Camphor-10-sulfonamide-based prolinamide organocatalyst for the direct intermolecular aldol reaction between ketones and aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2010.04.018

Prolinamides derived from L-proline and N,N-dialkyl 2-aminocamphor-10- sufonamides have been synthesized and used as organocatalysts in the direct intermolecular aldol reaction. Reactions of several aromatic aldehydes with cyclohexanone, cyclopentanone, 4

Full text of DOI:10.1016/j.tetasy.2010.04.018

Tetrahedron: Asymmetry 21 (2010) 775–779
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Camphor-10-sulfonamide-based prolinamide organocatalyst for the direct
intermolecular aldol reaction between ketones and aromatic aldehydes
*
Rashmi Rani, Rama Krishna Peddinti
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Prolinamides derived from L-proline and N,N-dialkyl 2-aminocamphor-10-sufonamides have been syn-
Received 2 February 2010
Accepted 19 April 2010
Available online 24 May 2010
thesized and used as organocatalysts in the direct intermolecular aldol reaction. Reactions of several aro-
matic aldehydes with cyclohexanone, cyclopentanone, 4-oxa and 4-sulfa-cyclohexanones and acetone
are investigated employing 1a as an organocatalyst. Very high to excellent selectivities are obtained in
these direct aldol reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Asymmetric organocatalysis has emerged as a rapidly growing
and important field in organic chemistry.1–4 Most attention has
been focused on the use of the amino acid proline due to its ready
availability in both enantiomeric forms and the highly versatile
nature of its reactivity. In particular, proline-catalyzed aldol reac-
tions have attracted great attention, because of their synthetic va-
lue as well as interesting mechanistic aspects.4–6 This powerful
organocatalytic protocol allows the direct cross-coupling between
ketones and aldehydes. One of the drawbacks associated with pro-
line catalysis is its poor solubility in common organic solvents.
Most of the reactions catalyzed by proline or proline-embedded
molecules are performed in polar solvents such as DMF and
DMSO.7 We envisaged that the novel catalyst architectures 1a–c
bearing amide linkage8,9 would catalyze the aldol reaction via
hydrogen bonding between the amide moiety of the catalyst with
the aldehyde and the alkyl groups on nitrogen of sulfonamide
moiety would block one of the faces of the substrate leading to
diastereo- and enantioselective formation of the products. In addi-
tion, the solubility of these catalysts is expected to increase in polar
as well as non-polar organic solvents due to N,N-dialkyl camphor-
sulfonamide moiety. Herein we present our preliminary results on
novel camphorsulfonamide-based prolinamides-mediated organo-
catalytic direct intermolecular aldol reaction (Fig. 1).
H
N
H
N
H
N
N
H
N
H
N
H
O
N
O
N
O
N
O
O
O
S
S
S
O
O
O
1a
1b
1c
Figure 1. Structures of organocatalysts 1a–c.
reaction was performed under neat conditions and in water, polar
and relatively non-polar solvents (Table 1). These screening studies
identified chloroform as the optimal solvent for the reaction. Thus
the reaction in chloroform at room temperature produced the aldol
product 2a in three days in excellent chemical yield and diastere-
oselectivity with 97% ee for the major anti-isomer.
Encouraged by the preliminary data, we carried on to modify the
hydrophobic groups on the nitrogen of the camphorsulfonamide
moiety of the catalyst to examine the effect on rate, yield and dia-
stereo- and enantioselectivities of the reaction. The prolinamides
1b and 1c derived from N,N-diisopropyl camphor-10-sufonamide
and N,N-dicyclohexyl camphor-10-sufonamide, respectively, were
used as catalysts for the aldol reaction of cyclohexanone with 2-ni-
tro- and 4-nitrobenzaldehydes (Table 2). However, the results ob-
tained when 20 mol % of 1a was employed as catalyst in the
reaction are better.
2. Results and discussion
With optimal catalyst and reaction parameters established, a
variety of aromatic aldehydes were then evaluated as substrates
and the results are summarized in Table 3. All the reactions pro-
ceeded smoothly at room temperature and reached completion in
2–4 days providing the products in high to excellent yields and
diastereomeric ratios in almost all cases studied. The anti-aldol
products were obtained as major adducts in high to excellent
As a prelude to this objective, we synthesized the organocata-
lysts 1a–c and carried out the aldol reaction between cyclohexa-
none and 2-nitrobenzaldehyde in the presence of 1a. The
* Corresponding author. Tel.: +91 13 3228 5438; fax: +91 13 3227 3560.
E-mail addresses: rkpedfcy@iitr.ernet.in, ramakpeddinti@rediffmail.com (R.K.
Peddinti).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.018

776
R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 775–779
Table 1
4b derived from tetrahydrothiopyran-4-one is better than that of
p-nitro product 3b derived from tetrahydropyran-4-one. The reac-
tions of cyclopentanone were also investigated. The results are
summarized in Table 3. Though the diastereoselective outcome of
these reactions is not impressive, both the syn and anti products
were obtained in good enantioselectivities.
Effect of solvents on direct aldol reaction of cyclohexanone with 2-nitrobenzaldehyde
in the presence of 1aa
O
O
O
OH NO2
20 mol% 1a
H
+
To examine the generality of this organocatalytic approach, the
reaction of acetone was investigated with nitro- and halo-benzal-
dehydes. The reaction of acetone with 2-nitrobenzaldehyde in
the presence of 20 mol % 1a at room temperature afforded the aldol
adduct 6a in 88% yield and 77% ee in 24 h. When we performed the
same reaction at 0 °C, the adduct 6a was obtained in excellent
chemical yield and enantiomeric excess (Fig. 2). The reactions of
acetone with halo-benzaldehydes were carried out under similar
conditions. The asymmetric induction in organocatalyst 1a medi-
ated aldol reaction of acetone is very high. The organocatalyst used
in this study provided very high selectivities. For instance, the re-
sults obtained from 1a-catalyzed aldol reaction with those ob-
tained from proline-catalyzed reaction5a,10 are compared in
Table 4.
According to the stereochemical outcome in the current reac-
tions catalyzed by 1a, we propose that N,N-dibenzyl camphorsulf-
onamide-based prolinamide catalyst could catalyze the direct aldol
reaction via the transition state shown in Figure 3. The aldehyde
could be activated by the hydrogen bonding with NH of the cata-
lyst. The bulky benzyl group on the catalyst framework could effec-
tively shield the Re-face of the enamine, leaving its Si-face exposed
for enantioselective bond formation on the Re-face of the aldehyde
that leads to (1R,2S)-isomer.
NO2
2a
Entry
Solvent
Temp
Time (h)
Yield (%)
dr (anti:syn)b
eec
1
2
3
4
5
6
7
8
Neat
Neat
H2O
DMF
CH2Cl2
CHCl3
DMSO
CH3CN
rt
0 °C
rt
rt
rt
rt
rt
rt
7
90
89
92
92
90
96
88
89
97:3
92:8
93:7
95:5
90:10
99:1
85:15
94:6
51
72
17
80
50
97
80
80
10
20
72
78
66
96
96
a
Reactions were performed with cyclohexanone (0.4 mM) and 2-nitrobenzal-
dehyde (0.2 mM) in the presence of catalyst 1a (20 mol %) in 0.5 mL of solvent.
Determined by 1H NMR of the crude sample.
b
c
Of anti-isomer and determined by HPLC analysis (Chiralcel OD-H).
enantioselectivities (89–100%). Thereactionsof cyclohexanonewith
o-bromo- and o-chloro-benzaldehydes provided the corresponding
aldol adducts 2d and 2f in good diastereoselectivity (96:4) and
enantioselectivity (92% and 96% ee). The products 2e and 2g
with p-bromo- and p-chloro-substitutions were obtained in compa-
rable diastereoselectivity (92:8) and enantioselectivities (94% and
92% ee). The reaction of cyclohexanone with 1-naphthaldehyde
furnished anti adduct 2k as major product along with 15% of syn-
isomer. The anti-aldol adduct 2k was obtained in >99.9% enantio-
meric purity, (Table 3, entry 11). The reactions of benzaldehydes
bearing electron-withdrawing group are relatively faster than those
with halo-substituent. No product was observed under the reaction
conditions when benzaldehyde was used as a substrate.
Encouraged by the results obtained with cyclohexanone, we
next probed the aldol reaction between aryl aldehydes and other
six-membered cyclic ketones using catalyst 1a. Again in these reac-
tions, the aldol adducts were obtained in excellent diastereoselec-
tivities and enantioselectivities. The reactions of tetrahydropyran-
4-one and tetrahydrothiopyran-4-one with o-nitrobenzaldehyde
provided the corresponding adducts 3a and 4a in P95:5 diastereo-
meric ratios and 98% ee. The enantioselectivity of p-nitro product
3. Conclusion
In conclusion, we have synthesized camphorsulphonamide-
based prolinamides and investigated their catalytic behaviour in
direct aldol reaction. The organocatalyst 1a showed remarkable
selectivities in the reactions between cyclic/acyclic ketones and
aromatic aldehydes. The excellent results displayed by 1a may be
attributed to the stabilization of transition state via hydrogen
bonding between aldehyde and amide moiety of the enamine
formed from catalyst and ketone and effective shielding of one of
the faces of enamine by benzyl moiety of the catalyst. Further stud-
ies focusing on the application of these novel organocatalysts in
other organic transformations are in progress in our laboratory.
Table 2
Screening of organocatalystsa
O
O
O
OH
Catalyst
H
2a: 2-NO2
2c: 4-NO2
NO2
+
CHCl3, r.t.
NO2
Entry
Catalyst (mol %)
Time (h)
Product
Yield (%)
dr (anti:syn)b
eec (%)
1
2
3
4
5
6
7
8
1a (10)
1a (20)
1a (30)
1b (20)
1c (20)
1a (20)
1b (20)
1c (20)
120
66
68
72
96
72
96
98
2a
2a
2a
2a
2a
2c
2c
2c
89
96
95
91
93
96
89
91
92:8
99:1
97:3
90:10
91:9
90:10
89:11
92:8
80
97
94
80
88
91
58
77
a
b
c
Reactions were performed with cycloalkanone (0.4 mM) and aldehyde (0.2 mM) in the presence of an organocatalyst 1 in 0.5 mL of CHCl3.
Determined by 1H NMR of the crude sample.
Of anti-isomer and determined by HPLC analysis (Chiralcel OD-H).

R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 775–779
777
Table 3
Aldol reaction of cyclohexanone and cyclopentanone with substituted benzaldehydes in the presence of 1aa
O
O
O
X
OH
S
20 mol% 1a
H
R
syn-isomer
+
+
CHCl3, r.t.
X
R
R
X = CH2, O, S, -
Entry
1
Product
Time (h)
66
Yield (%)
dr (anti:syn)b
eec (%)
97
O
OH NO2
96
94
99:1
2a
O
OH
NO2
2
3
4
5
72
72
88
90
95:5
90:10
96:4
90
91
92
91d
2b
O
OH
96
89
91
2c
NO2
O
O
OH Br
OH
2d
92:8
2e
Br
O
O
OH Cl
OH
6
7
88
90
90
92
96:4
92:8
96
92
2f
2g
Cl
O
O
OH
OH
8
88
93
79:21
92
2h
F
9
72
72
95
90
94:6
95:5
92d
89
2i
2j
CN
O
O
OH OMe
OH
10
11
72
92
85:15
>99e
2k
O
OH NO2
12
13
14
60
62
60
96
94
97
95:5
98:2
97:3
98
3a
3b
4a
O
O
OH
86d
98
O
O
NO2
OH NO2
S
(continued on next page)

778
R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 775–779
Table 3 (continued)
Entry
Product
Time (h)
62
Yield (%)
95
dr (anti:syn)b
eec (%)
95d
O
OH
15
96:4
4b
S
NO2
O
OH NO2
OH
16f
17f
40
48
90
89
60:40
45:55
90 (74)d,g
90 (78)g
5a
5b
5c
O
O
NO2
OH
18f
52
60
91
85
53:47
40:60
86 (84)d,g
92 (85)d,g
NO2
Br
O
OH
19f
5d
a
Reactions were performed with cycloalkanone (0.4 mM) and aldehyde (0.2 mM) in the presence of 20 mol % 1a in 0.5 mL of CHCl3 at rt.
Determined by 1H NMR (500 MHz) of the crude sample.
Of anti-isomer and determined by HPLC analysis (Chiralcel OD-H) unless otherwise mentioned.
Of anti-isomer and determined by HPLC analysis (Chiralpak AD-H).
Of anti-isomer and determined by HPLC analysis (Chiralcel OD-H & Chiralpak AD-H).
The structure of anti-isomer is shown.
b
c
d
e
f
g
Value in parenthesis is of syn-isomer.
O
OH NO2
O
OH
O
OH Cl
O
N
N
H
O
Br
H
Si-face (open)
O
S
6a
6b
48 h, 88%
91% ee
6c
Re-face (blocked)
O
N
36 h, 98%
91% ee
48 h, 90%
92% ee
Figure 2. Aldol products derived from acetone.
Figure 3. Possible transition state.
2–4 days at room temperature. The reaction was monitored by
TLC at regular intervals. On completion of reaction, solvent was re-
moved under reduced pressure and the crude product was submit-
ted for 1H NMR (500 MHz) to determine the diastereomeric excess.
The residue was subjected to column chromatography on silica gel
to afford pure product. The HPLC of the aldol product was per-
formed on a chiral stationary phase using hexane–isopropanol as
4. Experimental
4.1. Typical procedure for the enantioselective aldol reaction
catalyzed by organocatalyst 1a
A solution of aldehyde (0.2 mmol), organocatalyst 1a (20 mol %)
and cycloalkanone (0.4 mmol) in CHCl3 (0.5 ml) was stirred for
Table 4
Comparison of results from 1a and proline-catalyzed reactionsa
Entry
Catalyst (mol %)
Product
Yield (%)
dr (anti:syn)
ee (%)
1
2
1a (20)
Proline (30)
O
OH
96
65
90:10
63:37
91
89
NO2
Br
2c
OH
3
4
1a (20)
Proline (30)
O
O
88
74
—
—
91
65
6b
OH Cl
5
6
1a (20)
Proline (30)
90
94
—
—
92
69
6c
a
Organocatalyst 1a-catalyzed reactions were performed in chloroform and proline-catalyzed reactions were performed in DMSO.

R. Rani, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 775–779
779
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