Rh2(DOSP)4-catalyzed reaction of 2- or 3-methyl-N-Boc-
indoles with donor-acceptor carbenoids.5
Table 1. Reaction Optimizationa
Since the pioneering works by Nishiyama and co-workers,6
Ru-catalyzed alkene cyclopropanation has been extensively
investigated.7 However, there are limited examples on
ruthenium-catalyzed carbenoid C-H insertion reactions in
the literature. Recently, we showed that [RuCl2(p-cymene)]2
can effect catalytic stereoselective intramolecular carbenoid
C-H insertion reactions, and cis-ꢀ-lactams were obtained
in excellent yields.8e As our continuing interest to develop
catalytic C-H bond functionalizations,8 herein we describe
regioselective C2 carbenoid C-H functionalization of NH
free indoles using [RuCl2(p-cymene)]2 as catalyst, and
2-indolyl aryl carboxylic esters were obtained in 80-90%
yields. Indeed, direct C3-selective indole functionalizations
are well established,9 the analogous regioselective C2
functionalization remains challenging.10 A recent work by
Carretero and co-workers showed that regioselective Pd-
catalyzed C2 alkenylation of indoles and pyrroles can be
achieved by employing a N-(2-pyridyl)sulfonyl moiety as a
directing group.10i To date, there are few examples on direct
C2-selective functionalization of NH-free indoles.10d,h,l
Treatment of indole 1a (0.5 mmol) with methyl phenyl-
diazoacetate 2a (0.25 mmol) and [RuCl2(p-cymene)]2 (2 mol
%) in DCM at room temperature for 0.5 h produced 3aa in
96% isolated yield (Table 1, entry 1). The molecular structure
of a chlorinated derivative 3fa has been established by X-ray
entry
solvent
temp (°C)
time (h)
yield (%)b
1
DCM
rt
0.5
7
7
4
1
18
18
18
18
18
96c
60
18
70
2d
3d
4
toluene
toluene
toluene
DCE
CH3CN
THF
MeOH
dioxane
DMF
40
100
rt
rt
rt
rt
rt
rt
rt
5
6
7
8
9
10
52
trace
trace
trace
e
-
e
-
a Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), solvent (2 mL). b Yields were determined by GC-
FID with tetradecane as internal standard. The percentage yield is based
on the amount of the limiting reagent. c 2 mol % of catalyst was used;
isolated yield. d 1a:2a ) 1:1. e No detectable product formation.
crystallography (see the Supporting Information). In this
work, a one-pot protocol was effective for the reactions of
diazoesters with indole; no dimer formation was detected
by GC-MS analysis. Without the Ru catalyst, no 3aa was
formed with full recovery of the starting materials.
(4) (a) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67, 6247. (b) Antos,
J. M.; Francis, M. B. J. Am. Chem. Soc. 2004, 126, 10256.
For the reaction of 1a with 2a, higher reaction temperature
(40-100 °C) gave poorer results with some dimer formation
(entries 2 and 3). While employing toluene and DCE as
solvent for the indole functionalization would give 3aa in
lower yields (entries 4 and 5), little or no product formation
was observed if CH3CN, THF, MeOH, dioxane, or DMF
was employed as the solvent (entries 6-10). Moreover, use
of exogenous ligands (e.g., pybox, PPh3, and acetate) led to
no product formation based on GC-MS analysis.
(5) Hedley, S. J.; Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.;
Davies, H. M. L. J. Org. Chem. 2006, 71, 5349.
(6) (a) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki,
K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247. (b) Nishiyama, H.; Itoh,
Y.; Sugawara, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc.
1994, 116, 2223.
(7) For a review, see: Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. ReV. 2003, 103, 977.
(8) (a) Yu, W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S.-C. Org. Lett. 2009,
11, 3174. (b) Yu, W.-Y.; Tai, Y.-T.; Zhou, Z.; Chan, A. S. C. Org. Lett.
2009, 11, 469. (c) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan,
A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (d) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (e) Choi, M. K.-W.; Yu,
W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081. (f) Cheung, W.-H.; Zheng,
S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org. Lett. 2003, 5, 2535.
(9) For selected examples of C3-selective alkylations of indoles, see:
(a) Hong, L.; Wang, L.; Chen, C.; Zhang, B.; Wang, R. AdV. Synth. Catal.
2009, 351, 772. (b) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte,
M. Angew. Chem., Int. Ed. 2008, 47, 593. (c) Itoh, J.; Fuchibe, K.; Akiyama,
T. Angew. Chem., Int. Ed. 2008, 47, 4061. (d) Dong, H.-M.; Lu, H.-H.;
Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J. AdV. Synth. Catal. 2007, 349, 1597.
(e) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C.
Org. Biomol. Chem. 2007, 5, 816. (f) Blay, G.; Ferna´ndez, I.; Pedro, J. R.;
Vila, C. Org. Lett. 2007, 9, 2601. (g) Yang, H.; Hong, Y.-T.; Kim, S. Org.
Lett. 2007, 9, 2281. (h) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.;
Xiao, W.-J. Org. Lett. 2007, 9, 1874. (i) Bartoli, G.; Bosco, M.; Carlone,
A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403.
(10) For C2 arylation of indoles, see: (a) Joucla, L.; Djakovitch, L. AdV.
Synth. Catal. 2009, 351, 673. (b) Phipps, R. J.; Grimster, N. P.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 8172. (c) Lebrasseur, N.; Larrosa, I.
J. Am. Chem. Soc. 2008, 130, 2926. (d) Wang, X.; Gribkov, D. V.; Sames,
D. J. Org. Chem. 2007, 72, 1476. (e) Stuart, D. R.; Villemure, E.; Fagnou,
K. J. Am. Chem. Soc. 2007, 129, 12072. (f) Toure, B. B.; Lane, B. S.;
Sames, D. Org. Lett. 2006, 8, 1979. (g) Lane, B. S.; Sames, D. Org. Lett.
2004, 6, 2897. (h) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125,
5274. For C2 alkenylation of indoles, see: (i) Garc´ıa-Rubia, A.; Arraya´s,
R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48–6511. (j) Maehara,
A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159. (k) Capito,
E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854. (l) Grimster, N. P.;
Guantlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005,
44, 3125.
To scrutinize for any N-H/C3 alkylation,11 we undertook
GC-MS analysis of the reaction mixture. To our delight, only
3aa and the unreacted indole were observed, and no N-H
and C3 alkylated products were detected. The outcome of
the Ru-catalyzed indole functionalization is dependent upon
the N-substituents. For example, treatment of N-Boc (Boc
) tert-butoxycarbonyl) or N-phenylindole with 2a under our
experimental conditions failed to afford any desired products
with complete recovery of the indoles and diazo reagents.
Yet, N-methylindole reacted with 2a to give the 3-alkylated
product (52%) exclusively without any 2-alkylated products
being isolated.
Table 2 depicts the results of the Ru-catalyzed indole
functionalization by various aryldiazoesters. The substituted
aryldiazoesters 2b-g (substituent ) Me, F, Cl, Br, CF3, NO2)
can effectively transform 1a to its corresponding 2-alkylated
indoles in 48-92% yields (entries 2-7). With the methoxy-
substituted diazoesters 2h and 2i, the Ru-catalyzed transfor-
mations furnished the desired products in 83% and 84%
(11) Deng, Q.-H.; Xu, H.-W.; Yuen, A. W.-H.; Xu, Z.-J.; Che, C.-M.
Org. Lett. 2008, 10, 1529.
Org. Lett., Vol. 12, No. 3, 2010
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