site, especially in route a. Because of the higher nucleo-
philic character of the C3 and C6 positions of the carba-
zole, the electrophilic substitution at the C3 and/or C6
positions constitutes an efficient alternative approach for
the direct functionalization of the carbazole skeleton.6 As a
consequence of this electronic distribution, substitution at
the less activated C1 and C8 of the carbazole typically
requires prior protection of the 3,6-positions.2aꢀc,5
In stark contrast to the tremendous progress made with
related nitrogen aromatic systems,7 methods for the cata-
lytic direct CꢀH functionalization of the carbazole core
are quite rare, and only recently have the first successful
examples appeared. Chu, Wu and co-workers disclosedthe
PdII-catalyzed direct ortho-arylation of carbazoles bearing
a N-(pyridin-2-yl) directing group with potassium aryl-
trifluoroborates.8 Patureau et al. have reported the direct
dehydrogenative C1ꢀN carbazolation of NH-carbazoles by
the cooperative action of Ru and Cu catalysts.9 Within this
context, new methods for the regiocontrolled direct CꢀH
functionalization, providing orthogonal selectivities to
those currently available, as well as other types of function-
alization, are of great interest in carbazole synthesis.
We have recently reported the PdII-catalyzed direct
olefination of N-alkyl N-(2-pyridyl)sulfonyl anilines and
arylalkylamines.10 On the basis of the excellent structural
flexibility displayed by thismethod, we hypothesized thatit
could be also extended to the CꢀH functionalization of
carbazole derivatives. To our delight, this was indeed the
case, and herein we disclose a reliable protocol for the PdII-
catalyzed ortho-olefination of N-(2-pyridyl)sulfonyl carba-
zoles and structurally related heterocyclic systems. To the
best of our knowledge, our work constitutes the first
example of a Pd-catalyzed direct ortho-olefination of the
carbazole nucleus.11
Table 1. Optimization of the N-Directing/Protecting Group
entry
PG (substrate)
H (1)
[ox]
[Fþ]c
[Fþ]c
[Fþ]c
[Fþ]c
conv (%)a yield [6/7, (%)]b
d
€
(6) For instance, see: (a) Dierschke, F.; Grimsdale, A. C.; Mullen, K.
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
ꢀ
d
Synthesis 2003, 2470. (b) Maegawa, Y.; Goto, Y.; Inagaki, S.; Shimada,
T. Tetrahedron Lett. 2006, 47, 6957. (c) Kumar, G. G. K. S. N.; Laali,
K. K. Tetrahedron Lett. 2013, 54, 965.
Boc (2)
Ac (3)
Ts (4)
ꢀ
<5
<5
93
70
66
100
95
ꢀ
ꢀ
(7) For recent reviews on dehydrogenative Heck reaction: (a) Le
Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (c) Kozhushkov, S. I.; Ackermann, L.
Chem. Sci. 2013, 4, 886. For selected examples on oxidative olefination
of nitrogen-containing arenes and heteroarenes: (d) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed.
2005, 44, 3125. (e) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J.
J. Am. Chem. Soc. 2006, 128, 2528. (f) Maehara, A.; Tsurugi, H.; Satoh,
T.; Miura, M. Org. Lett. 2008, 10, 1159. (g) Li, J.-J.; Mei, T.-S.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2008, 47, 6452. (h) Beck, E. M.; Hatley, R.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004. (i) Wu, J.; Cui, X.;
Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888. (j)
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982. (k) Ye,
M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (l) Dai,
H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem.
Soc. 2011, 133, 7222. (m) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214. (n)
Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
1064. (o) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2011, 13, 706. (p) Wang, L.; Liu, S.; Li, Z.; Yu, Y. Org.
Lett. 2011, 13, 6137. (q)Wang, L.;Guo, W.;Zhang, X.-X.;Xia, X.-D.;Xiao,
W.-J. Org. Lett. 2012, 14, 740. (r) Kandukuri, S. R.; Schiffner, J. A.;
Oestreich, M. Angew. Chem., Int. Ed. 2012, 51, 1265. (s) Huang, Y.; Song,
F.; Wang, Z.; Xi, P.; Wu, N.; Wang, Z.; Lan, J.; You, J. Chem. Commun.
2012, 48, 2864. (t) Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Wang,
Y.-F.; Wang, Y.-Q. Org. Lett. 2012, 14, 5920. (u) Liang, Z.; Ju, L.; Xie, Y.;
Huang, L.; Zang, Y. Chem.;Eur. J. 2012, 18, 15816. (v) Zhao, P.; Niu, R.;
Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14, 4166. (w) Schroeder, N.;
Besset, T.; Glorius, F. Adv. Synth. Catal. 2012, 354, 579. (x) Li, B.; Ma, J.;
Wang, N.; Feng, H.; Xu, S. Org. Lett. 2012, 14, 736. (y) Ding, Z.; Yoshikai,
N. Angew. Chem., Int. Ed. 2012, 51, 4698. (z) Li, G.; Ding, Z.; Xu, B. Org.
Lett. 2012, 14, 5338. (aa) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y.
Angew. Chem., Int. Ed. 2012, 51, 7242. (ab) Wen, P.; Li, Y.; Zhou, K.; Ma,
C.; Lan, X.; Ma, C.; Huang, G. Adv. Synth. Catal. 2012, 354, 3125. (ac)
Zhang, G.; Ma, Y.; Wang, S.; Zhang, Y.; Wang, R. J. Am. Chem. Soc. 2012,
134, 12334. (ad) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14,
3400. (ae) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M.
J. Org. Chem. 2013, 78, 638. (af) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.;
Zhu, J. J. Am. Chem. Soc. 2013, 135, 468. (ag) Shang, Y.; Jie, X.; Zhou, J.;
Hu, P.; Huang, S.; Su, W. Angew. Chem., Int. Ed. 2013, 52, 1299.
ꢀSO2(2-pyridyl) (5) [Fþ]c
ꢀSO2(2-pyridyl) (5) [Fþ]c,e
ꢀSO2(2-pyridyl) (5) [Fþ]c,f
ꢀSO2(2-pyridyl) (5) [Fþ]c,g
ꢀSO2(2-pyridyl) (5) PhI(OAc)2
11/42
20/22
19/23
ꢀ/64
16/58
g
a Based on starting material recovered after chromatographic pur-
ification. b Isolated yield after chromatography. c [Fþ] = N-fluoro-2,4,6-
trimethylpyridinium triflate. d Complex reaction mixture. e 1.1 equiv of
butyl acrylate was used. f 1.0 equiv of oxidant was used. g 4 equiv of butyl
acrylate and 3.0 equiv of oxidant were used.
To evaluate the role of the protecting/directing group, a
set of potentially coordinating protecting groups (PG)
were examined in the reaction of carbazole derivatives
2ꢀ5 with butyl acrylate under the previously optimized
conditions:10 Pd(OAc)2 (10 mol %), N-fluoro-2,4,6-
trimethylpyridinium triflate ([Fþ], 2.0 equiv) as the oxidant12
in ClCH2CH2Cl at 110 °C (Table 1, entries 1ꢀ5). Both the
unprotected NH-carbazole (1) and the N-Boc derivative 2
led to a complex mixture of products (entries 1 and 2),
with the latter result suggesting that the Boc protecting
group is too labile under the reaction conditions. Switch-
ing to an N-Ac group (substrate 3) or an N-Ts group (4)4d
resulted in the full recovery of the unreacted starting
(11) For the ortho-directed lithiation/functionalization of carbazole:
Katrizky, A. R.; Rewcastle, G. W.; Vazquez de Miguel, L. M. J. Org.
Chem. 1988, 53, 794.
(12) Among other oxidants examined, PhI(OAc)2 showed similar
performance as [Fþ], whereas Ce(SO4)2 and AgNO3 led to lower
reactivity while still maintaining poor monoselectivity. Other oxidants
such as Cu(OAc)2, 1,4-benzoquinone, Ag2O, K2S2O8, oxone, or Tempo
led to full recovery of the starting material. See Supporting Information
for other oxidant screening results.
(8) Chu, J.-H.; Wu, C.-C.; Chang, D.-H.; Lee, Y.-M.; Wu, M.-J.
Organometallics 2013, 32, 272.
(9) Louillat, M.-L.; Patureau, F. W. Org. Lett. 2013, 15, 164.
ꢀ
ꢀ
(10) Garcıa-Rubia, A.; Urones, B.; Gomez Arrayas, R.; Carretero,
J. C. Angew. Chem., Int. Ed. 2011, 50, 10927.
B
Org. Lett., Vol. XX, No. XX, XXXX