Synthesis of 2,3-dichloroquinoxalines via vilsmeier reagent chlorination

Article abstract of DOI:10.1002/jhet.56

A convenient and high-yielding synthesis of 2,3-dichloroquinoxalines from the corresponding 2,3- dihydroxyquinoxalines has been developed. Treatment of a slurry of the 2,3-dihydroxyquinoxaline 1a-j with N,N-dimethylformamide in the presence of excess thionylchloride in 1,2-dichloroethane results in the rapid and high-yielding formation of the 2,3-dichloroquinoxaline derivatives 2a-j. Simplified workup and purification procedures for these compounds are also described.

Full text of DOI:10.1002/jhet.56

March 2009
Synthesis of 2,3-Dichloroquinoxalines via Vilsmeier
Reagent Chlorination
317
Duane R. Romer*
The Dow Chemical Company, Research and Engineering Sciences, Chemistry and Catalysis
Laboratory, Midland, Michigan 48674
*
E-mail: drromer2@dow.com
Received July 28, 2008
DOI 10.1002/jhet.56
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
A convenient and high-yielding synthesis of 2,3-dichloroquinoxalines from the corresponding 2,3-
dihydroxyquinoxalines has been developed. Treatment of a slurry of the 2,3-dihydroxyquinoxaline 1a–j
with N,N-dimethylformamide in the presence of excess thionylchloride in 1,2-dichloroethane results in
the rapid and high-yielding formation of the 2,3-dichloroquinoxaline derivatives 2a–j. Simplified
workup and purification procedures for these compounds are also described.
J. Heterocyclic Chem., 46, 317 (2009).
INTRODUCTION
actual chlorinating reagent is undoubtedly the Vilsmeier
reagent, generated in situ from the reaction of N,N-DMF
with thionyl chloride.
The chemistry of 2,3-dichloroquinoxalines has
received considerable attention in the past [1]. This class
of compounds has previously been shown to exhibit a
broad range of biological activity. For example, various
derivatives of 2,3-dichloroquinoxalines have been shown
to exhibit fungicidal and bactericidal activity [2]. They
have also shown utility in industrial applications such as
use as reactive dyes for fibers [3].
We have recently synthesized a series of 2,3-dichloro-
quinoxalines using a similar approach of generating the
Vilsmeier reagent in situ by the addition of catalytic
amounts of N,N-DMF to a slurry of 2,3-dihydroxyqui-
noxalines and thionyl chloride in 1,2-dichloroethane.
Inspired by these earlier reports, we herein report the
general utility of this reaction protocol and give experi-
mental details for simplified workup and purification
procedures for the synthesis of 2,3-dichloroquinoxalines
via chlorination of 2,3-dihydroxyquinoxalines with the
Vilsmeier reagent.
These dichloroquinoxaline compounds have tradition-
ally been prepared by chlorination of the corresponding
quinoxaline 2,3-diones (2,3-dihydroxyquinoxalines) with
phosphorous-based chlorinating reagents. Phosphorus
oxychloride (POCl ) is the most common agent used,
3
usually in the presence of an initiator such as N,N-dime-
thylaniline [4], or phosphorus pentachloride (PCl5).
However, the hazards of handling phosphorus oxychlor-
ide or phosphorus pentachloride are not to be taken
lightly. Moreover, phosphorus containing waste streams
is becoming increasingly difficult to dispose of in indus-
trial settings.
RESULTS AND DISCUSSION
2,3-Dichloroquinoxalines, 2 (Scheme 1), can be read-
ily prepared by chlorination of 2,3-dihydroxyquinoxa-
lines, 1, which in turn can be prepared by the
Recently, Zimcik and coworkers [5] reported the syn-
thesis of 2,3-dichloro-6,7-dicyanoquinoxaline from 2,3-
dihy-droxy-6,7-dicyanoquinoxaline, using thionyl chlo-
ride in the presence of small amounts of N,N-dimethyl-
formamide (DMF). Similarly, Tanaka and coworkers [6]
has reported the synthesis of 2,3-dichloro-6-trifluorome-
thylquinoxaline from 2,3-dihydroxy-6-trifluoromethyl-
quinoxaline with an excess of thionyl chloride (SOCl2)
in N,N-DMF as the solvent. In both of these cases, the
Scheme 1
V
C
2009 HeteroCorporation

3
18
D. R. Romer
Vol 46
Table 1
EXPERIMENTAL
Physical and analytical data of compounds 2a–j.
General experimental procedures. All solvents and
reagents were reagent grade and were used without further pu-
ꢀ
Compound
X
Y
Time (h)
Mp ( C)
Yield (%)
1
13
rification. H and C NMR spectra were obtained on a Varian
XM-300 NMR. All yields reported are those of isolated mate-
1
rial judged homogeneous by H NMR.
a
2
2
2
a
b
c
H
NO
Cl
H
H
2
4
100–102
152–153
95
99
99
93
98
77
81
95
93
92
a
2
a
H
H
4
2
144
General procedure for the synthesis of 2,3-dihydroxyqui-
noxalines 1a–j.
a
b
b
2d
CH
F
3
113–114
143–145
239–240
2,3-Dihydroxyquinoxline (1a). A solution
2
2
e
f
H
2
of oxalic acid (27.1 g, 0.215 mol) in 4N aqueous HCl (50 mL)
was added to a solution of 1,2-diaminobenzene (20.9 g, 0.193
mol) in 4N HCl (150 mL), and the resulting solution was
heated to reflux for 2 h. The reaction mixture was cooled to
ambient temperature, and the resulting precipitate was isolated
by filtration, washed with water, and dried, giving 30.5 g
CN
H
H
2
2
b
2
2
g
h
CF
CH
Cl
3
91–93
b
b
b
3
NO
NO
NO
2
2
2
2
0.5
0.5
134–136
135–137
210–212
2
2
i
j
NO
2
a
Recrystallized from CH
Filtered through SiO
3
CN/H
with CH
2
O.
Cl
ꢀ
1
(
(
(
98%) of 1a as an off white powder, mp >300 C: H NMR
b
.
13
2
2
2
DMSO-d ): d 11.90 (s, 2H), 7.13–7.04 (m, 4H); C NMR
6
DMSO-d
General procedure for the nitration of 2,3-dihydroxyqui-
noxalines 1h–j. 2,3-Dihydroxy-6-nitro-7-methylquinoxaline
6
): d 155.12, 125.52, 122.91, 115.06.
condensation of commercially available 1,2-phenylene-
diamines with oxalic acid in aqueous hydrochloric acid
(
(
1h). To
a
10.0 g, 0.0574 mol) in H SO (124 mL) at 0 C was added, in
solution of 2,3-dihydroxy-6-methylquinoxaline
ꢀ
(
HCl) [1]. Mono and dinitroquinoxalines 1b and 1h–1j
2
4
were prepared by nitration of the parent dihydroxyqui-
noxaline with one or two equivalents of potassium ni-
trate (KNO ) in sulfuric acid (H SO ) [7].
3
several portions, KNO (6.39 g, 0.0632 mol), and the resulting
solution was allowed to warm to ambient temperature and
stirred overnight. The reaction mixture was carefully poured
into 500 mL of ice/water, stirred 30 min, filtered, washed with
water and dried, giving 12.2 g (96%) of 1h as a pale yellow
3
2
4
We have found that 2,3-dichloroquinoxalines 2a–2j
are readily formed by the drop wise addition of catalytic
amounts of N,N-DMF (10 mol %) to slurry of the corre-
sponding 2,3-dihydroxyquinoxalines 1a–1j in 1,2-
dichloroethene and an excess (2.5–3.0 molar equiva-
lents) of thionyl chloride (Table 1).
ꢀ
1
solid, mp >300 C. H NMR (DMSO-d
1
6
): d 12.20 (s, 1H),
13
2.02 (s, 1H), 7.72 (s, 1H), 6.95 (s, 1H), 2.47 (s, 3H);
C
6
NMR (DMSO-d ): d 155.10, 154.47, 142.21, 130.10, 128.69,
1
24.05, 117.70, 111.60, 20.31.
General procedure for the chlorination of dihydroxyqui-
noxalines. 2,3-Dichloroquinoxaline (2a). N,N-Dimethylfor-
In all cases, the desired 2,3-dichloroquinoxaline was
rapidly formed by bringing the reaction mixture to
reflux. After complete conversion, the reaction mixture
was cooled to ambient temperature, followed by concen-
tration to dryness. Purification of the desired product
can then be readily accomplished by recrystallization of
the crude product from acetonitrile/water, giving the
desired 2,3-dichloroquinoxaline in high yield and purity.
Alternatively, and particularly convenient for larger
scale reactions, the residual material obtained after evap-
oration of the excess thionyl chloride and 1,2-dichloro-
ethane can be purified by slurrying the initially isolated
residue in water, followed by filtration and re-dissolving
the crude product into methylene chloride (CH Cl ) and
mamide (0.045 g, 0.00062 mol, 0.1 eq) was added dropwise to
a slurry of 2,3-dihydroxyquinoxaline (2.0 g, 0.012 mol) and
thionyl chloride (3.7 g, 0.031 mol) in 1,2-dichloroethane (20
mL). The resulting reaction mixture was heated to reflux for 2
h then concentrated to dryness. The residue was dissolved in
1
,2-dichloroethane (25 mL) and concentrated to dryness. The
resulting solid was recrystallized from CH CN/H O, giving 2.3
3
2
ꢀ
1
g (95%) of 2a as fine, off white needles, mp 100–102 C; H
NMR (CDCl
13
C
3
): d 8.10–8.06 (m, 2H), 7.98–7.93 (m, 2H);
NMR (CDCl ) 144.50, 139.92, 131.67, 127.81. Anal. Calcd.
3
for C H Cl N : C, 48.28; H, 2.03; N, 14.07. Found: C, 47.87;
2 2
8
4
H, 2.1; N, 14.00.
,3-Dichloro-6-nitroquinoxaline (2b). This compound was
prepared from N,N-DMF (0.11 g, 0.0014 mol), 2,3-dihydroxy-
-nitroquinoxaline (3.0 g, 0.0145 mol) and thionylchloride
4.31 g, 0.035 mol) in 1,2-dichloroethane (30 mL) as previ-
ously described, to give 3.52 g (99%) of 2b after recrystalliza-
2
2
2
6
(
filtering through a plug of silica gel.
There are several advantages to this method over
those previously reported. First is that SOCl /DMF is
ꢀ
1
2
tion (CH CN/H O) as a tan powder, mp 152–153 C; H NMR
3 2
considerably less expensive and less hazardous than
using POCl /N,N-dimethylaniline. Also, in general, the
reaction requires much shorter reaction times. For exam-
ple, in our experiments, chlorination of 1c with POCl3/
N,N-dimethylaniline required refluxing for 6 days for
complete conversion and 2c was obtained in 76% yield.
(DMSO-d ) (d, J ¼ 2.4 Hz, 1H), 8.57 (dd, J ¼ 9.2, 2,5 Hz,
6
6
13
1H), 8.28 (d, J ¼ 9.2 Hz, 1H); C NMR (DMSO-d
48.07, 147.28, 142.3, 138.83, 129.68, 124.74, 123.67. Anal.
Calcd. for C Cl : C, 39.37; H, 1.24; N, 17.22. Found:
C, 39.11; H, 1.03; N, 16.99.
,3,6-Trichloroquinoxaline (2c). This compound was pre-
) 148.18,
3
1
8
H
3
2 3 2
N O
2
pared from N,N-DMF (0.074 g, 0.001 mol), 6-chloro-2,3-dihy-
droxyquinoxaline (2.0 g, 0.0102 mol), and thionylchloride
(3.02 g, 0.025 mol) in 1,2-dichloroethane (10 mL) after 4 h
reflux to give 3.52 g (99%) of 2c after recrystallization from
In contrast, chlorination of 1c with SOCl /DMF in 1,2-
2
dichloroethane led to complete reaction within 4 h, giv-
ing a near quantitative yield of 2c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
Synthesis of 2,3-Dichloroquinoxalines via Vilsmeier Reagent Chlorination
319
ꢀ
1
O as yellow needles, mp 144 C; H NMR (DMSO-
CH
d
(
1
1
1
3
CN/H
2
mL) after 2 h reflux to give 5.62 g (81%) of 2g after filtration
6
) 8.23 (d, J ¼ 2.2 Hz, 1H), 8.12 (d, J ¼ 8.9 Hz, 1H), 7.98
2 2
through a short column of silica gel, eluting with CH Cl , mp
1
3
ꢀ
1
91–93 C; H NMR (DMSO-d
dd, J ¼ 9.0, 2.3 Hz, 1H); C NMR (DMSO-d
6
) 145.87,
45.05, 140.28, 138.67, 135.91, 132.10, 129.57, 126.72,
26.72. Anal. Calcd. for C H Cl N : C, 41.15; H, 1.30; N,
6
): d 8.50 (bs, 1H), 8.30 (d, J ¼
8.8 Hz, 1H), 8.20 (dd, J ¼ 8.8, 2.0 Hz, 1H). Anal. Calcd. for
C H Cl F N : C, 40.48; H, 1.13; N, 10.49. Found: C, 40.20;
9
8
3
3
2
3
2 3 2
2.00. Found: C, 40.83; H, 1.22; N, 12.20.
,3-Dichloro-6-methylquinoxaline (2d). This compound was
prepared from N,N-DMF (0.083 g, 0.0011 mol), 2,3-dihy-
droxy-6-methylquinoxaline (2.0 g, 0.012 mol) and thionyl-
chloride (3.38 g, 0.028 mol) in 1,2-dichloroethane (20 mL) af-
H, 1.15; N, 10.50.
2
2,3-Dichloro-7-methyl-6-nitroquinoxaline (2h). This com-
pound was prepared from N,N-DMF (0.072 g, 0.00090 mol),
2,3-dihydroxy-6-nitro-7-methylquinoxaline (2.0 g, 0.00090
mol) and thionyl chloride (2.69 g, 0.023 mol) in 1,2-dichloro-
ethane (5 mL) after 2 h at reflux to give 5.62 g (81%) of 2h
after filtration through a short column of silica gel, eluting
3 2
ter 2 h at reflux. Recrystallized from CH CN/H O to give 2.25
g (93%) of 2d as fine, light tan colored needles, mp 113–
ꢀ
1
ꢀ
with CH Cl , mp 134–136 C; H NMR (DMSO-d ): d 8.66 (s,
2 2 6
13
1
1
(
(
14 C; H NMR (DMSO-d ): d 7.94 (d, J ¼ 8.3 Hz, 1H), 7.82
6
13
s, 1H), 7.77 (d, J ¼ 8.4 Hz, 1H), 3.38 (s, 3H); C NMR
1H), 8.18 (s, 1H), 2.67 (s, 3H). C NMR (DMSO-d ) d
6
DMSO-d ) d 144.27, 143.39, 142.33, 139.97, 138.34, 133.72,
150.56, 147.81, 146.48, 140.94, 137.57, 134.57, 130.88,
6
1
27.30, 126.54, 21.30. Anal. Calcd. for C
H, 2.84; N, 13.15. Found: C, 50.37; H, 2.88; N, 13.22.
,3-Dichloro-6-fluoroquinoxaline (2e). This compound was
9
H
6
Cl
2
N
2
: C, 50.73;
9 5 2 3 2
123.65, 19.00. Anal. Calcd. for C H Cl N O : C, 41.89; H,
1.95; N, 16.28. Found: C, 41.93; H, 1.22; N, 16.50.
2
2,3,6-Trichloro-7-nitroquinoxaline (2i). This compound was
prepared from N,N-DMF (0.364 g, 0.0050 mol), 2,3-dihy-
droxy-6-chloro-7-nitroquinoxaline (12.0 g, 0.0498 mol) and
thionyl chloride (14.8 g, 0.124 mol) in 1,2-dichloroethane (50
mL) after 30 min at reflux to give 12.8 g (93%) of 2i as a
golden yellow powder after filtration through short column of
prepared from N,N-DMF (0.41 g, 0.0056 mol), 6-fluoro-3-dihy-
droxyquinoxaline (10.0 g, 0.0555 mol) and thionyl chloride
(
16.5 g, 0.139 mol) in 1,2-dichloroethane (50 mL), and the
resulting reaction mixture was heated at reflux for 2 h. The
resulting solution was cooled to room temperature and concen-
trated to dryness. The resulting solid was slurried in water
ꢀ
1
silica gel, eluting with CH Cl , mp 135–137 C; H NMR
2
2
13
(
150 mL) for 30 min, then filtered and dried. The residue was
taken up in a minimum of CH Cl and filtered through a short
column of silica gel, eluting with CH Cl . Concentration then
gave 11.75 g (98%) of 2e as a pale yellow solid, mp 143–
(DMSO-d
) d 148.72, 148.58, 147.62, 140.88, 138.01, 130.35, 126.02,
124.72. Anal. Calcd. for C Cl : C, 34.50; H, 0.72; N,
6
): d 8.89 (s, 1H), 8.58 (s, 1H). C NMR (DMSO-
2
2
d
6
2
2
8
H
2
3 3 2
N O
15.09. Found: C, 34.52; H, 0.81; N, 15.11.
ꢀ
1
1
1
1
1
45 C; H NMR (DMSO-d ): d 8.18 (dd, J ¼ 9.2, 5.6 Hz,
6
H), 7.95 (dd, J ¼ 9.2, 2.7 Hz, 1H), 7.88 (dd, J ¼ 8.4, 2.7 Hz,
8 3 2 2
H). Anal. Calcd. for C H Cl FN : C, 44.27; H, 1.39; N,
REFERENCES AND NOTES
2.91. Found: C, 44.03; H, 1.33; N, 12.88.
,3-Dichloro-6-cyanoquinoxaline (2f). N,N-dimethylforma-
mide (0.039 g, 0.0005 mol) was added dropwise to a slurry of
-cyano-2,3-dihydroxyquinoxaline (1.0 g, 0.0054 mol) and thi-
2
[1] Cheeseman, G. W. H.; Cookson, R. F. In the Chemistry of
Heterocyclic Compounds; Weissberger, A.; Taylor, E. C., Eds.; Wiley;
New York, 1979; Vol. 35, Chapter 10.
6
[
2] (a) Hattori, J.; Sugiyama, H.; Yoshioka, K.; Koike, S. U.S.
onyl chloride (1.6 g, 0.013 mol) in 1,2-dichloroethane (5 mL),
and the resulting solution was heated at reflux for 2 h. The so-
lution was cooled and concentrated. The residue was slurried
in water (50 mL) for 30 min, then filtered and dried. The resi-
Patent 3,186,905; Chem Abstr 1965, 63, 6264; (b) Huffman, C. W.;
Krajewski, J. J.; Kotz, P. J.; Traxler, J. T.; Ristich, S. S. J Agric Food
Chem 1971, 1, 298; (c) Metzner, J.; Lippmann, E.; Weber, F. G.;
Westphal, G. Pharmazie 1981, 36, 368.
due was taken up in a minimum of CH
through a short column of silica gel, eluting with CH
Concentration gave 0.92 g (77%) of 2f as a light gray powder,
2
Cl
2
and filtered
[
3] (a) Hine, R. J.; McPhee, J. R. J Soc Dyers Colourists 1965,
2
Cl .
2
8
1
1, 268; (b) Cole, J. E., Jr.; Gumprecht, W. H. U.S. Patent 3,184,282,
965; Chem Abstr 1965; 63, 46301.
ꢀ
1
mp 239–240 C; H NMR (CDCl ): d 8.40 (d, J ¼ 1.8 Hz,
3
[
4] (a) Sastry, C. V. R.; Jogibhukta, M.; Krishnan, V. S. H.;
1
H), 8.15 (d, J ¼ 8.7 Hz, 1H); 7.97 (dd, J ¼ 8.7, 1.8 Hz, 1H);
3
Rao, P. S.; Vemana, K.; Shridhar, D. R.; Tripathi, R. M.; Verma, R.
K.; Kaushal, R. Ind J Chem 1988, 27B, 1110; (b) Zhang, L.; Qiu, B.;
Xiong, B.; Li, X.; Li, J.; Wang, X.; Li, J.; Shen, J. Bioorganic Med
Chem Lett 2007, 17, 2118.
13
C NMR (CDCl
32.49, 129.35, 117.47, 113.51. Anal. Calcd. for C
) d 147.58, 146.71, 141.42, 139.03, 133.74,
Cl
1
9
H
3
2 3
N :
C, 48.25; H, 1.35; N, 18.76. Found: C, 48.22; H, 1.15; N,
8.57.
,3-Dichloro-6-trifluoromethylquinoxaline (2g). This com-
1
[
5] Musil, Z.; Zimcik, P.; Miletin, M.; Kopecky, K.; Lenco,
2
J. Eur J Org Chem 2007, 27, 4535.
pound was prepared from N,N-DMF (0.19 g, 0.0026 mol), 2,3-
dihydroxy-6-trifluoromethylquinoxaline (6.0 g, 0.026 mol) and
thionyl chloride (7.8 g, 0.065 mol) in 1,2-dichloroethane (50
[6] Iwata, S.; Sakajyo, M.; Tanaka, K. J Heterocycl Chem
1994, 31, 1433.
[7] Cheeseman, G. W. H. J Chem Soc 1962, 1170.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet