Synthesis of 2-substituted indoles and indolines via Suzuki-Miyaura coupling/5-endo-trig cyclization strategies

Article abstract of DOI:10.1021/jo801985a

(Chemical Equation Presented) New strategies for the synthesis of 2-substituted indoles and indolines using acyclic, imide-derived enol phosphates, which were readily prepared from o-haloanilides, have been developed based on Suzuki-Miyaura coupling-cyclization sequences. A highly chemoselective cross-coupling of imide-derived enol phosphates with boron nucleophiles under Suzuki-Miyaura conditions allowed for the efficient preparation of various N-(o-halophenyl)enecarbamates that served as useful precursors for subsequent 5-endo-trig Heck or 5-endo-trig aryl radical cyclizations to furnish 2-substituted indoles or indolines, respectively. Furthermore, a one-pot Suzuki-Miyaura coupling-cyclization cascade starting from enol phosphates has been developed, which was successfully applied to the efficient synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor.

Full text of DOI:10.1021/jo801985a

Synthesis of 2-Substituted Indoles and Indolines via
Suzuki-Miyaura Coupling/5-endo-trig Cyclization Strategies
Haruhiko Fuwa* and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku UniVersity, 1-1
Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp
ReceiVed September 9, 2008
New strategies for the synthesis of 2-substituted indoles and indolines using acyclic, imide-derived enol
phosphates, which were readily prepared from o-haloanilides, have been developed based on Suzuki-Miyaura
coupling-cyclization sequences. A highly chemoselective cross-coupling of imide-derived enol phosphates
with boron nucleophiles under Suzuki-Miyaura conditions allowed for the efficient preparation of various
N-(o-halophenyl)enecarbamates that served as useful precursors for subsequent 5-endo-trig Heck or 5-endo-
trig aryl radical cyclizations to furnish 2-substituted indoles or indolines, respectively. Furthermore, a
one-pot Suzuki-Miyaura coupling-cyclization cascade starting from enol phosphates has been developed,
which was successfully applied to the efficient synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor.
Introduction
sized heterocycles from lactone- or lactam-derived enol phos-
phates, which are known to readily participate in an oxidative
addition to a triarylphosphane-ligated Pd(0) complex, was
reported by the Nicolaou group.4 Thereafter, a number of reports
regarding the use of lactone- or lactam-derived enol phosphates
in palladium-catalyzed reactions appeared.5 Meanwhile, recent
advances in this area have made it possible to employ ketone-
derived, nonactivated enol phosphates in palladium-catalyzed
reactions such as Heck, Suzuki-Miyaura, and Negishi. Begtrup
Over the past two decades, palladium-catalyzed reactions have
played a significant role in organic synthesis because of their
tolerance of virtually all functional groups, the mild reaction
conditions, and their anomalous ability to build up complex
molecular architectures.1 Enol triflates are widely used as
substrates for palladium-catalyzed reactions because of their high
reactivity as well as their availability from the corresponding
carbonyl precursors. However, two major drawbacks of enol
triflates are the need for expensive triflating reagents such as
Tf2O and PhNTf2 for their preparation and the inherent
instability problems. In this regard, enol phosphates are an
attractive alternative to the corresponding triflates due to their
sufficient stability and their low cost of preparation. Nonetheless,
utilization of enol phosphates as electrophilic components in
palladium chemistry has been less explored, and little is known
about their reactivity profile and applicability in palladium-
catalyzed reactions. Pioneering reports by Oshima and co-
workers in the 1980s focused on the palladium-catalyzed cross-
coupling of enol phosphates with trialkylaluminums as
nucleophiles.2 In addition, Kumada and his colleagues reported
a palladium-catalyzed cross-coupling of enol phosphates with
Me3SiCH2MgCl.3 Later, the synthesis of functionalized, medium-
(2) (a) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 2531.
(b) Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22,
1609. (c) Takai, K.; Sato, M.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1984, 57, 108. (d) Fugami, K.; Oshima, K.; Utimoto, K. Chem. Lett. 1987, 2203.
(3) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M. Synthesis
1981, 1001.
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J. Am. Chem. Soc. 1997, 119, 5467. (b) Nicolaou, K. C.; Shi, G.-Q.; Namoto,
K.; Bernal, F. Chem. Commun. 1998, 1757.
(5) (a) Huffman, M. A.; Yasuda, N. Synlett 1999, 471. (b) Buon, C.;
Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40, 701. (c) Lepifre, F.; Buon,
C.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40, 6373. (d)
Coe, J. W. Org. Lett. 2000, 2, 4205. (e) Buon, C.; Chacun-Lefevre, L.; Rabot,
R.; Boussyou, P.; Coudert, G. Tetrahedron 2000, 56, 605. (f) Lepifre, F.; Clavier,
S.; Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57, 6969. (g) Lo Galbo, F.;
Occhiato, E. G.; Guarna, A.; Faggi, C. J. Org. Chem. 2003, 68, 6360. (h)
Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324. (i)
Mousset, D.; Gillaizeau, I.; Hassan, J.; Lepifre, F.; Bouyssou, P.; Coudert, G.
Tetrahedron Lett. 2005, 46, 3703. (j) Mousset, D.; Gillaizeau, I.; Sabatie´, A.;
Bouyssou, P.; Coudert, G. J. Org. Chem. 2006, 71, 5993. (k) Claveau, E.;
Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem. 2007, 72, 4832. See
also: (l) Protti, S.; Fagnoni, M. Chem. Commun. 2008, 3611.
(1) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: New York, 2004.
212 J. Org. Chem. 2009, 74, 212–221
10.1021/jo801985a CCC: $40.75 2009 American Chemical Society
Published on Web 11/13/2008

Synthesis of 2-Substituted Indoles and Indolines
SCHEME 1. Strategies for the Synthesis of 2-Substituted
Indoles 4 and Indolines 5
and co-workers have reported a palladium-catalyzed Suzuki-
Miyaura coupling of an enol phosphate derived from N-(tert-
butoxycarbonyl)-4-piperidone with arylboronic acids.6 Very
recently, Skrydstrup et al. described palladium-catalyzed Heck
and Negishi couplings of nonactivated enol phosphates.7,8
We have independently reported the use of Suzuki-Miyaura
coupling of lactone-derived enol phosphates for convergent
synthesis of marine polycyclic ether natural products.9,10 Our
continuous efforts toward expanding the scope of palladium-
catalyzed reactions of R-heteroatom-substituted enol phosphates
have culminated in the development of some novel strategies
for the synthesis of important heterocycles such as dihydropy-
rans and indoles.11,12 We now report in detail our recently
developed strategies for the synthesis of 2-substituted indoles
and indolines starting from imide-derived enol phosphates,
exploiting their unique reactivity profile in palladium-catalyzed
reactions.13,14 The most salient features of our strategies include
(1) a highly chemoselective cross-coupling of imide-derived enol
phosphates, readily prepared from o-haloanilides, with boron
nucleophiles, and (2) generally disfavored 5-endo-trig Heck and
5-endo-trig aryl radical cyclizations. In addition, an efficient
synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor
based on our developed strategy is described.
and Bischler-Mo¨hlau20 indole syntheses have commonly been
adopted for the synthesis of 2-substituted indole derivatives.
However, these synthetic methods often suffer from harsh
reaction conditions and are of limited scope with regard to
functional group compatibility. In contrast, palladium-catalyzed
reactions have recently gained much attention due to their
powerful ability to form C-C and C-N bonds as well as their
mild reaction conditions that tolerate a wide range of functional
groups.21,22
Our strategies for the synthesis of 2-substituted indoles and
indolines starting from imide-derived enol phosphates are
depicted in Scheme 1. Thus, a highly chemoselective cross-
coupling of enol phosphates 2a-c, which are readily derived
from the corresponding imides 1a-c by treatment with KHMDS
and (PhO)2P(O)Cl, would give enecarbamates 3a-c. The
palladium-catalyzed cyclization of 3a-c would afford 2-sub-
stituted indole derivatives 4. In contrast, 5-endo-trig aryl radical
cyclization of 3a-c would furnish 2-substituted indolines 5,
although this type of cyclization is generally disfavored ac-
cording to Baldwin’s rules.23
Results and Discussion
Synthetic Strategies toward 2-Substituted Indoles and
Indolines. Indole is a privileged structural motif that is widely
found in biologically active natural products and pharmaceu-
ticals.15 2-Substituted indoles, especially 2-aryl and 2-heteroaryl
indoles, have frequently been utilized as a potential scaffold in
the search for novel, biologically active small molecules.16
Classical methods such as Fischer,17 Reissert,18 Madelung,19
(6) Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron Lett. 2005, 46, 4261.
(7) (a) Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup,
T. Angew. Chem., Int. Ed. 2006, 45, 3349. (b) Ebran, J.-P.; Hansen, A. L.; Gøgsig,
T. M.; Skrydstrup, T. J. Am. Chem. Soc. 2007, 129, 6931. (c) Hansen, A. L.;
Ebran, J.-P.; Gøgsig, T. M.; Skrydstrup, T. J. Org. Chem. 2007, 72, 6464. (d)
See also: Lindhart, A. T.; Skrydstrup, T. Chem.sEur. J. 2008, 14, 8756.
(8) A palladium-catalyzed Kumada coupling of unactivated enol phosphates
has appeared: Miller, J. A. Tetrahedron Lett. 2002, 43, 7111.
(9) (a) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K. Org. Lett. 1999,
1, 1075. (b) Sasaki, M.; Ishikawa, M.; Fuwa, H.; Tachibana, K. Tetrahedron
2002, 58, 1889. (c) Sasaki, M.; Fuwa, H. Synlett 2004, 1851. (d) Sasaki, M.;
Fuwa, H. Nat. Prod. Rep. 2008, 25, 401.
(10) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002, 4,
2891. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc.
2002, 124, 14983. (c) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003, 125,
14294. (d) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2005, 127,
4326. (e) Fuwa, H.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 9648.
(f) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am.
Chem. Soc. 2006, 128, 16989. (g) Ebine, M.; Fuwa, H.; Sasaki, M. Org. Lett.
2008, 10, 2275.
(11) (a) Fuwa, H.; Kaneko, A.; Sugimoto, Y.; Tomita, T.; Iwatsubo, T.;
Sasaki, M. Heterocycles 2006, 70, 101. (b) Fuwa, H.; Sasaki, M. Org. Biomol.
Chem. 2007, 5, 1849. (c) Fuwa, H.; Sasaki, M. Chem. Commun. 2007, 2876;
Chem. Commun. 2007, 3106 (Additions and Corrections). (d) Fuwa, H.; Sasaki,
M. Org. Lett. 2007, 9, 3347. (e) Fuwa, H.; Sasaki, M. Org. Lett. 2008, 10, 2549.
(f) Fuwa, H.; Naito, S.; Goto, T.; Sasaki, M. Angew. Chem., Int. Ed. 2008, 47,
4737.
Synthesis of Imide-Derived Enol Phosphates. Imide-derived
enol phosphates were synthesized starting from commercially
available o-haloanilides (Scheme 2). Thus, anilides 6a-c were
reacted with Boc2O/DMAP in THF at rt to deliver imides
1a-c.24 Treatment of 1a-c with KHMDS in the presence of
(PhO)2P(O)Cl afforded enol phosphates 2a-c. These phosphates
were stable enough to be isolated and purified by rapid flash
(16) For recent examples, see: (a) Kher, S.; Lake, K.; Sircar, I.; Pannala,
M.; Bakir, F.; Zapf, J.; Xu, K.; Zhang, S. H.; Liu, J. P.; Morera, L.; Sakurai, N.;
Jack, R.; Cheng, J. F. Bioorg. Med. Chem. Lett. 2007, 17, 4442. (b) Dykstra,
K. D.; Guo, L. Q.; Birzin, E. T.; Chan, W. D.; Yang, Y. T.; Hayes, E. C.; DaSilva,
C. A.; Pai, L. Y.; Mosley, R. T.; Kraker, B.; Fitzgerald, P. M. D.; DiNinno, F.;
Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg. Med. Chem. Lett. 2007,
17, 2322. (c) Samosorn, S.; Bremner, J. B.; Ball, A.; Lewis, K. Bioorg. Med.
Chem. 2006, 14, 857. (d) Shaw, D.; Chicchi, G. G.; Elliott, J. M.; Kurtz, M.;
Morrison, D.; Ridgill, M. P.; Szeto, N.; Watt, A. P.; Williams, A. R.; Swain,
C. J. Bioorg. Med. Chem. Lett. 2001, 11, 3031. (e) Cooper, L. C.; Chicchi, G. G.;
Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.;
Morrison, D.; Shaw, D. E.; Tsao, K. L.; Watt, A. P.; Williams, A. R.; Swain,
C. J. Bioorg. Med. Chem. Lett. 2001, 11, 1233. (f) Dinnell, K.; Chicchi, G. G.;
Dhar, M. J.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Ridgill, M. P.;
Rycroft, W.; Tsao, K. L.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem.
Lett. 2001, 11, 1237.
(12) For leading reviews on palladium(0)-catalyzed synthesis of heterocycles: (a)
Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644. (b) Humphrey, G. R.;
Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (c) Cacchi, S.; Fabrizi, G. Chem.
ReV. 2005, 105, 2873.
(13) For a preliminary report of this work, see ref 11d.
(14) Recently,
a very similar synthesis of N-aryl enecarbamates has
appeared: Cottineau, B.; Gillaizeau, I.; Farard, J.; Auclair, M.-L.; Coudert, G.
Synlett 2007, 1925.
(15) For recent reviews of indole-containing natural products, see: (a) Somei,
M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278. (b) Somei, M.; Yamada, F. Nat.
Prod. Rep. 2005, 22, 73. (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005,
22, 761. (d) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
(17) (a) Fischer, E.; Jordan, F. Chem. Ber. 1883, 16, 2241. (b) Fischer, E.;
Hess, O. Chem. Ber. 1884, 17, 551.
(18) Reissert, A. Chem. Ber. 1897, 30, 1030.
(19) Madelung, W. Chem. Ber. 1912, 45, 1128.
(20) (a) Bischler, A. Chem. Ber. 1892, 25, 2860. (b) Mo¨hlau, R. Chem. Ber.
1882, 15, 2480.
J. Org. Chem. Vol. 74, No. 1, 2009 213

Fuwa and Sasaki
TABLE 1. Screening of Reaction Conditionsa
SCHEME 2. Preparation of Enol Phosphates 2a-e
% yield
entry
substrate
solvent
temp (°C)
7
8
1
2
3
2a
2a
2a
2a
2a
2b
2c
1,4-dioxane
1,4-dioxane/H2O
THF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
60
50
50
50
rt
7a: 47
7a: 72
7a: 85
7a: 90
7a: 52
7b: 100
7c: 0
24
0
0
0
0
4
5b
6
50
50
0
0
7
chromatography on silica gel. However, in practice, the fol-
lowing Suzuki-Miyaura coupling reaction was performed
without chromatographic purification of these phosphates. The
enol phosphates 2d,e were prepared from commercially available
o-haloanilides 6d,e. Thus, Boc protection of the amide moieties
of 6d,e gave the respective imides 1d,e, which, upon treatment
with LDA, followed by quenching with (PhO)2P(O)Cl in the
presence of HMPA, afforded 2d,e. The geometry of the double
bond of 2d,e was assumed to be Z since it is known that lithium
enolates generated from acyclic amides by treatment with LDA
generally exist as (Z)-enolates.25
Highly Chemoselective Cross-Coupling of Imide-Derived
Enol Phosphates with Boron Nucleophiles. We first examined
a chemoselective Suzuki-Miyaura coupling26 of enol phos-
phates 2a-c with 1.1 equiv of phenylboronic acid under various
conditions (Table 1). When the reaction was performed using
2a, PhB(OH)2, 10 mol % of Pd(PPh3)4, and Cs2CO3 in 1,4-
dioxane at 60 °C, the desired enecarbamate 7a was isolated in
47% yield from 1a, along with a considerable amount of indole
a All reactions were performed using 10 mol % of Pd(PPh3)4, 1.1
equiv of PhB(OH)2, and 3 equiv of Cs2CO3 for 1-7 h. Yields are
overall from 1a,b. b Na2CO3 was used as base.
8 (entry 1). To suppress the formation of 8, we surveyed a series
of reaction conditions and found that the addition of H2O as a
co-solvent dramatically increased the yield of 7a. Thus, when
we employed Pd(PPh3)4 as a catalyst and Cs2CO3 as a base in
1,4-dioxane/H2O at 50 °C, the cross-coupling proceeded smoothly,
giving 7a in 72% overall yield from 1a (entry 2). The yield of
7a was improved when the reaction was carried out in THF/
H2O (entry 3). Further examination revealed that DMF/H2O is
the solvent of choice for the cross-coupling; a remarkable
chemoselectivity was attained under these conditions, giving
7a in 90% yield (entry 4). When the reaction was performed at
rt, the yield of 7a was moderate, indicating the necessity of
mild heating (entry 5). In each case, a trace amount (<5%) of
debrominated byproduct 7d was also detected in the reaction
mixture (entries 1-5). The aryl chloride 2b was also success-
fully cross-coupled with phenylboronic acid under the optimized
conditions, giving 7b in quantitative yield (entry 6). The possible
aryl-aryl, Suzuki-Miyaura coupling product was not observed
in all the above cases.27 On the other hand, the aryl iodide 2c
failed to undergo cross-coupling; it was observed that the
Pd(PPh3)4 catalyst began to decompose within 30 min, and the
desired product was not observed even after prolonged reaction
times, giving instead a complex mixture of unidentified products
(entry 7). Running the reaction at rt or at 80 °C did not lead to
any improvement.
(21) For recent examples, see: (a) Fuwa, H.; Tako, T.; Ebine, M.; Sasaki,
M. Chem. Lett. 2008, 37, 904. (b) Denmark, S. E.; Baird, J. D.; Regens, C. S.
J. Org. Chem. 2008, 73, 1440. (c) Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V.
Org. Lett. 2008, 10, 2617. (d) Cui, X.; Li, J.; Fu, Y.; Liu, L.; Guo, Q. X.
Tetrahedron Lett. 2008, 49, 3458. (e) Leogane, O.; Lebel, H. Angew. Chem.,
Int. Ed. 2008, 47, 350. (f) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5,
2214. (g) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007,
63, 1970. (h) Shen, Z. M.; Lu, X. Y. Tetrahedron 2006, 62, 10896. (i) Liu,
J. X.; Shen, M.; Zhang, Y. D.; Li, G. S.; Khodabocus, A.; Rodriguez, S.; Qu,
B.; Farina, V.; Senanayake, C. H.; Lu, B. Z. Org. Lett. 2006, 8, 3573. (j) Tang,
Z. Y.; Hu, Q. S. AdV. Synth. Catal. 2006, 348, 846. (k) Djakovitch, L.; Dufaud,
V.; Zaidi, R. AdV. Synth. Catal. 2006, 348, 715. (l) Palimkar, S. S.; Kumar,
P. H.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2006, 62, 5109. (m) Kaspar,
L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311. (n) Hiroya, K.; Itoh, S.;
Sakamoto, T. Tetrahedron 2005, 61, 10958. (o) Willis, M. C.; Brace, G. N.;
Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403. (p) Fang, Y.-Q.; Lautens,
M. Org. Lett. 2005, 7, 3549. (q) Mukai, C.; Takahashi, Y. Org. Lett. 2005, 7,
5793, and references cited therein. See also ref 28.
Palladium-Catalyzed Cyclization of o-Haloanilide-Derived
Enecarbamates. We then investigated the palladium-catalyzed
cyclization of 7a, as summarized in Table 2. Although there
are many examples of palladium-catalyzed cyclization of related
enamines and enaminones,28,29 the synthesis of 2-aryl and
2-heteroaryl indoles based on this strategy have been explored
less thoroughly, and, to the best of our knowledge, the use of
N-alkoxycarbonyl derivatives has not been reported. We initially
performed the cyclization of 7a using 10 mol % of Pd(PPh3)4
(22) (a) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
(b) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979. (c) Lane,
B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (d) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172. (e) Deprez, N. R.; Kalyani, R.;
Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (f) Bressy, C.;
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148, and references
cited therein.
(23) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(24) The choice of the protective group was found to be crucial for the success
in the preparation of enol phosphates. Upon treatment of N-(o-bromophenyl)ac-
etanilides having other types of electron-withdrawing, N-protective groups, such
as p-toluenesulfonyl, benzoyl, or trifluoroacetyl, with KHMDS in the presence
of (PhO)2P(O)Cl only resulted in loss of the acetyl group.
(25) For examples, see: (a) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita,
T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923.
(b) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans.
1 1999, 1295. (c) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233.
(26) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(27) Reports on leaving-group selectivities of palladium(0)-catalyzed
reactions: (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478. (b) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221. (c) Kamikawa,
T.; Hayashi, T. Tetrahedron Lett. 1997, 38, 7087. (d) Espino, G.; Kurbangalieva,
A.; Brown, J. M. Chem. Commun. 2007, 1742.
(28) For early examples: (a) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem.
1980, 45, 2938. (b) Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori,
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214 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2-Substituted Indoles and Indolines
TABLE 2. Screening of Reaction Conditionsa
nearly quantitative yield in a reasonable reaction time (24 h)
with a practical level of catalyst loading (10 mol % of Pd) (entry
6). The results of entries 3-6 suggested the possibility that in
situ formed CsOAc might accelerate the cyclization. However,
a control experiment using a Pd2dba3/X-Phos catalyst system
(10 mol % of Pd), Cs2CO3 (3 equiv) as a base, and CsOAc (80
mol %) as an additive in 1,4-dioxane at 100 °C resulted in only
ca. 62% conversion after 24 h, indicating that CsOAc has no
significant effect on the reaction rate. We also found that the
reaction rate of the cyclization of 7b using Pd(OAc)2/X-Phos
and Cs2CO3 in 1,4-dioxane could be significantly enhanced
under microwave heating conditions (160 °C for 30 min),
affording 8 in 87% yield (entry 7). Overall, the cyclization of
aryl chloride 7b was found to be best carried out using
Pd(OAc)2/X-Phos as a catalyst system and Cs2CO3 as a base in
1,4-dioxane at 100 °C (thermal heating) for 24 h or at 160 °C
(microwave heating) for 30 min.32
entry
1
base (equiv)
solvent
temp (°C)
yield (%)
K2CO3 (3)
K2CO3 (3)
Et3N (10)
Et3N (10)
i-Pr2NEt (10)
PMP (5)
DMF
CH3CN
DMF
DMF
DMF
DMF
100
80
100
100
100
100
48
71
76
94
38
18
2b c
,
3b c
,
4b
5b
6
a All reactions were carried out for 20-24 h, unless otherwise noted.
b Reactions performed in a sealed tube. c n-Bu4NCl (1 equiv) was used
as an additive.
Having secured reliable conditions for the cross-coupling and
cyclization processes, the present strategy was applied to a
variety of substrates, and the results are summarized in Table 4
and Scheme 3. Suzuki-Miyaura coupling of 2a-d with a range
of aryl and heteroaryl boronic acids proceeded without incident
to give enecarbamates 10-18. Compounds 17 and 18 existed
as a complex mixture of isomers in C6D6 solution at rt (600
and K2CO3 as a base in DMF at 100 °C (Table 2, entry 1). The
desired N-Boc-2-phenylindole 821b was isolated in 48% yield,
and the major byproduct was the dehalogenated 7d (22%). In
contrast, under the Jeffery conditions using n-Bu4NCl,30 the
desired product 8 was cleanly obtained in an improved 71%
yield, and the formation of 7d was completely suppressed (entry
2). When employing Et3N instead of K2CO3 as a base, further
improvement of the yield was attained (entries 3 and 4). Thus,
exposure of 7a to 10 mol % of Pd(PPh3)4 and Et3N in DMF at
100 °C afforded 8 in 94% yield, with no detectable amount of
7d. Changing the base to diisopropylethylamine (i-Pr2NEt) or
1,2,2,6,6-pentamethylpiperidine (PMP) was found to be detri-
mental due to the significant dehalogenation (entries 5 and 6).
Utilization of aryl chloride 7b in the palladium-catalyzed
cyclization was next explored (Table 3). Recent reports have
described the use of a Pd2dba3/X-Phos31 (X-Phos ) 2-dicyclo-
hexylphosphino-2′,4′,6′-triisopropylbiphenyl) catalyst system for
the related cyclizations of o-chloroaniline-derived enamines.29a,c
We, therefore, decided to employ a Pd2dba3/X-Phos catalyst
system and screened bases and solvents. Upon treatment of 7b
with NaOt-Bu or KOt-Bu in toluene at 110 °C, the cyclization
took place smoothly, but with complete loss of the Boc group,
affording 2-phenylindole 9 (entries 1 and 2). Although the use
of polar solvents such as DMF or DMA at an elevated
temperature (>110 °C) gave unsatisfactory results, when the
reaction was carried out using a Pd2dba3/X-Phos or Pd(OAc)2/
X-Phos catalyst system and K2CO3 as a base in 1,4-dioxane at
100 °C, the cyclization proceeded cleanly to give only the
desired 8 in good yields (entries 3 and 4). However, high catalyst
loading (30 mol % of Pd) and a prolonged reaction time (72 h)
were necessary under these conditions. Although a combination
of Pd2dba3/X-Phos and Cs2CO3 did not lead to any improvement
(entry 5), the use of Pd(OAc)2/X-Phos coupled with Cs2CO3
greatly enhanced the efficiency of the cyclization, giving 8 in
1
MHz H NMR) due to the presence of the sterically restricted
rotations around the nitrogen atom. Under the established
conditions [Pd(PPh3)4, Et3N, and DMF at 100 °C], cyclization
reactions of aryl bromides 10a, 11, 12a, 13, and 14 were
efficiently achieved, affording 2-aryl and 2-heteroaryl indoles
19-23 in good to excellent yields (entries 1-5). Aryl chlorides
10b, 12b, 15, and 16 were also cleanly cyclized under the
optimized conditions [Pd(OAc)2/X-Phos (Pd/L ) 1/2) and
Cs2CO3 in 1,4-dioxane at 100 °C (thermal heating) or at 160
°C (microwave heating)] to provide 2-aryl indoles 19, 21, 24,
and 25, respectively (entries 6-9). Thus, our strategy should
be generally applicable to the synthesis of 2-aryl and 2-het-
eroaryl indole derivatives.
In contrast, our efforts to extend the strategy to the synthesis
of 2,3-disubstituted indoles met with limited success. Upon
exposure of aryl bromide 17 to Pd(PPh3)4 and Et3N in DMF at
100 °C, the desired 2,3-disubstituted indole 26 was isolated in
only 7% yield, along with several unidentified byproducts
(Scheme 3). Interestingly, cyclization of 17 under the Jeffery
conditions [Pd(PPh3)4, K2CO3, and nBu4NCl in CH3CN at 80
°C] delivered dihydroquinoline 27 in high yield as the sole
isolable product. Using a Pd(OAc)2/X-Phos (10 mol %, Pd/L
) 1/2) catalyst system and Cs2CO3 in 1,4-dioxane at 100 °C,
indole 26 was obtained in only 5% yield, with dihydroquinoline
27 again being the major product (84% yield). A similar result
was obtained for aryl chloride 18. Thus, upon treatment of 18
with Pd(OAc)2/X-Phos (30 mol %, Pd/L ) 1/2) and Cs2CO3 in
1,4-dioxane at 100 °C for 96 h, indole 28 was not obtained at
all, and dihydroquinoline 29 was instead isolated in 52% yield.
DevelopmentofaOne-PotSuzuki-MiyauraCoupling-Cycli-
zation Cascade. We next investigated a one-pot Suzuki-Miyaura
coupling-cyclization cascade starting from enol phosphate 2a,
exploiting its unique reactivity profile. In the previous experi-
ment, we unexpectedly isolated indole 8 as a byproduct in 24%
(29) For recent examples: (a) Ackermann, L.; Sandmann, R.; Villar, A.;
Kaspar, L. T. Tetrahedron 2008, 64, 769. (b) Barluenga, J.; Fernandez, M. A.;
Aznar, F.; Valdes, C. Chem.sEur. J. 2005, 11, 2276. (c) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am.
Chem. Soc. 2006, 128, 8678. (d) Jia, J.; Zhu, J. J. Org. Chem. 2006, 71, 7826.
(e) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew. Chem.,
Int. Ed. 2004, 43, 4526. (f) Yamazaki, K.; Nakamura, Y.; Kondo, Y. J. Org.
Chem. 2003, 68, 6011. (g) Yamazaki, K.; Kondo, Y. J. Comb. Chem. 2002, 4,
191. (h) Edmonson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2,
1109. (i) Chen, C. Y.; Liberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J. J. Org. Chem. 1997, 62, 2676, and references cited therein.
(32) We have found that the use of 10 mol % of Pd(OAc)2/Cy3P catalyst
(Pd/L ) 1/2) in the presence of Cs2CO3 (3 equiv) in 1,4-dioxane at 100 °C also
gave indole 8 in 89% yield. In contrast, the use of Pd2dba3/Davephos, Pd2dba3/
S-Phos, Pd2dba3/Cy3P·HBF4, or Pd2dba3/t-Bu3P·HBF4 catalyst was less effective
for the present reaction.
(30) Jeffery, T. Tetrahedron 1996, 52, 10113.
(31) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653.
J. Org. Chem. Vol. 74, No. 1, 2009 215

Fuwa and Sasaki
TABLE 3. Screening of Reaction Conditionsa
yield (%)
entry
catalyst (equiv)
base (equiv)
solvent
toluene
temp (°C)
time (h)
8
9
1
2
3
4
Pd2dba3/X-Phos (0.05/0.20)
Pd2dba3/X-Phos (0.05/0.20)
Pd2dba3/X-Phos (0.15/0.60)
Pd(OAc)2/X-Phos (0.30/0.60)
Pd2dba3/X-Phos (0.15/0.60)
Pd(OAc)2/X-Phos (0.10/0.20)
Pd(OAc)2/X-Phos (0.10/0.20)
NaOtBu (3)
KOtBu (3)
K2CO3 (3)
K2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
110
110
100
100
100
100
160
48
48
72
96
72
24
0.5
0
0
61
85
0
0
0
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
86
70 (9)
84
96
87
5
6
0
0
7b
a Yields are from 7b. Yield in parentheses is recovered 7b. b Microwave heating was applied.
yield when the cross-coupling of 2a with phenylboronic acid
was performed in 1,4-dioxane at 60 °C (see Table 1, entry 1).
Under these conditions, however, further conversion of enecar-
bamate 2a to indole 8 stalled after ca. 24 h. Elevated temperature
(100 °C) and/or prolonged reaction time proved to be ineffective.
We, therefore, examined several reaction conditions, and the
results are summarized in Table 5. Upon exposure of 2a to 1.1
equiv of phenylboronic acid, Et3N, and Pd(PPh3)4 catalyst in
DMF directly afforded 8 in moderate yield (entry 1). Utilization
of Cs2CO3 as a base in combination with n-Bu4NCl (1 equiv)
in DMF/H2O at 50-100 °C gave a comparable result (entry 2).
Finally, we found that the cross-coupling-cyclization cascade
could be best realized using 10 mol % of Pd(PPh3)4, Cs2CO3
(3 equiv), arylboronic acid (1.1 equiv), and n-Bu4NBr (1 equiv)29
in DMF/H2O at 50-70 °C. Under these conditions, we isolated
N-Boc-2-substituted indole derivatives 8, 19, and 20 in moderate
to good yields (entries 3-5). Thus, fine-tuning of the reaction
conditions realized a highly efficient synthesis of 2-substituted
indole derivatives from imide-derived enol phosphates in a one-
pot manner.
Mechanistic Consideration of the Palladium-Catalyzed
Cyclization of o-Haloaniline-Derived Enecarbamates. Several
plausible mechanisms have been discussed for the palladium-
catalyzed cyclization of o-haloaniline-derived enamines. This
cyclization is often classified as an intramolecular Heck
reaction,11b,c,33 although a pathway that involves a six-membered
palladacycle intermediate has also been proposed34,35 (Scheme
4). The catalytic cycle is composed of (i) oxidative addition to
a palladium(0) complex (30 f 31), (ii) migratory insertion into
the enamine double bond (31 f 32), and (iii) syn-specific
ꢀ-hydride elimination (32 f 33). Although it is widely accepted
that 5-endo cyclization is generally disfavored due to geometric
constraints according to Baldwin’s rules,23 an intramolecular
Heck reaction pathway well accounts for the smooth cyclization
of enecarbamates represented by 30 and the difficulties in the
cyclization of enecarbamates 17 and 18 since anti-ꢀ-hydride
elimination is required for the latter substrates (i.e., 34 f 26
and 35 f 28). Moreover, the formation of dihydroquinolines
27 and 29 from 17 and 18, respectively, could be rationally
explained by an intramolecular C-H activation of the inter-
mediates 34 and 35, which is followed by reductive elimination
(36 f 38 and 37 f 39) and subsequent ring expansion (38 f
27 and 39 f 29).36 Additionally, our observation that enecar-
bamates 7a, 10a, 11, 12a, and 13 undergo smooth 5-endo-trig
aryl radical cyclization to yield N-Boc-2-arylindolines (vide
infra) suggests that 5-endo-trig Heck cyclization may also be
feasible for these enecarbamates.
Synthesis of an Indol-2-yl-1H-quinolin-2-one KDR Inhibi-
tor Based on the Suzuki-Miyaura Coupling-Cyclization
Strategy. Protein tyrosine kinases are involved in cellular signal
transduction pathways and many other important biological
functions. Impairment of tyrosine kinases is responsible for
diseases such as angiogenesis, cancer, and tumor growth.37
Kinase insert domain receptor (KDR), one of the human tyrosine
kinases, is expressed on activated endothelial cells and exhibits
a high affinity for vascular endothelial growth factor (VEGF).
Since VEGF is believed to be one of the prime mediators of
tumor-induced angiogenesis, the inhibition or modulation of
KDR by small organic molecules is predicted to be effective
for its prevention and treatment.38,39 Recently, researchers from
Merck have reported the synthesis of a series of 5-substituted
1H-indol-2-yl-1H-quinolin-2-ones (40-43), a novel class of
potent and selective KDR inhibitors (Figure 1).40 Lautens and
co-workers have reported an efficient synthesis of these inhibi-
tors by means of their palladium(0)-catalyzed tandem C-N/
Suzuki-Miyaura coupling methodology.41 Another report on
the synthesis of KDR inhibitor 41 utilizing a Sonogashira
coupling-cyclization strategy has also appeared in the litera-
ture.42 We envisioned that KDR inhibitor 40 could be derived
from enol phosphate 44 and the known boronic acid 45,41 based
on our strategy.
The synthesis started with alkylation of the known phenol
46, prepared from 3-bromophenol by nitration under standard
conditions (H2SO4, NaNO3, and H2O, 32% yield),43 by treatment
with 2-bromoethyl methyl ether/K2CO3, to give compound 47
in 100% yield (Scheme 5). Reduction of the nitro group of 47
with tin(II) chloride gave aromatic amine 48 (90% yield).
(33) For recent examples of 5-endo Heck cyclizations excluding enamine-
type compounds, see: (a) Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun.
2005, 4684. (b) Ichikawa, J.; Sakoda, K.; Mihara, J.; Ito, N. J. Fluorine Chem.
2006, 127, 489. (c) Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006,
4425.
(34) Latham, E. J.; Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1997,
2059.
(36) For a related process, see: (a) Liron, F.; Knochel, P. Tetrahedron Lett.
2007, 48, 4943.
(37) Carmeliet, P.; Jain, R. K. Nature 2000, 407, 249.
(38) Morin, M. J. Oncogene 2000, 19, 6574.
(39) Veikkola, T.; Karkkainen, M.; Claesson-Welsh, L.; Alitalo, K. Cancer
Res. 2000, 60, 203.
(35) Grigg, R.; Savic, V. Chem. Commun. 2000, 873.
216 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2-Substituted Indoles and Indolines
TABLE 4. Synthesis of 2-Substituted Indolesa
a All cross-coupling reactions were carried out using Pd(PPh3)4 (0.1 equiv), Cs2CO3 (3 equiv), and boron nucleophile (1.1-1.5 equiv) in DMF/H2O at
50 °C for 1-2 h. b Cyclization conditions A: Pd(PPh3)4 (0.1 equiv) and Et3N (10 equiv) in DMF at 100 °C for 20-24 h. Cyclization conditions B:
Pd(OAc)2 (0.1 equiv), X-Phos (0.2 equiv), and Cs2CO3 (3 equiv) in 1,4-dioxane at 100 °C for 12-24 h. Cyclization conditions C: Pd(OAc)2 (0.1 equiv),
X-Phos (0.2 equiv), and Cs2CO3 (3 equiv) in 1,4-dioxane at 160 °C for 30 min under microwave heating. c Yields in parentheses are the corresponding
N-deprotected indole.
Acylation of 48 with acetic anhydride and subsequent protection
of the resultant anilide with Boc2O afforded imide 49 in 68%
yield for the two steps. Enolization of 49 with KHMDS in the
presence of (PhO)2P(O)Cl gave enol phosphate 44 that, without
purification, was reacted with the known boronic acid 4541 (1.1
equiv) in the presence of 10 mol % of Pd(PPh3)4 and 3 equiv
of Cs2CO3 as a base in DMF/H2O at 50 °C, giving rise to
enecarbamate 50 in 96% yield from 49. The subsequent
palladium-catalyzed cyclization using 10 mol % of Pd(PPh3)4
and excess Et3N in DMF at 100 °C afforded indole 51 in 90%
yield. As noted above, the transformation of 44 to 51 could
also be achieved in a one-pot process. Thus, treatment of 44
with 1.1 equiv of 45, 10 mol % of Pd(PPh3)4, 3 equiv of Cs2CO3,
and 1 equiv of n-Bu4NBr in DMF/H2O at 50-70 °C directly
afforded indole 51 in 81% overall yield from 49. Finally,
hydrolysis under acidic conditions delivered Merck KDR
inhibitor 40 in 79% yield, with spectroscopic data matching
those reported previously.40 The present synthesis clearly
J. Org. Chem. Vol. 74, No. 1, 2009 217

Fuwa and Sasaki
SCHEME 3. Synthesis and Cyclization of Enecarbamates 17
and 18
be performed under mild conditions using SmI2 in the presence
of t-BuOH in THF/HMPA49 at rt (method B). The latter method
afforded 2-substituted indolines in somewhat better yields and
eliminated the need for tedious chromatographic separation of
tin byproducts.
Conclusion
The present study demonstrates the synthetic utility of acyclic
imide-derived enol phosphates as novel versatile precursors for
the synthesis of 2-substituted indoles and indolines by means
of palladium chemistry. Noteworthy is the remarkable chemose-
lectivity of Suzuki-Miyaura coupling; Suzuki-Miyaura cou-
pling using Pd(PPh3)4 catalyst and Cs2CO3 in aqueous DMF
allowed for a highly chemoselective cross-coupling of imide-
derived enol phosphates with aryl and heteroarylboronic acids,
leading to N-(o-halophenyl)enecarbamates in excellent yields.
Cyclization of the enecarbamates derived from o-bromoaniline
was efficiently performed using Pd(PPh3)4 catalyst and Et3N in
DMF at 100 °C, while that of o-chloroaniline-derived enecar-
bamates was best accomplished under the influence of a
Pd(OAc)2/X-Phos (Pd/L ) 1/2) catalyst system and Cs2CO3 in
1,4-dioxane at 100 °C (thermal heating) or at 160 °C (microwave
heating). Application of microwave heating to the palladium
cyclization significantly enhanced the reaction rate. Furthermore,
a one-pot Suzuki-Miyaura coupling-cyclization cascade has
been developed, and it was applied to an efficient synthesis of
an indol-2-yl-1H-quinolin-2-one KDR inhibitor. On the basis
of experimental evidence, we propose that the palladium-
catalyzed cyclization of o-haloaniline-derived enecarbamates
proceeds via a generally disfavored 5-endo-trig Heck cyclization
pathway. We have also succeeded in carrying out the 5-endo-
trig aryl radical cyclization of o-bromoaniline-derived enecar-
bamates, which constitutes an unprecedented example of a
successful application of a generally disfavored 5-endo-trig
cyclization for the synthesis of indoline derivatives. We believe
that our chemistry, described herein, significantly broadens the
scope and utility of enol phosphates in palladium-catalyzed
synthesis of nitrogen heterocycles. Further studies on the
development of new synthetic methodologies utilizing enol
phosphates and their application in the synthesis of complex
biologically active substances are currently underway and will
be reported in due course.
demonstrates the feasibility of our strategy for the synthesis of
structurally complex 2-aryl indole derivatives.
5-endo-trig Aryl Radical Cyclization of o-Bromoaniline-
Derived Enecarbamates Leading to 2-Substituted Indolines.
It is well-known that 5-exo-trig radical cyclization is a powerful
strategy for the construction of 3-substitued indoline deriva-
tives.44 To the best of our knowledge, however, application of
5-endo-trig radical cyclization for the synthesis of an indoline
system has not been reported.45-47 Nonetheless, we examined
the 5-endo-trig aryl radical cyclization of enecarbamates 7a,
10a, 11, 12a, and 13. To our delight, treatment of 7a, 10a, 11,
12a, and 13 with n-Bu3SnH in the presence of catalytic AIBN
in toluene at 100 °C (method A) gave a series of 2-substituted
indolines 5248 and 53-56 in moderate to good yields (Table
6). Furthermore, we found that radical cyclization could also
Experimental Section
General Procedure for the Synthesis of Imides 1a,b,d,e. The
synthesis of 1a is representative. To a solution of N-(2-bromophe-
nyl)acetanilide (1.01 g, 4.72 mmol) in THF (30 mL) were added
DMAP (0.75 g, 6.14 mmol) and Boc2O (1.41 mL, 6.14 mmol).
After being stirred at rt for 50 min, the reaction mixture was diluted
with EtOAc, washed with 1 M aqueous HCl, saturated aqueous
NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash
chromatography (silica gel, 10% EtOAc/hexanes) gave 1a (1.47 g,
99%).
(40) (a) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3975. (b)
Payack, J. F.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. J. Org. Chem.
2005, 70, 175. (c) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I. W.;
Hughes, D. L. J. Org. Chem. 2005, 70, 2555.
(41) Fang, Y.-Q.; Karisch, R.; Lautens, M. J. Org. Chem. 2007, 72, 1341.
(42) Palimkar, S. S.; More, V. S.; Kumar, P. H.; Srinivasan, K. V.
Tetrahedron 2007, 63, 12786.
(43) Ishida, J.; Arakawa, H.; Takada, M.; Yamaguchi, M. Analyst 1995, 120,
1083.
(47) For recent selected papers of 5-endo radical cyclization: (a) Curran, D. P.;
Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc. 2008, 130, 8437. (b) Bogen, S.;
Goddard, J.-P.; Fensterbank, F.; Malacria, M. ARKIVOC 2008, Viii, 126. (c)
Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229. (d) Guerrero, M. A.; Cruz-Almanza,
R.; Miranda, L. D. Tetrahedron 2003, 59, 4953. (e) Ishibashi, H.; Kodama, K.;
Higuchi, M.; Muraoka, O.; Tanabe, G.; Takeda, Y. Tetrahedron 2001, 57, 7629.
(f) Bryans, J. S.; Chessum, N. E. A.; Parsons, A. F.; Ghelfi, F. Tetrahedron
Lett. 2001, 42, 2901. (g) Davies, D. T.; Kapur, N.; Parsons, A. F. Tetrahedron
2000, 56, 3941.
(44) (a) Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. 1992, 57,
2873. (b) Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271. (c) Patel,
V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D. A.; Kennedy, J. H.; Mohamadi,
F.; Schultz, R. M.; Soose, D. J.; Spees, M. M. J. Org. Chem. 1997, 62, 8868.
(45) For reviews: (a) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695.
(b) Ishibashi, H. Chem. Rec. 2006, 6, 23.
(46) For a theoretical study: Chatgilialoglu, C.; Ferreri, C.; Guerra, M.;
Timokhin, V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765.
218 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2-Substituted Indoles and Indolines
TABLE 5. One-Pot Suzuki-Miyaura Coupling-Cyclization Cascade
entry
Ar
base (equiv)
additive (equiv)
conditions
DMF, 100 °C
DMF/H2O, 50-100 °C
DMF/H2O, 50-70 °C
DMF/H2O, 50-70 °C
DMF/H2O, 50-70 °C
yield (%)
1
2
3
4
5
Ph
Ph
Ph
Et3N (10)
none
8: 50
8: 50
8: 74
19: 77
20: 55
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
n-Bu4NCl (1)
n-Bu4NBr (1)
n-Bu4NBr (1)
n-Bu4NBr (1)
4-MeOC6H4
4-ClC6H4
SCHEME 4. Intramolecular Heck Cyclization Pathway
1a: Colorless crystals; mp 81-82 °C; IR (neat) νmax/cm-1 2979,
To a solution of imide 1a (131.9 mg, 0.4201 mmol) in THF (6
mL) were added HMPA (0.220 mL, 1.26 mmol) and diphenylphos-
phoryl chloride (0.105 mL, 0.507 mmol). The mixture was cooled
to -78 °C and treated with potassium bis(trimethylsilyl)amide (0.5
M solution in toluene, 1.0 mL, 0.5 mmol). After being stirred at
-78 °C for 30 min, the reaction mixture was treated with 3%
ammonium hydroxide and diluted with diethyl ether. The resultant
mixture was allowed to warm to rt over 20 min. The aqueous layer
was extracted with EtOAc, and the organic layer was washed with
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude enol phosphate 2a thus prepared was used
immediately without further purification.
1
1742, 1712, 1474, 1370, 1279, 1157, 1104, 759; H NMR (500
MHz, CDCl3) δ 7.61 (dd, J ) 7.6, 1.2 Hz, 1H), 7.33 (ddd, J )
7.6, 7.6, 1.2 Hz, 1H), 7.19 (ddd, J ) 7.6, 7.6, 1.2 Hz, 1H), 7.15
(dd, J ) 7.6, 1.2 Hz, 1H), 2.61 (s, 3H), 1.35 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 172.3, 151.6, 138.1, 132.9, 129.9, 129.4,
128.1, 123.0, 83.3, 27.7 (×3), 26.3; HRMS (FAB) calcd for
C13H1779BrNO3 [(M + H)+] 314.0392, found 314.0388.
General Procedure for the Suzuki-Miyaura Cross-Coupling
of 1a,b,d,e. The synthesis of enecarbamate 7a is representative.
To a solution of the above material in DMF (5 mL) were added
cesium carbonate (3 M aqueous solution, 0.420 mL, 1.26 mmol),
phenylboronic acid (56.4 mg, 0.463 mmol), and Pd(PPh3)4 (48.5
mg, 0.0420 mmol). The resultant mixture was heated at 50 °C for
7 h. After cooling, the reaction mixture was diluted with EtOAc,
washed with H2O and brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification of the residue by flash
chromatography (silica gel, 10% diethyl ether/hexanes) gave
enecarbamate 7a (140.9 mg, 90%).
7a: Colorless oil; IR (neat) νmax/cm-1 2977, 1715, 1622, 1475,
1299, 1164, 1088, 768, 696; 1H NMR (500 MHz, C6D6) δ 7.59 (d,
J ) 7.5 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 1H), 7.21 (d, J ) 8.0 Hz,
1H), 7.15s7.12 (m, 2H), 7.08 (dd, J ) 7.5, 7.5 Hz, 1H), 6.82 (dd,
J ) 8.5, 8.0 Hz, 1H), 6.58 (dd, J ) 7.5, 7.5 Hz, 1H), 4.97 (s, 1H),
4.83 (s, 1H), 1.22 (s, 9H); 13C NMR (125 MHz, C6D6) δ 152.4,
(48) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653.
(49) (a) Inanaga, J.; Ishkawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485.
(b) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008.
FIGURE 1. Structures of the Merck KDR inhibitors (40-43) and our
synthetic strategy toward 40.
J. Org. Chem. Vol. 74, No. 1, 2009 219

Fuwa and Sasaki
SCHEME 5. Synthesis of the Merck KDR Inhibitor 40
TABLE 6. 5-endo-trig Aryl Radical Cyclization of Enecarbamates
H2O and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash chromatog-
raphy (silica gel, 10% diethyl ether/hexanes) gave indole 19 (69.5
mg, 71%).
19: Colorless oil; IR (neat) νmax/cm-1 2978, 1730, 1504, 1453,
1328, 1247, 1161, 1038, 811, 747; 1H NMR (500 MHz, CDCl3) δ
8.20 (d, J ) 8.0 Hz, 1H), 7.54 (d, J ) 7.5 Hz, 1H), 7.35 (d, J )
9.0 Hz, 2H), 7.31 (dd, J ) 8.0, 7.5 Hz, 1H), 7.24 (m, 1H), 6.95 (d,
J ) 9.0 Hz, 2H), 6.51 (s, 1H), 3.85 (s, 3H), 1.36 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 159.2, 150.3, 140.4, 137.3, 129.9 (×2), 129.2,
127.4, 124.0, 122.8, 120.2, 115.2, 113.2 (×2), 109.4, 83.3, 55.3,
27.6 (×3); HRMS (EI) calcd for C20H21NO3 (M+) 323.1521, found
323.1529.
General Procedure for the Heck-Type Cyclization of 7b,
10b, 12b, and 16 (Thermal Heating). The synthesis of N-Boc-
2-phenylindole 8 is representative. To a solution of 7b (78.4 mg,
0.238 mmol) in 1,4-dioxane (2.5 mL) were added Cs2CO3 (232.9
mg, 0.7148 mmol), Pd(OAc)2 (5.4 mg, 0.024 mmol), and X-Phos
(22.7 mg, 0.0476 mmol). The resultant mixture was put into a
preheated oil bath (100 °C) for 24 h. After cooling to rt, the reaction
mixture was filtered through Celite and concentrated under reduced
pressure. Purification of the residue by flash chromatography (silica
gel, 5% diethyl ether/hexanes) gave indole 821b (67.0 mg, 96%).
General Procedure for the Heck-Type Cyclization of 7b,
10b, 12b, and 15 (Microwave Heating). The synthesis of N-Boc-
2-phenylindole 8 is representative. A 5 mL vial was charged with
7b (47.6 mg, 0.145 mmol), Cs2CO3 (141.4 mg, 0.434 mmol),
Pd(OAc)2 (3.2 mg, 0.014 mmol), X-Phos (13.8 mg, 0.0289 mmol),
and 1,4-dioxane (1.5 mL). The vial was flushed with argon, sealed,
and heated at 160 °C for 30 min under microwave irradiation. After
cooling to rt, the reaction mixture was filtered through Celite and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (silica gel, 5% diethyl ether/hexanes) gave
indole 821b (36.9 mg, 87%).
General Procedure for the Suzuki-Miyaura Coupling-Cycli-
zation Cascade. The synthesis of 8 is representative. To a solution
of 2a, prepared from 1a (131.5 mg, 0.4188 mmol) as desribed
above, in DMF (6 mL) were added cesium carbonate (3 M solution
in H2O, 0.420 mL, 1.26 mmol), phenylboronic acid (56.2 mg, 0.461
mmol), and Pd(PPh3)4 (48.4 mg, 0.0419 mmol). After being stirred
at 50 °C for 1 h, tetra-n-butylammonium bromide (135.0 mg, 0.4188
mmol) was added to the reaction mixture, which was further heated
at 70 °C for 20 h. After cooling to rt, the reaction mixture was
diluted with EtOAc, washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography (silica gel, 5% diethyl ether/
hexanes) gave 821b (91.4 mg, 74%).
a Method A: n-Bu3SnH, AIBN, toluene, 100 °C. Method B: SmI2,
t-BuOH, THF/HMPA, rt. b Reaction performed in the absence of
t-BuOH.
149.3, 143.4, 133.6, 129.8, 129.0, 128.5, 128.4 (×2), 128.3, 128.2,
126.5 (×2), 124.2, 108.1, 80.8, 27.8 (×3); HRMS (FAB) calcd for
C19H21NO279Br [(M + H)+] 374.0756, found 374.0756.
General Procedure for the Heck-Type Cyclization of 7a,
10a, 11, 12a, 13, and 14. The synthesis of compound 19 is
representative. In a heavy-walled Pyrex bottle was placed a solution
of 10a (122.2 mg, 0.3032 mmol) in DMF (5 mL). To this solution
were added Et3N (0.420 mL, 3.01 mmol) and Pd(PPh3)4 (35.0 mg,
0.0303 mmol). The Pyrex bottle was purged with argon, capped,
and put into a preheated oil bath (100 °C) for 20 h. After cooling
to rt, the reaction mixture was diluted with EtOAc, washed with
General Procedure for 5-endo-trig Aryl Radical Cyclization
(Method A). The synthesis of 53 is representative. To a solution
of 10a (119.9 mg, 0.2975 mmol) in toluene (4 mL) were added
220 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2-Substituted Indoles and Indolines
n-Bu3SnH (0.096 mL, 0.36 mmol) and AIBN (9.8 mg, 0.060 mmol).
The reaction mixture was heated at 100 °C for 1 h. After cooling
to rt, the reaction mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica gel, 10%
diethyl ether/hexanes) gave indoline 53 (82.1 mg, 85%).
6.96 (dd, J ) 7.5, 7.0 Hz, 1H), 6.80-6.77 (m, 2H), 5.30 (br, 1H),
3.76 (s, 3H), 3.63 (dd, J ) 16.0, 11.0 Hz, 1H), 2.93 (dd, J ) 16.0,
3.0 Hz, 1H), 1.34 (br, 9H); 13C NMR (125 MHz, CDCl3) δ 158.6,
152.4, 143.0, 137.0, 129.4, 127.5, 126.5 (×2), 124.8, 122.5 (×2),
114.7, 113.7, 80.6, 62.0, 55.2, 37.8, 28.2 (×3); HRMS (EI) calcd
for C20H23NO3 (M+) 325.1675, found 325.1680.
General Procedure for 5-endo-trig Aryl Radical Cyclization
(Method B). The synthesis of 53 is representative. To a solution
of SmI2 (0.1 M solution in THF, 15.5 mL, 1.55 mmol) and HMPA
(1.08 mL) at rt was added a solution of 10a (104.4 mg, 0.2591
mmol) and t-BuOH (0.150 mL) in THF (3 mL + 1 mL rinse).
After being stirred at rt for 6 h, the reaction mixture was treated
with saturated aqueous NH4Cl. The resultant mixture was extracted
with EtOAc. The organic layer was washed with H2O, saturated
aqueous Na2SO3, and brine. The organic layer was dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography (silica gel, 5% EtOAc/hexanes)
gave indoline 53 (72.5 mg, 86%).
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research for Young Scientists (B)
by the Ministry of Education, Culture, Sports, Science and
Technology, Japan (MEXT).
Supporting Information Available: Detailed experimental
procedures and characterization data not included in the
1
Experimental Section. Copies of H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
53: Colorless oil; IR (neat) νmax/cm-1 2975, 1702, 1608, 1483,
1388, 1248, 1171, 1036, 831, 752; 1H NMR (500 MHz, CDCl3) δ
7.89 (br, 1H), 7.20 (dd, J ) 7.5, 7.5 Hz, 1H), 7.11-7.09 (m, 3H),
JO801985A
J. Org. Chem. Vol. 74, No. 1, 2009 221