Synthesis and application of proline based organocatalyst for highly enantioselective aldol reaction by hydrogen bonding

Article abstract of DOI:10.1016/j.tetlet.2012.08.123

Using hydrogen bond based concept we have synthesized new organocatalysts and have applied them to catalyze direct asymmetric aldol reaction. Reaction proceeded efficiently and gave high yield with excellent diastereoselectivity and enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2012.08.123

Tetrahedron Letters 53 (2012) 6083–6086
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Tetrahedron Letters
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Synthesis and application of proline based organocatalyst for highly
enantioselective aldol reaction by hydrogen bonding
⇑
Prashant B. Thorat, Santosh V. Goswami, Bhimrao C. Khade, Sudhakar R. Bhusare
Department of Chemistry, Dnyanopasak College, Parbhani 431401, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Using hydrogen bond based concept we have synthesized new organocatalysts and have applied them to
catalyze direct asymmetric aldol reaction. Reaction proceeded efficiently and gave high yield with excel-
lent diastereoselectivity and enantioselectivity.
Received 16 July 2012
Revised 28 August 2012
Accepted 29 August 2012
Available online 7 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Diastereoselectivity
Enantioselectivity
Hydrogen bonding
Organocatalysis
Over the last decade, asymmetric organocatalysis has become
an important area of research in organic synthesis. The develop-
ment of organocatalyzed reactions for the stereoselective construc-
tion of carbon–carbon bonds has been intensively investigated.
more popularly with extraordinary success.21 In most of these
reactions, the N–H moiety is postulated to activate the substrates
by the formation of key hydrogen bonding interactions. The activa-
tion of a substrate and the organization of the transition state occur
through well-defined hydrogen-bonding interactions.22–24 Sigman
et al. and Corey et al. reported successful asymmetric Strecker
reaction via hydrogen bonding interaction without the formation
of enamine intermediate.25,26
On the basis of the success of hydrogen bonding organocataly-
sis, we sought to study the concept of pyrrolidine based organoca-
talysis in the absence of a Lewis basic primary or secondary amine
functionality, exclusively via hydrogen-bonding interaction. Our
aim was to develop new, neutral pyrrolidine organocatalysts that
display improved catalytic activity over the enamine catalysis.
Since the discoveries by List et al. that L-proline could mimic to
enantioselectively catalyze intermolecular aldol reactions,1 and
MacMillan’s organocatalytic Diels–Alder reaction,2 many organo-
catalysts have been synthesized with the aim of increasing their
reactivity and stereoselectivity.
The aldol reaction is recognized as one of the most powerful
carbon–carbon bond forming reaction in modern organic synthe-
sis.3,4 Amongst the organocatalysts developed so far for asymmet-
ric reactions, L-proline and proline-based compounds are known to
be powerful catalysts in direct asymmetric aldol reactions.5–8
Many of the organocatalysts such as primary amino acids,9–12 pyr-
rolidine-based catalysts,13,14 polymer supported organocatalysts,15
or proline-related systems16–19 often found to catalyze direct aldol
reactions leading to products with high enantioselectivities. These
reactions are a prototypical example of enamine based organoca-
talysis, proceeds via reversible condensation of the catalytic amine
with a ketone to provide a nucleophilic enamine intermediate. In
these reactions, the carboxylic acid functionality on proline was
found to be important and is postulated to activate and orient
the aldehyde acceptor via a hydrogen-bonding interaction.20
Moreover, hydrogen bonding is a ubiquitous force in nature.
Recently chemists have begun to implement this force in catalysis
O
N
Ts
HN
R
1
R= H
1a
1b
1c
R= CH3
R= Cl
R= F
1d
⇑
Corresponding author.
E-mail address: bhusare71@yahoo.com (S.R. Bhusare).
Figure 1. Pyrrolidine based organocatalysts.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.123

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P. B. Thorat et al. / Tetrahedron Letters 53 (2012) 6083–6086
With this aim, we designed and synthesized organocatalyst as
lower diastereoselectivity and enantioselectivity with decreased
yield of the product 4a (Entries 13–16), even with extended reac-
tion time.
shown in Figure 1. The utility of the N-sulfinyl group27–30 as both
a chiral directing group and acidic element in hydrogen-bonding
organocatalysts has been demonstrated. So, we restricted enam-
ine/imine formation by introducing N-sulfinyl group on active
nitrogen site in pyrrolidine ring and replaced carboxylic moiety
by amide group.
Having identified a 60:40 mixture of N,N-dimethylformamide
and water to be the best solvent system for the direct asymmetric
aldol reaction of p-nitrobenzaldehyde 2a with cyclohexanone 3,
influence of catalytic loading of 1d on the reaction was further
thoroughly investigated. The results are shown in Table 2. The
reaction showed a drop in diastereoselectivity and enantioselectiv-
ity with a decrease in quantity of the catalyst. When the loading of
the organocatalyst 1d was decreased from 10 to 5 mol %, there was
a significant decrease in the enantiomeric excess and the reaction
took 24 h to afford 26% 4a (Entry 1).
The catalytic performance of these neutral pyrrolidine organo-
catalysts was examined in a direct asymmetric aldol reaction
between p-nitrobenzaldehyde 2a and cyclohexanone 3 without
any additives at room temperature. The reaction was carried out
in water using 10 mol % of the synthesized organocatalysts
(Scheme 1).
As can be seen from the summarized results in Table 1, organ-
ocatalysts 1d were found to be effective of all the synthesized
organocatalysts but showed poor performance in water as solvent
(Entries 1–4). The reaction afforded 42% yield as a mixture of anti/
syn isomers (90/10) and enantioselectivity 60% for major anti iso-
mer 4a within 20 h (Entry 4). Although stereoselectivity of the
reaction was good, yield obtained was low. The effectiveness of
catalyst 1d was due to more active electron withdrawing group
as substituent to amide group which helps in stabilizing the inter-
mediate. Further optimization of reaction for solvent was carried
out using 10 mol % of organocatalyst 1d.
Many of the organocatalytic reactions have been carried out
successfully in solvent such as N,N-dimethylformamide, dimethyl
sulfoxide, and chloroform.31 We decided to screen the ability of
aforementioned solvents to catalyze the direct aldol reaction. The
reaction did not show any progress at room temperature in non-
polar solvent chloroform (Entry 5). The reaction proceeded
smoothly in 16 h at room temperature conditions in N,N-dimethyl-
formamide. Although the corresponding aldol 4a was obtained in
good yield 68%, the enantiomeric excess was very poor (39%; Entry
6). The reaction was sluggish (24 h) in dimethyl sulfoxide affording
moderate 57% yield, and diastereo- and enantioselectivity of the
reaction was found to decrease (Entry 7).
Furthermore, the reaction was examined with varying propor-
tion of N,N-dimethylformamide and water to increase the perfor-
mance. The reaction was influenced by proportions of water in
terms of catalytic efficiency. By running the reaction in the pres-
ence of a 50:50 of N,N-dimethylformamide and water, catalyst 1d
was able to promote reaction in 16 h to afford enhanced yield with
improved enantioselectivity 69% ee for anti-4a (Entry 8). The best
result with respect to yield, diastereoselectivity, and enantioselec-
tivity was observed with catalyst 1d and 60:40 of N,N-dimethyl-
formamide and water. The reaction was faster (14 h) and
afforded the corresponding aldol 4a in high yield (80%) with high-
est diastereoselectivity (95/5 for anti/syn) and good enantioselec-
tivity (78%; Entry 9). Further increase in the water proportion
although decreased the reaction time, gave no improvement with
respect to yield, diastereoselectivity, and enantioselectivity (Entry
10). Results showed a significant deviation from the aim of optimi-
zation. The aldol reaction under optimized condition was also
examined using other organocatalysts in 60:40 of N,N-dimethyl-
formamide and water. It was found that other catalysts showed
The breakthrough results were achieved when 12 mol % of cat-
alyst 1d was employed in 60:40 proportions of N,N-dimethylform-
amide and water. Up to 91% of the desired product 4a was obtained
with excellent selectivity (anti/syn was 99:1), the anti-aldol prod-
uct was obtained with excellent enantioselectivity 95% (Entry 2).
Further increase in the amount of organocatalyst 1d did not result
in an increase in yield or stereoselectivity (Entries 3–4).
Broadening the scope of our study, we studied aldol reaction
using an optimized protocol for various aromatic aldehydes. As
revealed in Table 3, the reactions proceeded smoothly with
12 mol % of catalyst and gave rise to highly enantio-enriched
adducts in good yields. The electron-deficient aromatic aldehydes
showed better yield and enantioselectivity requiring less reaction
time for completion. For the neutral and electron-rich aromatic
aldehydes, much longer reaction time was required. Additionally,
substrates with substituents at ortho position gave lower
yields than the ones with substituents at para position which is
due to steric hindrance; however enantioselectivity did not vary
very much.
Based on the results obtained, the mechanism of the direct aldol
reaction can be explained as depicted in Figure 2. Hydrogen bond-
ing interactions have the ability to tautomerize keto enol form.32
The tosyl group on nitrogen tautomerizes cyclohexanone to form
cyclohexenol via hydrogen bonding interaction to generate the
nucleophile. The hydrogen bonding interaction resulting from
amide N–H and protic solvent increases electrophilicity of the
aromatic aldehyde.31d,33 The role of water is to bring the catalyst
and reactants close together by hydrogen bonding to accelerate
the reaction and also to enhance stereoselectivity.34 The transition
state thus formed leads to the desired product.
In conclusion, we have designed and synthesized new type of
(neutral) pyrrolidine based organocatalysts. The synthesized
organocatalysts were successfully used to catalyze aldol reaction;
especially the organocatalyst (S)-N-(4-fluorophenyl)-1-tosylpyrr-
olidine-2-carboxamide (1d) was more effective to give high yield
and excellent stereoselectivity of aldol products. We have demon-
strated for the first time that pyrrolidine based catalysts can func-
tion not only by enamine/imine formation but also have the ability
to catalyze reactions through strong hydrogen bonding interac-
tions. This organocatalytic reaction shows productive result with
various other aldehydes. Aromatic aldehydes having electron
withdrawing substituent show the best results.
O
OH
O
O
H
+
NO2
O2N
3
4a
2a
Scheme 1. Asymmetric aldol reaction of p-nitrobenzaldehyde 2a with cyclohexanone 3 catalyzed by organocatalyst 1(a–d).

P. B. Thorat et al. / Tetrahedron Letters 53 (2012) 6083–6086
6085
Table 1
Effect of catalyst and solvent on aldol reactiond
Entry
Catalyst
Solvent
Time (h)
Yielda (%)
anti/synb
anti eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1a
1b
1c
Water
Water
Water
Water
27
30
24
20
24
16
20
16
14
12
24
24
20
18
20
17
29
30
38
42
—
68
57
76
80
70
65
55
57
46
40
67
78/22
81/19
85/15
90/10
—
88/12
89/11
93/7
54
48
59
60
—
39
26
70
78
72
42
54
48
79
66
82
Chloroform
N,N-Dimethylformamide
Dimethyl sulfoxide
DMF:Water (50:50)
DMF:Water (60:40)
DMF:Water (70:30)
DMSO:Water (50:50)
DMSO:Water (60:40)
DMSO:Water (70:30)
DMF:Water (60:40)
DMF:Water (60:40)
DMF:Water (60:40)
95/5
92/8
87/13
90/10
96/4
88/12
90/10
92/8
a
b
c
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
Progress of reaction was monitored by thin layer chromatography.
d
Table 2
Effect of catalyst loading 1d in solvent DMF:Water (60:40) on aldol reactiond
Entry
Catalyst loading (mol %)
Time (h)
Yielda (%)
anti/syn ratiob
anti eec (%)
1
2
3
4
5
12
15
20
24
10
14
16
26
91
72
60
76/24
99/1
89/11
90/10
30
95
43
30
a
b
c
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
Progress of reaction was monitored by thin layer chromatography.
d
Table 3
Reaction of cyclohexanone and aromatic aldehydese
O
OH
O
O
H
Organocatalyst 1d
DMF-H2O
+
R
4 (a-j)
R
3
2(a-j)
Yielda (%)
anti/syn ratiob
anti eec (%)
[a]
D
d
Entry
R
Time (h)
Product
1
2
3
4
5
6
7
8
9
4-NO2
3-NO2
4-F
4-Br
4-CN
4-Cl
3-Cl
H
2-OCH3
4-OCH3
10.00
10.00
10.00
10.30
10.00
11.30
11.00
12.30
12.30
15.00
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
89
92
84
90
82
85
80
79
78
99/1
95
92
91
89
91
88
89
87
88
88
À48.7
À70.0
À60.8
À51.8
À86.2
À56.3
À89.2
À15.7
À21.3
À31.5
100/00
100/00
98/2
99/1
100/00
97/3
98/2
96/4
93/7
10
4j
a
b
c
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
Specific rotation determined at 27 °C in ethyl acetate.
Progress of reaction was monitored by thin layer chromatography.
d
e

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