Tandem cyclopropane ring-opening/conia-ene reactions of 2-alkynyl indoles: A [3 + 3] annulative route to tetrahydrocarbazoles

Article abstract of DOI:10.1021/ol102627e

A Zn(NTf₂)₂ catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles

Full text of DOI:10.1021/ol102627e

ORGANIC
LETTERS
2011
Vol. 13, No. 2
220-223
Tandem Cyclopropane Ring-Opening/
Conia-ene Reactions of 2-Alkynyl
Indoles: A [3 + 3] Annulative Route to
Tetrahydrocarbazoles
Huck K. Grover, Terry P. Lebold, and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario, Canada N6A 5B7
makerr@uwo.ca
Received October 29, 2010
ABSTRACT
A Zn(NTf2)2 catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by
a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles. The adducts may be further elaborated to carbazoles.
It is unarguable that indoles rank among the most
important heterocyclic compounds. They remain prime
scaffolds for pharmaceutical drug discovery, and their
prominence in natural products is enormous. As such there
continues to be a large degree of activity devoted to the
efficient chemical elaboration of the benzopyrrole ring
system.1 A subset of the indoles is the carbazoles and their
hydro-derivatives. The preparations of these structures
have seen significant interest among the chemical com-
munity due in part to the carbazoles and their hydro-
derivatives’ presence in naturally occurring and bioactive
Figure 1. Representative carbazole natural products.
compounds.2 Figure 1, for example, shows a sampling of
carbazole natural products isolated in recent years.3 Given
our recent interest in the synthesis of carbazole natural
products,4 we were compelled to explore new ways to
access this ubiquitous ring system. Herein we present a
one pot, [3 + 3] annulative route to tetrahydrocarbazoles
(and subsequently carbazoles) via a tandem cyclopropane
ring-opening/Conia-ene cyclization of 2-alkynyl indoles.5
Our idea for the synthesis of tetrahydrocarbazoles in this
manner evolved from a general strategy shown in Scheme
1, which was fostered by our longstanding interest in the
chemistry of donor-acceptor cyclopropanes6 and their use
(1) For reviews on the synthesis and functionalization of indoles, see:
(a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (b)
Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (c) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (d) Sundberg, R. J. Indoles;
Academic: New York, 1996.
(2) Kno¨lker, H.-J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
(3) (a) Clausamines: Ito, C.; Katsuno, S.; Ruangrungsi, N.; Furukawa,
H. Chem. Pharm. Bull. 1998, 46, 344. (b) Staurosporine: Satoshi, O.;
Yuzuru, I.; Atushi, H.; Akira, N.; Juichi, A.; Hisae, T.; Yoko, T.; Rokurou,
M. J. Antibiot. 1977, 30, 275. (c) Aflavazole: TePaske, M. R.; Gloer, J. B.;
Wicklow, D. T.; Dowd, P. F. J. Org. Chem. 1990, 55, 5299.
(4) Lebold, T. P.; Kerr, M. A. Org. Lett. 2008, 10, 997. (b) Lebold,
T. P.; Kerr, M. A. Org. Lett. 2007, 9, 1883.
10.1021/ol102627e  2011 American Chemical Society
Published on Web 12/16/2010

by the fact that it is the harder, oxophilic Lewis acids which
are usually required for chelation with the geminal diester
moiety on the cyclopropane, while softer metals are usually
most successful in the Conia-ene reaction.
Scheme 1
.
Generalized Tandem Ring-Opening/Conia-ene
Process
Our study began with cyclopropane 12a (chosen for its
well-known reactivity in nucleophilic ring-opening chemis-
try) and indole 13a. Knowledge gained from our previous
work allowed us to arrive quickly at optimal reaction
conditions (Table 1); in fact, Zn(NTf2)2 at a loading of 5
Table 1. Optimization Studies
indole
entry (equiv)
time yield
(h) (%)
in the synthesis of heterocycles.7 Any nucleophilic moiety
(1) with a tethered alkynyl group could, in principle,
participate in a two-step sequence involving a nucleophilic
cyclopropane ring-opening reaction to yield a pendant
malonate and a subsequent Conia-ene8 reaction of the
malonate with the acetylenic group. Recently, we reported
successful examples of this process where the nucleophile
was an amino or a hydroxyl group resulting in the formation
of piperidines5a and tetrahydropyrans5b (Scheme 1). Given
that we have shown that indoles may nucleophilically open
cyclopropanediesters,9 we were curious whether indoles,
bearing an acetylene at the 2-position, would undergo the
tandem process described above with a net synthesis of
tetrahydrocarbazoles in what would be a formal [3 + 3]
cycloaddition.
catalyst
solvent
Sc(OTf)3 (10 mol %),
then ZnBr2 (3 equiv),
NEt3 (1 equiv)
Zn(NTf2)2 (20 mol %) benzene
Zn(NTf2)2 (10 mol %) benzene
Zn(NTf2)2 (5 mol %)
Zn(NTf2)2 (5 mol %)
Zn(NTf2)2 (5 mol %)
Zn(NTf2)2 (5 mol %)
1
2
3
4
5
6
7
1.1
1.1
1.4
1.4
1.4
1.4
1.4
benzene
1.5 63
2.0 84
2.0 87
4.0 88
24.0 n/a
23.0 84
benzene
toluene
CH2Cl2
ClCH2CH2Cl 1.5 84
mol % in refluxing dichloroethane emerged as the reaction
conditions of choice, giving tetrahydrocarbazole 15a in an
84% isolated yield (entry 7).
The main challenges for the implementation of the strategy
shown in Scheme 1 are twofold: (i) The nucleophiles’
reactivity must be orthogonal to that of the acetylenic group
(i.e., they must not react with each other), and (ii) a Lewis
acid must be found which can activate the cyclopropane
toward ring opening and also activate the acetylene in the
Conia-ene process. This last issue is somewhat complicated
(8) Thermal: (a) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1. Au
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Chem., Int. Ed. 2004, 43, 5350. (e) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. Pd mediated: (f) Corkey,
B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764. (g) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. In mediated: . (h)
Hatakeyama, S. Pure Appl. Chem. 2009, 81, 217. (i) Itoh, Y.; Tsuji, H.;
Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am.
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Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244. (k)
Tsuji, H.; Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura,
E. Angew. Chem., Int. Ed. 2007, 46, 8060. Cu/Ag cocatalyzed: (l) Deng,
C.-L.; Zou, T.; Wang, Z.-Q.; Song, R.-J.; Li, J.-H. J. Org. Chem. 2009, 74,
412. (m) Deng, C.-L.; Song, R.-J.; Guo, S.-M.; Wang, Z.-Q.; Li, J.-H. Org.
Lett. 2007, 9, 5111. Ni mediated: (n) Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang,
D. Org. Lett. 2005, 7, 2185. Ti mediated: (o) Kitigawa, O.; Suzuki, T.;
Inoue, T.; Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470. Co
mediated: (p) Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999,
55, 5113. (q) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org.
Chem. 1996, 61, 2699. (r) Cruciani, P.; Aubert, C.; Malacria, M. Tetrahedron
Lett. 1994, 35, 6677. Zn mediated: . (s) Morikawa, S.; Yamazaki, S.;
Tsukada, M.; Izuhara, S.; Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2007,
72, 6459. (t) Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke,
K.; Kakiuchi, K. J. Org. Chem. 2006, 71, 3540. (u) Nakamura, M.; Liang,
C.; Nakamura, E. Org. Lett. 2004, 6, 2015. (v) Cavicchioli, M.; Marat, X.;
Monteiro, N.; Hartmann, B.; Balme, G. Tetrahedron Lett. 2002, 43, 2609.
(w) Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845. Cu mediated: .
(x) Montel, S.; Bouyssi, D.; Balme, G. AdV. Synth. Catal. 2010, 352, 2315.
(9) (a) Harrington, P. E.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949.
(b) Kerr, M. A.; Keddy, R. G. Tetraheron Lett. 1999, 5671. (c) England,
D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66,
4704.
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8414.
(6) For reviews on donor-acceptor cyclopropanes, see: (a) Carson,
C. A.; Kerr, M. A. Chem. Soc. ReV. 2009, 38, 3051. (b) Rubin, M.; Rubina,
M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117. (c) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321. (d) Reissig, H.-U.; Zimmer, R. Chem.
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M. A. J. Am. Chem. Soc. 2008, 130, 4196. (b) Carson, C. A.; Kerr, M. A.
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Org. Lett., Vol. 13, No. 2, 2011
221

It should be noted that benzene and dichloromethane were
also effective media for the reaction; however, dichlo-
romethane required extended reaction times. As expected,
the harder Lewis acid Sc(OTf)3 was effective in the ring-
opening step but required the addition of NEt3 and excess
ZnBr2 to effect the Conia-ene ring closure (entry 1).
With optimal conditions in hand, we set out to investigate
the substrate scope. Gratifyingly, a variety of cyclopropanes
underwent the desired cyclization in excellent yield. Figure
2 shows the results of several indoles (varying in the
diminished yield; this is due the absence of a π-donor group
vicinal to the geminal diester moiety. Typically harder Lewis
acids, not compatible with Conia-ene chemistry, are required
to activate this cyclopropane successfully. If the cyclopropane
was used optically enriched, this was transferred with
stereochemical fidelity to the adducts (15a and 15k).
Figure 3 shows a short array of products using benzenoid-
substituted indoles. The purpose of this study was to see
Figure 3. Use of substituted indoles.
whether electron-withdrawing groups on the benzenoid ring
would attenuate the indoles’ nucleophilicity. We were happy
to observe that the presence of a trifluoromethyl or car-
bomethoxy moiety not only was tolerated but also produced
the adducts in superb yields.
We next investigated the effects of substitution on the
2-alkynyl moiety in the hopes of furthering functional group
inclusion for application to the synthesis of complex target
molecules. To our disappointment, we found that internal
alkynes (Figure 4) produced solely the acyclic products (14b,
14c, 14d), despite an exhaustive study of reaction conditions.
In addition to the formation of 14d, an additional 25% of
Figure 2. Substrate scope.
N-substitution) with a variety of 1,1-cyclopropanediesters.
As seen from the table, there was a wide tolerance for the
substituents on the cyclopropanediester. Both electron-rich
and electron-poor aryl substituents performed with equal
aplomb. Heterocycles were also well tolerated, although the
furan substituted adduct (15g) decomposed somewhat under
the reaction conditions. Both styrenyl and vinyl cyclopro-
panediesters gave good yields of products. As expected, the
parent cyclopropane (no substituent) produced 15l in greatly
Figure 4. Cyclization attempts using internal alkyne.
222
Org. Lett., Vol. 13, No. 2, 2011

15m was isolated, presumably via in situ desilylation and
subsequent ring closure. To overcome this drawback in
reaction scope, a methyl ester was used as the alkyne
substituent. With the ester present we obtained product 15v
in a 95% yield. Tetrahydrocarbazole 15v is most likely the
product of a conjugate addition reaction rather than a Conia-
ene cyclization. The ability to form 15v, however, allows a
strategy for further structural elaboration. We believe the
geometry of the alkene in 15v to be as shown based on the
absence of an NOE correlation, which is always apparent
between the indole N-methyl group and a proximal vinyl
hydrogen.
Scheme 3. Labeling Study To Elucidate Mechanism
A plausible mechanistic description is shown in Scheme
2 where initial coordination of diesters allows nucleophilic
formed, leading to product 22, the identity of which was
determined by comparison to the NOE spectra of the fully
protonated species. In 22, the relevant NOE observed in the
protio species 15a was absent, leading us to assign the olefin
geometry as shown. Since the deuterium was determined to
be cis to the N-methyl group on the indole, pathway a must
be operational for this process.
Scheme 2. Plausible Mechanism
To show that the adducts could be elaborated, 15a was
subjected to Krapcho dealkoxycarbonylation to yield the
monoester 23. Unsurprisingly, conjugation of the alkenyl
moiety occurred under these conditions, leading to a mixture
of products. Treatment of this mixture (23) with catalytic
palladium on charcoal in refluxing mesitylene resulted in
dehydrogenation to the carbazole (24) (Scheme 4); this
ring opening of the cyclopropanediester. Following the ring
opening, it is postulated that the Conia-ene ring closure could
occur through one of two mechanistic paths. Pathway a
occurs by having the Zn species coordinate to not only the
alkyne but also the oxygen of the ester (17) as well. This
arrangement sets the alkynyl hydrogen of the starting material
cis to the N-methyl group of the indole in the intermediate
product (18). Alternatively, pathway b has the Zn species
coordinate specifically to the alkyne (19) and has the malonic
nucleophile perform an attack on the activated alkyne anti
to the zinc. The end result would see the alkenylzinc moiety
cis to the N-methyl group of the indole in the penultimate
intermediate (20).
It should be noted that the nature of the Conia-ene ring
closure (specifically the role of the metal) is somewhat
ambiguous. Our depiction in Scheme 2 is reminiscent of that
shown by Toste in 2004 in which the role of the gold catalyst
in a Conia-ene ring closure was probed.8e In Toste’s case,
the two options put forth are gold activation similar to
pathway b in Scheme 2 and a carbometalation very much
similar to pathway a.
Scheme 4. Elaboration to Carbazoles
should be useful, given the ubiquity of carbazole natural
products.
In summary, we have successfully developed an efficient
method for producing substituted tetrahydrocarbazoles using
a tandem nucleophilic ring-opening Conia-ene reaction.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding. We
are grateful to Mr. Doug Hairsine of the University of
Western Ontario Mass spectrometry facility for performing
MS analyses. T.P.L. is a CGS-D awardee.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We were able to shed some light on the mechanistic
situation in a manner similar to that of Toste (see Scheme
3). The hydrogen on the alkyne compound 13a was replaced
with a deuterium (21) by deprotonation and quenching with
D2O. A standard reaction with compound 12a was per-
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