Since the renaissance of enamine catalysis in the early
2000s, this organocatalytic mode of activation has been
developed into a powerful synthetic tool for the preparation
of valuable chiral building blocks.3,4 Enamine catalysis
provides a mild and general solution for the in situ
transformation of aldehydes and ketones into their corre-
sponding enolate equivalents. In the past decade, a number
of reactions were developed that employ this strategy,
including aldol reactions,5 Mannich reactions,6 Michael
additions,7 and others.8 However, relatively few studies have
focused on reactions that involve the desymmetrization of
prochiral ketones,9 one of the prerequisites for the targeted
Friedla¨nder condensation. Whereas enamines are considered
to be important intermediates in the classical Friedla¨nder
process, relatively harsh reaction conditions are typically
required.10 Interestingly, proline has recently been used as
a catalyst in the Friedla¨nder synthesis of achiral quinolines.11
However, this reaction appears to be limited to the use of
highly activated amino-trifluoromethylketones while simul-
taneously requiring mild heating.
From the outset of our study, it was clear that several
challenges would have to be addressed. First, compared to
the relatively electron-poor benzaldehydes that have been
used predominantly in enamine-catalyzed asymmetric aldol
reactions, the corresponding o-aminobenzaldehydes are ap-
preciably more electron-rich and thus represent less reactive
electrophiles. Second, it was not clear if it would be possible
to conduct the necessary elimination step of the Friedla¨nder
sequence under mild enough conditions that would simul-
taneously allow for a highly enantioselective process. In
addition, it is well-known that o-aminobenzaldehydes tend
to self-condense, even under mild conditions.12
With these considerations in mind, we opted to investigate
the reaction of commercially available and relatively electron
poor 3,5-dibromoaminobenzaldehyde (3a) with 4-phenylcy-
clohexanone (2a). Among the readily available organocata-
lysts tested, only amino acids gave acceptable rates and
selectivities.13 As summarized in Table 1, proline derivatives
provided the best results. trans-4-Hydroxyproline (7a) gave
rise to a slightly higher ee as compared to proline itself.
Given the poor solubility of proline and trans-4-hydroxy-
proline in nonpolar solvents, more soluble silicon protected
trans-4-hydroxyproline derivatives were prepared.14 Gratify-
ingly, the reactivity and selectivity of these catalysts proved
to be very similar to that of unmodified trans-4-hydroxypro-
line.
(3) For selected reviews on organo/enamine catalysis, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Jarvo, E. R.;
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Chem., Int. Ed. 2004, 43, 5138. (d) List, B. Acc. Chem. Res. 2004, 37, 548.
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Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH:
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Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107,
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To improve the rate and selectivity of the reaction, catalyst
7b was tested in a broad range of solvents (Table 2).15
Several interesting observations were made in the course of
this study. Apolar solvents containing aromatic rings such
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