Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1,2-diamines

Article abstract of DOI:10.1016/S0040-4039(02)00715-3

We describe here a new synthesis of quinoxaline derivatives by a Bi-catalyzed oxidative coupling of epoxides and ene-1,2-diamines.

Full text of DOI:10.1016/S0040-4039(02)00715-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3971–3973
Direct and catalytic synthesis of quinoxaline derivatives from
epoxides and ene-1,2-diamines
a
b,
Sylvain Antoniotti and Elisabet Du n˜ ach *
a
Laboratoire Ar oˆ mes, Synth e` ses et Interactions, UMR CNRS 6001, Universit e´ de Nice-Sophia Antipolis, Facult e´ des Sciences,
Parc Valrose 06108, Nice cedex 2, France
b
Laboratoire de Chimie Bio-Organique, UMR CNRS 6001, Universit e´ de Nice-Sophia Antipolis, Facult e´ des Sciences,
Parc Valrose 06108, Nice cedex 2, France
Received 9 April 2002; accepted 12 April 2002
Abstract—We describe here a new synthesis of quinoxaline derivatives by a Bi-catalyzed oxidative coupling of epoxides and
ene-1,2-diamines. © 2002 Elsevier Science Ltd. All rights reserved.
Quinoxaline derivatives are an important class of nitro-
gen-containing heterocycles and they constitute useful
The synthesis of 2,3-disubstituted quinoxalines (Scheme
1) was achieved in yields of 53–70% using phenylene
diamine and internal epoxides (entries 1–4). The oxida-
tive coupling of 1,2-phenylene diamine and monosub-
1
intermediates in organic synthesis. They have been
2
reported for their applications in dyes, pharmaceuti-
3
,4
cals, and have also been used as building blocks for
stituted
styrene
oxide
derivatives
afforded
5,6
the synthesis of organic semiconductors. 2,3-Substi-
tuted quinoxalines can be prepared by condensation of
aryl-1,2-diamines and a-functionalized ketones, usually
2
-arylquinoxalines in 64–65% yields (entries 5 and 6).
The replacement of phenylene diamine by 2,3-
diaminomaleonitrile or by 2,3-diaminopyridine (entries
7
–10
a-dicarbonyl compounds or their equivalents.
To
the best of our knowledge, epoxides have never been
involved in quinoxaline synthesis, excepted in one
report, using a-sulfonyl epoxides and leading to 2-
phenyl quinoxalines in moderate yields. In all cases,
the reduced range of commercially available starting
materials results in multi-step reactions.
7
–9, respectively) led also to the expected heterocycles
in 53–71% yields, according to Scheme 2.
11
Among this series, we prepared some quinoxalines
bearing functional groups without observing any side
reactions or yield decrease. These functional groups,
e.g. chloride, nitrile or vinylic functions (entries 4, 6 and
We present here a new strategy to prepare differently
substituted quinoxalines directly from simple epoxides
and diaminoaryl compounds, in a oxidative coupling
catalyzed by bismuth powder. The use of bismuth, non
7
), allow further functionalization of the molecules.
The best results were obtained using 1.5 equiv. of the
diamino compound. Several attempts with only 1 equiv.
afforded lower yields. The change of 1,2-phenylene
diamine by 2,3-diaminopyridine or 2,3-diaminomaleo-
nitrile did not affect the reaction yield or the reaction
conditions.
1
2
toxic and commercially available, is an interesting
feature of the process.
The reaction proceeds in DMSO under molecular oxy-
gen in the presence of catalytic amounts of Bi(0) pow-
der and of copper triflate or triflic acid as additives. The
results obtained in the synthesis of quinoxaline deriva-
tives are summarized in Table 1.
The isolated yields of this series of quinoxalines were in
the range of 53 to 71%. Except for entries 3, 5 and 6,
almost no by-products were formed, but some polymer-
ization of the epoxide under the reaction conditions led
to a partial mass-loss.
Keywords: quinoxaline; epoxides; heterocycles; bismuth; catalysis.
*
Corresponding author. Fax: 33(0)492076151; e-mail: dunach@
unice.fr
In the case of coupling with styrene oxides (entries 5
and 6) the formation of 2-aryl-1,2,3,4-tetra-
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00715-3

3
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S. Antoniotti, E. Du n˜ ach / Tetrahedron Letters 43 (2002) 3971–3973
Table 1. Bi-catalyzed synthesis of quinoxaline derivatives from epoxides under O (1 atm), in DMSO at 100°C
2
hydroquinoxalines was observed (18–25%). These
resulted from the nucleophilic addition of the diamine to
the epoxide. On the other hand, in the case of cyclodo-
decene oxide (entry 3), the formation of cyclodode-
canone, from the acid-catalyzed isomerization of the
13,14
epoxide
was obtained in 12% yield.
No quinoxalines were obtained in the absence of Bi(0),
Scheme 1. Synthesis of 2,3-susbstituted quinoxaline derivatives
from epoxides and phenylene diamine.
DMSO or molecular oxygen. The use of Bi(0)/O /DMSO
2
or Bi(III)/O /DMSO as the catalytic system in the
2

S. Antoniotti, E. Du n˜ ach / Tetrahedron Letters 43 (2002) 3971–3973
3973
Scheme 2. Synthesis of tetrahydroquinoxaline derivatives from cyclohexene oxides and 1,2-enediamines.
oxidative ring opening of epoxides have already been
and trapping of the a-diketone or a-ketoaldehyde inter-
mediates.
1
5,16
reported.
The Bi(0)-catalyzed reaction did not take
place in the absence of an additive.
Two different additives, Cu(OTf) and TfOH, were used,
according to the epoxide structure. For monosubstituted
References
2
epoxides or for cyclohexene oxide, Cu(OTf) , used in 4–6
1. In the past ten years, the average number of publications
including keywords ‘synthesis’ and ‘quinoxaline’ has been
doubled. A large part of these papers concern highly
functionalized molecules with a quinoxaline skeleton,
designed for biological activities.
2
mol%, gave the best results. In contrast, for the other
disubstituted epoxides, the use of a strong Br o¨ nsted acid
such as TfOH, in 20–27 mol%, was the best compromise
between yield of quinoxaline and acid-catalyzed epoxide
polymerization.
2
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1
For the mechanistic aspects of this new transformation,
we propose a first oxidation of the epoxide to the
corresponding a-hydroxyketone and its further oxidation
to the a-diketone, in agreement with our recent results
3
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Bohmer, F. D. J. Med. Chem. 1996, 39, 2170–2177.
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B.; Graslund, A. J. Mol. Biol. 1998, 278, 31–56.
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1
7
in this field. This oxidation proceeds by oxidative ring
1
8
5. Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.;
opening of the oxirane by DMSO, catalyzed by an acidic
additive, leading to the corresponding a-hydroxyketone,
or a-hydroxyaldehyde. In a second step, the ketol (or
ketal) is oxidized to the a-diketone or to the a-ketoalde-
Wood, E. L. J. Mater. Chem. 2001, 11, 2238–2243.
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Thieme: New York, 1995; pp. 417–422, 434.
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hyde intermediates by the Bi(0)/O system, in a Bi(III)/
2
16
Bi(0) redox process. The in situ a-dicarbonyl compound
obtained affords the corresponding quinoxaline after the
double condensation/dehydratation with the 1,2-diamino
derivatives.
1
998, 28, 193–196.
. Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M.-P. Synthesis
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0. Petukhov, P. A.; Tkachev, A. V. Tetrahedron 1997, 53,
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1
1
1
1
The general procedure for 2,3-substituted quinoxaline
synthesis can be described as follows: a mixture of
bismuth(0) (0.25 mmol) and the additive (0.25 mmol) in
9
1. Taylor, E. C.; Maryanoff, C. A.; Skotnicki, J. S. J. Org.
Chem. 1980, 45, 2512–2515.
DMSO (15 ml) is heated at 100°C under O (1 atm). The
2
2. BiCl is as lethal as sodium chloride for the rat. See for
3
epoxide (5 mmol) in DMSO (5 ml) is then introduced
through a serum cap and the mixture is stirred at this
temperature until complete consumption of the epoxide
details: Irwing-Sax, N.; Bewis, R. J. Dangerous properties
of industrial materials; Van Nostrand Reinhold: New York,
1989, p. 283.
(
monitored by GC). The diamino compound (7.5 mmol)
1
1
3. Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212–8216.
4. Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B. J.;
Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527–1530.
5. Zevaco, T.; Du n˜ ach, E.; Postel, M. Tetrahedron Lett. 1993,
in DMSO (2 ml) is then introduced and the mixture is
kept until the reaction is completed. The reaction mixture
is hydrolyzed with brine (50 ml), and extracted with
diethyl ether (3×50 ml). The combined organic layers are
1
34, 2601–2604.
dried over MgSO and evaporated. The crude product is
4
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E. Eur. J. Org. Chem. 2001, 735–740.
7. Antoniotti, S.; Du n˜ ach, E. Chem. Commun. 2001, 24,
purified by column chromatography over silica gel with
pentane and dichloromethane as the eluent. The products
1
1
13
are identified by H and C NMR and mass spectroscopy,
2566–2567.
19
and compared with authentic samples or literature data.
18. Santosusso, T. M.; Swern, D. J. Org. Chem. 1975, 40,
764–2769.
2
The procedure is identical for the synthesis of 2-
arylquinoxalines, excepted that both the epoxide and the
diamino compounds are introduced simultaneously.
19. Several of the obtained quinoxalines are known compounds
to which the spectroscopic data were compared. For others,
data for 2,3-cyano-5,6,7,8-tetrahydroquinoxaline (entry 8),
for example, are: yellow powder, mp: 138.7–139.3°C. NMR
1
In conclusion, a new synthesis of mono- and disubstituted
quinoxalines has been achieved in one-pot reaction via
the Bi-catalyzed condensation of epoxides and diamino
derivatives. The process involves the in situ generation
(200 MHz, CDCl , 20°C, l
=0 ppm) H: 3.1–2.9 (4H,
3
TMS
13
m), 2.0–1.8 (4H, m); C: 158.5, 130.5, 113.2, 32.3, 21.6. MS:
184 (100%), 183 (67%), 169 (89%), 156 (20%), 144 (6%),
129 (6%), 77 (14%), 52 (14%), 41 (16%).