A facile method for the synthesis of polycyclic indole derivatives: The generation and reaction of tungsten-containing azomethine ylides

Article abstract of DOI:10.1021/ja027589h

Treatment of N-(o-alkynylphenyl)imine derivatives with W(CO)₅(L) induces the 5-endo-mode of cyclization of the imine nitrogen onto the electrophilically activated alkyne moiety to afford a novel reactive species, a metal-containing azomethine ylide. [3 + 2] cycloaddition of this ylide species with various electron-rich alkenes proceeds smoothly to give unstable carbene complexes, which in turn undergo 1,2-hydrogen-, alkyl-, and aryl-migration to afford in good yield 6-5-5 tricyclic indole skeletons having an alkyl or an aryl substituent at the 3-position of the indole nucleus. Copyright

Full text of DOI:10.1021/ja027589h

Published on Web 09/10/2002
A Facile Method for the Synthesis of Polycyclic Indole Derivatives: The
Generation and Reaction of Tungsten-Containing Azomethine Ylides
Hiroyuki Kusama, Jun Takaya, and Nobuharu Iwasawa*
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received July 8, 2002
Scheme 2
In this communication, we report a highly useful method for
the construction of polycyclic indole derivatives through the [3 +
2] cycloaddition of novel, metal-containing azomethine ylides
generated from N-(o-alkynylphenyl)imine derivatives and W(CO)5(L).
The indole skeleton is an important core framework for
pharmaceuticals, insecticides, etc., and the development of novel,
concise methods for the construction of polycyclic indole skeletons
is strongly required.1 We have considered the possibility of
generating metal-containing azomethine ylides 2,2 having an indole
nucleus, by the nucleophilic endo-attack of the imine nitrogen of
the N-(o-alkynylphenyl)imine derivatives 1 onto their ortho-alkynyl
group when activated by W(CO)5.3 The [3 + 2] cycloaddition of
such ylides with electron-rich alkenes would afford a novel method
for the construction of the polycyclic indole skeletons found in
various biologically active molecules (Scheme 1).
carbene complex 6a. Finally, 1,2-hydrogen migration to the carbene
occurs, affording the product 4a with regeneration of the pentac-
arbonyltungsten species (Scheme 2).
Scheme 1
As the desired reaction was found to proceed as expected, we
next examined its generality by employing various imine derivatives
and electron-rich alkenes (Table 1). Not only the ketene silyl acetal
3 but also mono- and disubstituted vinyl ethers (7 and 8, entries 1,
2), a trisubstituted enamine (9, entry 3), and 2-methoxyfuran (10,
entry 4) reacted smoothly with the tungsten-containing azomethine
ylide 2a to afford the corresponding tri- or tetracyclic indole
derivatives 11-14 as a mixture of diastereomers in good yield,
even with a 10 mol % amount of W(CO)6.7 Furthermore, N-(o-
ethynylphenyl)imidates 1b and 1c could also be employed as
precursors of a tungsten-containing azomethine ylide reacting with
the ketene silyl acetal 3 in the presence of W(CO)6 under
photoirradiation to give, after acidic workup, the corresponding
indole derivatives 5b and 5c in moderate to good yield. The
successful application of this methodology to such imidates is
notable because the resulting indole derivatives possess an N,O-
acetal, which should facilitate further functionalization of the
products.8
Another novel aspect of this reaction was revealed during
experiments using imine derivatives 15 containing an internal
instead of terminal alkyne moiety. Thus, when a mixture of pentynyl
derivative 15a and tert-butyl vinyl ether 7 was treated with a
stoichiometric amount of W(CO)6 in toluene under photoirradiation
for 1.5 h, the indole derivative 17a, having a propyl group at the
3-position of the indole nucleus, was obtained as the major product,
along with a small amount of a formal [4 + 2] adduct 18a (Table
2, entry 1).9 The formation of 17a clearly indicates that 1,2-
migration of the propyl group adjacent to the carbene carbon
occurred on formation of the unstable carbene intermediate 16a.
Furthermore, this type of 1,2-migration reaction also proceeded
for substrates having a methyl or phenyl substituent on the alkyne
First, the aldimine 1a, derived from o-ethynylaniline and
benzaldehyde, was chosen as the precursor for generating a
tungsten-containing azomethine ylide. Photoirradiation of a mixture
of 1a, ketene silyl acetal 3, and a stoichiometric amount of W(CO)6
in toluene at ambient temperature smoothly promoted the desired
reaction to give a tricyclic indole derivative 5a in 89% yield after
acidic workup (Scheme 2). Furthermore, the same reaction, but
using only a catalytic amount of W(CO)6, also proceeded smoothly,
affording the indole 5a in high yield (10 mol %, 94%; 5 mol %,
78%).4,5 We consider the mechanism of this reaction to be as
follows: photoinduced dissociation of a carbonyl ligand from
W(CO)6 generates a coordinatively unsaturated, pentacarbonyl-
tungsten species, which activates the alkyne moiety of 1a electro-
philically through π-complex formation.6 The 5-endo, nucleophilic
attack of the imine nitrogen onto this activated alkyne moiety
generates a tungsten-containing azomethine ylide 2a, which readily
undergoes [3 + 2] cycloaddition with 3 to give an unstable tungsten
* To whom correspondence should be addressed. E-mail: niwasawa@
chem.titech.ac.jp.
9
11592
J. AM. CHEM. SOC. 2002, 124, 11592-11593
10.1021/ja027589h CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
hν
nucleus, which is the basic structure of pharmaceutically valuable
natural products such as mitomycin C.13
W(CO)6
imine + alkene toluene, room temperature8 product
In summary, we have developed a novel method for the preparation
of polycyclic indole derivatives employing tungsten-containing
azomethine ylides generated from various N-(o-alkynylphenyl)imine
derivatives and W(CO)5(L). These species readily undergo [3 +
2] cycloaddition with various electron-rich alkenes to give syntheti-
cally useful, polycyclic indole derivatives through 1,2-migration
of a hydrogen, alkyl, or aryl substituent of the carbene intermediates.
(2 equiv)
1.5-24 h
Table 1. Reaction with Varioius Imines and Alkenes
Acknowledgment. This research was partly supported by the
Toray Science Foundation and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan. J.T. has been granted a Research
Fellowship of the Japan Society for the Promotion of Science for
Young Scientists.
Supporting Information Available: Preparative methods and
spectral and analytical data of compounds 1-18 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent examples of metal-catalyzed indole syntheses, see: (a) Hegedus,
L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (b) Takeda, A.; Kamijo,
S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662 and references
therein.
(2) For reviews on azomethine ylide, see: (a) Vedejs, E. AdVances in
Cycloaddition; JAI Press: Greenwich, CT, 1988; Vol. 1, pp 33-51. (b)
Kanemasa, S.; Tsuge, O. AdVances in Cycloaddition; JAI Press: Green-
wich, CT, 1993; Vol. 3, pp 99-159. (c) Grigg, R.; Sridharan, V. AdVances
in Cycloaddition; JAI Press: Greenwich, CT, 1993; Vol. 3, pp 161-204.
(d) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 4, pp 1069-1109.
(3) For our results on the generation and reaction of metal-containing carbonyl
ylides, see: Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001,
123, 5814.
a In the presence of MS4A. b Ten equivalents of alkene was employed.
c Acidic workup. d cis:trans ) 86:14. e cis:trans ) 44:56. f cis:trans ) 46:
54. g dr ) 53:47. h dr ) 54:46. i dr ) 71:29. j dr ) 77:23. (See Supporting
Information for details of the stereochemistry.)
Table 2. Reactions with Internal Alkynes
(4) Initial cycloadduct 4a was a mixture of two diastereomers (1:1).
(5) The reaction also proceeded using a catalytic amount of preformed
W(CO)5(thf) at room temperature to afford the same product 5a in 75%
yield after 7 days.
(6) For examples of electrophilic activation of alkynes with group 6 metals,
including the formation of vinylidene complexes, see: (a) McDonald, F.
E.; Chatterjee, A. K. Tetrahedron Lett. 1997, 38, 7687. (b) McDonald, F.
E. Chem.-Eur. J. 1999, 5, 3103. (c) Cutchins, W. W.; McDonald, F. E.
Org. Lett. 2002, 4, 749. (d) Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J.
Am. Chem. Soc. 2002, 124, 5260. (e) Miura, T.; Iwasawa, N. J. Am. Chem.
Soc. 2002, 124, 518 and references therein.
(7) Because the enamine moiety of the products 11 was fairly reactive as a
dipolarophile, [3 + 2] cycloaddition between 11 and the ylide intermediate
2a also proceeded to give 2:1 cycloadducts (see Supporting Information).
(8) For examples of Lewis acid-promoted, nucleophilic substitution reaction
onto N,O-acetals, see: (a) Smith, A. B., III; Kanoh, N.; Ishiyama, H.;
Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254. (b) Sugiura, M.; Hagio,
H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510
and references therein.
(9) The formation of formal [4 + 2] cycloadducts can be explained by Diels-
Alder reaction of the ylide intermediate with tert-butyl vinyl ether.
(10) For examples of the 1,2-migration of hydrogen or silicon groups in group
6 carbene complexes, see: (a) Dorwald, F. Z. Metal Carbenes in Organic
Synthesis; Wiley-VCH: Weinheim, 1999. (b) Iwasawa, N.; Saitou, M.;
Kusama, H. J. Organomet. Chem. 2001, 617-618, 741 and references
therein.
(11) 1,2-Alkyl migration of group 6 metal carbene intermediates is reported
in a few, specific cases. See: (a) Zora, M.; Herndon, J. W.; Li, Y.; Rossi,
J. Tetrahedron 2001, 57, 5097 and references therein. (b) Nagao, K.; Chiba,
M.; Kim, S.-W. Synthesis 1983, 197.
(12) For other examples of 1,2-alkyl migration in carbene complexes of the
late transition metals, see ref 10a. See also: Bly, R. S.; Bly, R. K.; Hossain,
M. M.; Lebioda, L.; Raja, M. J. Am. Chem. Soc. 1988, 110, 7723.
(13) For examples of the synthesis of mitomycin C and its analogues, see: (a)
Remers, W. A.; Iyenger, B. S. Recent Prog. Chem. Synth. Antibiot. 1990,
415. (b) Michael, J. P.; Koning, C. B.; Petersen, R. L.; Stanbury, T. V.
Tetrahedron Lett. 2001, 42, 7513 and references therein.
entry
imine
17/%
18/%
1
2
3
RdPr (15a)
RdMe (15b)
RdPh (15c)
76 (cis:trans ) 22:78)
55 (cis:trans ) 25:75)
61 (cis:trans ) 56:44)
21 (dr ) 94:6)
not detected
14 (dr ) 95:5)
terminus to give the corresponding substituted indole derivatives
in good yield (Table 2, entries 2, 3). In the carbene complexes of
group 6 metals, the facile 1,2-migration of hydrogen or even of a
silicon group is well-precedented;10 however, the 1,2-migration of
an alkyl or an aryl group has only rarely been reported.11,12 The
facile 1,2-migration disclosed herein is probably facilitated by strong
electron donation from the nitrogen atom to the σ* orbital of the
C-R bond in the carbene intermediate 16. As a synthetic method,
this protocol affords, in a single operation, the 6-5-5 tricyclic indole
ring skeleton with a substituent at the 3-position of the indole
JA027589H
9
J. AM. CHEM. SOC. VOL. 124, NO. 39, 2002 11593