Synthesis of chiral benzimidazole-pyrrolidine derivatives and their application in organocatalytic aldol and Michael addition reactions

Article abstract of DOI:10.1080/00397910701575335

An efficient and mild approach for the synthesis of pyrrolidine- benzimidazoles has been reported. They were further employed for the aldol and Michael addition reactions to afford the corresponding products with good yields and moderate enantioselectivit

Full text of DOI:10.1080/00397910701575335

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Synthesis of Chiral Benzimidazole‐Pyrrolidine
Derivatives and their Application in
Organocatalytic Aldol and Michael Addition
Reactions
K. Rajender Reddy a , G. Gopi Krishna a & C. V. Rajasekhar a
a Inorganic and Physical Chemistry Division , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 14 Dec 2007.
To cite this article: K. Rajender Reddy , G. Gopi Krishna & C. V. Rajasekhar (2007) Synthesis of Chiral
Benzimidazole‐Pyrrolidine Derivatives and their Application in Organocatalytic Aldol and Michael Addition
Reactions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:24, 4289-4299, DOI: 10.1080/00397910701575335
To link to this article: http://dx.doi.org/10.1080/00397910701575335
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Synthetic Communicationsw, 37: 4289–4299, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575335
Synthesis of Chiral Benzimidazole-
Pyrrolidine Derivatives and their
Application in Organocatalytic Aldol
and Michael Addition Reactions
K. Rajender Reddy, G. Gopi Krishna, and C. V. Rajasekhar
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Abstract: An efficient and mild approach for the synthesis of pyrrolidine-benzimida-
zoles has been reported. They were further employed for the aldol and Michael addition
reactions to afford the corresponding products with good yields and moderate
enantioselectivities.
Keywords: asymmetric aldol, benzimidazole, Michael addition, organocatalysis,
pyrrolidine
INTRODUCTION
The increasing demand of chemical and pharmaceutical industries for enantio-
merically pure compounds has prompted the development of several chiro-
technologies, which exert control over a chemical reaction by directing its
enantioselectivity.[1] Nature synthesizes a wide variety of chiral molecules
via biosynthetic routes.[2] Design and synthesis of chiral catalysts that
provide chiral molecules with high purity and high turnover numbers
(TON) have become an attractive as well as challenging approach. Ligands,
which are small organic molecules, play an important role for the activity
and selectivity in the metal-catalyzed enantioselective transformations.
Received in India May 8, 2007
Address correspondence to K. Rajender Reddy, Inorganic and Physical Chemistry
Division, Indian Institute of Chemical Technology, Hyderabad 500 037, India. E-mail:
rajender@iict.res.in
4289

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K. R. Reddy, G. G. Krishna, and C. V. Rajasekhar
However, in recent years, it was observed that the small organic molecules
themselves do act as catalysts, a process termed “organocatalysis.”[3]
Amino acids are the typical examples, which act as both ligands and
catalysts. In the past few years, several organocatalysts, particularly proline
and its derivatives, have been developed and successfully applied for a
variety of transformations, especially in aldol, Mannich, and Michael
addition reactions.[4]
The imidazole ring system is a key structural fragment found in many
natural products.[5] It also serves as a good ligand for various metal ions.
Metal binding properties of imidazole-based ligands have been explored in
detail because of their presence at the active site of metallo-proteins or
enzymes involved in several important metabolic processes.[6] More
recently, such ligands have attracted attention from a catalytic point of
view because of the tunable basicities associated with the ligating
nitrogen.[7] A change in ligand basicity has a marked effect on metal–
ligand bond strengths, which in turn effect the catalytic properties. Recently
Busacca et al. have shown the influence of N-substitution versus catalytic
activity with phosphinoimidazolines in palladium-catalyzed asymmetric
Heck reactions.[8] We have recently reported the preparation of different
N-substituted ortho-brominated benzimidazoles and their activity in
palladium-catalyzed Heck reactions.[9]
RESULTS AND DISCUSSION
In continuation of our interest on imidazole-based ligands and with the recent
focus of organocatalysis associated with pyrrolidine derivatives, we targeted
benzimidazoles whose electronic properties can be tuned flexibly by
varying the substituent on the aromatic ring. Herein, we report a new
synthetic route for the chiral benzimidazole-pyrrolidine derivatives (Fig. 1)
and preliminary investigations on organocatalytic aldol and Michael reactions.
Numerous synthetic approaches have been described for the synthesis of
imidazole and benzimidazole derivatives.[10] However, there are only few
reports associated with the chiral imidazole derivatives. Recently, Lacoste
et al. reported the synthesis of chiral benzimidazole-pyrrolidine by refluxing
aromatic diamine with proline in 5 N HCl for 4 days.[11] We preferred a con-
ventional and milder synthetic route for benzimidazoles over the direct HCl
Figure 1. Benzimidazole-pyrrolidine derivatives.

Chiral Benzimidazole-Pyrrolidine Derivatives
4291
Scheme 1.
route because of the difficulties associated with monitoring the reaction and
purification of the products.
We obtained the target molecule by the following synthetic approach
(Scheme 1). The synthesis of pyrrolidine-benzimidazole was readily
performed by the reaction of N-benzylproline and aromatic diamine using
ethyl chloroformate to give an amide 1a (R ¼ H), which was further
cyclized to benzimidazole 2a in acetic acid at room temperature. Pd(OH)2
debenzylation of 2a under a hydrogen atmosphere proceeded smoothly to
afford the target molecule 3a. The methodology was generalized with
R ¼ Me and COOMe.
With these catalysts in hand, we initially focused our attention on their
application in direct asymmetric aldol reaction to generate b-hydroxyketones.
Our aim was to investigate the effect of R-group of the benzimidazole ring on
the yields and enantioselectivities of the reaction. To begin with, we studied
the reaction of acetone with p-nitrobenzaldehyde. Reaction of acetone and
p-nitrobenzaldehyde catalyzed by 3a in NMP provided aldol product with
85% yield and 42% ee (Table 1, entry 1). In the case of 3b, the product was
obtained in 77% yield and 24% ee. However, with 3c the product was
obtained in quantitative yields (93%) with 46% ee in 2 h. All the three
catalysts screened provided the aldol adducts in good yields and moderate
ee’s without any sign of the dehydration product.
From the results, it was clear that the efficiency of the organocatalyst
depends on the R-group of the benzimidazole. The positive effect of the
ester group might be due to the electron-withdrawing property of the ester,
which makes the imidazole N-H proton more acidic compared to 3a and
3b, resulting in the stronger H-bond with the aromatic aldehyde in the tran-
sition state. The variation in the acidity affected the enantioselectivity,
yields, and reaction times. In parallel with these investigations, the effect of
solvents was also studied, and the results are summarized in Table 1. Dehy-
dration of the aldol adduct was found to be prominent in methanol. NMP
was found to be the best solvent.

4292
K. R. Reddy, G. G. Krishna, and C. V. Rajasekhar
Table 1. Direct asymmetric aldol reaction between acetone and nitro-
benzaldehyde with the catalysts 3(a–c) in various solvents
Entry
Catalyst
Solvent
Time (h)
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3c
3c
3c
3c
3c
NMP
NMP
4
3
85
77
93
88
84
60
79
73
42
24
46
39
29
22
8
NMP
DMSO
DMF
2
6
3
MeOH
Acetone
NMPc
1
1
10
54
aIsolated yield.
bDetermined by HPLC analysis.[12]
cTemperature 2108C.
With the optimized conditions in hand, we examined the scope of the
reaction with various aldehydes. All the reactions were performed at room
temperature under the conditions employing 15 mol% of the catalyst relative
to the aldehyde. All the aromatic aldehydes reacted smoothly with acetone
under optimal conditions to give the aldol adducts with excellent yields and
moderate enantioselectivities. Significantly, the enantioselectivity of the aldol
adducts increased with the electron-withdrawing nature of the aromatic
aldehydes. p-Bromo-, o-chloro-, p-cyano-, and p-nitrobenzaldehyes generated
aldol adducts with 36, 44, 49, and 46% ee respectively (Table 2). Naphthalde-
hyde gave aldol adduct with 65% yield and 27% ee (Table 2, entry 5).
Further utilization of these ligands was demonstrated with the Michael
addition of cyclohexanone to various aromatic nitroolefins. The reaction con-
ditions were optimized using the reaction between cyclohexanone and
b-nitrostyrene. Catalyst 3a demonstrated a better catalytic activity (95, 49%
ee) compared to 3b (85, 27% ee) and 3c (87, 15% ee) in methanol at rt in
2 h, both in terms of yields and enantioselectivities (Table 3, entries 1–3).
Reaction in tetrahydrafuran gave the Michael adduct in 7 h with 88% yield
and 24% ee. Cyclohexanone as solvent afforded the Michael adduct in 80%
yield and lower enantioselectivity of 6%. In dimethylsulphoxide (DMSO),
the yield was 84% with enantioselectivity of 12%. In a nonpolar solvent
such as dichloromethane, the reaction was very slow to be of any practical
use. With these optimized conditions, Michael addition reaction of cyclohex-
anone was probed with a variety of nitroolefins in methanol as solvent. As

Chiral Benzimidazole-Pyrrolidine Derivatives
4293
Table 2. Direct asymmetric aldol reaction between acetone and
aromatic aldehydes catalyzed by 3c in NMP
Entry
1
Ar
Time (h)
2
Yield (%)a
93
Ee (%)b
46
2
3
4
2.5
3
89
75
91
49
36
44
3
5
16
65
27
aIsolated yield.
bEnantiomeric excess determined by HPLC analysis.[12]
Table 3. Michael addition of cyclohexanone to b-nitrostyrene with 3a–c in
various solvents
Entry
Catalyst
Solvent
MeOH
MeOH
Time (h) Yield (%)a Ee (%)b
1
2
3
4
5
6
7
3a
3b
3c
3a
3a
3a
3a
2
2
95
85
49
27
15
24
12
—
6
MeOH
THF
2
87
88
7
DMSO
DCM
Cyclohexanone
2
92
15
3
,5
80
aIsolated yield.
bEnantiomeric excess determined by Chiralpak AS column, eluent: hexane–
2-propanol (77:23), 1 mL/min.[4f]

4294
K. R. Reddy, G. G. Krishna, and C. V. Rajasekhar
Table 4. Reaction of various aromatic nitrostyrenes catalyzed by 3a in methanol
Entry
1
Ar
Time (h) Yield (%)a Syn/antib
Ee (%)c
49
2
6
95
95
99/1
98/2
2
3
30
11
7
92
99/1
4
5
6
6
85
82
97/3
96/4
37
23
aIsolated yield.
1
bDetermined by H NMR.
cEnantiomeric excess determined by Chiralpak AS column, eluent: hexane–
2-propanol (77:23), 1 mL/min.[4f]
depicted in Table 4, the yields and enantioselectivities were substrate
dependent. The reaction with ortho-methoxy nitrostyrene resulted in the
Michael adduct with 95% yield and 35% ee (Table 4, entry 2). In contrast,
para-methoxy substitution yielded 92% of Michael adduct with lower enan-
tioselectivity of 11% (Table 4, entry 3). Heteroaromatic nitrostyrenes such
as furan and thiophene also underwent the Michael addition reaction with
excellent yields and moderate enantiselectivities in short reaction times
(Table 4, entries 4 and 5). In general, distereoselectivities were found to be
very high, irrespective of the substrates.
EXPERIMENTAL
Analytical-grade solvents were purchased from S. D. Fine Chem Ltd., India,
and used as such. All aromatic aldehydes were purchased from Aldrich.
Nitrostyrenes were prepared by the reported procedure.[13] 1H NMR spectra
were recorded at 300 MHz using CDCl3 as solvent and TMS as internal
reference. Chiral high performance liquid chromatography (HPLC) analyses

Chiral Benzimidazole-Pyrrolidine Derivatives
4295
were performed on a Shimadzu chromatographic system with photodiode
detector. The chiral columns were purchased from Daicel Chemical
Industries, Ltd.
General Procedure for the Synthesis of 1a–c
N-Benzyl-L-proline (10 mmol) and triethylamine (10 mmol) were dissolved
in THF (50 mL) and cooled down to 08C. To this solution, ethyl chloroformate
(10 mmol) was added dropwise for 15 min and stirred for a further 30 min. To
the resulting reaction mixture, amine (15 mmol) was added over 15 min,
stirred at 08C for 1 h and at room temperature for 16 h, and then refluxed
for 3 h. The progress of the reaction was monitored by thin-layer chromato-
graphy (TLC). After completion of the reaction, the mixture was allowed to
cool to room temperature and was diluted with ethyl acetate. After filtration,
the solvent was evaporated under reduced pressure, and the residue was
purified through column chromatography on silica gel (eluent, hexane/ethyl
acetate 70/30) to give 1a–c; yield: 68–74%.
Data for 1a–c
1
1a. Yield: 74%; H NMR (200 MHz, CDCl3): d 1.80–1.95 (m, 2H), 2.10
(m, 1H), 2.20–2.60 (m, 2H), 3.75 (m, 1H), 3.40 (dd, 1H), 3.60 (d, 1H,
J ¼ 13.0), 4.0 (d, 1H, J ¼ 13.0), 6.90 (m, 2H), 7.00–7.20 (m, 2H), 7.3–
1
7.55 (m, 5H), 9.3 (s, 1H). MS (EI) m/z 295. 1b. Yield: 72%; H NMR
(200 MHz, CDCl3): d 1.76–1.90 (m, 2H), 1.99–2.13 (m, 1H), 2.25 (s, 3H),
2.31–2.52 (m, 2H), 3.15 (m, 1H), 3.33 (dd, 1H), 3.63 (d, 1H, J ¼ 13.0),
4.05 (d, 1H, J ¼ 13.0), 6.93 (m, 2H), 7.16–7.40 (m, 6H), 9.10 (s, 1H). MS
1
(EI) m/z 310. 1c. Yield: 65%; H NMR (200 MHz, CDCl3): d 1.75–1.90
(m, 2H), 2.00–2.15 (m, 1H), 2.20–2.40 (m, 1H), 2.5–2.6 (m, 1H), 3.15
(m, 1H), 3.45 (dd, 1H), 3.74 (d, 1H, J ¼ 13.02), 3.85 (s, 3H), 3.95 (d, 1H,
J ¼ 13.02), 6.75 (m, 1H), 7.25–7.45 (m, 5H), 7.65–7.75 (s, 2H), 9.22
(s, 1H). MS (EI) m/z 353.
General Procedure for the Synthesis of 2a–c
Compounds 1a–c (5 mmol) were taken in 10 mL of acetic acid and stirred at
room temperature. The progress of the reaction was monitored by TLC. After
completion of the reaction, the acetic acid was removed under reduced
pressure and purified through column chromatography on silica gel (eluent,
hexane/ethyl acetate 60/40) to give 2a–c. Yield: 83–88%.

4296
K. R. Reddy, G. G. Krishna, and C. V. Rajasekhar
Data for 2a–c
2a. Yield: 88%; 1H NMR (200 MHz, CDCl3): d 1.8–2.0 (m, 3H), 2.35–2.55
(m, 2H), 3.17 (m, 1H), 3.50 (d, 1H, J ¼ 13.02), 3.90 (d, 1H, J ¼ 13.02), 4.1
(t, 1H), 7.25–7.40 (m, 7H), 7.65 (m, 2H). MS (EI) m/z 277. 2b. Yield:
1
83%; H NMR (200 MHz, CDCl3): d 1.8–2.0 (m, 3H), 2.30–2.41 (m, 2H),
2.47 (s, 1H), 3.13 (m, 1H), 3.42 (d, 1H, J ¼ 13.02), 3.91 (d, 1H, J ¼ 13.02),
4.0 (m, 1H), 6.96–7.04 (m, 1H), 7.18–7.50 (m, 7H). MS (EI) m/z 292. 2c.
1
Yield: 84%; H NMR (200 MHz, CDCl3): d 1.80–2.03 (m, 3H), 2.29–2.47
(m, 2H), 3.03–3.19 (m, 1H), 3.40 (d, 1H), 3.77–3.90 (m, 4H), 4.01
(m, 1H), 7.12–7.21 (m, 6H), 7.49–7.54 (m, 1H), 7.87–7.92 (m, 1H), 8.25
(s, 1H). MS (EI) m/z 335.
General Procedure for the Synthesis of 3a–c
Compounds 2a–c (5 mmol) and 20% Pd(OH)2 (300 mg) were taken in
methanol and stirred at room temperature under a hydrogen atmosphere
(1 atm). The progress of the reaction was monitored by TLC. After completion
of the reaction, the mixture was filtered through Celitew, and the filtrate was
evaporated under reduced pressure. The resulting residue was purified through
column chromatography on silica gel (eluent, methanol/choloroform 10/90)
to give 3a–c. Yield: 75–84%.
Data for 3a–c
1
3a. Yield: 82%; H NMR (200 MHz, CDCl3): d 1.80–2.40 (m, 4H), 3.09–
3.30 (m, 2H), 4.64 (t, 1H), 7.10 (m, 2H), 7.47 (m, 2H). MS (EI) m/z 187.
[a]D ¼ 254.0 (C ¼ 1, MeOH). 3b. Yield: 75%; 1H NMR (200 MHz,
CDCl3): d 2.00–2.60 (m, 6H), 3.31–3.52 (m, 2H), 4.97 (t, 1H), 6.90
(m, 1H), 7.30 (s, 1H), 7.30–7.4 (m, 2H). MS (EI) m/z 201. [a]D ¼ 229.1
1
(C ¼ 1, MeOH). 3c. Yield: 84%; H NMR (200 MHz, CDCl3): d 2.09–2.40
(m, 2H), 2.50–2.74 (m, 2H), 3.38–3.68 (m, 2H), 3.89 (s, 3H), 5.28 (t, 1H),
6.90 (m, 1H), 7.30 (s, 1H), 7.30–7.4 (m, 2H). MS (EI) m/z 245.
[a]D ¼ 220.0 (C ¼ 1, MeOH).
General Procedure for the Aldol Reaction of Acetone with Aromatic
Aldehydes Catalyzed by 3c
To the catalyst (0.15 mmol) in NMP (3 mL), acetone (0.5 mL) was added,
followed by aromatic aldehyde (1 mmol), and the mixture was stirred at
room temperature. After completion of the reaction (as monitored by TLC),
the reaction mixture was quenched with water and extracted with ethyl

Chiral Benzimidazole-Pyrrolidine Derivatives
4297
acetate twice. The resulting organic layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure. The crude product was chromato-
graphed on silica gel to afford the corresponding product in pure form. All
products gave satisfactory NMR spectral data.[12]
General Procedure for the Michael Addition of Cyclohexanone to
b-Nitrostyrenes Catalyzed by 3a
To the catalyst (0.15 mmol) in methanol (3 mL), cyclohexanone (0.5 mL) and
b-nitrostyrene (1 mmol) were added and stirred at room temperature. After
completion of the reaction (as monitored by TLC), the reaction mixture was
quenched with water and extracted with ethyl acetate twice. The resulting
organic layer was dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The crude product was chromatographed on silica gel to
afford the corresponding product in pure form. All products gave satisfactory
NMR spectral data.[4f]
CONCLUSION
In summary, we presented a methodology that provides an easy and con-
venient approach for synthesizing pyrrolidine-benzimidazole organocatalysts
with good yields. Further, we successfully employed the benzimidazoles for
the aldol and Michael addition reactions with good yields and moderate
enantioselectivities.
ACKNOWLEDGMENT
We thank the CSIR for financial support under the Task Force Project CMM-
0005. G. Gopi Krishna and C. V. Rajasekhar thank CSIR, India, for the
research fellowships.
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