An efficient protocol for the synthesis of quinoxaline derivatives at room temperature using molecular iodine as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.08.080

The use of molecular iodine as the catalyst for a one-pot synthesis of quinoxaline derivatives at room temperature is reported.

Full text of DOI:10.1016/j.tetlet.2005.08.080

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7183–7186
An efficient protocol for the synthesis of quinoxaline derivatives
at room temperature using molecular iodine as the catalyst
Rajesh S. Bhosale,a Swapnil R. Sarda,a Suresh S. Ardhapure,a Wamanrao N. Jadhav,a
Sudhakar R. Bhusareb and Rajendra P. Pawara,*
aOrganic Chemistry Synthesis Lab., Dnyanopasak College, Parbhani-431401, India
bDepartment of Chemistry, Shri Shivaji College, Parbhani-431401, India
Received 11 July2005; revised 7 August 2005; accepted 17 August 2005
Available online 6 September 2005
Abstract—The use of molecular iodine as the catalyst for a one-pot synthesis of quinoxaline derivatives at room temperature is
reported.
Ó 2005 Elsevier Ltd. All rights reserved.
Functionalized quinoxalines represent an important
class of nitrogen-containing heterocycles as they consti-
tute useful intermediates in organic synthesis and are
useful dyes.1 Quinoxaline derivatives are well known in
the pharmaceutical industryand have been shown to
possess a broad spectrum of biological activities includ-
ing antiviral, antibacterial, anti-inflammatoryand as
kinase inhibitors.2 In addition, quinoxaline derivatives
have been evaluated as anticancer and anthelmintic
agents.3 A number of synthetic strategies have been
developed for the preparation of substituted quinoxa-
lines.4 Byfar, the most common method relies on the
condensation of an aryl 1,2-diamine with a 1,2-dicar-
bonyl compound in refluxing ethanol or acetic acid for
2–12 h giving 34–85% yields.5 Recently, improved meth-
ods have been reported for the synthesis of quinoxaline
derivatives including the Bi-catalyzed oxidative coupling
of epoxides and ene-1,2-diamines,6 from a-hydroxy ke-
tones via a tandem oxidation process using Pd (OAc)2
or RuCl2-(PPh3)3-TEMPO7 and MnO2,8 a solid-phase
synthesis on SynphaseTM Lanterns,9 cyclization of
a-arylimino oximes of a-dicarbonyl compounds under
reflux in acetic anhydride10 and the condensation of
o-phenylene diamines and 1,2-dicarbonyl compounds
in MeOH/AcOH under microwave irradiation.11
In recent years, the use of molecular iodine in organic
synthesis has received considerable attention as an inex-
pensive, non-toxic, readilyavailable mild Lewis acid cat-
alyst for organic transformations such as dehydration of
12
tertiaryalcohols to alkenes,
synthesis of benzyl alkyl
ethers,13 synthesis of mixed ethers under hydrogen pres-
sure,14 synthesis of benzothiophenes,15 bis-indoles,16
deprotection of acetals,17 esterification,18 transesterifica-
tion19 and Michael addition.20 Recently, we reported the
use of iodine for the synthesis of b-keto-enol ethers21
and multicomponent dihydropyrimidinone synthesis.22
In this letter, we report the synthesis of functionalized
quinoxalines 3 by the iodine catalyzed cyclocondensa-
tion of 1,2-dicarbonyl compounds 1 and substituted
o-phenylene diamines 2 in excellent yields (Scheme 1).
In a model condensation reaction, benzil 1a and 1,2-
diaminobenzene 2a in DMSO were stirred at room tem-
perature using a catalytic amount of molecular iodine.
The progress of the reaction was monitored byTLC.
After completion of the reaction after 35 min, an aque-
ous work-up afforded 2,3-diphenylquinoxaline 3a (95%
yield). To evaluate the use of this procedure, a variety
of substituted o-phenylenediamines were condensed
with 1,2-disubstituted 1,2-dicarbonyl compounds. The
results are shown in Table 1. The reaction proceeds very
cleanlyat room temperature and no undesirable side-
reactions were observed. In the absence of iodine, the
reaction did not proceed, even after 10 h.
Keywords: 1,2-Diketones; o-Phenylenediamine; Molecular iodine;
Quinoxaline.
*
We have demonstrated an efficient and mild protocol
for the condensation of 1,2-dicarbonyl compounds and
Corresponding author. Fax: +91 2452 242466; e-mail: rppawar@
yahoo.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.080

7184
R. S. Bhosale et al. / Tetrahedron Letters 46 (2005) 7183–7186
H2N
R
R
O
R
N
DMSO, I (10mol%)
2
R1
R1
+
RT
H2
N
O
R
N
2
3a-l
1
Scheme 1.
Table 1. Synthesis of quinoxaline derivatives 3a–l
H2N
R
R
O
O
R
N
N
DMSO, I2 (10 mol%)
R1
+
R1
RT
H2N
R
2
3a-l
1
EntryProducts
a
3a–l
Time (min)
Yields (%)a
95
N
35
N
O
N
N
b
c
70
50
85
90
N
N
Me
H
3CO
N
d
40
92
N
H3CO
H3CO
O
N
N
e
75
60
88
90
H3CO
H3CO
N
N
CH3
f
H3CO
H3C
N
g
40
70
90
86
N
H3C
H3C
O
N
N
h
H3C

R. S. Bhosale et al. / Tetrahedron Letters 46 (2005) 7183–7186
7185
Table 1 (continued)
EntryProducts
3a–l
Time (min)
55
Yields (%)a
H3C
N
CH3
i
91
N
H3C
O
N
N
j
45
75
65
90
86
88
O
O
N
N
O
O
k
O
O
N
N
CH3
l
a Refers to isolated yield.
Chem. Lett. 2003, 13, 3097–3100; (c) Kim, Y. B.; Kim, Y.
H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. Lett. 2004,
14, 541–544.
different substituted o-phenylenediamines to give func-
tionalized quinoxalines at room temperature in DMSO
using a catalytic amount of molecular iodine in excellent
yields.
3. Sakata, G.; Makino, K.; Karasawa, Y. Heterocycles 1988,
27, 2481–2515, and references cited therein.
4. (a) Porter, A. E. A. In Comprehensive Heterocyclic
Chemistry; Katritsky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984, pp 157–197; (b) Woo, G. H. C.; Snyder, J.
K.; Wan, Z. K. Prog. Heterocycl. Chem. 2002, 14, 279.
5. Brown, D. J. Quinoxalines: Supplement II. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C.,
Wipf, P., Eds.; John Wiley& Sons: New Jersey, 2004.
6. Antoniotti, S.; Donach, E. Tetrahedron Lett. 2002, 43,
3971–3973.
General experimental procedure: A mixture of the 1,2-
diketone 1 (10 mmol), 1,2-diamino arene 2 (10 mmol)
and molecular iodine (10 mol %) in DMSO (10 ml)
was stirred at room temperature. The progress of the
reaction was monitored byTLC. After completion of
the reaction, the reaction mixture was poured onto
crushed ice and stirred for 10–15 min. The solid which
separated was filtered, washed with aqueous sodium
thiosulfate solution to remove iodine and subsequently
with water, and then recrystallized from ethanol to
afford pure quinoxaline 3.
7. Robinson, R. S.; Taylor, R. J. K. Synlett 2005, 1003–
1005.
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Biomol. Chem. 2004, 2, 788–796; (b) Raw, S. A.; Wilfred,
C. D.; Taylor, R. J. K. Chem. Commun. 2003, 2286–2287.
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10. Xekoukoulotakis, N. P.; Hadjiantonious, M. C. P.;
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55, 1106–1109.
The products 3a–l obtained were identified bycompari-
son with authentic samples byTLC and 1H NMR and
IR spectroscopy.
Acknowledgements
The authors are thankful to Dr. P. L. More, Principal,
Dnyanopasak College, Parbhani for providing the
necessaryfacilities.
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