has been observed. When 4-tert-butylphenyl formate
12
(35) was irradiated for 39 hours in benzene, 5-tert butyl-2-hydroxybenzaldehyde (5h) could
be isolated in 7% yield (Scheme 1.20).
49
OCHO
W-Bu
OH
W-Bu
CHO
h , 39 h
(7%)
OH
W-Bu
N(CHO)
3
(HCO)
2
NNa
(83%)
4h 35 5h
Scheme 1.20
1.3 Applications of the MgCl
2
-Et
3
N ortho-Formylation Method
Phenols 1 have been converted to salicylaldehydes 3 by ortho-formylation using MgCl
2
-
Et
3
N and (CH
2
O)
n
in THF and subsequently treated with aqueous NaOH/H
2
O
2
(Dakin
oxidation), affording the corresponding catechols 36 in a one-pot procedure (Scheme
1.21).
50
This method was used to develop a facile synthesis of combretastatins A-1 (42) and B-1
(43). The natural products were obtained by coupling MOM-protected iodomethoxycatechol
40 with 3,4,5-trimethoxyphenylacetylene (41) in a Sonogashira reaction followed by
reduction (Scheme 1.22).
51
13
Another application of the ortho-formylation method was accomplished by converting the
phenols 44 to salicylaldehydes 45, which subsequently were treated with (+)-(R,R)-1,2-
diammoniumcyclohexane mono-(+)-tartrate salt 46 affording the corresponding salen
ligands 47 in high yields. The reactions were conveniently carried out as a one-pot
procedure (Scheme 1.23).
52
This method afforded the salen ligands in more than twice the
yields previously reported by Jacobsen and co-workers.
16b
14
1.4 Other Applications of the MgCl
2
-Et
3
N Base System
The combination of MgCl
2
and Et
3
N is a useful base system in organic synthesis. This
combination is a considerably stronger base than Et
3
N alone and has been used in different
base induced reactions.
53
-Carboxylation of ketones 48 with carbon dioxide in the presence of MgCl
2
-Et
3
N,
followed by reaction with methyl vinyl ketone (MVK), gives the Michael adducts 51 in 42-
75% yields or the Robinson adducts 52 in 56-75% yields. This method reduced the
polymerization of MVK under strongly basic conditions (Scheme 1.24).
54

O O
O
O
Mg
O O
MgCl
2
-Et
3
N
CO
2
, CH
3
CN
MVK, EtOH
H
+
O
O
O

COO
-
Scheme 1.24
48 49 50 51
52
Acylation of diethyl malonate 53 with an acid chloride using MgCl
2
-Et
3
N as base system
gives adducts 54 in excellent yields (Scheme 1.25).
55
This method was also used for
preparation of -oxo esters from ethyl malonate mono potassium salt and acid chlorides in
92-99% yields.
56
In 2002 Evans et al.
57
used MgCl
2
-Et
3
N in anti-aldol reactions of chiral N-
acyloxazolidinones 55a-d in the presence of chlorotrimethylsilane. The adducts 56a-d were
formed with high diastereoselectivity (up to 32:1 dr) (Scheme 1.26).
15
Stereoselective imine aldol reactions of N-cyclohexylimine 57 with aromatic aldehydes in
the presence of MgCl
2
-Et
3
N at -45
o
C were examined recently by Hayashi et al.;
58
high
yields of products were obtained consisting essentially of the erythro isomer (Scheme 1.27).
1.5 Aim of the Study
The overall aim of this study was to employ the ortho-formylation method reported by
Skattebl and co-workers
34,35
for synthesis of natural products and compounds of medicinal
interest.
Also, the environmentally benign conditions in the Casnati-Skattebl
27,28,34,35
ortho-
formylation reaction inspired us to develop one-pot methods for the synthesis of useful
starting materials like ortho-hydroxycinnamate esters, salicylamines, and salicylnitriles.
Natural products have played an eminent role in the discovery and development of new
drugs. Over half of the nearly 1000 small-molecule drugs introduced on the market over the
past two-three decades are either natural products or in some way related to natural
products.
59
Hence, it is still of great interest to synthesize natural products and submit them
to biological testing.
16
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19. Smith, W. E. J. Org. Chem., 1972, 37, 3972.
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77279, 1983; (c) Virnig, M. J. Eur. Pat. Appl. EP 106653, 1984.
21. Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J. Chem. Soc., Perkin Trans. 1,
1980, 1862.
22. Sun, Y.; Tang, N. J. Mol. Catal. A: Chem., 2006, 255, 171.
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23. (a) Bauer, K.; Moelleken, R.; Fiege, H.; Wedemeyer, K. Ger. Offen. US 4119671, 1977; (b)
Hormel, T. S.; Kirchhoff, P. M.; Muench, W. C.; Robbins, L. A. U.S. Pat. US 4205188, 1980; (c)
Gradeff, P. S.; Murayama, S. T. U.S. Pat. US 4351962, 1982.
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D. R. Tetrahedron Lett., 1974, 15, 889.
25. Zwanenburg, D. J.; Reynen, W. A. P. Synthesis, 1976, 624.
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Oxford, 2000; pp 7182.
27. Casnati, G.; Crisafulli, M.; Ricca, A. Tetrahedron Lett., 1965, 6, 243.
28. Casiraghi, G.; Casnati, G.; Cornia, M.; Pochini, A.; Puglia, G.; Sartori, G.; Ungaro, R. J. Chem.
Soc., Perkin Trans 1, 1978, 318.
29. Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org. Chem., 1993, 58, 1515.
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JP 06056732, 1994.
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Chem. Soc., 1998, 120, 3332.
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38. Crochemore, M.; Rochin, C. Eur. Pat. Appl. EP 300861, 1989.
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40. Christensen, H. Synth. Commun., 1975, 5, 65.
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18

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19
2. RESULTS AND DISCUSSION
2.1 Application of the ortho-Formylation Method
2.1.1 Synthesis of ortho-Hydroxycinnamate Esters
The aim of this study was to develop a simple and efficient procedure for the synthesis of
cinnamic esters. Cinnamic esters and their derivatives are useful intermediates for the
synthesis of heterocyclic compounds
1
and they are also used as antioxidants.
2
One of the
most common procedures for the preparation of cinnamic esters is the Perkin reaction. In
this reaction, the respective aldehyde reacts with acetic anhydride and anhydrous sodium- or
potassium acetate, yielding an ,-unsaturated acid. Esterification with an alcohol affords
the corresponding cinnamate ester (Scheme 2.1).
3
However, the Perkin reaction is often
hampered by low yields,
4
especially for the preparation of ortho-hydroxycinnamate esters
from salicylaldehydes.
5
,-Unsaturated esters are readily available using the Wittig reaction between an aldehyde
and an ylide (Scheme 2.2).
6
20
The ortho-formylation of phenols (as mentioned in the introduction) to salicylaldehydes
was described by Skattebl et al.
7a,b
by heating a mixture of the phenol, anhydrous MgCl
2
,
triethylamine, and paraformaldehyde in refluxing THF. Different alkyl- and halogen-
substituted phenols afford excellent yields of the corresponding salicylaldehydes.
Since phenols are inexpensive and readily available, we wanted to use the Casnati-
Skattebl
7
ortho-formylation method to prepare ortho-hydroxycinnamate esters. Hansen
and Skattebl tried the Perkin reaction by a one-pot procedure but this protocol failed.
8
However, the Wittig reaction was successful. After the phenols were converted to
salicylaldehydes, a solution of methyl (triphenylphosphoranylidene)acetate in
dichloromethane was added dropwise. After stirring 48 hours at ambient temperature
conversion was completed (Scheme 2.3).
This reaction was carried out with both 2- and 4-halogen-substituted phenols as starting
materials and the corresponding cinnamates were obtained in 60-78% yields (Table 2.1).
Moreover, this one-pot process, with two or more transformations, offers a number of
advantages. In particular, the direct transformation of intermediates to the desired products
reduces the time normally spent on isolation and purification.
New compounds were characterized on the basis of spectral data. The (E)-configuration
which is normally observed for this type of Wittig reactions was established by
1
H NMR
spectroscopy displaying trans-coupling constants in the range J = 15.8-16.2 Hz (Paper I).
21
Table 2.1. One-pot synthesis of ortho-hydroxycinnamate esters.
In the case of alkyl (R = Me, t-Bu) and phenoxy-substituted phenols, the reactions did not
go to completion even after stirring at room temperature for 21 hours. However, after
heating for 210 hours at gentle reflux, complete conversion was observed. The methyl
ortho-hydroxycinnamates 68, 69, and 70 were accompanied by minor amounts of the
Phenol Product Overall
yield %
74
73
61
63
78
66
65
60
Compounds 60 and 66 are known; for references
see the Appendix.
22
corresponding coumarins 71, 72, and 73, respectively (Table 2.2). We anticipate that the
ortho-hydroxycinnamate esters, upon heating isomerize to the (Z)-isomers which cyclize to
the coumarins.
Table 2.2 One-pot synthesis of ortho-hydroxycinnamate esters.
2.1.2 Synthesis of Substituted Salicylamines
Salicylamines and their derivatives are useful intermediates for the synthesis of heterocyclic
compounds, such as benzoxazines,
9
benz[1,2,3]oxathiazine 2-oxides,
10
and benz[1,3]oxazin-
2-ones.
11
Some salicylamines were tested as potential metal complexing agents including
metal ions extractants.
12
They were also tested as catalyst components in organic
synthesis.
13
Some salicylamines possess antimalarial and antimicrobial activity.
14
Aminomethylation of phenols is traditionally achieved with formaldehyde and amines under
acidic conditions using the Mannich reaction,
15,16
which occurs readily in ortho- and para-
positions affording polysubstituted phenols.
17
The position and nature of the substituents as
well as the reaction conditions play an important role on the orientation of the Mannich
reaction (Scheme 2.4).
18
Phenol Product (Overall yield %)
Compounds 68, 69, and 71 are known; for references
see the Appendix.
23
OH
N
R
3
R
2
OH
N
R
3
R
2
N
R
3
R
2
OH
N
R
3
R
2
OH
N
R
3
R
2
R
4
OH
R
4
CH
2
O, NHR
2
R
3
R
1
R
1
OH
CH
2
O, NHR
2
R
3
R
2
= R
3
= Me or Et
Scheme 2.4 Synthesis oI substituted salicylamines employing the Mannich reaction
1 74 75
76
77 78

R
1
R
1
R
1 R
1
When 2-chlorophenol (1c) was treated with 37% aqueous formaldehyde and 2-bromoaniline
at room temperature, <10% yield of the Mannich product was obtained together with
polymeric material.
19
Pochini et al. reported that phenols 1a-d reacted with Eschenmosers salt (N,N-
dimethylmethylene iminium iodide) in the presence of potassium carbonate affording
exclusively ortho-substituted products 79-82 in yields ranging from 75-98% (Scheme 2.5).
20
Recently, Ley and co-workers reported one example of a carbonate exchange resin
catalyzed reaction between 2-allylphenol (1h) and Eschenmosers salt giving 2-allyl-6-
((dimethylamino)-methyl)phenol (84) in excellent yield. This method avoids distillation or
recrystallization (Scheme 2.6).
21

24
Eschenmosers salt is commercially available, but can be prepared from N,N,N',N'-
tetramethylmethylenediamine with CH
2
ClI or CH
2
I
2
in DMSO at ambient temperature.
22
We decided to use the combination of MgCl
2
-Et
3
N as the base system in the Mannich
reaction. Eschenmosers salt was added to a mixture of MgCl
2
-Et
3
N and 2-methylphenol
(1b) in dichloromethane. After stirring for 3 hours at ambient temperature, complete
conversion of the phenol was observed, and only one regioisomer of the Mannich base 80
was isolated in 82% yield (Scheme 2.7 and Table 2.3). Several other 2-substituted phenols
were subjected to the same conditions and the corresponding Mannich bases 81-88 were
obtained in 66-83% yields. An almost quantitative yield of the product 90 was obtained
when -naphthol (89) was subjected to these reaction conditions. According to the
1
H NMR
spectra of the crude reaction mixtures, complete regioselectivity was observed in all cases.
The products were identified by physical and spectral data (Paper II).
Mannich bases are versatile intermediates for the synthesis of a wide range of biologically
active compounds, and our protocol compares favorably with others when considering
yields, regioselectivity, and simplicity.
23
25
Table 2.3 Synthesis of substituted N,N-dimethylsalicylamines by Mannich reaction
Then we tried another iminium salt
24
under the same reaction conditions, but this was
unsuccessful. Since few other methods for the synthesis of salicylamines have been
reported,
25
facile and efficient procedures for the synthesis of mono N-substituted
salicylamines are still desirable. We turned our attention to the synthesis of N-substituted
salicylamines by a simple and regioselective method (Scheme 2.8).
26

Phenol Product Overall
yield %
Time (h)
/solvent
82
5/toluene
77
3/CH2Cl2
82
8/CH2Cl2
83
3/CH2Cl2
79
2/CH2Cl2
66
12/CH2Cl2
98
0.5/CH2Cl2
Compounds 80, 81, and 90 are known; for references see the
Appendix.
26
As previously described, the salicylaldehydes were prepared from phenols 1 and 4 by our
ortho-formylation method.
7a
A solution of an amine followed by addition of NaBH
4
was
then added in a one-pot procedure. After heating to reflux for 30 minutes and further stirring
the reaction mixture for another 210 hours at room temperature, the reaction mixture was
worked up in the usual manner. When necessary, the products 97-112 were purified by
column chromatography and characterized by physical and spectral data. This one-pot
procedure combining formylation and reductive amination was carried out with both alkyl
and halogen substituted phenols as starting materials, and the overall yields ranged from 51-
74% (Scheme 2.8 and Table 2.4).
Table 2.4 Syntheses of mono N-substituted salicylamines
Phenol Amine Product
Overall
yield %
NH
2
Br
91
51
OH
Br
1f
56
57
58
27
68
61
55
NH
2
OEt
94
56
61
51
64
63
NH
2
Br
91
74
28
73
66
69
Compounds 109 and 111 are known; for references see the Appendix.
2.1.3 One-pot Synthesis of Substituted Dihydro-2H-1,3-benzoxazines
The aforementioned protocol for the preparation of dihydro-2H-1,3-benzoxazines was
investigated further. The solution of mono N-substituted benzylamine was treated with two
equivalents of paraformaldehyde which gave, after purification, substituted dihydro-2H-1,3-
benzoxazines 113-116 in 38-53% isolated yields in a one-pot sequence (Scheme 2.9).
Benzoxazines have previously been reported to exhibit a wide range of interesting
biological activities.
27
The operational simplicity of this method makes it attractive for
preparative use as well as for the synthesis of screening libraries for drug discovery.
29
2.1.4 Synthesis of Substituted Salicylnitriles
The aim of this study was to convert phenols to substituted salicylnitriles by a mild and
reliable method.
Aromatic nitriles can be prepared by the Rosenmund-von Braun reaction
28,29
using metal-
mediated displacement of aromatic halides by cyanide ion (Scheme 2.10). These
compounds are versatile starting materials for amides, amines, esters, carboxylic acids, etc.,
as well as for the synthesis of heterocyclic and biologically active compounds.
30
The
disadvantage of this method is the use of toxic cyanide salts and high temperatures (>150-
160 C), which are not suitable for industrial applications. Hence, it is not surprising that
only few examples of the preparation of substituted salicylnitriles have been reported using
the Rosenmund-von Braun reaction.
31
There are few other methods to convert phenol (1a) to salicylnitrile (117, 2-
hydroxybenzonitrile) (Scheme 2.11);
32
however, several methods are known for the
transformation of salicylaldehyde to salicylnitrile via dehydration of aldoximes
33
or by
using reagents such as sodium bis(trimethylsilyl)amide,
34
aqueous ammonia/sodium
dichloroiodate,
35
and 1,1-dimethylhydrazine/dimethyl sulphate in the presence of K
2
CO
3
.
36
Recently, hypervalent iodine reagents such as 2-iodoxybenzoic acid (IBX) and Dess-Martin
periodinane (DMP) have attracted interest as oxidation agents.
37
These reagents are
commercially available or can be prepared from 2-iodobenzoic acid (Scheme 2.12).
38
30
The oxidation of imines to nitriles using IBX in aqueous ammonia was recently reported by
Akamanchi and co-workers (Scheme 2.13).
39
O

O
OH
R-CHO RCH=NH R-CN
Scheme 2.13
BX
NH
3
We decided to adapt this method for the synthesis of substituted salicylnitriles from
phenols. A complete regioselective introduction of the nitrile group, via oxidation of imine
intermediates from salicylaldehydes, was expected to give the desired salicylnitriles.
Furthermore, few substituted salicylnitriles are commercially available.
Salicylaldehydes were formed by the ortho-formylation of the corresponding phenols as
previously discussed, and subsequent treatment with aqueous ammonia afforded the
corresponding salicylimines. The imines were then oxidized with 1.2 equivalents of IBX
(SIBX) to salicylnitriles in a one-pot operation (Scheme 2.14).
2-Alkyl and 2-halogen substituted phenols 1b-f, h were subjected to this protocol, affording
the corresponding salicylnitriles 119-124 in 48-71% isolated yields over three steps. As
expected, the reaction of 4-substituted phenols 4c, h, j, l furnished the 5-substituted
31
salicylnitriles 125-128 in comparable yields. Similarly, 2,4-di-substituted phenol 44a gave
129 in 56% yield. (Table 2.5).
Table 2.5. One-pot synthesis of substituted salicylnitriles.
Compound 124 was useful for the synthesis of a benzofuran derivative as described by
Sekizaki et al.
40
Moreover, 2,3-(methylenedioxy)-phenol (118) was converted in 58% yield
to the corresponding salicylnitrile 130, which may be of interest as a starting material for
Phenol Product
Overall
yield %
Phenol Product
Overall
yield %
62
67
70
67
OH
W-Bu
1d
OH
W-Bu CN
121
71
54
48
70
55
56
53
58
Compounds 119, 120, 123, 124, 128, and 129 are known; for references see the Appendix.
32
the syntheses of some highly oxygenated natural products such as powelline, narciclasine
and pancratistatin (Figure 2.1).
41,42
As expected complete regioselectivity was observed in all cases. All products were
identified and characterized by physical and spectral data.
Starting from 2-chlorophenol (1c) we also tried to use DMP as the oxidant but the yield was
lower than with IBX under same reaction conditions (Scheme 2.15).
These results have been summarized in Paper I, II, and III.
33
2.2 Applications of the ortho-Formylation Method in Natural Product Synthesis
2.2.1 First Total Synthesis of ()-Powelline
The aim of this study was to achieve an efficient total synthesis of ()-powelline 132, a
natural product not previously synthesized.
The 2,3,4,4a-tetrahydro-1H,6H-5,10b-ethanophenanthridine (cis-3a-aryloctahydroindole
nucleus) skeleton characterizes the crinine sub-class of Amaryllidaceae alkaloids such as
crinine (131), powelline (132), crinamidine (133), and undulatine (134) (Figure 2.2).
43

(+)-Powelline 132 has been isolated from several Amaryllidaceae species like Crinum
bulbispermum
44
and Crinum moorei.
45
Several members in this class of alkaloids display interesting biological properties such as
acetylcholinesterase inhibition,
46
cytotoxicity,
47
and antimalarial
48
effects. Due to their
interesting structures, limited supply, and their bioactivities, these natural products
constitute obvious targets for total synthesis.
49
Our strategy was dependent on an intramolecular phenolic coupling reaction and an
intramolecular Michael addition as key steps (Figure 2.3).
34
We started our synthesis of this alkaloid with ortho-formylation of 2,3-
methylenedioxyphenol (118). The salicylaldehyde was, without isolation, treated with
tyramine (137) and NaBH
4
in a one-pot reaction as previously described
50
to yield the
secondary amine 138. Monoprotection of the amine group with TFA-anhydride and DMAP
as a base afforded 139. The attempted intramolecular phenolic coupling of 139 using the
hypervalent iodine reagent [bis(trifluoroacetoxy)iodo]-benzene (PIFA) in trifluoroethanol
failed to give compound 140. However, compound 141 has previously successfully
synthesized by Kodama et al. in 74% yield under the same reaction conditions.
51
Hence, we
decided to protect the methylenedioxyphenol hydroxyl group before performing the
intramolecular phenolic coupling reaction (Scheme 2.16).
35
Our new approach started with the preparation of salicylaldehyde 142 in 96% yield.
Protection of the hydroxyl group with MeI and K
2
CO
3
afforded 143 in 96% yield, followed
by reductive amination with tyramine (137) to the amine 136 in 82% yield (Scheme 2.17).
Although we no longer have our one-pot procedure we prepared 2-methoxy-3,4-
methylenedioxybenzaldehyde (143, croweacin aldehyde), which has been used as a key
intermediate for the syntheses of a variety of natural products (Figure 2.4).
52
It was first
obtained as an oxidative degradation product of 1-allyl-2-methoxy-3,4-
methylenedioxybenzene (144, croweacin), which occurs in the essential oil separated from
the leaves and terminal branchlets of Eriostemon crowei. At the same time, 143 was
synthesized from 7,8-dihydroxycoumarin (146, daphnetin).
53
Since then, croweacin
aldehyde (143) has been obtained by several routes. Apparently, the Vilsmeier formylation
of 148 is the best method reported in the literature, although the product was contaminated
by its regioisomer 149 (10-35%) (Scheme 2.18).
52c,54
We have developed a mild and reliable
method to synthesize 143 with excellent yield (92%) over two steps from 118, and with
complete regioselectivity using the Casnati-Skattebl ortho-formylation method.
7
36
Scheme 2.18
O
O
OMe
CHO
O
O
OMe
O
O
OMe
Me
OH
OH
O
O
HO
HO
OMe
O
O
COOH
144 Croweacin
146 Daphnetin
NaOH, Me
2
SO
4
O
3
[O]
KMnO
4
/Me
2
CO
Pb(OAc)
4
/AcOH
O
O
OMe
CHO
O
O
OMe
DMF/POCl
3
or PhN(Me)CHO/
POCl
3
+
145 143
147
143
148
149
(12-54%)
(10-35%)
The next step was monoprotection of the amine function in 136 with TFA-anhydride using
DMAP as a base in dichloromethane to afford 150. Reaction of the protected amine with the
hypervalent iodine reagent [bis(trifluoroacetoxy)iodo]-benzene (PIFA) in trifluoroethanol
gave compound 151 in 46% yield over the two steps (Scheme 2.19).
37
The intramolecular Michael cyclization reaction of compound 151 was achieved with
aqueous potassium hydroxide affording racemic oxopowelline 152. Subsequent Luche
reduction
55,56
using NaBH
4
and CeCl
3
gave alcohol 153 in 60% yield over the two steps
(Scheme 2.20). A NOE effect was observed between protons H-4a (3.02 ppm) and H-3
(4.16 ppm), confirming the relative stereochemistry depicted for compound 153 (Figure 2.5
and 2.6).
38
Figure 2.6. NOESY experiment of compound 153. The spectrum was recorded on a Bruker
Avance DPX- 600 MHz
Finally, Mitsunobu inversion
57
of the C-3 hydroxyl group yielded racemic powelline 132 in
50% yield with spectral data in accord with those previously reported
58,44
(Scheme 2.21).
39
Next, we tried reducing oxopowelline 152 to powelline 132 by an asymmetric reduction of
the carbonyl group. However, using both CBS catalysts ((R)-2-methyl-CBS-
oxazaborolidine and (S)-2-methyl-CBS-oxazaborolidine) and 2-(3-nitrophenyl)-1,3,2-
dioxaborolane-4S,5S-dicarboxylic acid failed to give the correct configuration of powelline,
instead complex diastereomeric mixtures of epipowelline and powelline were obtained.
Future work in our group includes total syntheses of crinamidine (133), undulatine (134),
and buphanidrine (154) from the common intermediate 152, as well as developing
asymmetric syntheses of the alkaloids 132, 133, 134, and 154 (Figure 2.7).
These results have been summarized in Paper IV and the experimental procedures, physical
data, and spectroscopic data have been presented in the Appendix.
40
2.2.2 First Total Synthesis of a Polyunsaturated Chromone
The aim of this study was to develop an efficient total synthesis of all-(Z)-5,7-dihydroxy-2-
(4,7,10,13,16-nonadecapentaenyl)chromone (155). To the best of our knowledge, no total
synthesis has previously been reported for this natural product (Figure 2.8).
Marine organisms have proven to be a rich source of biologically interesting secondary
metabolites.
59,60
The isolation and structural elucidation of dihydroxychromone 155 from
the pacific brown algae Zonaria tournefortii was reported in 1982 by Plattelli and Tringali
61
Later, this natural product was also isolated from two other Zonaria species.
62
Compound 155 contains the same number of methylene interrupted cis double bonds as
those present in eicosapentaenoic acid (156, EPA), which is a polyunsaturated fatty acid of
the -3 family found in fish oil (Figure 2.9).
Our retrosynthetic analysis lead to EPA and a protected phloroglucinol aldehyde as starting
materials (Figure 2.10).
A substantial amount of pharmacological and clinical data accumulated in the last 15-20
years indicates a wide spectrum of biological effects of EPA;
63
the chromone 155 may be
regarded as an analogue. Hence, it would be of interest to develop a total synthesis of 155 to
obtain sufficient material for biological testing.
41

Our synthesis of 155 started with the preparation of aldehyde 162 in 97% yield as
previously described.
64
The aldehyde was transformed to the terminal alkyne 159 by either a
Colvin rearrangement
65
(58% yield) or by the Corey-Fuchs reaction
66
(52% yield) (Scheme
2.22).
42
CO
2
Et CHO
161 162
159
DBAL-H,
toluene, -78
o
C
LDA, TMSCHN
2
,THF,
-78
o
C, (58%)
(97%)
Scheme 2.22
Br
Br
CBr
4
, PPh
3
,
Zn,CH
2
Cl
2
, r.t.
(82%)
MeLi, ether,
-78
o
C (63%)
163
The reaction of the lithium carbanion of 159 at -78
o
C with a THF solution of 2,4,6-
trimethoxybenzaldehyde (164) yielded the acetylene 165. Oxidation of 165 with MnO
2
afforded ketone 166 (Scheme 2.23).
OMe
OH
MeO
OMe
OMe
O
MeO
OMe
OMe
O
MeO
OMe
159 164
Q-BuLi (1.1 equiv)
THF, -78
o
C - r.t.
MnO
2
,
CH
2
Cl
2
, r.t.
+
165
(96%)
(58%)
166
Scheme 2.23
We expected that deprotection of 166, followed by an intramolecular Michael addition,
would yield the natural product 155. However, decomposition of the starting material was
43
observed with most common deprotection methods, such as AlCl
3
/CH
3
CN, BBr
3
/CH
2
Cl
2
,
and MeSNa/DMF.
67
Then, we decided to perform some model studies. Reaction of MOM-protected
salicylaldehyde 167 with the carbanion of 159 at -78
o
C gave the secondary alcohol 168 in
53% yield. Oxidization with MnO
2
produced the ketone 169 in 94% yield. Mild
deprotection of 169 with HCl in EtOH at ambient temperature afforded 170 in 67% yield.
An intramolecular Michael addition under mild basic conditions (K
2
CO
3
, acetone), afforded
the didehydroxy natural product 171 in 66% yield (Scheme 2.24).
We then prepared the known 2,4,6-tris(methoxymethoxy)benzaldehyde 172 according to a
literature procedure.
68
Addition of the aldehyde 172 in THF to the carbanion of 159 at -78
o
C yielded the secondary alcohol 173 in 60% yield. Oxidiation of 173 with MnO
2
yielded
the MOM-protected ketone 174 in 88% yield (Scheme 2.25).
44
OMOM
OH
MOMO
MOMO
OMOM
O
MOMO
MOMO
OMOM
O
MOMO
MOMO
159 172
Q-BuLi (1.1 equiv)
THF, -78
o
C - r.t.
MnO
2
,
CH
2
Cl
2
, r.t.
+
173
(88%)
(58%)
174
Scheme 2.25
Mild deprotection of 174 with HCl in EtOH at ambient temperature, followed by the
intramolecular Michael addition under basic conditions (K
2
CO
3
, acetone), afforded the
natural product 155 in 49% yield for the last two steps (Scheme 2.26). All spectral data (
1
H,
13
C, Dept-NMR, IR, MS, HRMS, and LC-MS) were in agreement with those previously
reported for the natural product.
61,62
These results have been described in Paper V and the experimental procedures, physical
data, and spectroscopic data have been compiled in the Appendix.
45
We are currently working on the synthesis of derivatives of this natural product, including
one with a saturated alkyl chain. Polyunsaturated fatty acids and their derivatives are
expected to show strong binding to peroxisome proliferator-activated receptors (PPARs).
Hence, these types of derivatives may be used as a basis for the development of drugs against
diabetes and metabolic syndrome.
69
The results from biological testing will be reported in due
course (Figure 2.11).
46
3. SUMMARY
We have reported the transformation of phenols into ortho-hydroxycinnamates,
salicylamines, benzoxazines, and salicylnitriles in good overall yields by simple,
regioselective, and one-pot procedures using the advantage of the ortho-formylation
method. Moreover, these one-pot processes offer the advantage of both economic and
environmentally benign methods. We also used the MgCl
2
-Et
3
N base system in the
Mannich reaction with complete regioselectity.
We have described the first total synthesis of ()-powelline in 10% overall yield over eight
steps.
We have reported the first total synthesis of the naturally occurring all-(Z)-5,7-dihydroxy-2-
(4,7,10,13,16-nonadecapentaenyl)chromone in six steps from the ethyl ester of
eicosapentaenoic acid with an overall of 14% yield.
47
References and Notes

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4. APPENDIX
52
Experimental
General Information
All reagents and solvents were used as purchased without further purification. Melting points
are uncorrected. Analytical TLC was performed using silica gel 60 F
254
Aluminium sheets
(Merck). Flash column chromatography was performed on silica gel 60 (4060 m, Fluka).
NMR spectra were recorded on a Bruker Avance DPX-300 MHz spectrometer for
1
H NMR and
75 MHz for
13
C NMR. Coupling constants (J) are reported in Hertz, and chemical shifts are
reported in parts per million () relative to CDCl
3
(7.26 ppm for
1
H and 77.0 ppm for
13
C),
DMSO-d
6
(2.49 ppm for
1
H and 39.5 ppm for
13
C), and CD
3
OD (3.31 ppm for
1
H and 49.15
ppm for
13
C). Mass spectra were recorded at 70 eV with Fissions VG Pro spectrometer. High
resolution mass spectra were performed with a VG Prospec mass spectrometer and with a
Micromass Q-TOF-2
TM
. The LC/MS analyses were performed on an Agilent Technologies
1200 Series (Eclipse XDB-C18 5m 4.6150mm), coupled with an Agilent 6310 ion trap.
2-(Methoxymethoxy)benzaldehyde (167) was prepared according to a literature procedure.
1
6-((4`-Hydroxyphenethylamino)methyl)-2,3-(methylenedioxy)-phenol (138)
Anhydrous magnesium chloride (0.95 g, 10 mmol), triethylamine (1.01 g, 10 mmol), and
paraformaldehyde (0.45 g, 15 mmol) were added to a dry THF solution (30 mL) of phenol 118
(0.69 g, 5 mmol). The reaction mixture was heated to reflux under an argon atmosphere for 4.5
h and the reaction was monitored by TLC (hexane/EtOAc 4:1). After complete consumption of
the phenol, a solution of the amine 137 (0.70 g, 5.1 mmol) in MeOH (5 mL) was added
dropwise. The reaction mixture was heated to reflux for 30 min and further stirred at room
temperature for an additional 2 h while monitored by TLC (hexane/EtOAc 1:4). After complete
consumption of the salicylaldehyde, a solution of NaBH
4
(0.38 g, 10 mmol) in MeOH (10 mL)

1. Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S. J. Org. Chem., 1988, 53, 3936.
53
was added dropwise over 15 min. The reaction mixture was stirred at ambient temperature for
10 h and the reaction monitored by TLC (hexane/EtOAc 1:4). After complete reduction of the
imine, the pH was adjusted to 5 by addition of HCl (1 N) and the reaction mixture extracted
with CH
2
Cl
2
(230 mL). The organic layer was washed with brine (20 mL), dried using
MgSO
4
, and the product purified by column chromatography (SiO
2,
hexane/EtOAc 1:1) to
afford 138 (0.96 g, 67%) as a yellow solid. Mp = 95-97
o
C.
1
H NMR (CD
3
OD): = 7.04 (d, J =
8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 7.9 Hz, 1H), 6.19 (d, J = 7.9 Hz, 1H), 5.84 (s,
2H), 3.94 (s, 2H), 3.73 (brs, 1H), 2.88-3.00 (m, 2H), 2.74-2.85 (m, 2H);
13
C NMR (CD
3
OD):
= 157.32, 150.12, 147.02, 136.72, 130.80, 130.34, 123.51, 119.03, 116.66, 101.90, 98.79, 51.46,
50.09, 34.52; MS: m/z 287 (M
+
, 100%).
N-Trifluoroacetyl-N-(2`-hydroxy-3`,4`-methylenedioxyphenylmethyl)-[2-(4-
hydroxyphenyl)]ethylamine (139)
A mixture of polymer-supported DMAP (1.0 g, 3 mmol, 3 equiv.) and amine 138 (0.29 g, 1
mmol) in CH
2
Cl
2
(10 mL) was cooled to 0
o
C. Trifluoroacetic acid anhydride (0.25 g, 1.2 mmol,
1.2 equiv.) was added dropwise through a syringe. The reaction mixture was allowed to warm
to room temperature overnight. The reaction mixture was filtered, washed with MeOH (315
mL) and concentrated in vacuo. The product was purified by flash chromatography (SiO
2
,
hexane/EtOAc 1:4) to afford 139 (0.25 g, 64%) as a white solid. Mp = 185-186
o
C.
1
H NMR
(DMSO-d
6
): = 9.88 (brs, 1H), 9.22 (brs, 1H), 6.92 (m, 2H), 6.64 (m, 3H), 6.45 (m, 1H), 5.98
(d, J = 1.8 Hz, 2H), 4.58 (s, 1H), 4.30 (s, 1H), 3.33 (s, 2H), 2.67-2.83 (m, 1H), 2.55-2.66 (m,
1H).
13
C NMR (DMSO-d
6
): = 156.02, 155.94, 155.83, 155.80, 155.48, 155.34, 148.09, 148.02,
139.23, 138.90, 134.58, 134.54, 129.54, 129.50, 128.20, 127.61, 122.77, 121.17, 118.41,
118.32, 118.18, 117.70, 115.34, 115.21, 115.14, 114.58, 114.49, 100.98, 100.90, 100.27, 48.09,
47.97, 45.66, 43.87, 33.41, 31.21; MS: m/z 383 (M
+
, 100%).
54
all-Z-1,1-Dibromoheneicosa-1,6,9,12,15,18-hexaene (163)
A mixture of triphenylphosphine (806 mg, 3.1 mmol), zinc (200 mg, 3.1 mmol) and
tetrabromomethane (1.02 g, 3.1 mmol) in CH
2
Cl
2
(15 mL) was stirred at room temperature for
20 h before a solution of freshly prepared aldehyde 162 (324 mg, 1.13 mmol) in CH
2
Cl
2
(5 mL)
was added. The mixture was stirred for 2 h at room temperature. Evaporation of the solvent at
reduced pressure and filtration through a plug of SiO
2
with hexane gave the dibromide 163 (410
mg, 82%) as a colorless oil.
1
H NMR (CDCl
3
): = 6.37 (t, J = 7.2 Hz, 1H), 5.51-5.22 (m, 10H), 2.66-2.96 (m, 8H), 1.96-
2.19 (m, 6H), 1.41-1.59 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H);
13
C NMR (CDCl
3
): = 138.46 (CH),
132.05 (CH), 129.18 (CH), 128.62 (CH), 128.58 (CH), 128.26 (CH), 128.24 (CH), 128.12
(CH), 128.10 (CH), 127.88 (CH), 127.01 (CH), 88.89 (C), 32.58 (CH
2
), 27.70 (CH
2
), 26.60
(CH
2
), 25.66 (CH
2
), 25.55 (CH
2
), 20.56 (CH
2
), 14.27 (CH
3
).
all-Z-Heneicosa-6,9,12,15,18-pentaen-1-yne (159)
A solution of the dibromide 163 (398 mg, 0.9 mmol) in dry ether (15 mL) was cooled to -78
o
C
before addition of methyllithium (1.6 M in ether, 1.0 mL, 1.6 mmol). The mixture was stirred
overnight at -78
o
C. A saturated aqueous solution of NH
4
Cl and hexane (20 mL) were added.
The organic layer was separated, washed with water, dried over anhydrous MgSO
4
and
evaporated under reduced pressure. The residue was purified by flash chromatography (SiO
2,
hexane/EtOAc 99:1) to yield 159 (160 mg, 63%).
all-Z-1-(2-(Methoxymethoxy)phenyl)docosa-7,10,13,16,19-pentaen-2-yn-1-ol (168)
n-BuLi (1.9 mL, 3 mmol, 1.6 M in hexane) was added to a solution of 167 (0.79 g, 2.8 mmol) in
THF (25 mL) under argon at -78 C and stirred at this temperature for 10 min. A solution of 159
(0.46 g, 2.8 mmol) in THF (15 mL) was added dropwise over 15 min. The mixture was stirred
at -78 C for 1 h before the solution was left to reach ambient temperature over 1 h. The
55
reaction was quenched by the addition of aqueous NH
4
Cl until pH = 8, and the mixture was
extracted with diethyl ether (320 mL). The combined organic layers were washed with brine
(30 mL), dried over anhydrous MgSO
4
, and the solvent removed in vacuo. The crude product
was purified by flash chromatography (SiO
2,
hexane/EtOAc 4:1) to yield 168 (0.66 g, 53%) as a
pale yellow oil;
1
H NMR (CDCl
3
): = 7.60 (dd, J = 7.6, 1.7 Hz, 1H), 7.24-7.80 (m, 1H), 7.00-
7.06 (m, 2H), 5.72-5.74 (m, 1H), 5.31-5.40 (m, 10H), 5.27, 5.24 (AB, J = 6.9 Hz, 2H), 3.50 (s,
3H), 2.76-2.83 (m, 8H), 2.29 (td, J = 7.2, 2.1 Hz, 2H), 2.15-2.21 (m, 2H), 2.07 (p, J = 7.5 Hz,
2H), 1.62 (p, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H);
13
C NMR (CDCl
3
): = 154.45 (C),
135.82 (CH), 132.03 (CH), 130.25 (C), 129.51 (CH), 129.01 (CH), 128.74 (CH), 128.30 (CH),
128.24 (CH), 128.11 (CH), 127.92 (CH), 127.87 (CH), 127.00 (CH), 122.09 (CH), 121.85
(CH), 114.55 (CH), 94.71 (CH
2
), 86.66 (C), 79.66 (C), 61.08 (CH), 56.29 (CH
3
), 28.53 (CH
2
),
26.39 (CH
2
), 25.62 (CH
2
), 25.53 (CH
2
), 20.55 (CH
2
), 18.41 (CH
2
), 14.26 (CH
3
); HRMS calcd.
for C
30
H
40
O
3
(M
+
): 448.2977, found: 448.2957.
all-Z-1-(2-(Methoxymethoxy)phenyl)docosa-7,10,13,16,19-pentaen-2-yn-1-one (169)
Manganese dioxide (1.93 g, 22.2 mmol, 20.0 equiv.) was added in small portions over 1.5 h to a
solution of alcohol 168 (0.50 g, 1.11 mmol) in CH
2
Cl
2
(15 mL). The resulting suspension was
stirred for 16 h, then filtered through a pad of celite. The celite was washed with CH
2
Cl
2
(415
mL), and the combined organics concentrated under reduced pressure to give the ketone 169 as
a pale yellow oil. The crude product was purified by flash chromatography (SiO
2,
hexane/EtOAc 4:1) to yield 169 (0.47 g, 94%) as a colorless oil;
1
H NMR (CDCl
3
): = 7.97
(dd, J = 7.8, 1.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.18-7.23 (m, 1H), 7.04-7.11 (m, 1H), 7.31-7.41
(m, 10H), 7.26 (s, 2H), 3.52 (s, 3H), 2.79-2.84 (m, 8H), 2.46 (t, J = 7.2 Hz, 2H), 2.23 (q, J =
7.5 Hz, 2H), 2.07 (p, J = 7.5 Hz, 2H), 1.72 (p, J = 7.3 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H);
13
C
NMR (CDCl
3
): = 177.06 (C), 157.02 (C), 134.37 (CH), 132.40 (CH), 129.30 (CH), 128.57
(CH), 128.46 (CH), 128.37 (CH), 128.28 (CH), 128.08 (CH), 128.04 (CH), 127.93 (C), 127.86
(CH), 127.00 (CH), 125.49 (CH), 121.53 (CH), 116.17 (CH), 94.93 (CH
2
), 94.61 (C), 82.00 (C),
56.39 (CH
3
), 27.79 (CH
2
), 26.41 (CH
2
), 25.66 (CH
2
), 25.62 (CH
2
), 25.53 (CH
2
), 20.55 (CH
2
),
18.77 (CH
2
), 14.27 (CH
3
); HRMS calcd. for C
30
H
38
O
3
(M
+
): 446.2821, found: 446.2829.
56
all-Z-2-(Nonadeca-4,7,10,13,16-pentaenyl)-4H-chromen-4-one (171)
To a stirred solution of 169 (0.36 g, 0.89 mmol) in ethanol (10 mL) was added dropwise HCl
(2.5 mL, 6 M). The mixture was stirred for 3 h, then diluted with water (10 mL) and extracted
with diethyl ether (210 mL). The organic layer was washed with brine (15 mL), dried with
MgSO
4
, and evaporated under reduced pressure. The residue was purified by silica gel column
chromatography (SiO
2,
hexane/EtOAc 9:1) to yield 170 (0.24 g, 67%) as a pale yellow oil. To a
solution of 170 (0.23 g, 0.57 mmol) in acetone (10 mL) was added K
2
CO
3
(0.24 g, 1.71 mmol, 3
equiv.). The resulting suspension was stirred for 2 h at room temperature, then heated at reflux
for 1 h, then cooled down to room temperature, diluted with water (10 mL), and extracted with
diethyl ether (220 mL). The organic layer was successively washed with brine (15 mL), dried
over anhydrous MgSO
4
, and evaporated under reduced pressure. The residue was purified by
flash chromatography (SiO
2,
hexane/EtOAc 4:1) to yield 171 (0.15 g, 66%) as a pale yellow oil;
1
H NMR (CDCl
3
): = 8.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.61-7.64 (m, 1H), 7.38-7.43 (m, 2H),
6.18 (s, 1H), 5.32-5.44 (m, 10H), 2.78-2.85 (m, 8H), 2.65 (t, J = 7.5 Hz, 2H), 2.17-2.23 (m,
2H), 2.10 (p, J = 7.5 Hz, 2H), 1.83 (p, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H);
13
C NMR
(CDCl
3
): = 178.31 (C), 169.41 (C), 156.51 (C), 133.43 (CH), 132.06 (CH), 129.23 (CH),
128.63 (CH), 128.60 (CH), 128.30 (CH), 128.29 (CH), 128.05 (CH), 128.02 (CH), 127.85
(CH), 127.00 (CH), 125.71 (CH), 124.92 (CH), 123.77 (C), 117.82 (CH), 109.92 (CH), 33.79
(CH
2
), 26.71 (CH
2
), 26.49 (CH
2
), 25.70 (CH
2
), 25.64 (CH
2
), 25.55 (CH
2
), 20.56 (CH
2
), 14.27
(CH
3
); MS EI m/z 402 (M
+
, 19%), 173 (100), 160 (28) HRMS calcd. for C
28
H
34
O
2
(M
+
):
402.2559, found: 402.2558.