Chiral diamides as efficient catalytic precursors for the borane-mediated asymmetric reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2007.03.034

Chiral diamides [(2S)-5-oxo-2-(arylamino)carbonylpyrrolidines] derived from the abundantly available (S)-glutamic/(S)-pyroglutamic acids were successfully utilized as effective chiral catalytic precursors in the borane-mediated asymmetric reduction of prochiral ketones in refluxing toluene, to provide the corresponding secondary alcohols with up to 91% enantiomeric purities.

Full text of DOI:10.1016/j.tetasy.2007.03.034

Tetrahedron: Asymmetry 18 (2007) 968–974
Chiral diamides as efficient catalytic precursors for the
borane-mediated asymmetric reduction of prochiral ketones
Deevi Basavaiah,* Kalapala Venkateswara Rao and Bhavanam Sekhara Reddy
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 26 February 2007; accepted 5 March 2007
Abstract—Chiral diamides [(2S)-5-oxo-2-(arylamino)carbonylpyrrolidines] derived from the abundantly available (S)-glutamic/(S)-pyro-
glutamic acids were successfully utilized as effective chiral catalytic precursors in the borane-mediated asymmetric reduction of prochiral
ketones in refluxing toluene, to provide the corresponding secondary alcohols with up to 91% enantiomeric purities.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
alcohols with high enantiomeric purities. In continuation
of our interest in finding suitable chiral catalysts for
the borane-mediated asymmetric reduction of prochiral
ketones,1,3–8 we herein report chiral diamides, (2S)-5-
oxo-2-(arylamino)carbonylpyrrolidines 2a–i derived from
abundantly available (S)-glutamic/(S)-pyroglutamic acids
(Fig. 1), as possible catalytic sources for the asymmetric
We have recently reported1 a simple and convenient meth-
odology for the borane-mediated asymmetric reduction of
prochiral ketones employing the chiral diamine,2 (2S)-2-
anilinomethylpyrrolidine 1, as an efficient chiral catalytic
source in refluxing toluene thus providing the secondary
H
H
H
H
O
O
O
O
O
O
N
H
N
H
N
N
H
H
HN
HN
HN
HN
2a
1
2c
2b
Cl
Br
H
H
H
O
O
O
N
O
N
O
H
O
N
H
HN
HN
H
HN
F
2d
2e
F
2f
NO2
F
H
H
O
O
H
N
O
O
H
O
N
H
O
HN
F
N
H
HN
HN
CF3
2g
2i
2h
F
CF3
Figure 1.
*
Corresponding author. Tel.: +91 40 23134812; fax: +91 40 23012460; e-mail: dbsc@uohyd.ernet.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.034

D. Basavaiah et al. / Tetrahedron: Asymmetry 18 (2007) 968–974
969
reduction of representative prochiral ketones, thus leading
to the synthesis of secondary alcohols in up to 91% enan-
tiomeric purities.
However, we decided upon using 5 mol % catalyst for fur-
ther studies as this provide slightly better selectivity (Table
1, entry 2).
With a view to examine the influence of amount of
BH3ÆSMe2 on the enantioselectivity and also to understand
the appropriate amount of BH3ÆSMe2 required to obtain
the maximum selectivity, we have carried out the asymmet-
ric reduction of phenacyl bromide 3a using 5 mol % (2S)-5-
oxo-2-anilinocarbonylpyrrolidine 2a with varying amounts
(0.9–1.8 equiv with respect to prochiral ketone) of
BH3ÆSMe2. Although there is not much effect on the enantio-
selectivity with 1–1.8 equiv of BH3ÆSMe2, 1.4 equiv of
BH3ÆSMe2 provides slightly better enantioselectivity (Eq.
2, Table 2, entry 4).
2. Results and discussion
The reduction of amides using BH3ÆSMe2 (THF) to provide
the corresponding amines is a well documented and useful
synthetic reaction in organic synthesis.9
It therefore occurred to us that the diamide, (2S)-5-oxo-2-
anilinocarbonylpyrrolidine 2a, could in principle be re-
duced in situ by BH3ÆSMe2 to the corresponding diamine,
(2S)-2-anilinomethylpyrrolidine 1, which could then be as
such used, without isolation, as a chiral catalytic precursor
for the reduction of prochiral ketones to produce the cor-
responding, enantiomerically enriched secondary alcohols.
This would mean that the diamide, (2S)-5-oxo-2-anilino-
carbonylpyrrolidine 2a, can itself directly act as the cata-
lytic precursor for the borane-mediated reduction of
prochiral ketones to provide the desired enantiomerically
enriched secondary alcohols in a one-pot process.
Table 2. Asymmetric reduction of phenacyl bromide 3a with varying
a,b
amounts of the BH3ÆSMe2
O
OH
Br
Br
2a (5 mol %)
/
BH3.SMe2
(Eq. 2)
Toluene, 110 oC, 15 min
4a
3a
Entry
BH3ÆSMe2 (equiv)
Yieldc (%) 4a
Enantiomeric
purityd (%) 4a
Accordingly we have synthesized (2S)-5-oxo-2-anilinocar-
bonylpyrrolidine 2a, via the reaction of (S)-glutamic acid
with aniline according to the literature procedure.10 We
have examined the potential of this diamide 2a, as a possi-
ble chiral catalytic precursor for the borane-mediated
reduction of prochiral ketones, first selecting phenacyl bro-
mide 3a as a substrate. The borane-mediated reduction was
performed with varying catalytic amounts of (2S)-5-oxo-2-
anilinocarbonylpyrrolidine 2a (2, 5, 7, 10 mol %) in order
to determine the minimum amount of catalyst required to
obtain the maximum selectivity (Eq. 1) and the enantio-
selectivities are shown in Table 1. From these results it is
clear that enantioselectivities are similar in all the cases.
1
2
3
4
5
6
0.9
1.0
1.2
1.4
1.6
1.8
84
88
84
86
87
85
81
89
88
91
89
89
a All reactions were carried out on 1 mM scale of phenacyl bromide 3a
with BH3ÆSMe2 in the presence of 5 mol % 2a in refluxing toluene for
15 min.
b The absolute configuration was assigned by comparison of the sign of the
specific rotation with that of the reported molecule.11
c Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
Table 1. Asymmetric reduction of phenacyl bromide 3a with varying
catalytic amounts of 2aa,b
Encouraged by these results and with a view for under-
standing the influence of different substitutions with vari-
ous steric and electronic requirements on the aromatic
(phenyl) ring of the diamide, (2S)-5-oxo-2-anilinocarbonyl-
pyrrolidine 2a, we selected eight diamides 2b–i to study.
The required diamides were conveniently prepared by the
reaction of (S)-pyroglutamic acid 5 with the corresponding
aryl amines according to Eq. 3 (no attempts were made to
optimize the yields). The structures of 2b, 2d, and 2f
were also established by the single crystal X-ray data
(Figs. 2–4).
O
OH
Br
Br
BH3.SMe2 (1 equiv) / 2a
(cat.)
(Eq. 1)
Toluene, 110 oC, 15 min
3a
Entry
4a
Catalyst 2a
(mol %)
Yieldc (%) 4a
Enantiomeric
purityd (%) 4a
1
2
3
4
2
5
86
88
83
85
87e
89
87
88
7
10
a All reactions were carried out on 1 mM scale of phenacyl bromide 3a
with BH3ÆSMe2 (1 mM) in the presence of 2a in refluxing toluene for
15 min.
i. Et3N
H
H
ii. EtOCOCl
O
O
O
b The absolute configuration was assigned by comparison of the sign of the
specific rotation with that of the reported molecule.11
N
CO2H
N
H
H
iii. ArNH2
THF
HN Ar
2b-i
5
c Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
e This reaction was carried out on 2 mM scale of phenacyl bromide 3a with
BH3ÆSMe2 (2 mM) in the presence of 2a in refluxing toluene for 15 min.
ðEq: 3Þ
35-53%
Ar = 4-Bromophenyl 2b; 4-Chlorophenyl 2c; 4-Fluorophenyl 2d;
4-Nitrophenyl 2e; 2,4-Difluorophenyl 2f; 3,5-Difluorophenyl 2g;
3,5-Bis(trifluoromethyl)phenyl 2h; 1-Naphthyl 2i

970
D. Basavaiah et al. / Tetrahedron: Asymmetry 18 (2007) 968–974
Table 3. Asymmetric reduction of phenacyl bromide 3a using the chiral
diamides 2a–i as chiral catalytic sourcesa,b
O
OH
Br
Br
(Eq. 4)
2a-i (5 mol %)
BH3.SMe2 (1.4 equiv) /
Toluene, 110 oC, 15 min
3a
4a
Yieldc (%) 4a
Enantiomeric
purityd (%) 4a
Figure 2. ORTEP diagram of 2b (hydrogen atoms were omitted for
clarity).
Entry
Chiral diamide
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
86
87
86
82
88
83
84
83
84
91
90
91
90
88
89
88
90
68
2g
2h
2i
a All reactions were carried out on 1 mM scale of phenacyl bromide 3a
with BH3ÆSMe2 (1.4 mM) in the presence of 5 mol % 2a–i in refluxing
toluene for 15 min.
Figure 3. ORTEP diagram of 2d (hydrogen atoms were omitted for
clarity).
b The absolute configuration was assigned by comparison of the sign of the
specific rotation with that of the reported molecule.11
c Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
Table 4. Asymmetric reduction of phenacyl chloride (3b) using the chiral
diamides 2a–i as chiral catalytic sourcesa,b
O
OH
Cl
Cl
(Eq. 5)
2a-i (5 mol %)
BH3.SMe2 (1.4 equiv) /
Figure 4. ORTEP diagram of 2f (hydrogen atoms were omitted for
clarity).
Toluene, 110 oC, 15 min
3b
Entry
4b
Chiral diamide
Yieldc (%) 4b
Enantiomeric
purityd (%) 4b
With a view to examining the chiral catalytic potential of
these diamides, we selected three representative prochiral
ketones, phenacyl bromide 3a, phenacyl chloride 3b, and
acetophenone 3c, as substrates in the borane-mediated
asymmetric reduction. Thus we first carried out the asym-
metric reduction of phenacyl bromide 3a in the presence of
5 mol % chiral diamide 2b–i with BH3ÆSMe2 (1.4 equiv) in
refluxing toluene for 15 min. The corresponding secondary
alcohol, (S)-2-bromo-1-phenylethanol 4a was obtained with
68–91% enantiomeric purities (Eq. 4, Table 3, entries 2–9).
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
83
82
84
80
85
82
83
87
81
88
87
89
88
86
87
87
89
67
2g
2h
2i
a All reactions were carried out on 1 mM scale of phenacyl chloride 3b
with BH3ÆSMe2 (1.4 mM) in the presence of 5 mol % 2a–i in refluxing
toluene for 15 min.
Similar borane-mediated reductions of phenacyl chloride
3b and acetophenone 3c using chiral diamides, 2a–i, as chi-
ral catalytic sources provided (S)-2-chloro-1-phenylethanol
4b and (R)-1-phenylethanol 4c in 67–89% (Eq. 5, Table 4,
entries 1–9) and 53–83% (Eq. 6, Table 5, entries 1–9) enan-
tiomeric excesses, respectively.
b The absolute configuration was assigned by comparison of the sign of the
specific rotation with that of the reported molecule.11
c Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
These results to some extent suggest that the substitution
on the phenyl group [of (2S)-5-oxo-2-anilinocarbonylpyrr-
olidine 2a] does not play any significant role with regards
to the chiral induction. However, the chiral diamide (2S)-
5-oxo-2-(1-naphthylamino)carbonylpyrrolidine 2i with a
1-naphthyl moiety provides inferior selectivities in all these
cases in comparison with other diamides 2a–h. The lower
enantioselectivity in the case of 2i might be attributed to
the competitive non-catalytic reduction of prochiral ketone
with BH3ÆSMe2 as the sterically bulky 1-naphthyl moiety
may to some extent disfavor the effective coordination of
prochiral ketone with the boron of the diazaborolidine
(which might be forming in situ) (Scheme 1).

D. Basavaiah et al. / Tetrahedron: Asymmetry 18 (2007) 968–974
971
Table 5. Asymmetric reduction of acetophenone 3c using the chiral
diamides 2a–i as chiral catalytic sourcesa,b
4. Experimental
4.1. Representative procedure13a for synthesis of (2S)-5-oxo-
O
OH
2-(4-bromoanilino)carbonylpyrrolidine 2b13b
2a-i (5 mol %)
BH3.SMe2 (1.4 equiv) /
(Eq. 6)
Toluene, 110 oC, 15 min
3c
Entry
H
4c
O
O
N
H
Chiral diamide
Yieldc (%) 4c
Enantiomeric
purityd (%) 4c
HN
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
76
74
72
74
76
74
75
73
77
82
81
83
79
77
78
82
81
53
Br
To a stirred mixture of (S)-pyroglutamic acid (5 mM,
0.6455 g) in THF (10 mL) was added a solution of Et3N
(5 mM, 0.7 mL) in THF (5 mL) at ꢀ15 ꢁC. After stirring
for 15 min, a solution of ethyl chloroformate (5.5 mM,
0.53 mL) in THF (5 mL) was added slowly at ꢀ15 ꢁC
and the reaction mixture was stirred for 15 min. A solution
of 4-bromoaniline (5 mM, 0.86 g) in THF (5 mL) was then
added at the same temperature to the above reaction mix-
ture and stirred at 0 ꢁC for 1 h followed by 14 h at room
temperature. The solvent was removed under reduced pres-
sure and the residue, thus obtained, was diluted with
EtOAc (150 mL) and saturated aqueous NaHCO3
(30 mL). Organic layer was separated and washed with sat-
urated aqueous NaHCO3 (3 · 30 mL) and dried over anhy-
drous Na2SO4. Solvent was removed under reduced
pressure and the residue, thus obtained, was purified by
column chromatography (silica gel, EtOAc) to provide
the desired (2S)-5-oxo-2-(4-bromoanilino)carbonylpyrrol-
2g
2h
2i
a All reactions were carried out on 1 mM scale of acetophenone 3c with
BH3ÆSMe2 (1.4 mM) in the presence of 5 mol % 2a–i in refluxing toluene
for 15 min.
b The absolute configuration was assigned by comparison of the sign of the
specific rotation with that of the reported molecule.12
c Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
3. Conclusion
idine 2b as a white solid (0.75 g) in 53% yield. Mp: 212–
We have successfully demonstrated the potential of the
chiral diamides, (2S)-5-oxo-2-(arylamino)carbonylpyrroli-
dines 2a–i, derived from the abundantly available (S)-
glutamic/(S)-pyroglutamic acids, as possible catalytic
sources in the borane-mediated asymmetric reduction of
prochiral ketones.
25
214 ꢁC (lit.13b 225–227 ꢁC); ½aꢁD ¼ þ13:0 (c 1.09, MeOH);
IR (KBr): m 3500–3000 (multiple bands), 1693, 1668
cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-d6 = 4:1)]: d
;
2.06–2.49 (m, 4H), 4.21–4.30 (m, 1H), 7.39 (d, 2H,
J = 8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.84 (s, 1H), 9.95
BH3.SMe2
O
N
HB
O
N
N
H
H
N
HB
N
N
BH3
HN Ar
N
HN
Ar
N
2
Ar
Ar
1
Ar
BH
OH
BH3
Ar'
R
O
If Ar = 1-Naphthyl
the rate of this step
may be reduced by
steric repulsion
(After work-up)
Ar'
R
Ar
Ar
N
H
N
H
B
R
N
B
R
N
O
H2B
O
H
BH3
Ar'
Ar'
Scheme 1.

972
D. Basavaiah et al. / Tetrahedron: Asymmetry 18 (2007) 968–974
(s, 1H); 13C NMR [50 MHz (CDCl3–DMSO-d6 = 4:1)]: d
24.51, 28.70, 56.31, 115.25, 120.78, 130.65, 136.94,
170.24, 177.47; LC–MS (m/z): 283 (M+H)+, 285
(M+2+H)+; Anal. Calcd for C11H11BrN2O2: C, 46.66; H,
3.92; N, 9.89. Found: C, 46.68; H, 3.92; N, 9.98.
(MꢀH)+; Anal. Calcd for C11H11N3O4: C, 53.01; H,
4.45; N, 16.86. Found: C, 53.15; H, 4.44; N, 16.80.
4.5. (2S)-5-Oxo-2-(2,4-difluoroanilino)carbonylpyrrolidine
2f
4.2. (2S)-5-Oxo-2-(4-chloroanilino)carbonylpyrrolidine 2c
H
O
O
N
H
HN
F
H
O
O
N
H
F
HN
25
Time:14 24 h; yield: 44%; mp: 138–140 ꢁC; ½aꢁD ¼ þ12:9 (c
Cl
1.02, MeOH); IR (KBr): m 3450–3100 (multiple bands),
1695, 1655 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;
25
Time:14 14 h; yield: 50%; mp: 194–196 ꢁC; ½aꢁD ¼ þ14:1 (c
d6 = 4:1)]: d 2.18–2.55 (m, 4H), 4.34–4.43 (m, 1H), 6.82–
6.96 (m, 2H), 7.72 (s, 1H), 7.89–8.00 (m, 1H), 9.36 (s,
1H); 13C NMR [100 MHz (CDCl3–DMSO-d6 = 4:1)]: d
24.19, 28.11, 55.14, 102.48 (dd, J = 24.0 and 25.8 Hz),
109.54 (dd, J = 3.6 and 21.1 Hz), 120.93 (dd, J = 3.2 and
11.3 Hz), 124.02 (dd, J = 2.2 and 9.0 Hz), 152.80 (dd,
J = 12.4 and 247.3 Hz), 157.57 (dd, J = 10.9 and
244.0 Hz), 170.35, 176.84; LC–MS (m/z): 239 (MꢀH)+;
Anal. Calcd for C11H10F2N2O2: C, 55.00; H, 4.20; N,
11.66. Found: C, 55.06; H, 4.21; N, 11.73.
1.04, MeOH); IR (KBr): m 3400–3000 (multiple bands),
1701, 1660 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;
d6 = 4:1)]: d 2.08–2.49 (m, 4H), 4.23–4.34 (m, 1H), 7.25
(d, 2H, J = 8.6 Hz), 7.64 (d, 2H, J = 8.6 Hz), 7.84 (s,
1H), 9.93 (s, 1H); 13C NMR [50 MHz (CDCl3–DMSO-
d6 = 4:1)]: d 24.24, 28.37, 55.93, 120.12, 127.06, 127.37,
136.28, 170.00, 177.00; LC–MS (m/z): 239 (M+H)+, 241
(M+2+H)+; Anal. Calcd for C11H11ClN2O2: C, 55.36; H,
4.65; N, 11.74. Found: C, 55.17; H, 4.64; N, 11.76.
4.3. (2S)-5-Oxo-2-(4-fluoroanilino)carbonylpyrrolidine 2d
4.6. (2S)-5-Oxo-2-(3,5-difluoroanilino)carbonylpyrrolidine
2g
H
O
O
N
H
H
HN
O
O
N
H
HN
F
F
25
Time:14 24 h; yield: 45%; mp: 178–180 ꢁC; ½aꢁD ¼ þ14:0 (c
;
1693, 1666 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
F
1.08, MeOH); IR (KBr): m 3450–3150 (multiple bands),
25
Time:14 24 h; yield: 35%; mp: 198–200 ꢁC; ½aꢁD ¼ þ13:4 (c
d6 = 4:1)]: d 2.18–2.52 (m, 4H), 4.22–4.34 (m, 1H), 6.93–
1.08, MeOH); IR (KBr): m 3400–3170 (multiple bands),
7.04 (m, 2H), 7.55–7.71 (m, 3H), 9.65 (s, 1H); 13C NMR
1697, 1676 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;
[100 MHz (CDCl3–DMSO-d6 = 4:1)]:
d 24.63, 28.80,
d6 = 4:1)]: d 2.16–2.53 (m, 4H), 4.23–4.32 (m, 1H), 6.49–
6.59 (m, 1H), 7.27–7.37 (m, 2H), 7.65 (s, 1H), 10.00 (s,
1H); 13C NMR [100 MHz (CDCl3–DMSO-d6 = 4:1)]: d
24.40, 28.54, 56.18, 97.72 (t, J = 25.5 Hz), 101.73 (dd,
J = 8.7 and 20.7 Hz), 140.09 (t, J = 13.1 Hz), 161.81 (dd,
J = 14.5 and 243.7 Hz), 170.60, 177.29; LC–MS (m/z):
241 (M+H)+; Anal. Calcd for C11H10F2N2O2: C, 55.00;
H, 4.20; N, 11.66. Found: C, 55.03; H, 4.18; N, 11.76.
56.37, 114.40 (d, J = 21.8 Hz), 120.86 (d, J = 8.0 Hz),
133.82 (d, J = 2.9 Hz), 158.09 (d, J = 241.5 Hz), 170.11,
177.65; LC–MS (m/z): 223 (M+H)+; Anal. Calcd for
C11H11FN2O2: C, 59.45; H, 4.99; N, 12.61. Found: C,
59.52; H, 5.01; N, 12.52.
4.4. (2S)-5-Oxo-2-(4-nitroanilino)carbonylpyrrolidine 2e
H
O
O
N
H
4.7. (2S)-5-Oxo-2-[3,5-bis(trifluoromethyl)anilino]carbonyl-
pyrrolidine 2h
HN
NO2
H
O
O
N
H
25
Time:14 24 h; yield: 38%; mp: 214–216 ꢁC; ½aꢁD ¼ þ21:0 (c
HN
CF3
0.60, MeOH); IR (KBr): m 3400–3000 (multiple bands),
1707, 1682 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;
CF3
d6 = 4:1)]: d 2.16–2.54 (m, 4H), 4.31–4.37 (m, 1H), 7.79
(s, 1H), 7.88 (d, 2H, J = 9.2 Hz), 8.15 (d, 2H,
J = 9.2 Hz), 10.37 (s, 1H); 13C NMR [50 MHz (CDCl3–
DMSO-d6 = 4:1)]: d 24.34, 28.43, 56.11, 118.27, 123.55,
141.83, 143.83, 170.88, 177.22; LC–MS (m/z): 248
25
Time:14 24 h; yield: 45%; mp: 182–184 ꢁC; ½aꢁD ¼ þ4:9 (c
2.09, MeOH); IR (KBr): m 3400–3000 (multiple bands),
1716, 1674 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;

D. Basavaiah et al. / Tetrahedron: Asymmetry 18 (2007) 968–974
973
d6 = 4:1)]: d 2.20–2.61 (m, 4H), 4.27–4.33 (m, 1H), 7.54 (s,
1H), 7.61 (s, 1H), 8.27 (s, 2H), 10.26 (s, 1H); 13C NMR
[100 MHz (CDCl3–DMSO-d6 = 4:1)]: 24.67, 28.73,
4.11. (2S)-5-Oxo-2-(2,4-difluoroanilino)carbonylpyrrolidine
2f
d
56.58, 115.85 (sept, J = 3.6 Hz), 118.87 (unresolved quar-
tet), 122.49 (q, J = 270.6 Hz), 130.89 (q, J = 32.7 Hz),
139.64, 171.20, 177.65; LC–MS (m/z): 341 (M+H)+; Anal.
Calcd for C13H10F6N2O2: C, 45.89; H, 2.96; N, 8.23.
Found: C, 45.71; H, 2.98; N, 8.22.
Empirical formula, C11H10F2N2O2; formula weight,
240.21; colorless, block crystal; crystal dimensions,
0.42 · 0.32 · 0.18 mm3; orthorhombic, lattice type, primi-
˚
˚
˚
tive; a = 4.8924(6) A, b = 8.9735(11) A, c = 23.921(3) A;
3
˚
a = 90.00; b = 90.00; c = 90.00; V = 1050.2(2) A ; space
group, P212121 (International Table No. 19); Z = 4;
Dcalcd = 1.519 g/cm3; F0 0 0 = 496; k(Mo Ka) = 0.71073 A;
˚
4.8. (2S)-5-Oxo-2-(1-naphthylamino)carbonylpyrrolidine 2i
R (I P 2r1) = 0.0670; wR2 = 0.1429. Detailed X-ray crys-
tallographic data are available from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK (CCDC No. 636932).
H
O
O
N
H
HN
4.12. Asymmetric reduction of phenacyl bromide 3a: syn-
thesis of (S)-2-bromo-1-phenylethanol 4a: representative
procedure
25
Time:14 24 h; yield: 36%; mp: 198–200 ꢁC; ½aꢁD ¼ þ15:0 (c
To a stirred mixture of (2S)-5-oxo-2-anilinocarbonylpyrr-
olidine 2a (0.05 mM, 10.2 mg) in toluene (5 mL) was added
BH3ÆSMe2 (1.4 mM, 1.4 mL, 1 M solution in toluene) at
room temperature and the reaction mixture was heated un-
der reflux for 15 min. A solution of phenacyl bromide 3a
(1 mM, 199 mg) in toluene (2 mL) was added slowly drop-
wise and heating was continued under reflux for further
15 min. The reaction mixture was then cooled to room tem-
perature and quenched with MeOH. Solvent was removed
under reduced pressure and the residue thus obtained
was purified by column chromatography (silica gel, 5% ethyl
acetate in hexanes) to provide the desired (S)-2-bromo-1-
phenylethanol 4a in 86% (173 mg) yield as a colorless oil.
1.09, MeOH); IR (KBr): m 3400–3150 (multiple bands),
1722, 1670 cmꢀ1 1H NMR [400 MHz (CDCl3–DMSO-
;
d6 = 4:1)]: d 2.21–2.61 (m, 4H), 4.42–4.54 (m, 1H), 7.42–
7.55 (m, 3H), 7.71 (d, 2H, J = 7.8 Hz), 7.83–7.92 (m,
2H), 8.01–8.07 (m, 1H), 9.75 (s, 1H); 13C NMR [50 MHz
(CDCl3–DMSO-d6 = 4:1)]: d 24.65, 28.70, 56.04, 121.00,
121.44, 124.52, 124.93, 125.05, 127.28, 131.82, 133.03,
170.85, 177.33; LC–MS (m/z): 253 (MꢀH)+. Anal. Calcd
for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.66; H, 5.55; N, 11.05.
4.9. Crystal data: (2S)-5-oxo-2-(4-bromoanilino)carbonyl-
pyrrolidine 2b
All alcohols 4a–c are already known in the literature.11,12
In fact, we have also prepared alcohols 4a–c and reported
their spectral data.6,8 The present spectral data (IR, 1H and
13C NMR) of 4a–c are in agreement with the earlier data.
Empirical formula, C11H11BrN2O2; formula weight,
283.13; colorless, needle crystal; crystal dimensions,
0.18 · 0.10 · 0.10 mm3; monoclinic, lattice type, primitive;
Acknowledgments
˚
˚
˚
a = 5.1189(6) A, b = 7.6470(9) A, c = 14.2151(16) A; a =
3
˚
90.00; b = 97.717(2); c = 90.00; V = 551.40(11) A ; space
We thank the CSIR (New Delhi) for funding this project.
We thank the UGC (New Delhi) for recognizing our Uni-
versity of Hyderabad as ‘University with Potential for
Excellence (UPE)’ and also recognizing the School of
Chemistry as a ‘Center for Advanced Studies in Chemistry’
and providing some instrumental facilities. K.V.R. and
B.S.R. thank the CSIR (New Delhi) for their research fel-
lowships. We also thank the National Single Crystal X-ray
Facility in our School of Chemistry funded by the DST
(New Delhi). We thank Professor Samudranil Pal for help-
ful discussions regarding the X-ray crystal structures.
group, P21 (International Table No. 4); Z = 2; Dcalcd
=
1.705 g/cm3; F0 0 0 = 284; k(Mo Ka) = 0.71073 A; R (I P
2r1) = 0.0360; wR2 = 0.0656. Detailed X-ray crystallo-
graphic data are available from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK (CCDC No. 636930).
˚
4.10. (2S)-5-Oxo-2-(4-fluoroanilino)carbonylpyrrolidine 2d
Empirical formula, C11H11FN2O2; formula weight, 222.22;
colorless, block crystal; crystal dimensions, 0.38 · 0.26 ·
0.26 mm3; monoclinic, lattice type, primitive; a =
References
˚
˚
˚
4.9456(8) A, b = 9.8911(15) A, c = 10.4695(16) A; a =
3
1. Basavaiah, D.; Venkateswara Rao, K.; Sekhara Reddy, B.
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˚
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=
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graphic data are available from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK (CCDC No. 636931).
˚

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