C-2/C-3 annulation and C-2 alkylation of indoles with 2- alkoxycyclopropanoate esters

Article abstract of DOI:10.1021/ja067821+

The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported. Both high efficiency and complete stereochemical control were observed in some cases with this annulation process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.

Full text of DOI:10.1021/ja067821+

Published on Web 07/14/2007
C-2/C-3 Annulation and C-2 Alkylation of Indoles with
2-Alkoxycyclopropanoate Esters
Barbora Bajtos, Ming Yu, Hongda Zhao, and Brian L. Pagenkopf*
Contribution from the Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, N6A 1Y2, Canada, and Department of Chemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
Received November 1, 2006; Revised Manuscript Received May 29, 2007; E-mail: bpagenko@uwo.ca
Abstract: The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported.
Both high efficiency and complete stereochemical control were observed in some cases with this annulation
process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four
new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an
intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.
Scheme 1
Introduction
The ubiquitous nature of the indole nucleus in important
bioactive alkaloids fuels research directed at new methods for
the synthesis of indoles and their derivatization. Recent examples
of indole functionalization include asymmetric C-3 Friedel-
Craft reactions,1-3 allylations,4,5 radical couplings,6 arylations,7-9
Michael-additions,10 C-H activation,11 and N-arylations.12 In-
doles containing a fused five-membered ring at the C-2 and
C-3 positions are well represented in nature and include the
penitrems13 and kopsane14 alkaloids.15 In this regard, it has been
reported by Kerr and co-workers that the annulation of indoles
with 1,3-dipoles is a successful strategy for rapidly increasing
the molecular complexity by simultaneous functionalization of
C-2 and C-3, although yields for the annulation products are
generally modest.16 This was of particular interest to us as we
have been developing methods for hetereocycle synthesis based
on the annulation of the related family of 2-alkoxycyclopro-
panoate esters with nitriles,17 pyridines,18 and other reaction
partners.19 We envisioned that the more nucleophilic nature of
the zwitterionic intermediates from these donor-acceptor cy-
clopropanes (i.e., an ester versus a malonate) may also undergo
annulation with indoles, and in this report we describe our
progress in indole annulation and C-2 alkylations.
Results and Discussion
(1) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006,
128, 8156-8157.
Reactions with Indoles. Our standard conditions developed
for the annulation of nitriles with donor-acceptor cyclopropanes
employ polar solvents such as nitromethane combined with a
Lewis acid activator, usually a silyl triflate.17 When the same
conditions were applied to the reaction of indole with cyclo-
propane 1 a clean reaction ensued giving 3 as a single
diastereomer in 78% isolated yield (Scheme 1).20 The structural
assignment of 3 was confirmed by single-crystal X-ray analysis
(Figure 1).21
(2) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am.
Chem. Soc. 2005, 127, 4154-4155.
(3) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am.
Chem. Soc. 2003, 125, 10780-10781.
(4) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 28, 6314-6315.
(5) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005,
127, 4592-4593.
(6) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
(7) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 4972-4973.
(8) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996-
4997.
The reaction scope was then evaluated with indole and
additional cyclopropanes offering different substitution patterns
(9) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148-
13149.
(10) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030-9031.
(11) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060-
1061.
(17) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122-8123.
(18) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang, J.;
Yu, M.; Pagenkopf, B. L. AdV. Synth. Catal. 2006, 2385-2390.
(19) (a) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321-347. (b) Gnad,
F.; Reiser, O. Chem. ReV. 2003, 103, 1603-1624. (c) Reissig, H. Y.;
Zimmer, R. Chem. ReV. 2003, 103, 1151-1196.
(20) Identical results (efficiency and stereoselectivity) were obtained from either
diastereotopic cyclopropane or mixtures. For the other experiments
described in this manuscript mixtures of diastereomers were employed.
(21) Structural assignment of the following compounds was confirmed by single
crystal x-ray crystallography: 3 (Table 1, entry 1), 6, 7, (Table 2, entry 8
and 10, where entry 10 has additional NMR analysis). See Supporting
Information for additional stereochemical proofs.
(12) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
11684-11688.
(13) Naik, J. T.; Mantle, P. G., Sheppard, R. N.; Waight, E. S. J. Chem. Soc.,
Perkin Trans. I 1995, 1121-1125.
(14) Achenbach, H.; Biemann, K. J. Am. Chem. Soc. 1965, 87, 4944-4950.
(15) (a) Cheng, K. F.; Cheung, M. K. J. Chem. Soc., Perkin Trans. I 1996,
1213-1218. (b) Magnus, P.; Gallagher, T.; Brown, P.; Huffman, C. J. Am.
Chem. Soc. 1984, 106, 2105-2114. (c) Kuehne, M. E.; Seaton, P. J. J.
Org. Chem. 1985, 50, 4790-4796.
(16) (a) England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002, 80,
992-998. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A.
J. Org. Chem. 2001, 66, 4704-4709.
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J. AM. CHEM. SOC. 2007, 129, 9631-9634
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A R T I C L E S
Bajtos et al.
Table 2. Scope of Annulations of Substituted Indoles with DA
Cyclopropanes
Figure 1. X-ray structure of 3.
Table 1. Annulation Reactions of Indole with Representative
DA-Cyclopropanes
a Single diastereomer isolated unless noted. b Stereochemistry determined
by analogy to entry 1, Table 1. c Reaction performed at -18 °C. d Stereo-
chemistry determined by NMR analysis. e Reaction performed at 0 °C. f See
Table 1 for relative stereochemistry of other diastereomer. g See ref 21.
h See ref 22. i See ref 23. j Stereochemistry not established.
a Single diastereomer unless noted. b See ref 21. c Stereochemistry
determined by NMR analysis of alcohol derivatives. d Stereochemistry
determined by analogy of entry 10, Table 2. e Stereochemistry not deter-
mined.
(Table 1), including those with the donor oxygen contained
within a pyranose (entry 2, 88%) or furanose ring (entry 3, 58%),
no extra substituents (entry 4, 62%), and one bearing a
quaternary carbon at C-2 (entry 5). In entry 2 the annulation
resulted in the formation of two inseparable diastereomers, and
the stereochemical assignments were made by analysis of the
corresponding alcohols prepared by LiAlH4 reduction.
The scope and generality of this annulation in terms of indole
substitution with a variety of representative DA cyclopropanes
is summarized in Table 2. These results show that more electron
rich 5-methoxy indoles give better yields than 5-iodo indoles
(compare entries 1 and 2, 7 and 8, 13 and 14). However, with
three of the cyclopropanes (entries 7-14) the methoxyindoles
displayed poorer stereoselectivity, whereas the other examples
gave single diastereomers. The reaction efficiency with N-methyl
indole is comparable to the yields obtained within the set for
each unique cyclopropane (entries 3 and 11). Substrates meth-
ylated at C-5 (entries 4 and 15), C-7 (entries 5 and 16) and C-2
and C-3 (entry 18) all gave favorable results.
Figure 2. X-ray structure of 6.
In the examples in Table 2 the only indole-containing products
isolated were those resulting from annulation at C-2/C-3. In
contrast, the use of 3-methyl indole was found to give the C-2
alkylation product 5 (Scheme 2), presumably arising from
migration of a C-3 alkylation intermediate followed by dehydra-
tion.16 Intramolecular cyclization of 5 gave the lactam 6, the
structure of which was confirmed by single-crystal X-ray
crystallography.21
The additional five examples summarized in Table 3 present
C-3 substituted indoles that highlight the compatibility of the
method with additional functional groups offering greater
synthetic potential. In entry 2, a 3-allyl substituent is introduced,
and the C-2 alkylation product was obtained in 74% yield.
Examples 3-6 illustrate indoles with C-3 side chains bearing
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Annulation and Alkylation of Indoles
A R T I C L E S
Figure 3. X-ray structure of entry 8, Table 2.
Scheme 2. Migration and Amide/Aminal Formation
Figure 4. X-ray structure of entry 10, Table 2, showing the trans ring
fusion.
Figure 5. Select NOESY data for diastereomers from entry 6a, Table 2.
Scheme 3. Origin of Stereochemical Control
Table 3. C-2 Alkylation of C-3 Substituted Indoles by DA
Cyclopropane 1
hetereoatoms. Specifically, entries 3 and 4 show that 3-(N-acyl-
2-aminoethyl) and 3-(methoxycarbonylethyl) side chains are
good reaction partners, giving the C-2 alkylated indoles in 60%
and 72% yield, respectively. In entry 5 a 3-(2-hydroxyethyl)
size chain gives the alkylation product in 50% yield, and this
was improved to 63% (entry 6) by acylation of the alcohol.
Origin of Stereochemistry and Stereochemical Assign-
ments. Regarding the stereochemistry of these annulation
products it is important to note that for three of the five classes
of cyclopropanes summarized in Tables 1 and 2, a representative
crystal structure has been obtained to unambiguously assign the
stereochemistry shown (cf., Table 2, entries 1-5; Figure 1,
entries 7-8; Figure 3, entries 10-12; Figure 4). Note that Figure
4 clearly shows the strained 5,5-trans ring fusion. For these
entries and several of the others the stereochemistry was
confirmed or established by extensive NMR analysis (Figure
5), whereas in other cases stereochemistry was assigned on the
basis of analogy or left unassigned. These annulation reactions
occur within a narrow temperature range, and in one case (entry
6, Table 2) complete diastereoselectivity was observed at low
temperature (-18 °C), whereas there was a loss of selectivity
at increased temperature (0 °C). It is also noteworthy that entries
6 and 9 in Table 2 have different relative stereochemistry
compared to the other entries within their cyclopropane class
(entries 1-5, Table 2; entries 7-8, Table 2; respectively) owing
to the unfavorable 1,2-eclipsing interaction between the C2-
methyl and the ester substituent.
From these X-ray structures (Figures 1, 3, and 4) and the
supporting NOESY information it can be seen that attack on
the oxo-carbenium ion intermediate from the indole Re or Si
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A R T I C L E S
Bajtos et al.
face occurred anti to the ester substituent (Scheme 3). Thus,
one of the non-enolizable stereocenters in the original cyclo-
propane (identified with an asterisk) is responsible for control-
ling the relative stereochemistry of up to four new stereocenters
formed in this reaction.
complete stereochemical control was observed in many cases
with this annulation process. A different reaction course was
encountered with 3-substituted indole substrates, and an inter-
vening C-3 to C-2-migration process arose that gives syntheti-
cally useful C-2 alkylated indoles.
Relative energies of four possible diastereomers in three
cyclopropane classes (entry 2, Table 1; entries 6 and 10, Table
2) were calculated using semiempirical(SE)/PM3 and Hartree-
Fock(HF)/3-21G methods. The most stable energy isomers were
the observed annulation products in all cases.24
Acknowledgment. This work was supported in part by
NSERC, Johnson and Johnson, and donors of the American
Chemical Society Petroleum Research fund. We thank Drs.
Vincent Lynch and Michael Jennings for determination of the
X-ray structures, and Prof. Michael A. Kerr for helpful
discussions.
Conclusion
The annulation reaction between various indoles and 2-alkoxy-
cyclopropanoate esters is reported. Both high efficiency and
Supporting Information Available: Experimental procedures
and characterization of all new compounds, CIF files, selected
NOESY and gCOSY data, and SE/PM3 and HF/3-21G energy
information. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) The structural assignment of entry 9, Table 2, was set by analogy to entry
6b, Table 2, that is consistent with the most stable energy product. All
energy values and calculations are in the Supporting Information.
(23) The structural assignments of entries 11 and 12, Table 2, were assigned on
the basis of analogy for the major diastereomer determined by NMR analysis
and single crystal X-ray of entry 10, Table 2, and its relative alcohol
derivatives.
(24) All energy values and calculations are in the Supporting Information.
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