An iodobenzene-catalysed domino route toward quinoxaline derivatives from simple ketones and o-phenylenediamines in one pot

Article abstract of DOI:10.3184/174751913X13758803237636

An iodobenzene-catalysed domino route to quinoxalines from ketones and o-phenylenediamines in one pot has been developed. This transformation consisted of the generation of Koser's generation, α-tosyloxylation of ketones, nucleophilic substitution and intramolecular dehydration with o-phenylenediamines, and dehydrogenation. Website

Full text of DOI:10.3184/174751913X13758803237636

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 579
SEPTEMBER, 579–581
An iodobenzene-catalysed domino route toward quinoxaline derivatives
from simple ketones and o-phenylenediamines in one pot
Xiaoqing Lia*, Can Zhoua, Zhiyan Hub and Xiangsheng Xua
aCollege of Chemical Engineering and Materials Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
bSchool of Science, Zhejiang Agriculture and Forestry University, Lin’an, Hangzhou, Zhejiang, 311300, P. R. China
An iodobenzene-catalysed domino route to quinoxalines from ketones and o-phenylenediamines in one pot has
been developed. This transformation consisted of the generation of Koser’s generation, α-tosyloxylation of ketones,
nucleophilic substitution and intramolecular dehydration with o-phenylenediamines, and dehydrogenation.
Keywords: iodobenzene, quinoxaline, ketones, o-phenylenediamines, tosyloxylation
Quinoxaline derivatives represent an important class of hetero-
cyclic compounds because of their bioactivities,1 pharmaceuti-
cal applications,2 and physical properties.3–4 Traditionally,
this type of heterocycle was synthesised by the coupling
of 1,2-diamine with prefunctionalised ketones, such as
α-hydroxyketones,5 α-halo-β-ketoesters,6 α-halo-ketones,7 and
1,2-dicarbonyl compound.8–11 Several domino routes in one
pot from simple ketones have also been developed to obviate
the prefunctionalisation of ketones, thus simplifying the opera-
tion.12,13 Recently, we developed a new domino protocol for
the synthesis of quinoxalines from simple ketones which
employs [Hydroxy(tosyloxy)iodo]benzene (HTIB) mediated
α-tosyloxylation of simple ketones (Scheme 1).14 However, it
has been reported that the α-tosyloxylation of simple ketones
can be achieved in a more environmentally friendly and eco-
nomical manner by using iodobenzene as catalyst in the pres-
ence of m-CPBA and p-toluenesulfonic acid (Scheme 1).15–17
Encouraged by our previous work, we envisioned that this
methodology might also be applied to the synthesis of quinox-
alines. Herein, we report the realisation of this goal leading
to a convenient HTIB-free method for the construction of
quinoxalines (Scheme 1).
acid was carried out at 50 °C for 5 h. Then the o-diaminoben-
zene was added and the mixture was stirred for another 9 h.
The desired product was isolated in 46% yield (Table 1, entry
2). Increasing the reaction temperature of the second stage
to 80 °C gave the desired product 3a in 80% yield (Table 1,
entry 3). In control reactions without iodobenzene as the
catalyst (Table 1, entry 4) or without m-CPBA as the oxidant
(Table 1, entry 5), none of the target product was obtained.
Table 1 Optimisation of the reaction conditionsa
Entry Variation from the “standard conditions” Yield/%b
1
2
3
4
5
6
One-stage reaction at 50 or 80 °C
Two-stage reaction at 50 °C
Standard conditions
0
46
80
0
Results and discussion
Our initial work focused on the reaction of acetophenone (1a)
with o-diaminobenzene (2a) (Table 1). When the reaction was
performed in one stage with 10 mol% of iodobenzene, 1.1
equiv. of m-CPBA and 1.1 equiv. of p-toluenesulfonic acid in
acetonitrile, none of the desired product (3a) was obtained
(Table 1, entry 1). We then tested the two-stage reactions in one
pot. In the first stage, iodobenzene-catalysed α-tosyloxylation
of acetophenone (1a) with m-CPBA and p-toluenesulfonic
No iodobenzene
No m-CPBA
0
Oxone® instead of m-CPBA
23
a Standard reaction conditions: the first stage: 1a (0.5 mmol),
iodobenzene (10 mol %), m-CPBA (0.55 mmol), p-toluenesul-
fonic acid (0.55 mmol), MeCN (3 mL), 50 °C, 5 h; the second
stage: 2a (0.6 mmol), 80 °C, 9h.
b Isolated yield.
Scheme 1 Proposed domino route toward quinoxalines.
* Correspondent. E-mail: xqli@zjut.edu.cn

580 JOURNAL OF CHEMICAL RESEARCH 2013
The yield decreased when m-CPBA was replaced to Oxone®
(Table 1, entry 6).
III 500 (500 MHz) instrument in CDCl3 using tetramethylsilane
(TMS) as the internal standard. Chemical shifts (δ) are reported in
ppm and coupling constants J are given in Hz.
To define the scope of the oxidative coupling reaction, we
applied this process to a series of acetophenones (Table 2,
entries 1–9). A variety of functional groups, including methyl,
methoxy, halo and naphthyl were tolerated under the optimised
conditions. Heteroarenes, such as 2-acetylfuran, 2-acetylthio-
phene, and 2-acetylpyridine also underwent the coupling to
give the corresponding quinoxalines 3l–n in moderate yields
(entries 10–12). We were pleased to see that under our opti-
mized reaction conditions, the reaction of α-substituted aceto-
phenones, such as 2-phenylacetophenone, propiophenone and
ethyl benzoylacetate proceeded smoothly to afford the desired
quinoxalines 3i–k (entries 13–15). Preliminary results have
shown that an aliphatic ketone, such as 3-pentanone also
worked for this reaction (entry 16). Finally, the reaction was
examined with 4,5-diCl and 4,5-diMe substituted o-diamino-
benzene, which were treated with acetophenone under the
standard reaction conditions. The reaction worked smoothly,
leading to the formation of the corresponding quinoxalines 3q
and 3r in 44% and 70% yields, respectively (entries 17 and 18).
In conclusion, we have developed a facile and economical
one-pot procedure for the synthesis of quinoxalines through
iodobenzene-catalysed oxidative coupling of ketones and
o-phenylenediamines in the presence of m-chloroperbenzoic
acid and p-toluenesulfonic acid. Compared with previous
reports, this novel protocol is distinguished by the freedom from
stoichiometric amounts of hypervalent iodine compounds.
Synthesis of quinoxalines 3a–r; general procedure
A mixture of ketones 1 (0.5 mmol), iodobenzene (10.2 mg, 0.05 mmol),
p-TsOH·H2O (104.7mg, 0.55 mmol), and m-CPBA (75% purity,
128.7 mg, 0.55 mmol) in MeCN (3 mL) was stirred at 50 °C for 5 h.
Then o-phenylenediamines 2 (0.6 mmol) was added and stirred at
80 °C until the intermediate for the first step disappeared. After the
reaction, the solvent was removed under reduced pressure, and the
residue was purified by chromatography on silica gel (100−200 mesh)
using petroleum ether/EtOAc (15/1, v/v) as the eluent to give products
3. The structures and yields of the products are given in Table 2. All
compounds 3 are known.
2-Phenylquinoxaline (3a): Yellow solid, m.p. 73–74 °C (lit.7 74–
1
76 °C); H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 8.10–8.07 (m,
2H), 8.06–8.00 (m, 2H), 7.68–7.61 (m, 2H), 7.41–7.39 (m, 3H).
2-p-Tolylquinoxaline (3b): Pale yellow solid, m.p. 88–90 °C (lit.7
90–91 °C); 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.16–8.10 (m,
4H), 7.79–7.71 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H).
2-o-Tolylquinoxaline (3c): Yellow solid, m.p. 88–89 °C (lit.5 91–
1
92 °C); H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.18–8.14 (m,
2H), 7.83–7.78 (m, 2H), 7.56 (dd, J = 7.8, 1.4 Hz, 1H), 7.43–7.36 (m,
3H), 2.48 (s, 3H).
2-(4-Chlorophenyl)quinoxaline (3d): White solid, m.p. 129–130 °C
(lit.7 127–128 °C); 1H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H),
8.18–8.13 (m, 4H), 7.83–7.75(m, 2H), 7.55 (d, J = 8.6 Hz, 2H).
2-(2-Chlorophenyl)quinoxaline (3e): White solid, m.p. 88–89 °C
(lit.7 86–88 °C); 1H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 8.20–8.17
(m, 2H), 7.82 (dd, J = 6.4, 3.4 Hz, 2H), 7.76–7.73 (m, 1H), 7.58–7.55
(m, 1H), 7.48–7.45 (m, 2H).
2-(4-Methoxyphenyl)quinoxaline (3f): White solid, m.p. 98–99 °C
(lit.7 100–101 °C); 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H),
8.20–8.17 (m, 2H), 8.14–8.09 (m, 2H), 7.79–7.75 (m, 1H), 7.72–7.70
(m, 1H), 7.10–7.07 (m, 2H), 3.91 (s, 3H).
2-(4-Fluorophenyl) quinoxaline (3g): Yellow solid, m.p. 119–
121 °C (lit.7 120–122 °C); 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H),
8.24–8.18 (m, 2H), 8.15–8.12 (m, 2H), 7.81–7.74 (m, 2H), 7.28–7.23
(m, 2H).
Experimental
All reagents and solvents were purchased from commercial suppliers
and were used without purification. Melting points were measured on
a Büchi B-545. 1H NMR spectra were obtained on a Bruker AVANCE
Table 2 Synthesis of substituted quinoxalinea
2-(4-Bromophenyl)quinoxaline (3h): White solid, m.p. 132–135 °C
(lit.7 136–139 °C); 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.17–
8.12 (m, 2H), 8.10 (d, J = 8.6 Hz, 2H), 7.82–7.76 (m, 2H), 7.72–7.69
(m, 2H).
2,3-Diphenylquinoxaline (3i): White solid, m.p. 128–129 °C
(lit.18 129–130 °C); 1H NMR (500 MHz, CDCl3) δ 8.21–8.17 (m, 2H),
7.80–7.76 (m, 2H), 7.55–7.50 (m, 4H), 7.39–7.32 (m, 6H).
2-Methyl-3-phenylquinoxaline (3j): White solid, m.p. 53–55 °C
1
(lit.13 55–57 °C); H NMR (500 MHz, CDCl3) δ 8.14–8.10 (m, 1H),
8.10–8.05 (m, 1H), 7.74 (m, 2H), 7.68–7.65 (m, 2H), 7.56–7.49 (m,
3H), 2.80 (s, 3H).
Entry
R1
R2
R3
Time/hb Product Yield/%c
Ethyl 3-phenylquinoxaline-2-carboxylate (3k): White solid, m.p.
45–47 °C (lit.19 46–48 °C); 1H NMR (500 MHz, CDCl3) δ 8.24–8.18
(m, 2H), 7.88–7.81 (m, 2H), 7.76–7.73 (m, 2H), 7.55–7.49 (m, 3H),
4.34 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).
1
2
Ph
p-MeC6H4
o-MeC6H4
p-ClC6H4
o-ClC6H4
p-MeOC6H4
p-FC6H4
p-BrC6H4
1-naphthyl
2-furanyl
2-thiophenyl
2-pyridinyl
Ph
H
H
H
H
9
8
3a
3b
3c
3d
3e
3f
80
58
40
48
42
36
29
85
47
53
65
57
21
57
38
32
44
70
3
H
H
10
6
7
2-(Furan-2-yl)quinoxaline (3l): Pale red solid, m.p. 96–97 °C (lit.5
97–98 °C); 1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 8.13–8.07 (m,
2H), 7.79–7.75 (m, 1H), 7.74–7.70 (m, 2H), 7.34 (dd, J = 3.5, 0.6 Hz,
1H), 6.65 (dd, J = 3.5, 1.7 Hz, 1H).
4
H
H
5
H
H
6
H
H
10
10
7
7
H
H
3g
3h
3p
3l
8
H
H
2-(Thiophen-2-yl)quinoxaline (3m):12 Pale yellow solid, m.p. 113–
114 °C (lit. 110–112 °C); 1H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H),
8.09–8.06 (m, 2H), 7.87 (dd, J = 3.7, 0.9 Hz, 1H), 7.77–7.74 (m, 1H),
7.72–7.68 (m, 1H), 7.55 (dd, J = 5.0, 0.9 Hz, 1H), 7.21 (dd, J = 5.0,
3.7 Hz, 1H).
9
H
H
6
10
11
12
13
14
15
16
17
18
H
H
6
H
H
7
3m
3n
3i
H
H
7
Ph
Me
COOEt
Et
H
H
11
9
2-(Pyridin-2-yl)quinoxaline (3n): Pink solid, m.p. 110–112 °C
(lit.12 110–111 °C); 1H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 8.80
(d, J = 3.8 Hz, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.17 (dd, J = 6.5, 3.0 Hz,
2H), 7.94–7.91 (m, 1H), 7.83–7.77 (m, 2H), 7.43 (dd, J = 6.9, 5.0 Hz,
1H).
Ph
H
3j
Ph
H
8
3k
3o
3q
3r
Et
H
10
9
Ph
Me
Cl
Ph
H
9
2-Ethyl-3-methylquinoxaline (3o): White solid, m.p. 58–59 °C (lit.19
55 °C); 1H NMR (500 MHz, CDCl3) δ 8.04–7.96 (m, 2H), 7.69–7.65
(m, 2H), 3.04 (q, J = 7.5 Hz, 2H), 2.77 (s, 3H), 1.42 (t, J = 7.5 Hz,
3H).
a Standard reaction conditions: the first stage: 1 (0.5 mmol),
iodobenzene(10mol%),m-CPBA(0.55mmol),p-toluenesulfonic
acid (0.55 mmol), MeCN (3 mL), 50 °C, 5 h; the second stage:
2 (0.6 mmol), 80 °C.
b Reaction time of the second stage.
2-(Naphthalen-2-yl)quinoxaline (3p): Brown solid, m.p. 137–
c Isolated yield.
139 °C (lit.5 140–142 °C); 1H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H),

JOURNAL OF CHEMICAL RESEARCH 2013 581
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6,7-Dimethyl-2-phenylquinoxaline (3q): White solid, m.p. 126–
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8.15 (d, J = 7.1 Hz, 2H), 7.89 (s, 1H), 7.84 (s, 1H), 7.57–7.48 (m, 3H),
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156 °C (lit.7 153–156 °C); 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H),
8.28 (s, 1H), 8.24 (s, 1H), 8.19 (dd, J = 8.0, 1.6 Hz, 2H), 7.60–7.56
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Received 22 March 2013; accepted 1 July 2013
Paper 1301853 doi: 10.3184/174751913X13758803237636
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