(S)-Mandelate-mediated dynamic kinetic resolution of α-bromo esters for asymmetric syntheses of aminoflavones, dihydroquinoxalinones and dihydrobenzoxazinones

Article abstract of DOI:10.3987/COM-09-11700

(S)-Mandelate-mediated dynamic kinetic resolution of α-bromo esters in nucleophilic substitution reaction has been investigated. Reactions of various aryl amine nucleophiles in the presence of TBAI and DIEA can provide the substitution products 2 and 7-19

Full text of DOI:10.3987/COM-09-11700

HETEROCYCLES, Vol. 78, No. 9, 2009
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HETEROCYCLES, Vol. 78, No. 9, 2009, pp. 2233 - 2244. © The Japan Institute of Heterocyclic Chemistry
Received, 9th March, 2009, Accepted, 11th May, 2009, Published online, 11th May, 2009.
DOI: 10.3987/COM-09-11700
(S)-MANDELATE-MEDIATED DYNAMIC KINETIC RESOLUTION OF
α-BROMO ESTERS FOR ASYMMETRIC SYNTHESES OF
AMINOFLAVONES, DIHYDROQUINOXALINONES AND
DIHYDROBENZOXAZINONES
Yoon Min Lee and Yong Sun Park*
Department of Chemistry and Bio/Molecular Informatics Center, Konkuk
University, Seoul, 143-701, Korea; e-mail: parkyong@konkuk.ac.kr
Abstract – (S)-Mandelate-mediated dynamic kinetic resolution of -bromo esters
in nucleophilic substitution reaction has been investigated. Reactions of various
aryl amine nucleophiles in the presence of TBAI and DIEA can provide the
substitution products 2 and 7-19 up to 95% yield and 96:4 dr. Also, the simple
procedure with spontaneous removal of the chiral auxiliary provides a practical
protocol for asymmetric syntheses of dihydroquinoxalinones 20-26 and
dihydrobenzoxazinones 27-30 up to 97:3 er.
INTRODUCTION
Chiral auxiliary mediated dynamic resolution of -haloacyl compounds has been recently developed as
an effective synthetic method for asymmetric syntheses of -substituted carboxylic acid derivatives.1
Although a high level of stereoselectivity in the dynamic resolution is achieved by several chiral
auxiliaries, it is still desirable to find effective chiral auxiliaries amenable to easily scalable processes
under mild and simple reaction conditions. Herein we report the first successful example of
(S)-mandelate-mediated dynamic kinetic resolution of -bromo esters in nucleophilic substitution with
various aryl amines.
RESULTS AND DISCUSSION
Treatment of methyl (S)-mandelate with racemic -bromo--phenylacetic acid in the presence of DCC
and DMAP provided -bromo--phenyl ester (RS)-1 in 69% yield with 50:50 diastereomeric ratio (dr).
When the two diastereomeric mixture of (RS)-1 was treated with p-anisidine (p-MeOPhNH2, 1.5 equiv),
tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH2Cl2 at

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HETEROCYCLES, Vol. 78, No. 9, 2009
O
Ph
O
Ph
Br
Br
O
CO2Me
O
CO2Me
TBAI
DIEA
Ph
Ph
(αR)-1
(αS)-1
p-anisidine
OMe
OMe
Et3N
O
Ph
HN
CO2Me
HN
MeOH
O
CO2Me
Ph
(R)-3 95:5 er
Ph
(αR)-2
95:5 dr
Scheme 1. (S)-Mandelate-mediated asymmetric nucleophilic substitution
room temperature for 12 h, the amino acid derivative 2 was produced in 86% yield with 95:5 dr as shown
in Scheme 1. Subsequent removal of the chiral auxiliary with MeOH and Et3N gave N-aryl
phenylglycinate (R)-3 in 88% yield with 95:5 enantiomeric ratio (er).2 The results imply that α-bromo
stereogenic center is configurationally labile with respect to the rate of substitution and (αRS)-1 is
dynamically resolved under the reaction condition.
In order to understand the reaction pathway and the origin of stereoselectivity, we carried out a series of
reactions as shown in Table 1. When the mixture of two epimers of 1 (50:50 dr or 70:30 dr) was
allowed to reach thermodynamic equilibrium in the presence of TBAI and DIEA, the epimeric ratio of
1
recovered 1 was analyzed by H NMR, and determined to be 51:49 in both cases. (entries 1 and 2)
These results indicate that α-bromo ester 1 is configurationally labile under the reaction condition and the
Table 1. Dynamic kinetic resolution of α-bromo ester 1
Entry
Substrate (Dr)a
1 (50:50)
Conditionb
DIEA, TBAI
Product (Dr)a
1 (51:49)
1 (51:49)
2 (95:5)
1
2
3
4
1 (70:30)c
1 (71:29)c
2 (83:17)c
DIEA, TBAI
DIEA, TBAI, p-anisidine
DIEA, TBAI, p-anisidine
2 (83:17)
(a) The drs are determined by 1H NMR. (b) The reactions were carried out
in CH2Cl2. (c) The mixtures are prepared by column chromatography with
fractional collection.

HETEROCYCLES, Vol. 78, No. 9, 2009
2235
thermodynamic stabilities of two epimers are almost same, ruling out dynamic thermodynamic resolution
(DTR) as a primary pathway.3 In the reaction of 1 (71:29 dr) with p-anisidine, DIEA and TBAI as
shown in entry 3, same dr of 2 (95:5 dr) was observed as in the reaction of 1 of 50:50 dr. Thus, the dr of
product 2 is not dependent on the starting ratio of two epimers of 1. When the configurational stability
of 2 (83:17 dr) was examined by the treatment with p-anisidine (1.5 equiv), TBAI (1.0 equiv) and DIEA
1
(1.0 equiv) in CH2Cl2 for 24 h, no epimerization was detected by H-NMR, which can rule out the
possibility of epimerization after the nucleophilic substitution reaction. (entry 4) These preliminary
results indicate that the epimerization promoted by TBAI and DIEA is sufficiently fast with respect to the
rate of substitution and the primary pathway of the asymmetric induction is a dynamic kinetic resolution
(DKR).
Table 2. Reactions of 1 and 4-6 with various aryl amine nucleophiles
O
Ph
O
Ph
nucleophile
TBAI, DIEA
Nuc
Br
O
CO2Me
O
CO2Me
R
R
1, 4-6
2, 7-19
Entrya
1
R
Nucleophile
%Yieldb
Drc
Ph (1)
93 (2)
96:4
NH2
2
3
4
Me (4)
Et (5)
88 (7)
95 (8)
82 (9)
90:10
91:9
MeO
n-Bu (6)
90:10
5
6
Ph (1)
83 (10)
70 (11)
93:7
NH2
OMe
Me (4)
86:14
7
8
Ph (1)
Me (4)
Et (5)
80 (12)
73 (13)
78 (14)
61 (15)
53 (16)
42 (17)
51 (18)
96:4
88:12
90:10
89:11
94:6
MeO
NH2
9
10
11
12
13
n-Bu (6)
Ph (1)
Me (4)
Et (5)
Ph
O
85:15
85:15
NH2
O
O
Ph
NH2
14
Ph (1)
33 (19)
87:13
O
(a) The reactions were carried out in MeCN. (b) Isolated yields. (c) The drs
are determined by 1H NMR of reaction mixture.

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HETEROCYCLES, Vol. 78, No. 9, 2009
The scope of the dynamic kinetic resolution has been investigated with various aryl amines in MeCN as
shown in Table 2. The treatment of 1 with p-anisidine (1.5 equiv) in MeCN for 24 h at room
temperature gave 2 in 93% yield with 96:4 dr. (entry 1) Under the same reaction condition, the reactions
of α-alkyl α-bromoacetates 4-6 gave amino esters 7-9 with slightly lower drs.4 (entry 2-4) In the
reactions with two different anisidines, similar stereoselectivities were obtained with m-anisidine (entries
7-10), whereas o-anisidine gave slightly lower stereoselectivities (entries 5-6). In our continuing
investigation on the stereoselective preparation of flavonoid derivatives and their activity studies,5 we
have attempted to synthesize enantioenriched N-carboxyalkylated flavones 16-19 as shown in entries
11-14. When α-bromoacetate 1 was treated with 6-aminoflavone, DIEA and TBAI for 24 h, the
substitution provided 16 in 53% yield with 94:6 dr. Analogous to the reactions with p-anisidine, the
reaction of α-alkyl α-bromoacetates 4 and 5 with 6-aminoflavone gave lower selectivity of 85:15 dr.
(entries 12 and 13) The substitution of 1 with 7-aminoflavone, however, was slower than the reaction
with 6-aminoflavone under the same condition (entry 14) and the reactions of 4-6 with 7-aminoflavone
did not provide the substituted products. Limited results indicate that the substituents of aryl amine
nucleophile may have a little effect on stereoselectivity, but that it significantly affected the rate of
substitution.
Encouraged by the high enantioselectivities in the reactions of α-bromo acetates 1 and 4-6 with various
aryl amines, we set out to examine the DKR in substitutions with 1,2-diaminobenzene and
2-aminohydroxybenzene nucleophiles for asymmetric syntheses of dihydroquinoxalinones and
dihydrobenzoxazinones as shown in Table 3. Dihydroquinoxalinone and dihydrobenzoxazinone
structural cores are of interest as important pharmacophores in many biologically active compounds and
there is growing interest in the asymmetric preparation of them.6,7 When α-bromo-α-phenylacetate 1
was treated with 1,2-phenylenediamine, TBAI and DIEA in MeCN for 24 h at room temperature, the
substitution and following spontaneous cyclization gave 3-phenyl dihydroquinoxalinone 20-22 in 92-87%
yields with 97:3-94:6 ers. (entries 1-3) As with α-alkyl-α-bromoacetates 4-6, the reactions in MeCN
took place to afford 3-alkyl substituted dihydroquinoxalinones 23-26 with slightly lower
stereoselectivities of 92:8-87:13 ers. (entries 4-7) In addition, we were very pleased to demonstrate that
this methodology is also efficient for the asymmetric preparation of 3-phenyl dihydrobenzoxazinones
27-30 with high selectivities and good yields as shown in entries 8-11. For example, when
α-bromo-α-phenylacetate 1 was treated with 2-aminophenol in CH2Cl2 for 6 h, dihydrobenzoxazinone 27
was obtained in 71% yield with 91:9 er. Also, the reactions of 1 with various substituted
2-aminophenols produced dihydrobenzoxazinones 28-30 with similar yields and enantioselectivities.
Curiously, when the reactions were carried out in MeCN, 27-30 were obtained with lower yields
(50-40%) and enantioselectivities (88:12-81:19 er) compared to the reaction in CH2Cl2.

HETEROCYCLES, Vol. 78, No. 9, 2009
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Table 3. Asymmetric syntheses of dihydroquinoxalinones and dihydrobenzoxazinones
Y
NH2
H
Y
O
Ph
N
R
O
XH
Br
O
CO2Me
X
TBAI, DIEA
R
X = NH, O
1, 4-6
20-30
Entrya
1
R
Nucleophile
%yieldb
er (R:S)c
NH2
NH2
Ph
92 (20)
96:4
Cl
NH2
2
3
Ph
Ph
87 (21)
90 (22)
97:3
94:6
Cl
NH2
NH2
Me
Me
NH2
NH2
NH2
NH2
4
5
6
Me
Me
Et
79 (23)
88 (24)
81 (25)
89:11
87:13
92:8
Me
Me
Me
Me
NH2
NH2
NH2
NH2
7
n-Bu
71 (26)
90:10
NH2
NH2
OH
8
9
Ph
Ph
71 (27)
79 (28)
91:9
Me
NH2
90:10
OH
NH2
OH
10
11
Ph
Ph
68 (29)
80 (30)
90:10
91:9
Me
t-Bu
NH2
OH
(a) The reactions were carried out in MeCN for 20-26 and CH2Cl2 for
27-30. (b) Isolated yields. (c) The ers are determined by CSP-HPLC
(Chiralcel OJ-H column for 20-26 and OD column for 27-30).

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Next, we tested the stereocontrolling ability of mandelate in nucleophilic substitution with a
2-aminothiophenol. Treatment of α-bromo-α-phenylacetate 1 with 2-aminothiophenol in the presence of
TBAI and DIEA gave no amino-substituted product and instead produced thio-substituted product,
dihydrobenzothiazinone 31 in 85% yield with 69:31 dr as shown in Scheme 2. The low selectivity
observed in the reaction of the thiol nucleophile might be attributed to their incapability for the hydrogen
bonding interaction. It is well known that the origin of the high diastereoselectivity in the reactions of
α-haloacyl compounds with amine nucleophiles is due essentially to the formation of an intermolecular
hydrogen bond that facilitates delivery of the nucleophile.1a,1h,1i
NH2
S
Ph
O
O
Ph
SH
Br
O
CO2Me
N
H
TBAI, DIEA
Ph
1
31 69:31 er
Scheme 2. Synthesis of a dihydrobenzothiazinone
We conclude that (S)-mandelate is an effective and convenient chiral auxiliary for dynamic kinetic
resolution of -bromo esters in nucleophilic substitution with aryl amines. The methodology can
provide a general procedure for asymmetric syntheses of (R)-dihydroquinoxalinones and
(R)-dihydrobenzoxazinones. Since both enantiomers of mandelic acid are readily available, this method
enables one to prepare (S)-products as well. Simple and easy procedure in obtaining optically active
N-aryl amino acid derivatives suggests that this DKR approach should be further developed.
EXPERIMENTAL
(S)-Mandelic acid derived -bromoacetates 1 and 4-6 were prepared by the coupling reaction of methyl
13
mandelate and -bromoacetic acid derivatives with DCC and DMAP.1i 1H and C NMR spectra were
1
acquired on Bruker 400 (400MHz H, 100.6MHz 13C) spectrometer using chloroform-d or DMSO-d6.
13
The purities (>95%) of products were estimated by C NMR. Analytical chiral stationary phase (CSP)
HPLC was performed on pump system coupled to absorbance detector (215nm). Chiralcel OJ-H column
(25cm×4.6mm i.d.) and Chiralcel OD column (25cm×4.6mm i.d.) with isopropanol/ hexane mobile phase
were used to determine enantiomeric ratios.
General procedure for asymmetric nucleophilic substitution of -bromo esters: To a solution of
-bromoacetate (1.0 mmol) in CH2Cl2 or MeCN (ca. 0.1 M) at rt were added DIEA (1.0 equiv),
TBAI (1.0 equiv) and an aryl amine nucleophile (1.5 equiv). After the resulting reaction mixture

HETEROCYCLES, Vol. 78, No. 9, 2009
2239
was stirred at rt for 6-24 h, the solvent was removed under reduced pressure and the crude material was
purified by column chromatography to give a product.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(p-methoxyanilino)-(R)-phenylacetate (2) A yellow oil was
obtained in 86% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.47 (m, 2H), 7.28 (m, 8H),
6.71 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.9 Hz, 2H), 5.93 (s, 1H), 5.22 (d, J = 4.8 Hz, 1H), 4.60 (d, J = 4.8
Hz, 1H), 3.66 (s, 3H), 3.65 (s, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer) 171.9, 169.2, 153.1,
140.6, 137.6, 133.7, 129.6, 129.3, 129.1, 128.9, 127.9, 127.7, 115.3, 75.5, 62.1, 56.1, 53.2. For removal
of chiral auxiliary, the mixture of 2 and Et3N (10 equiv) in MeOH (0.05 M) was stirred at rt for 1
day. The solvent was evaporated and the crude material was purified by column chromatography to
give (R)-3 in 88% yield. 1H NMR (CDCl3, 400 MHz) 7.48-7.25 (m, 5H), 6.69 (d, J = 8.9 Hz, 2H), 6.52
(d, J = 8.9 Hz, 2H), 5.00 (s, 1H), 4.67 (br, 1H), 3.72 (s, 3H), 3.67 (s, 3H). The spectral data of 3 were
identical to those of the authentic material reported in ref. 1e. Chiral HPLC: 95:5 er, tR (S)-minor
enantiomer, 73.7 min; tR (R)-major enantiomer, 65.9 min; (Chiralcel OJ-H column; 20% 2-propanol in
hexane; 0.5 mL/min).
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(p-methoxyanilino)-(R)-propionate (7) A colorless oil was
obtained in 88% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.43-7.34 (m, 5H), 6.75 (d, J =
8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.96 (s, 1H), 4.22 (q, J = 6.8 Hz, 1H), 3.93 (s, 1H), 3.69 (s, 3H),
13
3.64 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); C NMR (CDCl3, 100 MHz, major diastereomer) 174.6, 169.4,
153.2, 141.1, 134.1, 129.7, 129.3, 128.1, 115.5, 115.3, 75.1, 56.1, 53.4, 53.1, 19.3.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(p-methoxyanilino)-(R)-butanoate (8) A colorless oil was
obtained in 95% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.42-7.32 (m, 5H), 6.75 (d, J =
8.8 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.96 (s, 1H), 4.09 (t, J = 6.3 Hz, 1H), 3.87 (br, 1H), 3.69 (s, 3H),
3.64 (s, 3H), 1.95-1.77 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major
diastereomer) 174.0, 169.4, 153.2, 141.3, 134.1, 129.7, 129.2, 128.1, 115.5, 115.1, 75.0, 59.1, 56.1, 53.0,
26.7, 10.5.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(p-methoxyanilino)-(R)-hexanoate (9) A colorless oil was
obtained in 82% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.36 (m, 5H), 6.76 (d, J = 8.9
Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 5.96 (s, 1H), 4.13 (t, J = 6.5 Hz, 1H), 3.88 (br, 1H), 3.70 (s, 3H), 3.65
13
(s, 3H), 1.88-1.75 (m, 2H), 1.41-1.28 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, 100 MHz,
major diastereomer) 174.2, 169.3, 153.2, 141.3, 134.2, 129.8, 129.3, 127.9, 115.5, 115.3, 75.1, 58.0, 56.1,
53.0, 33.3, 28.1, 22.9, 14.3.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(o-methoxyanilino)-(R)-phenylacetate (10) A yellow oil was
obtained in 83% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.52-7.26 (m, 10H), 6.75 (m,
2H), 6.67 (m, 1H), 6.47 (m, 1H), 5.94 (s, 1H), 5.40 (d, J = 6.0 Hz, 1H), 5.28 (d, J = 6.0 Hz, 1H), 3.83 (s,

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13
3H), 3.68 (s, 3H); C NMR (CDCl3, 100 MHz, major diastereomer) 171.6, 169.2, 147.5, 137.5, 136.4,
133.7, 129.5, 129.3, 129.1, 128.8, 127.9, 127.6, 121.5, 118.0, 111.3, 110.0, 75.5, 61.2, 55.9, 53.1.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(o-methoxyanilino)-(R)-propionate (11) A colorless oil was
obtained in 70% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.41-7.35 (m, 5H), 6.85-6.75
(m, 2H), 6.71 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 5.95 (s, 1H), 4.79 (d, J = 7.8 Hz, 1H), 4.22 (m,
1H), 3.81 (s, 3H), 3.68 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major
diastereomer) 174.3, 169.3, 147.5, 136.8, 133.9, 129.6, 129.3, 127.7, 121.5, 118.1, 111.1, 110.2, 75.0,
55.8, 53.1, 52.2, 19.2.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(m-methoxyanilino)-(R)-phenylacetate (12) A yellow oil was
obtained in 80% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.48 (m, 2H), 7.27 (m, 8H),
7.00 (m, 1H), 6.28 (m, 1H), 6.22 (m, 1H), 6.16 (m, 1H), 5.93 (s, 1H), 5.27 (d, J = 5.8 Hz, 1H), 4.88 (d, J
= 5.8 Hz, 1H), 3.68 (s, 6H); 13C NMR (CDCl3, 100 MHz, major diastereomer) 171.6, 169.2, 161.2, 147.7,
137.4, 133.6, 130.5, 129.6, 129.4, 129.1, 128.9, 127.8, 127.6, 106.9, 104.1, 100.0, 75.6, 61.2, 55.4, 53.2.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(m-methoxyanilino)-(R)-propionate (13) A colorless oil was
obtained in 73% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.41-7.33 (m, 5H), 7.08 (m,
1H), 6.31-6.20 (m, 3H), 5.97 (s, 1H), 4.29 (q, J = 6.8 Hz, 1H), 4.21 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H),
13
1.48 (d, J = 6.8 Hz, 3H); C NMR (CDCl3, 100 MHz, major diastereomer) 174.3, 169.3, 161.3, 148.3,
133.9, 130.5, 129.7, 129.3, 127.9, 106.8, 104.2, 99.8, 75.2, 55.4, 53.1, 52.4, 19.1.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(m-methoxyanilino)-(R)-butanoate (14) A colorless oil was
obtained in 78% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.41-7.35 (m, 5H), 7.07 (t, J =
8.0 Hz, 1H), 6.31-6.25 (m, 2H), 6.21 (s, 1H), 5.97 (s, 1H), 4.17 (m, 2H), 3.75 (s, 3H), 3.68 (s, 3H),
13
1.97-1.79 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); C NMR (CDCl3, 100 MHz, major diastereomer) 173.6,
169.3, 161.3, 148.6, 133.9, 130.5, 129.7, 129.2, 128.0, 106.8, 104.3, 99.9, 75.1, 58.2, 55.4, 53.0, 26.4,
10.4.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-(m-methoxyanilino)-(R)-hexanoate (15) A colorless oil was
obtained in 61% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.38 (m, 5H), 7.07 (t, J = 8.1
Hz, 1H), 6.31-6.25 (m, 2H), 6.21 (m, 1H), 5.98 (s, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.75 (s, 3H), 3.69 (s,
3H), 1.78 (m, 2H), 1.34 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major
diastereomer) 173.8, 169.3, 161.2, 148.6, 134.1, 130.5, 129.8, 129.2, 127.9, 106.8, 104.3, 99.8, 75.0, 56.9,
55.5, 53.0, 33.0, 28.0, 22.8, 14.3.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-[(4-oxo-2-phenyl-4H-chromen-6-yl)amino]-(R)-phenylacetate
(16) A yellow oil was obtained in 53% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.88 (m,
2H), 7.50 (m, 5H), 7.38-7.26 (m, 10H), 7.04 (m, 1H), 6.74 (s, 1H), 5.95 (s, 1H), 5.43 (d, J = 6.3 Hz, 1H),
13
5.13 (d, J = 6.3 Hz, 1H), 3.72 (s, 3H); C NMR (CDCl3, 100 MHz, major diastereomer) 178.1, 171.3,

HETEROCYCLES, Vol. 78, No. 9, 2009
2241
169.1, 163.1, 150.2, 143.8, 136.7, 133.5, 132.5, 131.7, 129.6, 129.4, 129.3, 129.1, 129.0, 127.8, 127.6,
126.6, 125.1, 121.7, 119.5, 107.1, 106.0, 75.8, 61.0, 53.2.
2-Methoxy-2-oxo-(S)-1-phenylethyl
2-[(4-oxo-2-phenyl-4H-chromen-6-yl)amino]-(R)-propanoate
(17) A yellow oil was obtained in 42% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.91 (m,
2H), 7.53-7.34 (m, 10H), 7.05 (m, 1H), 6.78 (s, 1H), 5.98 (s, 1H), 4.46 (m, 1H), 4.38 (m, 1H), 3.70 (s,
13
3H), 1.56 (d, J = 6.7 Hz, 1H); C NMR (CDCl3, 100 MHz, major diastereomer) 178.7, 174.0, 169.2,
163.2, 150.3, 144.5, 133.6, 132.5, 131.7, 129.9, 129.4, 129.2, 128.0, 126.6, 125.2, 121.9, 119.6, 107.1,
105.7, 75.4, 53.1, 52.3, 19.0.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-[(4-oxo-2-phenyl-4H-chromen-6-yl)amino]-(R)-butanoate (18)
A yellow oil was obtained in 51% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 7.90 (m, 2H),
7.51-7.35 (m, 10H), 7.07 (m, 1H), 6.77 (s, 1H), 5.99 (s, 1H), 4.45 (br, 1H), 4.36 (q, J = 5.9 Hz, 1H), 3.69
13
(s, 3H), 2.07-1.85 (m, 2H), 1.03 (t, J = 7.8 Hz, 1H); C NMR (CDCl3, 100 MHz, major diastereomer)
178.7, 173.2, 169.2, 163.2, 150.3, 144.8, 133.9, 132.5, 131.7, 129.7, 129.3, 129.2, 128.0, 126.6, 125.2,
121.9, 119.5, 107.1, 105.8, 75.4, 58.1, 53.1, 26.3, 10.2.
2-Methoxy-2-oxo-(S)-1-phenylethyl 2-[(4-oxo-2-phenyl-4H-chromen-7-yl)amino]-(R)-phenylacetate
(19) A yellow oil was obtained in 33% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer) 8.06-7.26
(m, 15H), 6.69 (m, 3H), 6.53 (s, 1H), 6.00 (s, 1H), 5.52 (d, J = 5.6 Hz, 1H), 5.39 (d, J = 5.6 Hz, 1H), 3.74
(s, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer) 178.1, 170.7, 169.0, 162.8, 158.8, 150.9, 136.0,
133.3, 132.5, 131.5, 129.7, 129.6, 129.3, 129.0, 128.8, 127.7, 127.6, 127.3, 126.5, 116.1, 113.8, 107.8,
98.8, 75.8, 60.7, 53.3.
3-Phenyl-3,4-dihydro-1,4-quinoxalin-2-one (20) A white solid was obtained in 92% yield. m.p.
1
192-194 °C; H NMR (CDCl3, 400 MHz) 7.95 (br, 1H), 7.43-6.70 (m, 9H), 5.08 (s, 1H), 4.28 (br, 1H).
The spectral data were identical to those of the authentic material reported in ref. 8a. Chiral HPLC: 96:4
er, tR (S)-minor enantiomer, 38.3 min; tR (R)-major enantiomer, 35.7 min; (Chiralcel OJ-H column; 20%
2-propanol in hexane; 0.5 mL/min).
6,7-Dichloro-3-phenyl-3,4-dihydro-1,4-quinoxalin-2-one (21) A white solid was obtained in 87% yield.
1
m.p. 230-231 °C; H NMR (DMSO-d6, 400 MHz) 10.1 (br, 1H), 7.88-7.75 (m, 5H), 7.50-7.48 (m, 2H),
13
6.77 (br, 1H), 5.55 (s, 1H); C NMR (DMSO-d6, 100 MHz) 166.1, 140.6, 134.9, 129.3, 128.8, 127.7,
126.9, 125.9, 120.5, 116.7, 115.1, 60.5; Chiral HPLC: 97:3 er, tR (S)-minor enantiomer, 40.6 min; tR
(R)-major enantiomer, 35.6 min; (Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethyl-3-phenyl-3,4-dihydro-1,4-quinoxalin-2-one (22) A white solid was obtained in 90% yield.
m.p. 203-204 °C; 1H NMR (CDCl3, 400 MHz) 8.44 (br, 1H), 7.41-7.28 (m, 5H), 6.50 (s, 2H), 5.01 (s, 1H),
4.11 (br, 1H), 2.15 (s, 3H), 2.14 (s, 3H). The spectral data were identical to those of the authentic material
reported in ref. 8a. Chiral HPLC: 94:6 er, tR (S)-minor enantiomer, 43.3 min; tR (R)-major enantiomer,

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HETEROCYCLES, Vol. 78, No. 9, 2009
32.6 min; (Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min).
3-Methyl-3,4-dihydro-1,4-quinoxalin-2-one (23) A white solid was obtained in 79% yield. m.p.
150-151 °C; 1H NMR (CDCl3, 400 MHz) 8.81 (br, 1H), 6.91-6.67 (m, 4H), 4.02 (q, J = 6.6 Hz, 1H), 3.85
(br, 1H), 1.46 (d, J = 6.6 Hz, 3H). The spectral data were identical to those of the authentic material
reported in ref. 8a. Chiral HPLC: 89:11 er, tR (R)-major enantiomer, 36.9 min; tR (S)-minor enantiomer,
39.0 min; (Chiralcel OJ-H column; 10% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethyl-3-methyl-3,4-dihydro-1,4-quinoxalin-2-one (24) A white solid was obtained in 88% yield.
m.p. 195-196 °C; 1H NMR (DMSO-d6, 400 MHz) 10.02 (br, 1H), 6.51 (s, 1H), 6.48 (s, 1H), 5.69 (br,
1H), 4.11 (br, 1H), 3.68 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 1.23 (d, J = 6.6 Hz, 3H). The spectral data
were identical to those of the authentic material reported in ref. 8a. Chiral HPLC: 87:13 er, tR (R)-major
enantiomer, 23.3 min; tR (S)-minor enantiomer, 21.6 min; (Chiralcel OJ-H column; 20% 2-propanol in
hexane; 0.5 mL/min).
6,7-Dimethyl-3-ethyl-3,4-dihydro-1,4-quinoxalin-2-one (25) A pale yellow oil was obtained in 81%
yield. 1H NMR (CDCl3, 400 MHz) 8.44 (br, 1H), 6.51 (s, 1H), 6.49 (s, 1H), 3.80 (m, 2H), 2.15 (s, 6H),
1.79 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). The spectral data were identical to those of the authentic material
reported in ref. 8a. Chiral HPLC: 92:8 er, tR (R)-major enantiomer, 24.1 min; tR (S)-minor enantiomer,
33.2 min (Chiralcel OJ-H column; 15% 2-propanol in hexane; 0.5 mL/min).
1
3-Butyl-3,4-dihydro-1,4-quinoxalin-2-one (26) A colorless oil was obtained in 71% yield. H NMR
(CDCl3, 400 MHz) 8.84 (br, 1H), 6.90-6.66 (m, 4H), 3.95 (br, 1H), 3.90 (m, 1H), 1.80 (m, 2H), 1.37 (m,
4H), 0.91 (t, J = 7.0 Hz, 3H). The spectral data were identical to those of the authentic material reported
in ref. 8a. Chiral HPLC: 90:10 er, tR (R)-major enantiomer, 21.5 min; tR (S)-minor enantiomer, 25.4
min; (Chiralcel OJ-H column; 10% 2-propanol in hexane; 0.5 mL/min).
3-Phenyl-3,4-dihydro-1,4-benzoxazin-2-one (27) A yellow oil was obtained in 71% yield. 1H NMR
(CDCl3, 400 MHz) 7.40-6.80 (m, 9H), 5.07 (s, 1H), 4.24 (s, 1H); The spectral data were identical to those
of the authentic material reported in ref. 7a. Chiral HPLC: 91:9 er, tR (R)-major enantiomer, 16.2 min; tR
(S)-minor enantiomer, 20.0 min; (Chiralcel OD column; 20% 2-propanol in hexane; 0.5 mL/min).
6-Methyl-3-phenyl-3,4-dihydro-1,4-benzoxazin-2-one (28) A yellow oil was obtained in 79% yield.
1H NMR (CDCl3, 400 MHz) 7.38 (m, 5H), 6.92 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H),
13
5.04 (s, 1H), 4.17 (s, 1H), 2.29 (s, 3H); C NMR (CDCl3, 100 MHz) 165.7, 139.3, 137.0, 135.5, 132.4,
129.4, 129.3, 127.7, 121.4, 117.1, 115.7, 59.7, 21.4; Chiral HPLC: 90:10 er, tR (R)-major enantiomer,
18.8 min; tR (S)-minor enantiomer, 25.9 min; (Chiralcel OD column; 20% 2-propanol in hexane; 0.5
mL/min).
7-Methyl-3-phenyl-3,4-dihydro-1,4-benzoxazin-2-one (29) A pale yellow oil was obtained in 68%
yield. 1H NMR (CDCl3, 400 MHz) 7.38 (m, 5H), 6.85 (s, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 7.9

HETEROCYCLES, Vol. 78, No. 9, 2009
2243
Hz, 1H), 5.01 (s, 1H), 4.14 (s, 1H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz) 165.7, 141.3, 136.9, 130.8,
130.2, 129.4, 129.3, 127.9, 126.1, 117.8, 115.2, 59.9, 21.0; Chiral HPLC: 90:10 er, tR (R)-major
enantiomer, 21.3 min; tR (S)-minor enantiomer, 35.1 min; (Chiralcel OD column; 20% 2-propanol in
hexane; 0.5 mL/min).
6-tert-Butyl-3-phenyl-3,4-dihydro-1,4-benzoxazin-2-one (30) A brown oil was obtained in 80% yield.
1H NMR (CDCl3, 400 MHz) 7.38 (m, 5H), 6.92 (d, J = 8.5 Hz, 1H), 6.88 (m, 1H), 6.82 (s, 1H), 5.01 (s,
13
1H), 4.19 (s, 1H), 1.29 (s, 9H); C NMR (CDCl3, 100 MHz) 165.9, 149.0, 139.2, 136.9, 132.2, 129.4,
129.3, 128.1, 117.9, 116.8, 112.4, 60.0, 34.9, 31.8; Chiral HPLC: 91:9 er, tR (R)-major enantiomer, 14.7
min; tR (S)-minor enantiomer, 23.3 min; (Chiralcel OD column; 20% 2-propanol in hexane; 0.5 mL/min).
2-Phenyl-3,4-dihydro-1,4-benzothiazin-3-one (31) A yellow oil was obtained in 85% yield. 1H NMR
(CDCl3, 400 MHz) 8.74 (s, 1H), 7.38-6.88 (m, 9H), 4.69 (s, 1H). The spectral data were identical to those
of the authentic material reported in ref. 8b. Chiral HPLC: 69:31 er, tR major enantiomer, 44.4 min; tR
minor enantiomer, 60.8 min; (Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min).
ACKNOWLEDGEMENTS
This work was supported by grants from the Korea Research Foundation (KRF-2006-005-J03402) and
Seoul R&BD Program (WR090671).
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