General and efficient synthesis of indoles through triazene-directed c-h annulation

Article abstract of DOI:10.1002/anie.201301742

Unprotected indoles are prepared with the title method, which has a wide scope for alkynes. Excellent regioselectivity was accomplished for aryl-alkyl and alkyl-alkyl disubstituted acetylenes. This reaction features an unusual 1,2 rhodium migration and ring-contraction-triggered N-N bond cleavage. It allows rapid conversion of the reaction products into several functional molecules. Copyright

Full text of DOI:10.1002/anie.201301742

Angewandte
Chemie
DOI: 10.1002/anie.201301742
Synthetic Methods
General and Efficient Synthesis of Indoles through Triazene-Directed
C–H Annulation**
Chengming Wang, Huan Sun, Yan Fang, and Yong Huang*
Indole is one of the most abundant and important class of
heterocycles found in natural products, pharmaceuticals, and
other functional molecules.[1] Despite more than 100 years of
efforts and numerous methods developed, organic chemists
continue to search for more straightforward and economical
ways to make various substituted indoles.[2] Among them,
the popular Larock indole synthesis (Scheme 1a).[6] Glorius
and co-workers reported palladium(II)-catalyzed oxidative
cyclization reaction of N-aryl enamines derived from anilines
and b-dicarbonyl compounds to afford the corresponding
indoles (Scheme 1c).[6b,c] The research groups of Jiao,[6d]
Cacchi,[6e] Zhao,[6f] and Liang[6g] explored different metals
and oxidants for the parallel CDC reactions. Yoshikai and co-
workers recently reported significantly improved reaction
conditions and substrate scope.[6h]
Directed intermolecular C–H annulation represents
a straightforward and attractive strategy to access indoles.[7]
Fagnou and co-workers reported an NHAc-directed dehy-
drogenative cyclization between internal alkynes and arenes
catalyzed by rhodium (Scheme 1d).[7a–c] A method employing
Ru and other NH protecting groups was later reported by
Ackermann and others.[7d,f] Owing to the static nature of these
directing groups (DGs), only protected indoles could be
accessed. Further functionalization of the indole NH would
require an additional deprotection step. The direct access to
unprotected indoles by using this strategy remains a challeng-
ing task. In addition, regioselectivity is a major issue, since
asymmetrically substituted internal alkynes often gave a mix-
ture of region isomers.[5c] Herein, we report the first general
protocol to synthesize unprotected indoles through directed
C–H annulation between arenes and alkynes by using
a triazene as the DG. Excellent regioselectivity was achieved
for both aryl–alkyl and alkyl–alkyl internal alkynes.
transition-metal-catalyzed
aniline–alkyne
cyclizations
emerged as the most widely adopted protocols
(Scheme 1a).[1h,2b,c,e,3] However, preactivation of substrates
by halogenation or alkynylation was required, which often is
not trivial. Advantageous over these methods is that the
direct C–H activation and functionalization bypasses the need
for preactivated reaction partners and also tolerates a much
wider substrate scope with controlled regioselectivity.[4]
Recently, several indole syntheses using C–H activation
were developed.
Takemoto and co-workers reported an isocyanide inser-
tion and benzylic C–H activation strategy to access certain
substituted indoles (Scheme 1b).[5] However, both reaction
substrates need to be preactivated. Cross-dehydrogenative
coupling (CDC) reactions were explored as an alternative to
Our recent work on removable directing groups (DG) for
C–H activation and functionalization led to the discovery of
triazenes as a class of highly efficient and manipulable DGs
for oxidative Heck coupling reactions (Scheme 2a).[8]
Inspired by the report by Yamane and Zhu on cinnoline
synthesis using ortho-iodo triazenyl arenes and alkynes
(Scheme 2b),[9] we attempted to develop a directed C–H
activation route to cinnoline. To our surprise, no desired
cinnoline product was observed despite intensive condition
search. Instead, the corresponding unprotected indole was
isolated (Scheme 2c). It prompted us to investigate this
unprecedented transformation.
Our initial study was carried out by examining triazenyl
arene 1e and diphenylacetylene 2a in the presence of
[{RhCp*Cl2}2] and Cu(OAc)2·H2O in MeOH under argon
atmosphere. The indole product 3e was isolated in 20% yield
(Table 1, entry 3). Other catalysts did not promote this
reaction (for comprehensive reaction investigations, see the
Supporting Information). Solvents proved to be critical and
only MeOH promoted this reaction (Table 1, entry 6–8). A
stoichiometric amount of copper oxidant was essential, and
catalytic noncoordinating counter ion silver salts could
further improve the yields. The use of a triazene bearing
Scheme 1. Transition-metal-catalyzed indole synthesis. DG=directing
group.
[*] C. Wang, H. Sun, Y. Fang, Prof. Dr. Y. Huang
Key Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Peking University, Shenzhen Graduate School
Shenzhen (China)
E-mail: huangyong@pkusz.edu.cn
Homepage: http://scbb.szpku.edu.cn/huang
[**] This work is financially supported by grants of the National Basic
Research Program of China (2010CB833201, 2012CB722602),
grants of Shenzhen special funds for the development of biomed-
icine (JC201104210111A, JC201104210112A), Shenzhen innovation
funds (GJHZ20120614144733420), and the Shenzhen Peacock
Program (KQTD201103).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301742.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Scheme 2. Indole synthesis through triazene-directed C–H annulation.
Cp*=pentamethylcyclopentadienyl.
a five-membered pyrrolidine led to significant conversion
enhancement, and the product was isolated in 90% yield
(Table 1, entry 9). Triazenes containing other cyclic or acylic
side chains gave inferior results. Eventually the following
conditions were chosen for examination of the reaction scope:
[{RhCp*Cl2}2] (5 mol%), AgSbF6 (20 mol%), and
Cu(OAc)2·H2O (2 equiv) in methanol under argon at 908C
(oil-bath temperature).
Various triazenyl arenes and alkynes were examined
under standard conditions (Scheme 3). Aromatic substrates
with a broad substitution pattern and of different electronic
nature were tolerated, and indoles bearing substitutions at 5-,
6-, and/or 7-positions were synthesized in good to excellent
yields. In reactions with arenes having strong electron-
donating substituents major side reactions occurred, resulting
in compromised yields. Halogens did not interfere with this
transition-metal-catalyzed process (3a–c, 3e,f). The relatively
low yield observed for ortho-iodo triazenyl benzene was likely
due to low reactivity (steric reasons), as the starting material
partially remained after 24 h (3h). Aryl–aryl, aryl–alkyl, and
alkyl-alkyl disubstituted acetylenes were all well-tolerated,
thereby further broadening the substrate scope. In particular,
Scheme 3. Substrate scope. Reactions were carried out on a 0.3 mmol
scale. Yields of isolated products are given.
asymmetric alkynes afforded excellent regioselectivity (3p–
3r). For various alkyl phenyl acetylenes, only one regioisomer
was obtained (3q–r). Significantly, excellent steric differ-
entiation (regioisomeric ratio > 10:1) was accomplished for
alkyl–alkyl acetylenes (3p). This result represented a major
advantage over the protocol reported by Fagnou and co-
workers. The authors explored a detour strategy to address
this selectivity issue: by using sp2–sp3 disubstituted acetylene
followed by hydrogenation.[7c] Reactions involving terminal
alkynes were compromised by side reactions such as alkyne
dimerization.
Table 1: Conditions screening.[a]
This method allowed quick access to a number of func-
tional molecules (Scheme 4). Product 3n was converted to
a popular organic light-emitting device 4a with improvements
in turn-on voltage, efficiency, and color-purity characteristics
in two steps: methylation and subsequent Suzuki coupling.[10]
A indole N-substituted aminohydroxypropane 4b, which
structurally resembles a potent BACE1 inhibitor for the
potential treatment of Alzheimerꢀs disease, was synthesized
from 3g by following a standard alkylation–epoxidation
opening sequence in 60% yield.[11] In addition, product 3r
obtained from an asymmetric internal alkyne was alkylated to
produce 4c, an analogue of bazedoxifene.[12] These three
examples of our triazene-directed C–H annulation method
demonstrated clear advantages over the use of other DGs, for
Entry
Solvent
Oxidant
Additive
Yield [%][b]
1
2
3
4
5
6
7
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
CuCl2
Cu(OTf)2
Cu(OAc)2·H2O
–
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
–
–
–
–
–
–
20
<5
35
67
–
AgOAc
AgSbF6
AgSbF6
AgSbF6
AgSbF6
8
CH3CN
MeOH
–
90
9[c]
[a] n=2 for all entries, except entry 9 (n=1). [b] Yields of isolated
products. [c] 2 equivalents of alkyne were used.
2
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K
H/D = 2.7 indicated that the C–H activation
was the rate-determining step. Subjecting the
indole product to the standard conditions
resulted in fast NH proton exchange.
Based on these facts and literature prece-
dence,[7b] we propose an Rh3+–Rh+–Rh3+ cata-
lytic cycle triggered by an N-ligand shift
(Scheme 6). First, an active Rh3+ acetate species
is generated from [{RhCp*Cl2}2], AgSbF6, and
copper acetate. This is followed by a reversible
À
C H bond insertion directed by the middle
nitrogen atom of the triazene moiety.
The resulting 7-membered metallacycle,
presumably quite unstable, quickly rearranges
to a more stable six-membered Rh complex.
Reductive elimination releases the indole prod-
=
uct. Alternatively, N N insertion to Rh–C,
followed by subsequent reduction and hydrol-
ysis would also generate the desired hetero-
cycle. It is not clear whether the appending
diazonium residue undergoes solvolysis prior to
Scheme 4. Demonstration of product utilities.
À
or after reductive elimination. The crucial N1
which an independent deprotection step to reveal the indole
NH group would be required.
N2 bond cleavage may be promoted by HOAc generated from
the C–H activation. The lack of reaction in the absence of an
external oxidant (Table 1, entry 4) indicated that triazene did
not act as an internal oxidant for this tranformation, which
would naturally lead to the cinnoline product.[14]
To probe the reaction mechanism, isotope experiments
were carried out (Scheme 5). Experiments with a 15N sub-
strate confirmed that the indole nitrogen came from the
triazene nitrogen directly attached to the aromatic ring. A
mild inverse nitrogen kinetic isotope effect was observed in
a competition experiment (K14N/15N = 0.9), indicating the N–N
cleavage was not the rate-limiting step. Interestingly, the 15N
substrate afforded significantly higher yields than the corre-
sponding 14N compound (80% vs. 50%). The C–H activation
step was reversible as indicated by the 25% H/D scrambling
in the product.[7b,e–f,13] The H/D exchange of the unreacted
ortho-C-H proton complicated the KIE measurement for the
C–H insertion step. Separate experiments using a pentadeu-
terated substrate were carried out to independently assess the
rates of reaction for ortho-C-H vs. C-D. A measurement of
In summary, we have developed a general synthesis of
unprotected indoles through a triazene-directed C–H annu-
lation using alkynes. This reaction is proposed to undergo
=
a 1,2-rhodium shift ring contraction or an N N insertion
mechanism. A broad scope of substrates was well tolerated.
Excellent regioselectivity was achieved by asymmetrically
substituted alkynes, which found immediate synthetic appli-
cations. Further exploration of the synthetic utilities of this
chemistry and in-depth mechanistic study are currently in
progress and will be reported in due course.
Scheme 6. Proposed mechanism of the triazene-directed NH indole
Scheme 5. Reactions using isotope-labeled substrates.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
synthesis.
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2010, 110, 749; e) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder,
J. M. Murphy, J. F. Hartwig, Chem. Rev. 2010, 110, 890; f) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; g) T. Satoh, M.
Miura, Chem. Eur. J. 2010, 16, 11212; h) L. Ackermann, Chem.
Rev. 2011, 111, 1315; i) L. McMurray, F. OꢀHara, M. J. Gaunt,
Chem. Soc. Rev. 2011, 40, 1885; j) W. R. Gutekunst, P. S. Baran,
Chem. Soc. Rev. 2011, 40, 1976; k) P. B. Arockiam, C. Bruneau,
P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; l) F. W. Patureau, F.
Wencel-Delord, F. Glorius, Aldrichimica Acta 2012, 45, 31;
m) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res.
2012, 45, 788; n) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F.
Glorius, Angew. Chem. 2012, 124, 10382; Angew. Chem. Int. Ed.
2012, 51, 10236.
Experimental Section
[{Cp*RhCl2}2] (9.3 mg, 0.0015 mmol, 5 mol%), triazene 1 (0.3 mmol,
1.0 equiv), Cu(OAc)2·H2O (120 mg, 0.6 mmol, 2.0 equiv), and AgSbF6
(22 mg, 0.060 mmol, 0.2 equiv) were subsequently weighed into an
oven-dried Schlenk tube. The reaction vessel was capped and
evacuated/flushed with argon three times. A solution of alkyne
(0.6 mmol, 2.5 equiv) in methanol (3.0 mL) was added through the
side arm by using a syringe. The reaction was stirred under an argon
balloon at 908C, and the progress of the reaction was monitored by
TLC. Upon complete consumption of 1, the mixture was cooled to
room temperature. Volatile solvent and reagents were removed by
rotary evaporation and the residue was purified by silica gel flash
chromatography using petroleum ether/EtOAc (50:1 to 10:1) to
afford the indole product 3.
[5] T. Nanjo, C. Tsukano, Y. Takemoto, Org. Lett. 2012, 14, 4270.
[6] For a recent review on indole synthesis by CDC, see: a) Z. Z.
Shi, F. Glorius, Angew. Chem. 2012, 124, 9354; Angew. Chem. Int.
Ed. 2012, 51, 9220; For recent reports, see: b) S. Wꢁrtz, S.
Rakshit, J. J. Neumann, T. Drçge, F. Glorius, Angew. Chem.
2008, 120, 7340; Angew. Chem. Int. Ed. 2008, 47, 7230; c) J. J.
Neumann, S. Rakshit, T. Drçge, S. Wꢁrtz, F. Glorius, Chem. Eur.
J. 2011, 17, 7298; d) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y.
Cui, N. Jiao, Angew. Chem. 2009, 121, 4642; Angew. Chem. Int.
Ed. 2009, 48, 4572; e) R. Bernini, G. Fabrizi, A. Sferrazza, S.
Cacchi, Angew. Chem. 2009, 121, 8222; Angew. Chem. Int. Ed.
2009, 48, 8078; f) W. Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11,
2417; g) Z.-H. Guan, Z.-Y. Yan, Z.-H. Ren, X.-Y. Liu, Y.-M.
Liang, Chem. Commun. 2010, 46, 2823; h) Y. Wei, I. Deb, N.
Yoshikai, J. Am. Chem. Soc. 2012, 134, 9098.
[7] For indole synthesis through directed C–H activation, see:
a) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K.
Fagnou, J. Am. Chem. Soc. 2008, 130, 16474; b) D. R. Stuart, P.
Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132,
18326; c) M. P. Huestis, L. N. Chan, D. R. Stuart, K. Fagnou,
Angew. Chem. 2011, 123, 1374; Angew. Chem. Int. Ed. 2011, 50,
1338; d) Z. Feng, X. L. Han, X. Y. Lu, Tetrahedron Lett. 2011, 52,
4681; e) L. Ackermann, S. V. Fenner, Org. Lett. 2011, 13, 6548;
f) L. Ackermann, A. V. Lygin, Org. Lett. 2012, 14, 764.
[8] a) C. Wang, H. Chen, Z. F. Wang, J. A. Chen, Y. Huang, Angew.
Chem. 2012, 124, 7354; Angew. Chem. Int. Ed. 2012, 51, 7242;
b) C. M. Wang, Y. Huang, Synlett 2013, 145; c) Q. Zhang, H.-Z.
Yu, Y.-T. Li, L. Liu, Y. Huang, Y. Fu, Dalton Trans. 2013, 42,
4175.
Received: February 28, 2013
Published online: && &&, &&&&
À
À
Keywords: C H activation · indole · N N cleavage · rhodium ·
triazene
.
[1] a) R. J. Sundberg, Indoles, Academic Press, San Diego, 1996;
b) T. Eicher, S. Hauptmann, The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications, 2nd ed., Wiley-
VCH, Weinheim, 2003; c) M. Somei, F. Yamada, Nat. Prod. Rep.
2004, 21, 278; d) M. Somei, F. Yamada, Nat. Prod. Rep. 2005, 22,
73; e) T. Kawasaki, K. Higuchi, Nat. Prod. Rep. 2005, 22, 761;
f) K. Krꢁger nꢂe Alex, A. Tillack, M. Beller, Adv. Synth. Catal.
2008, 350, 2153; g) A. J. Kochanowska-Karamyan, M. T.
Hamann, Chem. Rev. 2010, 110, 4489; h) M. Inman, C. J.
Moody, Chem. Sci. 2013, 4, 29, and references therein.
[2] For recent reviews on indole synthesis, see: a) G. W. Gribble, J.
Chem. Soc. Perkin Trans. 1 2000, 1045; b) S. Cacchi, G. Fabrizi,
Chem. Rev. 2005, 105, 2873; c) G. R. Humphrey, J. T. Kuethe,
Chem. Rev. 2006, 106, 2875; d) L. Ackermann, Synlett 2007, 507;
e) S. Cacchi, G. Fabrizi, Chem. Rev. 2011, 111, 215; f) D. F. Taber,
P. K. Tirunahari, Tetrahedron 2011, 67, 7195; g) M. Shiri, Chem.
Rev. 2012, 112, 3508.
[3] For a recent review, see: a) G. Zeni, R. C. Larock, Chem. Rev.
2006, 106, 4644; For representative examples, see: b) R. C.
Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689; c) R. C.
Larock, E. K. Yum, M. D. Refvik, J. Org. Chem. 1998, 63, 7652;
d) L. Ackermann, L. T. Kaspar, C. J. Gschrei, Chem. Commun.
2004, 2824; e) M. Shen, G. S. Li, B. Z. Lu, A. Hossain, F.
Roschangar, V. Farina, C. H. Senanayake, Org. Lett. 2004, 6,
4129; f) R. Yanada, S. Obika, M. Oyama, Y. Takemoto, Org.
Lett. 2004, 6, 2825; g) R. Yanada, S. Obika, T. Inokuma, K.
Yanada, M. Yamashita, S. Ohta, Y. Takemoto, J. Org. Chem.
2005, 70, 6972; h) M. H. Shen, B. E. Leslie, T. G. Driver, Angew.
Chem. 2008, 120, 5134; Angew. Chem. Int. Ed. 2008, 47, 5056;
i) R. Bernini, S. Cacchi, G. Fabrizi, G. Forte, F. Petrucci, A.
Prastaro, S. Niembro, A. Shafir, A. Vallribera, Green Chem.
2010, 12, 150; j) S. Cacchi, G. Fabrizi, A. Goggiamani, A.
Perboni, A. Sferrazza, P. Stabile, Org. Lett. 2010, 12, 3279; k) B.
Lu, Y. D. Luo, L. Z. Liu, L. W. Ye, Y. Z. Wang, L. M. Zhang,
Angew. Chem. 2011, 123, 8508; Angew. Chem. Int. Ed. 2011, 50,
8358.
[9] C. Zhu, M. Yamane, Tetrahedron 2011, 67, 4933.
[10] M. S. Kim, B. K. Choi, J. J. Park, T. Y. Noh, L. S. Pu, J. M. Son,
W. J. Paek, Y. M. Son, O. H. Kwon, C. U. Yang, S. Tamura, US
20070072002A1, 2007.
[11] V. Asso, E. Ghilardi, S. Bertini, M. Digiacomo, C. Granchi, F.
Minutolo, F. Rapposelli, A. Bortolato, S. Moro, M. Macchia,
ChemMedChem 2008, 3, 1530.
[12] a) J. H. Pickar, B. S. Komm, WO 1999/059581 A1, 1999; b) C. P.
Miller, M. D. Collini, B. D. Tran, H. A. Harris, Y. P. Kharode,
J. T. Marzolf, R. A. Moran, R. A. Henderson, R. H. W. Bender,
R. J. Unwalla, L. M. Greenberger, J. P. Yardley, M. A. Abou-
Gharbia, C. R. Lyttle, B. S. Komm, J. Med. Chem. 2001, 44, 1654.
[13] L. Ackermann, L. H. Wang, R. Wolfram, A. V. Lygin, Org. Lett.
2012, 14, 728 – 731.
[14] For a review discussing a directing group as an internal oxidant,
see: a) F. W. Patureau, F. Glorius, Angew. Chem. 2011, 123, 2021;
Angew. Chem. Int. Ed. 2011, 50, 1977; For examples of C – H
activations using N – O as the internal oxidant, see: b) Y. Tan,
J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 3676; c) N. Guimond,
C. Gouliaras, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 6908; Si –
H as the internal oxidant: d) T. Ureshino, T. Yoshida, Y.
Kuninobu, K. Takai, J. Am. Chem. Soc. 2010, 132, 14324.
[4] For recent reviews on C–H activation reactions, see: a) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009, 121,
9976; Angew. Chem. Int. Ed. 2009, 48, 9792; b) R. Giri, B.-F. Shi,
K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38,
3242; c) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev.
2010, 110, 624; d) D. Balcells, E. Clot, O. Eisenstein, Chem. Rev.
4
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Communications
Synthetic Methods
C. Wang, H. Sun, Y. Fang,
Y. Huang*
&&&& — &&&&
General and Efficient Synthesis of Indoles
through Triazene-Directed C–H
Annulation
Unprotected indoles are prepared with
the title method, which has a wide scope
of alkynes. Excellent regioselectivity was
accomplished for aryl–alkyl and alkyl–
alkyl disubstituted acetylenes. This reac-
tion features an unusual 1,2 rhodium
migration and ring-contraction-triggered
À
N N bond cleavage. It allows rapid
conversion of the reaction products to
several functional molecules.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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