Heterocyclizations via TosMIC-based multicomponent reactions: A new approach to one-pot facile synthesis of substituted quinoxaline derivatives

Article abstract of DOI:10.1055/s-0028-1087518

A novel multicomponent reaction involving o-phenylenediamines, aldehydes and p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of a base leading to the formation of quinoxalines in very good yields is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087518

3
02
LETTER
Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New
Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives
H
C
eterocyclization
o
s
via TosMI
n
C-BasedMu
s
lticompon
t
ent Re
a
actions ntinos Neochoritis, Julia Stephanidou-Stephanatou,* Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
Fax +30(2310)997679; E-mail: ioulia@chem.auth.gr; E-mail: tsolerid@chem.auth.gr
Received 6 August 2008
group apart from its inherent advantage of possessing also
Abstract: A novel multicomponent reaction involving o-phe-
an isonitrile functionality, which can serve as a handle for
further manipulation, the possibility of its use in multi-
nylenediamines, aldehydes and p-toluenesulfonylmethyl isocya-
nide (TosMIC) in the presence of a base leading to the formation of
quinoxalines in very good yields is described.
component reactions has not been greatly appreciated.
TosMIC has most commonly been used in heterocyclic
ring construction,24 in particular, of oxazole and pyrrole
moieties, but comparatively rarely in multicomponent re-
actions.25
Key words: multicomponent reactions, TosMIC, quinoxalines
Quinoxalines are widely used as intermediates in medici-
1
,2
Since the reaction between imines and TosMIC in basic
media constitutes a trusted method for the synthesis of
nal chemistry, since they exhibit a wide range of biolog-
ical activities, such as antiviral, antibacterial, anti-
2
6
3
–10
1
,5-disubstituted imidazoles and in continuation to our
inflammatory and kinase inhibitor properties.
The
2
7
1
1
12
previous work we speculated that formation of quinoxa-
lines would be possible, through a multicomponent reac-
tion, by using o-phenylenediamines with equimolar
amounts of an aldehyde and TosMIC.
echinomycin and the triostins are well-known antibiot-
ic families of quinoxaline derivatives. Furthermore, they
1
3a
have found applications as dyes, efficient electrolumi-
nescent materials,
droannulenes, cavidands and chemically controllable
1
3b
13c
organic semiconductors,
dehy-
1
3d
13e
Initially, a three-component reaction was performed be-
tween o-phenylenediamine, benzaldehyde and TosMIC in
the presence of DBU as base, using toluene as solvent at
room temperature for eight hours to afford the quinoxaline
1
3f
switches. Thus, a number of methods have been devel-
oped for the synthesis of substituted quinoxalines involv-
ing condensation of 1,2-phenylenediamines with a-
1
4
diketones, also under microwave irradiation, 1,4-addi-
3
a in 45% yield along with the classical benzaldehyde–
1
5
tion of 1,2-diamines to diazenylbutenes, oxidation trap-
TosMIC reaction product, the oxazole 4a in 40% yield. In
order to minimize the oxazole formation, the reaction was
repeated by heating at 80 °C for four hours (Scheme 1),
whereupon the yield of 3a was improved considerably
1
6
ping of a-hydroxyketones with 1,2-diamines, oxidative
1
7
cyclization of phenacyl bromides or vicinal diols with o-
1
8
19
phenylenediamines, oxidative coupling of epoxides or
2
0
ketones with 1,2-diamines. Very recently, quinoxalines
were also synthesized in 33–55% yield, through a two-
step reaction sequence, the first step involving a multi-
component reaction between o-phenylenediamines, alde-
hydes and isonitriles in hydrochloric methanolic solution,
whereas in the second step a DDQ oxidation of the isolat-
(
65%), whereas that of 4a was decreased to 27%. By using
a milder base, DABCO instead of DBU, the optimum
yield of 3a (91%) was achieved. However, in the presence
of other bases, such as Et N and K CO , the three-compo-
3
2
3
nent reaction did not take place, so in the first case only
N-benzyl-2-phenylbenzimidazole was isolated (45%
yield), whereas in the second only the oxazole 4a in 74%
yield.
2
1
ed dihydroquinoxalines was involved.
Sequential transformations and one-pot multicomponent
reactions (MCRs) offer significant advantages over con-
ventional linear step syntheses, by reducing time and sav-
ing money, energy and raw material thus resulting in both
Concerning the experimental procedure, a TosMIC–base
toluene solution was added to an o-phenylenediamine–
benzaldehyde solution, which had already been stirred for
five minutes. The reaction also proceeded, but with lower
yields, by simultaneously mixing all of the reactants. In
contrast, initial stirring of o-phenylenediamine–benzalde-
hyde for longer periods resulted in substantially lower
yields, most probably because of double Schiff base for-
mation. This hypothesis is supported by the fact that qui-
noxaline 3 was not formed after an initial stirring for two
hours.
2
2
economic and environmental benefits. Moreover, multi-
component synthesis has been established as a valuable
tool to the pharmaceutical industry for construction of low
molecular weight compound libraries through combinato-
2
3
rial strategies and parallel synthesis. Although p-toluene-
sulfonylmethyl isocyanide (TosMIC) is a versatile,
widely applicable reagent that constitutes a densely func-
tionalized building block bearing an active methylene
Having established the best protocol for the formation of
3, all subsequent reactions were performed by using
DABCO, although in some cases for comparison purposes
the reactions were also repeated with DBU, and the results
SYNLETT 2009, No. 2, pp 0302–0305
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087518; Art ID: D29508ST
x
x.
x
x.
2
0
0
8
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Heterocyclizations via TosMIC-Based Multicomponent Reactions
303
R1
NH2
NH2
R1
R2
N
N
Ar
N
+
ArCHO + TosCH2NC
+
Ar
R2
O
4
1
2
3
Scheme 1 Reagents and conditions: DBU or DABCO, toluene 80 °C, 4 h
are presented in Table 1 (entries 1–8). Analogous results (entries 1 vs. 2, 6 vs. 7 and 11 vs. 12), but also on the
were obtained by using the chloro-substituted diamine strength of the base, which affects the rate and the extent
(
entries 9 and 10), whereas by using the dimethyl-substi- of the TosMIC anion formation, thus reacting more readi-
tuted diamine the quinoxaline yields were optimized, ly with aldehydes carrying electron-withdrawing substitu-
when the stronger base DBU was used (entries 11–13). ents.
DBU was also the best base, when heterocyclic aldehydes
Quinoxaline formation can be rationalized via a plausible
were used (entries 14–18), though the yields were gener-
mechanism depicted in Scheme 2. It is conceivable that
ally lower. Finally, the bulky anthracenealdehyde reacted
the initial step is the formation of the imine 5 followed by
formation of the intermediate 6 through a nucleophilic at-
analogously (entries 19 and 20).
From a careful inspection of the results given in Table 1 it tack of the base-activated TosMIC to the imine polarized
can be concluded that the outcome of the competitive re- double bond. Subsequent ring closure by intramolecular
actions (quinoxaline versus oxazole formation) depends nucleophilic attack of the second NH group and loss of
2
not only on the substituents of the diamine and the alde- the tosyl moiety leads to the tetrahydroquinoxaline inter-
hyde, affecting the extent of imine (Shiff base) formation
Table 1 Quinoxalines 3 Synthesized in this Work
Entry
R1
H
R2
H
Ar
Base
Quinoxaline (%)
3a (65)
Oxazole (%)
1
2
3
4
5
6
7
8
9
phenyl
DBU
4a (27)
H
H
phenyl
DABCO
DABCO
DABCO
DABCO
DBU
3a (91)
–
H
H
2-methylphenyl
2,4-dimethylphenyl
4-methoxyphenyl
4-chlorophenyl
4-chlorophenyl
4-nitrophenyl
phenyl
3b (89)
3c (81)
–
H
H
–
H
H
3d (82)
3e (63)
–
H
H
4e (30)
–
H
H
DABCO
DABCO
DBU
3e (84)
H
H
3f (80)
4f (10)
4a (56)
4a (16)
–
H
Cl
Cl
Me
Me
Me
H
3g (45)a
3g (79)a
3h (86)
3h (72)
3i (85)
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
0
H
phenyl
DABCO
DBU
Me
Me
Me
H
phenyl
phenyl
DABCO
DBU
4a (trace)
–
2-methylphenyl
2-furyl
DBU
3j (46)
4j (40)
4k (40)
–
H
H
2-thienyl
DBU
3k (47)
3k (trace)
3l (49)
H
H
2-thienyl
DABCO
DBU
H
H
3-thienyl
4l (40)
–
H
H
3-thienyl
DABCO
DBU
3l (trace)
3m (52)
3m (trace)
H
H
9-anthryl
4m (42)
–
2
H
H
9-anthryl
DABCO
a
Isolated as a mixture of regioisomers in ca. 1:2 ratio.
Synlett 2009, No. 2, 302–305 © Thieme Stuttgart · New York

3
04
C. Neochoritis et al.
LETTER
O
Me
S
O
CH2
N
C
DBU or
DABCO
Ar
R1
NH2
R1
R2
N
R1
R2
N
CHAr
Tos
+
ArCHO
+ TosCHNC
NC
R2
NH2
NH2
NH2
1
2
5
6
Ar
H
R1
R2
NH
R1
R2
N
Ar
R1
R2
N
N
Ar
oxidation
Tos
NC
.
.
NH2
N
H
NC
7
3
Scheme 2 Plausible mechanism for the formation of quinoxalines 3
H
tended to heterocyclic 1,2-diamines and N-monoalkylated
diamines.
3'
H
2'
Cl
H
H
4'
5'
8
H
H
N
N
2
1'
7
6
6
'
References and Notes
H
3
H
5
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CH
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Synlett 2009, No. 2, 302–305 © Thieme Stuttgart · New York

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1
13
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