The vinyl moiety as a handle for regiocontrol in the preparation of unsymmetrical 2,3-aliphatic-substituted indoles and pyrroles

Article abstract of DOI:10.1002/anie.201006381

Rho-Rho-Rho your boat: A rhodium catalyst effects the regioselective oxidative coupling of enynes with N-aryl ureas (X=NR₂) and N-vinylacetamides (X=C(O)Me), affording the corresponding 2-alkenylindoles and 2-alkenylpyrroles in good yield. Simple hydrogenation delivers the C2/C3-aliphatic-substituted indole or pyrrole (see scheme).

Full text of DOI:10.1002/anie.201006381

Communications
DOI: 10.1002/anie.201006381
Heterocycles
The Vinyl Moiety as a Handle for Regiocontrol in the Preparation of
Unsymmetrical 2,3-Aliphatic-Substituted Indoles and Pyrroles**
Malcolm P. Huestis,* Lina Chan, David R. Stuart, and Keith Fagnou†
Since their introduction in the 1880s, the Fischer indole
synthesis[1] (Scheme 1a) and the Paal–Knorr pyrrole syn-
thesis[2] have ranked among the most utilized reactions in
fundamental step in the formation of various heterocycles.[9]
This mode of reactivity is particularly desirable since the cost
to install activating functionality, such as halides, is obviated.
A particular focus has been placed on annulative couplings of
nitrogen-substituted aryl or vinyl groups with internal alkynes
catalyzed by rhodium(III) complexes.[10] Our group has
previously exploited this approach, developing reactions
forming indoles[11,12a] (Scheme 1c), pyrroles,[12a] isoquino-
lines,[13a] and isoquinolones.[14a]
Despite these recent advances, a pharmaceutically rele-
vant target[15] that continues to represent a significant
synthetic challenge is the unsymmetrical 2,3-aliphatic-substi-
tuted indole (Scheme 1). To the best of our knowledge, all
methods for constructing indoles with 2,3-aliphatic substitu-
tion other than methyl require multistep procedures, and the
opposite C2/C3 regioisomer cannot be accessed by the same
method.[4] In the context of rhodium(III)-catalyzed annula-
tions, the difficulties associated with this substrate class derive
from poor regioselectivity in the 1,2-migratory insertion
across unsymmetrical aliphatic-substituted internal alkynes
as well as rate inhibition by dialkyl-substituted internal
alkynes.[12a]
Previous studies on the mechanism of our indole-forming
reaction revealed that, while there is little influence from
steric effects in the alkyne insertion event, this step is largely
controlled by electronic effects.[12a] Therefore, in cases we
have investigated in which there is one aryl (or sp2 hybridized)
substituent on the alkyne, this group is delivered proximal to
the indole nitrogen atom with very high regioselectivity.[16] On
the basis of these results a working hypothesis was conceived
in which an enyne would function as a coupling partner with a
bias for highly regioselective alkyne insertion leading to the
production of a C2-vinyl-substituted heterocycle (Scheme 2).
Herein, we report the realization of this goal, namely the
ability to control which regioisomer is obtained by employing
the appropriate enyne, and formation of unsymmetrical 2,3-
aliphatic-substituted indoles and pyrroles by facile hydro-
genation of the resulting alkene at the C2 position of the
heterocycle. The nonhygroscopic, bench-weighable complex
[Cp*Rh(MeCN)3](SbF6)2 catalyzed the annulation reaction
under mild reaction conditions (20–608C), required no inert
atmosphere, and displayed broad substrate scope with respect
to the formation of both indoles and pyrroles.[17]
Scheme 1. Challenges in the synthesis of 2,3-aliphatic indoles.
heterocyclic chemistry.[3] However, the general importance of
these heterocycles have driven chemists to continue devel-
oping novel methods to access differentially substituted
indoles[4] and pyrroles.[5] Over 100 years later, Larockꢀs
indole synthesis[6] (Scheme 1b) aptly highlighted the utility
of transition-metal catalysis in the formation of aromatic
heterocycles.[7] In the subsequent decade, palladium has
continued to play a central role in this diverse reaction class.[8]
More recently, an increasing number of examples have
appeared in the literature featuring a transition metal
À
catalyzed oxidative C H bond functionalization event as a
[*] M. P. Huestis,[+] L. Chan, D. R. Stuart, Prof. Dr. K. Fagnou
Department of Chemistry, University of Ottawa
10 Marie Curie, Ottawa, ON K1N 6N5 (Canada)
E-mail: malcolm.huestis@gmail.com
[+] Current address: Discovery Chemistry, Genentech, Inc.
Our studies were initiated by the reaction of an enyne with
acetanilide under our first-generation reaction conditions.[11]
Despite a low yield of the isolated product (11%), the
reaction yielded exclusively the desired 2-alkenyl indole
regioisomer (Table 1, entry 1). The incompatibility of enynes
with acetanilide under more mild reaction conditions
(entry 2) led us to examine a wide variety of anilides,[18]
1 DNA Way, South San Francisco, CA 94080 (USA)
[†] Deceased November 11, 2009.
[**] NSERC, University of Ottawa, The Sloan Foundation, Merck-Frosst,
Amgen, Eli Lilly, and AstraZeneca are acknowledged for financial
support. We thank Derek J. Schipper is for valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006381.
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Angew. Chem. Int. Ed. 2011, 50, 1338 –1341

(entry 8). Finely powered copper(II) acetate provided an
additional improvement (entry 9), and stoichiometric
amounts secured the final reaction conditions (entry 10).
Peroxides can also be used in place of metal or atmospheric
oxidants.[19]
Under the optimal reaction reaction conditions, a variety
of 2-alkenylindoles were constructed (Scheme 3). A number
of functional groups were compatible on the benzo ring, such
Scheme 2. The vinyl moiety as an element of regiocontrol.
Table 1: Optimization of indole synthesis with enynes.[a]
Entry
R
solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
Me
Me
NHMe
NEt2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
acetone
iPrOAc
toluene
toluene
toluene
(11)[c]
n.r.
n.r.
7[d]
16[d] (15)
14
Scheme 3. Scope of the rhodium-catalyzed 2-alkenylindole formation.
Reaction conditions: N-aryl urea (1 equiv), [Cp*Rh(MeCN)3](SbF6)2 (5
mol%), and Cu(OAc)2 H2O (2.1 equiv) were placed in a test tube, a
solution of enyne (1.1 equiv) in toluene (0.2m) was added, and the
mixture was stirred at 608C overnight. [a] Employed 3 equiv of enyne.
Boc=tert-butylcarbamate, TBS=tert-butyldimethylsilyl, Tr=triphenyl-
methyl.
35
.
46 (48)
57[e]
76 (74)[e,f]
[a] Reaction conditions: Anilide (1 equiv), [Cp*Rh(MeCN)3](SbF6)2
(5 mol%), and Cu(OAc)2 H2O (0.2 or 2.1 equiv) were placed in a test
.
tube, a solution of enyne (1.1 equiv) in solvent (0.2m) was added. The
test tube was capped with a septum, fitted with an oxygen balloon, and
the mixture was stirred at 608C overnight. [b] Yields determined by GC
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
an internal standard, and the yields of the isolated products are given in
parentheses. [c] Reaction performed at 1208C with 2.1 equiv Cu-
as m-trifluoromethyl, p-methoxy, p-chloro, o-methyl, and
1-naphthyl (1b–1 f). Compounds 1g–1j not only demonstrate
that a,b-unsaturated esters were tolerated, but also tert-
butylcarbamate-protected amines and triphenylmethyl
ethers. Notably, Z alkenes can be employed without evidence
of olefin isomerization (1i) and 2,2-disubstituted alkenes
function as well (1k). Finally, an allylic alcohol, protected as
the tert-butyldimethylsilyl ether, was also installed alongside
another aromatic heterocycle (1l).
.
(OAc)2 H2O in place of oxygen atmosphere. [d] Reaction performed at
1
.
808C and yield was determined by H NMR analysis. [e] Cu(OAc)2 H2O
.
was ground with a mortar and pestle. [f] 2.1 equiv of Cu(OAc)2 H2O
without an oxygen atmosphere. t-AmOH=2-methyl-2-butanol, n.r. =no
reaction.
Extension of the enyne chemistry to the synthesis of
2-alkenyl pyrroles was accomplished at room temperature
using an enamide coupling partner. During reaction develop-
ment we found that when the inexpensive cyclohexanone[20]
was used as a solvent, it provided superior yields to our
previously reported conditions employing acetone.[12a,18] Con-
sistent with the indole chemistry, triphenylmethyl and tert-
butyldimethylsilyl ethers were well tolerated on the enyne
eventually revealing N-aryl ureas as competent substrates for
the desired coupling (entries 3–5).[9a] Thus, reaction of N,N-
dimethyl-N’-phenylurea afforded the target 2-alkenyl indole
in 15% yield as a single regioisomer (entry 5). The reaction
outcome was significantly influenced by changes in solvent
(entries 5–8), guiding us to a 46% yield with toluene
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Communications
coupling partner (Scheme 4; 2b and 2c), as were tert-
butylcarbamate-protected amines (2d). A pyrrole having
a styryl substituent at C2 was also prepared (2 f), and
Scheme 5. Hydrogenation of C2-alkenylindoles and pyrroles. Reaction
conditions: Indole (1 equiv) and 10% Pd/C (5 mol%), were dissolved
in EtOH under an atmosphere of hydrogen (1 atm) and stirred
overnight, or pyrrole (1 equiv), 10% Pd/C (5 mol%) and ammonium
formate (10 equiv) were dissolved in EtOH and refluxed overnight
under an argon atmosphere.
Scheme 4. Scope of the rhodium-catalyzed 2-alkenylpyrrole formation.
Reactions conditions: methyl 2-acetamidoacrylate (1 equiv), [Cp*Rh-
(MeCN)3](SbF6)2 (5 mol%), and Cu(OAc)2.H2O (20 mol%), were
placed in a test tube and a solution of enyne (1.1 equiv) in cyclo-
hexanone (0.2m) was added. The reaction vessel was purged with
oxygen and stirred overnight. [a] N-Vinylacetamide (3 equiv) was used
as coupling partner. TMS=trimethylsilyl.
N-vinylacetamide also participates as the enamide compo-
nent, providing direct access to 2,3-disubstituted pyrroles,
albeit in diminished yield (2i). Access to pyrroles not
possessing functionality at C3 was possible through the use
of TMS-functionalized enynes (2g and 2h).[21]
Scheme 6. Preparation of a C2/C3 regioisomeric series.
In accordance with our desired goal of obtaining single
regioisomers of unsymmetrical 2,3-aliphatic-substituted
indoles and pyrroles, we secured conditions for the efficient
hydrogenation of the resultant compounds having alkene
substituents at C2 (Scheme 5). Reduction of the 2-alkenylin-
doles proved to be facile under standard hydrogenation
conditions with Pd/C and H2 atmosphere in ethanol at room
temperature (Scheme 5; 3a–3c). For the reduction of the
2-alkenylpyrroles, ammonium formate was employed as the
hydrogen source in refluxing ethanol (3d–3e). In these cases,
loss of the N-acetyl group occurs concomitantly with alkene
hydrogenation.
After considerable optimization, we found that heating
compound 1a in ethanol/saturated aqueous potassium hy-
droxide (3:1) in a sealed vessel delivered the 2-alkenyl indole
4a in 80% yield [Eq. (1)].
To additionally establish the power of the methodology,
two members of the regioisomeric series represented in
Scheme 6 were prepared as single regioisomers. Coupling of
the enamide with 5-methylhex-1-en-3-yne or 2-methyl-1-en-3-
yne provided pyrrole 2j or 2k, respectively, as single
regioisomers. Hydrogenation under our established condi-
tions then provided 2-ethyl-3-isopropylpyrrole (3 f) or
3-ethyl-2-isopropylpyrrole (3g) as single regioisomers.[22]
Finally, conditions for removal of the robust dimethylurea
protecting group from the indole series were developed.[23]
In conclusion, unsymmetrical 2,3-aliphatic-substituted
indoles and pyrroles may be accessed under mild conditions
by the rhodium-catalyzed union of enynes with simple
nitrogen-containing starting materials, and subsequent facile
hydrogenation. The mild nature of the reaction (room
temperature or 608C) should facilitate its practical applica-
tion in settings that feature multiple labile functional groups.
This method also provides direct access to 2-alkenyl indoles
and pyrroles, scaffolds whose value is demonstrated by the
recent interest in direct C2 alkenylations.[24]
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Angew. Chem. Int. Ed. 2011, 50, 1338 –1341

Received: October 11, 2010
Published online: December 29, 2010
J. Am. Chem. Soc. 2008, 130, 12414 – 12419; p) L. Li, W. W.
Brennessel, W. D. Jones, Organometallics 2009, 28, 3492 – 3500.
[10] A recent review: T. Satoh, M. Miura, Chem. Eur. J. 2010, 16,
11212 – 11222.
[11] D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou,
J. Am. Chem. Soc. 2008, 130, 16474 – 16475.
Keywords: enynes · homogeneous catalysis ·
.
nitrogen heterocycles · regioselectivity · rhodium
[12] a) D. R. Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem.
Soc. 2010, DOI: 10.1021/ja1082624
; b) S. Rakshit, F. W.
[1] a) E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241 –
2245; b) E. Fischer, O. Hess, Ber. Dtsch. Chem. Ges. 1884, 17,
559 – 568; c) S. Banerjee, E. Barnea, A. L. Odom, Organo-
metallics 2008, 27, 1005 – 1014.
Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9585 – 9587.
[13] a) N. Guimond, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 12050 –
12051; b) T. Fukutani, N. Umeda, K. Hirano, T. Satoh, M. Miura,
Chem. Commun. 2009, 5141 – 5143.
[2] a) L. Knorr, Ber. Dtsch. Chem. Ges. 1884, 17, 2863 – 2870; b) C.
Paal, Ber. Dtsch. Chem. Ges. 1884, 17, 2756 – 2767; c) L. Knorr,
Ber. Dtsch. Chem. Ges. 1885, 18, 299 – 311; d) C. Paal, Ber. Dtsch.
Chem. Ges. 1885, 18, 367 – 371.
[3] a) Name Reactions in Heterocyclic Chemistry (Ed.: J.-J. Li),
Wiley, Hoboken, New Jersey, 2005; b) Heterocyclic Chemistry
(Eds.: J. A. Joule, K. Mills), Blackwell Science, Oxford, 2000.
[4] a) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875 –
2911; b) K. Krꢁger (nꢂe Alex), A. Tillack, M. Beller, Adv. Synth.
Catal. 2008, 350, 2153 – 2167; c) L. Ackermann, Synlett 2007,
507 – 526.
[5] T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 1999, 2849 – 2866.
[6] a) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689 –
6690; b) R. C. Larock, E. K. Yum, M. D. Refvik, J. Org. Chem.
1998, 63, 7652 – 7662; For an analogous pyrrole-formating
reaction, see: c) M. L. Crawley, I. Goljer, D. J. Jenkins, J. F.
Mehlmann, L. Nogle, R. Dooley, P. E. Mahaney, Org. Lett. 2006,
8, 5837 – 5840.
[7] a) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127 –
2198; b) L. S. Hegedus, Angew. Chem. 1988, 100, 1147 – 1161;
Angew. Chem. Int. Ed. Engl. 1988, 27, 1113 – 1126.
[14] a) N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem. Soc.
2010, 132, 6908 – 6909; b) S. Mochida, N. Umeda, K. Hirano, T.
Satoh, M. Miura, Chem. Lett. 2010, 39, 744 – 746; c) T. K. Hyster,
T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565 – 10569; d) G. Song,
D. Chen, C.-L. Pan, R. H. Crabtree, X. Li, J. Org. Chem. 2010,
75, 7487 – 7490.
[15] Representative commercial drugs with this structural motif:
Eccoxolac, see: a) R. Martel, US 4533551, 1985; b) L. G.
Humber, C. A. Demerson, P. Swaminathan, J. Med. Chem.
1986, 29, 871 – 874; Moban, see: c) M. Finizio, US 4065453, 1977;
d) D. E. Comings, B. Kovacs, J. Macmurry, US 0156078, 2002;
Indosin-SR, see: e) A. Robert, US 4061742, 1977; f) R. E.
Dempski, G. N. Mehta, J. C. Saboe, US 4173626, 1979; g) R.
Brouard, G. Remuzzi, WO 002556, 2000.
[16] When 1-phenylpropyne is employed as a coupling partner, the
regioselectivity for C2-phenyl/C3-phenylindole is > 40:1 by GC–
MS. For 3-phenyl propiolate esters, the phenyl group is delivered
proximal to the indole or the pyrrole nitrogen over the ester
moiety, see Ref. [12].
[17] [Cp*Rh(MeCN)3](SbF6)2 will be available shortly from Strem
Chemicals, Inc., but can be easily prepared in one step from
commercially available [{Cp*RhCl2}2] and AgSbF6. See the
Supporting Information.
[8] a) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285 – 2309; b) S.
Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873 – 2920; c) T.
Sakamoto, Y. Kondo, H. Yamanaka, Heterocycles 1988, 27,
2225 – 2249.
[18] For full details of reaction development, see the Supporting
Information.
[9] For examples with PdII, see: a) C. E. Houlden, C. D. Bailey, J. G.
Ford, M. R. Gagnꢂ, G. C. Lloyd-Jones, K. I. Booker-Milburn,
J. Am. Chem. Soc. 2008, 130, 10066 – 10067; b) C. E. Houlden,
M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler, M. R. Gagnꢂ,
G. C. Lloyd-Jones, K. I. Booker-Milburn, Angew. Chem. 2009,
121, 1862 – 1865; Angew. Chem. Int. Ed. 2009, 48, 1830 – 1833;
c) S. Wꢁrtz, S. Rakshit, J. J. Neumann, T. Drꢃge, F. Glorius,
Angew. Chem. 2008, 120, 7340 – 7343; Angew. Chem. Int. Ed.
2008, 47, 7230 – 7233; d) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding,
Y. Cui, N. Jiao, Angew. Chem. 2009, 121, 4642 – 4646; Angew.
Chem. Int. Ed. 2009, 48, 4572 – 4576; e) Z. Shi, Y. Cui, N. Jiao,
Org. Lett. 2010, 12, 2908 – 2911; f) S. Ding, Z. Shi, N. Jiao, Org.
Lett. 2010, 12, 1540 – 1543; g) Y. Tan, J. F. Hartwig, J. Am. Chem.
Soc. 2010, 132, 3676 – 3677. For an example with CuII, see: h) R.
Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew. Chem. 2009,
121, 8222 – 8225; Angew. Chem. Int. Ed. 2009, 48, 8078 – 8081.
For examples with catalytic RhIII, see: i) K. Ueura, T. Satoh, M.
Miura, Org. Lett. 2007, 9, 1407 – 1409; j) K. Ueura, T. Satoh, M.
Miura, J. Org. Chem. 2007, 72, 5362 – 5367; k) N. Umeda, H.
Tsurugi, T. Satoh, M. Miura, Angew. Chem. 2008, 120, 4083 –
4086; Angew. Chem. Int. Ed. 2008, 47, 4019 – 4022; l) M. Shimizu,
K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2009, 74, 3478 –
3483; m) S. Mochida, M. Shimizu, K. Hirano, T. Satoh, M. Miura,
Chem. Asian J. 2010, 5, 847 – 851; n) Y. Su, M. Zhao, K. Han, G.
Song, X. Li, Org. Lett. 2010, 12, 5462 – 5465. For examples with
stoichiometric RhIII, see: o) L. Li, W. W. Brennessel, W. D. Jones,
[19] It was later discovered that tert-butylhydroperoxide could be
used in this reaction instead of metal or atmospheric re-oxidants
(70% yield of isolated product, see the Supporting Information).
[20] According to Sigma–Aldrich, ACS reagent grade cyclohexanone
is $39 L USD, while acetone is $29 L USD.
[21] For cleavage of the aryl-TMS linkage on compound 2h, see the
Supporting Information.
[22] Use of 2-methylhex-3-yne resulted in a 1:1 mixture of insepa-
rable regioisomers; see the Supporting Information for addi-
tional details.
[23] Literature conditions did not preserve the stereochemical
integrity of the C2 double bond: C. G. Hartung, A. Fecher, B.
Chapell, V. Snieckus, Org. Lett. 2003, 5, 1899 – 1902.
[24] a) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt,
Angew. Chem. 2005, 117, 3185 – 3189; Angew. Chem. Int. Ed.
2005, 44, 3125 – 3129; b) E. M. Beck, N. P. Grimster, R. Hatley,
M. J. Gaunt, J. Am. Chem. Soc. 2006, 128, 2528 – 2529; c) E. M.
Beck, R. Hatley, M. J. Gaunt, Angew. Chem. 2008, 120, 3046 –
3049; Angew. Chem. Int. Ed. 2008, 47, 3004 – 3007; d) Y. Nakao,
K. S. Kanyiva, S. Oda, T. Hiyama, J. Am. Chem. Soc. 2006, 128,
8146 – 8147; e) A. Garcꢄa-Rubia, R. G. Arrayꢅs, J. C. Carretero,
Angew. Chem. 2009, 121, 6633 – 6637; Angew. Chem. Int. Ed.
2009, 48, 6511 – 6515; f) D. J. Schipper, M. Hutchinson, K.
Fagnou, J. Am. Chem. Soc. 2010, 132, 6910 – 6911; g) F. W.
Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9982 – 9983;
h) R. Gao, C. S. Yi, J. Org. Chem. 2010, 75, 3144 – 3146.
Angew. Chem. Int. Ed. 2011, 50, 1338 –1341
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