Rh2(S-biTISP)2-catalyzed asymmetric functionalization of indoles and pyrroles with vinylcarbenoids

Article abstract of DOI:10.1021/ol300632p

Asymmetric functionalization of N-heterocycles by vinylcarbenoids in the presence of catalytic amounts of Rh₂(S-biTISP)₂ has been successfully developed. This bridged dirhodium catalyst not only selectively enforces the reaction to o

Full text of DOI:10.1021/ol300632p

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1934–1937
Rh2(S-biTISP)2-Catalyzed Asymmetric
Functionalization of Indoles and Pyrroles
with Vinylcarbenoids
Yajing Lian and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta,
Georgia 30322, United States
hmdavie@emory.edu
Received March 12, 2012
ABSTRACT
Asymmetric functionalization of N-heterocycles by vinylcarbenoids in the presence of catalytic amounts of Rh2(S-biTISP)2 has been successfully
developed. This bridged dirhodium catalyst not only selectively enforces the reaction to occur at the vinylogous position of the carbenoid but also
affords high levels of asymmetric induction.
Asymmetric methods for the selective functionalization
of indoles or pyrroles are in great demand1 because these
electron-rich heterocycles are constituents of many natural
products and pharmaceutical agents.2 The most widely
used approach has been the conjugate addition of hetero-
cycles to R,β-unsaturated carbonyl compounds using
chiral transition-metal catalysts3 or organocatalysts.4
An alternative approach has been to use carbenoid inter-
mediates.5 We have demonstrated that chiral 4-substituted
indoles can be generated in a cascade sequence involving a
combined CÀH functionalization/Cope rearrangement.5a
Fox5b and Hashimoto5g have shown that the electro-
philic substitution reactions of methyl 2-diazoalkanoate
generate chiral 3-substituted indoles with high levels of
asymmetric induction. In this paper, we describe an alter-
native carbenoid approach for the asymmetric synthesis
of 3-substituted indoles by exploiting the vinylogous
electrophilic character of vinylcarbenoids (Scheme 1).
This transformation occurs with substrates that are too
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1060. (b) DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M.
J. Am. Chem. Soc. 2011, 133, 1650. (c) Davies, H. M. L.; Hedley, S. J.
Chem. Soc. Rev. 2007, 36, 1109. (d) Johansen, M. B.; Kerr, M. A. Org.
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r
10.1021/ol300632p
Published on Web 03/27/2012
2012 American Chemical Society

sterically crowded to react with the carbenoid site of the
vinylcarbenoid.
the catalysts in our study produced the alkylation product
6 in excellent yields (up to 93%). The two most versatile
chiral catalysts for the asymmetric transformations of
donor/acceptor carbenoids, Rh2(S-PTAD)4 (7) and Rh2-
(S-DOSP)4 (8), failed to give high levels of asymmetric
induction in the test reaction. The more bulky catalysts
Rh2(S-TISP)4 (9) gave slightly higher enantioselectvity
than Rh2(S-DOSP)4 (26% ee vs 10% ee), but the bulky
and conformationally constrained catalyst Rh2(S-biTISP)2
(10)9 gave 0% ee.
Scheme 1
We have recently described the functionalization of
electron-rich heterocycles using 2-diazo-3-pentenoates as
the carbenoid source.6 These reactions proceed by attack
of the heterocycles at the vinylogous position of the
vinylcarbenoid.6,7 Vinylogous reactivity of the carbenoid
is more pronounced in (Z)-vinylcarbenoids than (E)-
vinylcarbenoids.6 For example, the reaction of (Z)-2-
diazopentenoate 1a with 1,2,5-trimethylpyrrole (2) gave
Figure 1. Chiral dirhodium catalysts.
Scheme 2
Table 1. Asymmetric Alkylation of Indole 5 by
(Z)-Vinyldiazoacetate 1a
the vinylogous alkylation product 3 in 78% yield exclu-
sively (Scheme 2), whereas the major product from the
reaction with the (E)-2-diazopentenoate 1b and 2 was 4,
derived from electrophilic attack at the carbenoid center.6
The objective of the current study was to identify suitable
chiral catalysts that enable the application of this unusual
vinylogous reactivity to the asymmetric functionalization
of electron-rich heterocycles.
entry
catalyst
yield (%)
ee (%)a
1
2
3
4
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-TISP)4
Rh2(S-biTISP)2
88
93
84
90
48
À10
À26
0
a Negative value indicates opposite asymmetric induction.
We initiated this study by exploring the enantioinduc-
tion by some of the standard chiral dirhodium catalysts
that have been developed for the reactions of vinyldiazoa-
cetates (Figure 1).8 The alkylation of indole 5 with (Z)-
vinyldiazoacetate 1a was used as the standard screening
reaction, and the results are summarized in Table 1. All of
Having failed to achieve high levels of asymmetric
induction with the (Z)-vinyldiazoacetate 1a, we decided
to re-explore the possibility of using (E)-vinyldiazoacetate
1b as an effective reagent for vinylogous reactivity.
Recently, we calculated that the s-cis configuration
(conformer B) of (Z)-vinyldiazoacetates is sterically
unfavorable.10 In contrast, (E)-vinyldiazoacetates exist as
equilibrating mixture of s-trans and s-cis conformers
(conformers C and D) (Figure 2). On the basis of the
reactivity patterns we have observed to date,6,10 we pro-
pose that carbenoids in s-trans configurations (conformers
A and C) are more likely to display vinylogous reactivity
than carbenoids in s-cis configurations (conformers Band D).
(6) Lian, Y.; Davies, H. M. L. Org. Lett. 2010, 12, 924.
(7) For other examples of vinylcarbenoids displaying electrophilic
character at the vinylogous position, see: (a) Davies, H. M. L.; Saikali,
E.; Clark, T. J.; Chee, E. H. Tetrahedron Lett. 1990, 31, 6299. (b) Davies,
H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696. (c)
Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem.
1994, 59, 4535. (d) Davies, H. M. L.; Yokota, Y. Tetrahedron Lett. 2000,
41, 4851. (e) Yue, Y.; Wang, Y.; Hu, W. TetrahedronLett. 2007, 48, 3975.
(f) Sevryugina, Y.; Weaver, B.; Hansen, J.; Thompson, J.; Davies,
H. M. L.; Petrukhina, M. A. Organometallics 2008, 27, 1750. (g) Hansen,
J. H.; Davies, H. M. L. Chem. Sci. 2011, 2, 457. (h) Wang, X. C.; Xu,
X. F.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc. 2011, 133, 16402. (i)
Xu, X. F.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle, M. P. Org. Lett. 2011,
13, 6122.
(9) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.
(10) (a) Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440.
(b) Hansen, J. H.; Gregg, T. M.; Ovalles, S. R.; Lian, Y.; Autschnach, J.;
Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 5076.
(8) Hansen, J. H.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545.
Org. Lett., Vol. 14, No. 7, 2012
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The double bond geometry of the products derived
from vinylogous reactivity is indicative of the reacting
conformation of the carbenoid.6 Thus, the reaction of
(Z)-vinyldiazoacetate with indole 5 proceeds through the
s-trans conformer, leading to the formation of (Z)-6.
Donor/acceptor carbenoids are known to be sensitive to
steric effects, and if the nucleophile is sterically demanding,
reactions at the vinylogous position of the carbenoid are
enhanced.7c We, therefore, hypothesized that it would be
possible to enhance the vinylogous reactivity of (E)-vinyl-
diazoacetates by re-enforcing the s-trans conformation of
the carbenoid through the use of highly bulky catalysts.
Table 2. Asymmetric Alkylation of Indole 5 with
(E)-Vinyldiazoacetate 1b
ratioa of
yieldb of
entry
catalyst
Rh2(OAc)4
6/11/12
6 (%)
ee of 6 (%)
1
2
3
4
5
6
7
62/33/5
49/44/7
74/26/0
76/16/8
26/38/36
89/6/5
57
43
52
55
22
66
66
Rh2(TFA)4
Rh2(esp)2
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-TISP)4
Rh2(S-biTISP)2
À8
17
39
89
88/9/3
a Ratio was the average of two runs and determined from the 1H
NMR of the crude reaction mixture. b Isolated yield.
Figure 2. Steric influence on the conformation and reactivity of
vinylcarbenoids.
To explore this hypothesis, three standard achiral cata-
lysts and four chiral catalysts were screened in the
rhodium(II)-catalyzed decomposition of the (E)-vinyldia-
zoacetate 1b with 1,2-dimethylindole 5 (Table 2). These
reactions afforded variable mixtures of three products (6,
11, and 12). Products 6 and 11 arise from the vinylogous
reactivity of the s-trans and s-cis conformers of the vinyl-
carbenoid, respectively. Product 12 is derived from attack
of the heterocycle at the carbenoid center and could, in
principle, be derived from reaction with either conformer
of the vinylcarbenoid. The product ratio is dependent on
the catalyst structure. While the sterically less crowded
catalysts Rh2(OAc)4 and Rh2(TFA)4 give considerable
amounts of 11 and 12 (entries 1 and 2), the bulkier catalysts
Rh2(esp)2, Rh2(S-PTAD)4, Rh2(S-TISP)4, and Rh2(S-
biTISP)2 show a strong preference for the formation of 6
(entries 3, 4, 6, and 7). Most notable is the comparison
between Rh2(S-DOSP)4, which gives near equimolar
amounts of the three compounds (entry 5), and Rh2(S-
TISP)4, which gives about an 8:1 preference for 6 over the
two other products (entry 6). Furthermore, in the Rh2(S-
biTISP)2-catalyzed reaction, 6 is isolated in 66% yield
(after purification) and in 89% ee (entry 7).
The Rh2(S-biTISP)2-catalyzed asymmetric vinylogous
alkylation is applicable to a range of substituted indoles, as
illustrated in Figure 3. The desired transformation was
Figure 3. Substrate scope of asymmetric vinylogous reactivity.
aReactions were conducted at À20 °C.
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Org. Lett., Vol. 14, No. 7, 2012

observed for all substrates tested, and the (Z)-pent-2-
enoates 13À24 were produced in 48À86% yields with good
levels of enantioselectivity (82À95% ee). Protected and
unprotected 2-methylindoles are both effective in produc-
ing the vinylogous alkylation products, although increas-
ing the size of the protecting group enhanced the
asymmetric induction slightly (compare 13, 6, 14À16).
This transformation was also successful with 2-methylin-
doles bearing different functionalities on the 5-position.
However, 3-substitutedindoles did notresult in anefficient
transformation. Good yields and excellent enantioselec-
tivities were achieved with indoles containing bulky groups
at the 2-position, such as TMS and pinacol boronate ester
(23 and 24). The generation of 23 and 24 may offer the
opportunity for further functionalization. The absolute
configuration of 17 was unambiguously assigned by X-ray
crystallography,11 and the other products were assigned by
analogy.
This reaction can be extended to pyrrole derivatives, as
shown in Figure 4. Due to the decreased reactivity of
pyrroles, the reaction was conducted at À20 °C instead
of À45 °C.12 Even so, the alkylation products 25À27 were
obtained in good yield with high levels of enantioselectivity
(87À91% ee). The absolute configuration of these pro-
ducts was assigned by analogy to the absolute configura-
tion of 17.
Figure 4. Scope of asymmetric vinylogous reactivity with
pyrroles.
methyl (E)-2-diazo-3pentenoate is an effective method for
C-3 functionalization of indoles and pyrroles. This work
illustrates the subtle controlling elements of dirhodium
catalysts on the chemistry of donor/acceptor carbenoids.
Acknowledgment. This research was supported by the
National Institutes of Health (GM099142). We thank
Dr. Kenneth I. Hardcastle (Emory University) for the
X-ray crystallographic analysis.
In conclusion, the Rh2(S-biTISP)2-catalyzed asym-
metric vinylogous alkylation between N-heterocycles and
Supporting Information Available. Full experimental
data, X-ray crystallographic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) The crystal structure of 17 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC
#830585 has been allocated.
(12) Mayer, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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