Bismuth(III)-catalyzed rapid synthesis of 2,3-disubstituted quinoxalines in water

Article abstract of DOI:10.1055/s-0028-1083230

A variety of 2,3-disubstituted quinoxalines are readily prepared in high yields under extremely mild conditions by cyclocondensation of arene-1,2-diamines with 1,2-dicarbonyls using a catalytic amount of bismuth(III) triflate. The reactions of 2,3-diamino

Full text of DOI:10.1055/s-0028-1083230

PAPER
3787
Bismuth(III)-Catalyzed Rapid Synthesis of 2,3-Disubstituted Quinoxalines in
Water
B
ismuth(I
h
II)-Catalyzed
i
Synth
l
esis of
l
Q
uinox
u
alinesinWater S. Yadav,* Basi V. Subba Reddy, Kokku Premalatha, Kattela Shiva Shankar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 26 June 2008; revised 25 July 2008
of arene-1,2-diamines with 1,2-ketones (I2, DMSO; I2,
Abstract: A variety of 2,3-disubstituted quinoxalines are readily
prepared in high yields under extremely mild conditions by cyclo-
condensation of arene-1,2-diamines with 1,2-dicarbonyls using a
catalytic amount of bismuth(III) triflate. The reactions of 2,3-di-
MeCN; Montmorillonite K-10; PEG-400; solid phase;
CAN; MeOH–AcOH (9:1); Ac2O, reflux), oxidative cy-
clization of a-hydroxy ketones with 1,2-diamines (MnO2;
aminopyridine with 1,2-dicarbonyls produce pyrido[2,3-b]pyrazine 1 mol% MnO2, microwaves; Pd(OAc)2; MnO2–NaBH4;
derivatives under similar conditions.
PEG-400), cyclization–oxidation of phenacyl bromides
with 1,2-diamines (HClO4–silica gel), and oxidative cou-
pling of epoxides with ene-1,2-diamines [bismuth pow-
der, Cu(OTf)2].6–10 However, many of these methods
suffer from several drawbacks such as the use of strong
oxidizing agents, expensive metal catalysts, and harsh re-
action conditions and also the yields are far from satisfac-
tory. Therefore, the development of a simple, convenient,
and general approach would certainly be useful in gener-
ating combinatorial libraries for drug discovery.
Key words: bismuth(III) compounds, 1,2-dicarbonyls, vicinal-di-
amines, quinoxalines
Quinoxaline derivatives represent an important class of
nitrogen containing heterocycles as they are useful inter-
mediates in organic synthesis. They have received consid-
erable interest from the pharmaceutical industry because
of their interesting therapeutic properties such as antiviral,
antibacterial, anti-inflammatory, and antiprotozoal and as
kinase inhibitors.1 They have also been evaluated as anti-
cancer, anthelmintic, antifungal and insecticidal agents.2
In addition, the quinoxaline nucleus is a part of several an-
tibiotics such as echinomycin, levomycin, and actinomy-
cin that are known to inhibit the growth of gram-positive
bacteria and are active against various transplantable tu-
mors.3 Besides this, they have found applications as dyes,
electroluminescent materials, organic semiconductors,
cavitands, chemically controllable switches, and DNA
cleaving agents.4,5 Since they display a broad spectrum of
biological properties, they are considered as privileged
structures in combinatorial drug discovery. Drug formula-
tions containing quinoxalines such as Lamprene are cur-
rently available (Figure 1).
Recently, water has been received as a green solvent for
various organic transformations. In addition to its abun-
dance, for economical and safety reasons water has natu-
rally become as a substitute and an alternative
environmentally benign solvent in organic synthesis.11
This becomes further sophisticated if these reactions can
be performed using inexpensive reagents. Lanthanide tri-
flates are unique Lewis acids that are currently of great in-
terest.12 The high catalytic activity, low toxicity, moisture
and air tolerance, and their recyclability, make the use of
lanthanide triflates attractive alternatives to conventional
Lewis acids.13 However, lanthanide triflates are expensive
and their use in large-scale synthesis is limited. Therefore,
inexpensive and more efficient catalysts are desirable. In
this direction, bismuth(III) triflate has evolved as a re-
markable Lewis acid catalyst for effecting various organic
transformations.14 Compared to lanthanide triflates, bis-
Consequently, various methods have been developed for
the synthesis of quinoxalines, which include condensation
Cl
N
O
Cl
MeO
N
N
N
N
O
OH
Cl
N
N
N
N
X
O
MeO
H
N
H
Me
Me
Clofazimine (Lamprene for leprosy)
BMS-238497 (Kinase inhibitor)
XK-469 (anticancer)
Figure 1 Lamprene, BMS-238497, and XK-469
SYNTHESIS 2008, No. 23, pp 3787–3792
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083230; Art ID: Z14808SS
© Georg Thieme Verlag Stuttgart · New York

3788
J. S. Yadav et al.
PAPER
muth(III) triflate is inexpensive and is easy to prepare phatic 1,2-diamines reacted well with benzil to produce
even on a multigram scale, from commercially available cycloadducts 3r and 3s (Table 1, entries 18 and 19).
bismuth oxide and triflic acid.15 However, there have been
Unlike reported methods, the present protocol does not re-
no reports on the use of bismuth(III) triflate for the synthe-
quire harsh or drastic conditions to produce quinoxalines
sis of quinoxalines.
or pyrazines. In the absence of the catalyst, the reaction
In this article, we wish to report a novel procedure for the did not proceed even after long reaction times (8–12 h).
synthesis of quinoxalines from 1,2-dicarbonyl com- The scope and generality of this process are illustrated
pounds and 1,2-diamines using 10 mol% of bismuth(III) with respect to various arene-1,2-diamines and 1,2-dicar-
triflate in water. Accordingly, treatment of benzil (1) with bonyls and the results are summarized in Table 1. A plau-
o-phenylenediamine (2) in the presence of 10 mol% of sible reaction mechanism and the role of bismuth(III)
bismuth triflate in water resulted in the formation of 2,3- catalyst are depicted in Scheme 2.
diphenylquinoxaline (3a) in 97% yield (Scheme 1,
Table 1, entry 1).
The effects of various Lewis acids such as Sm(OTf)3,
Yb(OTf)3, Ce(OTf)3, Zn(OTf)2, Cu(OTf)2, In(OTf)3, and
Sn(OTf)2 were tested in the preparation of 3a reaction
rates and the results are presented in Table 2. As seen
from Table 2, the products were obtained in comparative-
O
H2N
H2N
N
N
Bi(OTf)3 (10 mol%)
H2O, r.t.
+
ly low yields when zinc triflate, copper(II) triflate and
tin(II) triflate were used. Alternatively, 10 mol% of scan-
dium(III) triflate was found to be equally effective for this
conversion. In the absence of a catalyst, the reaction was
rather sluggish in water and resulted in very low yields
(20–35%) of quinoxalines even after long reaction times
(5–7 h). Thus, bismuth(III) triflate is particularly attrac-
tive because it can be used in water. Since a water solution
of bismuth(III) triflate is acidic it may be possible that the
true catalyst is triflic acid produced from hydrolysis of
bismuth(III) triflate.16 However, triflic acid is not as effec-
tive as bismuth(III) triflate as a catalysis for the condensa-
tion of benzil (1) with o-phenylenediamine (2) (30%
TfOH, 25 °C, 1.5 h, 65%) and this suggests that a Lewis
acid is most likely involved in activating the diketone. No
effect on yield was observed even in the presence of pro-
ton scavengers. Also, the practical use of bismuth(III) tri-
flate is highly valuable as triflic acid is very corrosive and
difficult to handle. The recovered bismuth(III) triflate
from the aqueous layer was reused in two subsequent runs
with a gradual decrease in activity. For example, treat-
ment of benzil (1) with o-phenylenediamine (2) in the
presence of 10 mol% bismuth(III) triflate in water (2 mL)
for ten minutes gave the desired product 3a in 97%, 85%,
and 71% yields over three cycles. Thus, bismuth(III) tri-
flate was found to be an effective catalyst for the synthesis
of quinoxalines in water. However, comparatively lower
yields (65–80%) and extended reaction times (3–5 h) were
observed, when reactions were carried out using 5 mol%
of bismuth(III) triflate. The best conversions were
achieved in short reaction times with 10 mol% catalyst
(Table 1).
O
1
2
3a
Scheme 1
Similarly, various arene-1,2-diamines, such as mono- and
disubstituted amines, reacted efficiently with 1,2-dicarbo-
nyl compounds to give the corresponding 2,3-disubstitut-
ed quinoxalines (Table 1). The heteroaryl-fused pyrazines
are also referred to as heterocyclic quinoxalines, they rep-
resent a related class of nitrogen-containing heterocycles
that have attracted our attention. Unlike quinoxalines, het-
erocyclic variants are prone to undergo unwanted poly-
merization during their preparation under conventional
heating conditions that result in lower yields. Encouraged
by the results obtained with arene-1,2-diamines, we
turned our attention to 2,3-diaminopyridines. Interesting-
ly, 2,3-diaminopyridine underwent smooth coupling with
benzil to afford the corresponding pyrido[2,3-b]pyrazine
3d in 90% yield (Table 1, entry 4).
Similarly, several 1,2-dicarbonyl compounds such as phe-
nylglyoxal, ninhydrin, furil, isatin, and acenaphthene-1,2-
quinone also reacted rapidly with 1,2-diamines to produce
a variety quinoxaline derivatives (Table 1, entries 5–16).
In all cases, the reactions proceeded rapidly at room tem-
perature with high efficiency. The products were charac-
1
13
terized by H and C NMR, IR, and mass spectroscopic
data and also by comparison with authentic samples.6 In
addition, cyclohexane-1,2-one also participated effective-
ly in this reaction (Table 1, entry 17). Gratifyingly, ali-
Bi(III)
+
O
HO
..
H2N
H
R2
R2
N
R2
R1
N
N
Bi(OTf)3
+
H2O, r.t.
H2N
– 2 H2O
R1
O
R1
H2N
O
Scheme 2
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Bismuth(III)-Catalyzed Synthesis of Quinoxalines in Water
3789
Table 1 Bismuth(III) Triflate Catalyzed Synthesis of Quinoxalines and Pyrazinones
Entry Dicarbonyls
Diamines
Producta
Time (min) Yieldb (%) Ref.
H2N
H2N
N
N
O
1
2
3
4
3a
3b
3c
3d
5
7
97
95
95
90
10a
10a
10a
10a
O
Me
H2N
H2N
O
O
Me
N
N
Me
Me
H2N
H2N
O
O
Me
Me
N
N
7
H2N
N
N
O
O
10
N
H2N
N
H2N
H2N
O
O
N
N
5
6
3e
3f
3
4
4
5
6
6
6
97
96
95
92
94
91
91
10b
10e
10b
7a
H2O⋅H
H2O⋅H
H2O⋅H
H2O⋅H
H
H
H
H
H2N
H2N
Me
O
O
Me
N
N
H2N
H2N
Me
Me
O
O
Me
Me
N
N
7
3g
3h
3i
H2N
H2N
O
O
N
N
8
N
N
O
N
N
H2N
H2N
9
10c
10c
10c
O⋅H2O
O⋅H2O
O⋅H2O
O
O
O
O
O
N
N
Me
H2N
H2N
Me
10
11
3j
O
O
N
N
Me
Me
H2N
H2N
Me
Me
3k
O
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J. S. Yadav et al.
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Table 1 Bismuth(III) Triflate Catalyzed Synthesis of Quinoxalines and Pyrazinones (continued)
Entry Dicarbonyls
Diamines
Producta
Time (min) Yieldb (%) Ref.
O
N
N
H2N
12
3l
5
7
90
95
10c
9e
O⋅H2O
N
H2N
N
O
O
O
N
N
H2N
H2N
O
O
13
O
3m
O
O
O
O
O
Me
Me
N
N
H2N
H2N
Me
Me
O
O
14
15
O
3n
3o
7
7
95
80
O
N
N
H2N
10d
N
H
N
O
H2N
H2N
H
N
O
16
17
3p
3q
7
90
O
H2N
H2N
N
O
N
N
10
90c
10b
10a
H2N
O
H2N
H2N
O
N
N
18
19
3r
3s
5
5
85c
O
H2N
H2N
N
N
O
O
82c
10a
a All products were characterized by 1H NMR, IR, and MS.
b Yields refers to pure products after chromatography.
c The reactions were carried out in EtOH.
using TMS as internal standard. Mass spectra were recorded on a
Finnigan MAT 1020 mass spectrometer operating at 70 eV. All
know compounds were adequately characterized (see Table 1 for
literature references). Data for novel compounds are given below.
In summary, we have demonstrated a simple, convenient
and efficient protocol for the preparation of highly substi-
tuted quinoxalines using a catalytic amount of bis-
muth(III) triflate under mild conditions. The use of water
as a solvent makes this procedure attractive and environ-
mentally benign. In addition to its efficiency and simplic-
ity, this method provides high yields of biologically
potent quinoxalines in short reaction times.
2,3-Disubstituted Quinoxalines 3a–s; General Procedure
To a stirred suspension of 1,2-dicarbonyl compound 1 (1.0 mmol)
and 1,2-diamine 2 (1.2 mmol) in H2O (2 mL) was added Bi(OTf)3
(10 mol%). The resulting mixture was stirred at r.t. for the specified
time (see Table 1). When the reaction was complete (TLC), the
mixture was extracted with EtOAc (2 × 10 mL). Evaporation of the
solvent followed by purification on silica gel (Merck, 100–200
mesh, EtOAc–hexane, 5:95) afforded pure quinoxaline. The reac-
tion was tested up to 10 mmol scale using this procedure.
Melting points were recorded on Buchi R-535 apparatus and are un-
corrected. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c
spectrophotometer using KBr optics. 1H NMR spectra were record-
ed on Gemini-200 and Varian Bruker-300 spectrometer in CDCl3
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Bismuth(III)-Catalyzed Synthesis of Quinoxalines in Water
3791
Table 2 The Effects of Various Lewis Acids for the Preparation of
3a
References
(1) (a) He, W.; Meyers, M. R.; Hanney, B.; Sapada, A.; Blider,
G.; Galzeinski, H.; Amin, D.; Needle, S.; Page, K.; Jayyosi,
Z.; Perrone, H. Bioorg. Med. Chem. Lett. 2003, 13, 3097.
(b) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg.
Med. Chem. Lett. 2004, 14, 541.
Entry
Catalysta
Sm(OTf)3
Yb(OTf)3
Ce(OTf)3
Zn(OTf)2
Cu(OTf)2
In(OTf)3
Sn(OTf)2
Sc(OTf)3
Bi(OTf)3
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
30
30
30
30
30
30
30
15
5
80
65
70
45
55
50
35
93
97
(2) Sakata, G.; Makino, K.; Kuraswa, Y. Heterocycles 1988, 27,
2481; and references cited therein.
(3) (a) Dell, A.; William, D. H.; Morris, H. R.; Smith, G. A.;
Feeney, J.; Roberts, G. C. K. J. Am. Chem. Soc. 1975, 97,
2497. (b) Bailly, C.; Echepare, S.; Gago, F.; Waring, M.
Anti-Cancer Drug Des. 1999, 15, 291. (c) Sato, S.;
Shiratori, O.; Katagiri, K. J. Antibiot. 1967, 20, 270.
(4) (a) Katoh, A.; Yoshida, T.; Ohkanda, J. Heterocycles 2000,
52, 911. (b) Thomas, K. R. J.; Velusamy, M.; Lin, J. T.;
Chuen, C. H.; Tao, Y. T. Chem. Mater. 2005, 17, 1860.
(c) Dailey, S.; Feast, W. J.; Peace, R. J.; Sage, I. C.; Till, S.;
Wood, E. L. J. Mater. Chem. 2001, 11, 2238.
(5) (a) Sessler, J. L.; Maeda, H.; Mizuno, T.; Lynch, V. M.;
Furuta, H. J. Am. Chem. Soc. 2002, 124, 13474.
a 10 mol% used for each reaction.
(b) Crossley, M. J.; Johnston, L. A. Chem. Commun. 2002,
1122. (c) Yamaguchi, T.; Matsumoto, S.; Watanabe, K.
Tetrahedron Lett. 1998, 39, 8311.
b Yield refers to pure products after chromatography.
(6) (a) Brown, D. J. Quinoxalines: Supplement 11, In The
Chemistry Heterocyclic Compounds, Vol. 61; Taylor, E. C.;
Wipf, P., Eds.; John Wiley & Sons: New Jersey, 2004.
(b) Bhosale, R. S.; Sarda, S. R.; Andhapure, S. S.; Jadhav,
W. N.; Bhusare, S. R.; Pawar, R. P. Tetrahedron Lett. 2005,
46, 7183. (c) More, S. V.; Sastry, M. N. V.; Wang, Ch.; Yao,
C. F. Tetrahedron Lett. 2005, 46, 6345. (d) Huang, T.-k.;
Wang, R.; Shi, L.; Lu, X.-x. Catal. Commun. 2008, 9, 1143.
(7) (a) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Org. Biomol.
Chem. 2004, 2, 788. (b) Kim, S. Y.; Park, K. H.; Chung, Y.
K. Chem. Commun. 2005, 1321. (c) Robinson, R. S.;
Taylor, R. J. K. Synlett 2005, 1003. (d) Cho, C. S.; Renb,
W. X.; Shim, S. C. Tetrahedron Lett. 2007, 48, 4665.
(8) (a) Singh, S. K.; Gupta, P.; Duggineni, S.; Kundu, B. Synlett
2003, 2147. (b) Antoniotti, S.; Dunach, E. Tetrahedron Lett.
2002, 43, 3971. (c) Das, B.; Lu, K. V.; Suneel, K.; Majhi, A.
Tetrahedron Lett. 2007, 48, 5371.
(9) (a) Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M.-P. Synthesis
1985, 313. (b) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K.
Chem. Commun. 2003, 2286. (c) Cohen, Y.; Meyer, A. Y.;
Rabinovitz, M. J. Am. Chem. Soc. 1986, 108, 7039.
(d) Xekoukoulotakis, N. P.; Hadjiantoniou, M.; Maroulis, A.
J. Tetrahedron Lett. 2000, 41, 10299. (e) More, S. V.;
Sastry, M. N. V.; Yao, C. F. Green Chem. 2006, 8, 91.
(f) Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W.
H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett. 2004, 45,
4873. (g) Goswami, S.; Adak, A. K. Tetrahedron Lett. 2005,
46, 221.
2,3-Di(2-furyl)-6,7-dimethylquinoxaline (3n)
Solid; mp 134–136 °C.
IR (KBr): 3427, 2983, 1605, 1567, 1442, 879, 743 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.5 (s, 6 H), 6.50–6.52 (m, 2 H),
6.59–6.62 (m, 2 H), 7.55–7.63 (m, 2 H), 7.75–7.84 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 39.8, 115.5, 131.1, 131.6, 147.6,
159.0, 160.10, 160.18, 163.0.
MS (ESI): m/z = 291 [M + 1].
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
71.01; H, 5.35; N, 11.69.
Acenaphtho[1,2-b]quinoxaline (3p)
Solid; mp 242–245 °C.
IR (KBr): 3443, 3047, 2922, 2361, 1614, 1481, 1434, 1207, 831,
759 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.70–7.75 (m, 2 H), 7.98 (t, J = 7.7
Hz, 2 H), 8.15 (d, J = 7.7 Hz, 2 H), 8.18–8.22 (m, 2 H), 8.42 (d,
J = 7.7 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 125.7, 126.8, 127.2, 128.2, 128.9,
129.6, 130.1, 133.2, 142.5, 145.3.
MS (EI): m/z (%) = 254 (M+, 100), 142 (20), 43 (30).
HRMS (ESI): m/z [M + H]+ calcd for C18H11N2: 255.0922; found:
255.0932.
(10) (a) Mohsenzadesh, F.; Aghapoor, K.; Darabai, H. R. J. Braz.
Chem. Soc. 2007, 18, 297. (b) Cho, C. S.; Oh, S. G. J. Mol.
Catal. A: Chem. 2007, 276, 205. (c) Popp, F. D. J.
Heterocycl. Chem. 1972, 9, 1399. (d) Takekuma, S.-i.;
Katayama, S.; Takekuma, H. Chem. Lett. 2000, 614.
(e) Sarkis, G. Y.; Al-Badri, H. T. J. Heterocycl. Chem. 1980,
17, 813.
Anal. Calcd for C18H10N2: C, 85.02; H, 3.96; N, 11.02. Found: C,
84.91; H, 3.90; N, 10.83.
Acknowledgment
The authors thank CSIR, New Delhi for the award of fellowships.
(11) (a) Grieco, P. A. Organic Synthesis in Water; Blackie
Academic and Professional: London, 1998. (b) Li, C. J.;
Chan, T. H. Organic Reactions in Aqueous Media; John
Wiley and Sons: New York, 1997, 159.
(12) (a) Imamoto, T. Lanthanides in Organic Synthesis;
Academic Press: London, 1994. (b) Molander, G. A. Chem.
Rev. 1992, 92, 29.
Synthesis 2008, No. 23, 3787–3792 © Thieme Stuttgart · New York

3792
J. S. Yadav et al.
PAPER
(13) (a) Kobayashi, S. K. Synlett 1994, 689. (b) Kobayashi, S. K.
J. Synth. Org. Chem., Jpn. 1995, 53, 370. (c) Kobayashi, S.
Eur. J. Org. Chem. 1999, 15.
(14) (a) Leonard, M. N.; Wieland, L. C.; Mohan, R. S.
Tetrahedron 2002, 58, 8373. (b) Gaspard-Iloughmane, H.;
Le Roux, C. Eur. J. Org. Chem. 2004, 2517.
(15) Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 2002, 43, 993.
(16) (a) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2004,
45, 49. (b) Ollevier, T.; Nadeau, E.; Guay-Bégin, A. A.
Tetrahedron Lett. 2006, 47, 8351. (c) Frank, W.; Reiss, G.
J.; Schneider, J. Angew. Chem., Int. Ed. Engl. 1995, 34,
2416.
Synthesis 2008, No. 23, 3787–3792 © Thieme Stuttgart · New York