2-one 2,7 and neutral formaldehyde N,N-dialkyl-hydrazones
38 (Figure 1).
reactions were observed with these substrates under a variety
of conditions and catalysts.
Scheme 1. Nucleophilic Addition of
1-Methyleneaminopyrrolidine 4 to Enoate Surrogates
Figure 1. Reagents used as formyl anion equivalents in the
asymmetric conjugate addition to R,â-unsaturated carbonyl com-
pounds.
Unfortunately, the umpolung strategies used in the catalytic
Stetter reaction fail in the formaldehyde case due to oligo-
merizations (the formose reaction).9 Thus, the lack of
catalytic approaches for this reaction encouraged studies
directed to develop catalytic conjugate additions of achiral
N,N-dialkylhydrazones to enoate surrogates.
Besides the use of chiral Lewis acids as catalysts,10 often
troublesome due to the concurrence of side reactions,8a,11 the
use of milder species as H-bonding organocatalysts12 was
found to be effective in the activation of imines13 and appears
a priori to be particularly appropriated to this reaction. We
wish to report here on the thiourea-catalyzed enantioselective
addition of 1-methyleneaminopyrrolidine 4 to â,γ-unsaturated
R-keto esters 5.
Initially, alkylidene malonates 6 and R-hydroxy enones
714 were also considered as potential enoate surrogates.
During the preliminary reactivity tests, however, no addition
(6) (a) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. Synthesis
1981, 74-76. (b) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. J.
Chem. Soc., Perkin Trans. 1 1981, 1284-1286.
Therefore, further experiments were conducted with gly-
oxylate 5a and 1-methyleneaminopyrrolidine 4 as model
reactants. Other considered N,N-dialkylamino groups such
as N,N-dimethyl, N,N-diisopropyl, N-tert-butyl-N-methyl, and
piperidin-1-yl had a detrimental effect on the reactivities and
selectivities of their corresponding formaldehyde hydrazones.
BINOL (11), BINOL-phosphate (12), mandelic acid (13),
and a series of (thio)ureas 14a-g and 1515 were used as
potential catalysts. BINOL 11 showed a moderate catalytic
activity in toluene but afforded 8a in racemic form, whereas
stronger Brønsted acids 12 and 13 were inefficient, probably
because of deactivation by the basic reagent 4. Thioureas
(7) Gaul, C.; Seebach, D. HelV. Chim. Acta 2002, 85, 772-787.
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