group under very simple reaction conditions. This is the
first N-alkyl indole synthesis via directed CÀH activation.
We recently reported the first Rh(III)-catalyzed indole
synthesis using a removable triazene directing group and
stoichiometric Cu(OAc) as an oxidant. However, this
2
reaction only worked for electron-neutral aryl triazenes.
Electron-deficientand -richsubstratesaffordedpooryields
Although the corresponding N-nitroso group for directed
9
oxidative Heck reactions was recently reported by Zhu,
no information has been found regarding the use of
NÀNO for Rh(I) oxidation. We decided to pursue this
designer traceless directing strategy (TDS) for indole
synthesis, in which the N-nitroso group kills two birds
with one stone by serving as both a directing group for the
CÀH activation and an internal oxidant (via NÀN clea-
vage, Scheme 1e).
5
f,7
(Scheme 1d). Subsequently, we decided to expand the
substrate scope of our triazene method. More importantly,
we wanted to eliminate the need for 2 equiv of Cu(OAc) in
2
order to turn over the Rh catalyst, which resulted in poor
atom economy and was notoriously difficult to work with
on large scales. Almost all redox-neutral CÀH activation
reactions have employed a NÀO bond as the internal
Scheme 1. Indoles Synthesis via CÀH Functionalization
6
,8
oxidant for Rh turnover. Experimentally, the N2ÀN3
bond of the triazene did not have enough oxidative poten-
5
f
tial to convert Rh(I) to Rh(III). In the absence of an
external oxidant, the reaction afforded only ∼5% of the
indole product. We envisioned that a more electron-
extracting NÀNO bond might be a sufficient internal oxi-
dant. An additional benefit of this design was that it would
allow for the installation of an alkyl group on the nitrogen
attached to the arene, leading to N-alkyl indole products.
(
4) For a recent review on the synthesis of indoles via oxidative
coupling, see: (a) Shi, Z.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
220. For recent examples of indole synthesis using an oxidative
9
coupling strategy, see: (b) W u€ rtz, S.; Rakshit, S.; Neumann, J. J.; Dr o€ ge,
T.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230. (c) Zhao, J.;
Larock, R. C. Org. Lett. 2005, 7, 701. (d) Shen, M.; Leslie, B. E.; Driver,
T. G. Angew. Chem., Int. Ed. 2008, 47, 5056. (e) Shi, Z.; Zhang, C.; Li, S.;
Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572.
(
f) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int.
Ed. 2009, 48, 8078. (g) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11,
417. (h) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.; Liu, X.-Y.; Liang, Y.-M.
2
Chem. Commun. 2010, 46, 2823. (i) Neumann, J. J.; Rakshit, S.; Dr o€ ge,
T.; W u€ rtz, S.; Glorius, F. Chem.;Eur. J. 2011, 17, 7298. (j) Lu, B.; Luo,
Y.; Liu, L.; Ye, L.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50,
8
9
358. (k) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134,
098. (l) Shi, Z.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 9220. (m)
Nanjo, T.; Tsukano, C.; Takemoto, Y. Org. Lett. 2012, 14, 4270. (n)
Breazzano, S. P.; Poudel, Y. B.; Boger, D. L. J. Am. Chem. Soc. 2013,
135, 1600. (o) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett.
2013, 15, 1802. (p) Besandre, R.; Jaimes, M.; May, J. A. Org. Lett. 2013,
15, 1666.
(
5) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326.
Our initial investigation was performed by examining
N-methyl-N-phenylnitrous amide 1a and diphenylacetylene
2a in the presence of [RhCp*(CH CN) ][SbF ] and KOAc
(
c) Huestis, M. P.; Chan, L. N.; Stuart, D. R.; Fagnou, K. Angew. Chem.,
Int. Ed. 2011, 50, 1338. (d) Zhou, F.; Han, X.; Lu, X. Tetrahedron Lett.
011, 52, 4681. (e) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764.
f) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew. Chem., Int. Ed. 2013,
2, 5795.
2
(
5
3
3
6 2
in MeOH under air. Gratifyingly, the indole product 3a
was obtained in 38% GC-MS yield (Table 1, entry 1; for a
comprehensive investigation of the conditions, see Support-
ing Information). This result demonstrated that the Rh
catalyst was indeed recycled by the nitroso directing group
through internal oxidation. The acetate counterion was
critical for efficient Rh insertion, as other salts failed to pro-
mote the reaction. This suggested a concerted metalationÀ
deprotonation (CMD) mechanism for the CÀH activation.
MeOH was essential for decent conversion (Table 1, entries
(
(
6) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676.
7) (a) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y. Angew.
Chem., Int. Ed. 2012, 51, 7242. (b) Wang, C.; Huang, Y. Synlett 2013,
45.
8) For examples of redox neutral CÀH activation, see: (a) Wu, J.;
Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888.
b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
1
(
(
132, 6908. (c) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc.
2010, 132, 12862. (d) Ureshino, T.; Yoshida, T.; Kuninobu, Y.; Takai,
K. J. Am. Chem. Soc. 2010, 132, 14324. (e) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (f) Ackermann,
L.; Fenner, S. V. Org. Lett. 2011, 13, 6548. (g) Liu, G.; Shen, Y.; Zhou, Z.;
Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033. (h) Shen, Y.; Liu, G.; Zhou,
Z.; Lu, X. Org. Lett. 2013, 15, 3366. While this work was under review, a
redox-neutral synthesis of indoles using hydrazides as a traceless directing
group appeared online, see: (i) Zhao, D.; Shi, Z.; Glorius, F. Angew. Chem.
Int. Ed. 2013, DOI: 10.1002/anie.201306098.
1
À7). We reasoned that the particularly high conversions
observed for Cu(OAc) and AgOAc were due to the more
2
facile OAc exchange with chloride. We then examined
[RhCp*(OAc) ] in lieu of [RhCp*Cl ] and the acetate
2 2 2
additive. We were delighted to find that this complex
(9) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem.
Soc. 2013, 135, 468.
B
Org. Lett., Vol. XX, No. XX, XXXX