سند
سند
سند
1984,
49, 4409-4415
Registr 37813-
y No. 2, 95-9;
2166- 4d,
14-5; 3a, 92184-
23900- 43-5;
50-7; 3b, 58,
92144- 78331-
06-4; 3c, 70-1;
71124- 5b,
72-6; 3d, 91248-
2166- 34-9; 5c,
27-0; 3e, 25473-
92144- 58-9;
07-5; 3f, 5d,
92144- 92144-
08-6; 12-2; 5e,
92144- 92144-
09-7; 13-3; 5f,
3h, 92144-
92144- 14-4;
10-0; 5g,
4b, 92144-
92144- 15-5;
11-1; 4c, 5h,
4410 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
92144- 4
16-6; -
68, 822- 0
51-5; 4
6b, -
48892- 2
6; 6d, ;
27649-
43-0; 7,
1257-
25-6;
53379
-23-
0;
CH3C=
CCH3,
503-
17-3;
81-4;
0;
9
2
1
4
4411
CH3)2, line,
50473- 13654-
61-5; 4- 48-3; 1-
(1-ethyl- (1-ethyl-
l- l-
Anthony G. M. Barrett*
Department of Chemistry, Northwestern University, Evanston,
Illinois 60201
elegant A
synthes tenet of
is and organo
use of silicon
indole- chemis
4419
try is electro
the philes
general to
ization produc
that "a e 6 on
silicon accoun
— t of
carbon prefere
bond ntial
stabiliz formati
es a on of
carboni the
um ion Whela
ß to it". nd
5
For interme
exampl diate 5
e (Schem
diverse e I).
aryltri This
methyl ipso
silanes4 attack
underg may
o ipso overwh
substit elm the
ution effects
by of
4420 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
other lbenzo
directin phenon
g e on
substit Friedel
uents. -Crafts
Thus 2- benzoy
(trimet lation.
hylsilyl In
)benzoi princip
c acid le, such
reacted a
with reversa
bromin l of the
e to aromati
produc c
e 2- electro
bromo philic
benzoi substit
c acid, ution
wherea pattern
s 3- mediat
(trimet ed by a
hylsilyl trimeth
)toluen ylsilyl
e gave group
3methy should
4421
be ely to
applica lysergi
ble to c acid
indole (2)
chemis total
try. synthes
Indeed is.
the In
product 1960
ion of Smith
4- reporte
(trimet d6 that
hylsilyl indole
)indole (7b)
(7a) was
should reduced
be of under
relevan Birch
ce to conditi
C-4 ons to
electro produc
philic e an
substit insepar
ution able
and mixture
ultimat of 4,7-
4422 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
dihydro Barto
- and n, D.
4,5,6,7- H.
tetrahy R. ,
droindo Ollis, W.
les (8a D., Eds.;
and 9). Pergam
mon
(4) Kozik Press:
owski Oxford,
, A. P. 1979;
Heter Vol. 3, p
ocyct 539.
es, (6)
1981, O'Brie
16, n, S.;
267. Smith,
(5) Flemi D. C.
ng, I. C. J.
In Chem.
"Com soc.
prehe 1960,
nsive 4609.
Organ
01
ic
9
Chem
8
istry";
4423
4 a R
A
m R
er 2
ic b R
a
n 2
C
h 3
e
m 3
ic C
al O
S C
o H
ci C
et H
y C
l
=
C
O
C
H
=
C
4424 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
H Remers 7
2 and
CHelmkam
O p8 studied
C the
H reaction
C more
H carefully
O and
M defined
e condition
C s for the
O purificati
C on of 8a
H and
= related
Csystems.
9
H Intriguin
2 gly,
Ltryptop
co
han (3)
has also
been
1 0 smoothly
Birch
Subseque
reduced
ntly,
4425
to intermedi
produce ates by
4,7- electroph
dihydro- iles other
L- than a
tryptopha proton
n. 10 Since source.
the Birch Laguerre
reduction and
of an others12
aromatic have
substrate reduced
proceeds carbocycl
via the ic
radical aromatic
anion and substrates
cyclohex by using
adienyl chlorotri
anion ll methylsil
there is, ane and
of course, lithium in
the THF
opportuni solution.
ty to Thus,
intercept under
these these
4426 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
condition s should
s, provide a
benzene method
was for the
converted activation
into of the C-
2,5bis(tri 4 center.
methylsil
Results
yl)-1,4-
and
cyclohex
Discussi
adiene
on
which on
Synthes
air
is of 1,4-
oxidation
Bis(trime
gave 1,4-
thylsilyl)i
bis(trimet
ndole
hylsilyl)b
(7d). 1-
enzene.
(Trimeth
Clearly
ylsilyl)in
the Birch
dole (7c),
reduction
chlorotri
of indole
methylsil
(7b)
ane, and
under
lithium
silylating
metal in
condition
THF
4427
solution purificati
were on this
ultrasonic was
ally directly
agitated oxidized
for 4 h at using
5—10 o c 1,4benzo
and quinone
overnight in
at 45 0 C. dichloro
Evaporati methane
on of the solution.
solvent Chromat
gave an ography
off-white gave 1,4-
solid that bis(trimet
was air hylsilyl)i
sensitive ndole
and (7d)
presumab (55%).
ly The
contained structural
lithium assignme
chloride nt of 7d
and 8b. was in
Without full
4428 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
agreemen Pidacks,
t with all Weiss,
spectral M. J. J.
and org.
microana Chem.
lytical 1971, 36,
data. The 279.
I
H high- (8) Agh
resolutio more, J.
n NMR W.;
spectrum Helmkam
was p, G. K.
especiall Org.
y Prep.
informati Proced.
ve. Thus Int. 1976,
the 8, 223.
chemical (9) •Te
shifts and uber, H.
coupling J.;
constants Schmitt,
for the G. Chem.
aromatic Ber.
1969,
(7) Re
102, 713.
mers, W.
Remers,
Gibs, G.
4429
W. A.; M. J. J.
Weiss, org.
M. J. Chem.
Tetrahedr 1971, 36,
on Lett. 279.
1968, 81. (10) Yon
Remers, emitsu,
W. A.; 0.;
Gibs, G. Cerutti,
J.; P.;
Pidacks, Witkop,
C.; B. J. Am.
Weiss, Chem.
M. J. J. Soc.
Am. 1966, 88,
Chem. 3941.
soc. (11) Birc
1967, 89, h, A. J.
5513. Q. Rev.,
Remers, 1950, 4,
W. A.; 49.
Gibs, G. (12) Lac
J.; querre,
Pidacks, M.;
C.; Dunogue
Weiss, s, J.;
4430 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
Calas, R.; consisten
Duffaut, t with the
N. J. 1,4-
Organom disubstitu
et. tion
Chem., pattern.
1976, In
112, 49. addition,
Bikkofer, when
L.; differenc
Ramadan e NOE
, N. Ibid. experime
1972, 44, nts were
C41. used, the
Scheme
Il group
SiMe3 was
shown to
be close
to H-2
and H-7
whereas
the C—
protons SiMe3
C
CO Me H
2
1 3 C
Ac 1 H
4 1 5 2
Me
C Me Si
Et
0
16 2
8 E
t
CH Et
R
f
C
R H
C C
H H
4440 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
C (7a)
O and
1,4-
M bis(tr
e imethy
lsilyl
)indol
R e (7d)
reacte
*
d with
electr
C
ophile
H
s at
2
C-3
C
not
H
via
2
ipso
C
substi
0
tution
2
at C-
H
4.
Both Thus
4- 7a
(trime reacte
thylsi d with
lyl)in methyl
dole 3-
4441
methox (36%).
y-2- In
nitrop additi
ropeno on, 7d
ate reacti
(14) 16
on
or with
ethyl dimeth
2nitro ylmeth
soprop ylenea
enoate mmoniu
(15) 17
m
to chlori
produc de 19
e the in
expect dichlo
ed -18
16
rometh
C-3 ane
substi soluti
tuted on to
indole produc
deriva e 16c
tives (20—
16a 60%),
(43%) as the
and major
16b compou
4442 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
nd, amine
and (16c)
two was
additi conver
onal ted
produc into
ts 16d
tentat (97%),
ively 16e
identi (99%),
fied and
as 17a 16f
and (97%).
17b. Subseq
Again uent
when tri-n-
standa butyls
rd tannan
indole e
chemis reduct
try18'20 ion21
was of 16e
used, and
4- 16f
(trime gave
thylsi 16g
lyl)gr (32%)
4443
and was
16h due to
(76%), the
respec instab
tively ility
. In of the
these byprod
radica uct
l tribut
denitr yltin
ations nitrit
, e21 on
purifi the
cation second
of the suppor
produc t. As
t was an
most altern
effici ative,
ently ester
carrie 16g
d out was
on prepar
alumin ed
a, not direct
silica ly
. This from
4444 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
4- yields
(trime (S15%)
thylsi becaus
lyl)in e of
dole compet
(78) itive
by protod
reacti esilyl
on ation
with to
ethyl give
acryla 18.
te and The
alumin Friede
um l—
chlori Crafts
de. 18
Acylat
This ion of
reacti 4-
on, (Trime
with thylsi
severa lyl)in
l dole
Lewis (7a).
acids, Since
gave 4-
low (trime
4445
thylsi for
lyl)in ipso
dole substi
(78) tution
and at C-
1,4- 4.
bis(tr Thus
imethy the
lsilyl reacti
)indol on of
e (7d) I-
both acetyl
reacte -4-
d with (trime
electr thylsi
ophile lyl)in
s at dole
C-3, (7e)
it was with
necess acylat
ary to ing
deacti reagen
vate ts was
this invest
positi igated
on to .
allow Acetyl
4446 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
chlori M. E.;
de, Pigott
7e, , F.;
and Scheid
alu- l, F.;
Scott,
(16) Ka J. W.;
mlet, sun,
M. J. R. C.;
J. Townes
Org. end,
Chem. J. M.;
1956, Willia
24, ms, T.
714. H. J.
Hangar org.
tner, Chem.
U.; 1979,
Valent 44,
ine, 3741.
D., (17) Gi
Jr.; lchris
Johnso t, T.
n, K. L.;
K.; Lingha
Larsch m, D.
eid, A.;
4447
Robert In
s, T. "Compr
G. J. ehensi
Chem. ve
soc., Organi
Chem. c
Commun Chemis
. try";
1979, Barton
1089. , D.
Robert H. R.,
s, T. Ollis,
G. W. D.,
Ph.D. Eds.;
Thesis Pergam
, on
Univer Press:
sity Oxford
of ,
Liverp 1979;
ool, vol.
1979. 4, p
(18) Br 411.
own, (19) Bo
R. J.; hme,
Joule, H.;
J. A. Hartke
4448 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
, K. 1980,
Chem. 813.
Ber. (21) On
1960, o, N.;
93, Miyake
1305. , H.;
Kinast Tamura
, G.; , R.;
Tietze, L. Kaji,
F. A.
Angew. Tetrah
Chem., edron
Int. Ed. Lett.
Engl. 1981,
1976, 15, 1705.
239. J
(20) So .
mei,
M.; o
Karasa r
wa, g
Y.; .
Kaneko
C
, C.
h
Chem.
e
Lett.
m
4449
. reacte
, d
smooth
V ly
o togeth
l er to
. produc
e 1,4-
4 diacet
9 ylindo
, le
(7f)
N
(95%).
o
Again
.
the N-
l, C-4
2
substi
3
tution
,
patter
n
1
follow
9
ed
8
direct
4
ly
minum from
chlori the I
H
de NMR
4450 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
spectr reacte
um d with
7.44 7e and
(dd, 1 alumin
H, J = um
8.5, chlori
7.5 de to
Hz, 6- produc
H), e the
8.66 same
(ddd, produc
1 H, J t 7g
= 8.5, (75%,
1, 1 60%,
Hz, 7- respec
H)]. tively
Both ).
3- Clearl
chloro y both
propan 7f and
oyl 7g
chlori were
de and formed
propen via
oyl clean
chlori ipso
de substi
4451
tution (46%).
. Presum
Chloro ably
acetyl in
chlori this
de, case
howeve ipso
r, substi
reacte tution
d with was
7e to suppre
give a ssed
mixtur by
e of steric
compou conges
nds. tion
Chroma and
tograp reacti
hy on
gave took
the C- place
6 via 20
ketone with
s 19a 19b
(37%) being
and formed
19b via
4452 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
late 9.09
protod (s, 1
esilyl H, 74-
ation. 1)].
The I
H SiMe
NMR
spectr
um of
o
19a
was bR
fully S
consis
i
tent
M
with
e
the N- 3
l, C-
4, C-6
substi
tution
patter 2
n [ö
8.07
(d, 1
Prepa
H, J =
ration
1.3
of
Hz, 5-
Ketone
H),
4453
218. from
Uhle's 4-
ketone (trime
(21b) thylsi
is a lyl)in
pivota dole
l (7a).
interm Initia
ediate lly we
in the sought
early to
synthe cycliz
ses of e 7g.
lyserg Under
ic divers
acid e
(2). basic
Prompt condit
ed by ions
this 7g was
fact, conver
we set ted
out to into
explor 7h,
e its 7i, or
prepar 7j.
ation Neithe
4454 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
r with
under revers
these al of
condit order
ions in the
nor C—C
under bond
Lewis format
acidic ion
condit reacti
ions ons.
were Ester
any 16e
deriva was
tives reacte
of 21 d
produc sequen
ed. tially
Thus with
we tribut
examin ylstan
ed the nane
prepar and
ation sodium
of 21 hydrox
from ide to
78 produc
4455
e 16i Attemp
(53%) ted
on cycliz
acidif ation
icatio of 228
n. using
This oxalyl
was chlori
conver de
ted follow
into ed by
22a alumin
(31 um
% ) by chlori
sequen de did
tial not
reacti produc
on e
with isolab
sodium le
hydrid quanti
e and ties
triflu of
oroace 21b.
tic Howeve
anhydr r, the
ide. toluen
4456 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
e-4- sulfon
sulfon yl
ate chlori
22c de,
was and
succes methan
sfully olic
cycliz sodium
ed. hydrox
Ester ide.
16h On
was reacti
conver on
ted with
into diethy
22c by l
sequen chloro
tial phosph
reacti ate
on and
with alunin
potass um
ium chlori
hydrid de 22c
e, was
toluen conver
e-4- ted
4457
into a is
mixtur suffic
e of ient
compou to
nds. overwh
Chroma elm
tograp the
hy combin
gave ed
two direct
cyclic ing
produc influe
ts 218 nce of
22
(5%) the N-
and 23 toluen
(34%). e-4-
Clearl sulfon
y, the yl
angle group
strain and
associ the 4-
ated trimet
with hylsil
the yl
produc substi
tion tuent.
of 21a Thus,
4458 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
althou on to
gh we our
have studie
been s on
able indole
to , we
prepar briefl
e 21a, y
the examin
yield ed the
is reduct
extrem ion of
ely pyridi
poor. ne,
Furth 2,6-
er dimeth
Reduct ylpyri
ions dine,
Using quinol
Lithiu ine,
m— and
Chloro N,N-
trimet dimeth
hylsil ylbenz
ane. amide.
In
additi
4459
(22) Thus
Bowman reaction
, R. of these
E.; aromatic
Evans, substrates
D. D.; with
Guyett lithium
, J.; and
Nagy, chlorotri
J. G. methylsil
H.; ane
Weale, followed
J.; by 1,4-
Weyell benzoqui
, D. none or
J.; 2,3-
White, dichloro-
A. C.
5,6-
J.
dicyano-
Chem.
1,4-
soc.,
benzoqui
Perkin
none
Trans.
(DDQ)
1
gave
1972,
respectiv
1926.
ely 24823
4460 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
(74%), 24
24b 26
(42%),
25 28
Conclusi
(35%),
on
and 26
The
(42%).
reduction
Although
of indole
these
(7b) with
yields are
lithium
modest,
and
the
chlorotri
reaction
methylsil
provides
ane
an
followed
alternativ
by 1,4-
e
benzoqui
procedur
none
e for
oxidation
heteroare
provided
ne ring
a
silylation
convenie
.
nt
method
for the
CONMe
productio
4461
n of via ipso
4(trimeth substituti
ylsilyl)in on at C-
dole (7a). 4.
This Although
product the
reacted Uhle's
with ketone
electroph derivativ
iles at C- e 21a was
3. prepared
Alternati from 78,
vely the the
derived I- procedur
acetyl4- e was
(trimethy inapplica
lsilyl)ind ble to
ole (7e) lysergic
usually acid
underwen (2)
t synthesis
intermole on
cular account
Friedel- of poor
Crafts yields.
acylation
4462 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
Experim and dried
ental before
Section use.
Melting Ultrasoni
points cation
were was
determin carried
ed on a out in a
Kofler PUL55
hot stage Kerry
and are QH
uncorrect Ultrasoni
ed. c Bath
Reaction (Kerry
s were Ultrasoni
carried cs Ltd.,
out under England).
dry argon Organic
or extracts
nitrogen. were
All concentra
solvents ted by
and rotary
reagents evaporati
were on under
purified reduced
4463
pressure were
at S40 0 mixed
C. Unless together
stated to in an
the ultrasoni
contrary, c bath
chromato overnight
graphy when the
refers to temperat
flash ure
chromato increased
graphy from 20
on Merck to 45 0 C.
Kieselgel MesSiCl
H. (38 mL)
1- in THF
(Trimeth (50 mL)
ylsilyl)in was
dole (7c). added
Indole dropwise
(7b) at 0 o c
(23.4 g) and the
and NaH mixture
(7.2 g) in refluxed
THF for 5 h.
(100 mL) After
4464 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
evaporati thylsilyl)i
on the ndole
residue (7d).
was Method
leached A.
with MegSiCl
hexane (4.05 ml)
and the was
extract added
filtered. dropwise
Evaporati with
on gave stirring to
7c 24 1-
(35.2 g, (trimethy
93%) lsilyl)ind
which on ole (7c)
distillatio (2.0 g) in
n gave THF (30
pure 7c mL) at 0
(32.6 g, 0
C.
86%), bp Lithium
68-70 o c (186 mg)
(0.06 cut into
mmHg). 20 clean
1,4- pieces
Bis(trime was
4465
added to
and the maintain
mixture a
agitated nitrogen
in an atmosphe
ultrasoni re during
c bath at this
5-10 o c solvent
for 4 h change.
and The
subseque mixture
ntly was
overnight cooled to
at 45 o c. 0 o c and
The THF p-
was benzoqui
evaporate one (1.72
d in g) in
vacuo CH2C12
and (20 mL)
replaced was
by added.
CH2C12 After the
(10 mL). reaction
It was had
essential stirred 3
4466 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
h, the exane
CH2C12 (1:9, 130
was mL). The
removed combine
under d filtrates
reduced were
pressure, evaporate
the d to leave
residue a mixture
was of 7c and
leached 7d (2.53
with g, 3:7).
hexane, This was
and the flash
extract chromato
was graphed
directly on silica
filtered (70 g) to
through give
silica (35 [eluant
g) eluting hexane—
with hexane:C
hexane H2C12
(60 mL) (9:1)]
and pure 1,4-
CH2Cl:h bis(trimet
4467
hylsilyl)i H, J - 3.5,
ndole 1 Hz),
(7d) 7.12 (dd,
(1.52 g, 1 H, J =
55%): 9, 8 Hz),
mp 62.5 7.15 (d, 1
—63.5 o c H, J = 3.5
(from Hz), 7.25
hexane); (dd,
IR 1 H, J =
(Nujol) 8, 1 Hz),
1510, 7.47 (dt,
1400, J = 4, 1
1290, Hz);
1260, mass
1160, spectrum
915, 850, m/e 261
760 cm- (M+.),
I ; NMR 246.
(CDC13) Anal.
0.38 Calcd for
(s, 9 H), C14H23
0.53 (s, 9 NSi2: C,
H), 6.68 64.28; H,
(dd, 1 H, 8.87; N,
J = 3.5, 1 5.36.
4468 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
Found: H. F. J.
C, 64.28; org.
H, 8.93;, Chem.
N, 5.33. 1973, 38,
3324.
(23) Fisc Method
her, A.; B. When
Morgan, exactly
M. W.; the same
Eaborn, procedur
C. J. e was
Organom used,
et. Chem. reaction
1977, of indole
136, 323. (7b)
(24) Bir (1.24 g),
kofer, L.; Li (0.297
Richter, g),
P.; Ritter, MegSiCl
A. Chem. (4.6 g),
Ber. and p-
1960, 93, benzoqui
2804. none (2.3
Sundberg g)) gave
, R. J.; 7d (1.39
Russell, g, 50%)
4469
identical MeOH
with the (50 mL),
previous reevapor
sample. ated,
4- redissolv
(Trimeth ed in
ylsilyl)in hexane,
dole (78). and
1,4- reevapor
Bis(trime ated to
thylsilyl)i give 7a
ndole (1.85 g,
(7d) 98%).
(2.61 g) Recrystal
in dry lization
MeOH from
(50 mL) MeOH—
was H20 gave
refluxed 78 (1.70
for 5 g, 90%)
min, as white
evaporate plates:
d to mp 63.5-
dryness, 64 o c; IR
redissolv (CH2C12
ed in ) 3400,
4470 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
1400, (M +0,
1250, 174.
940, 840, Anal.
760, 735 Calcd for
cm-I ; CllH15N
NMR Si: C,
(CDC18) 69.76; H,
0.41 (s, 9 7.99; N,
H), 6.68 7.40.
(m, 1 H), Found:
7.20 (dd, C, 69.79;
1 H, J = H, 8.04;
8, 7 Hz), N, 7.40.
7.23 (m, I-
1 H), Acetyl-4-
7.29 (dd, (trimethy
1 H, J = lsilyl)ind
7, 1.5 ole (7e).
Hz), 7.40 NaH
(dt, 1 H, (0.252 g),
J = 7, 1.5 4(trimeth
Hz), 8.0- ylsilyl)in
8.3 (m, 1 dole (78)
H); mass (1.325 g),
spectrum, and THF
m/ e 189 (30 mL)
4471
were warmed
ultrasoni up to
cally room
agitated temperat
overnight ure (1 h)
when the and
temperat evaporate
ure d to
increased dryness.
from 20 The
to 40 D C. residue
After was
cooling extracted
to -78 o c, with
AcC1 CH2C12
(0.825 g) (30 mL),
in THF treated
(5 mL) with
was charcoal,
added filtered,
dropwise and
with evaporate
stirring. d to leave
The 7e (1.550
mixture g, 96%).
was Recrystal
4472 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
lization (d, 1 H, J
from = 8, 7
hexane Hz), 7.42
gave 7e (dd, 1 H,
as J = 7, 1.5
colorless Hz), 7.46
needles: (d, 1 H, J
mp 123- = 4 Hz),
124 o c•, 8.48 (br
IR d, 1 H, J
(CHC13) = 8 Hz);
1690, mass
1530, spectrum,
1400- m/e 231
1360, (M+.),
1320, 216, 189,
1250 cm l 174.
, NMR Anal.
(CDC13) Calcd for
0.39 (s, 9 C13H17
H), 2.64 NOSi: C,
(s, 3 H), 67.49; H,
6.77 (dd, 7.41; N,
1 H, J = 6.05.
4, 0.5 Found C,
Hz), 7.34 67.38; H,
4473
7.43; N, chloride
5.99. without
I- purificati
Acetyl- on of
4,6- intermedi
bis(trimet ates.
hylsilyl)i Recrystal
ndole lization
(13). of the
Crude crude
unchrom product
atograph gave 7e
ed (3.75 g).
1,4•bis(tr Chromat
imethylsi ography
lyl)indole of the
(7d) mother
(9.62 g) liquor on
was silica
reacted (eluant
with CH2C12:
methanol hexane
, sodium 7:3)
hydride, gave, in
and addition
acetyl to 7e and
4474 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
7k, crude (s, 3 H),
I-acetyl- 6.75 (dd,
4,6- 1 H, J =
bis(trimet 4, 0.5
hylsilyl)i Hz),
ndole 7.45 (d, 1
(13) (0.5 H, J = 4
g). Hz), 7.56
Repeated (d, 1 H, J
recrystall = 0.5
ization Hz), 8.68
from (br s, 1
cyclohex H); mass
ane gave spectrum,
13 as an m/e 303,
analytical (M+0,
ly pure 288, 246.
sample: Anal.
mp 122.5 Calcd for
—124 o c; C16H25
NMR NOSi2:
(CDC13) C, 63.27;
ö 0.33 (s, H, 8.31;
9 H), N, 4.66.
0.40 (s, 9 Found:
H), 2.64 C, 63.31;
4475
H, 8.30; under
N, 4.61. argon at
Methyl room
2-Nitro- temperat
3-[4- ure for
(trimethy 24 h. A
lsilyl)ind further
ol-3- equivalen
yl]propen t of 14
oate (0.145 g)
(16a). A was
mixture added
of 4- and the
(trimethy mixture
lsilyl)ind stirred
ole (7a) for a
(0.189 g) further
and 24 h. The
methyl 3- crude
ethoxy-2- material
nitroprop was
enoate chromato
(14) 16 graphed
(0.145 g) on Silica
were H (10 g)
stirred eluting
4476 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
with 1145,
CH2C12 1125,
to give 1105,
16a 835, 750
(0.138 g, cm-I ;
43%): NMR
mp 176- (CDC13)
179 o c 0.339,
with 0.345 (2
resolidifi s, 9 H),
cation, 3.942,
second 3.975 (2
mp 195 s, 3 H)
—202 o c 7.275-
(from 8.586
CC14'. (complex
benzene); , 5 H),
IR 8.75,
(Nujol) 8.83 (br,
3390, 1 H);
1710, mass
1615, spectrum,
1520, m/e 320,
1290, 319, 318
1270, (M+.),
1250, 305, 304,
4477
303, 286, (Trimeth
272, 259, ylsilyl)in
248, 229, dole (7a)
218, 202, (0.47 g)
184, 168, was
154, 141, dissolved
127. in dry
Anal. CH2C12
Calcd for (60 mL).
C15H18 Ethyl 3-
N204Si: bromo-2-
C, 56.56; (hydroxy
H, 5.70. imino)pr
Found: opanoate
C, 56.65; 17
(0.58 g)
H, 5.79. was
Ethyl 2- added to
(Hydroxy the
imino)-3- solution
[4- followed
(trimethy by
lsilyl)ind Na2C03
ol-3- (1.50 g).
yl]propan The
oate solution
(16b). 4- was
4478 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
stirred at g, 36%):
room mp 201
temperat —204 o c
ure for (from
16 h, EtOAc);
filtered IR
through (Nujol)
Celite, 3460,
and 3250
evaporate (br),
d in 1720,
vacuo. 1260,
The 1230,
residue 1215,
was 1130,
chromato 1015,
graphed 955, 850,
on Silica 760 cm-
H (20 g) I ; NMR
eluting [(CD3)2
with CO] 0.47
Et20:hex (s, 9 H),
anes 1.20 (t, 3
(70:30) H, J = 7
to give Hz), 4.17
16b (0.29 (q, 2 H J
4479
= 7 Hz), Anal.
4.25 (d, 2 Calcd for
H, J C16H22
= 1 Hz), N202Si:
6.88 (s, 1 C, 60.35;
H), 7.07 H, 6.96;
(dd, 1 H, N, 8.80.
J = 7.9, Found:
7.3 Hz), C, 60.71;
7.25 (dd, H, 7.25;
1 H, J = N, 8.80.
7.3, 1.3 3-
Hz), 7.42 [(Dimeth
(dd, 1 H, ylamino)
J = 7.9, methyl]-
1.3 Hz); 4-
mass (trimethy
spectrum, lsilyl)ind
m/e 318, ole (16c).
303, 301, N,N-
229, 228, Dimethyl
227, 204, methylen
202, 186, eammoni
185, 184, um
183, 174, chloride
155.
4480 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
19
(131 organic
mg) was layers
4- were
(Trimeth washed,
ylsilyl)in dried
dole (MgS04),
and
added to
1,4- evaporate
d.
bis(trimet
hylsilylin Chromat
ography
dole (7d)
of the
(261 mg)
residue
in dry
on silica
CH2C12
(12 g)
(10 mL).
gave the
After the
reaction following
in
was
sequence
stirred
of
for 4 h,
polarity
aqueous
(eluant
K2C03
CH2C12:
(10% , 8
EtOAc
mL) was
9:1 and
added
MeOH).
and the
4481
An oil —133 co
1570, h
1150 cm- e
I ; NMR m
(CDC13, .
60 MHz) ,
0.45 (s, 9
V
H), 2.7 (t,
o
2 H, J =
l
7.5 Hz),
.
3.25 (t,
2 H, J =
4
7.5 h),
9
3.7 (s, 3
,
H), 6.9-
7.5 (m, N
4 H), 8.1 o
(br m, 1 .
H);
J 2
. 3
,
o
r 1
4492 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
9 lsilyl)ind
8 ole (7e)
4 (0.231 g)
in dry
mass CH2C12
spectrum, (5 mL)
m/e 275 was
(M+0, added to
202, 186. a solution
Anal. of AIC13
Calcd for (0.667 g)
C15H21 in dry
NOSi: C, CH2C12
65.41; H, (10 mL)
7.68; N, under
5.08. N2. The
Found: mixture
C, 65.25; was
H, 7.86; stirred
H, 5.11. overnight
1,4- at room
Diacetyli temperat
ndole ure when
(70. I- HCl—
Acetyl-4- H20
(trimethy (0.25 M,
4493
20 mL) the
was residue
added. on silica
The (6 g)
aqueous gave
layer was (eluant
extracted CH2C12)
with 1,4-
CH2C12 diacetyli
(3 X 15 ndole
mL) and (7f)
the (0.191 g,
combine 95%):
d organic mp 110
extracts —113 o c
were (from
washed cyclohex
with ane); IR
H20, (CH2C12
dried )
(MgS04), 1710,
and 1675,
evaporate 1580;
d. Flash 1530,
chromato 1380,
graphy of 1320,
4494 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
1180, spectrum,
980, 935 m/e 201
cm-I ; (M+0,
NMR 159, 144,
(Me2CO- 116.
d6) 2.66 Anal.
(s, 3 H), Calcd for
2.71 (s, 3 C 12 H
H), 7.41 11N02:
(dd, 1 H, C, 71.63;
J = 4, 1 H, 5.51;
Hz), 7.44 N, 6.96.
(dd, 1 H, Found:
J = 8.5, C, 71.58;
7.5 Hz), H, 5.51;
7.91 (d, 1 N, 6.93.
H, J = 4 I-
Hz), 7.95 Acetyl-4-
(dd, 1 H, (3-
J = 7.5, 1 chloropro
Hz), 8.66 panoyl)in
(ddd, 1 dole (7g).
H, J = Method
8.5, 1, 1 1.
Hz); Reaction
mass of (0.23
4495
g), cyclohex
AIC13 ane); IR
(0.667 g), (CH2C12
and ) 1710,
CICH2C 1670,
H2COCl 1580,
(0.635 g) 1535,
in 1320,
CH2C12 1170,
(15 mL) 1120,
gave on 1010,
workup 930 cm-
and I ; NMR
chromato (CDC13)
graphy 2.67 (s,
on silica 3 H), 3.57
(8 g) (t, 2 H, J
(eluant = 6.5
CH2C12: Hz),
pentane 3.97 (t,
7:3) 7g 2 H, J =
(0.186 g, 6.5 Hz),
75%): 7.43
mp 120- (dd,
122 o c 1 H, J =
(from 8, 8 Hz),
4496 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
7.51 (dd, H, 4.84;
1 H, J = N, 5.61.
4, 0.5 Found C,
Hz), 7.57 62.47; H,
(d, 1 H, J 5.00; N,
= 4 Hz), 5.38.
7.84 (dd, Method
1 H, J = 2.
8, 0.5 Reaction
Hz), 8.74 of I-
(br d, 1 acetyl-4-
H, J = 8 (trimethy
Hz); lsilyl)ind
mass ole (7e)
spectrum, (200 mg)
m/e 251, in
249 CH2C12
(M+0, (5 ml,)
213, 209, with
207, 186, CHFCH
144, 116. COCI
Anal. (392 mg)
Calcd for and
C13H12 AIC13
ClN02: (577 mg)
C, 62.53; in
4497
CH2C12 CICH2C
(10 mL) OCl
gave on (0.565 g,
HCl— 0.39 mL)
H20 was
workup added
7g (130 and the
mg, resulting
60%). solution
I- stirred
Acetyl-6- until all
(chloroac the
etyl)-4- aluminu
(trimethy m
lsilyl)ind chloride
ole (19a). was
Anhydro solubilize
us AIC13 d. A
(0.667 g) solution
was of I-
suspende acetyl-4-
d in dry (trimethy
CH2C12 lsilyl)ind
(10 mL) ole 7e
under (0.231 g)
argon. in dry
4498 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
CH2C12 was
(5 mL) evaporate
was d in
added vacuo
dropwise and the
and the residue
resulting chromato
solution graphed
stirred at on silica
room H (20 g)
temperat eluting
ure for with
15 h. CH2C12
Hydrochl to give
oric acid 19a
(20 mL, (0.114 g,
0.25) was 37%):
added mp 194-
and the 196 o c;
organic IR
phase (nujol)
separated 1715,
after 1680,
washing. 1585,
The 1515,
CH2C12 1400,
4499
1330, (s, 1 H);
1295, mass
1240, spectrum,
1210, m/e 307
1190, (M+•)
1130, 292, 259,
1105, 258, 250,
955, 870, 235, 224,
840, 217, 216,
790 cm- 202, 186,
I ; NMR 172, 158,
(CDC13) 144.
0.42 (s, Anal.
9H), 2.69 Calcd for
(s, 3 H), C15H18
4.83 (s, 2 ClN02Si:
H), C, 58.52;
6.83 (br H, 5.89;
d, 1 H, J N, 4.55.
= 4 Hz), Found:
7.66 (d, 1 C, 58.44;
H, J = 3 H, 5.85;
Hz), 8.07 N, 4.54.
(d, 1 H, J Further
= 1.3 elution
Hz), 9.09 (CH2C12
4500 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
) of the I ; NMR
chromato (CDC13)
graphic 2.70 (s, 3
column H), 4.84
gave (s, 2 H),
crude 6.72 (d, 1
19b H, J = 4.0
(0.108 g, Hz), 7.63
46%): (d, 1 H, J
mp 186 = 4.0
—188 D Hz), 7.67
C; IR (d, 1 H, J
(nujol) = 8.0
1715, Hz), 7.95
1695, (dd, 1 H,
1525, J = 8.0,
1340, 1.2 Hz),
1320, 9.08 (s, 1
1255, H); mass
1215, spectrum,
1150, m/e 235
1120, (M +0,
1040, 193, 186,
950, 835, 145, 144,
785, 760, 130, 116,
740 cm-
4501
115, 100, the
89. residue
I- and the
Acetyl-4- mixture
propenoy extracted
lindole with
(7h). CH2C12
NaOH in (25 mL,
H20 (2 2 x 15
M, 0.5 mL). The
mL) was organic
added to layer was
7g (249 washed
mg) in with
THF (20 H20,
mL) and dried
the (MgS04),
mixture and
refluxed evaporate
for 6 h. d.
After Chromat
evaporati ography
on water of the
(10 mL) residue
was on silica
added to (8 g)
4502 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
gave 1 H, J =
(eluant 17, 1.5
CH2C12: Hz), 7.23
hexane (dd, 1 H,
7:3) 7h J = 17,
(0.178 g, 11 Hz),
84%): 7.41
mp 105 (dd, 1 H,
—108 o c J - 3.5,
(from 0.5 h),
cyclohex 7.43 (dd,
ane); IR 1 H, J =
(CH2C12 8, 8 Hz),
) 1710, 7.56 (d, 1
1660, H, J = 3.5
1320, Hz), 7.81
1180, (dd, 1 H,
1125 cm- J = 8, 0.7
I ; NMR Hz), 8.72
(CDC18) (br d, 1
2.69 (s, 3 H, J = 8
H), 5.95 Hz);
(dd, 1 H mass
J = 11, spectrum,
1.5 Hz), m/ e 213
6.44 (dd, (M +0,
4503
171, 144, mL) were
116. stirred at
Anal. room
Calcd for temperat
C13HllN ure for
02: C, 30 min.
73.22; H, HOAc
5.20; N, (53 mg)
6.57. was
Found: added
C, 73.47; and
H, 5.31; solvents
N, 6.55. were
4-(3- removed
Methoxy under
propanoy reduced
l)indole pressure.
(7i). The
K2C03 residue in
(34 mg) CH2C12
and 7h was
(50 mg) washed
in MeOH twice
— with
Me2CO H20,
(7:3, 5 dried
4504 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
(MgS04), = 6 Hz),
and 7.0-7.85
evaporate (m, 5 H),
d to leave 8.3—8.8
7i (52 (br m, 1
mg): mp H); mass
94—95 o spectrum,
c (from m/e 203
cyclohex (M+•),
ane); IR 171, 144,
(CH2C12 116, 89.
) 3460, Anal.
1665, Calcd for
1500, C12H13
1340, N02: C,
1115, 70.92; H,
1040 cm- 6.45; N,
I ; NMR 6.89.
(CDC13, Found:
60 MHz) C, 70.69;
3.35 H, 6.45;
(s, 3 H), N, 6.64.
3.33 (t, 2 4-
H, J = 6 Propenyli
Hz), 3.85 ndole
(t, 2 H, J (7j). As
4505
in the propenoy
foregoing lindole
experime (7j) (86
nt, mg,
reaction 97%) as
of 7g an
(129 mg) unstable
with yellow
K2C03 oil: NMR
(72 mg) (CDC13,
in MeOH 60 MHz)
— 5.81 (dd,
Me2CO 1 H, J =
(7:3, 10 11, 2.5
mL) for Hz), 6.37
0.5 h at (dd, 1 H,
room J = 17,
temperat 2.5 Hz),
ure, 6.83-7.78
quenchin (m, 6 H),
g with 8.8—9.4
HOAc (br m, 1
(0.3 mL), H); mass
and spectrum,
workup m/e 171
gave 4-
4506 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
(M+•), M, 6.5
144, 116. mL) and
3-[1- MeOH
(Trifluor (25 mL)
oacetyl)- for 30
4- min.
(trimethy After
lsilyl)ind evaporati
ol-3- on of the
yl]propan MeOH
oic Acid the
(228). residue
The was
crude dissolved
ester 16g, in H20
prepared (15 mL)
from the and
Bu3SnH CH2C12
denitratio (10 mL).
n of 16e H3P04—
(433 H20
mg), was (10%)
refluxed was
with cautiousl
aqueous y added
NaOH (1 to the
4507
aqueous residue
layer to was
pH 2.6 chromato
maintaini graphed
ng the on Si02
temperat (10 g) to
ure at O Q give
C. This (eluant
was EtOAc:C
saturated H2C12
with 4:6) the
NH4Cl crude
and carboxyli
extracted c acid 16i
with (158 mg,
EtOAc (4 53%):
x 20 NMR
mL). (Me2CO-
After d6, 60
drying MHz) ö
(MgS04), 0.42 (s, 9
the H), 2.5-
organic 2.9
layer was (br t, 2
evaporate H, J = 8
d and the Hz),
4508 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
3.05-3.42 mixture
(br t, 2 H, was
J=8 cooled
Hz), down to
6.82-7.55 —50 o c
(m, 4 H), when
9.7— trifluorac
10.15 (m, etic
1 H). The anhydrid
crude e (260
product AIL) was
16i (158 added.
mg) was The
dissolved mixture
in DMF was
(2.5 mL) warmed
and NaH up to
(44 mg) room
was temperat
added. ure and
After the
ultrasoni solvent
c removed
agitation under
for 2 h reduced
the pressure.
4509
Chromat 910 and
ography 840 cm-I;
on silica NMR
gave (Me2CO-
(eluant d6,
CH2C12: 60 MHz)
EtOAc 0.48 (s, 9
9:1) the H), 2.4-
N- 3.0 (br t,
trifluoroa 2 H, J =
cetyl 6 Hz),
derivativ 3.0-3.37
e 22a (br t, 2 H,
(67 mg, J=6
31 Hz),
170—173 7.17-7.7
o
c (from (m, 3 H),
cyclohex 8.42 (dd,
ane); IR 1 H, J =
(CH2C12 8, 1.5
) Hz);
3500- mass
2500, spectrum,
1725, m/e 357
1200, (M+•),
1160, 342, 226.
4510 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
Anal. was
Calcd for added to
C16H18 KH (35%
F3N03Si: in oil, 36
C, 53.77; mg) in
H, 5.08; THF at
N, 3.92. —50 0 C.
Found: The
C, 53.61; mixture
H, 5.32; was
N, 3.87. stirred at
Methyl —30 o c
3-[4- for 45
(Trimeth min
ylsilyl)- when
1-(tolyl- TsCl (52
4- mg) in
sulfonyl)i THF (1
ndol- mL) was
3yl]propa added.
noate The
(22b). yellow
Ester 16h suspensio
(50 mg) n was
in THF stirred at
(1.5 mL) room
4511
temperat gave
ure for (eluant
30 min. CH2C12:
After hexane
evaporati 85:15)
on the the N-
residue tosyl
was derivativ
dissolved e 22b (75
in Et20, mg,
washed 94%) as
with pH an oil: IR
4 buffer, (CHC13)
aqueous 1730,
NaHC08 1450,
(10% ), 1380,
and H20, 1170 cm-
dried I ; NMR
(Na2S04) (CDC13,
, and 60 MHz),
evaporate 0.4 (s, 9
d. H), 2.3
Chromat (s, 3 H),
ography 2.7
on silica (m, 2 H),
(4 g) 3.1 (m, 2
4512 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
H), 3.65 (156 mg)
(s, 3 H), was
7.1 (d, 2 dissolved
H, J = 8 in MeOH
Hz), 7.3 (1.6 mL),
(m, 3 H), aqueous
7.65 (d, 2 NaOH (1
H, J = 8 M, 0.4
Hz), 8.0 mL) was
(dd, 1 H, added,
J = 8, 1.5 and the
Hz); mixture
mass was
spectrum, heated at
m/e 429 60 o c for
(M+•), 3 h. After
414, 340. evaporati
Cyclizat on the
ion of the residue
Indolepro was
panoic suspende
Acid d in PhH
Derivativ and
e 22c. reevapora
Methyl ted
ester 22b (twice).
4513
The solid was
was dried added
overnight and the
under mixture
vacuum. was
CH2C12 stirred
(15 mL) overnight
followed at room
by temperat
(EtO)2P( ure.
O)CI (53 Water
#1,) were was
added at added
0 o c and and the
the aqueous
mixture layer was
was extracted
stirred at with
room CH2C12.
temperat The
ure for 30 combined
min. organic
Freshly layers
resublime were
d AIC13 dried
(97 mg) (NaS04)
4514 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
and hexane)
evaporate (lit.m mp
d. 143—
Chromat 144 o c);
ography IR
of the (CDC13)
residue 1690,
on silica 1435,
(8 g) 1360,
gave 1300,
(eluant 1180,
CH2Cb:E 1110,
tOAc 1:0, 1030 cm-
95:5, 1:1) I ; NMR
the (CDC13)
following 2.35 (s, 3
in order H), 2.85
of (t, 2 H, J
increasin = 8 Hz),
g 3.2 (dt, 2
polarity. H, J = 8,
21a (6 1.5 Hz),
mg, 5%): 7.25 (d, 2
mp 142 H, J = 8
—143 o c Hz), 7.35
(from (t, 1 H, J
4515
= 1.5 —154 c o
Celite (from
and Et20 at
concentra —60 0
ted. C); IR
Chromat (KBr)
ography 3040,
of the 2985,
residue 2885,
on silica 1645,
gel (25 g) 1515,
with 1495,
Et20:hex 1465,
anes 1400,
(80:20) 1255, We
gave have
N,N- recently
dimethyl- described
4- a
(trimethy convenie
lsilyl)ben nt, high-
zamide yield
(26) synthesis
(0.98 g, of the
42%): novel
mp 45— four-
4528 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
membere toluenesu
d lfonic
heterocyc acid
le 3- monohyd
oxo1,2- rate
diazetidin (Scheme
ium 1). 1 With
tosylate the
(2) by ultimate
hydrolysi objective
s of l,l- of
diphenyl introduci
methylen ng
e-3-oxo- substitue
1,2- nts into
diazetidin the
ium inner diazetidin
salt 1 one ring
(available system
in two capable
steps of
from eventual
benzophe intramole
none cular
hydrazon cyclizatio
e) with p- n to give
4529
bridgehea normal
d aza strategies
analogue for the
s of the synthesis
ß-lactam of
antibiotic carbapen
s, we ems from
have monocycl
initiated ic ß-
a lactams,
program the
aimed at intramole
functiona cular
lization carbene
of 2 at N- insertion
l, N-2, reaction,3
and C-4. was
We have applied
already to the
described aza-ß-
our lactam
unexpect system.
ed Other
results2 strategies
when one based on
of the intramole
4530 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
cular 1981,
Wittig,4 103,
Horner— 7743.
Emmons, (2) Tay
5
aldol,6 or lor, E. C.;
Dieckma Davies,
nn H. M. L.
cyclizatio J. org.
ns7 would Chem.
require as 1984, 49,
precursor 113.
s a side- (3) (a)
chain Cama, L.
aldehyde. D.;
In order Christens
to apply en, B. G.
the Tetrahedr
on Lett.
Tay 1978,
(1)
material
Tso .
3
Table
8
1.
C
Synthe
6
sis of
H
I-
4
Substit
C
uted
l
1,2-
-
Diazeti
4
din-3-
H
ones
H C—CH3
o 7
o 8
3
4535
b C
C H
H 3
— 9
C 5
H CH—
C CHC6H5
6
H CH2CH3
5 95
H
CH2C6H
H 5 CH372
44
8 C
2 H
C 8
H 3g
= CHs12
C 36
H
C 3i
6 —
H CHC6H5
5 CH8
H 70
4536 J. Org. Chem., Vol. 49, No. 23, 1984 Barrett et al.
ones
— with
CHC6H5 latent
CH3 CHs aldehyd
81 e
substitu
latter
ents at
three
position
procedu
1. We
res to
also
the
report
preparat
our
ion of
initial
bicyclic
results
1,2diaz
etidin- 0 1984
3-ones American
(aza-ß- Chemical
lactams Society
), we
have
prepare
da
number
of 1,2-
diazetid
in-3-
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