Iodine-mediated efficient synthesis of 2,3-dihydro-pyrazines

Article abstract of DOI:10.3184/174751915X14360237431600

The synthesis of 2,3-dihydro-pyrazines has been developed by an efficient protocol of annulations of 1,2-diketones and ethylenediamine. A variety of 2,3-dihydro-pyrazines were prepared in high yields in the presence of a catalytic amount of iodine.

Full text of DOI:10.3184/174751915X14360237431600

430 RESEARCH PAPER
VOL. 39 JULY, 430–432
JOURNAL OF CHEMICAL RESEARCH 2015
Iodine-mediated efficient synthesis of 2,3-dihydro-pyrazines
Yansheng Dong, Li Huang and Fengping Yi*
School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, P.R. China
The synthesis of 2,3-dihydro-pyrazines has been developed by an efficient protocol of annulations of 1,2-diketones and ethylenediamine.
A variety of 2,3-dihydro-pyrazines were prepared in high yields in the presence of a catalytic amount of iodine.
Keywords: 2,3-dihydro-pyrazines, 1,2-diketones, ethylenediamine, iodine-mediated, organic reaction
The synthesis of heterocycles has received much attention
solvents at the optimal reaction temperature. Although these
reactions also provided 2a in moderate to good yields in the
other testing solvents, the highest yield of 2a was observed in
1-3
owing to their biological activity. As a category of important
N-heterocycles, 2,3-dihydro-pyrazines have shown some
significant biological activities, such as DNA strand-breakage
CH CN, which is the solvent of choice (Table 1, entries 4–7
3
4
5
6
7,8
activity, antibacterial, apoptosis induction, cytotoxicity, and
versus entry 3).
9,10
inhibition of enzyme activity.
Several synthetic methods have been developed for the
synthesis of 2,3-dihydro-pyrazines. One of the most efficient
strategies towards the formation of 2,3-dihydro-pyrazines is use
Under the optimal reaction conditions (Table 1, entry 3), we
tested the scope with other 1,2-diketones. As shown in Table 2, a
variety of 1,2-diketones provided the corresponding 2,3-dihydro-
pyrazines in high yields. For example, the reaction of 1a and
11,12
13-15
of ethylenediamine and 1,2-diketones as starting materials.
ethylenediamine in the presence of 10 mol% of iodine in CH CN at
3
However, limitations in this approach, including the range of
substrates, led us to the development of a new catalyst system
for the synthesis of 2,3-dihydro-pyrazines owing to their
important biological activities.
o
6
0 Cfor6hoursaffordedtheproduct2ain96%yield(Table2, entry
1). Although both electron-donating and electron-withdrawing
substituted 1,2-diketones gave the corresponding products in high
yields (Table 2, entries 2–6 and 9–11), a slightly longer reaction
time (10 hours) was needed for the completion of the reaction for
most of the 1,2-diketones with electron-donating substitutions
Iodine, which is inexpensive and has low toxicity, has been
16-21
used as a good mediator and catalyst in organic synthesis.
Recently, we have developed a Cu-catalysed synthesis of
(Table 2, entries 3, 8–11). It is found that some functional groups,
2
2
1
,2-diketones. Based on this work, we herein report an
such as fluoro, ester, nitrile, and nathphyl groups are tolerated in
the reaction to provide the corresponding 2,3-dihydro-pyrazines in
high yields (Table 2, entries 4–8 and entry 11).
In conclusion, we have developed an efficient iodine-mediated
reaction for the synthesis of 2,3-dihydro-pyrazines. Various
efficient method for the formation of 2,3-dihydro-pyrazines
through annulations using 1,2-diketones and ethylenediamine.
Using this protocol, 2,3-dihydro-pyrazines were obtained in
excellent yields in the presence of a catalytic amount of iodine
as a mediator.
2
,3-dihydro-pyrazines were prepared in high yields by the
Initially, we chose benzil (1a) and ethylenediamine as
the starting materials to investigate the formation of the
annulations of 1,2-diketones and ethylenediamine in the presence
of a catalytic amount of iodine. A variety of functional groups
were tolerated in the present reaction.
2
5
,3-dihydro-pyrazine (2a). The reaction gave product 2a in
6% yield by the treatment of 1a and ethylenediamine in
the presence of 10 mol% of iodine at room temperature in
Experimental
acetonitrile (CH CN) for 6 hours (Table 1, entry 1). Increasing
3
CH CN was distilled over CaH under N . All commercial reagents
3
2
2
the reaction temperature afforded higher yields, and the
excellent yield (96%) was obtained when the reaction was
were used without further purification. Compound 1a was purchased
and used without further purification. Compounds 1b–k were prepared
according to reported procedures. NMR spectra were recorded on a 400
o
performed at 60 C (Table 1, entries 2 and 3). We tested several
11
1
13
MHz spectrometer (400 MHz for H, 100 MHz for C) with deuteriated
Table
1
Iodine-mediated synthesis of 2,3-dihydro-pyrazine (2a);
chloroform (CDCl ) as a solvent at 298K. Chemical shifts are reported
3
a
optimisation of the reaction conditions
1
in δ ppm referenced to an internal SiMe standard for H NMR and
4
O
13
N
Ph
Ph
I
2
(10 mol %)
CDCl (δ 77.16) for C NMR. Where: s, singlet; d, doublet; t, triplet; m,
3
Ph
NH2
+
Ph
2
H N
multiplet. High-resolution mass spectra were obtained with a Q-TOF MS
spectrometer.
solvent, Temp., 6 h
N
O
1
a
2a
Synthesis of 2,3-dihydro-pyrazines 2; general procedure
o
b
Entry
Temp./ C
Solvent
Yield/%
56
76
96
54
79
89
85
I2 (2.5 mg, 0.01 mmol) was added to a stirred solution of 1,2-diketone
1
2
3
4
5
6
7
rt
CH CN
3
1
(0.1 mmol) and ethylenediamine (0.15 mmol) in CH CN (1.0 mL).
3
40
60
60
60
60
60
CH CN
o
3
The solution was stirred at 60 C in air until all the starting material
was consumed. The mixture was cooled to room temperature. After
evaporation of the solvent, the residue was purified by preparative thin-
layer chromatography on silica gel with petroleum ether/EtOAc (10/1) as
an eluent to give the corresponding 2,3-dihydro-pyrazine 2.
CH CN
3
Toluene
EtOAc
EtOH
DMSO
5,6-Diphenyl-2,3-dihydro-pyrazine (2a): White solid; 22.5 mg (96%
o
1
a
yield); m.p. 155–156 C; H NMR (400 MHz, CDCl ) δ 7.42–7.38 (m,
3
13
The reactions were performed in a tube with benzil (1a) (0.1 mmol), ethylenediamine
0.15 mmol), I2 (0.01 mmol) in solvent (1.0 mL) at the designated temperature for 6 h
(
4H), 7.34–7.29 (m, 2H), 7.27–7.22 (m, 4H), 3.70 (s, 4H); C NMR (100
in air.
Isolated yield.
MHz, CDCl ) δ 45.92, 128.00, 128.23, 129.75, 137.85, 160.41. Data are
consistent with literature values.
3
b
23
*
Correspondent. E-mail: yifengping@sit.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 431
Table 2 Iodine-mediated synthesis of 2,3-dihydro-pyrazines
O
R2
N
N
R2
2
I (10 mol %)
R1
+
NH2
H N
2
CH
CN, 60 oC, 6 h
3
R1
O
1
2
a
Entry
1
Diketone
O
Product
Yield/%
96
N
Ph
Ph
Ph
N
Ph
O
1
a
2a
Me
Me
OMe
F
O
N
N
2
Ph
86
90
95
99
85
89
O
Ph
1
b
2
b
OMe
O
N
N
c
3
Ph
O
Ph
1
c
2
c
F
O
N
N
4
5
6
Ph
O
Ph
1
d
2
d
CO
2
Me
CO
2
Me
O
N
Ph
O
N
Ph
1
e
2
e
CN
CN
O
N
N
Ph
O
Ph
1
f
2
f
O
N
N
b
Ph
7
O
Ph
1
g
2
g
O
b
N
8
94
O
N
MeO
1
h
2
h
OMe
Me
Me
O
N
N
b
9
87
88
93
O
MeO
1
i
2
i
OMe
OMe
OMe
O
N
N
b
1
0
O
MeO
1
j
2
j
OMe
F
F
O
N
b
1
1
O
N
MeO
1
k
2
k
OMe
o
The reactions were performed in a tube with diketone (1) (0.1 mmol), ethylenediamine (0.15 mmol), I (0.01 mmol) in CH CN (1.0 mL) at 60 C for 6 h in air.
2
3
a
c
Isolated yield; 10 h.

432 JOURNAL OF CHEMICAL RESEARCH 2015
5
-Phenyl-6-(p-tolyl)-2,3-dihydro-pyrazine (2b): White solid;
5,6-Di(4-Methoxyphenyl)-2,3-dihydro-pyrazine (2j): Yellow solid;
o
1
o
1
2
1.4 mg (86% yield); m.p. 115–116 C; H NMR (400 MHz, CDCl ) δ
25.9 mg (88% yield); m.p. 118–120 C; H NMR (400 MHz, CDCl )
3
3
7
4
1
.42–7.38 (m, 2H), 7.34–7.22 (m, 5H), 7.05 (d, J = 8.0 Hz, 2H), 3.68 (s,
δ 7.38–7.35 (m, 4H), 6.79–6.76 (m, 4H), 3.78 (s, 6H), 3.64 (s, 4H);
13
H), 2.30 (s, 3H); C NMR (100 MHz, CDCl ) δ 21.48, 45.84, 45.95,
13
3
C NMR (100 MHz, CDCl ) δ 45.81, 55.39, 113.59, 129.71, 130.63,
3
27.99, 128.00, 128.22, 128.93, 129.68, 135.00, 138.07, 139.92, 160.19,
24
1
59.72, 160.82. Data consistent with literature values.
160.55. HRMS (ESI) calcd for C H N (M+H)+, 249.1392, found
17 17 2
5-(4-Fluorophenyl)-6-(4-methoxyphenyl)-2,3-dihydro-pyrazine
2
49.1389.
-(4-Methoxylphenyl)-6-phenyl-2,3-dihydro-pyrazine (2c): White
o
1
(
2k): White solid; 26.3 mg (93% yield); m.p. 130–131 C; H NMR (400
5
MHz, CDCl ) δ 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H),
o
1
3
solid; 23.8 mg (90% yield); m.p. 93–94 C; H NMR (400 MHz, CDCl )
δ 7.45–7.38 (m, 2H), 7.37–7.30 (m, 3H), 7.26 (t, J = 7.3 Hz, 2H), 6.75 (d,
J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.67 (s, 4H); C NMR (100 MHz, CDCl )
3
6
4
.95 (t, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.66 (s,
13
H); C NMR (100 MHz, CDCl ) δ 45.71, 45.89, 55.39, 104.48, 113.68,
13
3
3
115.34 (d, J = 22.0 Hz), 129.69, 130.12 (d, J = 8.0 Hz), 130.14, 134.30
δ 45.78, 46.00, 55.36, 113.59, 128.02, 128.25, 129.68, 129.70, 130.31,
(
d, J = 3.0 Hz), 159.44, 160.14 (d, J = 163.0 Hz), 162.39. HRMS (ESI)
138.25, 159.56, 160.56, 160.88. HRMS (ESI) calcd for C H N O
17 17 2
+
+
calcd for C H N OF(M+H) , 283.1247, found 283.1250.
(
M+H) , 265.1341, found 265.1338.
-(4-Fluorophenyl)-6-phenyl-2,3-dihydro-pyrazine (2d): White
17 16
2
5
o
1
This work was supported by the Natural Science Foundation of
China.
solid; 24.0 mg (95% yield); m.p. 87–88 C; H NMR (400 MHz, CDCl )
δ 7.43–7.30 (m, 5H), 7.29–7.24 (m, 2H), 6.96–6.91 (m, 2H), 3.69 (s,
3
13
4H); C NMR (100 MHz, CDCl ) δ 45.83, 45.87, 115.35 (d, J = 21.0
3
Hz), 128.00, 128.35, 129.88, 130.12 (d, J = 9.0 Hz), 133.94 (d, J = 4.0
Hz), 137.75, 159.29, 160.16, 163.65 (d, J = 249.0 Hz). HRMS (ESI)
Received 8 May 2015; accepted 30 June 2015
Paper 1503353 doi: 10.3184/174751915X14360237431600
Published online: 9 July 2015
+
calcd for C H N F(M+H) , 253.1141, found 253.1137.
16
14
2
5
-(4-Carboxymethoxylphenyl)-6-phenyl-2,3-dihydro-pyrazine
o
1
(
(
2e): Yellow solid; 28.9 mg (99% yield); m.p. 126–127 C; H NMR
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3
1
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+
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18
17
2
2
5
-(4-Cyanophenyl)-6-phenyl-2,3-dihydro-pyrazine (2f): Yellow
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9
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o
1
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3
13
2
4
1
2
3
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17
14
3
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2
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5
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379.
o
1
2
8
7
(
1
5.3 mg (89% yield); m.p. 58–59 C; H NMR (400 MHz, CDCl ) δ
.10 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 5.6 Hz, 2H), 7.48–7.41 (m, 2H),
.38–7.32 (m, 4H), 7.13 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 2H), 3.84
s, 4H); C NMR (100 MHz, CDCl ) δ 45.79, 45.91, 124.88, 124.98,
26.16, 126.88, 127.10, 127.58, 127.99, 128.64, 129.63, 129.75, 130.49,
33.77, 135.87, 137.29, 161.27, 161.39. HRMS (ESI) calcd for C H N
3
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3
12
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1
(
2
0
17
2
+
13 H. K. Kadam, S. Khan, R.A. Kunkalkar and A.G. Tilve, Tetrahedron Lett.,
013, 54, 1003.
14
M+H) , 285.1392, found 285.1388.
-(4-Methoxyphenyl)-6-naphthyl-2,3-dihydro-pyrazine (2h): Yellow
2
5
Y.L. Liu, B.L. Wang, J.J Cao, Chen, L.Y.X. Zhang, C. Wang, J. Zhou, J.
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o
1
solid; 29.6 mg (94% yield); m.p. 53–55 C; H NMR (400 MHz, CDCl )
δ 8.09 (d, J = 9.0 Hz, 1H), 7.82–7.79 (m, 2H), 7.48–7.43 (m, 2H), 7.37 (d, J
4.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.85-3.76
m, 4H), 3.65 (s, 3H); C NMR (100 MHz, CDCl ) δ 45.66, 46.01, 55.22,
13.41, 124.96, 125.04, 126.16, 126.87, 127.04, 128.63, 129.24, 129.66,
29.82, 130.54, 133.83, 136.30, 160.41, 160.70, 161.52. HRMS (ESI)
calcd for C H N O(M+H) , 315.1497, found 315.1495.
3
15
=
(
1
1
2
009, 39, 569.
13
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3
+
21
19
2
2
0
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5
-(4-Methoxyphenyl)-6-(4-methylphenyl)-2,3-dihydro-pyrazine
o
1
(
2i): White solid; 24.2 mg (87% yield); m.p. 108–109 C; H NMR (400
MHz, CDCl ) δ 7.36 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.06
d, J = 8.1 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.64 (s, 4H),
.31 (s, 3H); C NMR (100 MHz, CDCl ) δ 21.48, 45.77, 45.88, 55.33,
13.53, 127.97, 128.92, 129.66, 130.48, 135.35, 139.79, 159.67, 160.32,
60.79. HRMS (ESI) calcd for C H N O (M+H)+, 279.1497, found
21
3
(
2
1
1
2
2
2
3
13
3
18 19 2
279.1501.
24 L.Fan, W. Chen and C. Qian, Tetrahedron Lett., 2013, 54, 231.