Palladium-catalyzed sp3 C-H activation of simple alkyl groups: Direct preparation of indoline derivatives from N-alkyl-2-bromoanilines

Article abstract of DOI:10.1021/ol800425z

The sp³ C-H activation of a simple alkyl group catalyzed by palladium(O) provides a novel and convenient strategy for the synthesis of various indolines from simple precursors, such as N-alkyl-2-bromoanilines. This study demonstrates that assisting moieties In the substrate such as a pyridine or quaternary carbon are not always necessary for sp³ C-H activation.

Full text of DOI:10.1021/ol800425z

ORGANIC
LETTERS
Palladium-Catalyzed sp3 CsH Activation
of Simple Alkyl Groups: Direct
Preparation of Indoline Derivatives from
N-Alkyl-2-bromoanilines
2008
Vol. 10, No. 9
1759-1762
Toshiaki Watanabe, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received February 24, 2008
ABSTRACT
The sp3 C-H activation of a simple alkyl group catalyzed by palladium(0) provides a novel and convenient strategy for the synthesis of
various indolines from simple precursors, such as N-alkyl-2-bromoanilines. This study demonstrates that assisting moieties in the substrate
such as a pyridine or quaternary carbon are not always necessary for sp3 C-H activation.
Over the past decade, transition-metal-catalyzed C-H bond
activation has become an extremely powerful tool for the
synthesis of useful compounds including industrial materials,
medicines, and natural products.1 In contrast to the relatively
facile sp2 C-H bond activation due to the existence of
π-electrons that interact with metal complexes,2–4 activation
of sp3 C-H bonds is one of the current challenges in organic
chemistry. Except for the activation of sp3 C-H bonds at
the benzylic position5 or those next to heteroatoms,6 most
of the reported examples of unactivated simple C-H bonds7
rely upon the assistance of a pyridine8 or R-quaternary carbon
moiety9 in the substrates. We expect that sp3 C-H activation
(5) (a) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289.
(b) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462. (c) Ren,
H.; Li, Z.; Knochel, P. Chem. Asian. J. 2007, 2, 416.
(1) For recent reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem.
ReV. 1997, 97, 2879. (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
(2) For recent reviews, see: (a) Crabtree, R. H. J. Organomet. Chem.
2004, 689, 4083. (b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003,
(6) (a) Dyker, G. Angew. Chem., Int. Ed. 1992, 31, 1023. (b) Dyker, G.
J. Org. Chem. 1993, 58, 6426. (c) DeBoef, B.; Pastine, S. J.; Sames, D.
J. Am. Chem. Soc. 2004, 126, 6556. (d) Li, Z.; Bohle, D. S.; Li, C.-J. Proc.
Natl. Acad. Sci. U. S. A. 2006, 103, 8928. (e) Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220.
345, 1077
.
(7) For rhodium-catalyzed sp3 C-H activation of simple alkanes without
using any assisting groups in the substrate, see: Chen, H.; Schlecht, S.;
Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.
(3) For recent examples of sp2 C-H activation, see: (a) Campeau, L.-
C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
(b) Garcia-Cuadrado, D.; Mendoza, P.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (c) Terao, Y.; Wakui,
H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407.
(8) (a) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405.
(b) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935. (c) Kalyani, D.; Deprez, N. R.;
Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d)
Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (e) Zaitsev, V. G.;
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (f) Reddy,
B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (g) Chen, X.;
Goodhue, C. E.; Yu, J.-Q J. Am. Chem. Soc. 2006, 128, 12634. (h) For
pyridine- or oxime-assisted reactions, see: Desai, L. V.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 9542.
(d) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496
.
(4) (a) For our related works, see: Ohno, H.; Miyamura, K.; Takeoka,
Y.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647. (b) Ohno, H.;
Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44,
5103. (c) Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H.
Chem. Commun. 2007, 43, 4516. (d) Ohno, H.; Iuchi, M.; Fujii, N.; Tanaka,
T. Org. Lett. 2007, 9, 4813
.
10.1021/ol800425z CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

Scheme 1
.
sp3 C-H Activation of N-Alkyl-2-bromoaniline
Table 1. Optimization of Reaction Conditions
Derivatives
yield (%)a
entry
ligandb
base
additive
2
1
of N-alkyl-2-bromoaniline derivatives (Scheme 1) would
provide a straightforward access to the construction of the
indoline framework that is a common structural motif found
in many biologically active compounds including indoline
alkaloids.10,11 Herein, we report the palladium-catalyzed
cyclization of functionalized N-alkyl-2-bromoanilines via sp3
C-H activation, leading to various indolines, as well as the
2,3-dihydropyrrolo[3,2-b]pyridine derivative.12 This study
includes the first palladium-catalyzed sp3 C-H activation
of a simple alkyl group without the assistance of a pyridine
or quaternary carbon (R1 and/or R2 ) H, Scheme 1).
We first investigated the palladium-catalyzed cyclization
of N-protected 2-bromo-N-tert-butylaniline 1, since this
would have the benefit of a quaternary carbon as well as
nine reactive C-H bonds in the vicinity of the palladium
atom when forming the arylpalladium(II) intermediate.
Among various ligands examined (Table 1, entries 1-5),
1
2
3
4
5
Davephos
PPh3
XPhos
K2CO3
K2CO3
K2CO3
56
51
6
2
66
96
20
46
94
93
33
4
P(t-Bu)3·HBF4 K2CO3
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
K2CO3
6
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuCO2H >99 (98)
8c
9d
10
t-BuCO2H
t-BuCO2H
52
97
5
2
e
f
g
t-BuCO2H >99 (98)
a Yields based on 1H NMR (isolated yields in parentheses). b Structures
of DavePhos and XPhos are shown below. c DMA was used in place of
xylene. d Reaction time was 5 h. e Pd/ligand ) 2/4 mol %. f Pd/ligand )
3/6 mol %. g With 1.4 equiv of Cs2CO3.
13
PCy3·HBF4 was found to be the most effective for this
cyclization: treatment of aniline 1 with Pd(OAc)2 (5 mol %)
in the presence of PCy3·HBF4 (10 mol %) and K2CO3 at 140
°C gave the desired indoline 2 in 66% yield with 33%
recovery of the starting material (entry 5). When Cs2CO3
was used instead of K2CO3, the yield was improved to 96%
(entry 6). A more promising result was obtained by the
addition of pivalic acid (30 mol %) to the reaction mixture,
as reported by Fagnou and co-workers quite recently (entry
7).3d,9f,12 Polar solvents such as DMA were not suitable for
this cyclization (entry 8). Lowering the catalyst loading to 2
mol % slightly decreased the yield of 2 (97%, entry 9), while
a comparable result to entry 7 was obtained when using 3
mol % of Pd(OAc)2 and 1.4 equiv of Cs2CO3 (quant., entry
10).
Under the optimized conditions (Table 1, entry 10), we
examined the reaction of a variety of 2-halo-N-tert-butyla-
niline derivatives (Table 2). First, we investigated the
influence of the halogen atom on the cyclization and found
the chloride 3 and iodide 4 showed lower reactivity than the
bromide 1 to afford the indoline 2 in 47% and 84% respective
yields (entries 1 and 2).14 The reaction of the N-unprotected
substrate 5a led to the recovery of the starting material (93%)
without producing any detectable amounts of the desired
indoline 5b (entry 3).15 In contrast, N-trifluoroacetamide 6a
gave 87% yield of the corresponding indoline 6b. Next, the
reaction of bromoanilines 7a-13a bearing various substit-
uent(s) on the arene was investigated (entries 5-10). The
monomethyl and dimethyl-substituted anilines 7a and 8a
underwent smooth ring closure providing the indolines 7b
(9) (a) Dyder, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. (b)
Baudoin, O.; Herrbach, A.; Gue´ritte, F. Angew. Chem., Int. Ed. 2003, 42,
5736. (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685. (d) Hitce, J.; Retailleau, P.; Baudoin,
O. Chem. Eur. J. 2007, 13, 792. (e) Giri, R.; Maugel, N.; Li, J.-J.; Wang,
D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007,
129, 3510. (f) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 14570
.
(10) (a) Llabres, J. M.; Viladomat, F.; Bastida, J.; Codina, C.; Rubiralta,
M. Phytochemistry 1986, 25, 2637. (b) Ghosal, S.; Rao, P. H.; Jaiswal,
D. K.; Kumar, Y.; Frahm, A. W. Phytochemistry 1981, 20, 2003. (c) Kam,
T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M. Tetrahedron Lett. 2004,
(14) Decreased yield in entry 2 can be attributed to catalyst poisoning
by the iodide anion, see for example: Campeau, L.-C.; Parisien, M.; Jean,
A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
(15) (a) The unsuccessful result with the N-unprotected substrate 5a
might be due to the formation of the four-membered azapalladacycle 18.
For related azapalladacycles, see: Sole´, D.; Serrano, O. Angew. Chem., Int.
Ed. 2007, 46, 7270. (b) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia,
M.; Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587. (c) See also: Gies,
A.-E.; Pfeffer, M.; Sirlin, C.; Spencer, J. Eur. J. Org. Chem, 1999, 8, 1957.
(d) Vicente, J.; Abad, J.-A.; Frankland, A. D.; Ram´ırez de Arellano, M. C.
Chem. Eur. J. 1999, 5, 3066.
45, 5995
.
(11) For synthesis of indolines, see: (a) Witulski, B.; Stengel, T. Angew.
Chem., Int. Ed. 1999, 38, 2426. (b) Thansandote, P.; Raemy, M.; Rudolph,
A.; Lautens, M Org. Lett. 2007, 9, 5255, and references therein
.
(12) During the course of our investigation and preparation of this
manuscript, a related Pd(0)-catalyzed sp3 C-H activation of 2-tert-butoxy-
bromobenzene in the presence of pivalic acid and its related substrates to
form 2,2-dialkyldihydrobenzofurans has appeared in the literature: see ref
9f. Mechanistic consideration as well as the effect of pivalic acid based on
DFT calculations was also reported.
(13) This phosphonium salt was used because it is more stable than the
corresponding free phosphine.
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Org. Lett., Vol. 10, No. 9, 2008

Table 2. Pd-Catalyzed Cyclization of N-tert-Butylaniline
Table 3. Pd-Catalyzed Cyclization of N-Alkylaniline
Derivativesa
Derivativesa
a Reaction conditions: substrates (0.2 mmol), Pd(OAc)2 (3 mol %),
PCy3·HBF4 (6 mol %), Cs2CO3 (0.28 mmol), and t-BuCO2H (0.06 mmol),
xylene (2.0 mL), 140 °C. b Yields of isolated products. c With 5 mol % of
Pd(OAc)2.
assisted by a quaternary carbon can be readily understood
by the formation of the azaindoline derivative 13b in 98%
yield (entry 11).16
We next investigated the C-H activation without using
the assistance of an R-quaternary carbon (Table 3). Upon
treatment of N-isopropylaniline 14a under optimal reaction
conditions, the expected cyclization via C-H activation
proceeded smoothly thus providing the indoline 14b in 80%
yield (entry 1). Although the reaction of N-cyclohexylaniline
15a required a longer reaction time (16 h) presumably due
to the decreased number of reactive C-H bonds and steric
factors, the trans-fused tricyclic product 15b was obtained
in 76% yield (entry 2). The C-H activation of the N-sec-
butylaniline derivative 16a regioselectively proceeded at the
methyl group on the carbon bearing the nitrogen atom to
afford 2-ethylindoline 16b as the sole product (entry 3). It
should be clearly noted that C-H activation of an ethyl group
is also possible: by use of N-ethylaniline 17a, the desired
indoline 17b was obtained in 38% yield along with 22% of
a Reaction conditions: substrates (0.2 mmol), Pd(OAc)2 (3 mol %),
PCy3·HBF4 (6 mol %), Cs2CO3 (0.28 mmol) and t-BuCO2H (0.06 mmol),
xylene (2.0 mL), 140 °C. b Yields of isolated products. c The starting material
was recovered at 49%. d The starting material was recovered at 93%. eWith
5 mol % of Pd(OAc)2.
and 8b in essentially quantitative yields (entries 5 and 6).
Cyclization of the fluoroaniline derivative 9a under identical
conditions led to the formation of the fluoroindoline 9b in
94% yield (entry 7). Similarly, the reaction of the aniline
derivatives 10a-12a having an electron-withdrawing group
such as trifluoromethyl, methoxycarbonyl, or nitro group,
afforded the corresponding indolines 10b-12b in high yields
(entries 8-10). The wide applicability of this C-H activation
(16) (a) Related aza-oxindole derivatives are known as potent kinase
inhibitors, see : Adams, C.; Aldous, D. J.; Amendola, S.; Bamborough, P.;
Bright, C.; Crowe, S.; Eastwood, P.; Fenton, G.; Foster, M.; Harrison,
T. K. P.; King, S.; Lai, J.; Lawrence, C.; Letallec, J.-P.; McCarthy, C.;
Moorcroft, N.; Page, K.; Rao, S.; Redford, J.; Sadiq, S.; Smith, K.; Souness,
J. E.; Thurairatnam, S.; Vine, M.; Wyman, B. Bioorg. Med. Chem. Lett.
2003, 13, 3105. (b) Wood, E. R.; Kuyper, L.; Petrov, K. G.; Hunter, R. N.;
Harris, P. A.; Lackey, K. Bioorg. Med. Chem. Lett. 2004, 14, 953.
Org. Lett., Vol. 10, No. 9, 2008
1761

the debrominated product 17c (entry 4). These are the first
examples of palladium(0)-catalyzed sp3 C-H activation of
a simple alkyl group without the need for an assisting group
in the substrate.17
Scheme 2. Proposed Mechanism for the Cyclization of 1
A possible mechanism for this reaction is shown in
Scheme 2. The oxidative addition of arylbromide 1 to
palladium(0) followed by ligand exchange would give the
arylpalladium pivalate complex B. The intramolecular acti-
vation of the sp3 C-H bond of a methyl group with a high
energy barrier could be efficiently promoted by the basicity
of the pivalate in the proximity of the C-H bond,9f,12 as
well as by the formation of energetically favorable pallada-
cycles C.8 Finally, reductive elimination would produce the
indoline derivative 2, and the regeneration of the reactive
palladium(0) species.
In conclusion, we have developed an efficient method for
the construction of an indoline skeleton through sp3 C-H
activation. This study has demonstrated for the first time that
palladium(0)-catalyzed sp3 C-H activation of a simple alkyl
group can be performed without the need for beneficial
substrates having a pyridine or quaternary carbon moiety.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Encouragement of Young Scientists (A)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, a Research Fellowship for Young
Scientists from the Japan Society for the Promotion of
Science (JSPS), 21st Century COE Program “Knowledge
Information Infrastructure for Genome Science”, Targeted
Proteins Research Program, and the Program for Promotion
of Fundamental Studies in Health Sciences of the National
Institute of Biomedical Innovation (NIBIO).
Supporting Information Available: Representative ex-
1
perimental procedure, as well as H and 13C NMR spectra
for the novel compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) For a related C–H activation of an isopropyl group assisted by a
quaternary carbon, see ref 9d.
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