Asymmetric synthesis of 3-Substituted morpholinones and piperazinones by L-Malate-mediated dynamic kinetic resolution of a-bromo esters

Full text of DOI:10.5012/bkcs.2011.32.11.4067

Notes
Bull. Korean Chem. Soc. 2011, Vol. 32, No. 11 4067
http://dx.doi.org/10.5012/bkcs.2011.32.11.4067
Asymmetric Synthesis of 3-Substituted Morpholinones and Piperazinones by
L-Malate-mediated Dynamic Kinetic Resolution of α-Bromo Esters
Jinho Baek, Jung In Jang and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea. *E-mail: parkyong@konkuk.ac.kr
Received August 26, 2011, Accepted September 5, 2011
Key Words : Dynamic kinetic resolution, Nucleophilic substitution, Malic acid, Chiral auxiliary, Asymmetric
synthesis
Chiral auxiliary-mediated dynamic resolution of α-halo
yield. Subsequent reductive cleavage of (αR)-2b using
LiAlH4 furnished the enantioenriched N,N-dibenzyl 2-
aminoalcohol (R)-3 in 77% yield with 88:12 enantiomeric
ratio (er). The results imply that α-bromo carbon center is
configurationally labile and α-bromo esters 1a-b are
dynamically resolved under the reaction condition.
A series of reactions were examined with diisopropyl ester
1b and dibenzylamine to assess the effect of solvent and
temperature on yield and selectivity as shown in Table 1.
Most of the solvents explored gave similar selectivities to
give 2b with 87:13 dr in CH3CN, 85:15 dr in ethyl acetate,
88:12 dr in p-dioxane and 87:13 dr in THF. However, the
selectivity was reduced in DMSO (entry 5) and the reaction
was very slow in n-hexane. Decreasing reaction temperature
reduced the rate of the reaction significantly with a lower
selectivity of 84:16 dr while similar selectivity was observed
at 40 °C (entries 7 and 8).
Next, we examined five different alkyl amine nucleophiles
to evaluate the scope of the dynamic kinetic resolution as
shown in Table 2. The treatment of diisopropyl ester 1b with
N-benzyl-2-phenethylamine for 24 h at room temperature
gave 4 in 83% yield with 86:14 dr (entry 1). Notably, when
cyclic secondary amine nucleophiles were used, the reac-
tions gave much lower stereoselectivities (entries 2-3). Also,
the reactions with two primary amines provided the products
7-8 with lower selectivities compared to the reactions with
esters has been known as an effective method for asym-
metric synthesis of α-heteroatom substituted carboxylic acid
derivatives.1 While the synthetic method can achieve a
useful level of stereoselectivity, it is still of interest to find
novel ways to utilize the dynamic resolution for practical
synthesis. We have previously reported L-malate-mediated
dynamic kinetic resolution of α-bromo esters with various
aryl amines for asymmetric synthesis of N-aryl substituted
amino acid derivatives.2 Herein we report our results on the
extension of the methodology to various alkyl amines for
practical asymmetric syntheses of morpholin-2-ones and
piperazin-2-ones.
Initial studies on L-malate-mediated dynamic kinetic re-
solution were performed with α-bromo esters 1a-b and di-
benzylamine (Bn2NH) as shown in Scheme 1. When the
diastereomeric mixture (1:1) of dimethyl ester (αRS)-1a was
treated with tetrabutylammonium iodide (TBAI, 1.0 equiv),
diisopropylethylamine (DIEA, 1.0 equiv) and dibenzylamine
(1.5 equiv) in CH2Cl2 at room temperature for 24 h, the
amino acid derivative (αR)-2a was produced in 76% yield
with 85:15 diastereomeric ratio (dr). Also, we examined the
substitution of diisopropyl ester (αRS)-1b under the same
reaction condition. The reaction of 1b gave amino acid
derivative (αR)-2b with a slightly higher dr of 88:12 in 73%
Table 1. Solvent and temperature effect on stereoselectivity
Entrya
Solvent
Temp
Yieldb (%)
Drc
1
2
3
4
5
6
7
CH3CN
Ethyl acetate
Dioxane
THF
rt
rt
65
68
81
77
43
19
77
87:13
85:15
88:12
87:13
78:12
84:16
87:13
rt
rt
DMSO
rt
CH2Cl2
0 °C
40 °C
CH2Cl2
c
aAll reactions are carried out for 24 h. bIsolated yields. The drs are
determined by 1H NMR of reaction mixture.
Scheme 1. L-Malate-mediated dynamic kinetic resolution in nucleo-
philic substitution.

4068 Bull. Korean Chem. Soc. 2011, Vol. 32, No. 11
Table 2. Reactions with various alkyl amine nucleophiles
Notes
Table 4. Asymmetric synthesis of 3-phenyl piperazinones
Entrya
1
Nucleophile
Yieldb (%)
Drc
83 (4)
86:14
2
3
59 (5)
76 (6)
72:28
80:20
4
5
75 (7)
62 (8)
84:16
80:20
Entrya
1
Nucleophile
Yield (%)
Erd (R;S)
aThe reactions were carried out in methylene chloride. Isolated yields.
b
H2NCH2CH2NH2
33
45b
(76:24)c
87
71:29
84:16
88:12e
84:16
b
cThe drs are determined by 1H NMR of reaction mixture.
2
BnHNCH2CH2NH2
3
BnHNCH2CH2NHBn
non-cyclic secondary amine nucleophile (entries 4-5).
Limited results in Table 2 indicate that the size of amine
nucleophile significantly affect the stereoselectivity of the
nucleophilic substitution.
aThe reactions are carried out in methylene chloride for 12 at rt. Com-
bined isolated yields of 16 and 17. cThe ratio (16:17) was determined by
H NMR of the reaction mixture. dErs are determined by CSP-HPLC. eEr
of minor product 17.
Encouraged by the high enantioselectivities in the reac-
tions with non-cyclic secondary amines, we set out to ex-
amine the substitutions with N-substituted 2-aminoethanol
nucleophiles for asymmetric syntheses of 3-substituted
morpholin-2-ones as shown in Table 3.3 When diisopropyl
ester 1b was treated with N-benzyl 2-aminoethanol, TBAI
and DIEA for 48 h, we were pleased to observe that the
substitution and following spontaneous cyclization gave N-
benzyl 3-phenyl-morpholin-2-one 10 in 65% yield with
90:10 er (entry 1). The reaction of α-bromo propionate 9
afforded 3-methyl-morpholin-2-one 11 with a lower stereo-
selectivity of 82:18 er (entry 2). In an effort to improve the
stereoselectivity, we tested three different 2-aminoethanol
nucleophiles. The reactions with two N-benzyl 2-amino-
ethanol derivatives produced morpholin-2-ones 12 and 13
with similar yields and enantioselectivities (entries 3-4). As
with N-p-methoxyphenyl 2-aminoethanol nucleophile, the
reaction provided 3-phenyl-morpholin-2-one 14 with a
higher stereoselectivity (94:6 dr) compared to the reaction
with N-benzyl 2-aminoethanol (entry 5).
For asymmetric synthesis of 3-phenyl piperazin-2-ones we
have investigated L-malate-mediated dynamic kinetic re-
solution of 1b with various ethylenediamine nucleo-
philes.4 When the diastereomeric mixture of diisopropyl
ester 1b was treated with TBAI, DIEA and ethylenediamine
(H2NCH2CH2NH2) for 12 h, the substitution and spontane-
ous cyclization produced piperazin-2-one (R)-15 in 33%
yield with 71:29 er as shown in Table 4, entry 1. When N-
benzyl ethylenediamine (BnHNCH2CH2NH2) was used as a
nucleophile, the reaction produced two regioisomers; 1-
benzyl piperazin-2-one (16)as a major product with 84:16 er
and 4-benzyl piperazin-2-one (17) as a minor product with
88:12 er. (entry 2) The regioselectivity of 76:24 indicates the
higher reactivity of sterically less hindered primary amino
group of the nucleophile. In addition, the reaction of 1b
with N,N-dibenzyl ethylenediamine (BnHNCH2CH2NHBn)
nucleophile gave (R)-1,4-dibenzyl piperazin-2-one (18) with
a comparable er of 84:16.
Table 3. Asymmetric synthesis of 3-substituted morpholinones
Entrya
R'
R''
Yieldb (%)
Erc (R;S)
1
2
3
4
5
Ph
Me
Ph
Ph
Ph
PhCH2
PhCH2
65 (10)
69 (11)
71 (12)
61 (13)
74 (14)
90:10
82:18
88:12
89:11
94:6
We conclude that dynamic kinetic resolution of L-malate-
derived α-bromo esters in nucleophilic substitution with
alkyl amines can be successfully applied towards the pre-
paration of various enantioenriched amino acid derivatives.
The results showed that stereoselectivity depends on solvent,
temperature and the structure of amine nucleophiles. In the
substitution with N-substituted 2-aminoethanol or ethylene-
m-Me-PhCH2
p-MeO-PhCH2
p-MeO-Ph
aAll reactions are carried out for 48 h in methylene chloride at rt.
bIsolated yields. cErs are determined by CSP-HPLC.

Notes
Bull. Korean Chem. Soc. 2011, Vol. 32, No. 11 4069
(R)-α-(3,4-Dihydro-2(1H)-isoquinolinyl)phenylacetic
diamine, subsequent spontaneous cyclization can provide a
convenient procedure for asymmetric syntheses of 3-sub-
stituted morpholin-2-ones and piperazin-2-ones. The simple
protocol with mild condition and the spontaneous removal
of chiral auxiliary suggests further applications to asym-
metric syntheses of various heterocyclic compounds.
1
Acid L-diisopropyl Malate Ester (6). H NMR (CDCl3,
400 MHz, major diastereomer) 7.52-7.08 (m, 9H), 5.45 (m,
1H), 5.08 (m, 1H), 4.84 (m, 1H), 4.35 (s, 1H), 3.72 (m, 1H),
2.88-2.78 (m, 6H), 1.28-1.06 (m, 12H); 13C NMR (CDCl3,
100 MHz, major diastereomer) 170.7, 168.4, 168.2, 134.3,
128.9, 128.7, 128.6, 128.5, 126.7, 126.1, 125.6, 72.9, 69.7,
69.1, 68.8, 53.6, 48.2, 36.5, 28.9, 21.7, 21.6.
Experimental
(R)-α-(Benzylamino)phenylacetic Acid L-diisopropyl
1
General Procedure for the Asymmetric Nucleophilic
Substitution via Dynamic Kinetic Resolution. To a solu-
tion of α-bromo ester (1 and 9) in CH2Cl2 (ca. 0.1 M) at
room temperature were added DIEA (1.0 equiv), TBAI (1.0
equiv) and an amine nucleophile (1.5 equiv). After the
resulting reaction mixture was stirred at room temperature
for 12-48 h, the solvent was evaporated and the crude
material was purified by column chromatography to give a
α-amino ester. The drs of 2 and 4-8 were determined by 1H
NMR integration of hydrogens of two diastereomers and the
ers of 10-18 were determined by chiral stationary phase
HPLC.
Malate Ester (7). H NMR (CDCl3, 400 MHz, major
diastereomer) 7.40-7.26 (m, 10H), 5.45 (m, 1H), 5.08 (m,
1H), 4.84 (m, 1H), 4.51 (s, 1H), 3.81 (m, 2H), 2.76 (m, 2H),
1.25 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.10 (d, J
= 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3,
100 MHz, major diastereomer) 171.9, 168.5, 168.1, 139.0,
137.2, 128.7, 128.6, 128.2, 127.8, 127.7, 127.3, 69.8, 69.4,
68.8, 63.9, 51.3, 36.4, 21.7, 21.6.
(R)-α-(Phenethylamino)phenylacetic Acid L-diisopropyl
1
Malate Ester (8). H NMR (CDCl3, 400 MHz, major
diastereomer) 7.35-7.19 (m, 10H), 5.41 (m, 1H), 5.05 (m,
1H), 4.82 (m, 1H), 4.49 (s, 1H), 2.85-2.73 (m, 6H), 1.92 (br,
1H), 1.25-1.02 (m, 12H); 13C NMR (CDCl3, 100 MHz, major
diastereomer) 172.1, 168.5, 167.9, 139.7, 137.6, 128.6,
128.4, 128.1, 127.6, 126.2, 69.8, 69.2, 68.7, 65.2, 49.1, 36.4,
21.7, 21.5.
(R)-α-(Dibenzylamino)phenylacetic Acid L-diisopropyl
1
Malate Ester (2b). H NMR (CDCl3, 400 MHz, major
diastereomer) 7.39-7.20 (m, 15H), 5.60 (m, 1H), 5.17 (m,
1H), 4.95 (m, 1H), 4.71 (s, 1H), 3.80 (s, 4H), 2.85 (m, 2H),
1.32 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.15 (d, J
= 6.0 Hz, 3H), 1.10 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz, major diastereomer) 171.3, 168.6, 168.3, 139.6,
136.5, 129.0, 128.9, 128.8, 128.3, 128.2, 127.8, 127.0, 69.8,
69.0, 68.8, 65.4, 53.9, 36.6, 21.8, 21.7. Subsequent reductive
cleavage of 2b using LiAlH4 furnished (R)-2-dibenzylamino-
N-Benzyl-3-(R)-phenyl-morpholin-2-one (10). 1H NMR
(CDCl3, 400 MHz) 7.58-7.24 (m, 10H), 4.55 (dt, J = 11.0
Hz, 3.1 Hz, 1H), 4.37 (m, 1H), 4.26 (s, 1H), 3.77 (d, J = 13.4
Hz, 1H), 3.17 (d, J = 13.3 Hz, 1H), 2.99 (m, 1H), 2.64 (m,
1H). The spectral data were identical to those of the authentic
material reported previously.3b CSP-HPLC (Chiralpak AD-
H column; 10% 2-propanol in hexane; 0.5 mL/min) 90:10 er,
20.1 min (major enantiomer), 24.5 min (minor enantiomer).
N-Benzyl-3-(R)-methyl-morpholin-2-one (11). 1H NMR
(CDCl3, 400 MHz) 7.34-7.28 (m, 5H), 4.32 (m, 2H), 3.96 (d,
J = 13.4 Hz, 1H), 3.42 (q, J = 6.9 Hz, 1H), 3.33 (d, J = 13.4
Hz, 1H), 2.86 (dt, J = 12.9 Hz, 3.7 Hz, 1H), 2.52 (m, 1H),
1.56 (d, J = 6.7 Hz, 3H). The spectral data were identical to
those of the authentic material reported previously.3b CSP-
HPLC (Chiralpak AD-H column; 2% 2-propanol in hexane;
0.5 mL/min) 82:18 er, 39.8 min (major enantiomer), 45.9
min (minor enantiomer).
N-(m-Methylbenzyl)-3-(R)-phenyl-morpholin-2-one (12).
1H NMR (CDCl3, 400 MHz) 7.58-7.03 (m, 9H), 4.54 (dt, J =
11.4 Hz, 3.0 Hz, 1H), 4.34 (m, 1H), 4.24 (s, 1H), 3.73 (d, J =
13.3 Hz, 1H), 3.12 (d, J = 13.3 Hz, 1H), 2.97 (m, 1H), 2.62
(m, 1H), 2.32 (s, 3H). The spectral data were identical to
those of the authentic material reported previously.3b CSP-
HPLC (Chiralpak AD-H column; 10% 2-propanol in hexane;
0.5 mL/min) 88:12 er, 17.7 min (major enantiomer), 20.8
min (minor enantiomer).
1
2-phenylethanol 3. H NMR (CDCl3, 400 MHz) 7.44-7.25
(m, 15H), 4.14 (dd, J = 10.6, 10.6 Hz, 1H), 3.96-3.90 (m,
3H), 3.62 (m, 1H), 3.15 (d, J = 13.4 Hz, 1H), 3.01 (br, 1H).
The enantiomeric ratio of 3 was determined to be 88:12 in
favor of the R enantiomer by CSP-HPLC using racemic
material as a standard. (Chiralcel OD column; 10% 2-pro-
panol in hexane; 0.5 mL/min): 12.7 min (R), 19.4 min (S).
(R)-α-(N-Benzyl phenethylamino)phenylacetic Acid L-
diisopropyl Malate Ester (4). 1H NMR (CDCl3, 400 MHz,
major diastereomer) 7.34-6.97 (m, 15H), 5.57 (m, 1H), 5.11
(m, 1H), 4.92 (m, 1H), 4.77 (s, 1H), 3.91 (d, J = 14.4 Hz,
1H), 3.80 (d, J = 14.4 Hz, 1H), 2.92-2.80 (m, 6H), 1.27 (d, J
= 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.4 Hz,
3H), 1.10 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
major diastereomer) 171.4, 168.6, 168.3, 140.2, 139.8,
136.7, 128.9, 128.8, 128.7, 128.3, 128.2, 127.8, 126.9,
125.8, 69.8, 69.0, 68.8, 67.2, 55.1, 51.8, 36.6, 34.6, 21.8,
21.7.
(R)-α-(1-Pyrrolidinyl)phenylacetic Acid L-diisopropyl
1
Malate Ester (5). H NMR (CDCl3, 400 MHz, major
diastereomer) 7.48-7.27 (m, 5H), 5.41 (m, 1H), 5.03 (m, 1H),
4.85 (m, 1H), 4.02 (s, 1H), 2.79-2.46 (m, 6H), 1.79 (m, 4H),
1.29-1.03 (m, 12H); 13C NMR (CDCl3, 100 MHz, major
diastereomer) 170.8, 168.3, 168.2, 137.1, 128.6, 128.5,
128.3, 73.3, 69.6, 68.7, 67.4, 61.1, 52.4, 49.7, 36.5, 23.7,
23.4, 21.8, 21.4.
N-(p-Methoxybenzyl)-3-(R)-phenyl-morpholin-2-one
1
(13). H NMR (CDCl3, 400 MHz) 7.58-7.31 (m, 5H), 7.16
(d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.54 (dt, J =
11.0 Hz, 3.0 Hz, 1H), 4.37 (m, 1H), 4.24 (s, 1H), 3.79 (s,
3H), 3.71 (d, J = 13.2 Hz, 1H), 3.12 (d, J = 13.2 Hz, 1H),
2.99 (m, 1H), 2.64 (m, 1H). The spectral data were identical

4070 Bull. Korean Chem. Soc. 2011, Vol. 32, No. 11
Notes
to those of the authentic material reported previously.3b CSP-
HPLC (Chiralpak AD-H column; 10% 2-propanol in hexane;
0.5 mL/min) 89:11 er, 26.4 min (major enantiomer), 33.0
min (minor enantiomer).
column; 10% 2-propanol in hexane; 0.5 mL/min) 88:12 er,
28.0 min (major enantiomer), 35.4 min (minor enantiomer).
1,4-Dibenzyl-3-(R)-phenyl-piperazin-2-one (18). 1H
NMR (CDCl3, 400 MHz) 7.57-7.21 (m, 15H), 4.62 (d, J =
14.6 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H), 4.13 (s, 1H), 3.74
(d, J = 13.4 Hz, 1H), 3.42 (m, 1H), 3.13 (d, J = 13.4 Hz, 1H),
3.10 (m, 1H), 2.94 (m, 1H), 2.46 (m, 1H). The spectral data
were identical to those of the authentic material reported
previously.4 CSP-HPLC (Chiralcel OD column; 10% 2-
propanol in hexane; 0.5 mL/min) 84:16 er, 25.0 min (major
enantiomer), 29.9 min (minor enantiomer).
N-(p-Methoxyphenyl)-3-(S)-phenyl-morpholin-2-one
1
(14). H NMR (CDCl3, 400 MHz) 7.52-7.33 (m, 5H), 6.83
(d, J = 9.0 Hz, 2H), 6.61 (d, J = 9.0 Hz, 2H), 5.43 (s, 1H),
4.47 (m, 2H), 3.75 (s, 3H), 3.68 (m, 2H). The spectral data
were identical to those of the authentic material reported
previously.3b CSP-HPLC (Chiralpak AD-H column; 10% 2-
propanol in hexane; 0.5 mL/min) 94:6 er, 38.1 min (major
enantiomer), 42.8 min (minor enantiomer).
1
3-(R)-Phenyl-piperazin-2-one (15). H NMR (CDCl3,
Acknowledgments. This work was supported by a grant
from Korea Research Foundation (2009-0089650) and Seoul
R&BD Program (WR090671).
400 MHz) 7.44-7.29 (m, 5H), 6.57 (br, 1H), 4.59 (s, 1H),
3.53 (m, 1H), 3.39 (m, 1H), 3.16 (m, 1H), 3.08 (m, 1H), 1.95
(br, 1H). The spectral data were identical to those of the
authentic material reported previously.4 CSP-HPLC (Chiralcel
OJ-H column; 10% 2-propanol in hexane; 0.5 mL/min)
71:29 er, 52.3 min (major enantiomer), 55.3 min (minor
enantiomer).
References and Notes
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1
1-Benzyl-3-(R)-phenyl-piperazin-2-one (16). H NMR
(CDCl3, 400 MHz) 7.43-7.28 (m, 10H), 4.63 (m, 3H), 3.40
(m, 1H), 3.21 (m, 1H), 3.08 (m, 1H), 3.02 (m, 1H), 2.05 (br,
1H). The spectral data were identical to those of the authentic
material reported previously.4 CSP-HPLC (Chiralcel OD
column; 20% 2-propanol in hexane; 0.5 mL/min) 84:16 er,
47.1 min (major enantiomer), 26.4 min (minor enantiomer).
1
4-Benzyl-3-(R)-phenyl-piperazin-2-one (17). H NMR
2. Kang, K. H.; Jang, J. I.; Baek, S. B.; Ahn, J. H.; Park, Y. S. Bull.
Korean Chem. Soc. 2011, 32, 1741.
(CDCl3, 400 MHz) 7.55-7.26 (m, 10H), 6.60 (br, 1H), 4.06
(s, 1H), 3.75 (d, J = 13.4 Hz, 1H), 3.45 (m, 1H), 3.25 (m,
1H), 3.17 (d, J = 13.4 Hz, 1H), 2.98 (m, 1H), 2.51 (m, 1H).
The spectral data were identical to those of the authentic
material reported previously.4 CSP-HPLC (Chiralpak AD-H
3. (a) Devine, P. N.; Foster, B. S.; Grabowski, E. J. J.; Reider, P. J.
Heterocycles 2002, 58, 119. (b) Lee, Y. M.; Kang, K. H.; Min, H.-
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