Table 1. Oxindole Preparation using Stoichiometric and Catalytic Cu(II)a b
,
entry
base
Cu-source
solvent (temp)
DMF (110 °C)
DMF (110 °C)
DMF (110 °C)
DMF (110 °C)
PhMe (110 °C)
time
yield
98%
(14%)
(87%)84%
(20%)
81%
(75%)
92%
(<5%)
i
ii
KOtBu (1.1 equiv)
Cu(OAc)2·H2O (1 equiv)
Cu(OAc)2·H2O (5 mol %)
Cu(OAc)2·H2O (5 mol %)
Cu(OAc)2·H2O (5 mol %)
Cu(OAc)2·H2O (5 mol %)
1 h
16 h
5 h
16 h
20 h
24 h
1.5 h
1.5 h
KOtBu (1.1 equiv)
iii
iv
v
vi
vii
viii
Piperidine (10 equiv)c
-
-
-
-
-
d
Cu(OTf)2 (5 mol %)
PhMe (110 °C)
Cu(OAc)2·H2O (5 mol %)
Cu(OAc)2·H2O (5 mol %)
Mesitylene (165 °C)e
Mesitylene (165 °C)f
a Unless stated otherwise, the base (if used) was added to a mixture of the substrate and the copper salt in the solvent specified; then a reflux condenser
fitted with a drying tube was inserted and the reaction heated for the time indicated. b Yields in parentheses determined using NMR spectroscopy against an
internal standard (1,1,2,2-tetrachloroethane). c With piperidine (1 equiv), the reaction was still incomplete after 16 h giving 2 in 47% NMR yield. d The
following copper salts (5 mol %) also effected the required transformation: CuBF4·4H2O, 67%; Cu(acac)2, 62%; [Me(CH2)3CH(Et)CO2]2Cu, 63%;
Cu(TC)2·MeOH, 70%; CuOAc, 51%; CuTC, 53%). A UK 1p coin (1980) also gave oxindole 2 (57%, 5 h). Little or no cyclization was observed using CuCl2,
CuBr2, CuSO4, CuCl2(phen), Cu2O, CuO, and CuCl. e No product formation was observed in the absence of Cu(OAc)2·H2O (or when the Cu(OAc)2·H2O was
replaced by KOAc). f Degassed and under an argon atmosphere.
Preliminary mechanistic studies3,4 indicated that the cycliza-
tion proceeds via deprotonation, radical generation, and then
homolytic aromatic substitution. Such a sequence involves
two separate one-electron oxidation processes, which would
require the use of 2 equiv of a Cu(II) source.
We were intrigued by the possibility that the above
cyclization reactions could be carried out using catalytic
quantities of Cu(II) salts by the use of a stoichiometric
reoxidant, preferably atmospheric oxygen, to recycle the
putative Cu(I) intermediate.6 Such a catalytic approach,
which would be of great value for larger scale processes,
seemed plausible given that the original reaction shown in
Scheme 1 used just 1 equiv of Cu(OAc)2·H2O and the
reaction vessel was open to the air. The preliminary studies
toward the development of a Cu(II)-catalyzed procedure for
oxindole synthesis are shown in Table 1.
We next carried out a control reaction in the absence of
added base but were amazed to observe that oxindole 2 was
still formed in approximately 20% yield (entry iv). Initially,
we reasoned that the thermal decomposition of DMF at
elevated temperature would release dimethylamine,7 which
could act as the base. However, changing the solvent to
toluene (entry v), again using 5 mol % Cu(OAc)2·H2O with
no added base, resulted in a much improved 81% isolated
yield after 20 h at 110 °C.
With this remarkable result in hand, we set out to further
optimize this reaction by varying the copper source whilst
keeping toluene as solvent. A range of copper salts were
screened and several were successful with Cu(OTf)2 giving
the best result (entry vi) but none were superior to
Cu(OAc)2·H2O. It is also noteworthy, given its use by Ku¨ndig
et al.,4 that CuCl2 was completely ineffective for this
transformation. In addition, replacement of toluene as solvent
by mesitylene at reflux gave a dramatic improvement in yield
and a reduction of reaction time (92%, 1.5 h; entry vii).
Finally in this preliminary study, the importance of aerial
oxidation was confirmed (entry viii); when the reaction was
carried out using the mesitylene conditions but with degas-
sing under an argon atmosphere, less than 5% of oxindole 2
was formed.
Repeating the original3 stoichiometric Cu(OAc)2·H2O/
KOtBu/DMF conditions gave a near quantitative yield for
the conversion of anilide 1 into 3,3-disubstituted oxindole 2
after 1 h at 110 °C (entry i), whereas the use of 5 mol %
Cu(OAc)2·H2O under the same conditions resulted in only
14% yield of oxindole 2 after 16 h (entry ii). However, this
partial success (ca. 3 turnovers) in DMF was in contrast to
the fact that little or no cyclization was observed when
Cu(OAc)2·H2O was employed in other solvents such as THF
or MeCN. Replacement of KOtBu by organic bases was
investigated next and a dramatic improvement was realized
using Cu(OAc)2·H2O/piperidine/DMF (entry iii); with an
excess of piperidine (10 equiv) an 84% yield of oxindole 2
was isolated with a reaction time of only 5 hours.
Having devised an efficient cyclization procedure using
catalytic Cu(OAc)2·H2O in mesitylene, we went on to test
the substrate scope using differently substituted anilides 5
(Scheme 2). As can be seen, several R-carbonyl substituents
were compatible with the cyclization conditions producing
oxindoles 6a-6c in good yields. In addition, substitution of
the aryl ring with electron donating groups (4-OMe and
2-OMe) made little difference, with oxindoles 6d and 6e
being isolated in 88 and 75% yield, respectively. Furthermore
(6) For a review on aerobic copper catalysis, see: (a) Gamez, P.; Aubel,
P. G.; Driessen, W. L.; Reedijk, J. Chem. Soc. ReV. 2001, 30, 376. For
more recent references, see: (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (c) Villalobos, J. M.; Srogl, J.;
Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734.
(7) Muzart, J. Tetrahedron 2009, 65, 8313.
Org. Lett., Vol. 12, No. 15, 2010
3447
Klein, Johannes E. M. N.
