Enantioselective benzoylation of racemic amines using chiral benzimidazolide as a benzoylating agent

Article abstract of DOI:10.1016/j.tetasy.2007.12.006

Enantioselective acylation/kinetic resolution of racemic amines has been achieved by using a chiral benzimidazolide, namely, (S)-1-benzoyl-2-(α-acetoxyethyl)benzimidazole 2. This nonenzymatic acylating reagent requires mild reaction conditions and proceeds with good enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2007.12.006

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 45–48
Enantioselective benzoylation of racemic amines using chiral
benzimidazolide as a benzoylating agent
Anil V. Karnik* and Suchitra S. Kamath
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai 400 098, India
Received 18 October 2007; accepted 18 December 2007
Abstract—Enantioselective acylation/kinetic resolution of racemic amines has been achieved by using a chiral benzimidazolide, namely,
(S)-1-benzoyl-2-(a-acetoxyethyl)benzimidazole 2. This nonenzymatic acylating reagent requires mild reaction conditions and proceeds
with good enantioselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(1S,2S)-bis(trifluoromethanesulfonamide) to give acetam-
ide derivative with up to 84% ee at room temperature
and up to 90% ee at ꢀ20 °C.7g
Chiral amino functionality is found in several important
pharmaceutical compounds with varying chemotherapeutic
properties.1 Enantiomerically pure amines are used as
resolving agents,2 chiral auxiliaries3 and catalysts4 in stereo-
selective organic synthesis. The increasing need for non-
racemic amines has accelerated the development of
various efficient methodologies for resolution and asym-
metric synthesis for their production. Despite the advances
that have been achieved in the asymmetric synthesis of
amines,5 kinetic resolution remains a valuable alternative
for obtaining individual stereoisomers. Kinetic resolution
of racemates includes both enzymatic and nonenzymatic
processes. Several enzymatic processes have been
reported,6 and the development of nonenzymatic enantio-
selective nucleophilic acylating agents for kinetic resolu-
tion of amines has received significant attention in recent
years.7
Several enzymes work with excellent stereoselectivities.6a
Achieving a comparable level of stereoselection with non-
enzymatic enantioselective acylating agents requires some
basic structural features in the acylating agent. The enan-
tioselective acylation/kinetic resolution requires facile acyl
transfer process involving an electrophilic acyl group and
a suitable chiral influence within the acylating agent. This
challenge has inspired many groups to develop different
enantioselective acylating agents as mentioned above. Azo-
lides have an electrophilic acyl group, and different carbon
and heteroatom nucleophiles react easily with this under
mild conditions. Moreover, the azole part offers an effective
leaving group in acylation reactions. The presence of a ste-
reogenic centre within the azolide can offer a solution to the
search for nonenzymatic acylating agent for kinetic resolu-
tion. We, accordingly, selected a chiral benzimidazolide for
the purpose of enantioselective acylation.
Fu et al. achieved the enantioselective acylation of racemic
amines using planar-chiral DMAP derivatives as acylating
agents to give products with up to 91% ee at ꢀ78 °C.7c
Atkinson et al. developed enantioselective acylating agents
for the kinetic resolution of amines derived from 3-(N,N-
diacylamino)quinazolin-4(3H)-ones (DAQs) to give prod-
ucts with excellent levels of enantioselectivity (up to 95%
ee).7d The kinetic resolution of ( )-1-phenylethylamine
was achieved by Mioskowski et al. using N-acetyl-
2. Results and discussion
We have recently established that (S)-1-benzoyl-2-(a-acet-
oxyethyl)benzimidazole 2 (Fig. 1) serves as an effective
enantioselective benzoylating agent for racemic a-amino
esters.8
*
We now extend the use of (S)-1-benzoyl-2-(a-acetoxyeth-
Corresponding author. Tel.: +91 022 26526091; fax: +91 022
26528547; e-mail: avkarnik@chem.mu.ac.in
yl)benzimidazole as an effective chiral acylating agent for
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.006

46
A. V. Karnik, S. S. Kamath / Tetrahedron: Asymmetry 19 (2008) 45–48
PhCOCl
H
O
N
N
Pyridine
CH3
H
O
H
O
N
N
N
0 oC
O
CH3
CH3
N
H
O
O
O
CH3
O
CH3
CH3
1
2
2
Figure 1. (S)-1-Benzoyl-2-(a-acetoxyethyl)benzimidazole.
Scheme 1. Preparation of chiral benzimidazolide.
kinetic resolution of amines. The racemic amines 3a–d used
for the purpose are shown in Figure 2.
ated the (S)-isomer of amines to yield (S)-N-benzoyl
amides 4a–d. The unreacted amines were converted to N-
benzoyl amides 5a–d and were found to be of (R)-
configuration.
CH3
NH2
CH3
NH2
H3C
Acylation reactions of racemic amines with (S)-1-benzoyl-
2-(a-acetoxyethyl)benzimidazole were performed at ꢀ10 °C.
The enantiomeric excesses of (S) and (R) isomers of N-
benzoyl amides obtained by the reaction of (S)-1-benzoyl-
2-(a-acetoxyethyl)benzimidazole with racemic amines are
shown in Table 1.
CH3
3b
3a
CH3
NH2
CH3
H3C
H3C
NH2
Considerably high enantioselectivity was observed in case
of 1-phenylethylamine (89.9%) (Table 1, compound 4a)
as compared to other amines. The presence of an aryl ring
in the substrate usually introduces nonbonded interactions
such as p–p interactions and p–H attractive interaction.
These usually enhance stereodiscrimination and accord-
ingly the stereoselection was found to be slightly better in
the resolution of 1-phenylethylamine compared to the
remaining amines, 3b–d. In the case of aliphatic amines
without an aryl substituent, 3b–d, the level of stereoselec-
tion was found to be almost the same for all the aliphatic
amines under study. In aliphatic amines, 3b–d, the non-
bonded interactions seem to be absent and the enantiodis-
crimination observed seems to be entirely due to steric
3c
3d
Figure 2. Racemic amines.
The chiral benzimidazolide, (S)-1-benzoyl-2-(a-acetoxyeth-
yl)benzimidazole 2 was prepared by benzoylation of (S)-2-
(a-acetoxyethyl)benzimidazole 1 (Scheme 1).
The reaction of 1 equiv of (S)-1-benzoyl-2-(a-acetoxyeth-
yl)benzimidazole was carried out with 2 equiv of racemic
amines (Scheme 2). The stereochemical preference of (S)-
1-benzoyl-2-(a-acetoxyethyl)benzimidazole appeared the
same as for a-amino esters,8 that is, it preferentially acyl-
2 (0.5 equiv.)
THF
-10 oC
R
H
O
R
H
O
N
R
H
R'
+
N
H
+
CH3
R'
NH2
H
N
H
O
H2N
R'
R< R'
R< R'
3a-d
CH3
(S) Isomer
1
PhCOCl
Pyridine
0 oC
4a-d
R
O
R'
N
H
H
R< R'
(R) Isomer
Unreacted amine converted to
N-Benzoyl amide
5a-d
Scheme 2. Enantioselective benzoylation of racemic amines.

A. V. Karnik, S. S. Kamath / Tetrahedron: Asymmetry 19 (2008) 45–48
Table 1. Enantioselective benzoylation of racemic amines
47
Entry
Substrate
(S)-Isomera
eeb (%)
(R)-Isomer (unreacted amine
converted to N-benzoyl amide)
eeb (%)
Conversionc (%)
Selectivity factord
1
2
3
4
3a
3b
3c
3d
4a
4b
4c
4d
89.9
82.8
83.2
83.3
5a
5b
5c
5d
89.2
78.7
82.9
76.7
49.8
48.7
49.9
47.9
56.5
25.3
27.8
25.2
a Absolute configurations of N-benzoyl amides were established by comparison with the specific rotation of authentic compounds reported in the
literature.
b Enantiomeric excesses of N-benzoyl amides were determined by HPLC using a chiral stationary phase (Chiralcel OD, n-hexane/2-propanol 98:2).
c Conversion was calculated by the equation: conversion = (ee of starting material)/[(ee of starting material) + (ee of product)].
d Equation used to calculate the selectivity factor (s = kfast/kslow): s = ln[1 ꢀ conversion(1 + ee of product)]/ln[1 ꢀ conversion(1 ꢀ ee of product)].
factors. The better enantiodiscrimination observed in the
case of a-amino esters observed earlier,8 can be accounted
for the presence of an ester functionality along with an aryl
ring in a few cases.
4.2.1. (S)-N-Benzoyl-1-phenylethylamine 4a. Mp: 122–
19 26
123 °C; ½aꢁD ¼ ꢀ17:9 (c 1, CHCl3) {lit.9 ½aꢁD ¼ ꢀ20:1 (c
1.02, CHCl3)}; IR (KBr): 3357, 3082, 3054, 3030, 2974,
1
2932, 1634, 1602, 1578, 1518, 1488, 1454 cmꢀ1; H NMR
(300 MHz, CDCl3): d 7.77 (d, J = 7.0 Hz, 2H; ArH),
7.53–7.27 (m, 8H; ArH), 6.32 (br d, J = 6.2 Hz, 1H;
NH), 5.40–5.30 (m, 1H; CH), 1.62 (d, J = 7.0 Hz, 3H;
CH3); Anal. Calcd for C15H15NO: C, 80.00; H, 6.67; N
6.22. Found: C, 79.95; H, 6.65; N, 6.29.
3. Conclusion
The resolving agent employed, namely, (S)-1-benzoyl-2-(a-
acetoxyethyl)benzimidazole 2 is easily accessible, inexpen-
sive and offers resolution under mild conditions with satis-
factory levels of enantioselectivity. Several azolides are
excellent acylating agents and the introduction of a stereo-
genic centre in the same compound is an achievable task.
This work offers an opportunity for the development of
new chiral azolides for the same purpose.
4.2.2. (S)-N-Benzoyl-3-methyl-2-butylamine 4b. Mp: 73–
19
75 °C; ½aꢁD ¼ þ12:4 (c 1, CHCl3); IR (KBr): 3317, 3056,
1
2965, 2924, 2873, 1629, 1578, 1532, 1491, 1457 cmꢀ1; H
NMR (300 MHz, CDCl3): d 7.73 (d, J = 7.8 Hz, 2H;
ArH), 7.49–7.38 (m, 3H; ArH), 5.96 (br s, 1H; NH),
4.13–4.04 (m, 1H; CH), 1.87–1.76 (m, 1H; CH), 1.18 (d,
J = 6.3 Hz, 3H; CH3), 0.98 (d, J = 3.9 Hz, 3H; CH3),
0.95 (d, J = 3.3 Hz, 3H; CH3); Anal. Calcd for
C12H17NO: C, 75.39; H, 8.90; N 7.33. Found: C, 75.45;
H, 8.94; N, 7.26.
4. Experimental
4.1. General
4.2.3. (S)-N-Benzoyl-2-heptylamine 4c. Mp: 70–71 °C;
19
25
½aꢁD ¼ þ14:6 (c 1, CHCl3) {lit.10 ½aꢁD ¼ þ9:0 (c 1, CHCl3,
Optical rotations were measured on Jasco DIP-1000 digital
polarimeter. Enantiomeric excesses were determined on
HPLC Thermo Finnigan spectra system using Daicel
51% ee)}; IR (KBr): 3300, 3067, 2966, 2952, 2923, 2851,
1633, 1603, 1579, 1537, 1489, 1467, 1457 cmꢀ1; H NMR
1
(300 MHz, CDCl3): d 7.75 (d, J = 6.6 Hz, 2H; ArH),
7.52–7.40 (m, 3H; ArH), 5.90 (br d, J = 7.3 Hz, 1H;
NH), 4.26–4.12 (m, 1H; CH), 1.58–1.50 (m, 2H; CH2),
1.40–1.28 (m, 6H; 3 ꢂ CH2), 1.23 (d, J = 6.6 Hz, 3H;
CH3), 0.88 (t, 3H; CH3); Anal. Calcd for C14H21NO: C,
76.71; H, 9.59; N 6.39. Found: C, 76.77; H, 9.63; N, 6.33.
1
Chiralcel OD column with UV detector. H NMR spectra
were scanned in CDCl3 on Bruker 300 MHz spectrometer
with TMS as an internal standard. IR spectra were
recorded on Shimadzu FTIR-4200. Elemental analyses
were carried on Carlo Enra instrument EA-1108 Elemental
analyzer. All melting points are uncorrected. Temperatures
are recorded in °C. Boiling point of petroleum-ether used
was in the range of 60–80 °C. (S)-1-Benzoyl-2-(a-acetoxy-
ethyl)benzimidazole 2 was prepared according to our previ-
ously reported procedure.8
4.2.4. (S)-N-Benzoyl-2-butylamine 4d. Mp: 86–88 °C;
19
½aꢁD ¼ þ12:5 (c 1, CHCl3); IR (KBr): 3296, 3066, 2969,
1
2930, 2875, 1629, 1602, 1578, 1539, 1489, 1454 cmꢀ1; H
NMR (300 MHz, CDCl3): d 7.74 (d, J = 6.9 Hz, 2H;
ArH), 7.49–7.37 (m, 3H; ArH), 5.95 (br s, 1H; NH),
4.16–4.07 (m, 1H; CH), 1.62–1.53 (m, 2H; CH2), 1.23 (d,
J = 6.9 Hz, 3H; CH3), 0.97 (t, 3H; CH3); Anal. Calcd for
C11H15NO: C, 74.58; H, 8.47; N 7.91. Found: C, 74.54;
H, 8.43; N, 7.99.
4.2. Representative procedure for the enantioselective
benzoylation of racemic amines
A solution of 2 (2 mmol) and racemic amine 3a–d (4 mmol)
in 30 mL of THF was stirred at ꢀ10 °C for 12 h. The reac-
tion was quenched with aq HCl and extracted with CHCl3.
The organic extract was dried over anhyd Na2SO4 which
on evaporation afforded (S)-N-benzoyl amide 4a–d. The
unreacted amine was recovered from aqueous layer and
on derivatization with benzoyl chloride in the presence of
pyridine yielded (R)-N-benzoyl amide 5a–d.
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