Diacetone-D-glucose-mediated asymmetric syntheses of dihydroquinoxalinones

Article abstract of DOI:10.3987/com-06-10910

Asymmetric syntheses of dihydroquinoxalinones by diacetone-D-glucose mediated nucleophilic substitution of α-bromo esters have been investigated. Stereoselective reactions with various 1,2-phenylenediamine nucleophiles in the presence of TBAI and DIEA and

Full text of DOI:10.3987/com-06-10910

HETEROCYCLES, Vol. 71, No. 1, 2007
5
HETEROCYCLES, Vol. 71, No. 1, 2007, pp. 5 - 11. © The Japan Institute of Heterocyclic Chemistry
Received, 11th October, 2006, Accepted, 17th November, 2006, Published online, 24th November, 2006. COM-06-10910
DIACETONE-D-GLUCOSE-MEDIATED ASYMMETRIC SYNTHESES
OF DIHYDROQUINOXALINONES
Yongtae Kim, Min Hee Lee, Eui Ta Choi, Eun Sun No, and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea
e-mail: parkyong@konkuk.ac.kr
Abstract
–
Asymmetric
syntheses of dihydroquinoxalinones by
diacetone-D-glucose mediated nucleophilic substitution of α-bromo esters have
been investigated. Stereoselective reactions with various 1,2-phenylenediamine
nucleophiles in the presence of TBAI and DIEA and following spontaneous
removal of the chiral auxiliary can provide dihydroquinoxalinones (3-9) up to
92% yield and 97:3 er. In addition, we have described the regio- and
stereoselective reactions of non-symmetric 1,2-phenylenediamine nucleophiles to
provide 10-14 up to 90:10 regioisomeric ratio and 98:2 er.
Dihydroquinoxalinone core is of interest as an important pharmacophore in many biologically active
compounds.1a-d
Accordingly, there is growing interest in the preparation of enantioenriched
dihydroquinoxalinones and several methods have been developed. Most strategies of previous reports
are based on nucleophilic aromatic substitution of o-fluoronitrobenzene derivatives with optically pure
amino acids in harsh reaction conditions.1c-h Consequently, these synthetic routes are limited by the
availability of optically pure amino acids and suffer from racemization.1c,1e Thus an alternative general
strategy has been developed in our laboratory, based on our recent findings of stereoselective nucleophilic
substitution mediated by diacetone-D-glucose.2 Herein we wish to report our recent results on
asymmetric syntheses of dihydroquinoxalinones by stereoselective nucleophilic substitution of
diacetone-D-glucofuranosyl α-bromo acetates with various 1,2-phenylenediamine nucleophiles.
We have previously reported that reactions of diacetone-D-glucofuranosyl α-halo acetates with various
amine nucleophiles in the presence of tetrabutylammonium iodide (TBAI) and diisopropylethylamine
(DIEA) provided the substitution products with high stereoselectivities.2 The chiral information of
D-glucose is transferred to the substitution at α-halo carbon center via dynamic kinetic resolution in the
nucleophilic substitution with amine nucleophiles. For example, the α-bromo stereogenic center of
α-bromo-α-phenylacetate (1) undergoes rapid epimerization in the presence of DIEA and TBAI, and
(αR)-1 reacts with a nucleophile preferentially.3 We envisaged that the stereoselective nucleophilic

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HETEROCYCLES, Vol. 71, No. 1, 2007
substitution of 1 with 1,2-phenylenediamine and subsequent intramolecular amide formation could lead to
highly enantioenriched 3-substituted dihydroquinoxalinones. As shown in scheme 1, initial studies were
carried out with two diastereomeric mixture (1:1) of α-bromo-α-phenylacetate (1) and
1,2-phenylenediamine (1.5 equiv) in the presence of TBAI (1.0 equiv) and DIEA (1.0 equiv) in CH2Cl2 at
room temperature.4 To our delight (S)-3-phenyldihydroquinoxalinone (3) was obtained in 90% yield
with 96:4 er (enantiomeric ratio) in the one-pot reaction for 18 h.5 The observed er and yield of the
product (3) suggest that the α-bromo stereogenic center is configurationally labile with respect to the rate
of substitution and two diastereomers of 1 are dynamically resolved under the reaction condition. It is
noteworthy that mono-alkylated product (2) is not prone to react with another equivalent of electrophile
and no trace of bis-alkylation product was detected. The exclusive formation of mono-alkylated product
is attributed to the steric hindrance of the bulky ortho-substituent for the second substitution. Instead,
spontaneous intramolecular amide formation of the amino group took place to remove chiral auxiliary and
furnished 3-phenyl dihydroquinoxalinone (3).
O
O
O
O
O
O
Br
Ph
Br
Ph
O
O
TBAI,
DIEA
O
O
O
O
O
O
(αS)-1
(αR)-1
NH2
NH2
H
N
O
Ph
Ph
O
O
O
H
N
N
H
(S)-3
O
O
O
H2N
O
90% yield
96:4 er
2
Scheme 1. Dynamic kinetic resolution of α-bromo-α-phenylacetate (1).
With the identification of diacetone-D-glucose as an effective and convenient stereocontrolling element
for asymmetric syntheses of dihydroquinoxalinones, we set out to examine the scope of this methodology
with various 1,2-phenylenediamine nucleophiles and α-bromo acetates as shown in Table 1. Treatment

HETEROCYCLES, Vol. 71, No. 1, 2007
7
of 1 with 4,5-dimethyl-o-phenylenediamine, TBAI and DIEA for 18 h at room temperature gave
3-phenyldihydroquinoxalinone (4) in 92% yield with 95:5 er (entry 1). This methodology is also
efficient for the asymmetric preparation of dihydroquinoxalinone (5) with 4,5-dichloro-o-
phenylenediamine nucleophile (entry 2). In addition, reaction of α-bromo-α-(o-fluorophenyl)acetate
with 1,2-phenylenediamine under the same condition provided 3-(o-fluorophenyl)dihydroquinoxalinone
(6) in 63% yield with 97:3 er (entry 3).
Table 1. Asymmetric syntheses of dihydroquinoxalinones (4-9).
X
X
NH2
NH2
O
O
H
N
X
X
R
O
Br
R
O
TBAI, DIEA
N
H
O
O
O
O
4-9
Nucleophile
R
Entrya
1
Product
Yield (%)b Er (S:R)c
H
N
H3C
NH2
H3C
H3C
Ph
Ph
Ph
92
81
63
88
85
73
95:5
97:3
N
H
O
H3C
NH2
(4)
(5)
H
Cl
Cl
N
Ph
O
Cl
Cl
NH2
NH2
2
3
4
5
6
N
H
H
N
NH2
Ph-o-F
o-F-Ph
CH3
CH3
97:3
N
H
O
NH2
(6)
H
N
CH3
NH2
NH2
90:10
86:14
93:7
N
H
O
(7)
H
N
H3C
H3C
NH2
NH2
H3C
H3C
CH3
O
N
H
(8)
H
N
CH2CH2CH2CH3
O
NH2
NH2
n-Butyl
N
H
(9)
(a) All reactions were carried out in CH2Cl2. (b) Isolated yields. (c) The ers are determined by
CSP-HPLC (Chiralcel OJ-H column).
Encouraged by the observation of high enantioselectivities in the reactions of α-aryl-α-bromoacetates, we
examined the dynamic kinetic resolution of α-alkyl-α-bromoacetates for asymmetric syntheses of

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HETEROCYCLES, Vol. 71, No. 1, 2007
3-alkyldihydroquinoxalinones as shown (entries 4-6). The reaction of α-bromo-α-methylacetate with
1,2-phenylenediamine afforded 3-methyldihydroquinoxalinone (7) with slightly lower stereoselectivity
(90:10 er, entry 4). As with 4,5-dimethyl-o-phenylenediamine nucleophile, the reaction in CH2Cl2
successfully took place to afford dihydroquinoxalinone (8) in 85% yield with 86:14 er (entry 5). When
α-bromo-α-butyl acetate was treated with TBAI and DIEA for 48 h, 3-butyldihydroquinoxalinone (9)
was obtained in 73% yield with 93:7 er (entry 6). The higher reaction temperature (50 °C) increases the
rate of cyclization but has no effect on stereoselectivity. Considering the important role of solvent for
the appropriate DKR conditions of α-bromoacetates, we have examined various solvents in the
asymmetric syntheses of 8 and 9.3 In both cases, however, solvent appeared to have little influence on
the stereoselectivity. 3-Methyldihydroquinoxalinone (8) was obtained with 84:16 er in THF, 83:17 er in
CH3CN, 87:14 er in ether, 83:17 er in chloroform and 86:14 er in toluene.
Also,
3-butyldihydroquinoxalinone (9) was obtained with 93:7 er in chloroform and 92:8 er in toluene.
Reactions of non-symmetric 1,2-phenylenediamine nucleophiles can produce two regioisomeric
dihydroquinoxalinones. In an effort to understand how two different amino groups affect the
regiochemistry of the substitution, we initially examined 2,3-diaminotoluene as a nucleophile as shown in
Table 2 (entry 1). Treatment of α-bromo-α-methyl acetate with the nucleophile, TBAI and DIEA for 48
h gave 3-methyl-8-methyldihydroquinoxalinone (10a) as a major product with 90:10 er and
3-methyl-5-methyldihydroquinoxalinone (10b) as a minor product with 89:11 er (entry 1). The
regioselectivity of 90:10 suggests significantly different reactivities of two amino groups. The sterically
less hindered amino group of the nucleophile is more reactive than the amino group with two
ortho-substituents. The regiochemistry of 10a was assigned by comparison to the 1H-NMR of authentic
material individually prepared.6 Also, the reaction of α-bromo-α-phenylacetate with 2,3-
diaminotoluene gave 8-methyl-3-phenyldihydroquinoxalinone (11a) as a major product with 97:3 er and
5-methyl-3-phenyldihydroquinoxalinone (11b) as a minor product with 90:10 er in a regioisomeric ratio
of 90:10. The regiochemistry of 11 was assigned by analogy to the regiochemistry of 10. Furthermore,
we attempted the substitution reactions with 4-fluoro- and 4-chloro-1,2-phenylenediamine nucleophiles as
shown in Table 2 (entries 3-5). Treatment of α-bromo-α-ethylacetate with 4-fluoro-1,2-phenyl-
enediamine, TBAI and DIEA in CH3CN gave 3-ethyl-7-fluorodihydroquinoxalinone (12a) as a major
product with 83:17 er and 3-ethyl-6-fluorodihydroquinoxalinone (12b) as a minor product with 81:19 er
in a regioisomeric ratio of 87:13 (entry 3). The amino group para to the fluoro group reacted faster than
the amino group meta to the fluoro group. Two regioisomers of 12 were produced in 65% yield after 96
h stirring at room temperature and non-cyclized product is also isolated in 23% yield. The higher
reaction temperature (80 °C) increases the rate of cyclization but has no effect on stereoselectivity. The
1
regiochemistry of 12 was assigned by comparison to the H NMR of authentic material reported

HETEROCYCLES, Vol. 71, No. 1, 2007
9
Table 2. Regioselective asymmetric syntheses of dihydroquinoxalinones (10-14).
NH2
NH2
O
O
H
N
R
O
Br
R
O
X
O
TBAI, DIEA
N
H
O
X
O
O
10-14
Product
Yield (%)b
Er (S:R)d
Entrya
Nucleophile
R
major
minor
(major:minor)c major minor
CH3
H
N
H
N
NH2
CH3
O
CH3
O
63
1
Me
90:10 89:11
(90:10)
NH2
CH3
N
H
N
H
CH3
10b
10a
CH3
H
H
NH2
N
Ph
O
N
Ph
O
73
2
Ph
97:3 90:10
(90:10)
NH2
CH3
N
H
N
H
CH3
11b
11a
H
N
H
F
F
Et
O
N
Et
NH2
65
3
4
5
Et
Ph
Ph
83:17 81:19
(87:13)
N
H
F
F
N
H
O
F
NH2
12a
12b
H
N
H
N
Ph
O
Ph
O
NH2
NH2
75
94:6 96:4
(90:10)
N
H
N
H
F
13b
13a
H
N
H
N
Cl
Ph
O
Ph
O
NH2
NH2
82
98:2 96:4
(71:29)
N
H
Cl
N
H
Cl
14b
14a
(a) All reactions were carried out in CH2Cl2, except for the reaction in CH3CN of entry 3. (b) Isolated yields of
1
two regioisomers. (c) The regioisomeric ratios were determined by H-NMR and confirmed by HPLC. (d) The
ers were determined by CSP-HPLC (Chiralcel OJ-H for 10, 11, 13, 14 and Chiralcel OB-H for 12)).
previously.1d The reactions of α-bromo-α-phenylacetate with 4-fluoro-1,2-phenylenediamine and
4-chloro-1,2-phenylenediamine provided 13 and14 in 75% and 85% yields, respectively, with higher
enantioselectivities than those of 12. The regiochemistry of 13 and 14 was assigned by analogy to the
regiochemistry of 12. The regiochemical aspects of the results showed that regioselectivity depends
critically on the steric effect of ortho- and meta-substituents on 1,2- phenylenediamine nucleophile.

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HETEROCYCLES, Vol. 71, No. 1, 2007
We conclude that readily available diacetone-D-glucose is an effective and convenient chiral auxiliary for
asymmetric syntheses of dihydroquinoxalinones. Since various α-bromo acetates can be easily obtained
in racemic form and configurational lability of them is readily induced, the process is quite general and
does not rely on the availability of optically pure amino acids. To the best of our knowledge, there is no
previous report of the general strategy for regio- and enantioselective syntheses of dihydroquinoxalinones.
Spontaneous removal of chiral auxiliary and simple protocol with mild conditions suggest further
development of this DKR approach. Application of this methodology to the asymmetric syntheses of
various kinds of heterocyclic compounds is underway.
ACKNOWLEDGEMENTS
This work was supported by Konkuk University in 2006.
REFERENCES AND NOTES
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2005, 331, 159. (b) D. Gupta, N. N. Ghosh, and R. Chandra, Bioorg. Med. Chem. Lett., 2005, 15,
1019. (c) D.-S. Su, M. K. Markowitz, R. M. Dipardo, K. L. Murphy, C. M. Harrell, S. S. O’Malley,
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Freidinger, and M. G. Bock, J. Am. Chem. Soc., 2003, 125, 7516. (d) P. E. Mahaney, M. B. Webb, F.
Ye, J. P. Sabatucci, R. J. Steffan, C. C. Chadwick, D. C. Harnish, and E. J. Trybulski, Bioorg. Med.
Chem., 2006, 14, 3455. (e) C.-L. Tung and C.-M. Sun, Tetrahedron Lett., 2004, 45, 1159. (f) C.
Jamieson, M. S. Congreve, D. F. Emiabata-Smith, S. V. Ley, J. J. Scicinski, Org. Process. Res. Dev.,
2002, 6, 823. (g) R. J. Holland, I. R. Hardcastle, and M. Jarman, Tetrahedron Lett., 2002, 43, 6435.
(h) E. Laborde, B. T. Peterson, and L. Robinson, J. Comb. Chem., 2001, 3, 572.
2. (a) H. J. Kim, Y. Kim, E. T. Choi, M. H. Lee, E. S. No, and Y. S. Park, Tetrahedron, 2006, 62, 6303.
(b) H. J. Kim, E.-k. Shin, J.-y. Chang, Y. Kim, and Y. S. Park, Tetrahedron Lett., 2005, 46, 4115.
3. It has been proposed by several examples that the epimerization promoted by TBAI (or TBAB) via
nucleophilic displacement of the halide ion and/or base via keto-enol tautomerization. (a) N. R.
Treweeke, P. B. Hitchcock, D. A. Pardoe, and S. Caddick, Chem. Commun., 2005, 1868. (b) J.-y.
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HETEROCYCLES, Vol. 71, No. 1, 2007
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Org. Chem., 1999, 64, 7700.
4. General procedure for the preparation of dihydroquinoxalinones (3-14): To a solution of diacetone
glucofuranosyl α-bromoacetate (1.0 mmol) in CH2Cl2 (ca. 0.1 M) at rt were added DIEA (1.0 equiv),
TBAI (1.0 equiv) and 1,2-phenylenediamine (1.5 equiv). After the resulting reaction mixture was
stirred at rt for 18 h, the mixture was quenched with aq. 5%-HCl solution (10mL). The resulting
mixture was extracted with CH2Cl2 (10 mL × 2) and the combined extracts were washed with brine.
The solvent was removed under reduced pressure and the crude material was purified by column
chromatography to give a dihydroquinoxalinone.
5. In references 2a and 2b, we have established that (S)-products were provided in the substitution of
diacetone-D-glucofuranosyl α-haloacetates with various aliphatic and aromatic amine nucleophiles.
We proposed that (αR)-1 is the faster reacting diastereomer due to the formation of an
intermolecular hydrogen bond that facilitates delivery of the nucleophile.2a The absolute
configurations of dihydroquinoxalinones (3-14) are provisionally assigned by analogy. The
specific rotation of 12a {[α]2D0 = +10.6° (c = 0.19, DMSO)} compared with the data in literature
allowed us to confirm the (S)-configuration.1d
1
6. The regiochemistry of 10 was assigned by comparison of H-NMR with authentic material
1
individually prepared from the procedure shown below. H NMR (CDCl3, 400 MHz) 10a, 8.11 (br,
1H), 6.80-6.56 (m, 3H), 3.98 (q, J = 6.6 Hz, 1H), 3,83 (br, 1H), 2.25 (s, 3H), 1.46 (d, J = 7.2 Hz,
3H); 10b, 8.69 (br, 1H), 6.80-6.56 (m, 3H), 4.04 (q, J = 6.6 Hz, 1H), 3,71 (br, 1H), 2.17 (s, 3H), 1.49
(d, J = 6.8 Hz, 3H).
Br
CH3
H
N
NO2
NH2
CH3
O
Cl
O
1.
N
H
2. SnCl2-2H2O
3. TBAI, DIEA
CH3
CH3
10a