Rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles

Article abstract of DOI:10.1021/ol9028385

Chemical Equation Presentation An unusual rhodium carbenoid approach for introduction of 4-substltuted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles is described. These studies show that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids to react at the vinylogous position of the carbenoid rather than at the carbenoid center

Full text of DOI:10.1021/ol9028385

ORGANIC
LETTERS
2010
Vol. 12, No. 5
924-927
Rhodium Carbenoid Approach for
Introduction of 4-Substituted
(Z)-Pent-2-enoates into Sterically
Encumbered Pyrroles and Indoles
Yajing Lian and Huw M. L. Davies*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia
hmdaVie@emory.edu
Received December 8, 2009
ABSTRACT
An unusual rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles
is described. These studies show that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids to react at the vinylogous position
of the carbenoid rather than at the carbenoid center.
Highly functionalized indoles and pyrroles are constituents
of a variety of natural products and pharmaceutical targets.1
The development of novel strategies to these targets is still
an active field of organic synthesis.2 In particular, the
selective introduction of functionalized alkyl groups into the
heterocycles has drawn considerable attention.3 In this paper
we describe a rhodium carbenoid approach for introduction
of 4-substituted (Z)-pent-2-enoates into sterically encumbered
pyrroles and indoles.
For some time, we have explored the reactions of rhodium-
stabilized donor/acceptor carbenoids with pyrroles and in-
doles.4 The rhodium-catalyzed reaction of vinyldiazoacetates
with N-Boc-pyrroles offers a direct entry into tropanes by
means of a tandem cyclopropanation/Cope rearrangement.5
When N-methylpyrroles are used as substrates, alkylation
occurs rather than cyclopropanation.5a The reaction of
aryldiazoacetates with N-Boc-pyrrole results in double cy-
clopropanation of the pyrrole rings.6 Similarly, reaction of
N-Boc-indoles with aryldiazoacetates causes double cyclo-
propanation of the benzene ring to occur.6 However, if the
indole is 6-substituted, C-H functionalization of a side-chain
becomes the preferred reaction.6 Francis has shown that
vinyldiazoacetates will alkylate 3-alkylindoles and that this
can be used to selectively derivatize proteins.7 Rainier has
reported an unusual reaction between vinylcarbenoids and
(1) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach; John Wiley& Sons Inc.: Chichester, 2009. (b) Barton, D. H. R.;
Nakanishi, K.; MethCohn, O.; Kelly, J. W. ComprehensiVe Natural Products
Chemistry; Pergamon Press: Oxford, 1999.
(2) For representative reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem.
ReV. 2005, 105, 2873. (b) Maryanoff, B. E.; Zhang, H.; Cohen, J. H.; Turchi,
I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431. (c) Saracoglu, N. Top.
Heterocycl. Chem. 2007, 11, 1.
(3) For recent achievements, see: (a) Arai, T.; Yokoyama, N. Angew.
Chem., Int. Ed. 2008, 47, 4989. (b) Poulsen, T. B.; Jørgensen, K. A. Chem.
ReV. 2008, 108, 2903. (c) Trost, B. M.; Mu¨ller, C. J. Am. Chem. Soc. 2008,
130, 2438. (d) Evans, D. A.; Fandrick, K. R.; Song, H.; Scheidt, K. A.;
Xu, R. J. Am. Chem. Soc. 2007, 129, 10029. (e) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (f) Sun, Y.; Li, N.; Zheng,
Z.; Liu, L.; Yu, Y.; Qin, Z.; Fu, B. AdV. Synth. Catal. 2009, 351, 3113.
(4) Davies, H. M. L.; Hedley, S. J. Chem. Soc. ReV. 2007, 36, 1109.
(5) (a) Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991,
56, 5696. (b) Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.;
Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095. (c)
Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312.
(6) Hedley, S. J.; Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.;
Davies, H. M. L. J. Org. Chem. 2006, 71, 5349.
10.1021/ol9028385  2010 American Chemical Society
Published on Web 02/01/2010

thioindoles, which generates indolinethiones by means of
ylide formation, followed by proton transfer and a [3,3]-
sigmatropic rearrangement.8
Rhodium-stabilized vinylcarbenoids could in principle
exist in two possible conformations, s-cis (conformer A) and
s-trans (conformer B) (Figure 1). The catalyst face is
One of the more unusual features of the chemistry of
vinylcarbenoids is the occurrence of vinylogous reactivity when
the vinyl group is unsubstituted.5a,9 The reaction with pyrroles
leads to 4-pyrrolylbutenoates,5a and this reactivity can be
enhanced by using either polar solvents,5a bulky esters on
the carbenoid,9 or diruthenium catalysts.10 In this paper we
describe a new approach to enhance vinylogous reactivity,
which led to a practical method to functionalize indoles and
pyrroles.
The impetus for this investigation was an unexpected result
observed during studies on the reaction of N-methylpyrroles
with vinyldiazoacetates (Scheme 1). The Rh2(esp)2-catalyzed11
Figure 1. Conformations of vinylcarbenoids.
Scheme 1
considered to be a steric wall, but neither conformer A nor
conformer B would be expected to have significant interfer-
ence with this wall. Few studies have been carried out to
determine which of the two conformers is likely to be the
most reactive form in rhodium vinylcarbenoid chemistry.14
The formation of 5 as the (Z)-isomer is indicative that the
vinylogous reactivity occurs through conformer B. This leads
us to propose that the highly substituted pyrrole 4 is sterically
too crowded for an effective reaction at the carbenoid center
and leads to competing vinylogous reactivity, occurring
through conformer B. We then became intrigued with the
concept that the vinylogous reactivity could be enhanced if
the (Z)-vinylcarbenoid was used as substrate. In this case,
the s-cis conformation of the carbenoid (conformer C) would
be expected to interfere with the catalyst wall, and so the
(Z)-vinylcarbenoid would be expected to preferentially exist
in the s-trans conformation (conformer D).
decomposition of (E)-vinyldiazoacetate 2 with N-methylpyrrole
1 (6 equiv) afforded the expected aromatic substitution product
3. This is a well-precedented type of product from the reaction
of carbenoids with electron-rich heterocycles.12
To probe the role of the vinylcarbenoid geometry, the
reactions of N-methylpyrrole (1) and 1,2,5-trimethylpyrrole (4)
were repeated using the (Z)-vinyldiazoacetate 7 as the carbenoid
source (Scheme 2). The reaction with N-methylpyrrole still
When the reaction was repeated with the more bulky substrate
1,2,5-trimethylpyrrole 4, an unexpected product 5 was formed
(28% yield) in addition to the expected aromatic substitution
product 6. Two features of this reaction were intriguing. First,
5 was formed exclusively as the Z isomer. Second, 5 is the
type of product that would be generated from attack at the
vinylogous position of the vinylcarbenoid.9 This type of
reactivity profile had not been seen previously in rhodium-
catalyzed reactions of vinylcarbenoids with a substituent at the
vinyl terminus.13 Therefore, we decided to explore further this
unusual reactivity.
Scheme 2
(7) (a) Antos, J. M.; Francis, M. B. J. Am. Chem. Soc. 2004, 126, 10256.
(b) Antos, J. M.; McFarland, J. M.; Iavarone, A. T.; Francis, M. B. J. Am.
Chem. Soc. 2009, 131, 7558.
(8) (a) Boyarskikh, V.; Nyong, A.; Rainier, J. D. Angew. Chem., Int.
Ed. 2008, 47, 5374. (b) Nyong, A. M.; Rainier, J. D. J. Org. Chem. 2005,
70, 746. (c) Novikov, A. V.; Kennedy, A. R.; Rainier, J. D. J. Org. Chem.
2003, 68, 993.
(9) Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem.
1994, 59, 4535
.
(10) Sevryugina, Y.; Weaver, B.; Hansen, J.; Thompson, J.; Davies,
H. M. L.; Petrukhina, M. A. Organometallics 2008, 27, 1750.
(11) Rh2(esp)2: Bis[rhodium(RR, R′,R′-tetramethyl-1,3-benzene-
dipropionic acid)]. For a leading reference, see: Zalatan, D. N.; Bois,
J. D. J. Am. Chem. Soc. 2009, 131, 7558.
(12) Muthusamy, S.; Gnanaprakasam, B. Tetrahedron Lett. 2008, 49, 475.
Org. Lett., Vol. 12, No. 5, 2010
925

preferentially formed the normal alkylation product 8, but a trace
of the vinylogous substitution product 9 was also formed. In
contrast, the reaction with 1,2,5-trimethylpyrrole 4 led to the
formation of the vinylogous substitution product 5 in 78% yield,
exclusively as the Z isomer without any detectable amount of
the product derived from reaction at the carbenoid center. The
reaction could also be conducted with some of the more standard
catalysts such as rhodium acetate and rhodium trifluoroacetate,
but the highest yield of 5 was obtained using Du Bois’
Rh2(esp)2.11
When this reaction was extended to N-methylindole 14,
the standard substitution product 15 was isolated in 78% yield
(Scheme 4). This result is consistent with the data obtained
Scheme 4
Normally, the reaction of vinylcarbenoids at the carbenoid
site is very sensitive to steric crowding,15 and this may
explain why vinylogous reactivity is more favored in a
crowded substrate. Consequently, we explored if a double
alkylation process was feasible. The Rh2(esp)2-catalyzed
reaction using 5 equiv of the (Z)-vinyldiazoacetate 7 with
1,2,5-trimethylpyrrole (4) generated the bis-alkylated product
10 in 86% yield (Scheme 3). 10 was formed as a mixture of
from the pyrrole derivatives that a sterically crowded
aromatic systems is essential to achieve highly selective
vinylogous reactivity.
The vinylogous reaction can be applied to indoles as long as
they are sufficiently crowded. Representative examples are
shown in Figure 3. The reactions could be conducted at
Scheme 3
diastereomers, as would be expected for this type of reaction
conducted with an achiral catalyst.
The vinylogous reactions of diazoacetate 7 are applicable to
other sterically crowded pyrroles, forming the alkylated pyrroles
11-13 in 59-87% yield (Figure 2). Not only N-protected
Figure 3. Vinylogous reaction of 7 with indoles.
temperatures as low as -45 °C, presumably because of the
greater nucleophilicity of indoles over pyrroles.17 Both unpro-
tected and protected (methyl or benzyl) 2-methylindoles af-
forded the vinylogous products in good yields. Typically,
substitution at the 2-position of the indole is necessary for the
vinylogous reactivity to occur. However, a similar effect can
be achieved when a bulky substituent is introduced at the
4-position of the indole, as illustrated in the formation of 18.
To further extend this transformation to less crowded indoles,
the use of a (Z)-vinyldiazoacetate approach combined with a
complementary strategy for enhancing vinylogous reactivity was
examined. Increasing the size of the ester group enhances
vinylogous reactivity,8 and so, tert-butyl (Z)-vinyldiazoacetate
22 was prepared and tested (Scheme 5). The Rh2(esp)2-catalyzed
Figure 2. Vinylogous reaction of 7 with pyrroles.
pyrroles undergo the alkylation with vinyldiazoacetate 7, but
also an N-unprotected pyrrole was able to furnish the vinylogous
product 11. The regiochemistry in the formation of 12 and 13
reveals that N-TIPS is acting as a bulky protecting group,16
blocking the reactivity at the 2-position and forcing the reaction
to occur at the 3-position to form 13.
926
Org. Lett., Vol. 12, No. 5, 2010

for Transformative Chemical Research on Stereoselective
C-H Functionalization (CHE-0943980) for a sample of
Rh2(esp)2.
Scheme 5
Supporting Information Available: Full experimental
data for the compounds described in the paper. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9028385
(13) Vinylogous reactivity of substituted vinylcarbenoids has been
observed with silver catalysis and diruthenium catalysis. For examples, see:
(a) Yue, Y.; Wang, Y.; Hu, W. Tetrahedron Lett. 2007, 48, 3975. (b) Ref
9.
reaction of 22 with 6.0 equiv of N-methylpyrrole 1 caused a
major change in the reaction outcome. No evidence of the
regular alkylation product was observed, and the vinylogous
product 23 could be isolated in 50% yield.
In summary, these studies demonstrate that (Z)-vinylcar-
benoids have a greater tendency than (E)-vinylcarbenoids
for reaction at the vinylogous position of the carbenoid rather
than at the carbenoid center. This type of reactivity leads to
an effective method for the functionalization of pyrroles and
indoles.
(14) The models used to describe the reactions of vinylcarbenoids
have assumed that the reaction occurs through a particular carbenoid
conformation. For example, the combined C-H activation/Cope
rearrangement and a [3 + 2] cycloaddition have been proposed to involve
a reaction where the vinylcarbenoid is in the s-cis conformation. For
details, see: (a) Davies, H. M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126,
10862. (b) Davies, H. M. L.; Xiang, B.; Kong, N.; Stafford, D. G. J. Am.
Chem. Soc. 2001, 123, 746. Recently, we proposed that the [3 + 2]
annulation of indoles by vinylcarbenoids may occur via the s-trans
conformation of the vinylcarbenoid. For details, see: (c) Lian, Y.; Davies,
H. M. L. J. Am. Chem. Soc. 2010, 132, ASAP.
(15) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1. (b)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(16) For a leading review, see: Jolicoeur, B.; Chapman, E. E.; Thompson,
A.; Lubell, W. D. Tetrahedron 2006, 62, 11531.
Acknowledgment. This research was supported by the
National Institutes of Health (GM080337). We thank Prof.
Justin Du Bois (Stanford University) through the NSF Center
(17) Mayer, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
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