Preparation and 1,3-dipolar cycloaddition reactions of β-carboline azomethine ylides: A direct entry into C-1- and/or C-2-functionalized indolizino[8,7-b]indole derivatives

Article abstract of DOI:10.1021/jo951520t

Treatment of norharman with (trimethylsilyl)methyl triflate in dichloromethane gave 2-N[(trimethylsilyl)methyl]-β-carboline triflate (10). The latter reacted with diethyl acetylenedicarboxylate (11a) or ethyl propiolate (11b) in the presence of cesium fluoride to afford, via 1,3-dipolar cycloaddition, the indolizino[8,7-b]indole derivatives 13a or 13b, respectively. In a similar manner, the (trimethylsilyl)methyl triflate salt of ethyl 9-N-(p-toluenesulfonyl)-β-carboline-3-carboxylate (16) reacted with 11a to give the cycloaddition product 17. The (trimethylsilyl)methyl triflates of 3,4-dihydro-β-carbolines were also prepared (20a-c) and shown to be more reactive than their fully aromatic counterparts 10 and 16 in cycloaddition reactions. Thus, the 9-N-benzyl derivative 20b reacted with 11a in the presence of cesium fluoride to give the cycloaddition products 21 and 22 as well as the novel azepine derivative 23. Moreover, unlike 10 and 16, the azomethine ylides generated from 20a-c reacted with electron-deficient olefins, producing 1,2,3,5,6,11b-hexahydroindolizino[8,7-b]indole derivatives. In the case of symmetrically substituted olefins (dimethyl maleate, dimethyl fumarate, fumaronitrile), the cycloaddition reactions were completely stereospecific. However, with unsymmetrically substituted olefins (methyl acrylate, acrylonitrile), cycloaddition reactions were generally neither regio- nor diastereoselective. In the case of 20b, both the regio- and the diastereoselectivities of the cycloaddition reactions were greatly improved compared to 20a and 20c, suggesting that these two stereochemical factors can be controlled by manipulation of the protecting group at the 9-N position of the 3,4-dihydro-β-carbolines. The hexahydroindolizino[8,7-b]indoles 33 and 37 could be selectively dehydrogenated at the 11b, 1 positions using potassium permanganate in THF to afford the tetrahydroderivatives 58 and 50, respectively. Treatment of 58 with 1 equiv of DDQ led to further selective dehydrogenation at the 2,3 positions, producing the 5,6-dihydro compound 60. Alternatively, 33 and 37 could be completely dehydrogenated using 3 equiv of DDQ to give the fully aromatic indolizino[8,7-b]indole-1,2-dicarboxylates 56 and 57, respectively.

Full text of DOI:10.1021/jo951520t

J . Org. Chem. 1996, 61, 2273-2282
2273
P r ep a r a tion a n d 1,3-Dip ola r Cycloa d d ition Rea ction s of
â-Ca r bolin e Azom eth in e Ylid es: A Dir ect En tr y in to C-1- a n d /or
C-2-F u n ction a lized In d olizin o[8,7-b]in d ole Der iva tives
Guillaume Poissonnet,†,1 Marie-He´le`ne The´ret-Bettiol,‡,1 and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique,
91198 Gif-sur-Yvette Cedex, France
Received August 16, 1995X
Treatment of norharman with (trimethylsilyl)methyl triflate in dichloromethane gave 2-N-
[(trimethylsilyl)methyl]-â-carboline triflate (10). The latter reacted with diethyl acetylenedicar-
boxylate (11a ) or ethyl propiolate (11b) in the presence of cesium fluoride to afford, via 1,3-dipolar
cycloaddition, the indolizino[8,7-b]indole derivatives 13a or 13b, respectively. In a similar manner,
the (trimethylsilyl)methyl triflate salt of ethyl 9-N-(p-toluenesulfonyl)-â-carboline-3-carboxylate (16)
reacted with 11a to give the cycloaddition product 17. The (trimethylsilyl)methyl triflates of 3,4-
dihydro-â-carbolines were also prepared (20a -c) and shown to be more reactive than their fully
aromatic counterparts 10 and 16 in cycloaddition reactions. Thus, the 9-N-benzyl derivative 20b
reacted with 11a in the presence of cesium fluoride to give the cycloaddition products 21 and 22 as
well as the novel azepine derivative 23. Moreover, unlike 10 and 16, the azomethine ylides
generated from 20a -c reacted with electron-deficient olefins, producing 1,2,3,5,6,11b-hexahydroin-
dolizino[8,7-b]indole derivatives. In the case of symmetrically substituted olefins (dimethyl maleate,
dimethyl fumarate, fumaronitrile), the cycloaddition reactions were completely stereospecific.
However, with unsymmetrically substituted olefins (methyl acrylate, acrylonitrile), cycloaddition
reactions were generally neither regio- nor diastereoselective. In the case of 20b, both the regio-
and the diastereoselectivities of the cycloaddition reactions were greatly improved compared to
20a and 20c, suggesting that these two stereochemical factors can be controlled by manipulation
of the protecting group at the 9-N position of the 3,4-dihydro-â-carbolines. The hexahydroindolizino-
[8,7-b]indoles 33 and 37 could be selectively dehydrogenated at the 11b, 1 positions using potassium
permanganate in THF to afford the tetrahydro derivatives 58 and 59, respectively. Treatment of
58 with 1 equiv of DDQ led to further selective dehydrogenation at the 2,3 positions, producing the
5,6-dihydro compound 60. Alternatively, 33 and 37 could be completely dehydrogenated using 3
equiv of DDQ to give the fully aromatic indolizino[8,7-b]indole-1,2-dicarboxylates 56 and 57,
respectively.
Sch em e 1
In tr od u ction
Indolizino[8,7-b]indole derivatives (general formula 1,
Scheme 1) have over several decades been used as
synthetic intermediates for the preparation of more
complex alkaloids. Most of these preparations have been
based on the propensity of the quaternized form of 1 (i.e.
2) to undergo nucleophile-induced ring opening, yielding
an indolic species having a fused 9-membered ring (3), a
dominant theme found in a good number of naturally
occurring substances. This general strategy was used
successfully by both Wenkert2 and Kutney3 in their
approaches to the synthesis of quebrachamine and
provided a general entry to iboga and vinca alkaloids.4
The preparation of dihydrocleavamines was also based
on this principle.5 The 3-oxo derivatives of 1, in addition
to being a newly described class of naturally occurring
alkaloids,6 have proven to be useful as intermediates for
the preparation of canthinones7 and of trichotomine,8,9
a
blue pigment of plant origin, as well as serving as a
â-turn dipeptide mimic.10
Molecules of general structure 1 have primarily been
constructed by reacting a tryptamine or tryptophan
derivative with species carrying an aldehyde (or ketone)
and a second functional group (usually an ester) sepa-
† Present address: Institut de Recherches International Servier, 11,
rue des Moulineaux, 92150 Suresnes, France.
‡ Present address: Department of Chemistry, The University of
Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE1 7RU, Great Britain.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) G.P. and M.-H.T.-B. contributed equally to the synthetic work
presented in this paper.
(6) Yahara, S.; Donato, H.; Sugimura, C.; Nohara, T.; Niiho, Y.;
Nakajima, Y.; Ito, H. Phytochemistry 1994, 37, 1755.
(7) Hagen, T. J .; Narayanan, K.; Names, J .; Cook, J . M. J . Org.
Chem. 1989, 54, 2170.
(8) Iwadare, S.; Shizuri, Y.; Yamada, K.; Hirata, Y. Tetrahedron
1978, 34, 1457.
(9) Irikawa, H.; Enomoto, M.; Shimoda, Y.; Atsumi, T.; Okumura,
Y.; Iijima, K. Bull. Chem. Soc. J pn. 1994, 67, 1931.
(10) de la Figuera, N.; Rozas, I.; Garcia-Lopez, T.; Gonzalez-Muniz,
R. J . Chem. Soc., Chem. Commun. 1994, 613.
(2) Wenkert, E.; Garratt, S.; Dave, K. G. Can. J . Chem. 1964, 42,
489.
(3) Kutney, J . P.; Abdurahman, N.; Gletsos, C.; Le Quesne, P.; Piers,
E.; Vlattas, I. J . Am. Chem. Soc. 1970, 92, 1727.
(4) Kutney, J . P.; Cretney, W. J .; Le Quesne, P.; McKague, B.; Piers,
E. J . Am. Chem. Soc. 1970, 92, 1712.
(5) (a) Harley-Mason, J .; Atta-ur-Rahman; Beisler, J . A. J . Chem.
Soc., Chem. Commun. 1966, 743. (b) Harley-Mason, J .; Atta-ur-
Rahman. J . Chem. Soc., Chem. Commun. 1967, 1048.
0022-3263/96/1961-2273$12.00/0 © 1996 American Chemical Society

2274 J . Org. Chem., Vol. 61, No. 7, 1996
Poissonnet et al.
Sch em e 2
Sch em e 3
rated by three carbon atoms.5a,7,9-12 Pictet-Spengler
condensation with the aldehyde first gives rise to an
intermediate tetrahydro-â-carboline derivative. The re-
sulting secondary amine then reacts intramolecularly
with the second functional group effecting ring closure.
Alternatively, tryptamine or tryptophan can first be
converted into their succinimide derivatives and cycliza-
tion to a â-carboline structure can be accomplished under
Bischler-Napieralski conditions3,8 or via mercuric acetate-
induced formation of an intermediate iminium species.4
In nearly all these cases, 3-oxo derivatives of 1 are
obtained and reduction of the amide is required to
produce a pyrrolidine nucleus. Reaction of a 3,4-dihydro-
â-carboline with 2-acetoxyacrylates has also been re-
ported to give, among other products, 3-oxo derivatives
of 1.13
One of the most powerful methods of forming pyrroli-
dine rings is the [3 + 2] cycloaddition reaction of
azomethine ylides (general formula 4, Scheme 2) with
olefins.14 The advantages of this approach reside in the
high degree of regio- and stereoselectivity observed in
these types of reactions as well as the great variety of
substituents which can be incorporated on the final
pyrrolidine product. This variety is tempered by the
necessity of utilizing electron-deficient unsaturated di-
polarophiles (i.e., 5) and, depending on how the ylide 4
is formed, the necessity of stabilizing the negative charge,
usually with an electron-withdrawing R3 group. The
introduction by Vedejs and Martinez15 of in situ fluoride
ion-induced desilylation of [(trimethylsilyl)methyl]imin-
ium triflates (7) as a mild procedure for the generation
of nonstabilized azomethine ylides (i.e., 8) has obviated
this last requirement. A large number of multiply
substituted pyrrolidine derivatives have been prepared
by this methodology which demonstrates the tremendous
versatility of the reaction.16
the transformation of a â-carboline nucleus into an
azomethine ylide has received little attention. Grigg and
co-workers20 have described methods by which tetrahy-
dro-â-carbolines are converted into iminium ions by
reaction of the secondary amine function with aldehydes.
Subsequent azomethine formation can be achieved by an
intramolecular proton shift, by base-promoted proton
abstraction, or by decarboxylation of an adjacent car-
boxylate group. Cycloadditions of these â-carboline ylides
with only one dipolarophile, N-methylmaleimide, have
been reported.
We have chosen to study the possibility of generating
â-carboline azomethine ylides using the desilylation
procedure. Although, as noted above, ylides produced
from pyridine by this method provide cycloaddition
products with acetylenic dipolarophiles but not with
olefins, this problem could be surmounted by using ylides
derived from the easily accessible, and presumably more
reactive 3,4-dihydro-â-carbolines. We report herein the
successful formation of azomethine ylides from fully
aromatic â-carbolines as well as from 3,4-dihydro-â-
carbolines via fluoride ion-promoted desilylation tech-
niques and the 1,3-dipolar cycloaddition reactions of these
ylides with acetylenic and acetylenic/olefinic dipolaro-
philes, respectively, to give 1- and/or 2-substituted in-
dolizino[8,7-b]indole derivatives.21
The pyridinium nucleus, via a (trimethylsilyl)methyl
triflate salt, readily forms an azomethine ylide, and
subsequent cycloaddition with electron-deficient acetyl-
enic dipolarophiles affords indolizine derivatives.17,18 With
ethylenic dipolarophiles, this reaction is not useful since
the main products observed result from transfer of the
methylene group from the pyridinium moiety to the olefin
(a process referred to as hydroalkylidenation).19
I. Rea ctivity of Azom eth in e Ylid es Der ived fr om
F u lly Ar om a tic â-Ca r bolin es. The feasibility of form-
ing reactive azomethine ylides in the â-carboline family
of compounds via desilylation of the R-silylmethonium
salts was first verified on the simplest representative,
norharman 9 (Scheme 3). Following the procedure
originally described by Vedejs and Martinez,15 quater-
Despite the obvious potential for the preparation of
substituted indolizino[8,7-b]indole derivatives of type 1,
(11) Corsano, S.; Algieri, S. Ann. Chim. (Italy) 1960, 50, 75.
(12) Chen, C.; Senanayake, C. H.; Bill, T. J .; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . J . Org. Chem. 1994, 59, 3738.
(13) (a) Giri, V. S.; Das, S. K.; Sankar, P. J .; Shoolery, J . N.; Keifer,
P. J . Heterocycl. Chem. 1992, 29, 767. (b) Giri, V. S.; Maiti, B. C.;
Mandal, S. B.; Pakrashi, S. C. J . Chem. Res., Synop. 1988, 342.
(14) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, 1984; Vol. 1, 2.
(19) (a) Tsuge, O.; Kanemasa, S.; Takenaka, S. Heterocycles 1983,
20, 1907. (b) Tsuge, O.; Kanemasa, S.; Kuraoka, S.; Takenaka, S.
Chem. Lett. 1984, 281. (c) Tsuge, O.; Kanemasa, S.; Takenaka, S.;
Kuraoka, S. Chem. Lett. 1984, 465.
(15) (a) Vedejs, E.; Martinez, G. R. J . Am. Chem. Soc. 1979, 101,
6452. (b) Vedejs, E.; Martinez, G. R. J . Am. Chem. Soc. 1980, 102,
7993.
(16) For reviews, see: (a) Vedejs, E.; West, F. G. Chem. Rev. 1986,
86, 941. (b) Terao, Y.; Aono, M.; Achiwa, K. Heterocycles 1988, 27,
981.
(20) (a) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond,
D. J . Chem. Soc., Chem. Commun. 1987, 47; 1987, 49. (b) Araill, H.;
Fontaine, X. L. R.; Grigg, R.; Henderson, D.; Montgomery, J .; Sridhran,
V.; Surendrakumar, S. Tetrahedron 1990, 46, 6449. (c) Grigg, R.;
Rankovic, Z.; Thornton-Pett, M.; Somasunderam, A. Tetrahedron 1993,
49, 8679.
(17) Tsuge, O.; Kanemasa, S.; Kuraoka, S.; Takenaka, S. Chem. Lett.
1984, 279.
(18) Miki, Y.; Hachiken, H.; Takemura, S.; Ikeda, M. Heterocycles
1984, 22, 701.
(21) Portions of this work have been presented as communications:
(a) Poissonnet, G.; Potier, P.; Dodd, R. H. Tetrahedron Lett. 1989, 30,
3423. (b) Poissonnet, G.; The´ret, M.-H.; Dodd, R. H. Heterocycles 1993,
36, 435.

Cycloaddition Reactions of â-Carboline Azomethine Ylides
J . Org. Chem., Vol. 61, No. 7, 1996 2275
Sch em e 4
nization of compound 9 with (trimethylsilyl)methyl tri-
flate in dichloromethane for 2 h at room temperature
gave the triflate salt 10 in quantitative yield. No
competitive N-9 alkylation was observed under the mild
conditions of this reaction. Subsequent treatment of 10
with cesium fluoride and diethyl acetylenedicarboxylate
(DEAD, 11a ) in refluxing dimethoxyethane afforded the
indolizino[8,7-b]indole derivative 13a in 35% yield via
1,3-dipolar cycloaddition of 11a with the â-carboline
azomethine ylide 12 formed in situ. Although the 3,11b-
dihydro derivative 14 would initially be formed by the
cycloaddition of DEAD with 12, only the fully aromatic
species 13a could be isolated from the reaction mixture.
This result is analogous to that obtained when acetylene
dicarboxylates react with azomethine ylides generated
from pyridinium or isoquinolinium N-[(trimethylsilyl)-
methyl]triflate salts.17,18,22 In contrast, nonaromatic
azomethine ylides react with acetylenic dipolarophiles to
give stable dihydropyrrole derivatives,23-25 but if a leav-
ing group is present (for example, in imidate and thio-
imidate derived dipoles),26,27 only pyrroles are isolated.
[3 + 2]-Dipolar cycloaddition reactions of azomethine
ylides with unsymmetrical dipolarophiles have generally
been observed to be highly regioselective. This regiose-
lectivity has been rationalized in terms of frontier mo-
lecular orbital (FMO) theory whereby the HOMO of the
dipole with the highest coefficient interacts with the
similar LUMO of the dipolarophile.14,28-31 Thus, in order
to verify the possible regioselectivity of cycloaddition
reactions to â-carboline ylides of type 12, the triflate salt
10 was reacted with ethyl propiolate 11b in the presence
of cesium fluoride. A single compound, corresponding to
regioisomer 13b, was obtained, albeit in low yield (8%).
The possibility of forming azomethine ylides from the
pharmacologically relevant alkyl esters of â-carboline-3-
carboxylic acid (e.g., 15, Scheme 4) using this methodol-
ogy was also investigated. However, N-2 alkylation of
15 with (trimethylsilyl)methyl triflate in dichloromethane
was somewhat recalcitrant, and only partial quaterniza-
tion was observed under the same reaction conditions (2
h at room temperature) that afforded complete quater-
nization of 9. Increasing reaction times and/or temper-
atures improved the levels of N-2 alkylation but also led
to competitive N-9 alkylation. The increased difficulty
of alkylating N-2 of â-carboline 15 may be ascribed to
both the steric hindrance and inductive effects provided
by the carboxylic ester group at C-3.32 Consequently,
compound 15 was transformed into its N-9 tosylated
derivative 16, thereby allowing subsequent N-2 alkyla-
tion with (trimethylsilyl)methyl triflate to proceed over
extended reaction periods without overt interference from
N-9 alkylation. Though complete N-2 alkylation could
not be achieved even after 5 h (decomposition products
beginning to appear beyond this time), the mixture of
quaternized 16 and unreacted 16 (∼9:1 by 1H NMR) was
used directly to effect a cycloaddition reaction. Thus,
treatment of this crude mixture in dimethoxyethane with
cesium fluoride and DEAD yielded cycloaddition product
17 together with unreacted 16. Compound 17 could then
be efficiently de-N-tosylated to provide 18 using a cata-
lytic quantity of sodium ethoxide in ethanol.
II. Rea ctivity of Azom eth in e Ylid es Der ived fr om
3,4-Dih yd r o-â-ca r bolin es. Although the preceding ex-
periments prove that â-carboline-derived azomethine
ylides are accessible by desilylation techniques, the yields
obtained in the cycloaddition reactions of these dipoles
with activated alkynes were disappointingly low. We
therefore decided to study the reactivity of azomethine
ylides generated from 3,4-dihydro-â-carbolines by similar
techniques in the hope that cycloadditions would be
favored by the nonaromatic character of the dihydropy-
ridinyl ring. For this purpose, the 3,4-dihydro-2-N-
[(trimethylsilyl)methyl]-â-carbolinium triflate salts 20a-c
were prepared in high yield and in analytically pure form
by treatment of 3,4-dihydronorharman (19a ),33 9-N-
1
The regiochemistry of 13b is evident from the H NMR
spectrum in which the pyrrole hydrogens H-2 and H-3
are observed as coupled doublets (J ) 3.0 Hz) at δ 7.22
and 7.33, respectively, a pattern compatible with the
presence of the carboxylic ester substituent at C-1 rather
than at C-2.23,27 This regioisomer corresponds to that
predicted by FMO theory, but the low yield of product
obtained makes it hazardous to draw conclusions regard-
ing regioselectivity of cycloaddition in the case of fully
aromatic â-carbolines. However, as will be seen in the
dihydro-â-carboline series where cycloaddition product
yields are higher (discussed below), lack of regioselectiv-
ity appears to be the rule.
(22) Kakehi, A.; Ito, S. Bull. Chem. Soc. J pn. 1974, 47, 938.
(23) Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. J . Org.
Chem. 1985, 50, 4006.
(24) Achiwa, K.; Motoyama, T.; Sekiya, M. Chem. Pharm. Bull. 1983,
31, 3939.
(25) Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 2646.
(26) Vedejs, E.; West, F. G. J . Org. Chem. 1983, 48, 4773.
(27) Padwa, A.; Haffmanns, G.; Tomas, M. J . Org. Chem. 1984, 49,
3314.
(28) (a) Houk, K. N.; Sims, J .; Duke, R. E.; Strozier, R. W.; George,
J . K. J . Am. Chem. Soc. 1973, 95, 7287. (b) Houk, K. N.; Sims, J .;
Watts, C. R.; Luskus, L. J . J . Am. Chem. Soc. 1973, 95, 7301. (c) Houk,
K. N. Acc. Chem. Res. 1975, 8, 361.
(29) Bianchi, G.; de Michelli, C.; Gandolfi, R. 1,3-Dipolar Cycload-
ditions Involving X ) Y Group. In The Chemistry of Double-Bonded
Functional Groups; Patai, S., Ed.; Wiley: New York, 1977; Part 1, p
639.
(30) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(31) For examples of nonregioselective cycloaddition reactions of
azomethine ylides, see: (a) Achiwa, K.; Imai, N.; Motoyama, T.; Sekiya,
M. Chem. Lett. 1984, 2041. (b) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa,
K. Chem. Pharm. Bull. 1985, 33, 896. (c) Imai, N.; Terao, Y.; Achiwa,
K. Heterocycles 1985, 23, 1107. (d) Imai, N.; Terao, Y.; Achiwa, K.
Chem. Pharm. Bull. 1987, 35, 2085. (e) Imai, N.; Achiwa, K. Chem.
Pharm. Bull. 1987, 35, 2646. (f) Imai, N.; Tokiwa, H.; Akahori, Y.;
Achiwa, K. Chem. Lett. 1986, 1113, as well as refs 15a, 16a, 23, and
27.
(32) Dodd, R. H.; Poissonnet, G.; Potier, P. Heterocycles 1989, 29,
365.

2276 J . Org. Chem., Vol. 61, No. 7, 1996
Poissonnet et al.
Sch em e 5
Sch em e 7
Sch em e 6
Sch em e 8
A two-dimensional carbon-proton shift NMR of 23
corroborated this structural assignment.
benzyl-3,4-dihydronorharman (19b),34 and 6-methoxy-
3,4-dihydronorharman (19c) with (trimethylsilyl)methyl
triflate (Scheme 5).
The formation of 1:2 adducts of type 23 is not a
particularity of the dihydro-â-carboline family of com-
pounds since reaction of DEAD with the ylide derived
from 3,4-dihydro-N-[(trimethylsilyl)methyl]isoquinolinium
triflate 25 (Scheme 7) also gave an azepine derivative
analogous to 23 (i.e., 27) together with the expected
pyrrolo[2,1-a]isoquinoline 26 in practically equivalent
yields (29% and 28%, respectively).
We next decided to study the stereospecificity of the
cycloaddition reaction of the dihydro-â-carboline-derived
azomethine ylides with symmetrically substituted electron-
poor olefins. Thus, 20a and dimethyl maleate (28) gave,
in the presence of cesium fluoride, a mixture of the cis-
1,2-dicarboxylic ester cycloaddition products (()-29 and
(()-30 in 38% and 24% yield, respectively (Scheme 8).
The structures of these compounds were elucidated with
the aid of homonuclear 1H-1H two-dimensional NMR
spectroscopy. Thus, the H-11b signals of 29 and 30
appeared as doublets at δ 4.62 and δ 4.23, respectively,
with J 11b,1 values of 9.0 Hz (cis) and 7.0 Hz (trans).35
Furthermore, the cis relationship of the ester functions
in 29 and 30 was indicated by H1-H2 coupling constants
of 9.0 Hz in both cases. These results demonstrate that
the cycloaddition reaction of the ylide derived from 20a
with dimethyl maleate is highly stereospecific, the cis
geometry of the former being completely retained in the
products 29 and 30.
Since the indolic nitrogen atom of 20a is sensitive to
alkylation by acetylenics, cycloadditions were first at-
tempted on the 9-N-benzyl triflate salt 20b. Exposure
of the latter to DEAD in the presence of cesium fluoride
led to the formation of three compounds, 21-23 (Scheme
6), which were separated by chromatography. The major
product, 21, results from the expected cycloaddition of
DEAD with the dipole produced by desilylation of dihy-
dro-â-carboline 20b to give an intermediate of type 14.
The latter undergoes a 1,3 hydrogen migration to the
thermodynamically more stable 1,11b-dehydro species 21.
The oxidation level of this molecule was indicated by
mass spectroscopy which showed the appropriate molec-
ular ion peak. The migration of the double bond to the
1
1,11b position was evident from the H NMR spectrum
in which H-2 and H-3 clearly comprised an ABM system.
Compound 22 is the product of partial dehydrogenation
of 21. In contrast to the cycloaddition reaction of DEAD
with 10, where the analogous compound 13a was the only
product observed, formation of 22 represents only a minor
reaction pathway. Compound 22 displayed a one-proton
singlet at δ 7.48 which corresponds to the uncoupled
pyrrolic hydrogen atom at C-3, while H-5 and H-6 showed
the typical A2B2 triplet pattern at δ 4.18 and 3.18,
respectively.
A more unusual product, 23, is formed by the reaction
of DEAD with the dipole generated from 20b. This 1:2
adduct was produced in almost the same yield as the 1:1
adduct 21. The incorporation of two molecules of DEAD
in 23 was evident from the mass spectrum, which
displayed the molecular ion peak, and its 1H NMR
spectrum in which the four ethyl ester groups were
clearly visible. Moreover, the position of the double bonds
in the azepine ring of 23 was evident from the ABM
pattern of H-4 and H-5 (analogous to H-2 and H-3 of 21).
Complete stereospecificity was also observed in the
cycloaddition reactions of the trans olefins dimethyl
fumarate (31) and fumaronitrile (32) with 20a , yielding
the 1,2-trans-substituted dicarboxylic esters (33 and 34)
and dinitriles (35 and 36), respectively (Scheme 9).
Similarly, the 6-methoxy-5,6-dihydro-â-carboline triflate
20c reacted with 31 in the presence of cesium fluoride
to give the expected trans cycloaddition products 37 and
38. The stereochemical assignments of compounds 33-
(35) These attributions are consistent with 1H NMR data published
for similarly substituted pyrrolidine compounds. For examples, see
refs 21, 23, 24, and 31d as well as: (a) Bende, Z.; To¨ke, L.; Weber, L.;
Toth, G.; J anke, F.; Csonka, G. Tetrahedron 1984, 40, 369. (b) Toth,
G.; Frank, J .; Bende, Z.; Weber, L.; Simon, K. J . Chem. Soc., Perkin
Trans. 1 1983, 1961.
(33) Kanaoka, Y.; Sato, E.; Ban, Y. Chem. Pharm. Bull. 1967, 15,
101.
(34) Norak, L.; Szantay, C. Chem. Ber. 1969, 102, 3959.

Cycloaddition Reactions of â-Carboline Azomethine Ylides
J . Org. Chem., Vol. 61, No. 7, 1996 2277
Sch em e 9
Sch em e 11
compounds 41 and 43, each formed in approximately 20%
yield, were shown by NMR and chemical transformations
to correspond to the two C-1 regioisomers arising from
exo and endo approaches of the dipole and the dipolaro-
phile, respectively. The identical regiochemistry of 41
and 43 was indicated by 1H NMR decoupling experiments
where H-11b appears as a doublet (J ) 6.0 and 9.0 Hz,
respectively) in both cases. Moreover, both compounds,
when treated with DDQ, gave the same 1-cyanoin-
dolizino[8,7-b]indole 45 (Scheme 11) in which H-2 and
H-3 appeared as coupled, vinylic protons. This pattern
is only possible if the cyano function is at C-1. The
relative stereochemistry at C-1 and C-11b was confirmed
by 13C NMR, both carbons resonating at higher field in
the cis derivative 43 (δ 31.3 and 60.3, respectively) than
in the trans derivative 41 (δ 32.3 and 62.5).36
Sch em e 10
In the case of the minor products 42 and 44, isolated
in 8% and 12% yields, respectively, the appearance of
1
H-11b as a doublet of doublets in their H NMR spectra
was consistent with the presence of the cyano group at
C-3 while the relative stereochemistries of H-11b and H-2
were determined by NOE difference NMR spectroscopy.37
Reaction of 20a with methyl acrylate (40) also gave
four products (46-49) which could be easily separated
by chromatography on silica gel. The regioselectivity was
similar to that obtained with acrylonitrile, the C-1 regio-
isomers (46 + 48: 40%) being favored over the C-2 regio-
isomers (47 + 49: 28%). Some preference for endo prod-
ucts (48 + 49: 39%) over exo products (46 + 47: 29%)
was observed, in contrast to the cycloaddition with acrylo-
nitrile where essentially no such selectivity was observed.
Interestingly, the formation of C-2 regioisomers was
significantly diminished when the ylide derived from the
9-N-benzyldihydro-â-carboline 20b was used in the cy-
cloaddition reactions. In the case of acrylonitrile as
dipolarophile, the ratio of C-1- to C-2-substituted cycload-
dition products (50 + 52:51 + 53) was 3:1 (compared
to 1.8:1 for the analogous compounds in the nonbenzyl-
ated series) while for methyl acrylate the ratio of these
regioisomers (54:55) was 10:1 (compared to 1.5:1 from
20a ). The N-benzyl group also had a favorable effect on
the diastereoselectivity of the latter cycloaddition reaction
since only the endo products (54, 55) were observed.
The reasons why the N-benzyl group of the dihydro-
â-carboline ylide has such a profound (and favorable)
effect on the stereochemical outcome of these cycloaddi-
tion reactions remain, for the moment, uncertain. The
N-benzyl group no doubt modifies the orbital coefficients
of the dipole HOMO and, consequently, the regioselec-
tivity. Moreover, regioselectivity may be strongly influ-
enced by the possibility of secondary orbital interactions,
for example between the aromatic ring of the benzyl
38 were based, as for 29 and 30, on the coupling
constants observed between H-11b and H-1 on one hand
1
and H-1 and H-2 on the other, as determined using H-
1H 2-D NMR. Thus, for 33-38, trans coupling constants
of 7 Hz or less were observed for H-1 and H-2. Moreover,
a trans relationship between H-11b and H-1 was assigned
to 33 and 37 based on the coupling constants of 6-7 Hz,
values inferior to the coupling constants of the same
protons in 34 and 38 (9 Hz), to which the cis geometry
was attributed. In the case of the dicyano derivatives
35 and 36, the H-11b, H-1 coupling constants were too
similar to allow unambiguous assignment of their rela-
tive geometries. The latter were thus determined by
performing NOE experiments.
(36) For all C-1-substituted hexahydroindolizino[8,7-b]indole deriva-
tives C-11b was always observed at higher field by 0.5-1.1 ppm in
the 13C NMR spectra when H-11b was cis to H-1 as compared to the
trans derivatives. The same observation was made for C-1 though in
this case the differences in ppm between the cis and trans isomers
were sometimes too small to permit reliable attributions. 13C NMR
has been shown to be a reliable method of determining cis/trans
geometries in the cyclopentane series. See: Chin, I. C.; Kohn, H. J .
Org. Chem. 1983, 48, 2857.
The regioselectivity of the cycloaddition reactions of
unsymmetrical electron-deficient olefins with the 3,4-
dihydro-â-carboline ylides was also investigated (Scheme
10). Thus, 20a reacted with acrylonitrile 39 under the
usual conditions to give four compounds, 41-44, which
were separated by HPLC and which all displayed identi-
cal molecular ion peaks in the mass spectrum and a cyano
function in the infrared spectrum. The major products,
(37) The relative configurations of H-11b and H-2 for all the C-2-
substituted compounds of Scheme 10 were determined by performing
NOE experiments.

2278 J . Org. Chem., Vol. 61, No. 7, 1996
Poissonnet et al.
Sch em e 12
in these molecules as compared to the starting materials.
Compound 58 underwent further partial dehydrogena-
tion to the 5,6-dihydro derivative 60 when exposed to 1
equiv of DDQ in CH2Cl2. However, in this case conver-
sion was incomplete and attempts to coax the reaction
to completion by slow addition of DDQ led to predominant
formation of the completely aromatic product 56.
In conclusion, the present results demonstrate that
azomethine ylides derived from â-carbolines can be
effectively generated by fluoride ion-induced desilylation
of 2-N-[(trimethylsilyl)methyl] triflate salts. These ylides
undergo in situ [3 + 2] dipolar cycloaddition reactions
with electron-deficient olefins and acetylenes to give
indolizino[8,7-b]indoles having functional groups at C-1
and/or C-2. Although yields of cycloaddition products
were relatively low when ylides derived from fully
aromatic â-carbolines were used, ylides formed from 3,4-
dihydro-â-carbolines gave better overall yields. Reactions
of the latter with symmetrically substituted olefins were
completely stereospecific, but with unsymmetrical olefins,
poor regioselectivities and diastereoselectivities were
generally observed. Although this may appear to be a
complicating factor in the exploitation of cycloaddition
reactions with â-carboline ylides generated by the desi-
lylation method, preliminary results with the 9-N-benzyl
derivatives suggest that these selectivities can be dra-
matically improved by varying the nature of this protect-
ing group. This possibility is currently being explored.
group and the unsaturated bonds of the dipolarophiles
(nitrile or carbonyl). Such interactions would also be in
favor of C-1 regioselectivity, as observed. The formation
of mainly exo adducts in the reaction of 20b with
acrylonitrile but of exclusively endo adducts with methyl
acrylate bears special mention. The latter dipolarophile
has also been observed by Plate and co-workers38 to give
mainly endo products in 1,3-dipolar cycloaddition reac-
tions with a â-carboline-derived nitrone, contrary to the
general predominance of exo products in the case of other
unsymmetrical olefins. Secondary interactions between
dipole and dipolarophile frontier orbitals were invoked
by these authors to rationalize this unusual result,
although the exact nature of these interactions could not
be defined. In our case, it is clear that both the presence
of substituents near the reactive centers of the dipole
(e.g., the N-benzyl group) as well as subtle differences
in the steric or electronic nature of the dipolarophiles
have substantial influence in directing the regio- and
stereochemical course of the cycloaddition reactions.
III. Sequ en tia l Deh yd r ogen a tion of th e Hexa h y-
d r oin d olizin o[8,7-b]in d ole Der iva tives 33 a n d 37.
The relatively mediocre yields of aromatic cycloaddition
products obtained in the reactions of acetylenes with the
ylides derived from aromatic â-carbolines 9 and 15
prompted us to investigate the possibility of obtaining
these compounds via dehydrogenation of their hexahydro
counterparts, since the latter can be produced very
efficiently from 3,4-dihydro-â-carboline derived ylides
(20a -c) and olefins. Thus, both 33 and the 8-methoxy
analogue 37 could be completely dehydrogenated by
treatment with 3 equiv of DDQ in methylene chloride at
0 °C (Scheme 12). The products, 56 and 57, respectively,
were obtained in good yield (70-80%) and had spectral
characteristics similar to the ethyl ester analogue 13a
formed via the acetylenic route.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra of
samples were obtained either as KBr pellets or in CHCl3 in
an NaCl cell. 1H NMR and 13C NMR chemical shifts are given
as δ values with reference to Me4Si as internal standard. TLC
and preparative chromatography were performed on Merck
silica gel 60 plates with fluorescent indicator. The plates were
visualized with UV light (254 or 366 nm) and, for TLC, with
a 3.5% solution of phosphomolybdic acid in ethanol. All
column chromatography was conducted on Merck 60 silica gel
(230-240 mesh) at medium pressure. All solvents were
distilled and stored over 4 Å molecular sieves before use. The
various unsaturated dipolarophiles were purchased from Al-
drich Chemical Co. and were used without further purification.
Elemental analyses were performed at the ICSN, CNRS, Gif-
sur-Yvette, France.
2-N-[(Tr im et h ylsilyl)m et h yl]-â-ca r b olin iu m Tr ifla t e
(10). To a solution of norharman (9, 0.98 g, 5.95 mmol) in
anhydrous CH2Cl2 (20 mL) was added dropwise under nitrogen
and at rt a solution of (trimethylsilyl)methyl triflate (1.55 mL,
7.14 mmol) in CH2Cl2 (3 mL). After completion of the addition,
the reaction mixture was stirred for 2 h. The solvent and
excess reagent were then removed under reduced pressure,
and the residual solid was crystallized from dichloromethane,
affording 10 (2.4 g, 99%) as a white solid: mp 174 °C; 1H NMR
(200 MHz, CDCl3) δ 0.26 (s, 9H), 4.40 (s, 2H), 7.53 (m, 1H),
7.70 (m, 2H), 8.10 (d, 1H, J ) 6.5 Hz), 8.28 (d, 1H, J ) 8.0
Hz), 8.45 (d, 1H, J ) 6.5 Hz), 9.41 (s, 1H), 9.51 (br s, 1H,
exchangeable with D2O); IR (KBr) 1650, 3250 cm-1; mass
spectrum (FAB) m/z 255 (M+). Anal. Calcd for C16H19F3N2O3-
SSi: C, 47.51; H, 4.73; N, 6.92; S, 7.93. Found: C, 47.79; H,
4.53; N, 6.65; S, 8.02.
Dieth yl In dolizin o[8,7-b]in dole-1,2-dicar boxylate (13a).
To a solution of cesium fluoride (0.19 g, 1.25 mmol) (freshly
flame-dried) and diethyl acetylenedicarboxylate (11a , 198 µL,
1.25 mmol) in anhydrous DME (20 mL), was added compound
10 (0.5 g, 1.23 mmol). The reaction mixture was refluxed
under nitrogen for 2 h, cooled, and diluted with CH2Cl2 (40
mL). The solution was washed with water (2 × 20 mL), the
organic phase was dried over Na2SO4, and the solvents were
removed under reduced pressure. The crude product was
purified by column chromatography on silica gel using CH2-
Cl2-ethanol (10:0.15) as developer, affording 13a (0.15 g, 35%)
as an oil which crystallized in a mixture of ethanol and
Compounds 33 and 37 could also be partially and
selectively dehydrogenated to the 2,3,5,6-tetrahydro de-
rivatives 58 and 59, respectively, using potassium per-
manganate in anhydrous THF as oxidant39 in ∼80%
1
yields. The H NMR spectra of 58 and 59 were similar
to the NMR spectrum of the N-benzyl analogue 21 and
clearly indicated that only H-11b and H-1 were absent
(38) Plate, R.; Hermkens, P. H. H.; Smits, J . M. M.; Ottenheijm, H.
C. J . J . Org. Chem. 1986, 51, 309.
(39) Misztal, S.; Cegla, M. Synthesis 1985, 1134.

Cycloaddition Reactions of â-Carboline Azomethine Ylides
J . Org. Chem., Vol. 61, No. 7, 1996 2279
hexane: mp 154 °C dec; 1H NMR (200 MHz, CDCl3) δ 1.36
(m, 6H), 4.41 (m, 4H), 7.31 (m, 1H, J ) 8.0 Hz), 7.41 (m, 1H,
J ) 8.0 Hz), 7.48 (d, 1H, J ) 7.0 Hz), 7.63 (d, 1H, J ) 8.0 Hz),
7.71 (s, 1H), 7.78 (d, 1H, J ) 7.0 Hz), 8.00 (d, 1H, J ) 8.0 Hz),
9.66 (br s, 1H, exchangeable with D2O); IR (KBr) 1730, 3340
cm-1; mass spectrum (EI) m/z 350 (M+). Anal. Calcd for
C20H18N2O4: C, 68.56; H, 5.17; N, 7.99. Found: C, 68.66; H,
5.06; N, 7.98.
able with D2O); IR (KBr) 1690, 1715, 1735, 3360 cm-1; mass
spectrum (EI) m/z 422 (M+). Anal. Calcd for C23H22N2O6: C,
65.39; H, 5.24; N, 6.63. Found: C, 65.33; H, 5.24; N, 6.48.
3,4-Dih yd r o-2-N-[(t r im et h ylsilyl)m et h yl]-â-ca r b olin i-
u m Tr ifla te (20a ). Following the same procedure as for the
preparation of 10, compound 20a was prepared from 3,4-
dihydro-â-carboline (19a )33 in 73% yield: mp 136 °C (ethanol);
1H NMR (200 MHz, CDCl3) δ 0.20 (s, 9H), 3.32 (t, 2H, J ) 8.0
Hz), 3.58 (s, 2H), 4.00 (t, 2H, J ) 8.0 Hz), 7.15 (t, 1H, J ) 7.2
Hz), 7.42 (m, 2H), 7.55 (d, 1H, J ) 7.2 Hz), 8.86 (br s, 1H,
exchangeable with D2O), 9.03 (s, 1H); IR (KBr) 1640, 3300
cm-1; mass spectrum (FAB) m/z 257 (M+). Anal. Calcd for
C16H21F3N2O3SSi: C, 47.28; H, 5.20; N, 6.89; S, 7.88. Found:
C, 47.60; H, 5.03; N, 6.78; S, 7.79.
9-N-Ben zyl-3,4-d ih yd r o-2-N-[(tr im eth ylsilyl)m eth yl]-â-
ca r bolin iu m Tr ifla te (20b). This compound was prepared
as above in 84% yield from 19b:34 mp 193-194 °C (ethanol);
1H NMR (200 MHz, CDCl3) δ 0.12 (s, 9H), 3.33 (t, 2H, J ) 9.0
Hz), 3.82 (s, 2H), 3.96 (t, 2H, J ) 9.0 Hz), 5.66 (s, 2H), 7.11
(m, 8H), 7.63 (d, 1H, J ) 7.8 Hz), 9.05 (s, 1H); IR (KBr) 1640
cm-1; mass spectrum (FAB) m/z 347 (M+). Anal. Calcd for
C23H27F3N2O3SSi: C, 55.62; H, 5.48; N, 5.64; S, 6.45. Found:
C, 55.87; H, 5.23; N, 5.38; S, 6.32.
3,4-Dih yd r o-6-m eth oxy-2-N-[(tr im eth ylsilyl)m eth yl)-â-
ca r bolin iu m Tr ifla te (20c). This compound was prepared
as above in 78% yield from 19c: mp 173 °C; 1H NMR (200
MHz, CDCl3) δ 0.26 (s, 9H), 3.13 (t, 2H, J ) 8.0 Hz), 3.45 (s,
2H), 3.68 (s, 3H), 3.82 (t, 2H, J ) 8.0 Hz), 6.58 (d, 1H, J ) 2.3
Hz), 6.84 (dd, 1H, J ) 7.8, 2.3 Hz), 7.55 (d, 1H, J ) 7.8 Hz),
8.74 (s, 1H), 9.68 (br s, 1H, exchangeable with D2O); IR (KBr)
1640, 3250 cm-1; mass spectrum (FAB) m/z 287 (M+). Anal.
Calcd for C17H23F3N2O4SSi: C, 46.77; H, 5.31; N, 6.41; S, 7.34.
Found: C, 46.47; H, 5.57; N, 6.31; S, 7.20.
Dieth yl (2RS)-11-N-Ben zyl-2,3,5,6-tetr ah ydr oin dolizin o-
[8,7-b]in d ole-1,2-d ica r boxyla te (21), Dieth yl 5,6-Dih yd r o-
11-N-ben zylin dolizin o[8,7-b]in d ole-1,2-d ica r boxyla te (22)
a n d Tetr a eth yl (4RS)-11-N-Ben zyl-4,5,7,8-tetr a h yd r oa ze-
p in o[1′,2′:1,2]p yr id o[3,4-b]in d ole-1,2,3,4-t et r a ca r b oxyl-
a te (23). Following the same procedure as for the preparation
of 13a , compound 20b (500 mg, 1.01 mmol) was refluxed for 1
h in DME (20 mL) in the presence of diethyl acetylenedicar-
boxylate (11a , 162 µL, 1.01 mmol) and cesium fluoride (154
mg, 1.01 mmol) affording, after the usual workup, three
products which were separated by column chromatography on
silica gel using CH2Cl2-ethyl acetate (10:0.5) as eluent.
Compound 22 (36 mg, 8%), obtained as an oil, was the first
product to be eluted: 1H NMR (200 MHz, CDCl3) δ 1.18 (t,
3H, J ) 8.0 Hz), 1.30 (t,3H, J ) 8.0 Hz), 3.18 (t, 2H, J ) 7.0
Hz), 3.88 (q, 2H, J ) 8.0 Hz), 4.18 (t, 2H, J ) 7.0 Hz), 4.30 (q,
2H, J ) 8.0 Hz), 5.50 (s, 2H), 7.00-7.34 (m, 8H), 7.48 (s, 1H),
7.60 (d, 1H, J ) 7.8 Hz); IR (CHCl3) 1720 cm-1; mass spectrum
(EI) m/z 442 (M+). Anal. Calcd for C27H26N2O4: C, 73.28; H,
5.92; N, 6.33. Found: C, 73.20; H, 6.01; N, 6.23.
Eth yl In d olizin o[8,7-b]in d ole-1-ca r boxyla te (13b). Fol-
lowing the same procedure as for the preparation of 13a ,
triflate 10 (100 mg, 0.25 mmol) was treated with cesium
fluoride (380 mg, 0.25 mmol) and ethyl propiolate (11b, 25 µL,
0.25 mmol) in DME (7 mL). After workup, the crude product
was purified by column chromatography on silica gel (toluene-
ethanol 9:0.25), yielding 13b (5.5 mg, 8%) as a white powder
which was crystallized from ethyl acetate: mp 149 °C; 1H NMR
(400 MHz, CDCl3) δ 1.47 (t, 3H, J ) 8.0 Hz), 4.46 (q, 2H,
J ) 8.0 Hz), 7.22 (d, 1H, J ) 3.0 Hz), 7.33 (t, 1H, J ) 7.8 Hz),
7.38 (d, 1H, J ) 3.0 Hz), 7.46 (m, 2H), 7.66 (d, 1H, J ) 7.8
Hz), 7.87 (d, 1H, J ) 7.2 Hz), 8.05 (d, 1H, 7.8 Hz), 11.52 (br s,
1H, exchangeable with D2O); IR (KBr) 1730, 3220 cm-1
;
mass spectrum (EI) m/z 278 (M+). Anal. Calcd for
C17H14N2O2: C, 73.36; H, 5.07; N, 10.06. Found: C, 73.33; H,
5.12; N, 10.14.
Eth yl 9-N-(p-Tolu en esu lfon yl)-â-ca r bolin e-3-ca r boxyl-
a te (16). A mixture of ethyl â-carboline-3-carboxylate (15, 2.32
g, 9.66 mmol), p-toluenesulfonyl chloride (2.2 g, 11.6 mmol),
tetra-n-butylammonium sulfate (0.5 g, 1.47 mmol), anhydrous
K2CO3 (4 g) and powdered NaOH (4 g) in CH2Cl2 (200 mL)
was vigorously stirred for 8 h at rt. The reaction mixture was
then filtered, the filtrate was washed with water (30 mL), and
the organic phase was dried over Na2SO4. Removal of the
solvent under reduced pressure left solid 16 (3.16 g, 83%)
which was crystallized from ethanol: mp 206 °C; 1H NMR (200
MHz, CDCl3) δ 1.50 (t, 3H, J ) 8.0 Hz), 2.36 (s, 3H), 4.56 (q,
2H, J ) 8.0 Hz), 7.25 (d, 1H, J ) 7.8 Hz), 7.60 (t, 1H, J ) 7.8
Hz), 7.76 (m, 4H), 8.23 (d, 1H, J ) 7.8 Hz), 8.46 (d, 1H, J )
7.8 Hz), 8.85 (s, 1H), 9.80 (s, 1H); IR (KBr) 1180, 1740 cm-1
;
mass spectrum (EI) m/z 394 (M+). Anal. Calcd for
C21H18N2O4S‚0.5H2O: C, 62.53; H, 4.74; N, 6.94. Found: C,
62.79; H, 4.72; N, 6.55.
Tr ieth yl 11-N-(p-Tolu en esu lfon yl)in d olizin o[8,7-b]in -
d ole-1,2,5-tr ica r boxyla te (17). A solution of compound 16
(100 mg, 0.25 mmol) in CH2Cl2 (10 mL) was treated dropwise
with a solution of (trimethylsilyl)methyl triflate (60.8 µL, 0.30
mmol) in CH2Cl2 (0.5 mL), and the reaction mixture was
stirred for 5 h at rt. The solvent and excess reagent were
removed under reduced pressure, the residue was dissolved
in DME (10 mL), and cesium fluoride (39 mg, 0.26 mmol)
followed by diethyl acetylenedicarboxylate (11a , 41.4 µL, 0.26
mmol) were added. The solution was refluxed for 5 h and then
cooled, diluted with CH2Cl2 (10 mL), and washed with water
(2 × 10 mL). The organic phase was dried over Na2SO4, and
the solvents were removed under reduced pressure leaving an
oily residue which crystallized in ethanol to give 17 (26 mg,
18%) as a bright yellow powder: mp 265 °C; 1H NMR (200
MHz, CDCl3) δ 1.39 (t, 3H, J ) 6.8 Hz), 1.51 (m, 6H), 2.16 (s,
3H), 4.43 (q, 2H, J ) 6.8 Hz), 4.60 (m, 4H), 6.86 (d, 2H, J )
8.0 Hz), 7.03 (d, 2H), 7.40 (m, 2H), 7.68 (d, 1H, J ) 7.0 Hz),
8.13 (s, 1H), 8.26 (d, 1H, J ) 7.3 Hz), 8.33 (s, 1H); IR (KBr)
1190, 1710 cm-1; mass spectrum (EI) m/z 576 (M+), 421 (M+
- tos). Anal. Calcd for C30H28N2O8S‚0.5H2O: C, 61.53; H, 4.99;
N, 4.78. Found: C, 61.46; H, 4.86; N, 4.76.
Tr iet h yl In d olizin o[8,7-b]in d ole-1,2,5-t r ica r b oxyla t e
(18). A solution of sodium hydride (5 mg, 0.125 mmol) (60%
dispersion in oil) and ethanol (0.01 mL) in anhydrous THF (8
mL) was stirred for 1 h at 0 °C. Compound 17 (50 mg, 0.09
mmol) was then added, and stirring was continued for 0.5 h.
The reaction mixture was quenched with ice-cold water (6 mL)
and extracted with CHCl3 (2 × 10 mL). The organic extracts
were combined and dried over Na2SO4, and the solvents were
removed under reduced pressure affording 18 (37 mg, 100%)
as a pale yellow solid which was crystallized from ethanol-
hexane: mp 137 °C; 1H NMR (200 MHz, acetone-d6) δ 1.58
(m, 9H), 4.60 (m, 6H), 7.58 (dt, 1H, J ) 8.0, 1.0 Hz), 7.72 (dt,
1H, J ) 8.0, 1.0 Hz), 8.13 (d, 1H, J ) 8.0 Hz), 8.40 (d, 1H, J
) 8.0 Hz), 8.93 (s, 1H), 9.37 (s, 1H), 12.05 (br s, 1H, exchange-
Continued elution of the column afforded compound 23 (248
mg, 40%) as an oil: 1H NMR (400 MHz, CDCl3) δ 1.21 (m, 9H),
1.31 (t, 3H, J ) 8.2 Hz), 2.49 (dd, 1H, J ) 11.0, 13.0 Hz), 2.85
(m, 1H), 3.11 (m, 1H), 3.21 (dd, 1H, J ) 11.0, 13.0 Hz), 3.26
(m, 1H), 3.35 (m, 1H), 4.05-4.31 (m, 9H), 5.43 (d, 1H, J )
16.0 Hz), 5.53 (d, 1H, J ) 16.0 Hz), 6.96 (m, 2H), 7.11-7.27
(m, 5H), 7.44 (d, 1H, J ) 7.0 Hz), 7.58 (d, 1H, J ) 7.0 Hz); 13
C
NMR (100 MHz, CDCl3) δ 14.6, 14.9, 23.2, 32.2, 44.0, 45.2,
50.8, 59.7, 61.0, 61.2, 61.9, 112.3, 119.8, 120.3, 120.6, 124.5,
125.2, 127.1, 127.2, 128.2, 164.2, 168.1, 170.7; IR (CHCl3) 1660,
1730 cm-1; mass spectrum (EI) m/z 614 (M+). Anal. Calcd
for C35H38N2O8: C, 68.39; H, 6.23; N, 4.55. Found: C, 68.58;
H, 6.22; N, 4.35.
Compound 21 (193 mg, 43%), also obtained as an oil, was
the last to be eluted from the column: 1H NMR (400 MHz,
CDCl3) δ 1.12 (t, 3H, J ) 8.0 Hz), 1.26 (t, 3H, J ) 8.0 Hz),
3.02 (t, 2H, J ) 6.0 Hz), 3.26 (t, 2H, J ) 6.0 Hz), 3.83 (dd, 1H,
J ) 6.0, 10.0 Hz), 3.88 (t, 1H, J ) 10.0, 10.0 Hz), 4.08 (dd, 1H,
J ) 6.0, 10.0 Hz), 4.17 (m, 4H), 5.44 (d, 1H, J ) 16.0 Hz), 5.66
(d, 1H, J ) 16.0 Hz), 6.85 (m, 2H), 7.09-7.20 (m, 4H), 7.34 (d,
1H, J ) 7.8 Hz), 7.56 (d, 1H, J ) 7.8 Hz); IR (CHCl3) 1660,
1720 cm-1; mass spectrum (EI) m/z 444 (M+). Anal. Calcd
for C27H28N2O4‚0.5H2O: C, 73.28; H, 5.92; N, 6.33. Found: C,
73.20; H, 6.01; N, 6.23.

2280 J . Org. Chem., Vol. 61, No. 7, 1996
Poissonnet et al.
3,4-Dih yd r o-2-N-[(t r im et h ylsilyl)m et h yl]isoq u in olin -
iu m Tr ifla te (25). Compound 25 was prepared in 78% yield
from 3,4-dihydroisoquinoline (24)40 and (trimethylsilyl)methyl
triflate following the same procedure as for 20a -c: mp 88 °C
spectrum (EI) m/z 328 (M+). Anal. Calcd for C18H20N2O4: C,
65.84; H, 6.14; N, 8.53. Found: C, 65.95; H, 5.98; N, 8.23.
Compound 30 (24%) was isolated as an oil after chroma-
tography of the mother liquor on silica gel (toluene-ethanol
9:1): 1H NMR (400 MHz, CDCl3) δ 2.80 (m, 1H), 2.93 (m, 2H),
3.15 (m, 1H), 3.29 (t, 1H, J ) 10.0 Hz superimposed on dd,
1H, J ) 7.0, 10.0 Hz), 3.53 (m, 1H), 3.64 (dd, 1H, J ) 9.0, 7.0
Hz), 3.73 (s, 3H), 3.90 (s, 3H), 4.23 (d, 1H, J ) 7.0 Hz), 7.15 (t,
1H, J ) 7.8 Hz), 7.20 (t, 1H, J ) 7.8 Hz), 7.45 (d, 1H, J ) 7.8
Hz), 7.58 (d, 1H, J ) 7.8 Hz), 8.68 (s, 1H, exchangeable with
D2O); IR (CHCl3) 1725, 3450 cm-1; mass spectrum (EI) m/z
328 (M+). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N,
8.53. Found: C, 65.69; H, 6.10; N, 7.72.
1
(ethanol); H NMR (200 MHz, CDCl3) δ 0.25 (s, 9H), 3.80 (t,
2H, J ) 8.0 Hz), 3.95 (s, 2H), 4.03 (t, 2H, J ) 8.0 Hz), 7.41 (d,
1H, J ) 7.2 Hz), 7.53 (t, 1H, J ) 7.2 Hz), 7.77 (m, 1H), 7.95
(d, 1H, J ) 7.0 Hz), 9.21 (s, 1H); IR (KBr) 1650 cm-1; mass
spectrum (FAB) m/z 218 (M+). Anal. Calcd for C14H20F3NO3-
SSi: C, 45.76; H, 5.48; N, 3.81; S, 8.72. Found: C, 45.76; H,
5.42; N, 3.84; S, 8.99.
Dieth yl 5,6-Dih yd r op yr r olo[2,1-a ]isoqu in olin e-1,2-d i-
ca r boxyla te (26) a n d Tetr a eth yl (4RS)-7,8-Dih yd r oa ze-
p in o[2,1-a ]isoqu in olin e-1,2,3,4-tetr a ca r boxyla te (27). Fol-
lowing the same procedure as for the preparation of 13a ,
compound 25 (300 mg, 0.8 mmol) was refluxed for 6 h in DME
(20 mL) in the presence of diethyl acetylenedicarboxylate (11a ,
136 µL, 0.8 mmol) and cesium fluoride (122 mg, 0.8 mmol).
After the usual workup, two products, 26 (70 mg, 28%) and
27 (112 mg, 29%), were isolated as oils following column
chromatography on silica gel using ethyl acetate-CH2Cl2 (8:
0.4) as developer. Compound 26: 1H NMR (200 MHz, CDCl3)
δ 1.33 (t, 3H, J ) 7.2 Hz), 1.41 (t, 3H, J ) 7.2 Hz), 3.08 (t, 2H,
J ) 5.8 Hz), 4.10 (t, 2H, J ) 5.8 Hz), 4.31 (q, 2H, J ) 7.2 Hz),
4.45 (q, 2H, J ) 7.2 Hz), 7.25 (m, 3H), 7.30 (s, 1H), 7.70 (d,
1H, J ) 6.9 Hz); IR (CHCl3) 1745 cm-1; mass spectrum (EI)
m/z 313 (M+). Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11;
N, 4.47. Found: C, 68.81; H, 6.28; N, 4.29.
Compound 27: 1H NMR (400 MHz, CDCl3) δ 1.22 (m, 9H),
1.32 (t, 3H, J ) 7.8 Hz), 2.74 (dd, 1H, J ) 10.0, 13.0 Hz), 2.85
(m, 1 H), 3.04 (m, 1H), 3.23 (dd, 1H, J ) 10.0, 13.0 Hz), 3.23
(m, 1H), 3.36 (m, 1H), 4.08-4.29 (m, 9H), 7.21 (d, 1H, J ) 6.8
Hz), 7.34 (d, 1H, J ) 6.8 Hz), 7.40 (d, 1H, J ) 6.8 Hz), 8.56 (d,
1H, J ) 6.8 Hz); 13C NMR (50 MHz, CDCl3) δ 14.2, 14.4, 31.2,
31.5, 42.5, 44.8, 59.1, 61.2, 61.4, 62.3, 126.1, 127.3, 131.1, 131.7,
164.5, 170.9; IR (CHCl3) 1670, 1720 cm-1; mass spectrum (EI)
m/z 485 (M+). Anal. Calcd for C26H31NO8: C, 64.31; H, 6.43;
N, 2.88. Found: C, 64.06; H, 6.43; N, 2.70.
Gen er a l P r oced u r e for 1,3-Dip ola r Cycloa d d ition of
Activa ted Eth ylen ic Der iva tives w ith th e â-Ca r bolin e
Azom eth in e Ylid es Gen er a ted fr om 20a -c. Solutions of
equimolar quantities of the N-[(trimethylsilyl)methyl]-3,4-
dihydro-â-carbolinium triflates 20a , 20b, or 20c, cesium
fluoride, and ethylenic dipolarophiles (28, 31, 32, 39, and 40)
in anhydrous DME were stirred at rt or at reflux under
nitrogen for 2-12 h. At the end of the reaction period (as
determined by TLC monitoring), the mixtures were concen-
trated in vacuo to one-quarter of their volume, the residues
were taken up in 5 volumes of ethyl acetate, and the solutions
were washed with water (2×). The combined aqueous wash-
ings were extracted with ethyl acetate, the organic extracts
were combined and dried over Na2SO4, and the solvents were
removed under vacuum. Addition of ethanol to the residue
sometimes led to precipitation of one of the diastereomers
which was collected by filtration. The other diastereomer(s)
could then be purified by chromatography of the mother liquor
on silica gel. In other cases, the residue was immediately
purified by chromatography on silica gel and/or by HPLC.
Reaction times, yields, and purification procedures are given
for each compound.
Dim eth yl (1R,2S,11bR)- a n d (1S,2R,11bS)-1,2,3,5,6,11b-
Hexah ydr oin dolizin o[8,7-b]in dole-1,2-dicar boxylate [(()-
33] an d Dim eth yl (1S,2R,11bR)- an d (1R,2S,11bS)-1,2,3,5,6,-
11b -H exa h yd r oin d olizin o[8,7-b]in d ole-1,2-d ica r b oxyl-
a te [(()-34]. These compounds were obtained from 20a and
dimethyl fumarate (31) after a reaction period of 4 h. Com-
pound 33 (51%) was isolated by crystallization of the crude
1
reaction mixture in ethanol: mp 169 °C; H NMR (400 MHz,
CDCl3) δ 2.59 (m, 1H), 3.00 (m, 2H), 3.28 (m, 4H), 3.30 (t, 1H,
J ) 11.0 Hz), 3.41 (m, 2H), 3.60 (s, 3H), 3.62 (t, 1H, J ) 7.0
Hz), 4.65 (d, 1H, J ) 7.0 Hz), 6.95 (t, 1H, J ) 7.8 Hz), 7.05 (t,
1H, J ) 7.8 Hz), 7.30 (d, 1H, J ) 7.8 Hz), 7.38 (d, 1H, J ) 7.8
Hz), 8.83 (br s, 1H, exchangeable with D2O); IR (KBr) 1725,
3450 cm-1; mass spectrum (EI) m/z 328 (M+). Anal. Calcd
for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C, 65.54;
H, 6.24; N, 8.23.
Compound 34 (36%) was isolated as an oil after chroma-
tography of the mother liquor on silica gel (CH2Cl2-ethyl
acetate 7:3): 1H NMR (400 MHz, CDCl3) δ 2.85 (m, 3H), 3.10
(t superimposed on m, 2H, J ) 10.0 Hz), 3.18 (dd, 1H, J )
6.0, 10.0 Hz), 3.45 (dd, 1H, J ) 9.0, 7.0 Hz), 3.51 (m, 1H), 3.73
(s, 3H), 3.78 (s, 3H), 4.51 (d, 1H, J ) 9.0 Hz), 7.09 (t, 1H, J )
8.0 Hz), 7.16 (t, 1H, J ) 8.0 Hz), 7.35 (d, 1H, J ) 8.0 Hz), 7.50
(d, 1H, J ) 8.0 Hz), 8.71 (br s, 1H, exchangeable with D2O);
IR (CHCl3) 1720, 3400 cm-1; mass spectrum (EI) m/z 328 (M+).
Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53.
Found: C, 65.58; H, 6.08; N, 8.51.
(1R,2R,11bR)- a n d (1S,2S,11bS)-1,2,3,5,6,11b-Hexa h y-
d r oin d olizin o[8,7-b]in d ole-1,2-d ica r bon itr ile [(()-35] a n d
(1S,2S,11b R)- a n d (1R,2R,11b S)-1,2,3,5,6,11b -H exa h y-
d r oin d olizin o[8,7-b]in d ole-1,2-d ica r b on it r ile [(()-36].
These compounds were obtained from 11a and fumaronitrile
(32) after a reaction period of 12 h. After the usual workup,
the crude reaction mixture was purified by HPLC on a silica
gel column (15-20 µm, 15 × 20 cm) using heptane-2-propanol
92:8 as eluent (flow rate ) 50 mL/min). Compound 36 (45%)
1
was first eluted: mp 169 °C (methanol); H NMR (300 MHz,
CDCl3) δ 2.88 (m, 2H), 3.07 (m, 1H), 3.17 (m, 1H), 3.32 (t, 1H,
J ) 8.0 Hz), 3.43 (m, 2H), 3.47 (m, 1H), 4.38 (d, 1H, J ) 8.0
Hz), 7.14 (dd, 1H, J ) 7.2 Hz), 7.22 (dd, 1H, J ) 7.2 Hz), 7.40
(d, 1H, J ) 7.2 Hz), 7.53 (d, 1H, J ) 7.2 Hz), 8.05 (br s, 1H,
exchangeable with D2O); 13C NMR (75 MHz, CDCl3) δ 17.9,
31.7, 36.7, 45.4, 53.7, 61.3, 108.0, 110.6, 116.0, 117.6, 118.1,
118.8, 125.6, 128.9, 135.9; IR (CHCl3) 2246, 3361 cm-1; mass
spectrum (EI) m/z 262 (M+). Anal. Calcd for C16H14N4‚
0.1H2O: C, 72.78; H, 5.38; N, 21.23. Found: C, 72.53; H, 5.46;
N, 21.55.
Dim eth yl (1S,2S,11bR)- a n d (1R,2R,11bS)-1,2,3,5,6,11b-
Hexah ydr oin dolizin o[8,7-b]in dole-1,2-dicar boxylate [(()-
29] an d Dim eth yl (1R,2R,11bR)- an d (1S,2S,11bS)-1,2,3,5,6,-
11b -H exa h yd r oin d olizin o[8,7-b]in d ole-1,2-d ica r b oxyl-
a te [(()-30]. These compounds were obtained from 20a and
dimethyl maleate (28) after a reaction period of 4 h. Com-
pound 29 (38%) was isolated by crystallization of the crude
Continued elution of the column afforded compound 35
(21%): mp 198 °C; 1H NMR (300 MHz, CDCl3) δ 2.89 (m, 3H),
3.13 (m, 1H, J ) 7.5, 9.8 Hz), 3.18 (m, 1H), 3.56 (m, 1H), 3.64
(dd, 1H, J ) 8.0, 9.0 Hz), 3.78 (dd, 1H, J ) 5.0, 6.7 Hz), 4.32
(d, 1H, J ) 6.8 Hz), 6.64 (dd, 1H, J ) 8.0 Hz), 6.72 (dd, 1H, J
) 8.0 Hz), 7.03 (d, 1H, J ) 8.0 Hz), 7.18 (d, 1H, J ) 8.0 Hz),
8.50 (br s, 1H, exchangeable with D2O); 13C NMR (62.5 MHz,
CDCl3) δ 20.2, 31.4, 36.7, 46.3, 55.8, 60.2, 108.0, 110.7, 117.5,
117.7, 118.4, 118.7, 121.4, 127.8, 128.1, 136.0; IR (CHCl3) 2246,
3381 cm-1; mass spectrum (EI) m/z 262 (M+). Anal. Calcd
for C16H14N4: C, 73.28; H, 5.34; N, 21.37. Found: C, 73.21;
H, 5.49; N, 21.10.
Dim eth yl (1R,2S,11bR)- a n d (1S,2R,11bS)-1,2,3,5,6,11b-
Hexa h yd r o-8-m eth oxyin d olizin o[8,7-b]in d ole-1,2-d ica r -
boxylate [(()-37] an d Dim eth yl (1S,2R,11bR)- an d (1R,2S,-
11bS)-1,2,3,5,6,11b-Hexa h yd r o-8-m eth oxyin d olizin o[8,7-
b]in d ole-1,2-d ica r boxyla te [(()-38]. These compounds were
1
reaction mixture in ethanol: mp 152 °C; H NMR (400 MHz,
CDCl3) δ 2.66 (m, 1H), 2.94 (m, 2H), 3.06 (dd, 1H, J ) 7.0,
10.0 Hz), 3.25 (m, 1H), 3.46 (t, 1H, J ) 10.0 Hz), 3.52 (m, 1H),
3.59 (s, 3H), 3.75 (s, 3H), 3.90 (t, 1H, J ) 9.0 Hz), 4.62 (d, 1H,
J ) 9.0 Hz), 7.10 (t, 1H, J ) 7.8 Hz), 7.16 (t, 1H, J ) 7.8 Hz),
7.32 (d, 1H, J ) 7.8 Hz), 7.49 (d, 1H, J ) 7.8 Hz), 8.21 (s, 1H,
exchangeable with D2O); IR (KBr) 1720, 3350 cm-1; mass
(40) Dale, W. J .; Starr, L.; Strobel, C. W. J . Org. Chem. 1961, 26,
2225.

Cycloaddition Reactions of â-Carboline Azomethine Ylides
J . Org. Chem., Vol. 61, No. 7, 1996 2281
obtained from 20c and dimethyl fumarate (31) after a reaction
period of 2 h. Compound 37 (46%) was isolated by crystal-
lization of the crude reaction mixture in ethanol: mp 129 °C;
1H NMR (200 MHz, CDCl3) δ 2.60 (m, 1H), 2.84 (m, 2H), 3.00
(dd, 1H, J ) 7.0, 9.0 Hz), 3.16 (m, 1H), 3.44 (m, 2H), 3.51 (s,
3H), 3.63 (s, 3H), 3.76 (s, 4H), 4.48 (d, 1H, J ) 9.0 Hz), 6.63
(dd, 1H, J ) 8.0, 2.0 Hz), 6.76 (d, 1H, J ) 2.0 Hz), 7.03 (d, 1H,
J ) 8.0 Hz), 7.84 (br s, 1H, exchangeable with D2O); IR (KBr)
1720, 3360 cm-1; mass spectrum (EI) m/z 358 (M+). Anal.
Calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.81. Found: C,
63.56; H, 6.14; N, 7.82.
Compound 38 (32%) was isolated as an oil after chroma-
tography of the mother liquor on silica gel (toluene-ethanol
9:1): 1H NMR (200 MHz, CDCl3) δ 2.77 (m, 3H), 3.16 (m, 3H),
3.49 (m, 2H), 3.52 (s, 3H), 3.79 (s, 6H), 4.11 (d, 1H, J ) 6.0
Hz), 6.69 (dd, 1H, J ) 8.0, 2.0 Hz), 6.80 (d, 1H, J ) 2.0 Hz),
7.11 (d, 1H, J ) 8.0 Hz), 8.36 (br s, 1H, exchangeable with
D2O); IR (CHCl3) 1720, 3450 cm-1; mass spectrum (EI) m/z
358 (M+). Anal. Calcd for C19H22N2O5: C, 63.67; H, 6.18; N,
7.81. Found: C, 63.76; H, 6.01; N, 7.68.
(1R,11bR)- a n d (1S,11bS)-1,2,3,5,6,11b-Hexa h yd r oin -
d olizin o[8,7-b]in d ole-1-ca r bon itr ile [(()-41], (2S,11bR)-
a n d (2R,11bS)-1,2,3,5,6,11b-Hexa h yd r oin d olizin o[8,7-b]-
in d ole-2-ca r bon itr ile [(()-42], (1S,11bR)- a n d (1R,11bS)-
1,2,3,5,6,11b-Hexa h yd r oin d olizin o[8,7-b]in d ole-1-ca r bo-
n itr ile [(()-43], an d (2R,11bR)- an d (2S,11bS)-1,2,3,5,6,11b-
H exa h yd r oin d olizin o[8,7-b]in d ole-2-ca r b on it r ile [(()-
44]. These compounds were obtained from 20a and acrylonitrile
(39) after a reaction period of 5 h. After the usual workup,
the crude reaction product was partially purified by column
chromatography on silica gel using ethyl acetate-heptane (30:
70) followed by ethyl acetate. Two fractions were obtained,
the first corresponding to a mixture of 41 and 42, the second
to 43 and 44. Each fraction was in turn purified by HPLC
either on a silica gel column (15-20 µm, 250 mm, heptane-
ethyl acetate gradient with a flow rate of 50 mL/min) (for 41
and 42) or a C18 column (47 × 300 mm, methanol-water 60:
40, 40 mL/min) (for 43 and 44):
Compound 41 (foam, 19%): 1H NMR (300 MHz, CDCl3) δ
2.26 (m, 1H), 2.44 (m, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 2.98
(m, 2H), 3.11 (m, 3H), 4.27 (d, 1H, J ) 6.0 Hz), 7.17 (dd, 1H,
J ) 7.8 Hz), 7.24 (dd, 2H, J ) 7.8 Hz), 7.37 (d, 1H, J ) 7.8
Hz), 7.52 (d, 1H, J ) 7.8 Hz), 8.20 (br s, 1H, exchangeable
with D2O); 13C NMR (75 MHz, CDCl3) δ 20.2, 29.2, 32.3, 47.2,
51.4, 62.5, 108.1, 111.4, 117.7, 118.6, 119.4, 122.4, 126.7, 131.5,
136.5; IR (CHCl3) 2240, 3448 cm-1; mass spectrum (EI) m/z
237 (M+). Anal. Calcd for C15H15N3: C, 75.95; H, 6.33; N,
17.72. Found: C, 75.82; H, 75.82; H, 6.32; N, 17.75.
136.4; IR (CHCl3) 2240, 3303, 3471 cm-1; mass spectrum
(HREI) calcd for C15H15N3 m/z 237.1266, found 237.1280.
Meth yl (1R,11bR)- a n d (1S,11bS)-1,2,3,5,6,11b-Hexa h y-
d r oin d olizin o[8,7-b]in d ole-1-ca r boxyla te [(()-46], Meth yl
(2S,11bR)- a n d (2R,11bS)-1,2,3,5,6,11b-Hexa h yd r oin d oliz-
in o[8,7-b]in dole-2-car boxylate [(()-47], Meth yl (1S,11bR)-
a n d (1R,11bS)-1,2,5,6,11b-Hexa h yd r oin d olizin o[8,7-b]in -
d ole-1-ca r boxyla te [(()-48], a n d Meth yl (2R,11bR)- a n d
(2S,11bS)-1,2,3,5,6,11b-Hexah ydr oin dolizin o[8,7-b]in dole-
2-ca r boxyla te [(()-49]. These compounds were obtained
from 20a and methyl acrylate (40) after a 2 h reaction period
at reflux. After the usual workup, the crude reaction mixture
was purified by column chromatography on silica gel using
first CH2Cl2 as eluent followed by a CH2Cl2-ethanol gradient
(9:0.1 to 9:1). The following compounds, listed in order of their
elution from the column, were obtained as foams:
Compound 46 (20%): 1H NMR (300 MHz, CDCl3) δ 2.30 (q,
2H), 2.88 (m, 2H), 3.02 (m, 1H), 3.12 (m, 3H), 3.21 (m, 1H),
3.86 (s, 3H), 4.29 (d, 1H, J ) 9.0 Hz), 7.10 (t, 1H, J ) 7.0 Hz),
7.17 (t, 1H, J ) 7.0 Hz), 7.36 (d, 1H, J ) 7.0 Hz), 7.48 (d, 1H,
J ) 7.0 Hz), 8.76 (br s, 1H, exchangeable with D2O); 13C NMR
(75 MHz, CDCl3) δ 17.6, 26.8, 47.8, 48.5, 51.8, 52.4, 60.7, 111.1,
118.3, 119.5, 121.7, 175.1; IR (CHCl3) 1737, 3262 cm-1; mass
spectrum (EI) m/z 270 (M+). Anal. Calcd for C16H18N2O2‚
0.17CCl4: C, 64.82; H, 6.07; N, 9.45. Found: C, 64.68; H, 6.05;
N, 9.98.
Compound 47 (9%): 1H NMR (300 MHz, CDCl3) δ 2.61 (m,
2H), 2.70 (m, 1H), 2.97 (m, 1H), 3.07 (m, 2H), 3.15 (t, 1H),
3.24 (m, 2H), 3.73 (s, 3H), 4.31 (t, 1H), 7.10 (t, 1H, J ) 7.0
Hz), 7.17 (t, 1H, J ) 7.0 Hz), 7.33 (d, 1H, J ) 7.0 Hz), 7.49 (d,
1H, J ) 7.0 Hz), 7.89 (br s, 1H, exchangeable with D2O); 13C
NMR (75 MHz, CDCl3) δ 18.4, 33.1, 41.8, 46.3, 52.1, 53.3, 57.7,
107.8, 111.1, 118.2, 119.9, 121.7, 127.2, 133.8, 136.4, 175.1;
IR (CHCl3) 1731, 3262 cm-1; mass spectrum (HREI) calcd for
C16H18N2O2 m/z 270.1347, found 270.1358.
Compound 48 (20%): 1H NMR (300 MHz, CDCl3) δ 2.15 (m,
2H), 2.61 (m, 1H), 2.81 (m, 1H), 3.00 (m, 1H), 3.12 (m, 1H),
3.22 (m, 2H), 3.40 (m, 1H), 3.58 (s, 3H), 3.69 (q, 1H, J ) 8.0
Hz), 4.78 (d, 1H, J ) 8.0 Hz), 7.07 (t, 1H, J ) 7.0 Hz), 7.16 (t,
1H, J ) 7.0 Hz), 7.33 (d, 1H, J ) 7.0 Hz), 7.44 (d, 1H, J ) 7.0
Hz), 8.97 (br s, 1H, exchangeable with D2O); 13C NMR (75
MHz, CDCl3) δ 17.7, 26.1, 46.7, 47.2, 49.8, 52.3, 60.0, 111.3,
118.4, 119.7, 122.4, 173.5; IR (CHCl3) 1737, 3294 cm-1; mass
spectrum (HREI) calcd for C16H18N2O2 m/z 270.1347, found
270.1358.
Compound 49 (19%): 1H NMR (300 MHz, CDCl3) δ 2.24 (m,
1H), 2.59 (m, 1H), 2.69 (m, 1H), 2.94 (m, 1H), 3.06 (m, 1H),
3.17 (m, 3H), 3.32 (m, 1H), 3.57 (s, 3H), 4.38 (dt, 1H), 7.09 (t,
1H, J ) 7.0 Hz), 7.25 (t, 1H, J ) 7.0 Hz), 7.32 (d, 1H, J ) 7.0
Hz), 7.47 (d, 1H, J ) 7.0 Hz), 8.06 (br s, 1H, exchangeable
with D2O); 13C NMR (75 MHz, CDCl3) δ 17.7, 32.9, 42.5, 52.0,
52.2, 56.8, 107.5, 110.9, 118.2, 119.5, 121.1, 127.1, 133.4, 136.3,
174.2; IR (CHCl3) 1731, 3125 cm-1; mass spectrum (HREI)
calcd for C16H18N2O2 m/z 270.1347, found 270.1359.
In d olizin o[8,7-b]in d ole-1-ca r bon itr ile (45). A solution
of compound 41 (20.5 mg, 0.09 mmol) in anhydrous CH2Cl2
was treated at 0 °C with DDQ (61.4 mg, 0.27 mmol). After 30
min, the reaction mixture was filtered through a pad of
alumina, and the filtrate was evaporated to dryness under
reduced pressure. The residue was purified by preparative
TLC on silica gel (CH2Cl2-ethanol 99:1), affording 45 (2.9 mg,
15%) as an unstable solid: 1H NMR (300 MHz, CDCl3) δ 7.01
(d, 1H, J ) 3.0 Hz), 7.31 (d, 1H, J ) 6.2 Hz), 7.35 (d, 1H, J )
3.0 Hz), 7.45 (t, 1H, J ) 9.0 Hz), 7.48 (t, 1H, J ) 9.0 Hz), 7.60
(d, 1H, J ) 8.0 Hz), 7.87 (d, 1H, J ) 6.2 Hz), 7.99 (d, 1H, J )
8.0 Hz), 9.20 (br s, 1H, exchangeable with D2O); IR (CHCl3)
3289, 2221 cm-1; mass spectrum (HREI) calcd for C15H9N3 m/z
231.0796, found 231.0791.
Compound 42 (oil, 8%): 1H NMR (300 MHz, CDCl3) δ 2.29
(m, 1H), 2.59 (m, 1H), 2.71 (m, 1H), 2.90 (m, 1H), 3.09 (m,
2H), 3.19 (m, 1H), 3.27 (m, 2H), 4.42 (dd, 1H, J ) 6.0, 9.0 Hz),
7.11 (t, 1H, J ) 8.0 Hz), 7.18 (t, 1H, J ) 8.0 Hz), 7.33 (d, 1H,
J
) 8.0 Hz), 7.49 (d, 1H, J ) 8.0 Hz), 7.97 (br s, 1H,
exchangeable with D2O); 13C NMR (62.5 MHz, CDCl3) δ 18.4,
26.6, 34.9, 46.0, 53.9, 56.8, 108.6, 111.1, 118.4, 119.9, 122.2,
127.1, 130.8, 136.3; IR (CHCl3) 2240, 3269, 3462 cm-1; mass
spectrum (HREI) calcd for C15H15N3 m/z 237.1266, found
237.1264.
1
Compound 43 (18%): mp 169 °C (ethyl acetate); H NMR
(300 MHz, CDCl3) δ 2.17 (m, 1H), 2.31 (m, 1H), 2.80 (t, 1H),
2.85 (t, 1H), 3.01 (dd, 1H), 3.17 (m, 2H), 3.35 (m, 1H), 3.60 (t,
1H, J ) 8.0 Hz), 4.58 (d, 1H, J ) 9.0 Hz), 6.97 (t, 1H, J ) 8.0
Hz), 7.03 (t, 1H, J ) 8.0 Hz), 7.25 (d, 1H, J ) 8.0 Hz), 7.38 (d,
1H, J ) 8.0 Hz), 8.74 (br s, 1H, exchangeable with D2O); 13C
NMR (62.5 MHz, CDCl3) δ 19.2, 28.6, 31.3, 46.7, 49.7, 60.3,
110.7, 111.4, 118.5, 119.6, 121.2, 122.3, 126.8, 129.7, 136.6;
IR (CHCl3) 2240, 3265, 3452 cm-1; mass spectrum (EI) m/z
237 (M+). Anal. Calcd for C15H15N3‚0.4H2O: C, 73.71; H, 6.47;
N, 17.20. Found: C, 73.94; H, 6.22; N, 17.93.
Compound 44 (foam, 12%): 1H NMR (300 MHz, CDCl3) δ
2.18 (m, 1H), 2.73 (m, 2H), 2.93 (m, 1H), 3.07 (dd, 2H), 3.18
(m, 2H), 3.33 (m, 1H), 4.36 (dd, 1H, J ) 7.5, 4.5 Hz), 7.14 (t,
1H, J ) 7.2 Hz), 7.18 (t, 1H, J ) 7.2 Hz), 7.38 (d, 1H, J ) 7.2
Hz), 7.50 (d, 1H, J ) 7.2 Hz), 7.85 (br s, 1H, exchangeable
with D2O); 13C NMR (62.5 MHz, CDCl3) δ 18.1, 26.5, 34.7, 45.8,
53.4, 56.3, 107.9, 111.1, 118.4, 119.8, 121.4, 122.0, 127.1, 133.3,
Similar treatment of compound 43 also gave 45 (18%).
(1R,11b R)- a n d (1S,11b S)-11-N-Ben zyl-1,2,3,5,6,11b -
h exa h yd r oin d olizin o[8,7-b]in d ole-1-ca r bon itr ile [(()-50],
(2S,11bR)- an d (2R,11bS)-11-N-Ben zyl-1,2,3,5,6,11b-h exah y-
d r oin d olizin o[8,7-b]in d ole-2-ca r bon it r ile [(()-51], (1S,-
11bR)- a n d (1R,11bS)-11-N-Ben zyl-1,2,3,5,6,11b-h exa h y-
d r oin d olizin o[8,7-b]in d ole-1-ca r bon itr ile [(()-52], a n d
(2R,11bR)- an d (2S,11bS)-11-N-Ben zyl-1,2,3,5,6,11b-h exah y-
d r oin d olizin o[8,7-b]in d ole-2-ca r bon itr ile [(()-53]. These

2282 J . Org. Chem., Vol. 61, No. 7, 1996
Poissonnet et al.
compounds were obtained from 20b and acrylonitrile (39) after
a reaction period of 1 h. After the usual workup, the crude
reaction mixture was purified by column chromatography on
silica gel using an ethyl acetate-heptane gradient (20:80 to
60:40) as eluent. The following compounds, listed in order of
their elution from the column, were obtained as oils:
through Celite, the filtrate was evaporated to dryness under
reduced pressure, and the residue was crystallized in ethanol,
affording compound 56 (31.8 mg, 65%): mp 163 °C; H NMR
1
(200 MHz, CDCl3) δ 4.05 (s, 3H), 4.10 (s, 3H), 7.43 (t, 1H, J )
8.0 Hz), 7.61 (m, 2H), 7.78 (d, 1H, J ) 8.0 Hz), 7.86 (s, 1H),
7.91 (d, 1H, J ) 7.2 Hz), 8.14 (d, 1H, J ) 8.0 Hz), 11.62 (br s,
Compound 51 (10%): 1H NMR (300 MHz, CDCl3) δ 2.08 (m,
1 H), 2.40 (m, 1H), 2.85 (m, 1H), 2.93 (m, 1H), 2.98 (m, 1H),
3.07 (m, 1H), 3.12 (m, 1H), 3.17 (m, 1H), 3.39 (m, 1H), 4.25 (t,
1H), 5.29 (pseudo q, 2H, J ) 18.0, 2.0 Hz), 6.95 (m, 2H), 7.18
(m, 3H), 7.29 (m, 3H), 7.58 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 20.0, 26.5, 35.2, 46.5, 47.2, 55.9, 63.6, 108.2, 109.5, 118.4,
119.6, 121.9, 122.0, 125.7, 126.6, 127.5, 128.9, 134.8, 137.2,
137.3; IR (CHCl3) 2231 cm-1; mass spectrum (HREI) calcd for
C22H21N3 m/z 327.1735, found 327.1730.
1H, exchangeable with D2O); IR (KBr) 1640, 1725, 3340 cm-1
;
mass spectrum (EI) m/z 322 (M+). Anal. Calcd for C18H14N2O4‚
1/4H2O: C, 65.25; H, 4.56; N, 8.45. Found: C, 65.11; H, 4.58;
N, 8.42.
Dim eth yl 8-Meth oxyin d olizin o[8,7-b]in d ole-1,2-d ica r -
boxyla te (57). This compound was prepared from 37 in 80%
yield following the same procedure as for the preparation of
1
56: mp 181 °C (ethanol); H NMR (200 MHz, CDCl3) δ 3.92
(s, 6H), 4.00 (s, 3H), 7.08 (dd, 1H, J ) 8.0, 3.2 Hz), 7.38 (m,
2H), 7.48 (d, 1H, J ) 7.2 Hz), 7.66 (s, 1H), 7.69 (d, 1H, J ) 8.0
Hz), 11.31 (br s, 1H, exchangeable with D2O); IR (KBr) 1640,
1660, 1720, 3325 cm-1; mass spectrum (EI) m/z 354 (M+).
Anal. Calcd for C19H16N2O5: C, 64.76; H, 4.57; N, 7.95.
Found: C, 64.66; H, 4.62; N, 7.90.
Compound 50 (40%): 1H NMR (300 MHz, CDCl3) δ 2.24 (m,
1H), 2.38 (m, 1H), 2.84 (m, 1H), 2.92 (m, 2H), 3.05 (m, 1H),
3.12 (m, 3H), 4.52 (d, 1H, J ) 6.0 Hz), 5.50 (pseudo q, 2H, J )
18.0, 3.0 Hz), 6.93 (dd, 2H), 7.17 (m, 2H), 7.25 (m, 4H), 7.57
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 18.9, 30.1, 32.8, 46.2,
47.4, 51.2, 61.3, 109.5, 109.9, 118.6, 119.8, 121.9, 122.8, 125.8,
Dim eth yl (2R,S)-2,3,5,6-Tetr a h yd r oin d olizin o[8,7-b]-
in d ole-1,2-d ica r boxyla te (58). A mixture of compound 33
(177 mg, 0.54 mmol) and potassium permanganate (1 g) in
THF was stirred for 1 h at 0 °C under nitrogen. The reaction
mixture was filtered through Celite, and the filtrate was con-
centrated under reduced pressure. Chromatography of the
residue on silica gel using CH2Cl2 as developer afforded com-
pound 58 as a yellow syrup (152 mg, 86%): 1H NMR (400 MHz,
CDCl3) δ 3.08 (m, 2H), 3.18 (m, 1H), 3.28 (m, 1H), 3.58 (dd,
1H, J gem ) 10.0 Hz, J vic ) 7.0 Hz superimposed on a pseudo t,
1H, J vic ) 10.0 Hz), 3.71 (s, 6H), 3.98 (dd, 1H, J ) 7.0, 10.0
Hz), 7.06 (t, 1H, J ) 8.0 Hz), 7.23 (t, 1H, J ) 8.0 Hz), 7.39 (d,
1H, J ) 8.0 Hz), 7.51 (d, 1H, J ) 8.0 Hz), 11.80 (br s, 1H,
exchangeable with D2O); IR (CHCl3) 1600, 1645, 1740, 3250
cm-1; mass spectrum (EI) m/z 326 (M+). Anal. Calcd for
C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.20; H,
5.55; N, 8.23.
Dim eth yl (2R,S)-8-Meth oxy-2,3,5,6-tetr a h yd r oin d oliz-
in o[8,7-b]in d ole-1,2-d ica r boxyla te (59). This compound
was prepared from 37 following the same procedure as for the
preparation of 58. The crude reaction product was purified
by chromatography on silica gel using CH2Cl2-ethanol (9:0.5)
as developer, affording 59 (83%) as a yellow syrup: 1H NMR
(200 MHz, CDCl3) δ 3.04 (m, 2H), 3.22 (m, 2H), 3.60 (dd, 2H,
J ) 9.0 Hz), 3.68 (s, 6H), 3.79 (s, 3H), 3.95 (dd, 1H, J ) 9.0,
10.0 Hz), 6.87 (m, 2H), 7.30 (d, 1H, J ) 8.0 Hz), 9.15 (br s,
1H, exchangeable with D2O); IR (CHCl3) 1600, 1660, 1745,
3180 cm-1; mass spectrum (EI) m/z 356 (M+). Anal. Calcd
for C19H20N2O5: C, 64.03; H, 5.65; N, 7.86. Found: C, 64.14;
H, 5.50; N, 7.61.
126.5, 127.3, 128.9, 133.2, 137.2, 137.7; IR (CHCl3) 2240 cm-1
;
mass spectrum (EI) m/z 327 (M+). Anal. Calcd for C22H21N3‚
0.06CCl4: C, 78.51; H, 6.24; N, 12.49. Found: C, 78.51; H,
6.26; N, 12.25.
Compound 53 (9%): 1H NMR (300 MHz, CDCl3) δ 2.07 (m,
1H), 2.60 (m, 1H), 2.86 (m, 1H), 2.95 (m, 2H), 3.02 (m, 1H),
3.11 (m, 1H), 3.21 (m, 3H), 4.25 (t, 1H), 5.25 (pseudo q, 2H, J
) 18.0, 3.0 Hz), 6.94 (m, 2H), 7.15 (m, 3H), 7.26 (m, 3H), 7.55
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 19.2, 26.7, 35.4, 46.6,
47.3, 54.9, 56.4, 107.9, 109.7, 118.6, 119.8, 121.3, 122.1, 126.7,
127.7, 129.0, 134.9, 137.3; IR (CHCl3) 2253 cm-1; mass
spectrum (HREI) calcd for C22H21N3 m/z 327.1735, found
327.1733.
Compound 52 (20%): 1H NMR (300 MHz, CDCl3) δ 2.41 (m,
2H), 3.10 (m, 3H), 3.26 (m, 3H), 3.36 (m, 1H), 4.47 (d, 1H, J )
8.3 Hz), 5.04 (d, 2H, J ) 18.0 Hz), 7.02 (m, 2H), 7.17 (m, 2H),
7.26 (m, 4H), 7.58 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7,
29.3, 33.0, 47.1, 48.2, 52.6, 60.1, 109.9, 118.8, 119.8, 119.9,
122.8, 126.1, 127.7, 129.0; IR (CHCl3) 2243 cm-1; mass spec-
trum (HREI) calcd for C22H21N3 m/z 327.1735, found 327.1697.
Meth yl (1S,11bR)- a n d (1R,11bS)-11-N-Ben zyl-1,2,3,5,6,-
11b-h exah ydr oin dolizin o[8,7-b]in dole-1-car boxylate [(()-
54] a n d Meth yl (2R,11bR)- a n d (2S,11bS)-11-N-Ben zyl-
1,2,3,5,6,11b -h e xa h yd r oin d olizin o[8,7-b]in d ole -1-ca r -
boxyla te [(()-55]. These compounds were obtained from 20b
and methyl acrylate (40) after a reaction period of 2 h. After
the usual workup, the crude reaction mixture was purified by
column chromatography on silica gel using an ethyl acetate-
heptane gradient (10-100% ethyl acetate) as eluent. Com-
pound 55 (oil, 6%) was eluted first: 1H NMR (300 MHz, CDCl3)
δ 2.01 (m, 1H), 2.53 (m, 1H), 2.95 (m, 2H), 3.01 (m, 1H), 3.11
(m, 1H), 3.20 (m, 2H), 3.26 (m, 1H), 3.70 (s, 3H), 4.26 (dd, 1H),
5.31 (pseudo q, 2H, J ) 18.0, 3.0 Hz), 6.96 (m, 1H), 7.14 (m,
3H), 7.26 (m, 4H), 7.55 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
19.8, 33.5, 41.8, 47.2, 47.5, 52.5, 55.3, 57.6, 107.5, 109.9, 118.6,
119.8, 122.2, 126.0, 126.1, 127.7, 129.1, 134.2, 137.5, 174.3;
IR (CHCl3) 1737 cm-1; mass spectrum (HREI) calcd for
C22H24N2O2 m/z 361.1915, found 361.1887.
Dim et h yl 5,6-Dih yd r o[8,7-b]in d ole-1,2-d ica r b oxyla t e
(60). A solution of compound 58 (100 mg, 0.31 mmol) in CH2-
Cl2 (10 mL) was maintained at 0 °C under nitrogen while DDQ
(70 mg, 0.31 mmol) was added in small portions over a period
of 2 h. The reaction mixture was then filtered through Celite,
the filtrate was evaporated to dryness under reduced pressure,
and the residue was purified by chromatography on silica gel
(CH2Cl2-ethanol 20:0.5), affording compound 60 (143 mg, 15%)
as a white solid: mp 193 °C (ethanol); 1H NMR (400 MHz,
CDCl3) δ 3.08 (t, 2H, J ) 7.0 Hz), 3.65 (s, 3H), 3.79 (s, 3H),
4.06 (t, 2H, J ) 7.0 Hz), 6.91 (m, 2H), 7.01 (s, 1H), 7.19 (d,
1H, J ) 8.0 Hz), 7.27 (d, 1H, J ) 8.0 Hz), 10.27 (br s, 1H,
Continued elution of the column afforded compound 54 as
an oil (60%): 1H NMR (300 MHz, CDCl3) δ 2.22 (m, 1H), 2.56
(m, 1H), 2.99 (m, 2H), 3.08 (m, 2H), 3.27 (s, 3H), 3.36 (m, 1H),
3.45 (m, 2H), 4.43 (d, 1H, J ) 9.0 Hz), 5.36 (pseudo q, 2H, J )
18.0, 3.0 Hz), 6.94 (m, 1H), 7.13 (m, 3H), 7.25 (m, 4H), 7.55
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 17.5, 27.7, 45.8, 46.8,
48.2, 51.7, 53.7, 60.3, 109.6, 118.1, 119.4, 121.7, 125.4, 127.0,
127.2, 128.4, 137.1, 137.4, 169.0; IR (CHCl3) 1737 cm-1; mass
spectrum (HREI) calcd for C22H24N2O2 m/z 361.1915, found
361.1890.
exchangeable with D2O); IR (KBr) 1600, 1670, 1710, 3380 cm-1
;
mass spectrum (EI) m/z 324 (M+). Anal. Calcd for
C18H16N2O4: C, 66.65; H, 4.97; N, 8.63. Found: C, 66.48; H,
4.85; N, 8.56.
Ack n ow led gm en t. We thank the French Ministry
of Research and Technology for doctoral fellowships
(G.P., M.-H.T.-B.) and Prof. P. Potier for helpful
discussions.
Dim eth yl In dolizin o[8,7-b]in dole-1,2-dicar boxylate (56).
A solution of compound 33 (50 mg, 0.152 mmol) in CH2Cl2 (5
mL) was treated at 0 °C and under nitrogen with DDQ (104
mg, 0.46 mmol). After 2 h, the reaction mixture was filtered
J O951520T