Biomimetic synthesis of quinoxalines in water

Article abstract of DOI:10.1016/j.tetlet.2009.08.033

Various quinoxalines have been synthesized for the first time in the presence of β-cyclodextrin in water. Biomimetic catalysis of β-cyclodextrin is explained by using ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2009.08.033

Tetrahedron Letters 50 (2009) 6025–6028
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Tetrahedron Letters
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Biomimetic synthesis of quinoxalines in water
*
B. Madhav, S. Narayana Murthy, V. Prakash Reddy, K. Rama Rao, Y. V. D. Nageswar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various quinoxalines have been synthesized for the first time in the presence of b-cyclodextrin in water.
Biomimetic catalysis of b-cyclodextrin is explained by using 1H NMR spectroscopy.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 June 2009
Revised 13 August 2009
Accepted 15 August 2009
Available online 20 August 2009
Quinoxalines and their derivatives are very important class of
nitrogen containing heterocycles, having various biological activi-
ties such as anti-viral, anti-bacterial, anti-biotic, anti-inflammatory
and kinase inhibition.1 They are potential building blocks for the
synthesis of organic semiconductors,2 electroluminescent mate-
rial,3 cavitands,4 dehydroannulenes,5 and dyes.6 Quinoxalines
serve as useful rigid subunits in macrocyclic receptors7 for molec-
ular recognition and chemically controllable switches.8
b-cyclodextrin in the reaction of benzene-1,2-diamines towards a
variety of phenacyl bromides, to give exclusively substituted quin-
oxalines (Scheme 1).
In general, a model reaction was carried out by the addition of
benzene-1,2-diamine with b-CD complex of phenacyl bromide,
formed in water at 50 °C, and by stirring the reaction mixture at
70 °C to give the corresponding quinoxaline.17 Similarly a variety
of phenacyl bromides were reacted with benzene-1,2-diamine in
the presence of b-CD at 70 °C resulting in the corresponding quin-
oxalines in quantitative yields (87–92%). This method is equally
effective with phenacyl bromides bearing electron-withdrawing
and electron-donating substituents in the aromatic ring (Table 2).
All these reactions have proceeded efficiently and produced high
yields without the formation of any side products. This is because
of the activation of phenacyl bromide by the complexation with b-
cyclodextrin. All the products were isolated and characterized by
1H NMR, 13C NMR, mass and by comparison with the known com-
pounds. b-CD can also be recovered and reused.
Consequently many methods have been developed for the syn-
thesis of quinoxaline derivatives, which include condensation of
1,2-diamines and 1,2-dicarbonyl compounds,9 oxidative cycliza-
tion of a
-hydroxy ketones with 1,2-diamines,10 oxidative coupling
of epoxides with ene-1,2-diamines,11 1,4-addition of 1,2-diamines
to diazenylbutenes,12 cyclization-oxidation of phenacyl bromides
13
with 1,2-diamines by HClO4ÁSiO2
and by using solid phase
synthesis.14
In comparison with broad spectrum utility of quinoxalines in
many fields, their preparation methods are limited in number.
However, these established procedures suffered from many draw-
backs such as drastic reaction conditions, expensive reagents and
complicated work-up. Therefore, there is a clear need for the devel-
opment of generally applicable and environmentally benign mild
methodology for the synthesis of quinoxaline derivatives. In con-
tinuation of our interest in the use of cyclodextrins as mild and
efficient biomimetic catalysts in promoting various transforma-
tions,15 we have been attempting the synthesis of biologically
important class of heterocycles. We report herein the preparation
of quinoxalines (3) from phenacyl bromides (1) and benzene-1,2-
diamine (2) in water, using b-cyclodextrin (b-CD) as a catalyst.
Cyclodextrins (CDs) are cyclic oligosaccharides possessing
hydrophobic cavities, which bind substrates selectively and cata-
lyze chemical reactions with high selectivity. They catalyze reac-
tions by supramolecular catalysis involving reversible formation
of host-guest complexes by non-covalent bonding as seen in en-
zymes. We describe, herein, the remarkable catalytic activity of
The reaction also takes place without b-CD but longer reaction
times (48 h) are required and the isolated yields of the products
O
N
H
3
Br
+
NH2
NH2
β-CD, H2O
N 2
70 ºC, 2-3h
R
R
1
2
3
Scheme 1. Biomimetic synthesis of quinoxalines in water.
Table 1
Catalyst optimization study
Entry
Catalyst (%)
Time (h)
Yield (%)
1
2
3
4
5
6
0
10
20
50
70
48
40
30
12
6
25
35
40
62
74
90
* Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
100
2
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.033

6026
B. Madhav et al. / Tetrahedron Letters 50 (2009) 6025–6028
Table 2
Synthesis of quinoxalines in the presence of b-CD in watera
Entry
Substrate
Product
Time (h)
2.0
Yieldb (%)
N
N
O
Br
1
90
N
N
O
Br
2
3
2.4
2.0
2.2
2.3
2.4
2.3
2.2
2.1
2.2
2.4
2.0
2.4
87
92
91
89
89
90
90
92
87
89
90
90
N
O
Br
N
MeO
OMe
N
N
O
Br
4
N
N
O
Br
5
N
O
Br
6
N
F
F
N
O
O
Br
7
N
Cl
Cl
N
N
Br
8
Br
Br
N
N
O
Br
9
N
N
N
O
Br
Br
N
10
11
12
13
N
N
O
N
Br
N
MeO
OMe
Br
N
OH O
OH
Br
N
N
O
Br
N
NC
CN

B. Madhav et al. / Tetrahedron Letters 50 (2009) 6025–6028
6027
Table 2 (continued)
Entry
Substrate
Product
Time (h)
2.5
Yieldb (%)
N
N
O
14
83
Br
O N
2
NO
2
N
N
O
O
S
15
16
2.3
2.3
91
87
S
Br
N
N
O
O
Br
a
Reaction conditions: phenacyl bromide (1 equiv), benzene-1,2-diamine (1 equiv), b-CD (1 equiv) and water (15 mL).
Yields of the isolated products.
b
obtained are very low (ꢀ25%). The catalytic amount of b-CD
(0.1 equiv) had no impact on the reaction. Increasing the amount
of b-CD at 70 °C has improved the yield of the product gradually.
These experiments (Table 1) indicate the substantial role of cyclo-
dextrin. To prove the role of cyclodextrin, NMR studies were car-
ried out on b-CD, b-CD complex of phenacylbromide (1) and
freeze-dried reaction mixture.
NH2
H2N
Br
H
O
H
O
O
Here, b-CD appears to be involved in activating the phenacyl
bromide by forming host-guest complex and promotes the reac-
tion. The complexation of phenacyl bromide with b-CD was con-
firmed by isolation of b-CD–phenacyl bromide complex and
study of 1H NMR. NMR spectroscopy is one of the most important
techniques used for characterization of inclusion complexes. The
formation of inclusion complex results in the shift changes in the
Figure 2. Plausible mechanistic pathway.
resonances of the protons of host cyclodextrin and the guest.16
A
benzene-1,2-diamine and phenacyl bromides in the presence of
b-cyclodextrin in water. This straightforward methodology may
find wide spread applications in organic and medicinal chemistry.
comparison of the 1H NMR spectra (D2O) of b-CD, b-CD:phenacyl
bromide (1) complex and freeze-dried reaction mixture of b-
CD:phenacyl bromide (1) complex with the benzene-1,2-diamine
at 1 h was studied (Fig. 1). It is observed from Figure 1 that there
is an upfield shift of H3 (0.041 ppm) and H5 (0.055 ppm) protons
of cyclodextrin in the b-CD:phenacyl bromide (1) complex as com-
pared to b-CD, indicating the formation of an inclusion complex of
phenacyl bromide (1) with b-CD from the secondary side of cyclo-
dextrin. In this biomimetic synthesis of quinoxalines,18 b-cyclodex-
trin plays a significant role by forming an inclusion complex with
phenacyl bromide from the secondary side and activating the mol-
ecule to undergo cyclocondensation with benzene-1,2-diamine as
shown in Figure 2.
Acknowledgement
B.M., S.N.M. and V.P.R. thank CSIR, New Delhi, India, for the
award of research fellowships.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.033.
In conclusion, we have presented an elegant and simple
methodology for the synthesis of quinoxaline derivatives from
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z 283 (M+H)+.
2-(4-Bromophenyl)quinoxaline (Table 2, entry 8): Pale yellow solid, 90%, mp
138 °C; Rf (20% EtOAc/n-hexane) 0.48; 1H NMR (200 MHz, CDCl3) d 7.64–7.85
(m, 4H, ArH), 8.03–8.2 (m, 4H, ArH), 9.32 (s, 1H, C3–H); 13C NMR (75 MHz,
CDCl3) d 125.0, 129.0, 129.6, 129.9, 130.5, 132.4, 135.5, 141.4, 142.2, 142.6,
150.6; MS (ESI): m/z 285 (M+H)+.
N,N-Diethyl-4-(quinoxalin-2-yl)benzenamine (Table 2, entry 9): Dark yellow
solid; yield 92%; mp 82–85 °C; Rf (20% EtOAc/n-hexane) 0.45; 1H NMR
(200 MHz, CDCl3) d 1.17–1.22 (m, 6H, CH3), 3.34–3.44 (m, 4H, CH2), 6.4–6.8
(m, 2H, ArH), 7.6–7.8 (m, 2H, ArH), 7.99–8.10 (m, 4H, ArH), 9.28 (s, 1H, C3–H);
13C NMR (75 MHz, CDCl3) d 12.0, 12.0, 43.8, 44.3, 110, 111.3, 111.6, 111.7,
128.2, 128.8, 128.9, 129.0, 129.05, 129.8, 130.8, 140.7, 142.5, 143; MS (ESI): m/
z 278 (M+H)+.
2-(4-(Pyrrolidin-1-yl) phenyl)quinoxaline (Table 2, entry 10): Yellow solid; yield
87%; mp 180–185 °C; Rf (20% EtOAc/n-hexane) 0.4; 1H NMR (200 MHz, CDCl3) d
2.05 (m, 4H, 2CH2), 3.39 (m, 4H, 2CH2), 6.69 (d, J = 8.68 Hz, 2H, ArH), 7.62–7.79
(m, 2H, ArH), 8.03–8.27 (m, 4H, ArH), 9.28 (s, 1H, C3–H); 13C NMR (75 MHz,
CDCl3) d 25.4, 47.7, 110.6, 112.3, 127.9, 128.3, 128.8, 129.3, 130.4, 130.6, 140.4,
140.5, 140.6, 140.7, 143.3, 149.6, 150.8; MS (ESI): m/z 276 (M+H)+.
2-(3-Bromo-4-methoxyphenyl)quinoxaline (Table 2, entry 11): Pale yellow solid;
yield 89%; mp 95–100 °C; Rf (20% EtOAc/n-hexane) 0.4; 1H NMR (200 MHz,
CDCl3) d 3.85 (s, 3H, OCH3), 6.98–7.14 (m, 2H, ArH), 7.80–8.02 (m, 2H, ArH),
8.20–8.28 (m, 3H, ArH), 9.25 (s, 1H, C3–H); 13C NMR (75 MHz, CDCl3) d 55.3,
114.5, 128.9, 129.0, 129.3, 130.2, 141.0, 142.2, 142.9, 151.3, 161.5; MS (ESI): m/
z 315 (M+H)+.
2-(Quinoxalin-2-yl)phenol (Table 2, entry 12): Pale yellow solid; yield 90%; mp
200–205 °C; Rf (20% EtOAc/n-hexane) 0.37; 1H NMR (200 MHz, CDCl3) d 6.96–
7.17 (m, 2H, ArH), 7.36–7.45 (m, 1H, ArH), 7.70–7.88 (m, 2H, ArH), 7.96–8.22
(m, 3H, ArH), 9.5 (s, 1H, C3–H), 10.2 (brs, 1H, OH). 13C (75 MHz, CDCl3) d 117.2,
118.8, 119.6, 126.7, 127.6, 129.0, 129.8, 131.2, 133.0, 138.4, 140.2, 142.2, 152.2,
160.9; MS (ESI): m/z 223 (M+H)+.
4-(Quinoxalin-2-yl)benzonitrile (Table 2, entry 13): Pale yellow solid; yield 90%;
mp 193–195 °C; Rf (20% EtOAc/n-hexane) 0.28; 1H NMR (200 MHz, CDCl3) d
7.82–7.88 (m, 4H, ArH), 8.13–8.20 (m, 2H, ArH), 8.33–8.36 (d, J = 8.309, 2H,
ArH), 9.35 (s, 1H, C3–H); 13C NMR (75 MHz, CDCl3) d 113.8, 118.4, 127.5, 128.0,
129.0, 129.8, 130.7, 130.9, 132.9, 140.6, 141.6, 142.3, 142.3, 149.6; MS (ESI): m/
z 232 (M+H)+.
2-(4-Nitrophenyl)quinoxaline (Table 2, entry 14): Pale yellow solid; yield 83%;
mp 185–190 °C; Rf (20% EtOAc/n-hexane) 0.2; 1H NMR (200 MHz, CDCl3) d
7.82–7.86 (m, 2H, ArH), 8.16–8.21 (m, 2H, ArH), 8.4 (s, 4H, ArH), 9.4 (s, 1H, C3–
H); 13C NMR (75 MHz, CDCl3) d 113.3, 128.0, 128.2, 130.3, 130.9, 140.0, 152.3,
160.0; MS (ESI): m/z 252 (M+H)+.
2-(Thiophen-2-yl)quinoxaline (Table 2, entry 15): Pale yellow solid; yield 91%;
mp 130–135 °C; Rf (20% EtOAc/n-hexane) 0.48; 1H NMR (200 MHz, CDCl3) d
7.17 (d, J = 4.53, 1H, thiophene H), 7.52 (d, J = 4.53, 1H, thiophene H), 7.65–7.75
(m, 2H, ArH), 7.84 (d, J = 3.02, 1H, thiophene H), 8.09 (d, J = 8.309, 2H, ArH), 9.2
(s, 1H, C3–H); 13C NMR (75 MHz, CDCl3) d 126.4, 127.0, 126.4, 127.0, 128.5,
128.5, 129.0, 129.0, 129.3, 130.0, 130.5, 141.0, 141.8, 142.1; MS (ESI): m/z 213
(M+H)+.
2-(Furan-2-yl)quinoxaline (Table 2, entry 16): Solid; yield 87%; mp 95–98 °C; Rf
(20% EtOAc/n-hexane) 0.45 L; 1H NMR (200 MHz, CDCl3) d 6.58–6.59 (m, 1H,
ArH), 7.28 (d, J = 3.5 Hz, 1H, Furan H), 7.65–7.7 (m, 3H, ArH), 8.0–8.08 (m, 2H,
Furan H), 9.5 (s, 1H, C3–H), 13C NMR (75 MHz, CDCl3) d 112.2, 112.8, 129.5,
129.6, 130.8, 141.6, 142.4, 142.4, 144.2, 145.4, 151.3; MS (ESI): m/z 197
(M+H)+.
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17. General Procedure for the synthesis of quinoxalines. Typical example: 2-
phenylquinoxaline (Table 2, entry 1): b-CD (1.135 g, 1 mmol) was dissolved in
water (15 mL) by warming to 50 °C until a clear solution was formed. Then,
phenacyl bromide (0.198 g, 1 mmol) dissolved in methanol (2 mL) was added
dropwise followed by benzene-1,2-diamine (0.108 g, 1 mmol) and the mixture
was stirred at 70 °C until the reaction was complete (as monitored by TLC)
(Table 2). The mixture was extracted with ethyl acetate, and the extract was
filtered. The organic layer was dried over anhydrous Na2SO4, the solvent was
removed under reduced pressure, and the resulting product 2-
phenylquinoxaline was further purified by column chromatography. The
aqueous layer was cooled to 5 °C to recover b-CD by filtration. Bright yellow
solid; yield 0.185 g, (90%); mp 75–78 °C; Rf (20% EtOAc/n-hexane) 0.5; 1H NMR
(200 MHz, CDCl3) d 7.52–7.61 (m, 3H, ArH), 7.73–7.83 (m, 2H, ArH), 8.13–8.22
(m, 4H, ArH), 9.33 (s, 1H, C3–H); 13C NMR (75 MHz, CDCl3) d 127.3, 129.0,
129.1, 129.5, 129.6, 130.1, 130.2, 136.7, 141.5, 142.2, 143.3, 151.7; MS (ESI): m/
z 207 (M+H)+.
18. Data for the representative examples of synthesized compounds:
2-(Naphthalen-2-yl)quinoxaline (Table 2, entry 4): Solid; yield 91%; dark yellow
solid; mp 135 °C; Rf (20% EtOAc/n-hexane) 0.45; 1H NMR (200 MHz, CDCl3) d
7.51–7.56 (m, 2H, ArH), 7.69–8.19 (m, 7H, ArH), 8.36–8.41 (m, 1H, ArH), 8.65(s,
1H, ArH), 9.50(s, 1H, C3–H); 13C NMR (75 MHz, CDCl3) d 127.1, 127.8, 127.9,
128.8, 128.9, 129.5, 129.7, 130.5, 135.3, 140.1, 140.2, 140.8, 141.0, 142.3, 142.7,
143.0, 151.0; MS (ESI): m/z 257 (M+H)+.
2-(Biphenyl)quinoxaline (Table 2, entry 5): Pale yellow solid; yield 89%; mp
130–131 °C; Rf (20% EtOAc/n-hexane) 0.46; 1H NMR (200 MHz, CDCl3) d 7.35–
7.54 (m, 3H, ArH), 7.70–7.82 (m, 6H, ArH), 8.11–8.30 (m, 4H, ArH), 9.38 (s, 1H,
C3–H); 13C NMR (75 MHz, CDCl3 ppm) d 127.1, 127.8, 127.9, 128.8, 128.9,
129.5, 129.7, 130.5, 135.3, 140.1, 141.0, 142.3, 142.7, 143.0, 151.4; MS (ESI): m/