Palladium(0)-catalyzed heteroarylation of 2- and 3-indolylzinc derivatives. An efficient general method for the preparation of (2-pyridyl)indoles and their application to indole alkaloid synthesis

Article abstract of DOI:10.1021/jo962169u

Palladium(0)-catalyzed coupling of (1-(benzenesulfonyl)-2-indolyl)zinc chloride (1) and (1-(tert-butyldimethylsilyl)-3-indolyl)zinc chloride (6) with diversely substituted (alkyl, methoxy, methoxycarbonyl, nitro, hydroxy) 2-halopyridines gives the corresponding 2- and 3-(2-pyridyl)indoles [4 and 7 (or 8), respectively] in excellent yields. A series of other 3-(heteroaryl)indoles (pyrazinyl, furyl, thienyl, indolyl) have been similarly prepared from 6. The potential of some of these (2-pyridyl)indoles in alkaloid synthesis is demonstrated. Thus, from 2-(2-pyridyl)indole 4b, a new synthetic entry to the indolo[2,3-a]quinolizidine system, involving stereoselective hydrogenation of the pyridine ring with subsequent electrophilic cyclization upon the indole 3-position from an appropriately N(b)-substituted 2-(2-piperidyl)indole, is reported. For this purpose, Pummerer cyclizations have been extensively studied. Whereas the indole-unprotected sulfoxide 17 gives the corresponding indoloquinolizidine 19 in low yield and mainly undergoes an abnormal Pummerer cyclization that ultimately leads to sulfide 18, the N(a)-protected sulfoxides 24a and 24b afford the respective indoloquinolizidines 25a,b in 70% yield. On the other hand, the conversion of 3-(2-pyridyl)indole 8k into tetracyclic ketone 35 by stereoselective hydrogenation, followed by cyclization of the resulting all-cis-3-(2-piperidyl)indole 34, represents a formal synthesis of Strychnos alkaloids with the strychnan skeletal type (tubifoline, tubifolidine, 19,20-dihydroakuammicine). A similar conversion of 8j into nordasycarpidone constitutes a formal synthesis of the alkaloids of the uleine group. Reduction of nordasycarpidone leads to tetracycle 37, an advanced intermediate in a previous synthesis of tubotaiwine, a Strychnos alkaloid with the aspidospermatan skeletal type. Finally, piperidylindole 34 was transformed into tetracycle 41, an ABDE substructure of akuammiline alkaloids, by a sequence involving the skeletal rearrangement of an intermediate spiroindolenine as the crucial step.

Full text of DOI:10.1021/jo962169u

3158
J . Org. Chem. 1997, 62, 3158-3175
P a lla d iu m (0)-Ca ta lyzed Heter oa r yla tion of 2- a n d 3-In d olylzin c
Der iva tives. An Efficien t Gen er a l Meth od for th e P r ep a r a tion of
(2-P yr id yl)in d oles a n d Th eir Ap p lica tion to In d ole Alk a loid
Syn th esis
Mercedes Amat,* Sabine Hadida, Grigorii Pshenichnyi, and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received November 19, 1996X
Palladium(0)-catalyzed coupling of (1-(benzenesulfonyl)-2-indolyl)zinc chloride (1) and (1-(tert-
butyldimethylsilyl)-3-indolyl)zinc chloride (6) with diversely substituted (alkyl, methoxy, meth-
oxycarbonyl, nitro, hydroxy) 2-halopyridines gives the corresponding 2- and 3-(2-pyridyl)indoles [4
and 7 (or 8), respectively] in excellent yields. A series of other 3-(heteroaryl)indoles (pyrazinyl,
furyl, thienyl, indolyl) have been similarly prepared from 6. The potential of some of these (2-
pyridyl)indoles in alkaloid synthesis is demonstrated. Thus, from 2-(2-pyridyl)indole 4b, a new
synthetic entry to the indolo[2,3-a]quinolizidine system, involving stereoselective hydrogenation
of the pyridine ring with subsequent electrophilic cyclization upon the indole 3-position from an
appropriately Nb-substituted 2-(2-piperidyl)indole, is reported. For this purpose, Pummerer
cyclizations have been extensively studied. Whereas the indole-unprotected sulfoxide 17 gives the
corresponding indoloquinolizidine 19 in low yield and mainly undergoes an abnormal Pummerer
cyclization that ultimately leads to sulfide 18, the Na-protected sulfoxides 24a and 24b afford the
respective indoloquinolizidines 25a ,b in 70% yield. On the other hand, the conversion of 3-(2-
pyridyl)indole 8k into tetracyclic ketone 35 by stereoselective hydrogenation, followed by cyclization
of the resulting all-cis-3-(2-piperidyl)indole 34, represents a formal synthesis of Strychnos alkaloids
with the strychnan skeletal type (tubifoline, tubifolidine, 19,20-dihydroakuammicine). A similar
conversion of 8j into nordasycarpidone constitutes a formal synthesis of the alkaloids of the uleine
group. Reduction of nordasycarpidone leads to tetracycle 37, an advanced intermediate in a previous
synthesis of tubotaiwine, a Strychnos alkaloid with the aspidospermatan skeletal type. Finally,
piperidylindole 34 was transformed into tetracycle 41, an ABDE substructure of akuammiline
alkaloids, by a sequence involving the skeletal rearrangement of an intermediate spiroindolenine
as the crucial step.
The monoterpenoid indole alkaloids have a common
biogenetic origin, being formed from tryptamine or tryp-
tophan and a C9- or C10-monoterpene moiety derived from
secologanin.1 In spite of the enormous variation in the
terpenoid structure of these alkaloids, a close examina-
tion reveals that they have some structural features in
common. In particular, a 2-piperidyl unit linked to the
2- or 3-position of an indole or modified indole ring
(indoline, indolenine) can be recognized in six of the eight
different skeletal types of Hesse’s classification.2 For
instance, the tetracyclic indolo[2,3-a]quinolizidine alka-
loids (e.g., corynantheidine) and the pentacyclic alkaloids
of the akuammiline group (e.g., strictamine), both of them
with the corynanthean skeletal type, incorporate a 2-(2-
piperidyl)indole moiety, whereas the tetracyclic alkaloids
of the uleine group and the more complex Strychnos
alkaloids, with either the strychnan (e.g., akuammicine)
or the aspidospermatan (e.g., tubotaiwine) skeletal varia-
tions, embody a 3-(2-piperidyl)indole fragment (Figure
1).
F igu r e 1.
These similarities prompted us to explore a general
synthetic strategy for the synthesis of indole alkaloids
from appropriately substituted 2- and 3-(2-piperidyl)-
indoles, which, in turn, would be easily accessible by
stereoselective reduction of the pyridine ring from the
corresponding (2-pyridyl)indoles. Although several meth-
ods for the preparation of (2-pyridyl)indoles have been
described,3,4 most of them have some limitations because
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Bisset, N. G. In Indole and Biogenetically Related Alkaloids;
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Zenk, M. H., Eds.; Academic Press: London, 1980; Chapter 2.
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Y. Chem. Pharm. Bull. 1956, 4, 16. (b) Caixach, J .; Capell, R.; Ga´lvez,
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S0022-3263(96)02169-X CCC: $14.00 © 1997 American Chemical Society

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3159
of their low yields, incompatibilities with functional
groups, or specific structural requisites. For this reason,
in order to develop a simple, general, and efficient
methodology for assembling 2- and 3-(2-pyridyl)indoles,
we focused our attention on the palladium(0)-catalyzed
cross-coupling reactions,5 in particular on those between
halopyridines and N-protected 2- and 3-indolylzinc ha-
lides,6 a novel class of indole metal derivatives that, at
the beginning of our studies,7 had received very little
attention.8-10
The use of palladium complex chemistry has been
extensively explored for the synthesis and functionaliza-
tion of indoles.11 However, with the exception of a few
early examples employing (1-methyl-2-indolyl)lithium12
or the corresponding magnesio13 or trialkylborate14 de-
rivatives, the intermolecular arylation at the 2- and
3-positions of the indole nucleus by Pd-catalyzed cross-
coupling reactions of organometal indole derivatives and
aryl or heteroaryl halides15 has only been extensively
developed during the last 3 years, using either indolyl-
stannanes16 or indolylzinc halides.9,17
metalation of the respective lithioindoles. In this man-
ner, 2-indolylzinc chloride 1 was easily attainable by
metalation of 1-(benzenesulfonyl)indole with LDA,18 fol-
lowed by treatment of the resulting 2-lithioindole with
anhydrous ZnCl2. However, attempts to prepare (1-
(benzenesulfonyl)-3-indolyl)zinc chloride from the corre-
sponding 3-lithioindole were unsuccessful due to the easy
rearrangement of the latter to the 2-lithio isomer.18-20
For this reason, we decided to use the bulky tert-
butyldimethylsilyl group as the indole protecting group.
It is known that silyl groups bearing bulky alkyl sub-
stituents on the silicon atom provide lateral protection
of the indole 2-position due to their steric requirements
and noncoordinating abilities21 and that the correspond-
ing 3-lithio-1-silylindoles are stable species, which do not
rearrange to the 2-lithio isomers even at room temper-
ature.22 As expected, the (1-silyl-3-indolyl)zinc derivative
6 could be satisfactorily prepared from 3-bromo-1-(tert-
butyldimethylsilyl)indole (5), by halogen-metal exchange
with tert-butyllithium, followed by transmetalation of the
resulting 3-lithioindole with ZnCl2.
Cross-coupling reactions of 1 and 6 (1.5 equiv) with
2-bromopyridine (2a ) or 2-chloropyridine (3a ) in the
presence of 2 mol % of a catalyst prepared from PdCl2-
(PPh3)2 and DIBAH (2 equiv) in refluxing THF (Negishi
method)23 afforded the corresponding (2-pyridyl)indoles
4a and 7a , respectively, in good yields. Further treat-
ment of the silylated 3-(2-pyridyl)indole 7a with a re-
fluxing ethanolic solution containing a catalytic amount
of p-TsOH yielded the deprotected derivative 8a in nearly
quantitative yield. However, from the synthetic stand-
point, to avoid partial desilylation during purification by
column chromatography, it was more convenient to
immediately desilylate the crude reaction mixture as
described above. In contrast with the success of direct
Pd(0)-catalyzed cross-coupling reactions between chloro-
pyrazines and indoles,15 1-(benzenesulfonyl)indole did not
react with halopyridines 2a and 3a in the presence of
Pd(PPh3)4 (3 mol %) under several reaction conditions.
In order to evaluate the scope of the process, we studied
the above cross-coupling reactions with a variety of
2-chloro- and 2-bromopyridines bearing substituents of
different electronic nature, either electron-releasing (alkyl,
methoxy, hydroxy) or electron-withdrawing (nitro, meth-
oxycarbonyl). The results are given in Table 1. The
reaction seems to be general, and the yields ranged from
P r ep a r a tion of N-P r otected 2- a n d 3-In d olylzin c
Ch lor id es. Syn th esis of 2- a n d 3-(2-P yr id yl)in d oles.
For the generation of the required 2- and 3-indolylzinc
halides, we selected the procedure based on the trans-
(4) 3-(2-Pyridyl)indoles: (a) Naito, T.; Iida, N.; Ninomiya, I. J . Chem.
Soc., Perkin Trans. 1 1986, 99. (b) Naito, T.; Iida, N.; Ninomiya, I. J .
Chem. Soc., Chem. Commun. 1981, 44. (c) Suzuki, T.; Sato, E.; Goto,
K.; Unno, K.; Kametani, T. Heterocycles 1980, 14, 433. (d) Kametani,
T.; Suzuki, T. J . Chem. Soc. (C) 1971, 1053. (e) Kametani, T.; Suzuki,
T. Chem. Pharm. Bull. 1971, 19, 1424. (f) Kametani, T.; Suzuki, T. J .
Org. Chem. 1971, 36, 1291. (g) Hamana, M.; Kumadaki, I. Chem.
Pharm. Bull. 1970, 18, 1742. (h) Powers, J . C. J . Org. Chem. 1965,
30, 2534.
(5) For a review on the formation of C-C bonds in heterocycles using
Pd-catalyzed reactions, see: Kalinin, V. N. Synthesis 1992, 413.
(6) (a) For
organozinc reagents, see: Erdik, E. Tetrahedron 1992, 48, 9577. (b)
For review on the preparation and reactions of polyfunctional
a review on transition metal catalyzed reactions of
a
organozinc reagents, see: Knochel, P.; Singer, R. D.Chem. Rev. 1993,
93, 2117.
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at the Eight European Symposium on Organic Chemistry (ESOC-8),
Sitges, Spain, August 1993. For preliminary reports, see: (b) Amat,
M.; Hadida, S.; Bosch, J . Tetrahedron Lett. 1993, 34, 5005. (c) Amat,
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25, 201.
(9) Almost simultaneously with our preliminary communications,7
the preparation and palladium-catalyzed arylation of 2-9a and
3-indolylzinc9b halides were reported: (a) Sakamoto, T.; Kondo, Y.;
Takazawa, N.; Yamanaka, H. Heterocycles 1993, 36, 941. (b) Sakamoto,
T.; Kondo, Y.; Takazawa, N.; Yamanaka, H. Tetrahedron Lett. 1993,
34, 5955. The full paper of these studies has recently been published:
(c) Sakamoto, T.; Kondo, Y.; Takazawa, N.; Yamanaka, H. J . Chem.
Soc., Perkin Trans. 1 1996, 1927.
(10) For the preparation and reactions of lithium indolyl(dimethyl)-
zincates, see: Kondo, Y.; Takazawa, N.; Yoshida, A.; Sakamoto, T. J .
Chem. Soc., Perkin Trans. 1 1995, 1207.
(11) For reviews, see: (a) Hegedus, L. S. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1113. (b) Martin, A. R.; Zheng, Q. In Advances in
Nitrogen Heterocycles; Pearson, W. H., Ed.; J AI Press, Inc.: Greenwich,
1990; Vol. 1, pp 71-120.
(12) Widdowson, D. A.; Zhang, Y.-Z. Tetrahedron 1986, 42, 2111.
(13) (a) Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada,
M. Tetrahedron Lett. 1981, 22, 5319. (b) Minato, A.; Suzuki, K.; Tamao,
K.; Kumada, M. J . Chem. Soc., Chem. Commun. 1984, 511.
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1989, 135.
(15) For Pd-catalyzed cross-coupling reactions of indole itself or
substituted indoles with chloropyrazines, see: (a) Akita, Y.; Inoue, A.;
Yamamoto, K.; Ohta, A. Heterocycles 1985, 23, 2327. (b) Akita, Y.;
Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull. 1989, 37, 1477.
(16) 2-Indolylstannanes: (a) Palmisano, G.; Santagostino, M. Synlett
1993, 771. (b) Palmisano, G.; Santagostino, M. Helv. Chim. Acta 1993,
76, 2356. (c) Fukuyama, T.; Chen, X.; Peng, G. J . Am. Chem. Soc. 1994,
116, 3127. (d) Labadie, S. S.; Teng, E. J . Org. Chem. 1994, 59, 4250.
(e) Hudkins, R. L.; Diebold, J . L.; Marsh, F. D. J . Org. Chem. 1995,
60, 6218. 3-Indolylstannanes: (f) Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1994, 35, 2405.
(17) For recent examples using 3-indolylboronic acids, see: (a)
Kawasaki, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44,
1831. Pd-catalyzed cross-coupling reactions of haloindoles with het-
eroaryl organometallics have received less attention: (b) Ishikura, M.;
Kamada, M.; Terashima, M. Synthesis 1984, 936. (c) Somei, M.;
Sayama, S.; Naka, K.; Yamada, F. Heterocycles 1988, 27, 1585. (d)
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(20) A similar result was reported in refs 9b and 9c. To avoid this
inconvenience, the authors prepared (1-(benzenesulfonyl)-3-indolyl)-
zinc iodide by oxidative addition of active zinc to the corresponding
3-iodoindole.
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1993, 36, 29.
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stituted indoles, see: (a) Amat, M.; Hadida, S.; Sathyanarayana, S.;
Bosch, J . J . Org. Chem. 1994, 59, 10. (b) Amat, M.; Sathyanarayana,
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3160 J . Org. Chem., Vol. 62, No. 10, 1997
Ta ble 1. Th e P a lla d iu m (0)-Ca ta lyzed Cou p lin g of In d olylzin c Der iva tives w ith Ha lop yr id in es
Amat et al.
a
Operating from a 1:1 mixture of halopyridines 3j and 3k .
Ta ble 2. Th e P a lla d iu m (0)-Ca ta lyzed Cou p lin g of
good to excellent. In all cases the corresponding 2,2′- or
3,3′-biindole (9 and 10, respectively) was formed in
approximately 10-15% yield (based on the starting
indole). The most significant conclusions are as follows:
(i) in 2-chloropyridines 3, the presence of an electron-
releasing substituent, such as methyl, decreases the yield
(entry b), whereas with electron-withdrawing substitu-
ents (entries g-m ) the cross-coupling products are
formed in excellent yield; (ii) in contrast, in the case of
2-bromopyridines 2, the nature of the substituent on the
pyridine ring has practically no effect on the yield (entries
a -e); (iii) there is no substantial difference in the
behavior of 2- and 3-indolylzinc halides; (iv) the reaction
works in the presence of ester groups (entries g-k ) or
acidic protons, although in the latter case the yields are
lower (entry f).
3-In d olylzin c 6 w ith Heter oa r yl Ha lid es
The heteroarylation at the indole 3-position using
3-indolylzinc chloride 6 was extended to heteroaryl
halides other than halopyridines, derived from both
π-excedent and π-deficient heterocycles (Table 2). Thus,
Pd(0)-catalyzed cross-coupling of 2-chloropyrazine and
3-indolylzinc chloride 6, followed by deprotection of the
indole nitrogen as in the above pyridyl series, afforded
3-(pyrazinyl)indole 12a in 91% yield. However, bromides
derived from π-excedent heterocycles such as thiophene,
furan, and indole gave lower yields. Moreover, the
corresponding 1-silyl-3-(heteroaryl)indoles 11b-e were
resistant to hydrolysis under acidic conditions, and in

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3161
Sch em e 1
Sch em e 2a
these cases, deprotection of indole had to be carried out,
after purification of 11, by treatment with tetrabutyl-
ammonium fluoride.
A New Syn th etic En tr y to th e In d olo[2,3-a ]qu in o-
lizid in e System fr om 2-(2-P yr id yl)in d oles. For the
construction of the indolo[2,3-a]quinolizidine ring system
from pyridylindoles 4, we devised a route involving
catalytic hydrogenation of the pyridine ring, introduction
of an appropriately functionalized two-carbon chain on
the piperidine nitrogen, and finally, closure of ring C by
cyclization on the indole 3-position. Although a number
of synthetic approaches have been developed for as-
sembling the indolo[2,3-a]quinolizidine ring system,24 the
strategy based on the elaboration of ring C by formation
of the C7-C7a bond from 2-(2-piperidyl)indoles has been
little explored.25 A related strategy involving the closure
of the C ring by the formation of the Nb-C6 bond had
already been employed3d in the conversion of pyridylin-
doles 4a and 4b to the zwitterionic indolo[2,3-a]quino-
lizine alkaloids26 indolopyridocoline and flavocarpine,
respectively (Scheme 1). For the key ring closure we
decided to investigate electrophilic cyclizations of thion-
ium ions generated either by Pummerer reaction27 of a
sulfoxide or by treatment of a dithioacetal with dimethyl-
(methylthio)sulfonium fluoroborate (DMTSF),28 proce-
dures that we had successfully used in the context of the
synthesis of Strychnos alkaloids.29,30
a
Key: (i) NaOH, H2O, EtOH, reflux, 96%; (ii) LDA, ClCO2Me,
THF, -78 °C, 64%; (iii) H2, PtO2, HCl, MeOH, 60%; (iv)
C6H5S(O)CHdCH2, MeOH, reflux, 89%; (v) TFAA, CH2Cl2, 25 °C,
then chlorobenzene, reflux, 73%; (vi) TFAA, CH2Cl2, 25 °C, 20%;
(vii) Bu3SnH, AlBN, benzene, reflux, 72%.
The required sulfoxide 17 was prepared from py-
ridylindole 4b as outlined in Scheme 2. Thus, after
deprotection of the indole nucleus and conversion of the
methyl group at the pyridine 4-position to a malonate
moiety31 (corresponding to C16, C17, and C22 in the
biogenetic numbering32), the pyridine ring of 15 was
stereoselectively hydrogenated to the cis-2,4-disubstitut-
ed piperidine 16, which was then treated with phenyl
vinyl sulfoxide to afford 17 as an epimeric mixture at the
sulfur atom. Both isomers could be easily separated by
column chromatography.
When a solution of amino sulfoxides 17 in CH2Cl2 was
treated with TFAA at rt, the expected tetracycle 19
(mixture of epimers at C7) was obtained in only 20% yield.
In some runs the secondary amine 16, resulting from
hydrolysis of the exocyclic iminium ion formed through
the equilibria thionium ion a vinyl sulfide (enamine) a
iminium ion, was also isolated.33 The reversibility of the
Pummerer cyclization when the indole ring is not deac-
tivated could favor this undesirable process. To avoid
the above N-dealkylation, the TFAA-induced Pummerer
cyclization was carried out in the presence of either TFA
or BF3‚Et2O, as it was expected that the formation of a
(24) For reviews, see: (a) Brown, R. T. In Indoles, The Monoterpe-
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cyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley: New
York, 1983; Vol. 25, Part 4, Chapter 3. (b) Saxton, J . E. Ibid., Chapter
9. (c) Lounasmaa, M.; Tolvanen, A. In Monoterpenoid Indole Alkaloids;
Saxton, J . E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor,
E. C., Ed.; Wiley: Chichester, 1994; Vol. 25, Supplement to Part 4,
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(25) (a) Rubiralta, M.; Diez, A.; Bosch, J .; Solans, X. J . Org. Chem.
1989, 54, 5591. (b) Rubiralta, M.; Diez, A.; Vila, C. Tetrahedron 1990,
46, 4443.
(26) For a review, see: Gribble, G. W. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed; Elsevier: Amsterdam, 1988; Vol. 1,
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(27) (a) De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40,
157. (b) Grierson, D. S.; Husson, H.-P. In Comprehensive Organic
Synthesis; Trost, B. M., Ed; Pergamon Press: Oxford, 1991; Vol. 6,
Chapter 4.7. (c) Kennedy, M.; McKervey, M. A. Ibid., Vol. 7, Chapter
2.4.
(28) (a) Smallcombe, S. H.; Caserio, M. C. J . Am. Chem. Soc. 1971,
93, 5826. (b) Trost, B. M.; Murayama, E. J . Am. Chem. Soc. 1981, 103,
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6299. (b) Amat, M.; Bosch, J . J . Org. Chem. 1992, 57, 5792.
(30) For a preliminary report of this part of the work, see: Amat,
M.; Hadida, S.; Sathyanarayana, S; Bosch, J . Tetrahedron Lett. 1996,
37, 3071.
(32) Le Men, J .; Taylor, W. I. Experientia 1965, 21, 508.
(33) Similar N-dealkylations have been observed from â-amino
sulfoxides under Pummerer reaction conditions: see ref 29b. For
related N-dealkylations of aminoacetaldehyde derivatives, see: (a)
Lathbury, D. C.; Parsons, P. J .; Pinto, I. J . Chem. Soc., Chem. Commun.
1988, 81. (b) Mehmandoust, M.; Marazano, C.; Das, B. C. J . Chem.
Soc., Chem. Commun. 1989, 1185. (c) Valls, N.; Segarra, V. M.; Maillo,
L. C.; Bosch, J . Tetrahedron 1991, 47, 1065. (d) Bosch, J .; Salas, M.;
Amat, M.; Alvarez, M.; Morgo´, I.; Adrover, B. Tetrahedron 1991, 47,
5269. See also ref 29a.
(31) Minor amounts (<5%) of compound 21 were isolated. All
attempts to introduce the alkoxycarbonyl substituent from 4b were
unsuccessful. Using NaH and CO3Et2 in refluxing toluene, the N-
ethoxycarbonyl derivative 14 was formed.

3162 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
Sch em e 3
Sch em e 4a
a
Key: (i) NCCO2Me, DMAP, acetonitrile, reflux, ∼85% or
(Boc)2O, DMAP, CH2Cl2, 25 °C, 97%; (ii) TMSOTf, DIPEA, CH2Cl2,
25 °C, ∼70%; (iii) HCO2H, 25 °C, 65%.
matographic purification of the crude mixture resulting
from the reaction of sulfoxide 17 with TFAA (CH2Cl2, rt)
and then to transform this material into sulfide 18 by
heating it in chlorobenzene in the presence of TFAA.
The following two reasons could explain the abnormal
course of the above Pummerer reactions: (a) the genera-
tion of the thionium ion by abstraction of an R-proton
from the (acyloxy)sulfonium intermediate derived from
â-amino sulfoxide 17 is slower than that in activated
sulfoxides such as â-keto sulfoxides, (b) the indole ring
is not deactivated by an electron-withdrawing group that
would diminish its nucleophilic character. Under these
circumstances, substitution at the sulfur in the (acyloxy)-
sulfonium intermediate by attack of the indole ring is
faster than generation of the thionium ion required in
the normal Pummerer cyclization.
In order to verify the latter interpretation, we decided
to study related Pummerer cyclizations from 2-(2-pip-
eridyl)indoles bearing an electron-withdrawing protecting
group on the indole nitrogen. The required N-protected
sulfoxides 24a and 24b were prepared in excellent yields
from 17 (Scheme 4) by treatment with methyl cyanofor-
mate and di-tert-butyl dicarbonate, respectively, in the
presence of DMAP.38 In fact, this protection could be
effected separately for each epimer of the starting sul-
foxide 17 to give the two separate epimers at the sulfur
atom of both 24a and 24b.
Pummerer cyclization of the indole-protected amino
sulfoxide 24a was initially tried with TFAA (4 equiv) in
the presence of TFA (4 equiv). Under these conditions
indoloquinolizidine 25a was obtained in 45% yield as a
separable mixture of C7 epimers. The use of TMSOTf in
the presence of Hu¨nig’s base gave higher yields (∼70%).
Similarly, the Na-Boc sulfoxides 24b underwent smooth
cyclization on treatment with TMSOTf-Hu¨nig’s base to
give indoloquinolizidine 25b also in approximately 70%
yield (two C7 epimers). Products arising from either
N-dealkylation or the above abnormal Pummerer rear-
rangement were not isolated. In the Na-Boc series, the
use of TFAA-TFA was not successful because of the easy
deprotection of the Na-Boc group under acidic condi-
tions: a mixture of sulfide 18 and indoloquinolizidines
piperidine salt or a piperidine-BF3 adduct34 would
prevent the formation of the exocyclic iminium ion.
However, under these conditions the desired indoloquino-
lizidine 19 was not isolated.
Surprisingly, when the crude reaction mixture result-
ing from treatment of 17 under the usual Pummerer
reaction conditions (TFAA, rt) was heated in chloroben-
zene for 2 h, sulfide 18 was obtained in 73% yield. The
use of nonacidic conditions did not improve the situa-
tion: TFAA-Hu¨nig’s base led to mixtures of 18 (major
component) and the secondary amine 16, whereas TM-
SOTf-Hu¨nig’s base promoted cyclization upon the indole
nitrogen to give tetracycles 22 (57% yield; two C6
epimers). In the latter case, only minor amounts of
indoloquinolizidines 19 were detected from the reaction
mixture.
Formation of sulfide 1835 can be rationalized as de-
picted in Scheme 3, by considering the nucleophilic
displacement of the acyloxy group by the indole ring in
the initially formed (acyloxy)sulfonium intermediate to
give sulfonium salt 23, which undergoes a subsequent
ring cleavage due to an external nucleophile attack
(CF3CO2- or OH-) on the R-carbon. This process involves
the formation of a seven-membered C ring intermediate
rather than the expected closure of a six-membered ring
by electrophilic cyclization of the intermediate thionium
ion on the indole 3-position.36 In accordance with this
interpretation, it was possible to isolate 23 as its conju-
gate base37 from the most polar fractions of the chro-
(34) There are very few examples of normal Pummerer cyclizations
from â-amino sulfoxides: (a) Pyne, S. G.; Dikic, B. J . Org. Chem. 1990,
55, 1932. (b) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1992,
48, 7803. (c) Takano, S.; Iida, H.; Inomata, K.; Ogasawara, K.
Heterocycles 1993, 35, 47. (d) Bonjoch, J .; Catena, J .; Valls, N. J . Org.
Chem. 1996, 61, 7106. See also ref 29b.
(35) For a preliminary communication of this and a related abnormal
Pummerer cyclization on the indole ring, see: Amat, M.; Bennasar,
M.-L.; Hadida, S.; Sufi, B. A.; Zulaica, E.; Bosch, J . Tetrahedron Lett.
1996, 37, 5217.
(36) (a) For a similar migration of an arylthio group to an electron-
rich aromatic ring under Pummerer reaction conditions, see: Pyne,
S. G.; Hajipour, A. R. Tetrahedron 1994, 50, 13501. For related
processes, see: (b) Kaneko, T. J . Am. Chem. Soc. 1985, 107, 5490. (c)
Terauchi, H.; Tanitame, A.; Tada, K.; Nishikawa, Y. Heterocycles 1996,
43, 1719. (d) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S.
V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61,
3375. (e) Bravo, P.; Capelli, S.; Meille, S. V.; Seresini, P.; Volonterio,
A.; Zanda, M. Tetrahedron: Asymmetry 1996, 7, 2321.
(37) For the isolation of 3-(dimethylsulfonio)indolides, see: (a)
Daves, G. D., J r.; Anderson, W. R., J r.; Pickering, M. V. J . Chem. Soc.,
Chem. Commun. 1974, 301. (b) Hocker, J .; Ley, K.; Merten, R.
Synthesis 1975, 334. (c) Park, K. H.; Gray, G. A.; Daves, G. D., J r. J .
Am. Chem. Soc. 1978, 100, 7475.
(38) Methoxycarbonylation of 17 under the conditions reported in
the preliminary communication (NCCO2Me, NaH, THF, TMDA, 25
°C)30 gave barely reproducible results, and in most runs, methoxycar-
bonylation also occurred at the methine carbon of the malonate moiety.

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3163
Sch em e 5a
19 and 25b was obtained. As could be expected, the
individual epimeric sulfoxides of each pair 24a -1/24a -2
and 24b-1/24b-2 behaved similarly under the Pummerer
reaction conditions, giving similar C7 epimeric mixtures
of the respective indoloquinolizidines 25a and 25b.
Deprotection of the indole ring was accomplished by
treatment of 25b with formic acid at room temperature:
a nearly equimolecular C7 epimeric mixture of indolo-
quinolizidines 19 was obtained starting from either of the
two C7 epimers of 25b. In accordance with this observa-
tion, each C7 epimer of 19 was separately equilibrated
to a 1:1 mixture of C7 epimers after being stirred in formic
acid for 12 h. This epimerization involves protonation
at the indole 3-position, followed by cleavage of the C7-
C7a bond and subsequent recyclization of the resulting
thionium ion. Finally, desulfurization of 19, either with
Raney Ni or with Bu3SnH-AIBN, led to the known39
indoloquinolizidine 20.
The above results not only indicate that the abnormal
Pummerer cyclization on the indole 3-position can be
avoided if the indole nitrogen bears an electron-with-
drawing substituent but also expand the scope of Pum-
merer cyclizations on the indole ring: this reaction can
now be used for the synthesis of b-annulated indoles
starting from 2-substituted indoles.40 To our knowledge,
the above cyclizations constitute the first examples of
synthetically useful Pummerer cyclizations on the indole
3-position in 3-unsubstituted indoles.41 In contrast,
Pummerer cyclizations upon either the indole 2-position42
or the indole 3-position in 3-substituted indoles43 have
received considerable synthetic attention.
a
Key: (i) ClCH2CON(OMe)Me, NaI, K2CO3, CH3CN, 45 °C,
92%; (ii) Red-Al, toluene, THF, -25 °C, then MeSH, BF3‚Et2O,
CH2Cl2, 0 °C: 27 (17%) and 30 (15%); (iii) Red-Al, toluene, THF,
-25 °C: 28 (30%), 29 (12%), 31 (30%), and 32 (4%); (iv) Et3SiH,
TFA, CH2Cl2, 70%.
intermediate iminium cation generated during the reduc-
tion, and lactam 32 (4%) were also isolated. This route
was not optimized given the satisfactory results obtained
in the above Pummerer cyclizations. Reduction of alcohol
28 with Et3SiH-TFA gave the same indoloquinolizidine
20 previously prepared from sulfide 19.
The second method we had planned to study for the
construction of the C ring of indolo[2,3-a]quinolizidines
from 2-(2-piperidyl)indole 16 required the introduction
of a 2,2-bis(methylthio)ethyl chain on the piperidine
nitrogen. This was attempted by alkylation of 16 with
N-methoxy-N-methylchloroacetamide (Scheme 5), fol-
lowed by partial reduction of the resulting amide 26 to
the corresponding aldehyde44 and subsequent dithio-
acetalization. However, when 26 was treated with Red-
Al and then with methanethiol in the presence of BF3‚
Et2O, a mixture of indoloquinolizidines 27 (17%; two
epimers at C7) and tetracycles 30 (15%; two epimers at
C6) was obtained instead of the expected dithioacetal.
Presumably, the intermediate thionium ion formed dur-
ing dithioacetalization undergoes cyclization, on either
C3 or the nitrogen of the indole ring. When the treatment
with methanethiol was omitted, the reduction of 26 led
to hydroxyindoloquinolizidine 28 (30%) and tetracyclic
alcohol 31 (30%), which arise from cyclization of the
initially formed aldehyde, probably promoted by the
alane generated during the process.45 Minor amounts of
indoloquinolizidine 29 (12%), formed by cyclization of the
The strategy developed here to build the indolo[2,3-a]-
quinolizidine system, combined with the flexible method
for the preparation of the starting 2-(2-pyridyl)indoles,
provides a short, general synthetic entry to this tetra-
cyclic system that may be applicable to the synthesis of
Corynanthe alkaloids.
F or m a l Syn th eses of Alk a loid s of th e Ulein e a n d
Str ych n os Gr ou p s fr om 3-(2-P yr id yl)in d oles. A com-
mon structural feature of the alkaloids of the uleine and
Strychnos groups, with either the aspidospermatan or the
strychnan skeletan type, is the presence of a 3-(2-
piperidyl)indole moiety included in a bridged polycyclic
system, in which all the piperidine substituents are cis.
Stereoselective hydrogenation of the pyridine ring of 3-(2-
pyridyl)indoles 8j and 8k , followed by cyclization of the
resulting all-cis-3-(2-piperidyl)indoles (36 and 34, respec-
tively) would provide rapid access to the hexahydro-1,5-
methanoazocino[4,3-b]indole system, characteristic of
these alkaloids.46
The required pyridylindoles 8j and 8k had efficiently
been obtained (85% overall yield) by Pd(0)-catalyzed
heteroarylation of 3-indolylzinc chloride 6 with a 1:1
mixture of methyl 2-chloro-3-(and 5)ethylisonicotinate (3j
and 3k , respectively), as indicated in Table 1, followed
by chromatographic separation. Alternatively, although
less efficiently, they were prepared in approximately 60%
overall yield from pyridylindoles 8c and 8d , as outlined
in Scheme 6, through a four-step sequence involving
protection of the indole nucleus as a N-benzenesulfonyl
derivative, oxidation of the methyl substituent at the
pyridine 4-position, deprotection of the indole ring, and,
finally, esterification of the resulting isonicotinic acid.47
(39) Grierson, D. S.; Vuilhorgne, M.; Husson, H.-P. J . Org. Chem.
1982, 47, 4439.
(40) For a recent application of these concepts to the synthesis of
geissoschizine, see: Bennasar, M.-L.; J ime´nez, J .-M.; Sufi, B. A.; Bosch,
J . Tetrahedron Lett. 1996, 37, 9105.
(41) For previous unsuccessful attempts, see: Bennasar, M.-L.;
Zulaica, E.; Sufi, B. A.; Bosch, J . Tetrahedron 1996, 52, 8601. See also
ref 42.
(42) Oikawa, Y.; Yonemitsu, O. J . Org. Chem. 1976, 41, 1118.
(43) Gallagher, T.; Magnus, P.; Huffman, J . C. J . Am. Chem. Soc.
1983, 105, 4750. See also refs 29b and 34d.
(44) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(45) For related cyclizations of N-(2-oxoethyl)piperidine derivatives
in the construction of the seven-membered C ring of Iboga alkaloids,
see: (a) Sundberg, R. J .; Amat, M.; Fernando, A. J . Org. Chem. 1987,
52, 3151. (b) Sundberg, R. J .; Gadamasetti, K. G. Tetrahedron 1991,
47, 5673.
(46) For a preliminary report of this part of the work, see: Amat,
M.; Sathyanarayana, S.; Hadida, S.; Bosch, J . Tetrahedron Lett. 1994,
35, 7123.

3164 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
Sch em e 6a
Sch em e 8a
a
Key: (i) C6H5SO2Cl, n-Bu4N+HSO4-, NaOH, H2O, benzene,
96%; (ii) SeO2, pyridine, 95 °C; (iii) NaOH, H2O, EtOH, reflux;
(iv) MeOH, H2SO4, ∼60% from 33.
Sch em e 7
a
Key: (i) HCl, MeOH, then H2, PtO2, MeOH, 60%; (ii) Ba(OH)2,
H2O, dioxane, reflux, then PPA, 85-90 °C, 36%; (iii) LiAlH4,
As expected, catalytic hydrogenation of 8k hydrochlo-
ride stereoselectively provided piperidine 34, with the
natural all-cis relative configuration48 (Scheme 7). The
cyclization of piperidine ester 34 to tetracyclic ketone
3549,50 and the conversion of 35 to the Strychnos alkaloids
(strychnan skeletal type) tubifoline, tubifolidine, and
19,20-dihydroakuammicine29a by construction of the five-
membered C ring had previously been effected in our
laboratory.51
dioxane, reflux, 33%.
reported the synthesis of tubotaiwine,52a a Strychnos
alkaloid with the aspidospermatan skeletal type.
In summary, formal total syntheses of alkaloids of the
uleine and Strychnos groups, the latter belonging to
either the strychnan or the aspidospermatan skeletal
series, have been accomplished from 3-(2-pyridyl)indoles
8j and 8k .
A Syn th etic En tr y to th e Tetr a cyclic ABDE Cor e
of Ak u a m m ilin e Alk a loid s. The akuammiline alka-
loids constitute a subgroup of corynanthean indole alka-
loids that remain synthetically inaccessible to date, which
are characterized by the presence of a C7-C16 bond,32
giving an additional ring E.54 Consequently, they incor-
porate a 1,5-methanoazocino[3,4-b]indole system (rings
ABDE) (Figure 1). In order to further illustrate the
synthetic potential of the above 3-(2-piperidyl)indoles,
e.g., 34, we decided to study the intramolecular alkylation
of the indole nucleus from derivatives bearing a good
leaving group on the substituent at the 4-position of the
piperidine ring.
In a similar way, the 2,3,4-trisubstituted pyridine
isomer 8j was hydrogenated to the all-cis-piperidylindole
3648 and then cyclized49a to the alkaloid nordasycar-
pidone4e,50 (Scheme 8). Taking account of previous
correlations,4e,52 this constitutes a formal synthesis of the
alkaloids dasycarpidone, dasycarpidol, uleine, and 17-
hydroxy-16,17-dihydrouleine as well as a notable im-
provement on previous syntheses of the alkaloids of the
uleine group.53 On the other hand, LiAlH4 reduction of
nordasycarpidone gave tetracycle 37, from which we have
(47) All attempts to directly oxidize the methyl substituent of 8c
were unsuccessful.
(48) The stereochemical assignment of all-cis-piperidines 34 and 36
was effected by comparison of their 13C NMR data with the data of
the cis and trans isomers of methyl 2-(3-indolyl)-4-piperidinecarboxy-
late: see ref 46.
(49) (a) Amat, M.; Hadida, S.; Llor, N.; Sathyanarayana, S.; Bosch,
J . J . Org. Chem. 1996, 61, 3878. For the cyclization of a mixture of 34
and other stereoisomers, see: (b) Bosch, J .; Rubiralta, M.; Domingo,
A.; Bolo´s, J .; Linares, A.; Minguillo´n, C.; Amat, M.; Bonjoch, J . J . Org.
Chem. 1985, 50, 1516.
(50) Minor amounts of the C-20 epimer were also isolated. For a
detailed discussion of this epimerization and related epimerizations
in 3-(2-piperidyl)indoles, see ref 49a.
(51) For recent reviews on the Strychnos alkaloids, see: (a) Sapi,
J .; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J . E., Ed.
In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;
Wiley: Chichester, 1994; Vol. 25, Supplement to Part 4, Chapter 7.
(b) Bosch, J .; Bonjoch, J .; Amat, M. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
(52) (a) Gra`cia, J .; Casamitjana, N.; Bonjoch, J .; Bosch, J . J . Org.
Chem. 1994, 59, 3939. (b) Blechert, S. Liebigs Ann. Chem. 1985, 2073.
(c) Borris, R. P.; Lankin, D. C.; Cordell, G. A. J . Nat. Prod. 1983, 46,
206. (d) J ackson, A.; Wilson, N. D. V.; Gaskell, A. J .; J oule, J . A. J .
Chem. Soc. (C) 1969, 2738. (e) J oule, J . A.; Ohashi, M.; Gilbert, B.;
Djerassi, C. Tetrahedron 1965, 21, 1717.
LiAlH4 reduction of ester 34, followed by protection of
the piperidine nitrogen with benzyl chloroformate and
mesylation of the resulting alcohol 39, led to the key
mesylate 40 in satisfactory overall yield. Treatment of
(53) For reviews, see: (a) J oule, J . A. In Indoles, The Monoterpenoid
Indole Alkaloids; Saxton, J . E., Ed. In The Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York,
1983; Vol. 25, Part 4, Chapter 6. (b) Alvarez, M.; J oule, J . A. In
Monoterpenoid Indole Alkaloids; Saxton, J . E., Ed. In The Chemistry
of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994;
Vol. 25, Supplement to Part 4, Chapter 6.
(54) For reviews, see: (a) J oule, J . A. In Indoles, The Monoterpenoid
Indole Alkaloids: Saxton, J . E., Ed. In The Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York,
1983; Vol. 25, Part 4, pp 244-264. (b) Alvarez, M.; J oule, J . In
Monoterpenoid Indole Alkaloids; Saxton, J . E., Ed. In The Chemistry
of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994;
Vol. 25, Supplement to Part 4, pp 248-259. For more recent work,
see: (c) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch, J . J . Org.
Chem. 1996, 61, 1239. (d) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.;
Bosch, J . Tetrahedron Lett. 1996, 37, 6611.

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3165
Sch em e 9a
Sch em e 10a
a
Key: (i) LiAlH4, THF, -30 °C, 95%; (ii) ClCO2CH2C6H5,
K2CO3, CHCl3, 25 °C, 43%; (iii) MeSO2Cl, pyridine, 25 °C, 90%;
(iv) t-BuOK, THF, 25 °C, 50%.
40 with potassium tert-butoxide directly afforded the
akuammiline-type tetracycle 41 in 50% yield (Scheme
9).55,56 The isomeric tetracycle with the [4,3-b] fusion
characteristic of uleine and Strychnos alkaloids was not
detected. The above result corroborates that the in-
tramolecular alkylation at C2 in 3-alkylindoles proceeds
through the intermediacy of a spiroindolenine, with
subsequent Wagner-Meerwein-like 1,2-shifts.57 The
higher migratory aptitude of an aminoalkyl group, as
compared with an alkyl group,58 in the initially formed
spiroindolenine, accounts for the observed regioselective
formation of 41.
Protection of the piperidine nitrogen is necessary for
the success of this approach to tetracyclic ABDE sub-
structures of akuammiline alkaloids. Thus, attempted
preparation of the N-alkylpiperidine mesylate 44 (Scheme
10) resulted in the unexpected formation of pyrrolidine
45. This result can be rationalized by considering an
intramolecular alkylation59 of the piperidine nitrogen in
the initially formed mesylate 44, followed by a gramine-
type fragmentation of the resulting quaternary salt
involving cleavage of the piperidine ring.
a
Key: (i) BrCH2CH(OMe)2, dioxane, K2CO3, NaI, 140 °C, 24h,
81%; (ii) LiAlH4, Et2O, -30 °C to 25 °C, 90%; (iii) MeSO2Cl,
pyridine, 25 °C, 35%.
SDS, 0.040-0.060 mm). Drying of the organic extracts during
the workup of reactions was performed over Na2SO4. Evapo-
ration of solvents was accomplished with a rotatory evaporator.
Microanalyses and HRMS were performed by Centro de
Investigacio´n y Desarrollo (CSIC), Barcelona. All compounds
were synthesized in the racemic series.
2-Br om o-3-eth yl-4-m eth ylp yr id in e (2c) a n d 2-Br om o-
5-et h yl-4-m et h ylp yr id in e (2d ). 3-Ethyl-4-methylpyridine
(100 mL, 780 mmol) was slowly added to a suspension of
NaNH2 (91 g, 2.3 mmol) in N,N-dimethylaniline (152 mL), and
the resulting mixture was heated at reflux for 12 h. The
temperature was lowered to 25 °C, and water (50 mL) was
added dropwise. The aqueous layer was separated and
extracted with Et2O. The combined organic extracts were
dried and concentrated to give an oil. Distillation (106 °C, 3
mmHg) afforded a 1:3 mixture of aminopyridines (56 g, 53%),
which were difficult to separate. Column chromatography
(hexane-AcOEt, increasing polarity) gave a pure sample of
each isomer. 2-Am in o-3-et h yl-4-m et h ylp yr id in e (minor
Exp er im en ta l Section
Melting points were determined in a capillary tube and are
uncorrected. NMR spectra were recorded at 200, 300, or 500
MHz (1H) and 50.3 or 75 MHz (13C). Only noteworthy IR
absorptions are listed. TLC was carried out on SiO2 (silica
gel 60 F254, Merck, 0.063-0.200 mm), and the spots were
located with iodoplatinate reagent. Column chromatography
was carried out on SiO2 (silica gel 60, SDS, 0.060-0.2 mm).
Flash chromatography was carried out on SiO2 (silica gel 60,
isomer): IR (CHCl3) 3401 cm-1; H NMR (CDCl3) δ 1.07 (t, J
1
) 7.5 Hz, 3 H), 2.22 (s, 3 H), 2.45 (q, J ) 7.5 Hz, 2 H), 4.88 (br
s, 2 H), 6.42 (d, J ) 5.1 Hz, 1 H), 7.77 (d, J ) 5.1 Hz, 1 H); 13
C
NMR (CDCl3) δ 11.7 (CH3), 18.6 (CH3), 20.1 (CH2), 116.9 (CH),
120.9 (C), 144.9 (CH), 145.4 (C), 157.3 (C). Anal. Calcd for
C8H12N2: C, 70.55; H, 8.88; N, 20.57. Found: C, 70.73; H,
8.53; N, 20.68. 2-Am in o-5-eth yl-4-m eth ylp yr id in e (major
isomer): IR (CHCl3) 3403 cm-1; H NMR (CDCl3) δ 1.14 (t, J
1
(55) For a preliminary report on this part of the work, see: Amat,
M.; Hadida, S.; Bosch, J . An. Quim., Int. Ed. 1996, 92, 62.
(56) For precedents on the synthesis of hexahydro-1,5-methanoa-
zocino[3,4-b]indoles, see: (a) Dolby, L. J .; Nelson, S. J . J . Org. Chem.
1973, 38, 2882. (b) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica,
E.; Bosch, J . J . Org. Chem. 1990, 55, 1156. See also ref 54c.
(57) (a) J ackson, A. H.; Naidoo, B. J . Chem. Soc., Perkin Trans. 2
1973, 548 and previous papers in this series. (b) Ganesan, A.;
Heathcock, C. H. Tetrahedron Lett. 1993, 34, 439. (c) Diez, A.; Vila,
C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M. Tetrahedron Lett. 1993,
34, 733.
(58) For a review, see: Ungemach, F.; Cook, J . M. Heterocycles 1978,
9, 1089.
(59) For related processes, see: (a) Wenkert, E.; Halls, T. D. J .;
Kwart, L. D.; Magnusson, G,; Showalter, H. D. H. Tetrahedron 1981,
37, 4017. (b) Kalaus, G.; Malkieh, N.; Katona, I.; Kajta´r-Peredy, M.;
Koritsa´nszky, T.; Ka´lma´n, A.; Szabo´, L.; Sza´ntay, C. J . Org. Chem.
1985, 50, 3760.
) 7.5 Hz, 3 H), 2.17 (s, 3 H), 2.48 (q, J ) 7.5 Hz, 2 H), 4.83 (br
s, 2 H), 6.29 (s, 1 H), 7.79 (s, 1 H); 13C NMR (CDCl3) δ 14.4
(CH3), 18.4 (CH3), 22.5 (CH2), 109.5 (CH), 128.2 (C), 146.6 (CH),
147.0 (C), 157.0 (C); mp 61-62 °C (Et2O-hexane). Anal.
Calcd for C8H12N2: C, 70.55; H, 8.88; N, 20.57. Found: C,
70.66; H, 8.82; N, 20.61. Bromine (11.1 mL, 216 mmol) and a
solution of NaNO2 (12.7 g, 184 mmol) in water (28 mL) were
added to a solution of the above mixture of aminopyridines
(10 g, 73 mmol) in 48% HBr (36 mL) maintained at -10 °C,
and the mixture was stirred at this temperature for 1 h 30
min. Then, a solution of NaOH (70 g) in water (100 mL) was
added, and the stirring was continued for 1 h at 25 °C. The
mixture was extracted with Et2O, and the organic solution was
dried and concentrated to give an oil. Distillation (120 °C, 1
mmHg) afforded a mixture of 2-bromopyridines 2c and 2d (14

3166 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
1
g, 96%), which were difficult to separate. Flash chromatog-
raphy (CH2Cl2) gave pure samples of both isomers. 2c: 1H
NMR (CDCl3) δ 1.69 (t, J ) 7.5 Hz, 3 H), 2.37 (s, 3 H), 2.80 (q,
J ) 7.5 Hz, 2 H), 7.02 (d, J ) 4.8 Hz, 1 H), 8.04 (d, J ) 4.8 Hz,
1 H); 13C NMR (CDCl3) δ 12.2 (CH3), 19.5 (CH3), 25.2 (CH2),
125.2 (CH), 138.9 (C), 144.9 (C), 147.0 (CH), 147.8 (C). Anal.
Calcd for C8H10NBr: C, 48.03; H, 5.09; N, 7.00; Br, 39.93.
Found: C, 47.82; H, 5.09; N, 6.88; Br, 39.99. 2d : 1H NMR
(CDCl3) δ 1.20 (t, J ) 7.5 Hz, 3 H), 2.28 (s, 3 H), 2.58 (q, J )
7.5 Hz, 2 H), 7.22 (s, 1 H), 8.07 (s, 1 H); 13C NMR (CDCl3) δ
13.7 (CH3), 18.1 (CH3), 22.7 (CH2), 128.5 (CH), 137.2 (C), 139.3
(C), 148.3 (C), 149.1 (CH). Anal. Calcd for C8H10NBr‚1/3H2O:
C, 46.62; H, 5.19; N, 6.79; Br, 39.93. Found: C, 46.60; H, 5.19;
N, 6.49.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-(2-P y-
r id yl)in d oles 4. A solution of LDA (1.5 M in cyclohexane,
1.1 equiv) was slowly added to a 0.6 M solution of 1-(benze-
nesulfonyl)indole in anhydrous THF at 0 °C, and the resulting
mixture was stirred for 30 min at this temperature. Then, a
0.45 M solution of anhydrous ZnCl2 (it was used after fusion
by flame-drying under reduced pressure) (1.1 equiv) in THF
was added, and the stirring was continued for 30 min at 25
°C. In a separate flask, a 0.8 M solution of the 2-halopyridine
2 or 3 in anhydrous THF was added to a solution containing
2 mol % of a catalyst prepared by reaction of a 0.027 M solution
of Cl2Pd(PPh3)2 in anhydrous THF with 2 equiv of diisobuty-
laluminum hydride (1.0 M in hexane), and the mixture was
stirred at 25 °C for 10 min. The resulting solution was
transferred via canula to the solution of (1-(benzenesulfonyl)-
2-indolyl)zinc chloride (1) prepared above. The mixture was
heated at reflux for 4 h, cooled, and poured into saturated
aqueous Na2CO3. The aqueous phase was extracted with Et2O,
and the organic extracts were concentrated to give a residue,
which was chromatographed (CH2Cl2).
1175 cm-1; H NMR (CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3 H), 2.44
(s, 3 H), 2.67 (q, J ) 7.5 Hz, 2 H), 6.68 (s, 1 H), 7.20 (d, J ) 4.9
Hz, 1 H), 7.40 (m, 6 H), 7.95 (dm, J ) 6.6 Hz, 2 H), 8.12 (d, J
) 8.2 Hz, 1 H), 8.41 (d, J ) 4.9 Hz, 1 H); 13C NMR (CDCl3) δ
13.7 (CH3), 19.0 (CH3), 22.8 (CH2), 111.8 (CH), 114.7 (CH),
121.1 (CH), 123.7 (CH), 124.7 (CH), 126.0 (CH), 127.3 (CH),
128.7 (CH), 129.7 (C), 133.5 (C), 135.9 (C), 137.8 (C), 139.0
(C), 139.2 (C), 145.6 (CH), 150.5 (C); mp 136-138 °C (Et2O-
hexane). Anal. Calcd for C22H20N2O2S: C, 70.18; H, 5.35; N,
7.44; S, 8.51. Found: C, 70.16; H, 5.38; N, 7.42; S, 8.52.
1-(Ben zen esu lfon yl)-2-(5-eth yl-4-m eth yl-2-p yr id yl)in -
d ole (4d ). Following the general procedure, from 2-bromo-
5-ethyl-4-methylpyridine (2d ) (550 mg, 2.7 mmol) and 1-(ben-
zenesulfonyl)indole (1.1 g, 4.1 mmol) were obtained 9 (100 mg,
10%) and 4d 3d (920 mg, 89%). 4d : IR (CHCl3) 1450, 1372
cm-1; H NMR (CDCl3) δ 1.30 (t, J ) 7.5 Hz, 3 H), 2.39 (s, 3
1
H), 2.72 (q, J ) 7.5 Hz, 2 H), 6.83 (s, 1 H), 7.31 (m, 7 H), 7.68
(dm, J ) 7.8 Hz, 2 H), 8.18 (d, J ) 8.1 Hz, 1 H), 8.42 (s, 1 H);
13C NMR (CDCl3) δ 14.1 (CH3), 18.6 (CH3), 23.5 (CH2), 114.6
(CH), 116.1 (CH), 121.1 (CH), 124.3 (CH), 124.7 (CH), 126.9
(CH), 127.2 (CH), 128.5 (CH), 130.4 (C), 133.4 (CH), 136.9 (C),
137.4 (C), 137.8 (C), 141.2 (C), 144.5 (C), 145.6 (C), 148.0 (CH).
1-(Ben zen esu lfon yl)-2-(3-m eth oxy-2-pyr idyl)in dole (4e).
Following the general procedure, from 2-bromo-3-methoxy-
pyridine (2e)62 (940 mg, 5.0 mmol) and 1-(benzenesulfonyl)-
indole (1.9 g, 7.4 mmol) were obtained 9 (200 mg, 10%) and
4e (1.5 g, 80%). 4e: IR (KBr) 1370, 1177 cm-1 1H NMR
;
(CDCl3) δ 3.87 (s, 3 H), 6.80 (s, 1 H), 7.15-7.42 (m, 7 H), 7.48
(dm, J ) 7.7 Hz, 1 H), 7.73 (dm, 2 H), 8.11 (d, J ) 8.1 Hz, 1
H), 8.32 (dd, J ) 4.6, 1.5 Hz, 1 H); 13C NMR (CDCl3) δ 55.5
(CH3), 113.3 (CH), 115.1 (CH), 117.7 (CH), 121.3 (CH), 123.8
(CH), 124.7 (CH), 124.9 (CH), 126.8 (CH), 128.7 (CH), 130.2
(C), 133.4 (CH), 136.7 (C), 137.4 (C), 137.8 (C), 140.5 (CH),
155.5 (C); mp 108 °C (Et2O). Anal. Calcd for C20H16N2O3S:
C, 65.92; H, 4.43; N, 7.69; S, 8.80. Found: C, 65.90; H, 4.39;
N, 7.75; S, 8.55.
1-(Ben zen esu lfon yl)-2-(3-h ydr oxy-2-pyr idyl)in dole (4f).
Following the general procedure, from 2-bromo-3-hydroxy-
pyridine (2f) (500 mg, 2.9 mmol) and 1-(benzenesulfonyl)indole
(1.9 g, 7.4 mmol) were obtained 9 (200 mg, 11%) and 4f (400
mg, 40%). 4f: IR (KBr) 3400-3600, 1369, 1176 cm-1; 1H NMR
(CDCl3) δ 6.74 (s, 1 H), 7.14-7.46 (m, 9 H), 7.70 (dm, J ) 8.0
Hz, 2 H), 8.08 (d, J ) 8.3 Hz, 1 H), 8.18 (dd, J ) 3.9, 2.0 Hz,
1 H); 13C NMR (CDCl3) δ 114.7 (CH), 115.2 (CH), 121.4 (C),
123.5 (CH), 123.9 (CH), 125.1 (CH), 126.8 (CH), 128.7 (CH),
130.1 (C), 133.6 (C), 136.5 (C), 136.8 (C), 137.2 (C), 139.5 (C),
153.3 (C); mp 202-203 °C (acetone-hexane). Anal. Calcd for
C19H14N2O3S: C, 65.13; H, 4.03; N, 8.00; S, 9.15. Found: C,
64.95; H, 4.01; N, 7.87; S, 9.17.
1-(Ben zen esu lfon yl)-2-(2-p yr id yl)in d ole (4a ). Following
the above procedure, from 2-bromopyridine (2a ) (920 mg, 5.8
mmol) and 1-(benzenesulfonyl)indole (2.3 g, 8.7 mmol) were
obtained [1,1′-bis(benzenesulfonyl)]-2,2′-biindole3b (9) (220 mg,
10%) and pyridylindole 4a (1.5 g, 78%). 4a :3d IR (KBr) 1448,
1
1372 cm-1; H NMR (CDCl3) δ 6.90 (s, 1 H), 7.23-7.53 (m, 7
H), 7.68 (dm, J ) 7.8 Hz, 2 H), 7.74 (ddd, J ) 8.0, 1.7, 1.1 Hz,
1 H), 7.82 (td, J ) 8.0, 1.7 Hz, 1 H), 8.23 (d, J ) 7.5 Hz, 1 H),
8.71 (ddd, J ) 5.0, 1.7, 1.1 Hz, 1 H); 13C NMR (CDCl3) δ 114.8
(CH), 115.8 (CH), 121.1 (CH), 122.7 (CH), 124.1 (CH), 125.1
(CH), 125.7 (CH), 126.5 (CH), 128.3 (CH), 129.9 (C), 133.2
(CH), 135.1 (CH), 137.6 (C), 140.7 (C), 148.4 (CH), 150.9 (C).
Operating as above, from 2-chloropyridine (3a ) (660 mg, 5.8
mmol) and 1-(benzenesulfonyl)indole (2.2 g, 8.7 mmol) were
obtained dimer 9 (220 mg, 10%) and pyridylindole 4a (1.45 g,
75%).
Meth yl 2-(1-(Ben zen esu lfon yl)-2-in d olyl)-3-p yr id in e-
ca r boxyla te (4g). Following the general procedure, from
methyl 2-chloro-3-pyridinecarboxylate (3g)63 (858 mg, 5.0
mmol) and 1-(benzenesulfonyl)indole (1.9 g, 7.4 mmol) were
obtained 9 (180 mg, 9%) and 4g (1.6 g, 80%). 4g: IR (KBr)
1-(Ben zen esu lfon yl)-2-(4-m eth yl-2-p yr id yl)in d ole (4b).
Following the general procedure, from 2-bromo-4-methyl-
pyridine (2b)60 (700 mg, 4.0 mmol) and 1-(benzenesulfonyl)-
indole (1.5 g, 6.0 mmol) were obtained 9 (160 mg, 10%) and
4b (1.3 g, 92%). 4b: IR (KBr) 1610, 1370 cm-1 1H NMR
;
1723, 1368 cm-1; H NMR (CDCl3) δ 3.78 (s, 3 H), 6.77 (s, 1
1
(CDCl3) δ 2.45 (s, 3 H), 6.85 (s, 1 H), 7.17 (d, J ) 5.0 Hz, 1 H),
7.20-7.35 (m, 5 H), 7.45 (d, J ) 7.7 Hz, 1 H), 7.53 (s, 1 H),
7.69 (dm, J ) 7.5 Hz, 2 H), 8.20 (d, J ) 8.1 Hz, 1 H), 8.54 (d,
J ) 5.0 Hz, 1 H); 13C NMR (CDCl3) δ 20.8 (CH3), 115.0 (CH),
116.2 (CH), 121.3 (CH), 124.2 (CH), 124.4 (CH), 125.3 (CH),
127.0 (CH), 128.7 (CH), 130.4 (C), 133.6 (CH), 137.1 (C), 138.1
(C), 141.2 (C), 146.7 (C), 148.6 (CH), 151.2 (C); mp 110 °C
(Et2O). Anal. Calcd for C20H16N2S: C, 68.95; H, 4.63; N, 8.04.
Found: C, 68.91; H, 4.63; N, 7.90. Operating as above, from
2-chloro-4-methylpyridine (3b)61 (637 mg, 5.0 mmol) and
1-(benzenesulfonyl)indole (1.9 g, 7.5 mmol) were obtained
dimer 9 (194 mg, 10%) and pyridylindole 4b (700 mg, 40%).
1-(Ben zen esu lfon yl)-2-(3-eth yl-4-m eth yl-2-p yr id yl)in -
d ole (4c). Following the general procedure, from 2-bromo-3-
ethyl-4-methylpyridine (2c) (500 mg, 2.5 mmol) and 1-(ben-
zenesulfonyl)indole (964 mg, 3.7 mmol) were obtained 9 (106
mg, 11%) and 4c (884 mg, 94%). 4c: IR (CHCl3) 1450, 1373,
H), 7.20-7.50 (m, 6 H), 7.51 (dd, J ) 8.0, 5.0 Hz, 1 H), 7.75
(dm, J ) 7.5 Hz, 2 H), 8.08 (d, J ) 8.2 Hz, 1 H), 8.40 (dd, J )
8.0, 1.7 Hz, 1 H), 8.84 (dd, J ) 5.0, 1.7 Hz, 1 H); 13C NMR
(CDCl3) δ 52.4 (CH3), 112.7 (CH), 114.5 (CH), 121.3 (CH), 123.3
(CH), 123.7 (CH), 125.0 (CH), 126.9 (CH), 128.8 (CH), 129.6
(C), 133.5 (CH), 136.1 (C), 137.7(C), 138.8 (C), 151.0 (CH),
151.4 (C), 165.6 (C); mp 135 °C (Et2O). Anal. Calcd for
C21H16N2O4S: C, 64.26; H, 4.11; N, 7.13; S, 8.17. Found: C,
64.87; H, 4.17; N, 7.14; S, 7.89.
Meth yl 2-(1-(Ben zen esu lfon yl)-2-in d olyl)-4-p yr id in e-
ca r boxyla te (4h ). Following the general procedure, from
methyl 2-chloro-4-pyridinecarboxylate (3h )64 (858 mg, 5.0
mmol) and 1-(benzenesulfonyl)indole (1.9 g, 7.4 mmol) were
(62) 2e was prepared in nearly quantitative yield by methylation
of 2-bromo-3-hydroxypyridine with CH2N2.
(63) Esters 3g and 3i were prepared by methylation of the corre-
sponding acids with CH2N2 in 78% and 95% yields, respectively.
(64) Chloropyridine 3h was prepared in 95% yield by treatment
(reflux, 12 h) of methyl isonicotinate N-oxide (4.6 g, 30 mmol)4d with
POCl3 (11 mL) in CHCl3 (11 mL).
(60) (a) Bosch, J .; Canals, C.; Granados, R. An. Quim. 1978, 74, 985.
(b) Case, F. H. J . Am. Chem. Soc. 1946, 68, 2574.
(61) Seide, O. Chem. Ber. 1924, 57, 791.

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3167
obtained 9 (200 mg, 10%) and 4h (1.9 g, 95%). 4h : IR (NaCl)
C14H20BrNSi: C, 54.18; H, 6.50; Br, 25.75; N, 4.51. Found:
C, 54.21; H, 6.60; Br, 25.52; N, 4.62.
1
1732, 1373 cm-1; H NMR (CDCl3) δ 4.00 (s, 3 H), 6.92 (s, 1
H), 7.20-7.42 (m, 5 H), 7.48 (dm, J ) 7.8 Hz, 1 H), 7.65 (dm,
J ) 7.5 Hz, 2 H), 7.90 (dd, J ) 5.1, 1.5 Hz, 1 H), 8.20 (d, J )
8.1 Hz, 1 H), 8.27 (d, J ) 1.5 Hz, 1 H), 8.83 (d, J ) 5.1 Hz, 1
H); 13C NMR (CDCl3) δ 52.7 (CH3), 115.9 (CH), 116.2 (CH),
121.5 (CH), 122.1 (CH), 124.5 (CH), 125.2 (CH), 125.6 (CH),
126.9 (CH), 128.6 (CH), 130.2 (C), 133.6 (CH), 136.8 (C), 136.9
(C), 138.1 (C), 140.1 (C), 149.6 (CH), 152.3 (C), 165.3 (C); mp
113-115 °C (Et2O). Anal. Calcd for C21H16N2O4S: C, 64.26;
H, 4.11; N, 7.13; S, 8.17. Found: C, 64.32; H, 4.04; N, 7.19; S,
7.98.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-(2-P y-
r id yl)in d oles 7 a n d 8. A solution of t-BuLi (1.7 M in pentane,
2.0 equiv) was slowly added to a 0.8 M solution of 3-bromo-
1-(tert-butyldimethylsilyl)indole (5) in anhydrous THF at -78
°C, and the resulting mixture was stirred for 10 min at this
temperature. Then, a 0.35 M solution of ZnCl2
(it was used
after fusion by flame-drying under reduced pressure) (1.1
equiv) in THF was added to this solution, and the stirring was
continued for 30 min at 25 °C. In a separate flask, a 0.54 M
solution of the 2-halopyridine 2 or 3 in anhydrous THF was
added to 2 mol % of a catalyst prepared by reaction of a 0.014
M solution of Cl2Pd(PPh3)2 in anhydrous THF with 2 equiv of
diisobutylaluminum hydride (1.0 M in hexane), and the
mixture was stirred at 25 °C for 5 min. The resulting mixture
was transferred via canula to the solution of the indolylzinc
chloride 6 (1.5 equiv) prepared as described above, and the
solution was heated at reflux for 4 h, cooled, and poured into
saturated aqueous Na2CO3. The aqueous phase was extracted
with Et2O, and the organic extracts were dried and concen-
trated. The residue was chromatographed (CH2Cl2) to afford
7. Alternatively, the above crude residue was dissolved in
EtOH, and a catalytic amount of TsOH was added. This
mixture was heated at reflux until the disappearance of the
starting material was observed by TLC. The solvent was
evaporated, and the residue was dissolved in CH2Cl2. The
solution was washed with saturated aqueous Na2CO3, dried,
and concentrated, and the resulting residue was chromato-
graphed to afford 8.
Meth yl 2-(1-(Ben zen esu lfon yl)-2-in d olyl)-5-p yr id in e-
ca r boxyla te (4i). Following the general procedure, from
methyl 2-chloro-5-pyridinecarboxylate (3i)63 (858 mg, 5.0
mmol) and 1-(benzenesulfonyl)indole (1.9 g, 7.4 mmol) were
obtained 9 (190 mg, 10%) and 4i (1.6 g, 83%). 4i: IR (KBr)
1724 cm-1; 1H NMR (CDCl3) δ 4.00 (s, 3 H), 7.00 (s, 1 H), 7.25-
7.40 (m, 3 H), 7.35 (dm, J ) 7.5 Hz, 2 H), 7.48 (dm, J ) 8.8
Hz, 1 H), 7.62 (dm, J ) 7.5 Hz, 2 H), 7.83 (d, J ) 8.3 Hz, 1 H),
8.21 (d, J ) 8.2 Hz, 1 H), 8.38 (dd, J ) 8.3, 2.0 Hz, 1 H), 9.28
(d, J ) 2.0 Hz, 1 H); 13C NMR (CDCl3) δ 52.3 (CH3), 116.5
(CH), 117.0 (CH), 121.8 (CH), 124.8 (CH), 124.9 (C), 125.7
(CH), 126.1 (CH), 127.0 (CH), 128.8 (CH), 130.2 (C), 133.8
(CH), 136.5 (CH), 138.2 (C), 140.5 (C), 150.2 (CH), 154.9 (C),
165.8 (C); mp 105 °C (Et2O). Anal. Calcd for C21H16N2O4S:
C, 64.26; H, 4.11; N, 7.13; S, 8.17. Found: C, 64.24; H, 4.56;
N, 6.72; S, 7.85.
1-(Ben zen esu lfon yl)-2-(5-n itr o-2-pyr idyl)in dole (4l). Fol-
lowing the general procedure, from 2-chloro-5-nitropyridine
(3l) (792 mg, 5.0 mmol) and 1-(benzenesulfonyl)indole (1.9 g,
7.4 mmol) were obtained 9 (220 mg, 11%) and 4l (1.8 g, 97%).
1-(ter t-Bu tyldim eth ylsilyl)-3-(2-pyr idyl)in dole (7a). Fol-
lowing the general procedure, from 2-chloropyridine (3a ) (500
mg, 4.4 mmol) and 3-bromo-1-(tert-butyldimethylsilyl)indole
(5) (2.0 g, 6.6 mmol) were obtained 1,1′-bis(tert-butyldimeth-
ylsilyl)]-3,3′-biindole (10) (200 mg, 13%) and pyridylindole 7a
1
4l: IR (KBr) 1519, 1352, 1173, 758 cm-1; H NMR (CDCl3) δ
7.12 (s, 1 H), 7.15-7.56 (m, 6 H), 7.61 (dm, J ) 7.0 Hz, 2 H),
7.98 (d, J ) 8.6 Hz, 1 H), 8.23 (d, J ) 8.3 Hz, 1 H), 8.58 (dd,
J ) 8.6, 2.6 Hz, 1 H), 9.51 (d, J ) 2.6 Hz, 1 H); 13C NMR
(CDCl3) δ 116.5 (CH), 118.6 (CH), 122.0 (CH), 125.0 (CH),
125.9 (CH), 126.6 (CH), 127.0 (CH), 128.7 (CH), 130.1 (C),
130.4 (CH), 133.9 (CH), 136.1 (C), 138.9 (C), 139.2 (C), 143.0
(C), 144.3 (CH), 156.2 (C); mp 174-176 °C (acetone). Anal.
Calcd for C19H13N3O4S: C, 60.15; H, 3.45; N, 11.08; S, 8.45.
Found: C, 60.18; H, 3.38; N, 11.14; S, 8.42.
(1.1 g, 80%). 10: IR (KBr) 2950-2850, 1451, 1139, 1004 cm-1
;
1H NMR (CDCl3) δ 0.66 (s, 12 H), 0.99 (s, 18 H), 7.19 (m, 4 H),
7.44 (s, 2 H), 7.57 (dm, J ) 7.2 Hz, 2 H), 7.78 (dm, J ) 7.7 Hz,
2 H); 13C NMR (CDCl3) δ -3.8 (CH3), 19.6 (C), 26.4 (CH3), 112.7
(C), 114.0 (CH), 119.8 (CH), 120.0 (CH), 121.7 (CH), 128.3
(CH), 130.3 (C), 141.5 (C); mp 197-198 °C (hexane). Anal.
Calcd for C28H35N2Si2: C, 73.04; H, 8.69; N, 6.08. Found: C,
73.01; H, 8.85; N, 6.19. 7a : 1H NMR (CDCl3) δ 0.61 (s, 6 H),
0.92 (s, 9 H), 7.04 (ddd, J ) 7.5, 5.0, 1.8 Hz, 1 H), 7.20 (m, 2
H), 7.53 (m, 1 H), 7.62 (td, J ) 7.5, 1.8 Hz, 1 H), 7.69 (dm, J
) 7.5 Hz, 1 H), 7.75 (s, 1 H), 8.28 (m, 1 H), 8.63 (ddd, J ) 5.0,
2.8, 1.0 Hz, 1 H); 13C NMR (CDCl3) δ -4.6 (CH3), 18.8 (C),
25.8 (CH3), 113.7 (CH), 118.9 (C), 119.7 (CH), 129.9 (CH), 120.4
(CH), 120.7 (CH), 121.5 (CH), 128.3 (C), 130.8 (CH), 135.7
(CH), 141.7 (C), 149.0 (CH), 154.4 (C).
1-(Ben zen esu lfon yl)-2-(3,5-din itr o-2-pyr idyl)in dole (4m ).
Following the general procedure, from 2-chloro-3,5-dinitro-
pyridine (3m ) (407 mg, 2.0 mmol) and 1-(benzenesulfonyl)-
indole (771 mg, 3.0 mmol) were obtained 9 (100 mg, 13%) and
1
4m (595 mg, 70%). 4m : IR (KBr) 1594, 1526, 1343 cm-1; H
NMR (CDCl3) δ 7.08 (s, 1 H), 7.27-7.51 (m, 6 H), 7.59 (d, J )
7.0 Hz, 2 H), 8.09 (d, J ) 8.4 Hz, 1 H), 9.22 (d, J ) 2.3 Hz, 1
H), 9.72 (d, J ) 2.3 Hz, 1 H); 13C NMR (DMSO-d6) δ 115.1
(CH), 117.5 (CH), 122.9 (CH), 125.2 (CH), 127.1 (CH), 128.8
(CH), 129.7 (C), 129.9 (CH), 134.5 (C), 135.3 (CH), 135.8 (C),
136.8 (C), 144.0 (C), 145.6 (C), 147.8 (CH), 149.1 (C); mp 184-
186 °C (acetone-hexane). Anal. Calcd for C19H12N4O6S: C,
53.77; H, 2.85; N, 13.20; S, 7.55. Found: C, 53.52; H, 2.70;
N,13.01; S, 7.46.
1-(ter t-Bu t yld im et h ylsilyl)-3-(4-m et h yl-2-p yr id yl)in -
d ole (7b). Following the general procedure, from 2-bromo-
4-methylpyridine (2b)60 (370 mg, 2.1 mmol) and 3-bromoindole
(5) (1.0 g, 3.2 mmol) were obtained dimer 10 (70 mg, 10%) and
pyridylindole 7b (630 mg, 93%). 7b: IR(NaCl) 1603, 1545,
1450 cm-1; 1H NMR (CDCl3) δ 0.66 (s, 6 H), 0.97 (s, 9 H), 2.41
(s, 3 H), 6.95 (dm, J ) 5.1 Hz, 1 H), 7.23 (m, 2 H), 7.55 (s, 1
H), 7.56 (dm, J ) 8.0 Hz, 1 H), 7.75 (s, 1 H), 8.28 (m, 1 H),
8.53 (d, J ) 5.1 Hz, 1 H); 13C NMR (CDCl3) δ -4.1 (CH3), 19.2
(CH3), 21.0 (CH3), 26.2 (C), 114.3 (CH), 119.5 (C), 120.8 (CH),
120.9 (CH), 121.5 (CH), 121.9 (CH), 128.9 (C), 131.4 (CH),
142.3 (C), 147.3 (C), 149.5 (CH), 154.9 (C).
3-Br om o-1-(ter t-bu tyld im eth ylsilyl)in d ole (5). To a
solution of indole (8g, 68 mmol) in anhydrous THF (200 mL)
at -78 °C was slowly added a solution of n-BuLi in hexane
(47 mL of a 1.6 M solution, 75 mmol), and the temperature
was raised to -10 °C. After 15 min the reaction mixture was
cooled to -50 °C, and a solution of TBDMSCl (11.6 g, 77 mmol)
in anhydrous THF (60 mL) was added dropwise. After the
mixture was stirred at 0 °C for 3 h, the temperature was
lowered to -70 °C, and freshly crystallized NBS (12.2 g, 68.4
mmol) was added. After 2 h the temperature was raised to
25 °C, and hexane (100 mL) and pyridine (1 mL) were added.
The resulting suspension was filtered through a Celite pad,
and the filtrate was concentrated to give a residue which was
purified by column chromatography (hexane) affording pure
5 (17.8 g, 84%) as a colorless solid: 1H NMR (CDCl3) δ 0.60
(s, 6 H), 0.93 (s, 9 H), 7.17 (s, 1 H), 7.20 (m, 2 H), 7.48 (m, 1
H), 7.54 (m, 1 H); 13C NMR (CDCl3) δ -4.0 (CH3), 19.3 (C),
26.2 (CH3), 93.6 (C), 114.0 (CH), 119.1 (CH), 120.5 (CH), 122.5
(CH), 129.6 (CH), 129.8 (C), 140.2 (C). Anal. Calcd for
3-(2-P yr id yl)in d ole (8a ). Following the general procedure,
from 2-bromopyridine (2a ) (450 mg, 3.1 mmol) and 3-bromo-
indole 5 (1.5 g, 4.7 mmol), after reflux of the crude mixture in
EtOH (31 mL) containing TsOH for 4 h and purification by
column chromatography, were obtained dimer 10 (eluent CH2-
Cl2, 130 mg, 12%) and pyridylindole 8a (eluent 98:2 CH2Cl2-
EtOH, 580 mg, 95%). 8a : IR (KBr) 3200-2700, 1602, 1530
1
cm-1; H NMR (CDCl3) δ 7.12 (dd, J ) 8.8, 4.9 Hz, 1 H), 7.24
(m, 2 H), 7.39 (m, 1 H), 7.71 (m, 2 H), 7.77 (d, J ) 2.8 Hz, 1
H), 8.30 (dm, J ) 7.0 Hz, 1 H), 8.66 (dm, J ) 4.9 Hz, 1H), 8.85
(br s, 1 H); 13C NMR (CDCl3) δ 111.7 (CH), 116.2 (C), 120.0
(CH), 120.2 (CH), 120.5 (CH), 121.0 (CH), 122.1 (CH), 125.0
(CH), 125.2 (C), 136.8 (CH), 148.9 (CH), 154.8 (C); mp 138-
140 °C (Et2O) [lit.4h mp 150-154 °C (benzene)]. Anal. Calcd

3168 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
for C13H10N2: C, 80.39; H, 5.19; N, 14.31. Found: C, 80.48;
H, 5.23; N, 14.31. Operating as above, from 2-chloropyridine
(3a ) (500 mg, 4.4 mmol) and 3-bromoindole 5 (2.0 g, 6.6 mmol)
were obtained dimer 10 (200 mg, 13%) and pyridylindole 8a
(717 mg, 84%).
136-138 °C (Et2O). Anal. Calcd for C14H12N2O: C, 74.98; H,
5.39; N, 12.49. Found: C, 74.98; H, 5.40; N, 12.48.
3-(3-Hyd r oxy-2-p yr id yl)in d ole (8f). Following the gen-
eral procedure, from 2-bromo-3-hydroxypyridine (2f) (500 mg,
2.9 mmol) and 3-bromoindole 5 (2.2 g, 7.2 mmol), after reflux
of the crude mixture in EtOH (28 mL) containing TsOH for
24 h and purification by column chromatography (AcOEt),
were obtained dimer 10 (240 mg, 15%) and pyridylindole 8f
(380 mg, 63%). 8f: IR (KBr) 3800-2800, 1455 cm-1; 1H NMR
(acetone-d6) δ 7.04 (dd, J ) 8.0, 4.6 Hz, 1 H), 7.17 (m, 2 H),
7.34 (dd, J ) 8.0, 1.4 Hz, 1 H), 7.50 (m, 1 H), 8.28 (dd, J ) 4.6,
1.4 Hz, 1 H), 8.40 (d, J ) 2.7 Hz, 1 H), 8.92 (dm, J ) 7.0 Hz,
1 H), 9.15 (br s, 1 H), 10.50 (br s, 1 H); 13C NMR (acetone-d6)
δ 111.8 (CH), 113.7 (C), 120.4 (CH), 120.6 (CH), 122.5 (CH),
124.0 (CH), 127.7 (C), 128.9 (CH), 137.2 (C), 140.4 (CH), 145.1
(C), 151.1 (C); mp 145-147 °C (benzene-CH2Cl2). Anal.
Calcd for C13H10N2O: C, 74,27; H, 4.79; N, 13.32. Found: C,
74.36; H, 4.51; N, 13.36.
3-(4-Meth yl-2-p yr id yl)in d ole (8b). Following the general
procedure, from 2-bromo-4-methylpyridine (2b)60 (369 mg, 2.1
mmol) and 3-bromoindole 5 (1.0 g, 3.2 mmol), after reflux of
the crude mixture in EtOH (21 mL) containing TsOH for 12 h
and purification by column chromatography, were obtained
dimer 10 (eluent CH2Cl2, 104 mg, 14%) and pyridylindole 8b
(eluent 98:2 CH2Cl2-EtOH, 416 mg, 93%). 8b: IR (KBr)
3200-2800, 1608 cm-1; 1H NMR (CDCl3-CD3OD) δ 2.39 (s, 3
H), 6.96 (d, J ) 5.1 Hz, 1 H), 7.21 (m, 2 H), 7.44 (m, 1 H), 7.58
(s, 1 H), 7.75 (s, 1 H), 8.12 (m, 1 H), 8.39 (d, J ) 5.1 Hz, 1 H),
10.46 (br s, 1 H); 13C NMR (CDCl3) δ 20.6 (CH3), 111.7 (CH),
115.7 (C), 119.7 (CH), 120.2 (CH), 121.3 (CH), 121.8 (CH),
124.4 (CH), 125.1 (CH), 125.3 (C), 136.9 (C), 148.2 (C), 148.4
(CH), 154.6 (C); mp 142-146 °C (EtOH). Anal. Calcd for
C14H12N2: C, 80.77; H, 5.77; N, 13.46. Found: C, 80.93; H,
5.95; N, 13.11. Operating as above, from 2-chloro-4-methyl-
pyridine (3b)61 (400 mg, 3.1 mmol) and 3-bromoindole 5 (1.5
g, 4.7 mmol) were obtained dimer 10 (130 mg, 12%) and
pyridylindole 8b (340 mg, 52%).
Meth yl 2-(3-In d olyl)-3-p yr id in eca r boxyla te (8g). Fol-
lowing the general procedure, from methyl 2-chloro-3-pyridi-
necarboxylate (3g)63 (500 mg, 2.9 mmol) and 3-bromoindole 5
(1.35 g, 4.36 mmol), after reflux of the crude mixture in EtOH
(30 mL) containing TsOH for 12 h and purification by column
chromatography (CH2Cl2), were obtained dimer 10 (100 mg,
10%) and pyridylindole 8g (660 mg, 90%). 8g: IR (KBr) 3200-
3-(3-Eth yl-4-m eth yl-2-p yr id yl)in d ole (8c).65 Following
the general procedure, from 2-bromo-3-ethyl-4-methylpyridine
(2c) (790 mg, 3.9 mmol) and 3-bromoindole 5 (1.8 g, 5.9 mmol),
after reflux of the crude mixture in EtOH (40 mL) containing
TsOH for 28 h and purification by column chromatography,
were obtained dimer 10 (eluent CH2Cl2, 190 mg, 14%) and
pyridylindole 8c (eluent 98:2 CH2Cl2-EtOH, 820 mg, 88%).
1
2800, 1712, 742 cm-1; H NMR (CDCl3) δ 3.67 (s, 3 H), 7.21
(m, 2 H), 7.26 (dd, J ) 7.8, 4.8 Hz, 1 H), 7.43 (dm, J ) 7.0 Hz,
1 H), 7.62 (d, J ) 2.8 Hz, 1 H), 7.81 (dm, J ) 7.0 Hz, 1 H),
8.08 (dd, J ) 7.8, 1.8 Hz, 1 H), 8.45 (br s, 1 H), 8.80 (dd, J )
4.8, 1.8 Hz, 1 H); 13C NMR (CDCl3) δ 52.4 (CH3), 111.6 (CH),
115.7 (C), 119.3 (CH), 120.0 (CH), 120.4 (CH), 122.1 (CH),
125.8 (CH), 126.0 (C), 126.4 (C), 136.2 (C), 137.8 (CH), 151.2
(CH), 153.4 (C), 169.0 (C); mp 140 °C (EtOH). Anal. Calcd
for C15H12N2O2: C, 71.43; H, 4.79; N, 11.10. Found: C, 71.50;
H, 4.80; N, 11.11.
1
8c: IR (KBr) 3200-2800, 1585, 1443 cm-1; H NMR (CDCl3)
δ 0.97 (t, J ) 7.5 Hz, 3 H), 2.41 (s, 3 H), 2.71 (q, J ) 7.5 Hz,
2 H), 6.90 (br s, 1 H), 7.06 (d, J ) 5.0 Hz, 1 H), 7.04-7.14 (m,
3 H), 7.60 (m, 1 H), 8.45 (d, J ) 5.0 Hz, 1 H), 9.5 (br s, 1 H);
13C NMR (CDCl3) δ 14.4 (CH3), 19.3 (CH3), 22.4 (CH2), 111.4
(CH), 115.1 (C), 119.5 (CH), 119.7 (CH), 121.4 (CH), 123.7
(CH), 124.1 (CH), 127.2 (C), 136.0 (C), 137.3 (C), 145.8 (CH),
145.9 (C), 153.7 (C); mp 170-172 °C (EtOH) (lit.4c mp 117-
119 °C). Anal. Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85.
Found: C, 81.32; H, 6.92; N, 11.85.
Meth yl 2-(3-In d olyl)-4-p yr id in eca r boxyla te (8h ). Fol-
lowing the general procedure, from methyl 2-chloro-4-pyridi-
necarboxylate (3h )64 (368 mg, 2.1 mmol) and 3-bromoindole 5
(1.0 g, 3.2 mmol), after reflux of the crude mixture in EtOH
(20 mL) containing TsOH for 12 h and purification by column
chromatography (CH2Cl2), were obtained dimer 10 (75 mg,
10%) and pyridylindole 8h (515 mg, 95%). 8h : IR (NaCl)
3-(5-Eth yl-4-m eth yl-2-p yr id yl)in d ole (8d ).65 Following
the general procedure, from 2-bromo-5-ethyl-4-methylpyridine
(2d ) (310 mg, 1.5 mmol) and 3-bromoindole 5 (720 mg, 2.3
mmol), after reflux of the crude mixture in EtOH (15 mL)
containing TsOH for 6 h and purification by column chroma-
tography, were obtained dimer 10 (eluent CH2Cl2, 50 mg, 10%)
and pyridylindole 8d (eluent 98:2 CH2Cl2-EtOH, 310 mg,
1
3400-2800, 1729, 767-746 cm-1; H NMR (CDCl3) δ 3.97 (s,
3 H), 7.23 (m, 2 H), 7.59 (d, J ) 5.5 Hz, 1 H), 7.60 (m, 1 H),
8.19 (s, 1 H), 8.40 (dm, J ) 8.0 Hz, 1 H), 8.74 (d, J ) 5.5 Hz,
1 H), 9.67 (br s, 1 H); 13C NMR (CDCl3) δ 53.2 (CH3), 112.3
(CH), 116.6 (C), 119.5 (CH), 120.2 (CH), 121.4 (CH), 121.6 (C),
123.2 (CH), 125.7 (C), 126.1 (CH), 137.6 (C), 138.2 (CH), 150.6
(CH), 156.8 (C), 166.7 (C); mp 163 °C (MeOH-Et2O) [lit.4a mp
161-162 °C (Et2O)]; MS, m/ e (relative intensity) 252 (M+, 40),
194 (21), 166 (12), 139 (11), 97 (6), 69 (33), 43 (100).
1
89%). 8d : IR (KBr): 3200-2800, 1607, 1551 cm-1; H NMR
(CDCl3) δ 1.25 (t, J ) 7.5 Hz, 3 H), 2.37 (s, 3 H), 2.67 (q, J )
7.5 Hz, 2 H), 7.12 (m, 2 H), 7.36 (m, 1 H), 7.50 (s, 1 H), 7.69
(d, J ) 2.7 Hz, 1 H), 8.26 (m, 1 H), 8.41 (s, 1 H), 8.85 (br s, 1
H); 13C NMR (CDCl3) δ 14.5 (CH3), 18.8 (CH3), 23.3 (CH2),
111.7 (CH), 116.4 (C), 120.3 (CH), 121.9 (CH), 122.1 (CH),
124.6 (CH), 125.2 (C), 134.6 (C), 137.0 (C), 145.5 (C), 148.4
(CH), 152.6 (C); mp 140-142 °C (Et2O) (lit.4c mp 119-120 °C).
Anal. Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85.
Found: C, 81.40; H, 6.89; N, 11.86.
Meth yl 2-(3-In d olyl)-5-p yr id in eca r boxyla te (8i). Fol-
lowing the general procedure, from methyl 2-chloro-5-pyridi-
necarboxylate (3i)63 (500 mg, 2.9 mmol) and 3-bromoindole 5
(1.3 g, 4.4 mmol), after reflux of the crude mixture in EtOH
(30 mL) containing TsOH for 12 h and purification by column
chromatography (CH2Cl2), were obtained dimer 10 (120 mg,
12%) and pyridylindole 8i (710 mg, 97%). 8i: IR (KBr) 3368,
1719 cm-1; 1H NMR (CDCl3-CD3OD) δ 3.99 (s, 3 H), 7.29 (m,
2 H), 7.50 (m, 1 H), 7.84 (dd, J ) 8.4, 0.8 Hz, 1 H), 7.95 (s, 1
H), 8.26 (m, 1 H), 8.32 (dd, J ) 8.4, 2.2 Hz, 1 H), 9.21 (dd, J
) 2.2, 0.8 Hz, 1 H); 13C NMR (CDCl3) δ 51.9 (CH3), 111.8 (CH),
115.2 (C), 119.4 (CH), 120.1 (CH), 120.8 (CH), 121.3 (C), 122.2
(CH), 124.8 (C), 126.8 (CH), 137.1 (C), 137.3 (CH), 150.1 (CH),
158.9 (C), 166.1 (C); mp 184-186 °C (EtOH) (lit.4c mp 203-
206 °C). Anal. Calcd for C15H12N2O2: C, 71.43; H, 4.79; N,
11.10. Found: C, 71.33; H, 4.88; N, 10.99.
3-(3-Meth oxy-2-p yr id yl)in d ole (8e). Following the gen-
eral procedure, from 2-bromo-3-methoxypyridine (2e)62 (500
mg, 2.7 mmol) and 3-bromoindole 5 (1.2 g, 4.0 mmol), after
reflux of the crude mixture in EtOH (26 mL) containing TsOH
for 24 h and purification by column chromatography (eluent
CH2Cl2), were obtained dimer 10 (90 mg, 10%) and pyridyl-
indole 8e (460 mg, 77%). 8e: IR (KBr) 3600-2800, 1449 cm-1
;
1H NMR (CDCl3) δ 3.95 (s, 3 H), 7.10 (dd, J ) 8.2, 4.6 Hz, 1
H), 7.23 (m, 3 H), 7.39 (m, 1 H), 8.05 (d, J ) 2.7 Hz, 1 H), 8.36
(dd, J ) 4.6, 1.4 Hz, 1 H), 8.40 (br s, 1 H), 8.70 (m, 1 H); 13C
NMR (CDCl3) δ 55.1 (CH3), 111.0 (CH), 112.7 (C), 117.0 (CH),
120.1 (CH), 120.4 (CH), 122.0 (CH), 122.5 (CH), 126.5 (C),
127.4 (CH), 135.9 (C), 140.5 (CH), 145.4 (C), 152.5 (C); mp
Meth yl 3-Eth yl-2-(3-in d olyl)-4-p yr id in eca r boxyla te (8j)
a n d Meth yl 5-Eth yl-2-(3-in d olyl)-4-p yr id in eca r boxyla te
(8k ). Following the general procedure, from an equimolecular
mixture of methyl 2-chloro-3-ethyl-4-pyridinecarboxylate (3j)
(65) From the synthetic standpoint it was more convenient to use a
mixture of bromopyridines 2c and 2d in the cross-coupling reaction,
because pyridylindoles 8c and 8d could be separated by column
chromatography (AcOEt) much more efficiently than 2c and 2d .

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3169
and methyl 2-chloro-5-ethyl-4-pyridinecarboxylate (3k )66 (5.8
g, 29.0 mmol), and 3-bromoindole 5 (13.5 g, 43.6 mmol), after
reflux of the crude mixture in EtOH (435 mL) containing TsOH
for 12 h and purification by column chromatography (1:1
AcOEt-hexane), were obtained dimer 10 (1.0 g, 10%) and
pyridylindoles 8k (3.5 g, 43%) and 8j (3.4 g, 42%). 8j: IR (KBr)
1 H); 13C NMR (CDCl3) δ 111.6 (CH), 113.5 (C), 120.8 (CH),
121.1 (CH), 122.7 (CH), 124.9 (C), 125.4 (CH), 136.8 (C), 139.8
(CH), 141.6 (CH), 144.0 (CH), 151.6 (C); mp 157-160 °C (Et2O).
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found:
C, 73.81; H, 4.77; N, 21.39.
1-(ter t-Bu t yld im et h ylsilyl)-3-(2-t h ien yl)in d ole (11b ).
Following the general procedure for the preparation of 7, from
2-bromothiophene (500 mg, 3.1 mmol) and 3-bromoindole 5 (1.4
g, 4.6 mmol) were obtained 2,2′-bithiophene (eluent hexane,
70 mg, 27%), thienylindole 11b (eluent hexane, 470 mg, 50%),
and dimer 10 (eluent 3:1 hexane-AcOEt, 330 mg, 31%).
11b: 1H NMR (CDCl3) δ 0.63 (s, 6 H), 0.96 (s, 9 H), 7.11 (dd,
J ) 5.1, 3.4 Hz, 1 H), 7.17-7.25 (m, 3 H), 7.27 (dd, J ) 3.4,
1.0 Hz, 1 H), 7.36 (s, 1 H), 7.52 (m, 1 H), 7.96 (m, 1 H); 13C
NMR (CDCl3) δ -3.9 (CH3), 19.4 (C), 26.3 (CH3), 113.7 (C),
114.2 (CH), 119.8 (CH), 120.5 (CH), 122.1 (CH), 122.5 (CH),
127.5 (CH), 128.7 (CH), 128.9 (C), 137.6 (C), 141.7 (C).
1-(ter t-Bu tyldim eth ylsilyl)-3-(3-th ien yl)in dole (11c). Op-
erating as above, from 3-bromothiophene (500 mg, 3.1 mmol)
and 3-bromoindole 5 (1.4 g, 4.6 mmol) were obtained 3,3′-
bithiophene (eluent hexane, 64 mg, 25%), thienylindole 11c
(eluent hexane, 430 mg, 45%), and dimer 10 (eluent 3:1
hexane-AcOEt, 310 mg, 29%). 11c: 1H NMR (CDCl3) δ 0.75
(s, 6 H), 1.08 (s, 9 H), 7.32 (m, 2 H), 7.46 (s, 1 H), 7.48-7.58
(m, 3 H), 7.68 (m, 1 H), 8.04 (m, 1 H); 13C NMR (CDCl3) δ
-4.0 (CH3), 19.3 (C), 26.2 (CH3), 114.1 (CH), 115.3 (CH), 118.5
(CH), 119.7 (CH), 120.2 (CH), 121.8 (CH), 125.3 (CH), 127.2
(CH), 128.4 (CH), 129.1 (C), 135.7 (C), 141.7 (C).
1-(ter t-Bu tyld im eth ylsilyl)-3-(3-fu r yl)in d ole (11d ). Op-
erating as above, from 3-bromofuran (500 mg, 3.4 mmol) and
3-bromoindole 5 (1.6 g, 5.1 mmol) were obtained furylindole
11d (eluent hexane, 121 mg, 12%) and dimer 10 (eluent 3:1
hexane-AcOEt, 420 mg, 36%). 11d : 1H NMR (CDCl3) δ 0.63
(s, 6 H), 0.96 (s, 9 H), 6.71 (br s, 1 H), 7.20 (m, 2 H), 7.26 (s, 1
H), 7.52 (m, 2 H), 7.76 (m, 2 H); 13C NMR (CDCl3) δ -3.9 (CH3),
19.4 (C), 26.3 (CH3), 109.9 (CH), 110.9 (C), 114.1 (CH), 114.5
(C), 119.7 (CH), 120.1 (CH), 121.8 (CH), 128.1 (CH), 129.1 (C),
137.6 (CH), 141.7 (C), 142.8 (CH).
1
3800-2800, 1737, 1450, 1293, 740 cm-1; H NMR (CDCl3) δ
1.04 (t, J ) 7.5 Hz, 3 H), 3.00 (q, J ) 7.5 Hz, 2 H), 3.97 (s, 3
H), 7.08-7.30 (m, 3 H), 7.12 (d, J ) 2.5 Hz, 1 H), 7.51 (d, J )
5.0 Hz, 1 H), 7.63 (dm, J ) 6.5 Hz, 1 H), 8.63 (d, J ) 5.0 Hz,
1 H), 9.05 (br s, 1 H, NH); 13C NMR (CDCl3) δ 15.9 (CH3), 23.1
(CH2), 52.6 (CH3), 111.3 (CH), 115.6 (C), 120.1 (CH), 120.3
(CH), 121.2 (CH), 122.3 (CH), 124.1 (CH), 127.1 (C), 135.9 (C),
137.5 (C), 138.8 (C), 146.8 (CH), 155.6 (C), 167.8 (C); mp 184-
186 °C [lit.4f mp 185-186 °C (MeOH-Et2O)]. 8k : IR (KBr)
3800-2600, 1714, 1249, 741 cm-1; 1H NMR (CDCl3) δ 1.25 (t,
J ) 7.5 Hz, 3 H), 2.94 (q, J ) 7.5 Hz, 2 H), 3.96 (s, 3 H), 7.20-
7.40 (m, 3 H), 7.73 (d, J ) 2.7 Hz, 1 H), 8.06 (s, 1 H), 8.35 (m,
1 H), 8.60 (s, 1 H), 8.80 (br s, 1 H); 13C NMR (CDCl3) δ 15.8
(CH3), 24.5 (CH2), 52.4 (CH3), 111.6 (CH), 116.3 (C), 120.0 (CH),
120.7 (CH), 120.8 (CH), 122.5 (CH), 124.6 (CH), 125.2 (C),
135.2 (C), 136.9 (C), 151.5 (CH), 153.4 (C), 167.2 (C); mp 100-
102 °C [lit.4f mp 99-100 °C (CHCl3-hexane)].
3-(5-Nitr o-2-p yr id yl)in d ole (8l). Following the general
procedure, from 2-chloro-5-nitropyridine (3l) (500 mg, 3.1
mmol) and 3-bromoindole 5 (1.5 g, 4.7 mmol), after reflux of
the crude mixture in EtOH (30 mL) containing TsOH for 2 h
and purification by column chromatography (CH2Cl2), were
obtained dimer 10 (140 mg, 13%) and pyridylindole 8l (670
mg, 89%). 8l: IR (KBr) 3371, 1590, 1540, 1336, 1278 cm-1
;
1H NMR (CDCl3) δ 7.30 (m, 2 H), 7.46 (m, 1 H), 7.81 (d, J )
8.8 Hz, 1 H), 8.0 (s, 1 H), 8.37 (m, 1 H), 8.43 (dd, J ) 8.8, 2.6
Hz, 1 H), 9.43 (d, J ) 2.6 Hz, 1 H), 10.0 (br s, 1 H); 13C NMR
(acetone-d6) δ 112.9 (CH), 116.1 (C), 119.5 (CH), 122.1 (CH),
122.9 (CH), 123.6 (CH), 126.4 (C), 129.8 (CH), 131.7 (CH),
138.5 (C), 141.4 (C), 145.9 (CH), 162.0 (C); mp 174-176 °C
(acetone). Anal. Calcd for C13H9N3O2: C, 65.27; H, 3.79; N,
17.56. Found: C, 65.40; H, 3.81; N, 17.44.
3-(3,5-Din itr o-2-p yr id yl)in d ole (8m ). Following the gen-
eral procedure, from 2-chloro-3,5-dinitropyridine (3m ) (500 mg,
2.4 mmol) and 3-bromoindole 5 (1.1 g, 3.6 mmol), after reflux
of the crude mixture in EtOH (24 mL) containing TsOH for 1
h and purification by column chromatography (97:3 CHCl3-
EtOH), were obtained dimer 10 (75 mg, 9%) and pyridylindole
1-(Ben zen esu lfon yl)-1′-(ter t-bu tyld im eth ylsilyl)-3,3′-bi-
in d ole (11e). Operating as above, from 1-(benzenesulfonyl)-
3-bromoindole (500 mg, 1.5 mmol) and 3-bromoindole 5 (693
g, 2.2 mmol) were obtained biindole 11e (400 mg, 55%) and
dimer 10 (200 mg, 39%) after column chromatography (95:5
hexane-AcOEt). 11e: 1H NMR (CDCl3) δ 0.59 (s, 6 H), 0.98
(s, 9 H), 7.10-7.78 (m, 10 H), 7.44 (s, 1 H), 7.81 (s, 1 H), 7.93
(dm, J ) 8.4 Hz, 2 H), 8.10 (d, J ) 7.8 Hz, 1 H); 13C NMR
(CDCl3) δ -4.1 (CH3), 19.3 (C), 26.1 (CH3), 110.3 (C), 113.7
(CH), 114.1 (CH), 119.6 (CH), 120.2 (CH), 120.7 (CH), 122.1
(CH), 122.1 (CH), 123.4 (CH), 124.8 (CH), 126.5 (CH), 129.0
(CH), 129.3 (CH), 130.3 (C), 130.8 (C), 133.6 (CH), 135.5 (C),
137.9 (C), 141.4 (C).
8m (550 mg, 80%). 8m : IR (KBr) 3361, 1540, 1328, 1241 cm-1
;
1H NMR (acetone-d6) δ 7.27 (m, 2 H), 7.59 (m, 1 H), 7.98 (s, 1
H), 8.20 (m, 1 H), 9.00 (d, J ) 2.4 Hz, 1 H), 9.65 (d, J ) 2.4
Hz, 1 H); 13C NMR (acetone-d6) δ 111.7 (C), 113.2 (CH), 122.3
(CH), 122.7 (CH), 124.2 (CH), 126.7 (C), 128.4 (CH), 130.6
(CH), 137.8 (C), 140.6 (C), 143.4 (C), 147.3 (CH), 152.6 (C);
mp 267-269 °C (acetone). Anal. Calcd for C13H8N4O4‚
1/3C3H6O: C, 55.34; H, 3.29; N, 18.45. Found: C, 54.72; H,
3.14; N, 18.45.
Gen er a l P r oced u r e for t h e Desilyla t ion of H et er o-
a r ylin d oles 11. A 1.0 M solution (1.1 equiv) of tetra-n-
butylammonium fluoride (TBAF) in THF was added to a 1.0
M solution of heteroarylindole 11 in THF. The mixture was
stirred at 25 °C for 10 min and poured into saturated aqueous
3-(2-P yr a zin yl)in d ole (12a ). Following the above general
procedure, from 2-chloropyrazine (438 mg, 3.8 mmol) and
3-bromoindole 5 (1.8 g, 5.7 mmol), after reflux of the crude
mixture in EtOH (38 mL) containing TsOH for 2.5 h and
purification by column chromatography (CH2Cl2), were ob-
tained dimer 10 (198 mg, 15%) and pyrazinylindole 12a (680
mg, 91%). 12a : IR (KBr) 3600-2800, 1545, 1511, 1131, 746
cm-1; 1H NMR (CDCl3) δ 7.30 (m, 2 H), 7.42 (m, 1 H), 7.83 (d,
J ) 2.8 Hz, 1 H), 8.35 (d, J ) 2.6 Hz, 1 H), 8.39 (m, 1 H), 8.60
(dd, J ) 2.6, 1.6 Hz, 1 H), 8.80 (br s, 1 H), 9.00 (d, J ) 1.6 Hz,
Na2
CO3. The aqueous layer was extracted with Et2O, and the
combined organic extracts were dried and concentrated to give
a residue, which was chromatographed (1:1 AcOEt-hexane).
3-(2-Th ien yl)in d ole (12b). Following the above general
procedure, from thienylindole 11b (440 mg, 1.4 mmol) and
TBAF (1.6 mL, 1.6 mmol) was obtained compound 12b67 (218
mg, 78%): IR (KBr) 1455, 744, 691 cm-1 1H NMR (CDCl3)
;
7.12 (dd, J ) 5.1, 3.3 Hz, 1 H), 7.25 (m, 4 H), 7.40 (m, 1 H),
7.41 (d, J ) 2.5 Hz, 1 H), 7.98 (m, 1 H), 8.20 (br s, 1 H); 13C
NMR (CDCl3) δ 111.4 (CH), 119.7 (C and CH), 120.5 (CH),
121.9 (CH), 122.4 (CH), 122.5 (CH), 125.1 (C), 127.5 (CH),
136.1 (C), 137.5 (C).
3-(3-Th ien yl)in d ole (12c). Following the above general
procedure, from thienylindole 11c (430 mg, 1.3 mmol) and
TBAF (1.5 mL, 1.5 mmol) was obtained compound 12c (220
mg, 80%): 1H NMR (CDCl3) δ 7.23 (m, 2 H), 7.41 (m, 5 H),
7.94 (m, 1 H), 8.10 (br s, 1 H); 13C NMR (CDCl3) δ 111.4 (CH),
(66) Chloropyridines 3j and 3k were prepared from methyl 3-ethyl-
isonicotinate52d by treatment (reflux, 12 h) of the corresponding
N-oxide4f (58 g, 320 mmol) with POCl3 (113 mL) in CHCl3 (113 mL).
Distillation (112 °C, 2.5 mmHg) gave a nearly equimolecular mixture
of 3j and 3k (43 g, 67%), which could not be separated. 3j (from the
mixture): 1H NMR (CHCl3) δ 1.24 (t, J ) 7.5 Hz, 3 H), 2.93 (q, J ) 7.5
Hz, 2 H), 3.95 (s, 3 H), 7.52 (d, J ) 4.9 Hz, 1 H), 8.32 (d, J ) 4.9 Hz,
1 H); 13C NMR (CDCl3) δ 13.0 (CH3), 29.6 (CH2), 52.2 (CH3), 122.0
(CH), 137.6 (C), 139.6 (C), 146.4 (CH), 152.6 (C), 165.4 (C). 3k (from
the mixture): 1H NMR (CHCl3) δ 1.24 (t, J ) 7.5 Hz, 3 H), 2.93 (q, J
) 7.5 Hz, 2 H), 3.95 (s, 3 H), 7.70 (s, 1 H), 8.36 (s, 1 H); 13C NMR
(CDCl3) δ 15.0 (CH3), 29.6 (CH2), 52.2 (CH3), 123.5 (CH), 137.1 (C),
138.5 (C), 151.3 (CH), 151.6 (C), 164.6 (C).
(67) Bergman, J . Acta Chem. Scand. 1971, 25, 1277.

3170 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
113.1 (C), 118.4 (CH), 119.7 (CH), 120.2 (CH), 121.8 (CH),
122.3 (CH), 125.5 (C and CH), 127.0 (CH), 135.7 (C), 136.3
(C); mp 133-135 °C (Et2O). Anal. Calcd for C12H9NS: C,
72.33; H, 4.35; N, 7.03; S, 16.09. Found: C, 72.21; H, 4.53; N,
7.09; S, 15.90.
3-(3-F u r yl)in d ole (12d ). Following the above general
procedure, from 3-(3-furyl)indole 11d (100 mg, 0.34 mmol) and
TBAF (370 µL, 0.37 mmol) was obtained compound 12d (40
mg, 65%): 1H NMR (CDCl3) δ 6.70 (dm, J ) 1.8 Hz, 1 H), 7.20
(m, 2 H), 7.30 (d, J ) 2.5 Hz, 1 H), 7.40 (m, 1 H), 7.51 (d, J )
1.8 Hz, 1 H), 7.78 (m, 1 H), 7.80 (s, 1 H), 8.20 (br s, 1 H); 13C
NMR (CDCl3) δ 109.1 (C), 109.8 (CH), 111.4 (CH), 119.6 (C),
119.8 (CH), 120.2 (CH), 121.4 (CH), 122.5 (CH), 125.7 (C),
136.5 (C), 137.7 (C), 142.9 (C); MS, m/ e (relative intensity)
183 (M+, 10), 149 (13), 83 (100), 57 (72), 55 (76).
cm-1; 1H NMR (CDCl3) δ 3.79 (s, 6 H), 4.71 (s, 1 H), 7.06 (s, 1
H), 7.10-7.25 (m, 2 H), 7.24 (d, J ) 5.0 Hz, 1 H), 7.36 (d, J )
8.0 Hz, 1 H), 7.64 (d, J ) 7.8 Hz, 1 H), 7.83 (s, 1 H), 8.54 (d,
J ) 5.0 Hz, 1 H), 9.93 (br s, 1 H); 13C NMR (CDCl3) δ 53.1
(CH3), 56.8 (CH), 101.2 (CH), 111.5 (CH), 120.2 (CH), 120.6
(CH), 121.3 (CH), 122.5 (CH), 123.4 (CH), 129.1 (C), 136.4 (C),
136.8 (C), 141.9 (C), 149.5 (CH), 151.1 (C), 167.5 (C); mp 130
°C (EtOH). Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97;
N, 8.64. Found: C, 66.96; H, 4.93; N, 8.52. From the mother
liquors, 1-(m eth oxyca r bon yl)-2-[1-(m eth oxyca r bon yl)-2-
in d olyl]-4-[b is(m et h oxyca r b on yl)m et h ylen e]-1,4-d ih y-
d r op yr id in e (21) was isolated in less than 5% yield: IR (KBr)
1
1556, 1602, 1738 cm-1; H NMR (CDCl3) δ 3.73 (s, 3 H), 3.77
(s, 3 H), 3.80 (s, 3 H), 3.95 (s, 3 H), 6.72 (s, 1 H), 7.15 (dd, J )
8.3, 2.5 Hz, 1 H), 7.20 (d, J ) 2.5 Hz, 1 H), 7.27 (td, J ) 7.5,
2.1 Hz, 1 H), 7.38 (td, J ) 7.8, 2.1 Hz, 1 H), 7.56 (d, J ) 7.5
Hz, 1 H), 7.76 (d, J ) 8.3 Hz, 1 H), 8.08 (d, J ) 7.8 Hz, 1 H);
13C NMR (CDCl3) δ 51.6 (CH3), 53.8 (CH3), 54.9 (CH3), 104.9
(C), 111.1 (CH), 112.0 (CH), 115.6 (CH), 117.2 (CH), 121.3
(CH), 123.5 (CH), 125.6 (CH), 128.8 (C), 131.4 (CH), 134.6 (C),
135.7 (C), 136.1 (C), 144.3 (C), 150.5 (C), 151.7 (C), 167.6 (C).
Anal. Calcd for C22H20N2O8: C, 59.99; H, 4.57; N, 6.36.
Found: C, 60.10; H, 4.75; N, 6.38.
1-(Ben zen esu lfon yl)-3,3′-biin d ole (12e). Following the
above general procedure, from 3,3′-biindole 11e (400 mg, 0.83
mmol) and TBAF (910 µL, 0.91 mmol) was obtained compound
12e (240 mg, 78%) after column chromatography (2:1
hexane-AcOEt): IR (KBr) 3426, 1447, 1371, 1187 cm-1 1H
;
NMR (CDCl3) δ 7.10-7.50 (m, 9 H), 7.55-7.79 (m, 2 H), 7.91
(dm, J ) 8.4 Hz, 2 H), 8.05 (d, J ) 7.8 Hz, 1 H), 8.30 (br s, 1
H); 13C NMR (CDCl3) δ 108.5 (C), 111.4 (CH), 113.8 (CH), 117.6
(C), 119.8 (CH), 120.3 (CH), 120.8 (CH), 122.2 (CH), 122.6
(CH), 122.7 (CH), 124.9 (CH), 126.1 (C), 126.7 (CH), 129.2
(CH), 130.3 (C), 133.7 (CH), 135.4 (C), 136.2 (C), 138.0 (C);
mp 214-216 °C (EtOH-CH2Cl2). Anal. Calcd for
C22H16N2SO2‚CH2Cl2: C, 60.39; H, 3.96; N, 6.12; S, 7.01.
Found: C, 59.99; H, 4.36; N, 6.35; S, 7.40.
Dim eth yl cis-2-(2-In d olyl)-4-p ip er id in em a lon a te (16).
A solution of pyridylindole 15 hydrochloride (1.5 g, 4.3 mmol)
in MeOH (100 mL) was stirred at 25 °C under hydrogen for
24 h in the presence of PtO2 (100 mg). The catalyst was
removed by filtration, and the solvent was evaporated. The
residue was dissolved in CH2Cl2, and the solution was washed
with aqueous Na2CO3, dried, and concentrated. Column
chromatography (97:3 AcOEt-EtOH) of the residue gave pure
2-(4-Meth yl-2-p yr id yl)in d ole (13). A solution of com-
pound 4b (2.0 g, 5.8 mmol) in EtOH (343 mL) and 10% aqueous
NaOH (34 mL) was heated at reflux for 12 h. The resulting
mixture was concentrated, and the residue was dissolved in
CH2Cl2 (100 mL). The organic solution was washed with water
and aqueous Na2CO3, dried, and concentrated. Column chro-
matography (CH2Cl2) of the residue afforded pure 13 (1.2 g,
1
piperidine 16 (851 mg, 60%): IR (KBr) 3458, 1736 cm-1; H
NMR (CDCl3) δ 1.32 (m, 1 H), 1.42 (q, J ) 11.7 Hz, 1 H), 1.75
(dm, J ) 12.7 Hz, 1 H), 2.02 (dm, J ) 11.7 Hz, 1 H), 2.35 (m,
1 H), 2.84 (td, J ) 12.2, 2.6 Hz, 1 H), 3.20 (dm, J ) 12.2 Hz,
1 H), 3.25 (d, J ) 9.0 Hz, 1 H), 3.72 (s, 3 H), 3.75 (s, 3 H), 3.93
(dd, J ) 11.3, 2.6 Hz, 1 H), 6.34 (s, 1 H), 7.00-7.20 (m, 2 H),
7.32 (d, J ) 7.8 Hz, 1 H), 7.54 (d, J ) 7.3 Hz, 1 H), 8.73 (br s,
1 H); 13C NMR (CDCl3) δ 29.8 (CH2), 36.3 (CH), 36.8 (CH2),
45.9 (CH2), 52.4 (CH3), 54.6 (CH), 57.2 (CH), 98.6 (CH), 110.9
(CH), 119.7 (CH), 120.4 (CH), 121.6 (CH), 128.0 (C), 136.0 (C),
141.0 (C), 168.8 (C); mp (picrate) 156-158 °C (EtOH). Anal.
Calcd for C24H25N5O11‚C2H6O: C, 51.57; H, 5.16; N, 11.56.
Found: C, 51.61; H, 5.24; N, 11.44.
1
96%): IR (CDCl3) 3440, 1610 cm-1; H NMR (CDCl3) δ 2.31
(s, 3 H), 6.91 (d, J ) 5.0 Hz, 1 H), 7.00 (d, J ) 1.2 Hz, 1 H),
7.05-7.15 (m, 2 H), 7.22 (d, J ) 7.8 Hz, 1 H), 7.61 (br s, 1 H),
7.64 (d, J ) 6.8 Hz, 1 H), 8.43 (d, J ) 5.0 Hz, 1 H), 10.89 (br
s, 1 H); 13C NMR (CDCl3) δ 20.9 (CH3), 100.5 (CH), 111.5 (CH),
120.0 (CH), 120.9 (CH), 121.1 (CH), 122.9 (CH), 123.3 (CH),
129.1 (C), 137.0 (C), 137.1 (C), 148.1 (C), 148.8 (CH), 150.6
(C); mp 164-165 °C (Et2O). Anal. Calcd for C14H12N2: C,
80.74; H, 5.81; N, 13.45. Found: C, 80.85; H, 5.80; N, 13.43.
Eth yl 2-(4-Meth yl-2-p yr id yl)-1-in d oleca r boxyla te (14).
A suspension of pyridylindole 4a (200 mg, 0.6 mmol), NaH (230
mg, 5.8 mmol, 60% oil dispersion), and diethyl carbonate (3
mL) was heated at reflux for 7 h. The resulting mixture was
poured into saturated aqueous NH4Cl and extracted with
AcOEt. The combined organic extracts were dried and con-
centrated, and the residue was chromatographed (CH2Cl2) to
give pure compound 14 (90 mg, 56%): 1H NMR (CDCl3) δ 1.35
(t, J ) 7.1 Hz, 3 H), 2.43 (s, 3 H), 4.68 (q, 2 H, J ) 7.1 Hz, 2
H), 6.84 (s, 1 H), 7.05 (d, J ) 5.1 Hz, 1 H), 7.13 (td, J ) 7.0,
1.1 Hz, 1 H), 7.25 (td, J ) 8.2, 1.1 Hz, 1 H), 7.42 (d, J ) 8.2
Hz, 1 H), 7.55 (s, 1 H), 7.66 (d, J ) 7.0 Hz, 1 H), 8.55 (d, J )
5.1 Hz, 1 H); 13C NMR (CDCl3) δ 15.4 (CH3), 21.0 (CH3), 39.3
(CH2), 103.4 (CH), 109.9 (CH), 119.6 (CH), 120.9 (CH), 122.2
(CH), 122.7 (CH), 124.1 (CH), 127.7 (C), 138.0 (C), 138.3 (C),
147.4 (C), 148.7 (C), 152.3 (CH); MS, m/ e (relative intensity)
280 (M+, 31), 189 (45), 179 (33), 149 (41), 140 (46), 115 (32),
113 (53), 106 (30), 100 (36), 94 (58), 92 (31), 88 (33), 86 (36),
83 (33), 76 (32), 75 (39), 73 (31), 65 (58), 63 (40), 57 (100), 53
(41), 51 (30), 50 (31), 48 (36), 46 (74).
Dim eth yl cis-2-(2-In d olyl)-1-[2-(p h en ylsu lfin yl)eth yl]-
4-p ip er id in em a lon a te (17). A solution of indolylpiperidine
16 (2.1 g, 6.4 mmol) and phenyl vinyl sulfoxide (1.1 mL, 8.3
mmol) in MeOH (31 mL) was heated at reflux for 48 h. The
mixture was cooled and concentrated, and the residue was
chromatographed (from 1:1 hexane-AcOEt to AcOEt) to give
two epimeric sulfoxides 17 (2.0 g and 975 mg; 89% overall
yield). 17 (major epimer, oil): 1H NMR (CDCl3) δ 1.62 (m, 2
H), 1.90 (m, 2 H), 2.27 (td, J ) 11.8, 2.4 Hz, 1 H), 2.38 (m, 2
H), 2.80 (m, 2 H), 3.11 (m, 1 H), 3.22 (d, J ) 9.2 Hz, 1 H), 3.30
(dt, J ) 11.8, 3.0 Hz, 1 H), 3.60 (dd, J ) 11.3, 2.7 Hz, 1 H),
3.68 (s, 3 H), 3.74 (s, 3 H), 6.31 (s, 1 H), 7.00-7.17 (m, 2 H),
7.42-7.58 (m, 7 H), 9.95 (s, 1 H); 13C NMR (CDCl3) δ 29.2
(CH2), 36.1 (CH), 39.4 (CH2), 47.0 (CH2), 51.5 (CH2), 52.3 (CH3),
54.5 (CH2), 56.8 (CH), 61.5 (CH), 100.1 (CH), 111.5 (CH), 119.2
(CH), 119.6 (CH), 121.1 (CH), 123.8 (CH), 128.0 (C), 129.0
(CH), 130.7 (CH), 136.5 (C), 140.3 (C), 143.6 (C), 168.4 (C). 17
(minor epimer): 1H NMR (CDCl3) δ 1.42 (qd, J ) 12.5, 3.8
Hz, 1 H), 1.59 (q, J ) 12.0 Hz, 1 H), 1.69 (dm, J ) 12.5 Hz, 1
H), 1.88 (dm, J ) 12.0 Hz, 1 H), 2.26 (m, 2 H), 2.56 (m, 2 H),
2.80 (m, 2 H), 3.14 (dm, J ) 11.6 Hz, 1 H), 3.17 (d, J ) 9.1 Hz,
1 H), 3.44 (dd, J ) 11.4, 2.7 Hz, 1 H), 3.67 (s, 3 H), 3.73 (s, 3
H), 6.28 (d, J ) 1.6 Hz, 1 H), 7.08 (m, 1 H), 7.16 (m, 1 H), 7.31
(m, 5 H), 7.37 (d, J ) 7.9 Hz, 1 H), 7.53 (d, J ) 7.8 Hz, 1 H),
9.15 (s, 1 H); 13C NMR (CDCl3) δ 29.1 (CH2), 35.9 (CH), 37.6
(CH2), 48.3 (CH2), 52.3 (CH3), 53.0 (CH2), 54.8 (CH2), 56.8 (CH),
61.2 (CH), 100.5 (CH), 111.1 (CH), 119.4 (CH), 119.9 (CH),
121.4 (CH), 123.6 (CH), 127.8 (C), 128.8 (CH), 130.6 (CH),
136.0 (C), 139.6 (C), 143.3 (C), 168.3 (C). MS, m/ e (relative
intensity) 483 (M+ + 1, 38), 482 (M+, 9), 357 (57), 352 (31),
314 (31), 182 (91), 144 (90), 143 (54), 141 (42), 127 (59), 126
(34), 111 (61), 109 (100); mp 155-156 °C. Anal. Calcd for
Dim eth yl 2-(2-In d olyl)-4-p yr id in em a lon a te (15). A so-
lution of LDA (1.5 M in cyclohexane, 22.4 mL, 33.7 mmol) was
slowly added to a solution of pyridylindole 13 (2.0 g, 9.6 mmol)
in anhydrous THF (60 mL) at -78 °C, and the mixture was
stirred for 30 min. Then, a solution of methyl chloroformate
(3.7 mL, 48 mmol) in anhydrous THF (10 mL) was added
dropwise, and the solution was stirred at -78 °C for 30 min
and at 25 °C for 3 h. The mixture was diluted with Et2O and
washed with aqueous Na2CO3. The organic layer was dried
and concentrated, and the resulting oil was crystallized (EtOH)
to give pure malonate 15 (2.0 g, 64%): IR (KBr) 3417, 1732

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3171
C26H30N2O5S‚1/2H2O: C, 63.52; H, 6.35; N, 5.70; S, 6.52.
Found: C, 63.40; H, 6.32; N, 5.60; S, 6.30.
solution of sulfoxides 17 (330 mg, 0.685 mmol) in CH2Cl2 (9
mL) containing DIPEA (410 µl, 2.4 mmol), and the mixture
was stirred at rt for 30 min. The solution was poured into
NaHCO3. The aqueous layer was extracted with CH2Cl2, the
combined organic extracts were dried and evaporated, and the
residue was chromatographed (1:2 AcOEt-hexane) to give the
separate C6 epimers of d im eth yl cis-6-(p h en ylth io)-6,7,10,-
11,12,12a -h exa h yd r o-9H-p yr id o[1′,2′:1,2]p yr a zin o[4,3-b]-
in d ole-11-m a lon a te (22). r-P h S ep im er : 80 mg (25%); IR
P u m m er er Cycliza tion of Su lfoxid e 17. Meth od A.
TFAA (257 µL, 1.82 mmol) was added to a solution of sulfoxides
17 (440 mg, 0.91 mmol) in CH2Cl2 (18 mL) at 0 °C, and the
mixture was stirred at 25 °C for 2 h. The solution was poured
into aqueous Na2CO3, and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were dried and
concentrated, and the resulting residue was chromatographed
(1:1 AcOEt-hexane) to give 17 mg of d im et h yl cis-7-
(p h en ylth io)in d olo[2,3-a ]qu in olizid in e-2-m a lon a te (19)
as a C7 epimeric mixture and 70 mg of pure R-PhS epimer (20%
1
(KBr) 1754, 1739 cm-1; H NMR (CDCl3) δ 1.24 (q, J ) 12.0
Hz, 1 H), 1.45 (qd, J ) 12.5, 4.0 Hz, 1 H), 1.71 (dt, J ) 13.0,
2.5 Hz, 1 H), 2.17-2.38 (m, 3 H), 2.98 (dt, J ) 11.2, 3.0 Hz, 1
H), 3.10 (dd, J ) 12.0, 3.0 Hz, 1 H), 3.23 (d, J ) 9.0 Hz, 1 H),
3.25 (dm, J ) 10.4 Hz, 1 H), 3.37 (dd, J ) 12.0, 1.4 Hz, 1 H),
3.77 (s, 3 H), 3.80 (s, 3 H), 5.61 (dd, J ) 3.0, 1.4 Hz, 1 H), 6.16
(s, 1 H), 7.12 (m, 2 H), 7.20-7.36 (m, 6 H), 7.52 (m, 1 H); 13C
NMR (CDCl3) δ 29.3 (CH2), 34.1 (CH2), 35.6 (CH), 52.4 (CH3),
52.5 (CH3), 54.5 (CH2), 57.2 (CH), 59.3 (CH), 59.6 (CH2), 61.6
(CH), 96.8 (CH), 110.8 (CH), 120.2 (CH), 121.0 (CH), 128.1
(CH), 128.7 (CH), 128.8 (C), 134.0 (C), 134.6 (C), 135.1 (C),
137.2 (C), 168.6 (C). â-P h S ep im er : 100 mg (32%); IR (KBr)
1753, 1738 cm-1; 1H NMR (CDCl3) δ 1.24-1.49 (m, 2 H), 1.60
(m, 1 H), 1.70 (dt, J ) 13.0, 3.0 Hz, 1 H), 2.14-2.32 (m, 2 H),
2.68 (dd, J ) 12.4, 10.0 Hz, 1 H), 2.90 (dm, J ) 10.0 Hz, 1 H),
2.98 (dt, J ) 11.3, 3.0 Hz, 1 H), 3.23 (d, J ) 8.5 Hz, 1 H), 3.43
(dd, J ) 12.4, 6.6 Hz, 1 H), 3.73 (s, 3 H), 3.78 (s, 3 H), 5.65
(dd, J ) 10.0, 6.6 Hz, 1 H), 6.18 (s, 1 H), 7.04 (dm, J ) 8.2 Hz,
2 H), 7.12-7.34 (m, 5 H), 7.55 (dm, J ) 7.0 Hz, 1 H), 7.93
(dm, J ) 7.4 Hz, 1 H); 13C NMR (CDCl3) δ 29.0 (CH2), 34.1
(CH2), 35.3 (CH), 52.5 (CH3), 52.6 (CH3), 54.2 (CH2), 57.0 (CH),
58.6 (CH2), 58.9 (CH), 59.4 (CH), 97.2 (CH), 112.9 (CH), 120.3
(CH), 120.4 (CH), 121.1 (CH), 128.7 (CH), 128.9 (CH), 134.9
(CH), 139.4 (C), 168.6 (C).
Dim eth yl cis-2-[1-(Meth oxyca r bon yl)-2-in d olyl]-1-[2-
(ph en ylsu lfin yl)eth yl]-4-piper idin em alon ate (24a). Meth-
yl cyanoformate (200 µL, 2.5 mmol) was added to a solution of
sulfoxide 17 (major epimer, 140 mg, 0.29 mmol) in acetonitrile
(2 mL) containing DMAP (40 mg, 0.32 mmol), and the mixture
was heated at reflux for 5 h. Water was added, and the
aqueous layer was extracted with AcOEt. The combined
organic extracts were dried and concentrated, and the residue
was chromatographed (15:1 Et2O-MeOH) to give pure sul-
foxide 24a -1 (139 mg, 89%): 1H NMR (CDCl3) δ 1.40 (q, J )
11.4 Hz, 1 H), 1.51 (m, 1 H), 1.70 (dm, J ) 11.4 Hz, 1 H), 2.04
(dm, J ) 12.5 Hz, 1 H), 2.27-2.49 (m, 3 H), 2.70-2.75 (m, 2
H), 3.19 (m, 2 H), 3.20 (d, J ) 8.8 Hz, 1 H), 3.69 (s, 3 H), 3.73
(s, 3 H), 4.07 (s, 3 H), 4.24 (dd, J ) 10.7, 2.0 Hz, 1 H), 6.63 (s,
1 H), 7.20 (m, 8 H), 8.00 (d, J ) 7.4 Hz, 1 H); 13C NMR (CDCl3)
δ 28.5 (CH2), 36.3 (CH), 36.9 (CH2), 46.1 (CH2), 52.3 (CH3),
52.8 (CH2), 53.6 (CH3), 55.2 (CH2), 56.9 (CH), 59.5 (CH), 108.4
(CH), 115.4 (CH), 120.5 (CH), 123.1 (CH), 123.7 (CH), 124.1
(CH), 128.9 (CH), 130.5 (CH), 136.0 (C), 142.5 (C), 143.8 (C),
152.2 (C), 168.5 (C). Operating as above, from 17 (minor
epimer, 140 mg) was obtained pure sulfoxide 24a -2 (83%): 1H
NMR (CDCl3) δ 1.34 (q, J ) 11.3 Hz, 1 H), 1.42 (qd, J ) 11.7,
2.7 Hz, 1 H), 1.68 (dm, J ) 11.7 Hz, 1 H), 1.98 (dm, J ) 11.3
Hz, 1 H), 2.25 (m, 2 H), 2.48 (m, 1 H), 2.77 (m, 3 H), 3.11 (dm,
J ) 12 Hz, 1 H), 3.12 (d, J ) 9.2 Hz, 1 H), 3.61 (s, 3 H), 3.66
(s, 3 H), 3.96 (s, 3 H), 4.18 (dd, J ) 10.5, 2.0 Hz, 1 H), 6.56 (s,
1 H), 7.12-7.32 (m, 7 H), 7.40 (d, J ) 7.3 Hz, 1 H), 7.95 (d, J
) 7.4 Hz, 1 H). Anal. Calcd for C28H32N2O7S: C, 62.20; H,
5.97; N, 5.18; S, 5.93. Found: C, 62.09; H, 6.11; N, 5.28; S,
5.90.
overall yield): IR (CHCl3) 3400, Bohlmann bands, 1750 cm-1
;
1H NMR (CDCl3) δ 1.26 (q, J ) 12.0 Hz, 1 H), 1.44 (qd, J )
12.0, 4.5 Hz, 1 H), 1.64 (dm, J ) 12.0 Hz, 1 H), 2.13 (dm, J )
12.0 Hz, 1 H), 2.27 (m, 1 H), 2.38 (td, J ) 12.0, 2.0 Hz, 1 H),
2.61 (dd, J ) 11.7, 10.0 Hz, 1 H), 2.90 (dm, J ) 12.0 Hz, 1 H),
3.20 (dd, J ) 11.7, 6.0 Hz, 1 H), 3.20 (d, J ) 8.4 Hz, 1 H), 3.25
(d, J ) 12.0 Hz, 1 H), 3.68 (s, 3 H), 3.70 (s, 3 H), 4.75 (ddd, J
) 10.0, 6.0, 2.0 Hz, 1 H), 7.00-7.40 (m, 8 H); 7.83 (br s, 1 H),
7.93 (dm, J ) 7.5 Hz, 1 H); 13C NMR (CDCl3) δ 29.3 (CH2),
33.4 (CH2), 35.8 (CH), 42.2 (CH), 52.6 (CH3), 54.2 (CH2), 57.0
(CH), 58.8 (CH), 60.4 (CH2), 107.7 (C), 110.8 (CH), 119.7 (CH),
120.6 (CH), 121.8 (CH), 126.5 (C), 126.9 (CH), 128.8 (CH),
132.1 (CH), 134.7 (C), 136.0 (C), 136.1 (C), 168.6 (C); MS, m/ e
(relative intensity) 465 (M+ + 1, 1), 358 (21), 357 (92), 356
(38), 355 (24), 133 (43), 111 (100), 101 (75). Anal. Calcd for
C26H28N2O4S: C, 67.22; H, 6.07; N, 6.03. Found: C, 67.18; H,
6.46; N, 5.69. When the column was washed with 70:30:5
Et2O-acetone-DEA, the conjugate base of 23 (275 mg, 65%)
was isolated: 1H NMR (CDCl3) δ 0.63 (qd, J ) 12.3, 3.9 Hz, 1
H), 1.20 (q, J ) 12.0 Hz, 1 H), 1.50 (dm, J ) 12.3 Hz, 1 H),
2.20 (m, 1 H), 2.29 (dm, J ) 12.0 Hz, 1 H), 2.57 (td, J ) 11.2,
2.4 Hz, 1 H), 2.80 (dt, J ) 11.2, 3.4 Hz, 1 H), 2.95 (dd, J )
15.0, 5.5 Hz, 1 H), 3.00 (d, J ) 8.0 Hz, 1 H), 3.28 (ddd, J )
15.0, 12.0, 3.7 Hz, 1 H), 3.61 (m, 1 H), 3.65 (s, 3 H), 3.70 (s, 3
H), 3.80 (m, 1 H), 4.02 (dd, J ) 11.3, 3.1 Hz, 1 H), 7.10 (m, 2
H), 7.49 (m, 6 H), 7.72 (m, 1 H); 13C NMR (CDCl3) δ 29.5 (CH2),
35.5 (CH), 37.2 (CH2), 48.3 (CH2), 51.3 (CH2), 52.2 (CH3), 52.4
(CH3), 53.9 (CH2), 56.8 (CH), 66.5 (CH), 67.4 (C), 114.0 (CH),
118.2 (CH), 119.4 (CH), 119.5 (CH), 125.9 (CH), 129.4 (CH),
130.1 (CH), 133.0 (C), 137.4 (C), 147.8 (C), 158.8 (C), 168.2
(C); MS, m/ e (relative intensity) 464 (M+, 10), 451 (45), 432
(45), 355 (54), 342 (39), 341 (100), 251 (77), 218 (72), 217 (41),
200 (34), 182 (52), 174 (45), 173 (25), 168 (25), 130 (28). Anal.
Calcd for C26H28N2O4S‚3/2H2O: C, 63.52; H, 6.36; N, 5.70; S,
6.52. Found: C, 63.55; H, 6.30; N, 5.89; S, 6.27.
Meth od B. TFAA (785 µL, 5.6 mmol) was added to a
solution of sulfoxide 17 (670 mg, 1.4 mmol) in CH2Cl2 (28 mL)
at 0 °C. The resulting mixture was stirred at 25 °C for 2.5 h
and concentrated under vacuum. Chlorobenzene (30 mL) was
added, and the solution was heated at reflux for 2 h and
concentrated. The residue was dissolved in CH2Cl2, and the
organic solution was washed with aqueous Na2CO3, dried, and
concentrated. Column chromatography of the residue (AcOEt)
afforded dim eth yl cis-1-(2-h ydr oxyeth yl)-2-[3-(ph en ylth io)-
2-in d olyl]-4-p ip er id in em a lon a te (18): 490 mg, 73%; IR
1
(NaCl) 3400, 3100, 1736 cm-1; H NMR (CDCl3) δ 1.50 (qd, J
) 12.0, 3.5 Hz, 1 H), 1.64 (q, J ) 12.0 Hz, 1 H), 1.72-1.85 (m,
2 H), 2.10 (dm, J ) 13.5 Hz, 1 H), 2.23 (td, J ) 12.0, 3.0 Hz,
1 H), 2.30 (m, 1 H), 2.72 (ddd, J ) 13.5, 10.0, 4.5 Hz, 1 H),
3.18 (d, J ) 8.5 Hz, 1 H), 3.28 (dm, J ) 12.0 Hz, 1 H), 3.41 (dt,
J ) 11.8, 4.0 Hz, 1 H), 3.55 (s, 3 H), 3.68 (s, 3 H), 3.71 (dm, J
) 11.8 Hz, 1 H), 4.03 (dd, J ) 11.5, 2.8 Hz, 1 H), 6.98-7.22
(m, 7 H), 7.33 (dm, J ) 8.0 Hz, 1 H), 7.55 (dm, J ) 7.6 Hz, 1
H), 9.90 (br s, 1 H); 13C NMR (CDCl3) δ 29.4 (CH2), 35.9 (CH),
37.6 (CH2), 52.3 (CH2), 52.4 (CH3), 56.4 (CH2), 56.7 (CH), 58.4
(CH2), 59.3 (CH), 99.7 (C), 111.6 (CH), 119.1 (CH), 120.6 (CH),
122.8 (CH), 124.6 (CH), 125.5 (CH), 128.7 (CH), 129.7 (C),
135.8 (C), 139.0 (C), 144.3 (C), 168.2 (C), 168.4 (C); MS, m/ e
(relative intensity) 482 (M+, 27), 451 (36), 342 (39), 341 (100),
238 (18), 200 (21); HRMS calcd for C26H30N2O5S 482.1870,
found 482.1870. Anal. Calcd for C26H30N2O5S‚1/2H2O: C,
63.52; H, 6.35; N, 5.70; S, 6.52. Found: C, 63.82; H, 6.44; N,
5.71; S, 6.26.
Dim eth yl cis-2-[1-(ter t-Bu toxyca r bon yl)-2-in d olyl]-1-
[2-(p h en ylsu lfin yl)eth yl]-4-p ip er id in em a lon a te (24b). A
mixture of 17 (major epimer, 200 mg, 0.42 mmol), DMAP (10
mg, 0.08 mmol), and di-tert-butyl dicarbonate (229 mg, 1.05
mmol) in anhydrous CH2Cl2 (4 mL) was stirred under Ar at
25 °C for 10 h. Evaporation followed by chromatography (12:1
Et2O-MeOH) gave pure sulfoxide 24b-1 (235 mg, 97%): 1H
NMR (CDCl3) δ 1.43 (m, 2 H), 1.70 (m, 1 H), 1.70 (s, 9 H), 2.02
(dm, J ) 12.3 Hz, 1 H), 2.24-2.53 (m, 3 H), 2.71 (m, 2 H),
3.13 (m, 2 H), 3.20 (d, J ) 9.0 Hz, 1 H), 3.69 (s, 3 H), 3.73 (s,
3 H), 4.34 (dd, J ) 11.0, 2.4 Hz, 1 H), 6.64 (s, 1 H), 7.20-7.50
(m, 8 H), 8.10 (d, J ) 7.8 Hz, 1 H); 13C NMR (CDCl3) δ 28.2
(CH3), 28.5 (CH2), 36.3 (CH), 36.8 (CH2), 46.2 (CH2), 52.4 (CH3),
Meth od C. TMSOTf (435 µL, 2.4 mmol) was added to a

3172 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
52.9 (CH2), 55.3 (CH2), 57.1 (CH), 59.4 (CH), 84.3 (C), 107.7
(CH), 115.4 (CH), 120.4 (CH), 122.7 (CH), 123.6 (CH), 123.7
(CH), 128.9 (CH), 130.6 (CH), 136.4 (C), 142.5 (C), 143.8 (C),
150.2 (C), 168.4 (CH). Anal. Calcd for C31H38N2O7S: C, 63.90;
H, 6.57; N, 4.81; S, 5.50. Found: C, 64.02; H, 6.84; N, 4.72; S,
5.31. Operating as above, from 17 (minor epimer, 200 mg)
was obtained pure sulfoxide 24b-2 (236 mg, 98%): 1H NMR
(CDCl3) δ 1.36 (q, J ) 12.3 Hz, 1 H), 1.48 (qd, J ) 12.3, 3.6
Hz, 1 H), 1.70 (s, 9 H), 1.76 (dm, J ) 12.3 Hz, 1 H), 2.03 (dm,
J ) 12.3 Hz, 1 H), 2.26 (m, 1 H), 2.34 (td, J ) 11.8, 2.3 Hz, 1
H), 2.59 (m, 1 H), 2.87 (m, 3 H), 3.18 (d, J ) 9.0 Hz, 1 H), 3.20
(dm, J ) 11.8 Hz, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H), 4.25 (dd, J
) 11.0, 2.7 Hz, 1 H), 6.60 (s, 1 H), 7.10-7.40 (m, 7 H), 7.43 (d,
J ) 7.5 Hz, 1 H), 8.05 (d, J ) 7.8 Hz, 1 H); 13C NMR (CDCl3)
δ 28.0 (CH3), 29.2 (CH2), 36.0 (CH), 38.5 (CH2), 47.3 (CH2),
52.2 (CH3), 53.0 (CH2), 54.4 (CH2), 56.9 (CH), 59.7 (CH), 84.3
(C), 107.6 (CH), 115.5 (CH), 120.2 (CH), 122.6 (CH), 123.5
(CH), 128.7 (CH), 130.6 (CH), 136.2 (C), 143.0 (C), 143.2 (C),
149.9 (C), 168.3 (C). Anal. Calcd for C31H38N2O7S: C, 63.90;
H, 6.57; N, 4.81; S, 5.50. Found: C, 63.55; H, 6.71; N, 4.71; S,
5.10.
(CH), 122.8 (CH), 124.3 (CH), 127.1 (CH), 127.8 (C), 129.0
(CH), 131.9 (CH), 136.0 (C), 136.7 (C), 138.6 (C), 149.8 (C),
168.5 (C); mp 139-140 °C. Anal. Calcd for C31H36N2O6S: C,
65.94; H, 6.43; N, 4.96; S, 5.68. Found: C, 65.78; H, 6.49; N,
4.89; S, 5.58. â-P h S ep im er : 112 mg (17%); IR (NaCl)
1
Bohlmann bands, 1732 cm-1; H NMR (CDCl3) δ 1.04 (q, J )
12.0 Hz, 1 H), 1.56 (m, 2 H), 1.67 (s, 9 H), 2.10 (dm, J ) 12.0
Hz, 1 H), 2.40 (m, 1 H), 2.80 (td, J ) 12.4, 2.5 Hz, 1 H), 3.02
(dm, J ) 12.4 Hz, 1 H), 3.06 (dd, J ) 12.0, 4.2 Hz, 1 H), 3.12
(d, J ) 9.4 Hz, 1 H), 3.17 (dd, J ) 12.0, 4.4 Hz, 1 H), 3.70 (s,
3 H), 3.73 (s, 3 H), 3.95 (dm, J ) 10.0 Hz, 1 H), 4.45 (br s, 1
H), 7.20-7.35 (m, 5 H), 7.41 (m, 2 H), 7.75 (d, J ) 7.3 Hz, 1
H), 8.11 (d, J ) 7.5 Hz, 1 H); 13C NMR (CDCl3) δ 27.7 (CH2),
28.0 (CH3), 33.1 (CH2), 36.3 (CH), 42.7 (CH), 52.3 (CH3), 52.4
(CH3), 54.3 (CH2), 55.5 (CH2), 57.6 (CH), 58.7 (CH), 84.4 (C),
115.4 (CH), 115.7 (C), 119.6 (CH), 122.7 (CH), 124.2 (CH),
127.1 (CH), 127.9 (C), 128.7 (CH), 132.7 (CH), 135.3 (C), 136.9
(C), 138.8 (C), 150.0 (C), 168.5 (C); mp 122-123 °C. Anal.
Calcd for C31H36N2O6S: C, 65.94; H, 6.43; N, 4.96; S, 5.68.
Found: C, 65.77; H, 6.33; N, 5.02; S, 5.57. Operating as above,
from sulfoxide 24b-2 (150 mg) was obtained compound 25b
(71%) as a 2:1 mixture of C7 epimers.
Dim eth yl cis-12-(Meth oxyca r bon yl)-7-(p h en ylth io)in -
d olo[2,3-a ]qu in olizid in e-2-m a lon a te (25a ). TMSOTf (200
µL, 1.01 mmol) was added under Ar to a solution of sulfoxide
24a -1 (130 mg, 0.24 mmol) and DIPEA (194 µL, 1.13 mmol)
in anhydrous CH2Cl2 (1 mL), and the mixture was stirred at
25 °C for 15 min. The solution was poured into aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2, the
combined organic extracts were dried and concentrated, and
the residue was chromatographed (1:1 AcOEt-hexane) to give
two epimeric indoloquinolizidines 25a . r-P h S ep im er : 60 mg
Dim eth yl cis-7-(P h en ylth io)in dolo[2,3-a ]qu in olizid in e-
2-m a lon a te (19). Compound 25b (major epimer, 130 mg, 0.23
mmol) was dissolved in formic acid (20 mL), and the solution
was stirred under Ar at 25 °C for 24 h. The solvent was
evaporated, and the residue was dissolved in CH2Cl2 and
washed with 10% aqueous Na2CO3. The organic solution was
dried and concentrated, and the resulting residue was chro-
matographed. Elution with Et2O successively afforded the
â-PhS and R-PhS epimers of 19 in an approximate ratio of 1:1
(70 mg, 65% overall yield). A similar result was obtained
starting from the minor epimer of 25b. 19 (â-PhS epimer):
1
(48%); IR (KBr) 1736 cm-1; H NMR (CDCl3) δ 1.45 (m, 3 H),
1.97 (dm, J ) 12.3 Hz, 1 H), 2.45 (m, 1 H), 2.85 (dd, J ) 12.3,
3.0 Hz, 1 H), 3.15 (m, 1 H), 3.20 (d, J ) 8.3 Hz, 1 H), 3.21 (m,
1 H), 3.45 (dd, J ) 12.3, 3.5 Hz, 1 H), 3.71 (s, 3 H), 3.72 (s, 3
H), 4.06 (s, 3 H), 4.43 (dd, J ) 10.7, 1.6 Hz, 1 H), 4.58 (t, J )
3.2 Hz, 1 H), 7.20 (m, 5 H), 7.53 (m, 2 H), 7.63 (dm, J ) 7.2
Hz, 1 H), 8.13 (dm, J ) 7.3 Hz, 1 H); 13C NMR (CDCl3) δ 25.1
(CH2), 30.1 (CH2), 36.9 (CH), 42.5 (CH), 51.0 (CH2), 52.4 (CH3),
53.7 (CH3), 54.3 (CH2), 57.1 (CH), 57.2 (CH), 115.0 (C), 115.6
(CH), 119.3 (CH), 123.1 (CH), 124.5 (CH), 127.1 (CH), 128.0
(C), 129.0 (CH), 132.0 (CH), 135.8 (C), 136.4 (C), 138.4 (C),
151.7 (C), 168.5 (C). Anal. Calcd for C28H30N2O6S: C, 64.35;
H, 5.79; N, 5.36; S, 6.14. Found: C, 64.31; H, 5.74; N, 5.35; S,
6.03. â-P h S ep im er : 32 mg (25%); IR (KBr) Bohlmann
1
IR (NaCl) 3400, Bohlmann bands, 1750, 1738 cm-1; H NMR
(CDCl3) δ 1.33 (q, J ) 12.0 Hz, 1 H), 1.64 (qd, J ) 12.0, 4.0
Hz, 1 H), 1.70 (m, 1 H), 2.15 (dm, J ) 12.0 Hz, 1 H), 2.33 (m,
1 H), 2.40 (td, J ) 11.5, 3.3 Hz, 1 H), 2.90 (dd, J ) 12.3, 3.5
Hz, 1 H), 2.98 (dt, J ) 11.2, 3.2 Hz, 1 H), 3.16 (dd, J ) 12.5,
1.0 Hz, 1 H), 3.21 (d, J ) 11.5 Hz, 1 H), 3.26 (d, J ) 9,0 Hz, 1
H), 3.76 (s, 3 H), 3.78 (s, 3 H), 4.56 (m, 1 H), 7.10-7.20 (m, 2
H), 7.25-7.30 (m, 4 H), 7.49 (m, 2 H), 7.62 (m, 1 H), 7.97 (br
s, 1 H); 13C NMR (CDCl3) δ 29.5 (CH2), 33.5 (CH2), 36.0 (CH),
42.7 (CH), 52.5 (CH3), 54.6 (CH2), 57.1 (CH), 58.9 (CH and
CH2), 107.6 (C), 111.0 (CH), 118.9 (CH), 119.8 (CH), 121.8
(CH), 126.2 (C), 126.7 (CH), 126.8 (CH), 133.0 (CH), 135.9 (C),
136.5 (C), 136.7 (C), 168.7 (C), 168.8 (C).
1
bands, 1737 cm-1; H NMR (CDCl3) δ 1.05 (q, J ) 11.0 Hz, 1
H), 1.45-1.65 (m, 2 H), 2.08 (dm, J ) 12.5 Hz, 1 H), 2.38 (m,
1 H), 2.77 (td, J ) 12.5, 3.5 Hz, 1 H), 3.05 (dm, J ) 12.5 Hz,
1 H), 3.14 (d, J ) 8.5 Hz, 1 H), 3.12-3.20 (m, 2 H), 3.73 (s, 3
H), 3.74 (s, 3 H), 3.85 (dm, J ) 11.0 Hz, 1 H), 4.03 (s, 3 H),
4.43 (m, 1 H), 7.20-7.35 (m, 5 H), 7.42 (m, 2 H), 7.75 (dm, J
) 7.2 Hz, 1 H), 8.12 (dm, J ) 7.3 Hz, 1 H); 13C NMR (CDCl3)
δ 27.8 (CH2), 33.6 (CH2), 36.9 (CH), 42.7 (CH), 52.4 (CH3), 53.8
(CH3), 54.5 (CH2), 55.7 (CH2), 57.4 (CH), 59.1 (CH), 115.3 (CH),
115.6 (C), 119.7 (CH), 123.1 (CH), 124.6 (CH), 127.3 (CH),
128.0 (C), 128.8 (CH), 132.9 (CH), 135.1 (C), 136.7 (C), 138.2
(C), 151.9 (C), 168.7 (C). Anal. Calcd for C28H30N2O6S: C,
64.35; H, 5.79; N, 5.36. Found: C, 64.11; H, 6.13; N, 5.42. A
similar result was obtained operating from sulfoxide 24a -2.
Dim eth yl cis-12-(ter t-Bu toxyca r bon yl)-7-(p h en ylth io)-
in dolo[2,3-a ]qu in olizidin e-2-m alon ate (25b). TMSOTf (956
µL, 4.8 mmol) was added under Ar to a solution of sulfoxide
24b-1 (700 mg, 1.2 mmol) and DIPEA (904 µL, 5.25 mmol) in
anhydrous CH2Cl2 (4 mL), and the mixture was stirred at 25
°C for 15 min. Workup as above, followed by chromatography
(1:1 AcOEt-hexane), gave two epimeric indoloquinolizidines
25b. r-P h S ep im er : 326 mg (48%); IR (NaCl) 1732 cm-1; 1H
NMR (CDCl3) δ 1.43 (m, 2 H), 1.68 (s, 9 H), 1.70 (m, 1 H), 1.94
(dm, J ) 12.3 Hz, 1 H), 2.45 (m, 1 H), 2.84 (dd, J ) 12.4, 2.3
Hz, 1 H), 3.13 (dm, J ) 13.0 Hz, 1 H), 3.19 (d, J ) 9.3 Hz, 1
H), 3.25 (td, J ) 13.0, 3.0 Hz, 1 H), 3.48 (dd, J ) 12.4, 3.5 Hz,
1 H), 3.71 (s, 3 H), 3.73 (s, 3 H), 4.55 (m, 2 H), 7.20-7.40 (m,
5 H), 7.55 (m, 2 H), 7.63 (dm, J ) 7.3 Hz, 1 H), 8.20 (d, J )
7.5 Hz, 1 H); 13C NMR (CDCl3) δ 24.5 (CH2), 28.0 (CH3), 29.3
(CH2), 36.4 (CH), 42.5 (CH), 49.7 (CH2), 52.4 (CH3), 54.1 (CH2),
56.4 (CH), 57.5 (CH), 84.4 (C), 114.0 (C), 115.8 (CH), 118.9
Dim et h yl cis-2-(2-In d olyl)-1-[(N-m et h oxy-N-m et h yl-
ca r ba m oyl)m eth yl]-4-p ip er id in em a lon a te (26). A mix-
ture of indolylpiperidine 16 (1.0 g, 3.0 mmol), K2CO3 (460 mg,
3.3 mmol), NaI (213 mg, 1.4 mmol), and N-methoxy-N-
methylchloroacetamide (460 mg, 3.3 mmol) in acetonitrile (33
mL) was stirred at 45 °C for 2 h. The solvent was evaporated,
and the residue was dissolved in CH2Cl2. The solution was
washed with aqueous Na2CO3, dried, and concentrated to give
an oil which, after column chromatography (8:2 AcOEt-
hexane), afforded compound 26 (1.2 g, 92%): IR (NaCl) 3391,
1734, 1661 cm-1; 1H NMR (CDCl3) δ 1.48-1.82 (m, 3 H), 1.91
(dm, J ) 12.8 Hz, 1 H), 2.30 (m, 1 H), 2.48 (td, J ) 11.6, 2.4
Hz, 1 H), 3.05 (d, J ) 16.2 Hz, 1 H), 3.08 (s, 3 H), 3.20 (dt, J
) 11.6, 3.7 Hz, 1 H), 3.23 (d, J ) 9.1 Hz, 1 H), 3.40 (s, 3 H),
3.43 (d, J ) 16.2 Hz, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H), 3.78 (dd,
J ) 11.1, 2.7 Hz, 1 H), 6.36 (d, J ) 1.4 Hz, 1 H), 7.10 (m, 2 H),
7.33 (d, J ) 8.1 Hz, 1 H), 7.53 (d, J ) 7.5 Hz, 1 H), 9.03 (br s,
1 H); 13C NMR (CDCl3) δ 29.3 (CH2), 31.8 (CH3), 36.0 (C), 38.0
(CH2), 52.3 (CH3), 53.1 (CH2), 54.1 (CH2), 56.9 (CH), 59.9 (CH),
60.9 (CH3), 100.6 (CH), 111.0 (CH), 119.5 (CH), 120.1 (CH),
121.6 (CH), 128.0 (C), 136.0 (C), 140.1 (C), 168.7 (C); mp 131-
133 °C (Et2O). Anal. Calcd for C22H29N3O6: C, 61.24; H, 6.77;
N, 9.74. Found: C, 61.27; H, 7.05; N, 9.56.
Redu ctive Cyclization of N-Meth oxyam ide 26. Meth od
A. A solution of Red-Al (3.4 M in toluene, 332 µL, 1.2 mmol)
was added to a solution of amide 26 (180 mg, 0.42 mmol) in
toluene (15 mL) and THF (4 mL) at -40 °C. The mixture was
stirred at -25 °C for 2 h, and the reaction was quenched with
saturated Rochelle’s salt solution (7.5 mL). To this solution
were added sequencially CH2Cl2 (7.5 mL), 10% aqueous HCl

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3173
(7.5 mL), and saturated aqueous Na2CO3 (19 mL). The
aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were dried and concentrated. The residue was
dissolved in CH2Cl2 (10 mL) and cooled to 0 °C. To the above
solution were added MeSH (excess, 1.0 mL) and BF3‚Et2O (53
µL, 0.42 mmol), and the mixture was stirred at 0 °C for 3.5 h,
poured into water, and basified with Na2CO3. The aqueous
layer was extracted with CH2Cl2, and the combined organic
extracts were dried and concentrated. Column chromatogra-
phy (1:1 AcOEt-hexane) of the residue successively afforded
30 (R-MeS; 11 mg, 7%), 27 (â-MeS; 20 mg, 12%), 30 (â-MeS;
13 mg, 8%), and 27 (R-MeS; 8 mg, 5%). Dim eth yl cis-7-
(m et h ylt h io)in d olo[2,3-a ]q u in olizid in e-2-m a lon a t e (27,
(masked, 1 H), 2.74 (dd, J ) 11.3, 8.8 Hz, 1 H), 3.07 (dm, J )
11.5 Hz, 1 H), 3.18 (dd, J ) 11.3, 5.4 Hz, 1 H), 3.26 (d, J ) 8.6
Hz, 1 H), 3.45 (dm, J ) 12.0 Hz, 1 H), 3.54 (s, 3 H), 3.76 (s, 3
H), 3.77 (s, 3 H), 4.60 (m, 1 H), 7.10 (m, 2 H), 7.30 (m, 1 H),
7.85 (dm, J ) 7.4 Hz, 1 H); 13C NMR (CDCl3) δ 28.5 (CH2),
32.7 (CH2), 35.9 (CH), 39.2 (CH3), 51.2 (CH2), 52.4 (CH3), 54.6
(CH2), 56.9 (CH), 58.3 (CH), 59.3 (CH), 59.8 (CH3), 108.4 (C),
110.6 (CH), 119.4 (CH), 121.0 (CH), 121.4 (CH), 126.9 (C),
136.0 (C), 136.7 (C), 168.7 (C). Anal. Calcd for C22H29N3O5‚
1/2H2O: C, 62.25; H, 7.12; N, 9.89. Found: C, 62.58; H, 6.95;
N, 9.58. Dim eth yl cis-6â-h yd r oxy-6,7,10,11,12,12a -h exa h y-
d r o-9H -p yr id o[1′,2′:1,2]p yr a zin o[4,3-b]in d ole -11-m a l-
on a te (31): IR (KBr) 3800-3400, 1734 cm-1; 1H NMR (CDCl3)
δ 1.30 (q, J ) 12.0 Hz, 1 H), 1.50 (masked, 1 H), 1.60 (m, 1 H),
2.19 (dm, J ) 13.5 Hz, 1 H), 2.28-2.44 (masked, 1 H), 2.32
(m, 1 H), 2.38 (dd, J ) 12.0, 8.2 Hz, 1 H), 2.80 (dm, J ) 12.0
Hz, 1 H), 3.00 (dm, J ) 12.0 Hz, 1 H), 3.20 (d, J ) 8.7 Hz, 1
H), 3.34 (dm, J ) 12.0 Hz, 1 H), 3.40 (dd, J ) 12.0, 5.0 Hz, 1
H), 3.75 (s, 3 H), 3.78 (s, 3 H), 5.72 (m, 1 H), 6.20 (s, 1 H), 7.13
(m, 2 H), 7.50 (dm, J ) 7.0 Hz, 1 H), 7.64 (dm, J ) 7.4 Hz, 1
H); 13C NMR (CDCl3) δ 28.5 (CH2), 34.4 (CH2), 35.4 (CH), 52.5
(CH3), 54.3 (CH2), 56.9 (CH), 59.0 (CH), 60.0 (CH2), 75.8 (CH),
96.8 (CH), 111.8 (CH), 120.0 (CH), 120.3 (CH), 121.4 (CH),
128.6 (C), 136.1 (C), 138.1 (C), 168.7 (C); MS, m/ e (relative
intensity) 373 (M+ + 1, 23), 372 (M+, 100), 371 (M+ - 1, 44),
355 (32), 354 (81), 353 (34), 241 (88), 239 (35), 223 (86), 197
(24), 169 (31), 168 (48), 130 (36), 69 (35), 59 (32), 57 (42), 55
(65). Anal. Calcd for: C20H24N2O5‚1/4H2O: C, 63.73; H, 6.55;
N, 7.43. Found: C, 63.74; H, 6.60; N, 7.41. Dim eth yl cis-
6-oxo-6,7,9,10,12,12a-h exah ydr o-9H-pyr ido[1′,2′:1,2]pyr azi-
n o[4,3-b]in d ole-11-m a lon a te (32): IR (KBr) 3200-2700,
1
â-MeS epimer): IR(CHCl3) 3392, 2800-2700 cm-1; H NMR
(CDCl3) δ 1.37 (q, J ) 12.0 Hz, 1 H), 1.53-1.80 (m, 2 H), 2.08
(s, 3 H), 2.20 (dm, J ) 12.0 Hz, 1 H), 2.30-2.54 (m, 2 H), 3.00
(dd, J ) 12.2, 3.7 Hz, 1 H), 3.06 (dm, J ) 11.6 Hz, 1 H), 3.20
(dm, J ) 12.2 Hz, 1 H), 3.23 (masked, 1 H), 3.27 (d, J ) 8.8
Hz, 1 H), 3.76 (s, 3 H), 3.79 (s, 3 H), 4.11 (br s, 1 H), 7.12 (m,
2 H), 7.30 (dm, J ) 7.4 Hz, 1H), 7.68 (dm, J ) 7.4 Hz, 1H),
7.95 (br s, 1 H); MS, m/ e (relative intensity) 402 (M+, 3), 356
(29), 355 (100), 223 (35). 27 (R-MeS epimer): IR(CHCl3) 3400,
1
2800-2700, 1734 cm-1; H NMR (CDCl3) δ 1.35 (q, J ) 12.0
Hz, 1 H), 1.50-1.80 (m, 2 H), 1.88 (s, 3 H), 2.25 (dm, J ) 12.0
Hz, 1 H), 2.35 (m, 1 H), 2.47 (td, J ) 11.6, 2.7 Hz, 1 H), 2.65
(dd, J ) 11.4, 10.5 Hz, 1 H), 3.05 (dm, J ) 11.6 Hz, 1 H), 3.20-
3.35 (m, 2 H), 3.30 (d, J ) 8.3 Hz, 1 H), 3.77 (s, 3 H), 3.79 (s,
3 H), 4.35 (m, 1 H), 7.16 (m, 2 H), 7.32 (dm, J ) 7.4 Hz, 1 H),
8.03 (dm, J ) 7.4 Hz, 1 H), 8.00 (br s, 1 H); MS, m/ e (relative
intensity) 402 (M+, 1), 356 (28), 355 (100), 354 (29), 353 (41),
223 (71), 221 (25), 219 (34), 169 (20), 168 (21), 59 (21).
Dim eth yl cis-6-(m eth ylth io)-6,7,10,11,12,12a -h exa h yd r o-
9H-pyr ido[1′,2′:1,2]pyr azin o[4,3-a ]in dole-11-m alon ate (30,
1
1754, 1716 cm-1; H NMR (CDCl3) δ 1.52 (q, J ) 11.0 Hz, 1
H), 1.64-1.86 (m, 2 H), 2.31 (td, J ) 11.7, 2.5 Hz, 1 H), 2.30-
2.50 (m, 2 H), 3.05 (dm, J ) 11.7 Hz, 1 H), 3.23 (d, J ) 16.8
Hz, 1 H), 3.32 (d, J ) 8.4 Hz, 1 H), 3.32 (masked, 1 H), 3.72
(d, J ) 16.8 Hz, 1 H), 3.77 (s, 3 H), 3.81 (s, 3 H), 6.35 (s, 1 H),
7.30 (m, 2 H), 7.50 (m, 1 H), 8.38 (m, 1 H); 13C NMR (CDCl3)
δ 29.0 (CH2), 33.3 (CH2), 35.1 (CH), 52.6 (CH3), 54.0 (CH2),
56.9 (CH), 57.4 (CH), 59.4 (CH2), 103.6 (CH), 116.1 (CH), 120.3
(CH), 124.2 (CH), 124.6 (CH), 129.6 (C), 134.3 (C), 138.8 (C),
165.6 (C), 168.5 (C).
Dim eth yl cis-In dolo[2,3-a ]qu in olizidin e-2-m alon ate (20).
A. F r om Su lfid e 19. A mixture of 19 (33 mg, 0.084 mmol),
Bu3SnH (38 µl, 0.143 mmol), and AIBN in benzene (5 mL) was
heated at reflux for 5 h. The mixture was concentrated, and
the resulting residue was chromatographed (Et2O) to give
indoloquinolizidine 2039 (20 mg, 72%).
1
â-MeS epimer): IR(CHCl3) 3000-2700, 1752, 1734 cm-1; H
NMR (CDCl3) δ 1.45 (m, 1 H), 1.79 (s, 3 H), 1.68-1.88 (m, 2
H), 2.26-2.44 (m, 3 H), 2.81 (dd, J ) 12.5, 10.5 Hz, 1 H), 3.05
(dm, J ) 11.0 Hz, 1 H), 3.28 (d, J ) 8.6 Hz, 1 H), 3.30 (masked,
1 H), 3.40 (dd, J ) 12.5, 6.5 Hz, 1 H), 3.78 (s, 3 H), 3.80 (s, 3
H), 5.39 (dd, J ) 10.5, 6.5 Hz, 1 H), 6.24 (s, 1 H), 7.14 (m, 2
H), 7.54 (dm, J ) 7.4 Hz, 1 H), 8.00 (d, J ) 7.4 Hz, 1 H); MS,
m/ e (relative intensity) 402 (M+, 2), 355 (61), 354 (96), 353
(59), 293 (13), 223 (100), 221 (51), 169 (34), 168 (56), 101 (25),
69 (20), 59 (44), 55 (29). 30 (R-MeS epimer): IR(CHCl3) 2920,
2800-2700, 1752, 1734 cm-1; 1H NMR (CDCl3) δ 1.47 (q, J )
11.4 Hz, 1 H), 1.55 (masked, 1 H), 1.78 (m, 1 H), 1.91 (s, 3 H),
2.22-2.44 (m, 3 H), 3.07 (dm, J ) 11.0 Hz, 1 H), 3.19 (dd, J )
12.1, 3.5 Hz, 1 H), 3.29 (d, J ) 9.0 Hz, 1 H), 3.35 (d, J ) 12.1
Hz, 1 H), 3.36 (masked, 1 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 5.34
(br s, 1 H), 6.20 (s, 1 H), 7.16 (m, 2 H), 7.48 (m, 1 H), 7.55
(dm, J ) 7.4 Hz, 1 H); MS, m/ e (relative intensity) 402 (M+,
12), 356 (30), 355 (100), 354 (31), 353 (22), 223 (62), 221 (20),
169 (16), 168 (19).
B. F r om Alcoh ol 28. Triethylsilane (135 µL, 0.85 mmol)
and TFA (0.2 mL, 2.6 mmol) were added to a solution of
compound 28 (93 mg, 0.25 mmol) in anhydrous CH2Cl2 (5 mL),
and the mixture was heated at reflux for 24 h. Aqueous K2-
CO3 was added, and the mixture was extracted with CH2Cl2.
The combined organic extracts were dried and concentrated
to give a residue which, after column chromatography (AcOEt),
afforded pure 2039 (62 mg, 70%): IR (KBr) 3600-3400, 2800-
Meth od B. Operating as described above, from amide 26
(1.8 g, 4.2 mmol) and Red-Al (2.8 mL, 9.7 mmol, 3.4 M in
toluene), but omitting the final treatment with MeSH, com-
pounds 32 (70 mg, 4%), 29 (180 mg, 12%), 31 (460 mg, 30%),
and 28 (470 mg, 30%) were successively obtained after column
chromatography (AcOEt). Dim eth yl cis-7â-h yd r oxyin d olo-
[2,3-a ]qu in olizid in e-2-m a lon a te (28): IR (KBr) 3800-3400,
1729 cm-1; 1H NMR (CDCl3) δ 1.35 (q, J ) 12.0 Hz, 1 H), 1.56
(qd, J ) 12.0, 4.1 Hz, 1 H), 1.73 (dm, J ) 11.5 Hz, 1 H), 2.22
(dm, J ) 12.0 Hz, 1 H), 2.37 (m, 1 H), 2.48 (td, J ) 11.5, 2.8
Hz, 1 H), 2.73 (dd, J ) 12.0, 2.6 Hz, 1 H), 3.00 (dm, J ) 11.5
Hz, 1 H), 3.10 (dd, J ) 12.0, 1.8 Hz, 1 H), 3.20 (dd, J ) 11.5,
2.2 Hz, 1 H), 3.25 (d, J ) 8.5 Hz, 1 H), 3.77 (s, 3 H), 3.78 (s, 3
H), 4.88 (br s, 1 H), 7.15 (m, 2 H), 7.30 (m, 1 H), 7.68 (m, 1 H),
8.00 (br s, 1 H); 13C NMR (CDCl3) δ 29.4 (CH2), 33.1 (CH2),
35.8 (CH), 52.5 (CH3), 54.5 (CH2), 56.7 (CH), 59.3 (CH), 61.5
(CH2), 62.0 (CH), 110.8 (C), 111.1 (CH), 118.4 (CH), 120.0 (CH),
121.8 (CH), 126.2 (C), 136.0 (C), 136.5 (C), 168.7 (C). Anal.
Calcd for C20H24N2O5: C, 64.50; H, 6.50; N, 7.52. Found: C,
64.49; H, 6.51; N, 7.44. Dim eth yl cis-7r-(N-m eth oxy-N-
m e t h yla m in o)in d olo[2,3-a ]q u in olizid in e -2-m a lon a t e
(29): IR(CHCl3) 3300, 2800-2700, 1759, 1729 cm-1; 1H NMR
(CDCl3) δ 1.35 (q, J ) 12.0 Hz, 1 H), 1.42-1.75 (m, 2 H), 2.14
(dm, J ) 12.0 Hz, 1 H), 2.37 (m, 1 H), 2.57 (s, 3 H), 2.61
1
2700, 1748, 1733 cm-1; H NMR (CDCl3) δ 1.39 (q, J ) 11.7
Hz, 1 H), 1.60 (qd, J ) 12.0, 4.3 Hz, 1 H), 1.75 (dm, J ) 12.0
Hz, 1 H), 2.22 (dm, J ) 11.7 Hz, 1 H), 2.36 (m, 1 H), 2.46 (td,
J ) 11.7, 3.0 Hz, 1 H), 2.56-2.80 (m, 2 H), 2.90-3.15 (m, 3
H), 3.29 (d, J ) 8.7 Hz, 1 H), 3.30 (masked, 1 H), 3.76 (s, 3 H),
3.78 (s, 3 H), 7.11 (m, 2 H), 7.32 (m, 1 H), 7.46 (dm, J ) 7.4
Hz, 1 H), 7.82 (br s, 1 H); 13C NMR (CDCl3) δ 21.6 (CH2), 29.6
(CH2), 33.7 (CH2), 36.0 (CH), 52.6 (CH3), 52.8 (CH2), 54.9 (CH2),
57.0 (CH), 59.3 (CH), 108.1 (C), 110.7 (CH), 118.0 (CH), 119.3
(CH), 121.3 (CH), 127.2 (C), 134.1 (C), 135.9 (C), 168.7 (C).
1-(Ben zen esu lfon yl)-3-(3-eth yl-4-m eth yl-2-p yr id yl)in -
d ole (33a ). Tetrabutylammonium hydrogenosulfate (16 mg),
50% aqueous NaOH (2.2 mL), and benzenesulfonyl chloride
(0.8 mL, 6.1 mmol) were added to a suspension of pyridylindole
8c (0.9 g, 3.8 mmol) in benzene (6.2 mL), and the resulting
mixture was stirred at 25 °C for 24 h. Water was added, and
the aqueous layer was extracted with AcOEt. The combined
organic extracts were dried and concentrated to give compound
33a (1.3 g, 98%) as a yellow solid: IR (KBr) 1579, 1363, 1136
1
cm-1; H NMR (CDCl3) δ 1.04 (t, J ) 7.5 Hz, 3 H), 2.41 (s, 3
H), 2.65 (q, J ) 7.5 Hz, 2 H), 7.09 (d, J ) 5.0 Hz, 1 H), 7.70 (s,

3174 J . Org. Chem., Vol. 62, No. 10, 1997
Amat et al.
1 H), 7.92 (dm, J ) 7.1 Hz, 2 H), 8.05 (d, J ) 8.1 Hz, 1 H),
8.40 (d, J ) 5.0 Hz, 1 H); 13C NMR (CDCl3) δ 14.5 (CH3), 19.2
(CH3Ar), 22.4 (CH2), 113.3 (CH), 121.1 (CH), 122.6 (C), 123.7
(CH), 124.1 (CH), 124.7 (CH), 124.9 (CH), 126.7 (CH), 129.2
(CH), 130.7 (C), 133.8 (CH), 134.7 (C), 137.5 (C), 138.0 (C),
146.6 (CH), 150.7 (C); mp 106-108 °C (benzene). Anal. Calcd
for C22H20N2O2S: C, 70.19; H, 5.35; N, 7.44; S, 8.52. Found:
C, 70.20; H, 5.37; N, 7.53; S, 8.46.
1-(Ben zen esu lfon yl)-3-(5-eth yl-4-m eth yl-2-p yr id yl)in -
d ole (33b). Operating as above, from pyridylindole 8d (2.3
g, 9.9 mmol) was obtained compound 33b (3.6 g, 96%): IR
(KBr) 1363, 1175 cm-1; 1H NMR (CDCl3) δ 1.25 (t, J ) 7.5 Hz,
3 H), 2.37 (s, 3 H), 2.67 (q, J ) 7.5 Hz, 2 H), 7.45 (s, 1 H),
7.20-7.60 (m, 5 H), 7.92 (dm, J ) 7.0 Hz, 2 H), 8.04 (m, 1 H),
8.30 (m, 1 H), 8.42 (s, 1 H); 13C NMR (CDCl3) δ 14.3 (CH3),
18.4 (CH3), 23.4 (CH2), 113.4 (CH), 122.1 (CH), 122.6 (CH),
123.0 (C), 123.8 (CH), 124.3 (CH), 124.9 (CH), 126.7 (CH),
128.8 (C), 129.2 (C), 133.8 (CH), 135.5 (C), 136.3 (C), 137.9
(C), 145.4 (C), 149.0 (CH), 150.2 (C); mp 164-166 °C (benzene).
Anal. Calcd for C22H20N2O2S: C, 70.19; H, 5.35; N, 7.44; S,
8.52. Found: C, 69.91; H, 5.31; N, 7.40; S, 8.30.
Meth yl 3-Eth yl-2-(3-in dolyl)-4-pyr idin ecar boxylate (8j).
A mixture of pyridylindole 33a (3.8 g, 10.2 mmol) and SeO2
(1.7 g, 15.3 mmol) in anhydrous pyridine (40 mL) was stirred
at 95 °C for 12 h. The resulting suspension was filtered
through a Celite pad, and the solution was concentrated. The
residue was dissolved in EtOH (600 mL) and 10% aqueous
NaOH (60 mL). The mixture was heated at reflux for 12 h,
neutralized with 6 N HCl, and concentrated to give a solid,
which was dried at 90 °C under vacuum overnight and
digested with absolute EtOH (3 × 250 mL). The ethanolic
solution was concentrated, and the residue was dissolved in
MeOH (160 mL) and H2SO4. The mixture was stirred at 25
°C for 3 h, poured into ice water, basified with Na2CO3, and
extracted with Et2O. The combined organic extracts were
dried and concentrated, and the resulting oil was chromato-
graphed (AcOEt) to afford pure compound 8j (2.8 g, 60%).
Meth yl 5-Eth yl-2-(3-in dolyl)-4-pyr idin ecar boxylate (8k).
Operating as above, from pyridylindole 33b (2.5 g, 6.6 mmol)
was obtained pure compound 8k (1.2 g, 64%) after purification
by column chromatography (AcOEt).
(1RS,5RS,12SR)-12-Eth yl-1,2,3,4,5,6-h exah ydr o-1,5-m eth -
a n oa zocin o[4,3-b]in d ole (37). A solution of nordasycarpi-
done (254 mg, 1.0 mmol) in anhydrous THF (10 mL) was slowly
added to a stirred slurry of LiAlH4 (380 mg, 10.0 mmol) in
refluxing anhydrous THF (40 mL). After being refluxed for 4
h, the mixture was cooled to 0 °C, and the excess of LiAlH4
was destroyed with 15% aqueous NaOH. The resulting
suspension was filtered through a Celite pad, and the filtrate
was concentrated to give a residue which, after column
chromatography (93:7 Et2O-DEA), afforded pure compound
3752a (80 mg, 33%) as a foam.
c-5-Eth yl-r -2-(3-in d olyl)-c-4-p ip er id in em eth a n ol (38).
A solution of ester 34 (286 mg, 1.0 mmol) in anhydrous THF
(25 mL) was added dropwise to a suspension of LiAlH4 (114
mg, 3.0 mmol) in anhydrous THF (20 mL) at -60 °C. The
reaction mixture was stirred at -30 °C for 90 min and at 25
°C for 2 h. The excess of LiAlH4 was destroyed with 5%
aqueous NaOH (10 mL), and the mixture was extracted with
CH2Cl2. The combined organic extracts were washed with
aqueous Na2CO3, dried, and concentrated to give amino alcohol
38 (245 mg, 95%): IR (CHCl3) 3400-3200, 2930 cm-1; 1H NMR
(CDCl3) δ 0.96 (t, J ) 7.1 Hz, 3 H), 1.30 (m, 2 H), 1.50-1.85
(m, 3 H), 2.01 (m, 1 H), 2.85 (dd, J ) 12.2, 1.7 Hz, 1 H), 3.26
(dd, J ) 12.2, 1.7 Hz, 1 H), 3.56 (m, 2 H), 4.00 (dd, J ) 11.0,
2.7 Hz, 1 H), 7.06-7.21 (m, 3 H), 7.31 (dm, J ) 7.0 Hz, 1 H),
7.73 (dm, J ) 7.0 Hz, 1 H), 8.20 (br s, 1 H); 13C NMR (CDCl3)
δ 12.3 (CH3), 16.6 (CH2), 31.6 (CH2), 36.1 (CH), 42.7 (CH), 48.6
(CH2), 54.0 (CH), 64.8 (CH2), 111.3 (CH), 118.8 (CH), 120.9
(CH), 121.5 (CH), 125.8 (C), 136.3 (C).
1-((Ben zyloxy)ca r b on yl)-c-5-et h yl-r -2-(3-in d olyl)-c-4-
p ip er id in em eth a n ol (39). A suspension of amino alcohol 38
(100 mg, 0.4 mmol), benzyl chloroformate (80 µL, 0.6 mmol),
and K2CO3 (138 mg, 1.0 mmol) in CHCl3 (10 mL) was stirred
at 25 °C for 2 h. Water (10 mL) was added, and the mixture
was stirred for 20 min. The aqueous layer was extracted with
CHCl3, and the combined organic extracts were dried and
concentrated. Column chromatography (9:1 Et2O-DEA) of the
residue afforded pure carbamate 39 (65 mg, 43%): IR (CHCl3)
3400, 2931, 1675 cm-1; 1H NMR (CDCl3) δ 0.91 (t, J ) 7.2 Hz,
3 H), 1.22 (m, 3 H), 1.78-2.10 (m, 3 H), 2.56 (dm, J ) 13.2
Hz, 1 H), 2.88 (t, J ) 13.5 Hz, 1 H), 3.19-3.44 (m, 2 H), 4.14
(dd, J ) 13.5, 5.0 Hz, 1 H), 5.16 (d, J ) 10.0 Hz, 1 H), 5.15 (d,
J ) 10.0 Hz, 1 H), 5.67 (br s, 1 H), 6.86 (s, 1 H), 7.02-7.33 (m,
8 H), 7.62 (d, J ) 7.3 Hz, 1 H), 8.40 (br s, 1 H); 13C NMR
(CDCl3) δ 11.5 (CH3), 22.5 (CH2), 29.2 (CH2), 36.8 (CH), 42.4
(CH2), 49.0 (C), 60.7 (CH2), 67.0 (CH2), 111.4 (CH), 116.1 (C),
119.0 (CH), 120.9 (CH), 121.7 (CH), 125.1 (C), 127.4 (CH),
127.7 (CH), 128.2 (CH), 136.6 (C), 136.7 (C), 155.9 (C); MS,
m/ e (relative intensity) 392 (M+, 10), 257 (100), 189 (41), 167
(20), 144 (36), 143 (55), 142 (24), 140 (69), 130 (70), 118 (25),
117 (30), 116 (20), 115 (27), 105 (22). Under acidic conditions
(CH2Cl2 and a drop of concd HCl, 2 min) carbamate 39 was
converted into the corresponding C2 epimer: IR (CHCl3) 3365,
2950, 1670 cm-1; 1H NMR (CDCl3) δ 0.90 (br, 3 H), 1.25 (m, 2
H), 1.51 (m, 1 H), 1.75 (m, 2 H), 2.10 (br d, J ) 13.5 Hz, 1 H),
2.32 (br s, 1 H), 2.85 (dd, J ) 13.7, 2.3 Hz, 1 H), 3.52 (m, 2 H),
4.11 (m, 1 H), 5.22 (dd, J ) 10.0 Hz, 1 H), 5.23 (dd, J ) 10.0
Hz, 1 H), 5.87 (br s, 1 H), 6.97-7.36 (m, 9 H), 7.53 (br s, 1 H),
8.25 (br s, 1 H); 13C NMR (CDCl3) δ 12.4 (CH3), 16.1 (CH2),
26.8 (CH2), 37.4 (CH), 37.6 (CH), 41.8 (CH2), 48.4 (CH), 65.2
(CH2), 67.3 (CH2), 111.2 (CH), 114.3 (C), 119.4 (CH), 119.6
(CH), 121.8 (CH), 122.7 (CH), 126.3 (C), 128.0 (CH), 128.4
(CH), 136.4 (C), 136.7 (C), 156.0 (C); MS, m/ e (relative
intensity) 392 (M+, 13), 347 (6), 301 (7), 283 (20), 258 (20),
257 (100), 245 (38), 144 (28), 143 (47), 140 (48), 130 (55).
(1R S ,4R S ,5R S )-2-((B e n z y lo x y )c a r b o n y l)-4-e t h y l-
1,2,3,4,5,6-h exa h yd r o-1,5-m et h a n oa zocin o[3,4-b]in d ole
(41). Methanesulfonyl chloride (50 µL, 0.6 mmol) was added
to a solution of alcohol 39 (120 mg, 0.3 mmol) in anhydrous
pyridine (2.5 mL) at 0 °C, and the resulting mixture was
stirred at 25 °C for 1 h. The solvent was evaporated, and the
residue was taken up with CH2Cl2 (50 mL). The solution was
washed with saturated aqueous Na2CO3, dried, and concen-
trated to give crude mesylate 40 (130 mg, 90%): IR (CHCl3)
3000, 1674, 1174 cm-1; 1H NMR (CDCl3) δ 0.95 (t, J ) 7.5 Hz,
3 H), 1.26 (q, J ) 7.5 Hz, 2 H), 1.83-2.32 (m, 2 H), 1.99 (s, 3
Meth yl c-5-Eth yl-r -2-(3-in d olyl)-c-4-p ip er id in eca r box-
yla te (34). A solution of indolylpyridine 8k hydrochloride (5.1
g, 16.1 mmol) in MeOH (30 mL) containing PtO2 (0.3 g) was
hydrogenated at 400 psi at 25 °C. The catalyst was removed
by filtration, and the filtrate was concentrated. The residue
was dissolved in AcOEt and washed with aqueous Na2CO3.
The organic solution was dried and concentrated, and the
residue was chromatographed (9:1 Et2O-DEA) to give in-
dolylpiperidine 3449b (3 g, 65%): IR (NaCl) 3400, 1728 cm-1
;
1H NMR (CDCl3) δ 0.94 (t, J ) 7.5 Hz, 3 H), 1.20 (m, 1 H),
1.75 (m, 1 H), 1.83-2.10 (m, 4 H), 2.81 (m, 1 H), 2.93 (dd, J )
12.5, 1.8 Hz, 1 H), 3.25 (dd, J ) 12.5, 1.8 Hz, 1 H), 3.69 (s, 3
H), 3.96 (dd, J ) 10.0, 4.4 Hz, 1 H), 7.00-7.20 (m, 3 H), 7.30
(dm, J ) 7.0 Hz, 1 H), 7.70 (dm, J ) 6.6 Hz, 1 H), 8.32 (br s,
1 H); 13C NMR (CDCl3) δ 12.2 (CH3), 19.1 (CH2), 29.9 (CH2),
37.6 (CH), 46.2 (CH), 48.6 (CH2), 51.4 (CH3), 53.6 (CH), 111.2
(CH), 119.1 (CH), 119.1 (CH), 119.3 (C), 120.9 (CH), 121.8
(CH), 126.0 (C), 136.3 (C), 175.1 (C).
Meth yl c-3-Eth yl-r -2-(3-in d olyl)-c-4-p ip er id in eca r box-
yla te (36). Operating as above, from indolylpyridine 8j
hydrochloride (5.6 g, 17.7 mmol) and PtO2 (0.3 g) was obtained
pure indolylpiperidine 364e (3.1 g, 60%) after column chroma-
tography (9:1 Et2O-DEA): IR (NaCl) 3450, 1738 cm-1 1H
;
NMR (CDCl3) δ 0.30 (t, J ) 7.5 Hz, 3 H), 1.20 (m, 1 H), 1.50
(m, 1 H), 1.70-2.00 (m, 3 H), 2.36 (m, 1 H), 2.78-2.89 (m, 2
H), 3.27 (ddd, J ) 12.0, 4.3, 2.3 Hz, 1 H), 3.69 (s, 3 H), 4.20 (d,
J ) 2.5 Hz, 1 H), 7.10-7.25 (m, 3 H), 7.38 (dm, J ) 7.0 Hz, 1
H), 7.68 (dm, J ) 6.6 Hz, 1 H), 8.18 (br s, 1 H); 13C NMR
(CDCl3) δ 14.5 (CH3), 17.8 (CH2), 22.9 (CH2), 42.8 (CH), 46.4
(CH), 46.6 (CH2), 51.4 (CH3), 58.6 (CH), 111.2 (CH), 117.9 (C),
118.9 (CH), 119.2 (CH), 120.9 (CH), 121.9 (CH), 125.8 (C),
136.2 (C), 175.2 (C).
(()-Nor d a syca r p id on e. Ester 36 was converted to the
alkaloid nordasycarpidone in 36% yield following the previ-
ously reported procedure.49a

Pd(0)-Catalyzed Heteroarylation of Indolylzincs
J . Org. Chem., Vol. 62, No. 10, 1997 3175
H), 2.68 (dm, J ) 14.0 Hz, 1 H), 2.91 (m, 2 H), 3.76 (t, J ) 9.0
Hz, 1 H), 4.00 (dd, J ) 9.0, 5.1 Hz, 1 H), 4.22 (dd, J ) 14.0,
4.5 Hz, 1 H), 5.15 (d, J ) 10.0 Hz, 1 H), 5.16 (d, J ) 10.0 Hz,
1 H), 5.73 (d, J ) 4.5 Hz, 1 H), 6.83 (s, 1 H), 7.02-7.32 (m, 8
H), 7.61 (d, J ) 7.3 Hz, 1 H), 8.92 (br s, 1 H); 13C NMR (CDCl3)
δ 11.4 (CH3), 23.1 (CH2), 29.2 (CH2), 34.3 (CH), 35.3 (CH3),
39.3 (CH), 42.2 (CH), 67.1 (CH2), 68.3 (CH2), 111.4 (CH), 116.4
(C), 119.5 (CH), 120.3 (CH), 122.1 (CH), 125.3 (C), 127.5 (CH),
to give pure 43 (542 mg, 90%) as a colorless oil: IR (NaCl)
3600, 2958 cm-1; 1H NMR (CDCl3) δ 1.05 (t, J ) 7.3 Hz, 3 H),
1.34 (m, 1 H), 1.62 (m, 1 H), 1.72-2.00 (m, 4 H), 2.08 (dd, J )
13.6, 5.4 Hz, 1 H), 2.20 (dd, J ) 11.4, 2.6 Hz, 1 H), 2.79 (dd, J
) 13.6, 4.8 Hz, 1 H), 2.92 (s, 3 H), 3.28 (s, 3 H), 3.30-3.65 (m,
4 H), 4.29 (t, J ) 5.2 Hz, 1 H), 7.11(m, 3 H), 7.29 (d, J ) 7.2
Hz, 1 H), 7.87 (d, J ) 7.4 Hz, 1 H), 8.22 (br s, 1 H); 13C NMR
(CDCl3) δ 12.3 (CH3), 17.8 (CH2), 33.4 (CH2), 37.2 (CH), 42.5
(CH), 52.3 (CH3), 54.4 (CH3), 56.0 (CH2), 56.8 (CH2), 61.7 (CH),
65.1 (CH2), 104.6 (CH), 111.1 (CH), 118.8 (CH), 119.0 (C), 120.5
(CH), 121.7 (CH), 122.2 (CH), 126.0 (C), 136.6 (C). Anal. Calcd
for C20H30N2O3: C, 69.33; H, 8.73; N, 8.09. Found: C, 69.27;
H, 8.81; N, 7.81.
127.8 (CH), 128.3 (CH), 136.6 (C), 137.0 (C), 155.8 (C).
A
mixture of 40 (100 mg, 0.2 mmol) and freshly sublimed
potassium tert-butoxide (36 mg, 0.3 mmol) in anhydrous THF
(5 mL) was stirred at 25 °C for 2 h, and the solvent was
evaporated under vacuum. The residue was dissolved in
CHCl3, and the solution was washed with water, dried, and
concentrated. Column chromatography (3:2 hexane-AcOEt)
of the residue afforded tetracycle 41 (40 mg, 50%): IR (CHCl3)
3400, 3000, 1675 cm-1; 1H NMR (major rotamer, CDCl3) δ 0.94
(t, J ) 7.0 Hz, 3 H), 1.30 (m, 2 H), 1.70 (m, 1 H), 2.00 (dm, J
) 12.6 Hz, 1 H), 2.16 (dm, J ) 12.6 Hz, 1 H), 2.30 (t, J ) 13.0
Hz, 1 H), 2.34 (m, 1 H), 2.70-2.88 (m, 2 H), 3.72 (dd, J ) 13.0,
5.0 Hz, 1 H), 5.08 (d, J ) 10.0 Hz, 1 H), 5.12 (d, J ) 10.0 Hz,
1 H), 5.42 (m, 1 H), 7.05-7.55 (m, 9 H), 8.12 (br s, 1 H); 13C
NMR (CDCl3) δ 11.4 (CH3), 19.8 (CH2), 24.1 (CH2), 28.4 (CH),
33.0 (CH2), 41.2 (CH), 43.2 (CH2), 44.8 (CH), 67.0 (CH2), 111.2
(CH), 111.7 (C), 118.3 (CH), 119.1 (CH), 121.9 (CH), 126.3 (C),
127.5 (CH), 127.8 (CH), 128.4 (CH), 135.8 (C), 136.7 (C), 156.2
(C); MS, m/ e (relative intensity) 374 (M+, 41), 169 (100), 168
(39), 91 (59); mp 108-110 °C (hexane). Anal. Calcd for
C24H26N2O2: C, 76.97; H, 7.00; N, 7.48. Found: C, 76.81; H,
7.15; N, 7.37.
(E)-cis-1-(2,2-Dim eth oxyeth yl)-3-eth yl-4-[2-(3-in d olyl)-
vin yl]p yr r olid in e (45). Methanesulfonyl chloride (360 µL,
4.6 mmol) was added to a solution of alcohol 43 (800 mg, 2.3
mmol) in anhydrous pyridine (4.0 mL) at 0 °C, and the
resulting mixture was stirred at 25 °C for 90 min. The solvent
was evaporated, and the residue was taken up with CH2Cl2
(40 mL). The solution was washed with saturated aqueous
Na2CO3, dried, and concentrated, and the residue was chro-
matographed (95:5 Et2O-DEA) to give pyrrolidine 45 (260 mg,
35%) as an oil: IR (NaCl) 3450, 1660, 1460 cm-1 1H NMR
;
(CDCl3) δ 0.91 (t, J ) 7.4 Hz, 3 H), 1.34 (m, 1 H), 1.63 (m, 1
H), 1.90 (m, 1 H), 2.40-2.80 (m, 4 H), 2.74 (dd, J ) 12.8, 5.5
Hz, 1 H), 2.91 (td, J ) 11.8, 3.0 Hz, 2 H), 3.39 (s, 6 H), 4.52 (t,
J ) 5.5 Hz, 1 H), 6.14 (dd, J ) 16.0, 8.5 Hz, 1 H), 6.55 (d, J )
16.0 Hz, 1 H), 7.10-7.26 (m, 3 H), 7.38 (dm, J ) 6.8 Hz, 1 H),
7.84 (dm, J ) 6.7 Hz, 1 H), 8.30 (br s, 1 H); 13C NMR (CDCl3)
δ 12.9 (CH3), 26.6 (CH2), 46.8 (CH), 49.4 (CH), 53.4 (CH3), 53.6
(CH3), 58.3 (CH2), 60.7 (CH2), 61.5 (CH), 103.3 (CH), 111.3
(CH), 114.6 (C), 119.8 (CH), 122.1 (CH), 122.4 (CH), 122.9
(CH), 125.4 (CH), 129.5 (CH), 136.7 (C); HRMS calcd for
C20H28N2O2 328.2153, found 328.2153.
Meth yl 1-(2,2-Dim eth oxyeth yl)-c-5-eth yl-r -2-(3-in dolyl)-
c-4-p ip er id in eca r boxyla te (42) was prepared in 81% yield
from piperidylindole 34 following the procedure previously
reported.49a
1-(2,2-Dim eth oxyeth yl)-c-5-eth yl-r -2-(3-in d olyl)-c-4-p i-
p er id in em eth a n ol (43). A solution of ester 42 (650 mg, 1.7
mmol) in anhydrous Et2O (60 mL) was slowly added to a
suspension of LiAlH4 (140 mg, 5.2 mmol) at -60 °C, and the
mixture was stirred at -30 °C for 90 min and at 25 °C for 2 h.
The excess of hydride was destroyed with 15% aqueous NaOH
(10 mL) and water (10 mL), and the suspension was filtered
through a Celite pad. The filtrate was dried and concentrated,
and the residue was chromatographed (98:2 AcOEt-MeOH)
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (project PB94-0214), is gratefully acknowl-
edged. G.P. thanks the DGICYT, Spain, for providing
a postdoctoral fellowship. Thanks are also due to the
Comissionat per a Universitats i Recerca, Generalitat
de Catalunya, for Grant SGR95-0428.
J O962169U