2
T. P. Kumar / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
As part of our screening studies, we conducted experiments on
catalyst loading and temperature conditions to establish the opti-
mal reaction conditions. As shown in Table 3, the reaction per-
formed at room temperature with 15:10 mol % catalyst/additive
ratio under solvent-free conditions was found to be more operative
and effective in overall terms (Table 3, entry 2), while reactions
conducted under other conditions suffered either from long reac-
tion times or a loss of yield with no considerable improvement
in stereoselectivities (Table 3, entries 1, 3, 4 and 5).
O
O
NO2
1
catalyst
NO2
H
H
solvent (0.5 mL)
rt
3a
2a
4a
Scheme 1. Michael addition of propaldehyde to nitrostyrene.
Table 1
Screening of solvents using 1a
Table 3
Yieldb (%)
66
Entry Solvent
Time (h)
24
(syn/anti)c eed(%)
Effect of temperature and catalyst loadinga
1
DMF
75:25
54
eed
Catalyst
(mol%)
20
15
15
10
5
Time
(h)
48
20
48
Yieldb
(syn/anti)c
Temp.
Entry
1
Toluene
36
74
8:2
65
2
(oC)
(%)
(%)
24
73
8:2
69
3
Hexane
87
94:6
93:7
91:9
91:9
9:1
0
RT
0
90
4
5
CH3CN
CH2Cl2
36
24
36
24
24
24
24
24
36
77
79
69
71
81
76
75
72
61
82:18
85:15
8:2
61
75
60
93
83
75
91
87
85
81
2
3
4
5
6
Dioxan
RT
RT
36
48
85:15
9:1
71
83
7
8
CHCl3
62
Neat
a
Reaction conditions: propaldehyde (5 mmol), nitrostyrene
9
THF
88:12
85:15
74
66
(1 mmol), PhCOOH (10 mol %).
10
b
EtOH
Isolated yields.
c
Determined by 1H NMR of crude product.
85:15
7:2
69
73
11
12
MeOH
d
H2O
Determined by chiral HPLC.
a
Reaction conditions: propaldehyde (5 mmol), nitrostyrene
(1 mmol), solvent (0.5 mL), catalyst (20 mol %).
b
Isolated yields.
With the optimal reaction conditions in hand, we next studied
the generality of this transformation using a series of aldehydes
and nitroolefins in different combinations. As shown in Tables 4
and 5, all substrate combinations involving variations in nitroole-
fins 3b–j reacted smoothly with propaldehyde 2a (Table 4, entries
1–9) and other aldehydes 2b–f (Table 5, entries 1–9) under the
optimized reaction conditions and the corresponding Michael
products 4b–j and 4k–s were obtained in good yields and with
high levels of diastereoselectivities and enantioselectivities,
regardless of the nature of the substitution pattern in the nitroole-
fins. However, reactions involving branched aldehydes (Table 5,
entries 5 and 9) or nitroolefins with electron donating substituents
(Table 4, entries 4 and 5) were found to be slightly inferior in
overall productivity. Overall, the catalytic performance of pyrroli-
dine–pyrazole catalyst for the conjugate addition of aldehydes to
nitroolefins was found to be effective and was in good agreement
with those reported in the literature.7
c
Determined by 1H NMR of crude product.
d
Determined by chiral HPLC.
the Michael reaction proceeded well in all solvents irrespective of
their polar/non-polar nature to afford the product -nitroaldehyde
c
4a in good yield and stereoselectivity (Table 1, entries 1–12). How-
ever, solvent-free conditions were found to be more effective in
terms of yield (81%), diastereoselectivity (syn/anti 9:1) and enanti-
oselectivity (83% ee) among the conditions screened and was
adopted for further studies. Encouraged by these initial results,
we next conducted additive screening experiments with the aim
of improving the catalytic activity. It has been well documented
that the presence of an acid additive can enhance catalytic effi-
ciency by acceleration of the enamine formation. In anticipation,
we examined the effect of various acid additives under solvent-free
conditions using 20 mol % of catalyst and 5 mol % of additive at
room temperature and the results are summarized in Table 2. Ben-
zoic acid turned out to be the most efficient additive in combina-
tion with catalyst 1 (Table 2, entries 1–6). The effect of loading
was tested using 10 and 15 mol % of benzoic acid (Table 2, entries
7 and 8, respectively). As evident from Table 2, the use of 10 mol %
of benzoic acid found to be the best value and subsequent experi-
ments were carried out using 10 mol % of benzoic acid in combina-
tion with catalyst 1.
The transition state7,9,10 model, that was proposed8h for the
asymmetric Michael reaction of
a,a-disubstituted aldehydes to
nitroolefins (Fig. 2) was used to rationalize the absolute stereo-
chemical outcome of this transformation. The pyrrolidine ring of
the catalyst activates the aldehyde towards enamine formation,
while the pyrazole template serves as an efficient stereo-control
element, by providing stereo-facial shielding and coordinating
with the nitroolefin through the benzoic acid via H-bonding inter-
action. This results in a compact transition state, wherein the
nucleophilic enamine attacks the nitroolefin from Si face and leads
to the formation of the desired products with high diastereoselec-
tivities and enantioselectivities.
Table 2
Screening of additivesa
(syn/anti)c
Entry additive
Time (h) Yieldb(%)
eed(%)
(mol%)
5
1
2
3
TFA
24
86
9:1
7:3
8:2
85
70
69
3. Conclusions
24
CSA
5
5
5
5
71
65
pTSA
PhOH
HCOOH
24
24
24
4
5
76
79
85:15
8:2
78
80
In conclusion, we have demonstrated the application of pyrrol-
idine–pyrazole 1 as an effective organocatalyst for enantioselective
Michael additions of aldehydes to nitroolefins. The catalytic cycle
was effective with 15 mol % of catalyst in combination with
10 mol % of benzoic acid. The resulting adducts were obtained in
high yields and with high stereoselectivities under solvent-free
reaction conditions at room temperature. Investigations into the
catalytic activity of the pyrrolidine–pyrazole as an organocatalyst
6
7
8
PhCOOH
5
24
20
20
9:1
87
92
92
87
94
94
PhCOOH
PhCOOH
10
15
93:7
94:6
a
Reaction conditions: propaldehyde (5 mmol), nitrostyrene
(1 mmol), catalyst 1 (20 mol %), neat, rt.
b
Isolated yields.
c
Determined by 1H NMR of crude product.
d
Determined by chiral HPLC.