Scheme 1
.
Current Methodology
Table 1. Reaction Optimization
dimedone
(equiv)
side
yield
(%)
entry catalysta solvent
aldehyde compd product
1
2
3
4
5
6
7
8
9
FeCl3
ACN
EtOH
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
1
1
1
0.9
1.2
1.5
1.5
1.5
1.5
1.5
2,4-Cl-Ph
2,4-Cl-Ph
2,4-Cl-Ph
2,4-Cl-Ph
2,4-Cl-Ph
2,4-Cl-Ph
Ph
Ph
Ph
Ph
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
yes
yes
yes
yes
yes
no
no
no
no
no
62
68
72
53
79
92
90
52
65
84
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
o
Yb(OTf)3*
Yb(OTf)3
#
10
a Catalyst concentration: 10 mol % except for 0.1 mol % (o), 1 mol %
(*), and 5 mol % (#).
enrichment is to use an enamine attached to a chiral auxiliary
in the presence of n-butyllithium (Scheme 1).10 While the
enrichment values for this method are good to excellent (∼84
to 96%), this approach reduces the reaction to three
components and limits the diversity of the corresponding
products. In this work, we sought to develop a relatively
benign and efficient method to produce enantio-enriched,
four-component Hantzsch products.
As a model reaction, we selected a known polyhydro-
quinoline that would afford one stereocenter (Table 1).
Consistent with previous reports, 1 equiv of dimedone (0.4
mmol), ethyl acetoacetate, a benzaldehyde, and ammonium
acetate, in the presence of Yb(OTf)3 (10 mol %), produced
product 4a in both ethanol and acetonitrile (entries 2-3,
Table 1). Workup consisted of precipitating with 1 mL of
ice/water, stirring for approximately 1 h, filtering the
precipitate, and recrystallizing the product from an ethanol/
water system (3:1 vol). Using this procedure, we found good
yields (68% in ethanol and 72% in acetonitrile), but the
reaction also resulted in formation of the symmetrical side
product, which lacked the dimedone. In an attempt to
minimize this competing pathway, the equivalents of dime-
done were systematically increased (entries 4-6, Table 1).
At 1.5 equiv, the yield increased to 90% with concomitant
reduction in the side product. Next, we attempted to reduce
the catalyst concentration by screening at 5.0, 1.0, and 0.1
mol %. In each case, decreasing the catalyst levels reduced
the yield (84, 65 and 52%, respectively; entries 8-10, Table
1). Based on these observations, we selected 10 mol % of
catalyst and 1.5 equiv of dimedone for further studies.
Using these conditions, our plan was to screen organo-
catalysts for those that would afford a high degree of
enantioselectivity. A limited number of chiral Lewis acids11
as well as proline and its derivatives12 have been explored
in this context, but these have produced modest stereose-
lectivity. Guided by those findings, we focused on a proline-
derived catalyst (I) and an expanded series of Lewis acid
catalysts (II-VII). To estimate the enantio-enrichment of the
products, we used polarimetry in combination with chiral
HPLC. Using this approach, we found that catalyst I provided
good yields (86%) but no appreciable enrichment. Next, a
series of phosphine-based ligands (BINAP-II and -III,
DPPF-IV, and DPEsV) was explored. These catalysts were
used at 10 mol % with 11 mol % of a cocatalyst, Pd(OAc)2,
which provided yields between 75 and 84% but no enantio-
enrichment. Finally, we synthesized13 and explored chiral
BINOL-phosphoric acid derivatives (VI and VII). Both
catalysts provided good yields (84-85%) and 98% ee (Table
2), suggesting that enantio-enriched dihydropyridines could
be assembled by this route.
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