A recyclable copper catalysis in quinoxaline synthesis from α-hydroxyketones and o-phenylenediamines

Article abstract of DOI:10.1016/j.jorganchem.2009.06.002

o-Phenylenediamines react with α-hydroxyketones in toluene at 100 °C in the presence of a catalytic amount of a copper catalyst along with MS 4A under O₂ atmosphere to afford the corresponding quinoxalines in high yields. The catalytic system c

Full text of DOI:10.1016/j.jorganchem.2009.06.002

Journal of Organometallic Chemistry 694 (2009) 3215–3217
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Journal of Organometallic Chemistry
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Note
A recyclable copper catalysis in quinoxaline synthesis from a-hydroxyketones
and o-phenylenediamines
*
Chan Sik Cho , Wen Xiu Ren
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
o-Phenylenediamines react with
a-hydroxyketones in toluene at 100 °C in the presence of a catalytic
Received 16 March 2009
Received in revised form 29 May 2009
Accepted 2 June 2009
amount of a copper catalyst along with MS 4A under O2 atmosphere to afford the corresponding quinox-
alines in high yields. The catalytic system could be easily recovered and reused several times without any
loss of catalytic activity.
Available online 6 June 2009
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
a-Hydroxyketones
Oxidative cyclization
o-Phenylenediamines
Quinoxalines
Recyclable copper catalyst
1. Introduction
the quinoline synthesis to the reaction of o-phenylenediam-
ines with
a
-hydroxyketones. Herein we describe a recyclable
-hydroxyketones
Transition metal-catalyzed in situ oxidation of alcohols to
carbonyl compounds followed by condensation (oxidative cycliza-
tion) frequently provides a convenient synthetic route for N-het-
erocycles. Several synthetic methods for N-heterocycles have
been exemplified with such a transition metal-catalyzed oxidative
cyclization. As the part of our ongoing studies on transition metal-
catalyzed carbon–carbon bond forming reactions using alcohols as
an electrophile, we recently disclosed on ruthenium- and palla-
dium-catalyzed coupling processes between ketones (or secondary
alcohols) and primary alcohols [1–10]. This type of carbon–carbon
bond forming reaction could be applied to the synthesis of
quinolines via transition metal-catalyzed oxidative cyclization of
2-aminobenzyl alcohol with ketones and secondary alcohols
[11–19]. Recently, we developed an economical reusable catalytic
system, CuCl2 combined with molecular sieve 4A (MS 4A) for this
oxidative cyclization [20]. It is also reported by us that vicinal-diols
are oxidatively cyclized with o-phenylenediamines in the presence
copper-catalyzed oxidative cyclization of
a
with o-phenylenediamines leading to quinoxalines (Scheme 1)
[27,28].
2. Results and discussion
Initial attempts for the oxidative cyclization of 2-hydroxyaceto-
phenone (2a) with o-phenylenediamine (1a) were carried out un-
der several conditions and the results are listed in Table 1. We
recently reported that 1a reacts with 2a in toluene at 100 °C for
3 h in the presence of a catalytic amount of CuCl2 under an atmo-
sphere of air afforded 2-phenylquinoxaline (3a) in 94% yield [26].
When the reaction was carried out with further addition of molec-
ular sieve 4A (MS 4A) as a recyclable medium to the copper cata-
lytic system, 3a was obtained in 80% isolated yield (entry 1) and
the copper catalytic system could be easily recovered by simple fil-
tration from the reaction mixture. No Cu in the filtrate was ob-
served by ICP-AES (inductively coupled plasma-atomic emission
spectroscopy) determination. However, although the recovered
CuCl2/MS 4A could be reused several times, the catalytic activity
during second to fourth runs was lower than that of first run. Per-
forming the reaction for a longer reaction time (10 h) gave an in-
creased yield of 3a and the recovered CuCl2/MS 4A could be
reused three times without any loss of catalytic activity (entry 2).
A slightly increased yield of 3a was observed with a higher molar
of a ruthenium catalyst to afford quinoxalines [21]. a-Hydroxyke-
tones were also found to undergo an oxidative cyclization with
o-phenylenediamines in the presence of a transition metal catalyst
to afford quinoxalines [22–26]. Under these circumstances,
the present work was disclosed during the course of the applica-
tion of the recyclable copper catalytic system (CuCl2/MS 4A) for
* Corresponding author. Tel.: +82 53 950 5586; fax: +82 53 950 6594.
E-mail address: cscho@knu.ac.kr (C.S. Cho).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.06.002

3216
C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 694 (2009) 3215–3217
Table 2
O
R
R
N
N
R'
R
R
NH2
NH2
CuCl2, O2
MS 4A, toluene
Recyclable copper-catalyzed synthesis of quinoxalines 3 from 1 and 2a
HO
+
R''
1
a
-Hydroxyketones 2
Quinoxalines 3
Yield (%)
R''
R'
1
2
3
Scheme 1.
N
O
HO
R
N
R
1a
2a R = Ph
3a R = Ph
95
88
88
88
89
87
84
88
89
84
77
95
85
84
86
83
83
81
84
90
83
73
96
85
84
85
83
83
82
84
90
85
72
2b R = 4-MeC6H4
2c R = 3-MeC6H4
2d R = 2-MeC6H4
2e R = 4-MeOC6H4
2f R = 3-MeOC6H4
2g R = 2-MeOC6H4
2h R = 4-FC6H4
2i R = 3-CF3C6H4
2j R = 2-naphthyl
2k R = 2-thienyl
3b R = 4-MeC6H4
3c R = 3-MeC6H4
3d R = 2-MeC6H4
3e R = 4-MeOC6H4
3f R = 3-MeOC6H4
3g R = 2-MeOC6H4
3h R = 4-FC6H4
3i R = 3-CF3C6H4
3j R = 2-naphthyl
3k R = 2-thienyl
Table 1
Copper-catalyzed reaction of 1a with 2a under several conditionsa
NH2
N
N
O
CuCl2
MS 4A, toluene
+
HO
Ph
Ph
NH2
1a
2a
3a
.
Entry
[2a]/[1a]
Atmosphere
Time (h)
Isolated yield (%)
1
2
3
4
5
6
58
57
56
N
O
1
2
3
1.0
1.0
1.1
1.1
1.1
1.1
Air
Air
Air
O2
O2
O2
3
80
91
95
90
41
95
67
86
95
91
38
95
63
84
90
88
40
96
66
85
90
86
43
95
HO
10
10
3
3
10
N
89
84
88
87
2l
O
3l
4
5b
6
N
63
87
61
87
60
87
HO
94
93
N
a
All reactions were carried out with 1a (0.5 mmol), CuCl2 (0.05 mmol) and MS 4A
(0.3 g) in toluene (5 mL) at 100 °C.
3m
2m
b
In the absence of CuCl2.
O
N
N
Me
Ph
HO
Ph
ratio of 2a to 1a and the recovered CuCl2/MS 4A could be reused
five times without any loss of catalytic activity (entry 3). Further-
more, performing the reaction under O2 atmosphere resulted in a
higher catalytic activity compared with that under air atmosphere
(entries 1 and 4) and the presence of CuCl2 was essential for the
effective formation of 3a (entry 5). As a result, the best result in
terms of both yield and catalytic activity of recovered CuCl2/MS
4A was accomplished by the standard set of reaction conditions
shown in entry 6 of Table 1.
After the reaction conditions have been established, various a-
hydroxyketones 2 were subjected to the reaction with o-phenylen-
ediamines 1 in order to investigate the reaction scope and several
representative results are summarized in Table 2. With a-hydroxy-
3n
2n
O
N
N
62
88
60
86
59
84
Ph
Ph
OH
3o
2o
Me
N
N
1b
2a
Me
Ph
3p
a
All reactions were carried out with
(0.05 mmol) and MS 4A (0.3 g) in toluene (5 mL) at 100 °C for 10 h under O2
1 (0.5 mmol), 2 (0.55 mmol), CuCl2
atmosphere.
ketones (2a–i) having aryl group attached to carbonyl carbon, the
corresponding quinoxalines (3a–i) were formed in the range of
84–95% yields without any identifiable side products. The position
and electronic nature of the substituent on the aromatic ring had
no relevance to the quinoxaline yield. As is the case for the reaction
of 1a with 2a, the copper combined with MS 4A as recyclable med-
ium also could be recovered and reused three times without any
loss of catalytic activity. 2-Hydroxy-20-acetonaphthone (2j) was
also oxidatively cyclized with 1a to give 2-(2-naphthyl)quinoxaline
in 84% yield and exhibited similar recycling potential. Although the
3. Conclusion
In summary, we have shown that a-hydroxyketones undergo an
oxidative cyclization with o-phenylenediamines in the presence of
a copper catalyst combined with MS 4A under O2 atmosphere to
give quinoxalines in high yields. The copper catalyst combined
with MS 4A could be easily recovered by a simple filtration and re-
used several times without any loss of catalytic activity. The pres-
ent reaction provides a cheaper catalytic method for quinoxalines
compared with known catalytic routes and further study of syn-
thetic applications using the present recyclable copper catalytic
system is currently under investigation.
reaction proceeds with
group attached to carbonyl carbon, the product yield was lower
than that when -hydroxyketones (2a–j) having aryl group at-
tached to carbonyl carbon were employed. Lower reaction rate
and yield were observed with -hydroxyketone 2l which has an al-
kyl group attached to carbonyl carbon. From the reaction between
1a and cyclic -hydroxyketone 2m, 6,7,8,9-tetrahydrophenazine
(3m) was also produced in 63% yield. Similar treatment of
hydroxyketones (2n and 2o), which have an alkyl group attached
to -carbon with 1a under the employed conditions afforded the
a-hydroxyketones 2k having a heteroaryl
a
a
4. Experimental
a
a
-
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a
Bruker Avance Digital 400 spectrometer using TMS as an internal
standard. ICP-AES was measured on a Thermo Jarrell Ash IRIS/AP.
The isolation of pure products was carried out via thin layer chroma-
tography (silica gel 60 GF254, Merck). Except for 1-hydroxyhexan-2-
one (2l), which was prepared by selective oxidation of diols [29], all
a
corresponding 3-alkyl substituted quinoxalines (3n and 3o). The
reaction of dimethyl-1,2-phenylenediamine (1b) with 2a also pro-
ceeds to give 6,7-dimethyl-2-phenylquinoxaline (3p) with similar
yield and recycling potential.
a-hydroxyketones were synthesized by direct a-hydroxylation of

C.S. Cho, W.X. Ren / Journal of Organometallic Chemistry 694 (2009) 3215–3217
3217
ketones with [bis(trifluoroacetoxy)iodo]benzene and trifluoroacetic
acid [30] as well as -bromination of of ketones followed by hydrox-
ylation [31,32]. Commercially available organic and inorganic com-
(0.3 g) and dry toluene (5 mL). After the system was connected to
an air balloon, the reaction mixture was allowed to react at
100 °C for 3 h. The reaction mixture cooled to room temperature
was filtered through a filter paper and washed with ethyl acetate.
After the filtrate was evaporated under reduced pressure, the res-
idue was dissolved in chloroform (30 mL) and poured into a separ-
atory funnel containing 5% HCl aqueous solution (200 mL). The
aqueous phase was subjected to ICP-AES measurement.
a
pounds were used without further purification.
4.1. Typical procedure for copper-catalyzed synthesis of quinoxalines
from o-phenylenediamines and a-hydroxyketones
To an organic reactor (Radleys Discovery Technologies) were
added o-phenylenediamine (0.054 g, 0.5 mmol), 2-hydroxyaceto-
phenone (0.075 g, 0.55 mmol), CuCl2 (0.007 g, 0.05 mmol), MS 4A
(0.3 g) and dry toluene (5 mL). After the system was flushed with
O2 from a balloon connected to the organic reactor, the reaction
mixture was allowed to react at 100 °C for 10 h. The reaction mix-
ture cooled to room temperature was filtered through a filter pa-
per, washed with ethyl acetate, dried under vacuo and subjected
to a second run by charging the reactor with 1a, 2a, toluene and
O2 substitution. Removal of the solvent from the filtrate left an
oil, which was purified by thin layer chromatography (silica gel,
ethyl acetate–hexane = 1/5) to give 2-phenylquinoxaline (3a)
(0.098 g, 95%). Except for 3i and 3o, which were characterized
spectroscopically as shown below, all quinoxalines exhibited char-
acteristics identical to those previously synthesized by our recent
reports [21,26].
Acknowledgement
This research was supported by Kyungpook National University
Research Fund (2008).
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4.1.1. 2-(3-Trifluoromethylphenyl)quinoxaline (3i)
Solid, m.p. 115 °C (from hexane–chloroform); 1H NMR (CDCl3) d
7.67 (t, J = 7.8 Hz, 1H), 7.74–7.82 (m, 3H), 8.12–8.17 (m, 2H), 8.36
(d, J = 7.8 Hz, 1H), 8.50 (s, 1H), 9.32 (s, 1H); 13C NMR (CDCl3) d
124.39 (q, J = 270.8 Hz), 124.81 (q, J = 3.9 Hz), 127.09 (q,
J = 3.6 Hz), 129.40, 129.81, 129.90, 130.28, 130.74, 130.79, 132.09
(q, J = 32.24 Hz), 137.73, 142.08, 142.37, 142.94, 150.28. Anal. Calc.
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N, 10.18.
4.1.2. 2-Butyl-3-phenylquinoxaline (3o)
Solid, m.p. 39–41 °C (from hexane–chloroform); 1H NMR
(CDCl3) d 0.84 (t, J = 7.5 Hz, 3H), 1.27–1.36 (m, 2H), 1.68–1.76 (m,
2H), 3.04 (t, J = 7.8 Hz, 2H), 7.48–7.54 (m, 3H), 7.60–7.62 (m, 2H),
7.67–7.75 (m, 2H), 8.07–8.12 (m, 2H); 13C NMR (CDCl3) d 13.96,
22.73, 31.30, 35.94, 128.66, 128.68, 128.95, 129.00, 129.30,
129.36, 129.75, 139.36, 140.87, 141.62, 155.22, 156.49. Anal. Calc.
for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.22; H, 7.02;
N, 10.48.
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4.2. ICP-AES measurement
To an organic reactor (Radleys Discovery Technologies) were
added o-phenylenediamine (0.054 g, 0.5 mmol), 2-hydroxyaceto-
phenone (0.068 g, 0.5 mmol), CuCl2 (0.007 g, 0.05 mmol), MS 4A