S. S. Chimni et al. / Tetrahedron: Asymmetry 20 (2009) 1722–1724
1723
Table 1
1a–g, varied with the pKa of the acid (Table 2). Thus we suggest
that the nature of the protonating acid has no effect on the stere-
oselective outcome of the aldol reaction; it is controlled by the
pH of the reaction mixture.
Another observation made during this study pertains to the
optimum pH range 4–5 (Table 1, entry 7) within which the enanti-
oselectivity was found to be highest. We believe that an optimal
equilibrium between the protonated and protonation free prolina-
mide catalyst in the aqueous medium (Eq. 1) is responsible for the
high enantioselectivity.7b
Effect of pH on the enantioselectivity and diastereoselectivity of the aldol producta
Entry
pH
Yieldb (%)
drc (anti:syn)
eed of anti (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6.41
6.26
6.01
5.70
5.36
5.03
4.54
4.09
3.51
3.08
2.45
2.05
1.51
0.94
92
91
92
92
90
91
92
92
91
90
88
81
76
20
68:32
73:27
77:23
84:16
90:10
91:9
92:8
93:7
95:5
95:5
96:4
97:3
94:6
94:6
71
88
88
89
92
95
96
95
93
93
92
94
93
93
H2
O
RNþH3Xꢀ ꢀ RNH2 þ Hþ þ Xꢀ
ð1Þ
This probably inhibits the general base catalysis of the aldol
reaction, thus allowing the reaction to proceed through enamine
catalysis. To further confirm the importance of pH in directing
the stereoselectivity of the direct aldol reaction irrespective of
the protonating acid we performed a set of aldol reactions of cyclo-
hexanone with 4-nitrobenzaldehyde while maintaining the pH of
the reaction mixture at 4.5 0.2 using different acids (Table 3).
a
Reaction conditions: 1 mmol aldehyde, 5 mmol ketone, 20 mol % catalyst,
2.5 mL water, 27 °C.
b
Isolated yield.
c
Determined from 1H NMR of crude reaction mixture.
d
Determined by HPLC using chiral phase AS–H column.
Table 3
between the pH range 4 and 5, being highest (ee 96%) at pH 4.54
(Table 1, entry 7). At a lower pH (beyond 2.05) the yield of the aldol
product decreased. Thus this study establishes that the pH of the
reaction mixture is important to obtain highly stereoselective
catalysis of the direct aldol reaction by prolinamide catalysts.
We further envisaged exploring the role of the conjugate base of
the acid on the stereoselective outcome of the reaction. The results
of the direct aldol reactions of cyclohexanone with 4-nitrobenzal-
dehyde using catalysts 1a–g, prepared by protonation with differ-
ent protic acids, are summarized in Table 2. The results indicate
that the protonating acid does have a large effect on the diastereo-
and enantioselectivity of the aldol product. This can be correlated
with the pKa of the protonating acids and the pH of the reaction
mixture. The catalysts protonated with acids having a higher pKa
value (Table 2, entries 1 and 2) catalyzed the aldol reaction less
selectively whereas those with a lower pKa (Table 2, entries 3–7)
yielded aldol products in high diastereo- and enantioselectivity.
Organocatalyzed direct aldol reaction at pH 4.5 0.2a
O
O
O
OH
Cat. 1 (20 mol%)
pH 4.5
+
0.2
O2N
NO2
3
4
2
Entry
Acid
Time (h)
Yieldb (%)
drc (anti:syn)
eed of anti
1
2
3
4
5
6
7
8
9
Acetic acid
TFA
HBr
HCl
HNO3
H2SO4
HBr/AcOH(33%)
ClSO3H
CF3SO3H
24
24
24
24
24
24
24
24
24
88
91
92
90
90
92
90
87
86
80:20
88:12
92:8
92:8
92:8
93:7
93:7
95:5
96:6
88
91
96
94
94
94
96
94
93
a
Reaction conditions: 1 mmol aldehyde, 5 mmol ketone, 20 mol % catalyst,
2.5 mL water, 27 °C.
Table 2
b
Isolated yield.
Effect of protonating acids on the diastereoselectivity and enantioselectivity of the
c
Determined from 1H NMR of crude reaction mixture.
aldol reactiona
d
Determined by HPLC using chiral phase AS–H column.
Yieldc
drd
(anti:syn) anti (%)
eee of
b
Entry Catalyst Acid
pKa
pH of
solution (%)
The enantioselectivity was nearly similar. The yield of the aldol
product 4, obtained by using catalysts 1f and 1g increases (Table 3,
entries 8 and 9) from that obtained at pH 1.9 (Table 2, entry 6) and
pH 1.57 (Table 2, entry 7), respectively. This suggests greater reac-
tivity of the catalysts in the optimal pH range.
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
CH3COOH
CF3COOH
HNO3
HCl
HBr
4.76 6.81
0.26 5.30
89
82
85
89
92
69
51
62:38
85:15
94:6
92:8
94:6
92:8
92:8
66
88
92
92
95
91
91
ꢀ1.30 4.07
ꢀ8.00 4.37
ꢀ9.21 4.01
ꢀ10.43 1.90
ꢀ13.00 1.57
ClSO3H
CF3SO3H
3. Conclusion
1g
a
Reaction conditions: 1 mmol aldehyde, 5 mmol ketone, 20 mol % catalyst,
In conclusion, we have demonstrated that high diastereoselec-
tivity and enantioselectivity of the protonated prolinamide-cata-
lyzed direct asymmetric aldol reaction in water are dependent on
the pH of the reaction medium. In general, the acidic pH favors
high stereoselectivity, whereas a pH range of 4–5 is optimum for
excellent diastereoselectivity and enantioselectivity in water.
2.5 mL water, 27 °C.
b
pKa of acid measured in water.10
c
Isolated yields.
d
Determined from 1H NMR of crude reaction mixture.
e
Determined by HPLC using chiralphase AS–H column.
However, with chlorosulfonic acid and trifluoromethanesulfo-
nic acid as protonating acids, the aldol product was obtained in
low yield, which can be attributed to the inhibiting effect of the
strong acids on the catalyst. Interestingly, the reaction was not
completely inhibited by protonating acids with low pKa values (Ta-
ble 1, entries 6–7), unlike the observations made by the groups of
Gryko and Najera where the acid additives with a pKa value of less
than zero inhibit the reaction completely.8d,9 In aqueous conditions
our catalysts are receptive to a broader range of acids. The pH of
the reaction mixture, containing 20 mol % of protonated catalysts
Acknowledgment
We are grateful for financial support from CSIR, India to S.S.C.
(research Grant No. 01/2168/07/EMR-II) and SRF(NET) fellowship
to S.S.
References
1. (a) Li, C.-J. Chem. Rev. 2005, 105, 3095–3165; (b) Minakata, S.; Komatsu, M.
Chem. Rev. 2009, 109, 711–724.