evaluation by systematic structural variation in a library
approach.
arylation and alkenylation of isatin substrates using a
combination of boronic acids13,14 and rhodium catalysts to
achieve the synthesis of 3-substituted 3-hydroxyoxindoles.
Experiments conducted with isatin 1a and 2 equiv of
phenylboronic acid 2a in the presence of a catalyst generated
in situ from 3 mol % of [(C2H4)2Rh(acac)] and 7 mol % of
P(OPh)3 lead to full conversion and 91% isolated yield of
3a after 4 h at reflux temperature (Scheme 1). Although this
There are a number of recent reports on the catalytic
enantioselective formation of quaternary carbon centers at
the 3-position of oxindoles.5 However, the catalytic enanti-
oselective formation of a tertiary alcohol at this position has
been elusive until now.6 The formation of quaternary carbon
centers7 via addition of carbon nucleophiles to ketone
derivatives still constitutes a major challenge for synthetic
chemistry.8 Catalytic enantioselective synthesis of R-hy-
droxycarbonyl compounds via addition of organometallic
nucleophiles to R-dicarbonyl substrates has so far been
limited to alkynylations9 and alkylation reactions using zinc
reagents.10 Inspired by the progress in the field of rhodium-
catalyzed additions of sp2-hybridized carbon nucleophiles to
a variety of electrophiles,11,12 we decided to investigate the
Scheme 1. Rhodium/Triphenylphosphite-Catalyzed Addition
of Arylboronic Acids to Isatin
(3) (a) Hewawasam, P.; Meanwell, N. A.; Gribkoff, V. K. U.S. Patent
5,602,169, 1997; Chem. Abstr. 1997, 126, 181369. (b) Gribkoff, V. K.;
Starrett, J. E., Jr.; Dworetzky, S. I.; Hewawasam, P.; Boissard, C. G.; Cook,
D. A.; Frantz, S. W.; Heman, K.; Hibbard, J. R.; Huston, K.; Johnson, G.;
Krishnan, B. S.; Kinney, G. G.; Lombardo, L. A.; Meanwell, N. A.;
Molinoff, P. B.; Myers, R. A.; Moon, S. L.; Ortiz, A.; Pajor, L.; Pieschl,
R. L.; Post-Munson, D. J.; Signor, L. J.; Srinivas, N.; Taber, M. T.; Thalody,
G.; Trojnacki, J. T.; Weiner, H.; Yeleswaram, K.; Yeola, S. W. Nat. Med.
2001, 7, 471. (c) Natarajan, A.; Fan, Y.-H.; Chen, H.; Guo, Y.; Iyasere, J.;
Harbinski, F.; Christ, W. J.; Aktas, H.; Halperin, J. A. J. Med. Chem. 2004,
47, 1882. (d) Natarajan, A.; Guo, Y.; Harbinski, F.; Fan, Y.-H.; Chen, H.;
Luus, L.; Diercks, J.; Aktas, H.; Chorev, M.; Halperin, J. A. J. Med. Chem.
2004, 47, 4979. (e) Cliffe, I. A.; Lien, E. L.; Mansell, H. L.; Steiner, K. E.;
Todd, R. S.; White, A. C.; Black, R. M. J. Med. Chem. 1992, 35, 1169.
(4) The synthesis of enantiomerically enriched 3-aryl-3-hydroxyoxin-
doles has been accomplished via the highly diastereoselective arylation of
mandelic acid: (a) Barroso, S.; Blay, G.; Cardona, L.; Ferna´ndez, I.; Garc´ıa,
B.; Pedro, J. R. J. Org. Chem. 2004, 69, 6821. For the synthesis of
enantiomerically enriched 3-aryl-3-hydroxyoxindoles by asymmetric hy-
droxylation using chiral oxaziridines, see ref 2b.
class of substrates represents highly activated carbonyl com-
pounds, to the best of our knowledge, this is the first report
of rhodium-catalyzed arylboronic acid addition to ketones.6,15
This reaction was applied to isatin substrates 1a-c and a
variety of arylboronic acids 2a-k (Table 1). As already
observed by Frost for the addition of arylboronic acids to
Table 1. Rhodium/Triphenylphosphite-Catalyzed 1,2-Addition
of Aryl- and Alkenylboronic Acids to Isatins
(5) Palladium-catalyzed intramolecular R-arylation: (a) Lee, S.; Hartwig,
J. F. J. Org. Chem. 2001, 66, 3402. Intramolecular Heck reaction: (b)
Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman, L.
E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125, 6261.
Organocatalytic acyl transfer: (c) Hills, I. D.; Fu, G. C. Angew. Chem.,
Int. Ed. 2003, 42, 3921. Biocatalytic desymmetrization of prochiral
substrates: (d) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto, K.; Naka,
T.; Kita, Y. J. Org. Chem. 2004, 69, 2478. Lewis-catalyzed R-fluorination
of carbonyl groups: (e) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura,
Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164. Palladium-catalyzed
allylation of prochiral nucleophiles: (f) Trost, B. M.; Frederiksen, M. U.
Angew. Chem., Int. Ed. 2005, 44, 308. Organocatalytic aldol reaction: (g)
Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.;
Tomasini, C. J. Org. Chem. 2005, 70, 7418.
(6) After submission of this manuscript, the group of Hayashi reported
the rhodium-catalyzed asymmetric addition of aryl- and alkenylboronic acids
to isatins: Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 3353.
(7) For reviews on the formation of quaternary carbon centers, see: (a)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (c) Ramo´n, D.
J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (d) Christoffers, J.; Baro, A.
AdV. Synth. Catal. 2005, 247, 1473. (e) Trost, B. M.; Jiang, C. Synthesis
2006, 369. (f) Christoffers, J., Baro, A., Eds. Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2005.
(8) For a recent review on enantioselective addition to ketones using
zinc reagents, see: (a) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004,
43, 284. For leading references in the field of catalytic enantioselective
additions of organometallic aryl and alkenyl reagents to carbonyl com-
pounds, see: (b) Garc´ıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641. (c) Li,
H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355. (d) Tomita, D.; Wada,
R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 4138.
(9) (a) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451. (b) Dhondi,
P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67.
(10) (a) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002,
124, 12668. (b) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781.
(c) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 5489.
entrya
isatin (R1)
boronic acid
product
yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
(H)
(Me)
(Cl)
(H)
(H)
(H)
(H)
(H)
(H)
(Cl)
(H)
(H)
(H)
2a
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
3a
3b
3c
3d
3e
3f
3g
3h
3i
91%
79%
99%
99%
99%
99%
98%
87%
66%
62%
43%
54%
96%
1b
1c
1a
1a
1a
1a
1a
1a
1c
1a
1a
1a
3j
3k
3l
3m
a All reactions were performed on 0.2 mmol scale in 2 mL of acetone at
reflux for 4 h with 2 equiv of arylboronic acid (2) in the presence of a
catalyst generated in situ from 3 mol % of [(C2H4)2Rh(acac)] and 7 mol %
of triphenylphosphite. b Isolated yields of 3 after column chromatography.
2716
Org. Lett., Vol. 8, No. 13, 2006