Rhodium-Catalyzed C-H Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3-Diaryl-Substituted Indoles

Article abstract of DOI:10.1002/anie.201503997

The direct C-H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3-disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3-diaryl substituted indoles. Herein, we report the rhodium(III)-catalyzed C-H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3-diaryl-substituted N-unprotected indoles with two different aryl groups. One of the aryl substituents is derived from N?C-aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.

Full text of DOI:10.1002/anie.201503997

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503997
German Edition: DOI: 10.1002/ange.201503997
Heterocycle Synthesis
À
Rhodium-Catalyzed C H Annulation of Nitrones with Alkynes:
A Regiospecific Route to Unsymmetrical 2,3-Diaryl-Substituted
Indoles**
Hao Yan, Haolong Wang, Xincheng Li, Xiaoyi Xin, Chunxiang Wang,* and Boshun Wan*
À
Abstract: The direct C H annulation of anilines or related
compounds with internal alkynes provides straightforward
access to 2,3-disubstituted indole products. However, this
transformation proceeds with poor regioselectivity in the
synthesis of unsymmetrically 2,3-diaryl substituted indoles.
À
Herein, we report the rhodium(III)-catalyzed C H annulation
of nitrones with symmetrical diaryl alkynes as an alternative
method to prepare 2,3-diaryl-substituted N-unprotected
indoles with two different aryl groups. One of the aryl
=
substituents is derived from N C-aryl ring of the nitrone and
the other from the alkyne substrate, thus providing the indole
products with exclusive regioselectivity.
I
ndole motifs are present in a wide variety of natural
products, pharmaceuticals, and agrochemicals.[1] Conse-
quently, their preparation has drawn much attention, and
a number of useful methods have been reported for the
preparation of functionalized indoles.[2–5] More recently,
transition-metal-catalyzed cross-dehydrogenative coupling
(CDC) reactions[6] as well as directing-group-assisted inter-
Scheme 1. Synthesis of unsymmetrically 2,3-diaryl substituted indoles
molecular C H annulation and other methods[8–11] have
[7]
À
À
by metal-catalyzed C H annulation.
emerged as powerful tools for their synthesis. Despite these
impressive advances, the synthesis of unsymmetrical 2,3-
diaryl-substituted indoles in a highly regioselective manner
remains challenging.
Previous studies revealed that electronic rather than steric
effects of the diaryl alkyne substituents had a dominant effect
on the regioselectivity.[7d,r] Therefore, it is difficult to predict
the regioselectivity with unsymmetrical diaryl alkynes,
although in some special cases excellent regioselectivity was
observed.[7q] In this context, the reaction with symmetrical
Well-established methods exist for the preparation
unsymmetrical 2,3-diaryl-substituted indoles from prefunc-
tionalized reactants or by multistep procedures.[8b,f,i,11] How-
À
ever, C H functionalization has been demonstrated to be
a more versatile and efficient strategy for the synthesis of
heterocycles.[12] For example, Yoshikai and co-workers[6g]
reported a significant palladium-catalyzed intramolecular
CDC reaction of N-aryl imines prepared from simple anilines
and ketones (Scheme 1a) in which the regioselectivity could
be controlled perfectly by the ketone moiety. A more
diaryl alkynes is more controllable. Recently, we observed
III
À
C H activation of the N-aryl ring of nitrones by a Rh
intermediate generated in situ.[13] In connection with the
challenges associated with the synthesis of unsymmetrically
À
2,3-diaryl substituted indoles, we envisioned that the C H
annulation of nitrones with symmetrical diaryl alkynes under
RhIII catalysis might provide a possibility to access indole
products (Scheme 1c). Nitrones for this reaction can be
prepared from readily available nitroarenes and aromatic
aldehydes.[14] The symmetrical alkyne acts as a one-carbon-
atom unit through carbon–carbon triple-bond cleavage[15] to
allow access to a broad range of unsymmetrical 2,3-diaryl-
substituted N-unprotected[16] indoles with exclusive regiose-
lectivity. Herein, we report our preliminary results.
À
intriguing method is the direct and atom-economical C H
annulation of anilines (or anilides) with unsymmetrical diaryl
alkynes (Scheme 1b).[7d,q,r] However, the control of regiose-
lectivity is still problematic in this type of annulation.
[*] H. Yan, Dr. H. L. Wang, Dr. X. C. Li, Dr. X. Y. Xin, Dr. C. X. Wang,
Prof. Dr. B. S. Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
E-mail: cxwang@dicp.ac.cn
An initial study was carried out with nitrone 1a and
alkyne 2a as model substrates in the presence of a RhIII
catalyst.[13] Gratifyingly, the unsymmetrical 2,3-diaryl-substi-
tuted indole 3a was obtained in 43% yield, along with 2,3-
diphenylindole (4a) and PhCHO as by-products (Table 1,
entry 1). The structure of 3a was confirmed unambiguously
bswan@dicp.ac.cn
[**] This research was supported by the NSFC (21372219).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503997.
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Table 1: Optimization of the reaction conditions.[a]
Entry
Change from the standard
conditions
3a/4a[b]
Yield of
3a [%][b]
1
2
none
1208C
10:1
8:1
43
31
3
4
808C
608C
3.4:1
5:1
30
31
5
6
1 equivalent of Cu(OAc)2
20 mol% of Cu(OAc)2
DCE/THF (1:1)
DCE/1,4-dioxane (1:1)
DCE/DME (1:1)
DCE/EDE (1:1)
DCE/EDE (1:4)
6.5:1
1:1
45
30
53
42
67
76
7[c]
8[c]
9[c]
10[c]
11[c]
>25:1
>25:1
>25:1
>25:1
>25:1
85 (81)[d]
[a] Standard reaction conditions: 2a (0.25 mmol), 1a (0.3 mmol,
1.2 equiv), [{Cp*RhCl2}2] (2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2
(2 equiv), DCE (2 mL), sealed tube, 1008C, 12 h. [b] The yield was
determined by GC analysis with naphthalene as an internal standard.
[c] The reaction was carried out with 1 equivalent of Cu(OAc)2; solvents
were combined in the v/v ratio indicated. [d] The yield of the isolated
product is given in parentheses. Cp*=1,2,3,4,5-pentamethylcyclo-
pentadienyl, DCE=1,2-dichloroethane, DME=1,2-dimethoxyethane,
EDE=1,2-diethoxyethane.
by X-ray crystal diffraction of its N-tosyl derivative (see the
Supporting Information). However, the result was not
improved by either increasing or lowering the reaction
temperature (Table 1, entries 2–4). Intriguingly, when
1 equivalent of Cu(OAc)2 was used, the yield of 3a was
improved to 45% (Table 1, entry 5). A further decrease in the
amount of Cu(OAc)2 to 20 mol% afforded the two products
in 60% combined yield (Table 1, entry 6). Unfortunately, the
amount of by-product 4a was also drastically increased. As
a mixed solvent proved to be crucial to reactivity in nitrone-
assisted C H activation,[13] we set out to evaluate the solvent
À
effect. To our delight, a 1:1 mixture of DCE and an ether
solvent efficiently promoted this reaction and almost com-
pletely inhibited the formation of 4a (Table 1, entries 7–10).
During further investigation of the components of the mixed
solvent, a 1:4 mixture of DCE and EDE gave the best result
(Table 1, entry 11).
Scheme 2. Synthesis of unsymmetrically 2,3-diaryl substituted indoles.
Reactions were carried out on a 0.25 mmol scale. Yields of the isolated
products are given. [a] The yield in parentheses is for a reaction on
a 2.5 mmol scale.
The scope of the reaction with respect to both the nitrone
and the diaryl alkyne substrate was then explored under the
optimized reaction conditions (Scheme 2). Variation of the C-
aryl ring (Ar1) of the nitrone was first examined. Substrates
with different substituents on the Ar1 ring were converted
into the corresponding unsymmetrically 2,3-diaryl substituted
indoles 3a–f in good yields, regardless of the electronic and
steric effects of the substituents. Nitrones bearing 2-furyl and
2-thienyl groups were transformed into the desired products
3g and 3h in 71 and 63% yield, respectively. Since only half of
the alkyne is regioselectively incorporated into the indole
ring, the use of unsymmetrical diaryl alkynes as coupling
partners is no longer necessary, thus avoiding the generation
of undesired regioisomers. Pleasingly, a variety of symmet-
rical diaryl alkynes containing electron-rich or electron-
deficient functional groups were well tolerated in this
reaction, and the desired products 3i–n were obtained in
good yields. Moreover, different combinations of electron-
withdrawing and electron-donating groups on the Ar1 and Ar2
substituents also afforded the products (compounds 3o–3t) in
good yields. In previous studies,[7d,q,r] reactions of unsym-
metrical diaryl alkynes with similar steric and electronic
characteristics commonly failed to provide pure regioisomers.
In contrast, our method enabled the regioselective prepara-
tion of structurally similar unsymmetrically 2,3-diaryl sub-
stituted indoles, for example, indoles 3a and 3i, 3b and 3j, 3c
and 3k, 3 f and 3n, and 3o and 3p. Indoles bearing
substituents at the 5-, 6-, and 7-positions were also synthesized
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in good yields (products 3u–y), although a slightly lower yield
was observed in one case (product 3x). Significantly, the 2-
aryl-3-alkyl indole 3z was synthesized from the corresponding
dialkyl alkyne in 65% yield.[17]
We conducted a series of experiments to probe the
reaction mechanism (Scheme 3). When nitrone 1a was
subjected to the standard conditions in the presence of
CH3COOD but without reaction partner 2a, significant
deuterium scrambling was observed (Scheme 3a). However,
no H/D exchange was observed on the indole ring when the
same reaction was performed in the presence of 2a; instead
23% deuteration was observed at the positions meta to the
involved in the rate-determining step.[19] Additionally, the
treatment of an equimolar amount of nitrones 1u (4-Me) and
1w (4-CO2Et) with alkyne 2a (0.83 equiv) afforded the
corresponding products 3u and 3w in a 2.9:1 molar ratio
(Scheme 3c). The preferential formation of product 3u with
À
an electron-rich substituent demonstrates that the C H
activation step might follow the electrophilic aromatic sub-
stitution pathway.[20]
To further understand the reaction process, we performed
a control experiment with a stoichiometric amount of the Rh
catalyst in the absence of Cu(OAc)2 (Scheme 3d). Interest-
ingly, by-product 4a was formed in 80% yield, and no 3a was
detected.[21] Furthermore, a catalytic amount of Cu(OAc)2
was sufficient to promote the reaction in moderate yield with
excellent selectivity (Scheme 3e). These results indicate that
the leading role of the Cu salt is probably to control the
selectivity and release the Rh catalyst from the product.[22]
Furthermore, when the reaction of 1a
À
methoxy group. These results indicated an irreversible C H
insertion step[18] on the indole ring under the reaction
conditions. Notable kinetic isotope effects (kH/kD = 2.6–4.0)
were observed in the isotope-labeling experiments (Sche-
À
me 3b), thus suggesting that the C H activation is probably
with 2a was stopped after 1 h, the 3H-
indole derivative 5 was isolated in 85%
yield (Scheme 3 f).
A plausible mechanism based on the
above results is proposed in Scheme 4.
The five-membered rhodacycle inter-
À
mediate A is first generated by C H
bond activation of nitrone 1a, followed
by alkyne coordination and insertion to
afford the seven-membered intermedi-
ate B (path a), which undergoes reduc-
tive elimination to provide the cationic
heterocyclic intermediate C. Intramolec-
ular oxygen-atom transfer occurs by the
tautomerization of C to C’, and the
subsequent oxidative addition of C’ and
intramolecular electrophilic attack of
the imino moiety furnishes intermediate
E. Intermediate 5 is then released by
transmetalation of the Rh catalyst with
the copper salt[23] and subsequent b-
hydride elimination. Finally, product 3a
is formed by elimination of one molecule
of PhCHO, as assisted by the copper
hydride generated in situ from F.[11b]
Alternatively, alkyne insertion at the N-
oxide side of the Rh center in A to
generate the rhodium–alkenyl inter-
mediate G is also possible (path b).[24]
However, N,a-diphenylnitrone reacted
preferentially
alkynes at the positively polarized or
less-hindered alkynyl atom (see
with
unsymmetrical
Scheme S1-8 in the Supporting Informa-
tion). These results reveal that path b is
less preferred; however, it could not be
completely ruled out at this stage.[24]
Indoline 6[25] could in principle be gen-
erated by the protonation of intermedi-
ate F. However, 6 was not isolated under
the standard conditions, and the
Scheme 3. Mechanistic studies.
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C. J. Moody, Chem. Sci. 2013,
4, 29; h) T. Guo, F. Huang, L.
Yu, Z. Yu, Tetrahedron Lett.
2015, 56, 296.
[3] For selected examples of
Fischer indole synthesis, see:
a) E. Fischer, F. Jourdan, Ber.
Dtsch. Chem. Ges. 1883, 16,
2241; b) E. Fischer, O. Hess,
Ber. Dtsch. Chem. Ges. 1884,
17, 559; c) S. Müller, M. J.
Webber, B. List, J. Am.
Chem. Soc. 2011, 133, 18534;
d) D. McAusland, S. Seo,
D. G. Pintori, J. Finlayson,
M. F. Greaney, Org. Lett.
2011, 13, 3667; e) S. Gore, S.
Baskaran, B. Kçnig, Org. Lett.
2012, 14, 4568; f) A. Porch-
eddu,
M. G.
Mura,
L.
De Luca, M. Pizzetti, M.
Taddei, Org. Lett. 2012, 14,
6112; g) D. Zhao, Z. Shi, F.
Glorius, Angew. Chem. Int.
Ed. 2013, 52, 12426; Angew.
Chem. 2013, 125, 12652.
[4] For selected examples of
Scheme 4. Proposed mechanism.
Larock indole synthesis, see:
a) R. C. Larock, E. K. Yum, J.
Am. Chem. Soc. 1991, 113, 6689; b) R. C. Larock, E. K. Yum,
M. D. Refvik, J. Org. Chem. 1998, 63, 7652.
attempted transformation of 6 into 3a failed (Scheme 3g),
thus indicating that indoline 6 might not be involved in this
reaction.[26]
In summary, we have developed a regioselective synthesis
of unsymmetrically 2,3-diaryl substituted N-unprotected
indoles through the rhodium(III)-catalyzed annulation of
[5] For selected examples of Buchwald indole synthesis, see: a) S.
Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120,
6621; b) S. Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem.
Soc. 1999, 121, 10251; c) J. L. Rutherford, M. P. Rainka, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 15168; d) A. DeAngelis,
D. H. Wang, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52,
3434; Angew. Chem. 2013, 125, 3518.
[6] For indole synthesis through CDC reactions, see: a) Z. Shi, F.
Glorius, Angew. Chem. Int. Ed. 2012, 51, 9220; Angew. Chem.
2012, 124, 9354; b) S. Würtz, S. Rakshit, J. J. Neumann, T. Drçge,
F. Glorius, Angew. Chem. Int. Ed. 2008, 47, 7230; Angew. Chem.
2008, 120, 7340; c) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi,
Angew. Chem. Int. Ed. 2009, 48, 8078; Angew. Chem. 2009, 121,
8222; d) W. Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11, 2417;
e) Z. H. Guan, Z. Y. Yan, Z. H. Ren, X. Y. Liu, Y. M. Liang,
Chem. Commun. 2010, 46, 2823; f) Z. He, W. Liu, Z. Li, Chem.
Asian J. 2011, 6, 1340; g) Y. Wei, I. Deb, N. Yoshikai, J. Am.
Chem. Soc. 2012, 134, 9098; h) X. L. Lian, Z. H. Ren, Y. Y.
Wang, Z. H. Guan, Org. Lett. 2014, 16, 3360; i) F. Huang, P. Wu,
L. Wang, J. Chen, C. Sun, Z. Yu, J. Org. Chem. 2014, 79, 10553;
j) J. J. Neumann, S. Rakshit, T. Drçge, S. Würtz, F. Glorius,
Chem. Eur. J. 2011, 17, 7298.
À
nitrones with symmetrical diaryl alkynes. Direct C H annu-
lations with unsymmetrical diaryl alkynes generally occur
with unpredictable regioselectivity. In our method, one of the
two aryl substituents on the indole ring is derived from the C-
aryl ring of the nitrone and the other from the alkyne moiety,
thus providing the indole products with exclusive regioselec-
tivity. We expect our findings to provide new opportunities in
indole chemistry and to find application in the synthesis of
complex structures.
À
Keywords: alkynes · C H activation · indoles · nitrones ·
rhodium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10613–10617
Angew. Chem. 2015, 127, 10759–10763
À
[7] For indole synthesis through directing-group-assisted C H
[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) T. Kawasaki, K. Higuchi, Nat. Prod. Rep. 2005,
22, 761; e) M. Somei, F. Yamada, Nat. Prod. Rep. 2005, 22, 73;
f) A. J. Kochanowska-Karamyan, M. T. Hamann, Chem. Rev.
2010, 110, 4489.
[2] For 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) S. Cacchi, G. Fabrizi, Chem. Rev. 2011,
111, PR215; e) D. F. Taber, P. K. Tirunahari, Tetrahedron 2011,
67, 7195; f) M. Shiri, Chem. Rev. 2012, 112, 3508; g) M. Inman,
annulation reactions, see: a) M. Shen, G. Li, B. Z. Lu, A.
Hossain, F. Roschangar, V. Farina, C. H. Senanayake, Org. Lett.
2004, 6, 4129; b) D. R. Stuart, M. Bertrand-Laperle, K. M.
Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 16474; c) Z.
Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew.
Chem. Int. Ed. 2009, 48, 4572; Angew. Chem. 2009, 121, 4642;
d) D. R. Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem.
Soc. 2010, 132, 18326; e) J. Chen, G. Song, C. L. Pan, X. Li, Org.
Lett. 2010, 12, 5426; f) M. P. Huestis, L. Chan, D. R. Stuart, K.
Fagnou, Angew. Chem. Int. Ed. 2011, 50, 1338; Angew. Chem.
2011, 123, 1374; g) J. Chen, Q. Pang, Y. Sun, X. Li, J. Org. Chem.
2011, 76, 3523; h) H. Wang, C. Grohmann, C. Nimphius, F.
Glorius, J. Am. Chem. Soc. 2012, 134, 19592; i) L. Ackermann,
10616 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Chemie
A. V. Lygin, Org. Lett. 2012, 14, 764; j) B. Liu, C. Song, C. Sun, S.
Zhou, J. Zhu, J. Am. Chem. Soc. 2013, 135, 16625; k) C. Wang, Y.
Huang, Org. Lett. 2013, 15, 5294; l) C. Wang, H. Sun, Y. Fang, Y.
Huang, Angew. Chem. Int. Ed. 2013, 52, 5795; Angew. Chem.
2013, 125, 5907; m) W. Song, L. Ackermann, Chem. Commun.
2013, 49, 6638; n) S. Cai, K. Yang, D. Z. Wang, Org. Lett. 2014,
16, 2606; o) L. Zheng, R. Hua, Chem. Eur. J. 2014, 20, 2352;
p) W. J. Chen, Z. Lin, Organometallics 2015, 34, 309; q) G.
Zhang, H. Yu, G. Qin, H. Huang, Chem. Commun. 2014, 50,
4331; r) Y. Hoshino, Y. Shibata, K. Tanaka, Adv. Synth. Catal.
2014, 356, 1577; s) Z. Fan, S. Song, W. Li, K. Geng, Y. Xu, Z. H.
Miao, A. Zhang, Org. Lett. 2015, 17, 310.
J. Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; Angew. Chem.
2009, 121, 5196; c) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010,
110, 1147; d) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew.
Chem. Int. Ed. 2012, 51, 8960; Angew. Chem. 2012, 124, 9092;
e) L. Ackermann, Acc. Chem. Res. 2014, 47, 281; f) X. S. Zhang,
K. Chen, Z. J. Shi, Chem. Sci. 2014, 5, 2146; g) H. Huang, X. Ji,
W. Wu, H. Jiang, Chem. Soc. Rev. 2015, 44, 1155; h) G. Song, X.
Li, Acc. Chem. Res. 2015, 48, 1007.
[13] C. Wang, D. Wang, H. Yan, H. Wang, B. Pan, X. Xin, X. Li, F.
Wu, B. Wan, Angew. Chem. Int. Ed. 2014, 53, 11940; Angew.
Chem. 2014, 126, 12134.
[14] N. Duguet, A. M. Z. Slawin, A. D. Smith, Org. Lett. 2009, 11,
3858.
[8] For indole synthesis involving o-alkynyl anilines or related
compounds, see: a) M. Nakamura, L. Ilies, S. Otsubo, E.
Nakamura, Org. Lett. 2006, 8, 2803; b) B. Z. Lu, W. Zhao,
H. X. Wei, M. Dufour, V. Farina, C. H. Senanayake, Org. Lett.
2006, 8, 3271; c) Z. Shen, X. Lu, Tetrahedron 2006, 62, 10896;
d) S. Cacchi, G. Fabrizi, A. Goggiamani, Adv. Synth. Catal. 2006,
348, 1301; e) N. Isono, M. Lautens, Org. Lett. 2009, 11, 1329; f) S.
Cacchi, G. Fabrizi, A. Goggiamani, A. Perboni, A. Sferrazza, P.
Stabile, Org. Lett. 2010, 12, 3279; g) T. Shibata, H. Hirashima, M.
Kasagawa, K. Tsuchikama, K. Endo, Synlett 2011, 2171; h) B.
Yao, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2012, 51, 12311;
Angew. Chem. 2012, 124, 12477; i) B. Z. Lu, H. W. Wei, Y. Zhang,
W. Zhao, M. Dufour, G. Li, V. Farina, C. H. Senanayake, J. Org.
Chem. 2013, 78, 4558; j) S. P. Breazzano, Y. B. Poudel, D. L.
Boger, J. Am. Chem. Soc. 2013, 135, 1600; k) D. Shan, Y. Gao, Y.
Jia, Angew. Chem. Int. Ed. 2013, 52, 4902; Angew. Chem. 2013,
125, 5002; l) P. Tao, Y. Jia, Chem. Commun. 2014, 50, 7367; m) X.
Zhang, Y. Li, H. Shi, L. Zhang, S. Zhang, X. Xu, Q. Liu, Chem.
Commun. 2014, 50, 7306; n) B. Zhou, Y. Yang, H. Tang, J. Du, H.
Feng, Y. Li, Org. Lett. 2014, 16, 3900.
[15] For reports on carbon–carbon triple-bond cleavage, see: a) H.
Liu, M. Feng, X. Jiang, Chem. Asian J. 2014, 9, 3360; b) T. Shen,
T. Wang, C. Qin, N. Jiao, Angew. Chem. Int. Ed. 2013, 52, 6677;
Angew. Chem. 2013, 125, 6809; c) N. Okamoto, M. Ishikura, R.
Yanada, Org. Lett. 2013, 15, 2571; d) Q. Liu, P. Chen, G. Liu, ACS
Catal. 2013, 3, 178; e) H. Z. Xie, Q. Gao, Y. Liang, H. S. Wang,
Y. M. Pan, Green Chem. 2014, 16, 2132; f) J. Sun, F. Wang, H. Hu,
X. Wang, H. Wu, Y. Liu, J. Org. Chem. 2014, 79, 3992; g) T.
Shimada, Y. Yamamoto, J. Am. Chem. Soc. 2003, 125, 6646;
h) D. Y. Lee, B. S. Hong, E. G. Cho, H. Lee, C. H. Jun, J. Am.
Chem. Soc. 2003, 125, 6372; i) S. Datta, C. L. Chang, K. L. Yeh,
R. S. Liu, J. Am. Chem. Soc. 2003, 125, 9294; j) Y. Liu, F. Song, S.
Guo, J. Am. Chem. Soc. 2006, 128, 11332; k) A. Wang, H. Jiang,
J. Am. Chem. Soc. 2008, 130, 5030; l) M. Gaydou, A. M.
Echavarren, Angew. Chem. Int. Ed. 2013, 52, 13468; Angew.
Chem. 2013, 125, 13710.
[16] Only a handful of examples of the synthesis of N-unprotected
À
indoles by intermolecular C H annulation with alkynes have
been reported; see Refs. [3g,7l,o,q].
[9] For indole synthesis involving azides, see: a) J. Bonnamour, C.
Bolm, Org. Lett. 2011, 13, 2012; b) K. Sun, S. Liu, P. M. Bec, T. G.
Driver, Angew. Chem. Int. Ed. 2011, 50, 1702; Angew. Chem.
2011, 123, 1740; c) B. J. Stokes, S. Liu, T. G. Driver, J. Am. Chem.
Soc. 2011, 133, 4702; d) Q. Nguyen, T. Nguyen, T. G. Driver, J.
Am. Chem. Soc. 2013, 135, 620; e) Y. Goriya, C. V. Ramana,
Chem. Commun. 2014, 50, 7790.
[17] Unfortunately, because of the instability of C-alkyl nitrones, we
have not yet succeeded in using this protocol to synthesize 2-
alkyl-3-aryl or 2-alkyl-3-alkyl-substituted indoles.
[18] T. K. Hyster, T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565.
[19] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066; Angew. Chem. 2012, 124, 3120.
[20] The high KIE values (2.6 – 4.0) observed in this reaction suggest
that slow hydrogen abstraction might occur after the electro-
[10] For other examples, see: a) T. Fukuyama, X. Chen, G. Peng, J.
Am. Chem. Soc. 1994, 116, 3127; b) H. Tokuyama, T. Yamashita,
M. T. Reding, Y. Kaburagi, T. Fukuyama, J. Am. Chem. Soc.
1999, 121, 3791; c) C. Mukai, Y. Takahashi, Org. Lett. 2005, 7,
5793; d) G. Babu, A. Orita, J. Otera, Org. Lett. 2005, 7, 4641;
e) K. G. Liu, A. J. Robichaud, J. R. Lo, J. F. Mattes, Y. Cai, Org.
Lett. 2006, 8, 5769; f) S. Tanimori, H. Ura, M. Kirihata, Eur. J.
Org. Chem. 2007, 3977; g) A. Saito, A. Kanno, Y. Hanzawa,
Angew. Chem. Int. Ed. 2007, 46, 3931; Angew. Chem. 2007, 119,
4005; h) M. Tursky, L. L. R. Lorentz-Petersen, L. B. Olsen, R.
Madsen, Org. Biomol. Chem. 2010, 8, 5576; i) Y. Tan, J. F.
Hartwig, J. Am. Chem. Soc. 2010, 132, 3676; j) S. Jana, M. D.
Clements, B. K. Sharp, N. Zheng, Org. Lett. 2010, 12, 3736; k) D.
Janreddy, V. Kavala, J. W. J. Bosco, C. W. Kuo, C. F. Yao, Eur. J.
Org. Chem. 2011, 2360; l) T. Nanjo, C. Tsukano, Y. Takemoto,
Org. Lett. 2012, 14, 4270; m) B. V. S. Reddy, M. R. Reddy, Y. G.
Rao, J. S. Yadav, B. Sridhar, Org. Lett. 2013, 15, 464; n) S. Zhu,
A. Das, L. Bui, H. Zhou, D. P. Curran, M. Rueping, J. Am. Chem.
Soc. 2013, 135, 1823; o) Y. Liang, K. Yu, B. Li, S. Xu, H. Song, B.
Wang, Chem. Commun. 2014, 50, 6130; p) M. K. Manna, A.
Hossian, R. Jana, Org. Lett. 2015, 17, 672.
À
philic attack of Rh on the N-phenyl ring in the C H activation
process. For similar observations, see Ref. [13]; see also: X.
Zhao, C. S. Yeung, V. M. Dong, J. Am. Chem. Soc. 2010, 132,
5837.
[21] With 0.25 equivalents of [{Cp*RhCl2}2] (50 mol% Rh), 4a was
isolated in 35% yield, and no 3a was detected.
[22] The use of Fe(OAc)2 or Mn(OAc)2 (1 equiv) instead of Cu-
(OAc)2 did not afford any product. The replacement of Cu-
(OAc)2 with Cu(OTf)2 (1 equiv) only gave 3a in 30% yield.
[23] F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2154.
[24] X. Zhang, Z. Qi, X. Li, Angew. Chem. Int. Ed. 2014, 53, 10794;
Angew. Chem. 2014, 126, 10970.
[25] During the preparation of this manuscript, the rhodium(III)-
catalyzed cyclization of aryl nitrones with diaryl alkynes was
reported to afford indolines in the absence of copper salts: R. B.
Dateer, S. Chang, J. Am. Chem. Soc. 2015, 137, 4908.
[26] For the formation of by-product 4a, see the Supporting
Information.
[11] a) G. A. Kraus, H. Guo, J. Org. Chem. 2009, 74, 5337; b) T. Kim,
K. Kim, Tetrahedron Lett. 2010, 51, 868; c) X. Dou, W. Yao, S.
Wen, Y. Lu, Chem. Commun. 2014, 50, 9469.
[12] For selected reviews, see: a) I. V. Seregin, V. Gevorgyan, Chem.
Soc. Rev. 2007, 36, 1173; b) X. Chen, K. M. Engle, D. H. Wang,
Received: May 1, 2015
Published online: July 14, 2015
Angew. Chem. Int. Ed. 2015, 54, 10613 –10617
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