atom at the 3-position of the oxindole ring. This is a case of
3-chlorooxindoles where the electronegativity of chlorine
will increase the acidity of the C3 proton. This approach not
only makes the use of unprotected 3-substituted oxindoles
as nucleophiles possible but also presents an opportunity to
introduce a chlorine atom at a quaternary center.
Scheme 1. Model Reaction between 3-Chloroxoindole 1a and
β-Nitrostyrene 2aa
To the best of our knowledge, no examples of using
3-chlorooxindoles as nucleophiles in asymmetric 1,4-
Michael addition reactions have been reported. This chemistry
will provide unconventional access to 3-chlorooxindoles
with a chiral quaternary center. A number of successful
examples of conjugated addition reactions to nitroolefins
using both protected and unprotected 3-aryl- and 3-alkyl-
oxindoles have been described previously by Barbas III,11
Shibasaki,10a Maruoka,12 Zhou,9b Enders,10b and others.
More recently, Melchiorre and co-workers reported a
similar transformation of 3-hydroxyoxindoles.13
The addition of oxindoles to nitroolefins serves as a
potent source of precursors in the synthesis of alkaloids
and their derivatives. Also, a number of pharmaceutical
agents contain chiral centers with chloro-substitution.14
Chiral thioureas15,16 and, more recently, squaramides17 are
widely used as catalysts to activate nitroolefins for Michael
addition reactions. In the conjugated addition reaction de-
scribed in the present work, the reactivity of both substrates,
3-chlorooxindole 1 and nitroolefin 2, can be tuned by the
appropriate catalyst.
a Reaction conditions: 0.1 mmol (1 equiv) of 1a, 0.12 mmol (1.2 equiv)
of 2a, and 0.05 or 0.1 mmol (5 or 10 mol %) of catalyst.
donor part of the catalyst would serve as an activator
to nitroolefin 2, whereas the tertiary amine subunit, as a
chiral base, would facilitate deprotonation/enolization of the
3-chlorooxindole 1, thus holding both reactants together and
promoting the CꢀC bond formation.
Our initial studies were focused on the reaction of
3-chlorooxindole 1a with β-nitrostyrene 2a (Scheme 1),
catalyzed by a thiourea or squaramide catalyst (Figure 1).
Preliminary screening of the catalysts was conducted in
chloroform at ambient temperature using 10 mol % of the
appropriate catalyst (4ꢀ10, Figure 1) (for details see
Supporting Information (SI)). This revealedthat, although
thioureas 5 and 8 (introduced by Soos18 and Takemoto19
ꢁ
respectively) provide high levels of diastereo- and enantio-
control, squaramides 9 and 10 proved superior in every
respect. Catalysts 9 and 10 yielded products with similar
enantioselectivities (93% and 90% ee respectively); how-
ever, the latter provided a slightly better diastereocontrol
(3:1 to 6:1, respectively) and was therefore chosen for
optimization studies. Screening of the temperature, cata-
lyst loading, and solvent identified the optimal conditions
for the reaction asfollows: chloroform asa solvent (0.5 M),
1 equiv of 1, 1.2 equiv of 2, and 5 mol % of catalyst 10 at
4 °C. Under these conditions, 3a was obtained in 95%
yield, 91% ee, and 10:1 dr (Table 1).
With optimal reaction conditions in hand, the substrate
scope was explored by reacting 3-chlorooxindole 1a with
different nitroolefins (Table 1). All the reactions were
complete within 24 h (Table 1). The substitution pattern
in the aromatic ring of the starting nitroolefin 2aꢀj did not
affect the efficacy of the process: the 3-chlorooxindoles
3aꢀj were uniformly obtained in high yields (90ꢀ96%)
and high enantio- or diastereoselectivities (ee up to 91%
and dr up to 11:1).
Figure 1. Catalysts used.
It was conjured that bifunctional thioureas or squaramides
represent an ideal choice for this role, where the H-bond
(15) For reviws, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713–5743. (b) McGilvra, J. D., Gondi, V. B., Rawal, V. H. In
Enantioselective organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007; pp 189ꢀ254.
(10) (a) Kato, Y.;Furutachi, M.;Chen,Z.;Mitsunuma, H.;Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168–9169. (b) Wang, C.;
Yang, X.; Enders, D. Chem.;Eur. J. 2012, 18, 4832–4835.
(11) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131,
8758–8759.
(16) Connon, S. J. Chem. Commun. 2008, 22, 2499–2510.
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(17) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem.;Eur.
J. 2011, 17, 6890–6899.
(12) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009,
131, 16620–16621.
(13) Retini, M.; Bergonzini, G.; Melchiorre, P. Chem. Commun. 2012,
48, 3336–3338.
ꢁ
ꢁ
(18) (a) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005,
7, 1967–1969. (b) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed.
2005, 44, 6367–6370. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 41, 4481–4483.
(14) Gribkoff, V. K.; Post-Munson, D. J.; Yeola, S. W.; Boissard,
C. G.; Hewawasam, P. WO 2002030868.
(19) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006,
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B
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