bonds,7 which is obviously limited to small-scale synthesis
because of the expensive catalytic system. Thus, a general
and practical method to prepare 3-acyloxindole is still
required.
Recently, we8 and others9-12 have reported that CuI-
catalyzed coupling of activated methylene compounds with
aryl halides can be conducted under relatively mild conditions
by using some additives such as L-proline, 2-phenylphenol,
chelating Schiff bases, and N,N′-dimethylethylenediamine.
Further exploration of the scope and limits of this reaction
revealed that â-keto amides were poor substrates under our
standard conditions, as the starting materials were recovered
(Scheme 1). Although the reason for this poor reactivity was
to be the formation of benzoxazoles because a similar
transformation had been mentioned by several groups.14 To
prevent this side reaction, we decided to employ N-
substituted amides as substrates. Accordingly, N-benzylamide
5a was elaborated following the same procedure used for
the preparation of 4. We were pleased to find that the reaction
of 5a, catalyzed by CuI/L-proline at 40 °C, provided the
desired 3-acyloxindole 6a in 43% yield (entry 1, Table 1).
Table 1. CuI/L-Proline-Catalyzed Intramolecular Coupling of
Amide 5aa
Scheme 1
entry
base
T (°C)
yieldb (%)
1
2
3
4
5
6
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
40
25
0
25
25
25
43
75
0
30
51
0c
Cs2CO3
a Reaction conditions: amide 5a (0.5 mmol), CuI (0.05 mmol), L-proline
(0.1 mmol), Cs2CO3 (2 mmol), DMSO (5 mL), 24 h. b Isolated yield. L-
Proline was not added.
c
not clear, we still envisioned that an intramolecular coupling
reaction of â-keto 2-iodoanilides could take place, thereby
giving 3-acyloxindoles directly. With this idea in mind, we
prepared amide 4 by heating a mixture of 2-iodoaniline with
2,2,6-trimethyl-4H-1,3-dioxin-4-one.13 However, the reaction
of 4 catalyzed by CuI/L-proline gave a complex mixture
under several conditions (temperatures, rt to 50 °C; solvent,
DMSO; base, Cs2CO3, K3PO4, K2CO3).
Since a relatively quick conversion was observed, we next
attempted to improve the yield by reducing the reaction
temperature. As we expected, a satisfactory yield was
obtained at room temperature (entry 2), although no conver-
sion was determined at 0 °C (entry 3). Changing the base to
K2CO3 and K3PO4 resulted in decreased yields (entries 4 and
5). Furthermore, no coupling reaction occurred in the absence
of L-proline (entry 6), indicating that the ligand effect is
essential for this coupling reaction. It is noteworthy that when
a bromide analogue of 5a was employed under these
conditions, none of the desired 6a was detected. Therefore,
iodides were used exclusively in the subsequent scope
studies.
With optimized conditions in hand, the scope of this
catalytic reaction was explored with various amides. The
results are summarized in Table 2. N-Methyl- and DMB (2,4-
dimethoxybenzyl)-substituted amides also gave good yields
(entries 1 and 2), indicating that variations at the 1-position
of 3-acyloxindoles are possible. Electronic effects on the
aromatic ring have little influence on this reaction as
complete conversion was observed in amides with both
electron-withdrawing groups and electron-donating groups
(compare entries 3-5 with entries 6-8). By using suitable
starting materials, 4-, 5-, or 6-substituted 3-acyl oxindoles
were elaborated (entries 3-8).
Although the side products in the above reaction were not
carefully analyzed, a possible side reaction was considered
(5) (a) Porcs-Makkay, M.; Simig, G. Org. Proc. Res. DeV. 2000, 4, 10.
(b) Sechi, M.; Sannia, L.; Carta, F.; Palomba, M.; Dallocchio, R.; Dessi,
A.; Derudas, M.; Zawahir, Z.; Neamati, N. AntiViral Chem. Chemother.
2005, 16, 41. (c) Kumar, P. R.; Goud, P. S.; Raju, S.; Reddy, G. O. IN
182470, 1999.
(6) (a) Lee, A.; Hartwig, J. J. Org. Chem. 2001, 66, 3402. (b) Beckett,
A. H.; Daisley, R. W.; Walker, J. Tetrahedron 1968, 24, 6093. (c) Crestini,
C.; Saladino, R. Synth. Commun. 1994, 24, 2835. (d) Sun, L.; Tran, N.;
Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J. Med. Chem. 1998,
41, 2588.
(7) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T. J. Org. Chem. 1990,
55, 1093.
(8) (a) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693. For related
studies from this group, see: (b) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao,
F. J. Am. Chem. Soc. 1998, 120, 12459. (c) Ma, D.; Xia, C. Org. Lett.
2001, 3, 2583. (d) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (e)
Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799. (f) Pan, X.; Cai, Q.; Ma, D. Org.
Lett. 2004, 6, 1809. (g) Ma, D.; Cai, Q. Synlett 2004, 1, 128. (h) Zhu, W.;
Ma, D. Chem. Commun. 2004, 888. (i) Ma, D.; Liu, F. Chem. Commun.
2004, 1934. (j) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(k) Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696. (l) Ma, D.; Cai, Q.;
Xie, X. Synlett 2005, 1767. (m) Cai, Q.; Zou, B.; Ma, D. Angew. Chem.,
Int. Ed. 2006, 45, 1276. (n) Cai, Q.; He, G.; Ma, D. J. Org. Chem. 2006,
71, 5268.
(9) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2703.
(10) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(11) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2004, 10, 5607.
(12) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
(13) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431.
(14) (a) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (b)
Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661. (c) Minami,
T.; Isonaka, T.; Okada, Y.; Ichikawa, J. J. Org. Chem. 1993, 58, 7009.
(15) (a) Gopalsamy, A.; Shi, M. Org. Lett. 2003, 5, 3907. (b) Yamamoto,
Y.; Watanabe, Y.; Ohnishi, S. Chem. Pharm. Bull. 1987, 35, 1860.
6116
Org. Lett., Vol. 8, No. 26, 2006