Conversion of cyclic ketones to 2,3-fused pyrroles and substituted indoles

Article abstract of DOI:10.1021/ja405043g

A highly effective synthesis of 2,3-fused pyrroles from cyclic ketones has been achieved. The transformation includes a rhodium-catalyzed reaction of 4-alkenyl-1-sulfonyl-1,2,3-triazoles featuring an unusual 4π electrocyclization. The methodology was furt

Full text of DOI:10.1021/ja405043g

Communication
pubs.acs.org/JACS
Conversion of Cyclic Ketones to 2,3-Fused Pyrroles and Substituted
Indoles
Joshua S. Alford, Jillian E. Spangler, and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
preliminary reaction development was conducted with 4-
cyclohexenyl-1-sulfonyl-1,2,3-triazoles6a,11 1 in the presence of
ABSTRACT: A highly effective synthesis of 2,3-fused
pyrroles from cyclic ketones has been achieved. The
transformation includes a rhodium-catalyzed reaction of 4-
alkenyl-1-sulfonyl-1,2,3-triazoles featuring an unusual 4π
electrocyclization. The methodology was further extended
to the synthesis of indoles using a one-pot reaction starting
from 1-ethynylcyclohexenes.
1.0 mol % Rh(II) catalyst (Table 1). The yield of the desired
a
Table 1. Optimization Studies
b
entry
substrate
−SO2R
Rh(II) cat.
solvent
yield (%)
47
yrroles are ubiquitous constituents in a wide variety of
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1a
1a
1a
Ts
Ts
Ts
Ts
Ms
Ts
Ts
Ts
Rh2(OAc)4
Rh2(TFA)4
Rh2(Oct)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
EtOAc
c
P
natural products, therapeutic agents, and high-value
materials.1 Consequently, the development of methods for
the synthesis of pyrroles has been an active area of research.
Traditional methods for pyrrole synthesis include the Knorr,
Hantzsch, and Paal−Knorr syntheses.2 Recently, many metal-
catalyzed methods for the synthesis of pyrroles have been
reported.3 However, the synthesis of highly functionalized
pyrroles remains challenging and often requires multiple steps
or harsh reaction conditions. In this communication, we
describe a novel approach to the synthesis of 2,3-fused pyrroles
via an intramolecular rhodium(II)-catalyzed cyclization of 4-
alkenyl-N-sulfonyltriazoles, which are readily derived from the
corresponding ketones (eq 1). We further extend this
methodology to the formation of substituted indoles from
cyclohexanones.
0
91
d
93 (94 )
81
53
91
92
PhCH3
CHCl3
a
Triazole 1a or 1b (0.30 mmol, 1.0 equiv) and Rh2Ln (0.0030 mmol,
0.01 equiv) were combined in solvent (2.0 mL) and heated at 60 °C
b
c
d
for 4 h. Isolated yields. N-Sulfonyltriazole was recovered. 5.0 mmol
scale (0.1 M).
product was found to be dependent on both the nature of the
sulfonyl group and the dirhodium catalyst. After exploring
several achiral Rh(II) catalysts, Rh2(esp)2 was identified as the
optimal catalyst for this transformation (entry 4). Increasing the
steric bulk of the N-sulfonyl substitutent provided improved
yields of the desired product (compare entries 4 and 5). The
effect of the solvent was less pronounced, which is in contrast
to the solvent effect we had observed in our previous reports
with N-sulfonyltriazoles.7b,10a
Having developed optimized reaction conditions for the
synthesis of 2, we subsequently explored the scope of this
transformation. The 4-alkenyl-1-tosyl-1,2,3-triazoles 1c−l and
1n were prepared from the cyclic ketones in three steps: vinyl
triflate formation, Kumada-type coupling with ethynylmagne-
sium bromide in the presence of 3 mol % Co(acac)3,12 and
copper(I) thiophene-2-carboxylate (CuTC)-catalyzed azide−
alkyne cycloaddition (CuAAC) with TsN3 (eq 2; see the
Supporting Information for details).11,13
The Davies group has had a long-standing interest in the
development of novel transformations of donor/acceptor
carbenes derived from diazo compounds.4 Fokin and
Gevorgyan recently reported the use of 1,2,3-triazoles as
alternative precursors for the formation of rhodium(II)-bound
donor/acceptor carbenes.5 The use of these iminocarbenes has
enabled the development of novel transformations,6 including
direct heterocycle syntheses7 and implementation of a
heteroatom as the donor group8 that otherwise could not be
achieved with traditional donor/acceptor carbenes.
Among the most broadly used donor/acceptor carbenes are
those in which the donor group is an alkenyl substituent.9
Therefore, we have begun a program to examine the use of
alkenyltriazoles as precursors to rhodium-bound alkenylcar-
benes.10 During the course of these studies, we discovered that
rhodium-bound iminoalkenylcarbenes undergo facile cycliza-
tion to pyrroles in the absence of a trapping agent. Our
We were pleased to find that the reaction of a variety of 2-
and 4-substituted cyclohexenyltriazole derivatives provided the
desired tetrahydro-1H-indoles 2c−i in excellent yields (86−
92%; Table 2, entries 1−7). Heteroatoms in the ring were also
Received: May 20, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja405043g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
2). For 5-cholestan-3-one, selective formation of vinyl triflate 4
and subsequent Co(III)-catalyzed coupling provided an enyne
that was subsequently subjected to the one-pot CuAAC/
rhodium-catalyzed cyclization sequence, furnishing pyrrole
product 5 in good yield (81%). With nootkatone (6), both
the kinetic and thermodynamic vinyl triflates could be formed
regioselectively and then independently subjected to palladium-
catalyzed coupling. The resulting enynes 7 and 9 were
subjected to the one-pot protocol, providing pyrroles 8 (67%
yield) and 10 (79% yield), respectively. Notably, electro-
cyclization to form the pyrrole was found to be preferred over a
number of potential side reactions.
a
Table 2. Alkenyl-N-tosyltriazole Scope
a
Scheme 2. Application to Complex Frameworks
a
1 (0.26 mmol, 1.0 equiv) and Rh2(esp)2 (0.0026 mmol, 0.01 equiv)
were combined in 1,2-DCE (2.0 mL) and heated at 60 °C for 2−6 h
until consumption of 1 was apparent by thin-layer chromatography
(TLC) analysis. Isolated yields of purified products are shown.
a
Reagents and conditions: (a) Tf2O, 2,6-lutidine, rt; (b) Tf2NPh,
LiHMDS, −78 °C; (c) Pd(PPh3)4, ethynylmagnesium bromide, rt.
Encouraged by the successful syntheses of 2,3-fused pyrroles,
our attention turned to the possibility of synthesizing
substituted indole derivatives by combining the electro-
cyclization with a 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) oxidation. To our delight, the reaction gave the
desired indole products in good to excellent yields (Table 3).
This one-pot reaction sequence can be extended to a variety of
substituted cyclohexenyl derivatives to provide substituted
indole products (entries 1−8). Notably, the siloxy derivative
provided 6-siloxyindole 11e, which may serve as a precursor for
cross-coupling at the 6-position (entry 5). The N-Boc-
protected piperidine derivative 3h provided ready access to 6-
azaindole 11h (entry 8).
A proposed mechanistic rationale for the formation of the
2,3-fused pyrrole is provided in Scheme 3. The heating of
triazole I in the presence of the dirhodium catalyst generates
rhodium-stabilized iminocarbene intermediate II via ring−chain
isomerization and nitrogen extrusion. The iminocarbene
intermediate has to adopt an s-trans geometry, after which it
participates in a 4π electrocyclization to form pyrrolylium
cation III.14 Proton elimination with aromatization gives
pyrrole IV. Termination by a unique protonation of the
vinylrhodium species would give the product, V, and complete
the catalytic cycle. An alternative possible mechanism for the
conversion of III to V would be two sequential 1,5-H shifts
followed by Rh release.
tolerated, as both the N-Boc-piperidinyl and pyranyl alkenyl-
triazoles 1j and 1k underwent the cyclization to provide
pyrroles 2j and 2k in good yields (entries 8 and 9). The 1,2-
dihydronaphthalen-2-yl derivative 1l provided the dihydroben-
zoindole product 2l in excellent yield (89%; entry 10). The
cyclopentenyl and cycloheptenyl triazole derivatives 1m and 1n
also reacted to provide the fused pyrroles 2m and 2n in high
yields (entries 11 and 12).
Since the CuAAC reaction can be performed in halogenated
solvents,6e,7b,8 it was feasible to perform the CuAAC reaction
and the rhodium-catalyzed cyclization in the same reaction
medium starting from enyne 3 (Scheme 1). The one-pot
reaction gave the desired 2,3-fused pyrrole product 2a in higher
overall yield (90%) than in the sequence in which the triazole
was isolated.
The utility of the one-pot 2,3-fused pyrrole synthesis was
demonstrated using more complex frameworks, namely, the
steroid skeletons of 5-cholestan-3-one and nootkatone (Scheme
Scheme 1. One-Pot 2,3-Fused Pyrrole Synthesis
In summary, we have developed a highly effective synthesis
of 2,3-fused pyrroles from readily available starting materials via
B
dx.doi.org/10.1021/ja405043g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. One-Pot Indole Synthesis from Cyclohexenyl
Derivatives
AUTHOR INFORMATION
■
a
Corresponding Author
hmdavie@emory.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE 1213246).
REFERENCES
■
(1) For reviews, see: (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795−
819. (b) Sundberg, R. J. In Comphensive Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, U.K., 1996; Vol. 2, pp 119−206. (c) Hoffmann, H.; Lindel, T.
Synlett 2003, 1753−1783. (d) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.
Chem. Rev. 2008, 108, 264−287. (e) Heugebaert, T. S. A.; Roman, B.
I.; Stevens, C. V. Chem. Soc. Rev. 2012, 41, 5626−5640. (f) Kathirav,
M. K.; Salake, A. B.; Chothe, A. S.; Dudhe, P. B.; Watode, R. P.;
Mukta, M. S.; Gadhwe, S. Bioorg. Med. Chem. 2012, 20, 5678−5698.
(2) For recent reviews, see: (a) Ferreira, V. F.; De Souza, M. C. B. V.;
Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int.
a
3 (1.00 mmol, 1.0 equiv), TsN3 (1.00 mmol, 1.0 equiv), and CuTC
(0.05 mmol, 0.05 equiv) were combined in 1,2-DCE (2.0 mL) for 3−4
h followed by Rh2(esp)2 (0.01 mmol, 0.01 equiv) in 1,2-DCE (1 mL)
with heating at 60 °C for 2−4 h until consumption of 1 was apparent
by TLC analysis. Then DDQ (2.00 mmol, 2.0 equiv) suspended in
1,2-DCE (3 mL) was added, and the mixture was heated at 60 °C for 1
́ ́
2001, 33, 411−454. (b) Estevez, V.; Villacampa, M.; Menendez, J. C.
Chem. Soc. Rev. 2010, 39, 4402−4421. (c) Young, I. S.; Thornton, P.
D.; Thompson, A. Nat. Prod. Rep. 2010, 27, 1801−1839.
(3) For reviews, see: (a) Furstner, A. Synlett 1999, 1523−1533.
̈
b
h. Isolated yields of purified products are shown. 4 h at 40 °C after
the addition of DDQ (2.0 equiv).
(b) Patil, N. T.; Yamamoto, Y. ARKIVOC 2007, No. x, 121−141. For
recent examples, see: (c) Dudnik, A. S.; Sromek, A. W.; Rubina, M.;
Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
1440−1452. (d) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12,
312−315. (e) Kim, J. H.; Lee, S. B.; Lee, W. K.; Yoon, D.; Ha, H.
Tetrahedron 2011, 67, 3553−3558. (f) Wang, H.; Mueller, D. S.;
Sachwani, R. M.; Kapadia, R.; Londino, H. N.; Anderson, L. L. J. Org.
Chem. 2011, 76, 3203−3221. (g) Chen, F.; Shen, T.; Cui, Y.; Jiao, N.
Org. Lett. 2012, 14, 4926−4929. (h) Billedeau, R. J.; Klein, K. R.;
Kaplan, D.; Lou, Y. Org. Lett. 2013, 15, 1421−1423.
Scheme 3. Proposed Mechanism for Pyrrole Formation
(4) For reviews, see: (a) Davies, H. M. L.; Denton, J. R. Chem. Soc.
Rev. 2009, 38, 3061−3071. (b) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417−424. (c) Davies, H. M. L.; Morton, D. Chem. Soc. Rev.
2011, 40, 1857−1869. (d) Davies, H. M. L. Morton, D. Science of
Synthesis: Stereoselective Synthesis; De Vries, J. G., Molander, G. A.,
Evans, A. P., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, p 513.
(5) (a) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463−4466.
(b) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2007, 46, 4757−4759. (c) Horneff, T.; Chuprakov, S.; Chernyak,
N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972−
14974.
(6) For other reactions of carbenes derived from triazoles, see:
(a) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J.
Am. Chem. Soc. 2009, 131, 18034−18035. (b) Grimster, N.; Zhang, L.;
Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510−2511. (c) Chuprakov,
S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. J. Am. Chem. Soc. 2011, 133,
10352−10355. (d) Selander, N.; Worrell, B. T.; Chuprakov, S.;
Velaparthi, S.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 14670−14673.
(e) Muira, T.; Biyajima, T.; Fujii, T.; Murakami, M. J. Am. Chem. Soc.
2012, 134, 194−196. (f) Miura, T.; Funakoshi, Y.; Morimoto, M.;
Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17440−
17443. (g) Selander, N.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134,
2477−2480. (h) Selander, N.; Worrell, B. T.; Fokin, V. V. Angew.
Chem. 2012, 124, 13231−13234.
an intramolecular rhodium-catalyzed cyclization of 4-alkenyl-1-
sulfonyl-1,2,3-triazoles. This reaction was further extended to a
one-pot synthesis of indoles starting from cyclic enynes. The
substrate scope of this transformation is broad and the products
are formed under mild reaction conditions, enabling the
extension of this methodology to more complex frameworks.
This novel transformation contrasts with the vast majority of
reactions of N-sulfonyltriazoles, which involve intermolecular
reactions of the iminocarbene intermediates.
(7) (a) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52,
1507−1510. (b) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am.
Chem. Soc. 2013, 135, 4716−4718. (c) Schultz, E. E.; Sarpong, R. J.
Am. Chem. Soc. 2013, 135, 4696−4699. (d) Chuprakov, S.; Kwok, S.
W.; Fokin, V. V. J. Am. Chem. Soc. 2013, 135, 4652−4655.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) Alford, J. S.; Davies, H. M. L. Org. Lett. 2012, 14, 6020−6023.
C
dx.doi.org/10.1021/ja405043g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(9) (a) Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991,
56, 5696−5700. (b) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J.
Am. Chem. Soc. 1996, 118, 10774−10782. (c) Doyle, M. P.; Hu, W.;
Timmons, D. J. Org. Lett. 2001, 3, 933−935. (d) Davies, H. M. L.;
Xiang, B.; Kong, N.; Stafford, D. G. J. Am. Chem. Soc. 2001, 123,
7461−7462. (e) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001,
3, 3741−3744. (f) Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. J.
Am. Chem. Soc. 2003, 125, 4692−4693. (g) Lian, Y.; Davies, H. M. L. J.
Am. Chem. Soc. 2010, 132, 440−442. (h) Wang, X.; Xu, X.; Zavalij, P.
Y.; Doyle, M. P. J. Am. Chem. Soc. 2011, 133, 16402−16405.
(i) Hansen, J.; Davies, H. M. L. Chem. Sci. 2011, 2, 457−461.
(j) Wang, X.; Abrahams, Q. M.; Zavalij, P. Y.; Doyle, M. P. Angew.
Chem., Int. Ed. 2012, 51, 5907−5910. (k) Davies, H. M. L.; Lian, Y.
Acc. Chem. Res. 2012, 45, 923−935. (l) Smith, A. G.; Davies, H. M. L.
J. Am. Chem. Soc. 2012, 134, 18241−18244.
(10) (a) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802−6805. (b) Parr, B. T.; Davies, H. M. L. Angew. Chem., Int. Ed.
2013, DOI: 10.1002/anie.201304310.
(11) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952−4955.
(12) Shirakawa, E.; Sato, T.; Imazaki, Y.; Kimura, T.; Hayashi, T.
Chem. Commun. 2007, 4513−4515.
(13) (a) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, L.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730−
1733. (b) Raushel, J.; Pitram, S. M.; Fokin, V. V. Org. Lett. 2008, 10,
3385−3388. (c) Zibinsky, M.; Fokin, V. V. Org. Lett. 2011, 13, 4870−
4872.
(14) (a) Alickmann, D.; Frohlich, R.; Maulitz, A. H.; Wurthwein, E.-
̈
̈
U. Eur. J. Org. Chem. 2002, 1523−1537. (b) Narayan, R.; Frohlich, R.;
̈
Wurthwein, E.-U. J. Org. Chem. 2012, 77, 1868−1879. For an example
of a similar mechanism with Au, see: (c) Yan, Z.; Xiao, Y.; Zhang, L.
̈
Angew. Chem., Int. Ed. 2012, 51, 8624−8627.
D
dx.doi.org/10.1021/ja405043g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX