Improved synthesis of substituted quinoxalines from new N=N-polymerbound 1,2-diaza-1,3-butadienes

Article abstract of DOI:10.1055/s-2003-39886

The first general protocol for the preparation of different N=N-polymer-bound 1,2-diaza-1,3-butadienes is reported. The utility of these supported reagents in the solid-phase in the preparation of 3-methyl quinoxaline-2-carboxylates by reaction with aroma

Full text of DOI:10.1055/s-2003-39886

LETTER
1183
Improved Synthesis of Substituted Quinoxalines from New N=N-Polymer-
bound 1,2-Diaza-1,3-butadienes
S
ynthesis of Subst
r
itute
d
Q
u
a
inoxalineszio A. Attanasi, Lucia De Crescentini, Paolino Filippone,* Fabio Mantellini,* Stefania Santeusanio
Istituto di Chimica Organica, Università degli Studi di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy
Fax +39(0722)2907; E-mail: filippone@uniurb.it
Received 20 March 2003
PSTsNHNH2
Abstract: The first general protocol for the preparation of different
N=N-polymer-bound 1,2-diaza-1,3-butadienes is reported. The util-
1
ity of these supported reagents in the solid-phase in the preparation
of 3-methyl quinoxaline-2-carboxylates by reaction with aromatic
1,2-diamines is presented.
O
O
O
O
THF/r.t.
R1
R1
Key words: 1,2-diaza-1,3-butadienes, hydrazones, Michael addi-
tion, quinoxalines, solid-phase synthesis
2a,b
Cl
2c–e
H
N
O
H
N
O
1,2-Diaza-1,3-butadienes are powerful tools in organic
synthesis, particularly in the construction of heterocyclic
rings.1–3 Recently, we reported their synthesis on solid
phase, starting from polymer-bound b-ketoester and free
hydrazine derivatives.4,5 In this case, the coupling site
with the resin was the ester group at position 4 of the azo-
ene system.
PSTs
N
R1
PSTs
N
R1
3a,b
Cl
4c–e
PTAB (1equiv)
r.t.
DIPEA (2 equiv)
CH2Cl2/r.t.
H
N
O
-HCl
In this report, we describe a new protocol to obtain
new N=N-polymer-bound 1,2-diaza-1,3-butadienes. The
methodology uses PS-Ts-NH-NH2, a resin bound equiva-
lent of p-toluenesulfonyl hydrazide, usually employed as
a scavenger of aldehydes and ketones.6 Such a resin is also
potentially useful as a polymeric reagent: for example, its
reaction with carbonyl compounds 2a–e furnishes resin-
bound a-alogenated sulfonyl hydrazones 4a–e.
PSTs
N
R1
Br
4a–b
O
DIPEA (2 equiv)
CH2Cl2/r.t.
-HBr
N
PSTs
N
R1
5a–e
O
S
PSTs=
Two different routes are possible for this synthesis. When
polymer-bound hydrazide 1 reacts with i-propyl or benzyl
acetoacetate 2a,b, the formation of corresponding poly-
mer-bound hydrazones 3a,b is observed. These are sub-
jected to bromination with phenyltrimethylammonium
tribromide (PTAB) in dichloromethane to permit the in-
troduction of the leaving group at the a-position of the
C=N function to give the pertinent polymer-bound hy-
drazones 4a,b. On the other hand, the reaction of 1 with
methyl or ethyl 2-chloroacetoacetate 2c,d or 2-chloro-
N,N-dimethyl-acetoacetamide 2e directly provides the
a-chloro-polymer-bound hydrazones 4c–e.
O
Scheme 1
ties,7 we decided to submit 1,2-diaza-1,3-butadienes in
solid-phase 5a–e to treatment with aromatic 1,2-diamines
6a–c.8
Reaction occurs in tetrahydrofuran (THF) under reflux
and gives directly free 3-methyl quinoxaline-2-carboxy-
lates 9a–h that were easily purified by chromatographic
methods (Scheme 2, Table 2). The reaction takes place by
the nucleophilic attack of an NH2 group of compounds 6
at position four of the azo-ene systems with formation of
1,4 adducts 7. Compounds 7 instantaneously result in fur-
ther internal attack of the second amino group at the C=N-
hydrazone group to give compounds 8 that, by loss of p-
toluenesulfonyl hydrazide and subsequent aromatization,
lead to a solution of the final products 9a–h.
Treatment of 4a–e with diisopropylethylamine (DIPEA)
in CH2Cl2 furnishes N=N-polymer-bound 1,2-diaza-1,3-
butadienes 5a–e (Scheme 1, Table 1).
In order to test the reactivity of these new polymer-bound
compounds and considering that quinoxaline derivatives
are attractive due to their wide range of biological activi-
In conclusion, the procedure described herein represents
one of the few examples reported in literature for the syn-
thesis of quinoxaline derivatives in solid phase.8,9
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1183,1185,ftx,en;D06503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1184
O. A. Attanasi et al.
LETTER
R2
R3
NH2
NH2
which reported the synthesis of a mixture of quinoxaline
isomers, we obtained pure final products.
H
N
O
R1
+
PSTs
N
Typical procedure for the synthesis of polymer-bound a-bro-
mo-hydrazones 4a,b
5a–e
6a–c
i-Propyl- or benzyl acetoacetate 2a,b (5 equiv) were added to a
magnetically stirred mixture of PS-Ts-NH-NH2 1 (0.500 g, 1.5
mmol per gram of resin) in THF (15 mL). The reaction mixture was
allowed to stand at room temperature for 8–10 h, to give polymer-
bound hydrazones 3a,b that were washed with THF (5 × 10 mL) and
CH2Cl2 (5 × 10 mL). To polymer-bound hydrazones 3a,b in CH2Cl2
(150 mL) PTAB (1 equiv) was added portionwise with magnetic
stirring. The reaction mixture was allowed to stand at room temper-
ature for 4 h to give polymer-bound a-bromo-hydrazones 4a,b, that
were washed with THF (5 × 10 mL) and CH2Cl2 (5 × 10 mL).
THF/reflux
H
N
O
PSTs
N
R1
NH
H2N
R3
Typical procedure for the synthesis of polymer-bound a-chloro-
hydrazones 4c–e
R2
Methyl or ethyl 2-chloroacetoacetate 2c,d or 2-chloro-N, N-dimeth-
yl-acetoacetamide 2e (5 equiv) were added to a magnetically stirred
mixture of PS-Ts-NH-NH2 1 (0.500 g, 1.5 mmol per gram of resin)
in THF (15 mL). The reaction mixture was allowed to stand at room
temperature for 5–10 h to give polymer-bound a-chloro-hydrazones
4c,d, that were washed with THF (5 × 10 mL) and CH2Cl2 (5 × 10
mL).
7
O
H
N
O
R1
PSTs
N
R1
N
N
HN
NH
H
Typical procedure for the synthesis of N=N-polymer-bound 1,2-
diaza-1,3-butadienes 5a–e
To polymer-bound a-halogenated-hydrazones 4a–e in CH2Cl2 (10
mL) was added under magnetic stirring DIPEA (2 equiv). The reac-
tion mixture was allowed to stand at room temperature for 0.1 h to
give N=N-polymer-bound 1,2-diaza-1,3-butadienes 5a–e that were
washed with THF (5 × 10 mL) and CH2Cl2 (5 × 10 mL).
R2
R3
R2
R3
9a–h
8
O
S
Typical procedure for the synthesis of 3-methyl quinoxaline-2-
carboxylates 9a–h
PSTs=
O
To N=N-polymer-bound 1,2-diaza-1,3-butadienes 5a–e in THF (20
mL) 4,5-dimethylbenzene-1,2-diamine 2a, benzene-1,2-diamine 2b
or naphtalene-2,3-diamine 2c (3 equiv) were added. The reaction
mixture was refluxed, with magnetic stirring, for 5–10 h furnishing
3-methyl quinoxaline-2-carboxylates 9a–h in solution. The residue
was washed with THF (5 × 10 mL) and CH2Cl2 (5 × 10 mL). After
evaporation of the solvent under reduced pressure, the residue was
purified by chromatography on a silica gel column (cyclohexane/
ethyl acetate) to give 9a–h, which were crystallized from diethyl
ether/petroleum ether (40–60 °C).
Scheme 2
In respect to our previous work in this field,8 this new
method simplifies the work-up procedure by avoiding the
cleavage step and permits the introduction of different
functional groups at position 2 of the quinoxaline system.
Furthermore, in contrast with the article of Wu and Ede,9
Table 1 Reaction Times for the Synthesis of Polymer Bound a-Halogenated Hydrazones 4a–e and Polymer-bound 1,2-Diaza-1,3-Butadienes
5a–e
2
R1
3
Reaction Time
(h)
4
Reaction Time
(h)
5
Reaction Time
(h)
2a
2b
2c
2d
2e
i-PrO
OBn
3a
3b
10.0
8.0
4a
4b
4c
4d
4e
4.0a
4.0a
10.0
5.0
5a
5b
5c
5d
5e
0.1
0.1
0.1
0.1
0.1
OMe
OEt
N(Me)2
7.0
a Reaction time for the bromination of 3a,b.
Synlett 2003, No. 8, 1183–1185 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Quinoxalines
1185
Table 2 Yield and Reaction Time for the Synthesis of 3-Methyl Quinoxaline-2-carboxylates 9a–h
5
R1
6
R2
Me
H
R3
Me
H
9
Reaction Time (h) Yield (%)
5a
5b
5c
5c
5d
5d
5d
Oi-Pr
OBn
OMe
OMe
OEt
OEt
OEt
6a
6b
6a
6b
6a
6b
6c
9a
9b
9c
9d
9e
9f
9g
8.0
7.0
31
28
38
24
25
27
19
Me
H
Me
H
7.0
5.0
Me
H
Me
H
8.0
6.0
10.0
5e
N(Me)2
6b
H
H
9h
5.0
15
(4) Attanasi, O. A.; Filippone, P.; Guidi, B.; Hippe, T.;
Acknowledgment
Mantellini, F.; Tietze, L. F. Tetrahedron Lett. 1999, 40,
9277.
This work was supported by financial assistance from the Ministero
dell’Università della Ricerca Scientifica Tecnologica
e
e
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Mantellini, F.; Tietze, L. F. Tetrahedron 2001, 57, 5855.
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Synlett 2003, No. 8, 1183–1185 ISSN 1234-567-89 © Thieme Stuttgart · New York