A new ruthenium-catalyzed approach for quinoxalines from o-phenylenediamines and vicinal-diols

Article abstract of DOI:10.1016/j.tetlet.2006.06.038

o-Phenylenediamines react with an array of vicinal-diols in diglyme in the presence of a catalytic amount of a ruthenium catalyst along with KOH to afford the corresponding quinoxalines in good yields.

Full text of DOI:10.1016/j.tetlet.2006.06.038

Tetrahedron Letters 47 (2006) 5633–5636
A new ruthenium-catalyzed approach for quinoxalines from
o-phenylenediamines and vicinal-diols
Chan Sik Choa,* and Sung Gi Ohb
aResearch Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, South Korea
bDepartment of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Received 14 April 2006; revised 5 June 2006; accepted 6 June 2006
Available online 27 June 2006
Abstract—o-Phenylenediamines react with an array of vicinal-diols in diglyme in the presence of a catalytic amount of a ruthenium
catalyst along with KOH to afford the corresponding quinoxalines in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
R1
R1
NH2
NH2
It is known that quinoxaline plays an important role as a
basic skeleton for the design of many pharmacologically
and biologically active compounds such as insecticides,
fungicides, herbicides and anthelmintics.1 Conventional
quinoxaline synthesis can be achieved by double con-
densation between o-phenylenediamines and 1,2-dicar-
bonyl compounds. However, the conventional process
has frequently suffered from the handling of highly reac-
tive dicarbonyl compounds. As an elegant alternative, it
was recently reported that a-hydroxy ketones are oxida-
tively cyclized with o-phenylenediamines in the presence
of a transition metal catalyst to give quinoxalines.1–3 As
part of our studies directed towards ruthenium-cata-
lyzed organic syntheses and transformations, we re-
cently found several coupling reactions between
carbonyl compounds and alcohols.4–6 These reactions
could be applied to modified Friedla¨ender quinoline
synthesis via ruthenium-catalyzed consecutive coupling
and cyclization of 2-aminobenzyl alcohol with ketones
and secondary alcohols, which is superior to conven-
tional Friedla¨ender method7–9 in a sense of price and
stability of 2-aminobenzyl alcohol.10–14 Prompted by
these findings, we have directed our attention to the syn-
thesis of N-heterocycles using such an intrinsic ruthe-
nium-catalyzed oxidative cyclization of alcohols.15–17
Herein, we report a ruthenium-catalyzed synthesis of
quinoxalines from o-phenylenediamines and vicinal-
diols in the presence of KOH.
HO
HO
R1
R1
N
N
RuCl2(PPh3)3
diglyme
+
R2
R2
1a R = H
1b R = Me
2
3
Scheme 1.
Initial attempts for the oxidative cyclization between
o-phenylenediamine (1a) and 1-phenyl-1,2-ethanediol
(2a, 2: R2 = Ph) were examined under several conditions
(Scheme 1). Treatment of equimolar amount of 1a and
2a in diglyme in the presence of a catalytic amount of
RuCl2(PPh3)3 and KOH at reflux for 20 h afforded 2-
phenylquinoxaline (3a, 3: R1 = H; R2 = Ph) in 50%
yield (Table 1, run 1). The yield of 3a was considerably
affected by the molar ratio of 2a to 1a, [2a]/[1a] = 2
being the choice of preference for the effective formation
of 3a (run 2). Recently, we observed on the dramatic
acceleration of reaction rate by the addition of a hydro-
gen acceptor for ruthenium-catalyzed coupling of
Table 1. Effect of molar ratio, bases and hydrogen acceptors on
RuCl2(PPh3)3-catalyzed synthesis of 3a from 1a and 2aa
Run
[2a]/[1a]
Base
Additives
Yield (%)
1
2
3
4
5
6
1
2
2
2
2
2
KOH
KOH
KOH
KOH
—
—
—
50
75
82
76
13
18
Benzalacetone
1-Dodecene
—
Keywords: Cyclization; o-Phenylenediamines; Quinoxalines; Ruthe-
nium catalyst; Vicinal-diols.
—
Benzalacetone
*
Corresponding author. Tel.: +82 53 950 7318; fax: +82 53 950
a Reaction conditions: 1a (0.5 mmol), RuCl2(PPh3)3 (0.02 mmol),
6594; e-mail: cscho@knu.ac.kr
KOH (2 mmol), additive (1 mmol), diglyme (5 mL), reflux, for 20 h.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.038

5634
C. S. Cho, S. G. Oh / Tetrahedron Letters 47 (2006) 5633–5636
secondary alcohols with primary alcohols and oxidative
cyclization of 2-aminobenzyl alcohol with secondary
alcohols.6,11 However, the addition of benzalacetone as
a hydrogen acceptor at the present reaction resulted in
a slightly increased yield of 3a to 82%, whereas that of
1-dodecene showed no significant change (runs 3 and
4).18 The presence of KOH was essential for the effective
formation of 3a. Performing the reaction in the absence
of KOH resulted in only 13% yield of 3a (run 5). Here
again, a slight increase in the yield of 3a was observed
with the addition of benzalacetone (run 6). It is
known that strong bases are used as promoters in
transition metal-catalyzed transfer hydrogenation from
alcohols.19
range of 63–82% yields without any identifiable side
product. The product yield was not significantly affected
by the position of the substituent on the aromatic ring of
2a–h, whereas the electronic nature of that had some rel-
evance to the product yield. The reaction proceeds like-
wise with 4,5-dimethyl-1,2-phenylenediamine (1b) to
give the corresponding quinoxalines (3i and 3j) in similar
yields. In the reaction of 1-(2-naphthyl)-1,2-ethanediol
(2i),20–22 2-(2-naphthyl)quinoxaline (3k) was also ob-
tained in 75% yield. The reaction of 1-(2-furyl)-1,2-
ethanediol (2j)20–22 with 1a also proceeds to give the cor-
responding quinoxaline 3l in 69% yield. 1,2-Diol 2k,
which has an alkyl substituent at carbon bearing hydr-
oxyl group, was also readily oxidatively cyclized with 1a
to afford 2-butylquinoxaline (3m) in 68% yield. Internal
vicinal-diol 2l, which has alkyl substituents at both car-
bons bearing hydroxyl group, was also reacted with 1a
to give 2,3-dimethylquinoxaline (3n) in similar yield.
From the reaction between 1a and cyclic 1,2-diol 2m
(cis- and trans-mixture), 6,7,8,9-tetrahydrophenazine
(3o) was produced in high yield.
Having established the reaction conditions, various vic-
inal-diols 2 were subjected to react with 1 in order to
investigate the reaction scope and several representative
results are summarized in Table 2. From the reactions
between 1a and 1-aryl-1,2-ethanediol (2a–h),20–22 the
oxidative cyclized products (3a–h) were formed in the
Table 2. Ruthenium-catalyzed synthesis of quinoxalines 3 from o-phenylenediamines 1 and vicinal-diols 2a
1
Diols 2
Quinoxalines 3
Yield (%)
82
HO
N
3a
2a
1a
HO
N
HO
HO
N
N
1a
1a
2b
2c
3b
3c
80
76
Me
Me
Me
Me
HO
HO
N
N
HO
N
Me
Me
1a
1a
2d
2e
3d
3e
81
73
HO
HO
N
N
HO
N
OMe
OMe
OMe
OMe
HO
HO
N
N
1a
1a
1a
2f
3f
76
72
63
HO
HO
N
N
OMe
OMe
2g
2h
3g
3h
HO
HO
N
N
F
F
HO
HO
Me
Me
N
N
1b
2a
3i
84

C. S. Cho, S. G. Oh / Tetrahedron Letters 47 (2006) 5633–5636
5635
Table 2 (continued)
1
Diols 2
Quinoxalines 3
Yield (%)
79
HO
Me
Me
N
N
1b
2b
3j
HO
Me
Me
HO
HO
N
N
1a
1a
1a
2i
3k
3l
75
69
68
HO
HO
N
N
2j
O
O
HO
HO
N
N
2k
3m
HO
HO
Me
Me
N
N
Me
Me
1a
1a
2l
3n
3o
79
82
HO
HO
N
N
2m
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), RuCl2(PPh3)3 (0.02 mmol), KOH (2 mmol), benzalacetone (1 mmol), diglyme (5 mL), reflux, for
20 h.
As to the mechanistic aspects for the present reaction, it
seems to proceed via an initial oxidation of diols 2 to
mono-carbonyls as well as di-carbonyls followed by
condensation with diamines. It is known that the oxida-
tion is catalyzed by a ruthenium along with a strong
base.19 Partial enhancement of the reaction by the addi-
tion of benzalacetone seems to be due to partial acceler-
ation of the initial oxidation by transfer hydrogenation
from 2 to benzalacetone.19
Acknowledgement
The present work was supported by a Research Profes-
sor Grant of Kyungpook National University (2005).
References and notes
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vicinal-diol (1 mmol), RuCl2(PPh3)3 (0.02 mmol), KOH
(2 mmol), benzalacetone (1 mmol) and diglyme (5 mL).
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