A green synthesis of quinoxalines and 2,3-dihydropyrazines

Article abstract of DOI:10.1055/s-0033-1338441

Quinoxaline and dihydropyrazine derivatives were obtained in high yields by simple addition of 1,2-diamines and 1,2-dicarbonyl compounds in water. In some cases, the products spontaneously precipitated from the reaction mixture, making it possible to recover and reuse the mother liquor for further condensations. The very mild reaction conditions, the high yields of the products, and the absence of any catalyst make this methodology an efficient and green route to quinoxalines and dihydropyrazines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338441

1546▌
PAPER
paper
A Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines
Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines
Camilla Delpivo, Gabriele Micheletti,* Carla Boga
Department of Industrial Chemistry ‘Toso Montanari’, Viale Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2092654; E-mail: gabriele.micheletti3@unibo.it
Received: 24.01.2013; Accepted after revision: 02.04.2013
ods rely on the condensation of an aryl-1,2-diamine with
a 1,2-dicarbonyl compound in refluxing ethanol or acetic
acid20 or at room temperature in methanol21a or in other
solvents such as a mixture water–ethanol21b or dimethyl
Abstract: Quinoxaline and dihydropyrazine derivatives were ob-
tained in high yields by simple addition of 1,2-diamines and 1,2-di-
carbonyl compounds in water. In some cases, the products
spontaneously precipitated from the reaction mixture, making it
possible to recover and reuse the mother liquor for further conden- sulfoxide21c in the presence of a catalyst. Recently, the
sations. The very mild reaction conditions, the high yields of the
products, and the absence of any catalyst make this methodology an
efficient and green route to quinoxalines and dihydropyrazines.
synthesis of quinoxalines by condensation of o-phenyl-
enediamine and a 1,2-dicarbonyl compound under micro-
wave irradiation has been reported.22,23
Key words: quinoxaline, dihydropyrazine, green, water, condensa-
tion
Other syntheses of quinoxaline derivatives were reported,
in which metal catalysts (such as manganese dioxide,24
palladium acetate25) were used, or α-arylimino oximes
were chosen as the starting material.26 Other quinoxaline
One of the main purposes of chemists in the last two de-
derivatives have been recently synthesized in water using
cades has been to find new synthetic processes character-
various catalysts, such as Amberlyst-15,27 cerium(IV) am-
ized by the lowest possible impact on the environment. In
monium nitrate (CAN),28 and gallium(III) triflate.29 In the
fact, one of the main problems in classical synthetic pro-
latter case, the synthesis does not permit to obtain prod-
cesses is the use of large amounts of organic solvents, of-
ucts from 1,2-dialkyl ketones.
ten hazardous by being flammable, explosive, and
2,3-Dihydropyrazine derivatives have assumed great im-
portance as flavorants30 and in medicine field, where they
are used for their DNA strand-breaking activity,31 which
may be related to the apoptotic activity of amino sugars,32
and also for their biological33 and cyclooxygenase
inhibitory34 activity. 2,3-Dihydropyrazines are generally
prepared by the procedure of Ishiguro35 from ethylenedi-
amine and a diketone in diethyl ether. Another synthesis
was performed starting from diketones and diamino com-
pounds in refluxing benzene.36 Recently, a synthesis start-
ing from α-hydroxy ketones and 1,2-diamines mediated
by MnO2 in refluxing CH2Cl2 has been reported.24a,37
sometimes carcinogenic. To try to limit the use of these
organic solvents, researchers are looking towards alterna-
tive syntheses under solvent-free conditions or using wa-
ter as the reaction medium.
The use of water as a solvent in organic chemistry has re-
ceived growing attention in recent years.1,2 There are
many advantages in replacing organic solvents with wa-
ter: it is cheap, not flammable, and more importantly, it is
not toxic. The possibility to use the aqueous medium effi-
ciently in organic synthesis is explained by the hypothesis
that the hydrophobic effect of water can generate an inter-
nal pressure that promotes the association of the reac-
tants.3
Most of these methods suffer from one or more limita-
tions, such as long reaction times, use of expensive or cor-
rosive reagents, tedious workup processes, special
apparatus, and harsh reaction conditions. Thus, the devel-
opment of a new efficient method in water at room tem-
perature is highly desirable.
Our interest lies in the possibility of synthesizing mole-
cules in aqueous medium and in this study we have fo-
cused our attention on the synthesis of 1,4-
diazaheterocycles such as quinoxaline and 2,3-dihydro-
pyrazine and their derivatives.
Recently, in a study focused on the development of new
routes to the synthesis of heterocyclic compounds using
green reactions, we obtained a series of hydantoins and
thiohydantoins in water at room temperature starting from
urea (and its derivatives) and dicarbonyl compounds us-
ing P4O10 as the condensing agent.38 These findings
prompted us to develop a methodology to produce simple
quinoxaline and 2,3-dihydropyrazine derivatives in water
at room temperature starting from 1,2-aryldiamines and
1,2-alkyldiamines respectively. The results obtained are
described herein.
Quinoxaline derivatives4 are important biological com-
pounds because of their activity as anti-inflammatories,5,6
kinase inhibitors,7–9 antibacterials,10,11 antivirals,12 and an-
tibiotics.13 In addition, they are well known for their appli-
cation as cavitands,14 dyes,15 DNA cleaving agents,16
dehydroannulenes,17 and electroluminescent materials.18
In the literature, several syntheses of quinoxaline deriva-
tives have been reported so far.19 The most common meth-
SYNTHESIS 2013, 45, 1546–1552
Advanced online publication: 08.05.2013
For the sake of simplicity the synthesis of quinoxalines
and 2,3-dihydropyrazine is discussed separately.
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338441; Art ID: SS-2013-Z0031-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines
1547
Synthesis of Quinoxalines
lines in higher yields (70–95%) with respect to those ob-
tained with P4O10 (Table 1).
The reaction between equimolar amounts of o-phenylene-
diamine derivatives 1, 2 and 1,2-dicarbonyl compounds The yields reported in Table 1 are obtained after extrac-
4a–g was first carried out in water at room temperature in tion of the products from the crude reaction mixture with
the presence of P4O10 (0.5 equiv). In these conditions, qui- CH2Cl2 followed by removal of the solvent. Moreover, in
noxaline derivatives 5a–g and 6a–g were obtained in 40– some cases the products precipitated thus making it possi-
50% yields. Since these low yields might be due to a com- ble to collect by simple filtration of the crude reaction
peting reaction between P4O10 and the starting amino mixture. In these latter cases, even if the yields are slightly
compound, the reaction was carried out in the absence of lower than those reported in Table 1, probably because of
P4O10, and it was found that the reaction gave quinoxa- the partial solubility of the products in water, it is possible
Table 1 Synthesis of Quinoxalines Using Different 1,2-Aryldiamines and 1,2-Dicarbonyl Compounds in Watera
R1
X
NH2
O
R1
X
N
H2O
r.t.
+
R2
NH2
N
R2
O
1–3
4a–l
5–7
Entry
Diamine
X
Dicarbonyl
R1
R2
Product
Yield (%)b
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
3
3
3
3
3
3
3
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
Me
Et
Me
Et
Et
Pr
Ph
H
5a
5b
5c
95
88
3
Me
Me
Me
Me
H
95
4
5d
5e
82
5
83
6
5f
85
7
4g
4h
4i
H
5g
5h
5i
76
8
(CH2)4
Ph
70
9
Ph
30c
10c
94
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4j
4-MeOC6H4
Me
Et
4-MeOC6H4
5j
Cl
4a
4b
4c
4d
4e
4f
Me
Et
Et
Pr
Ph
H
6a
6b
6cd
6dd
6ed
6fd
6g
7a
7b
7cd
7dd
7ed
7fd
7g
Cl
95
Cl
Me
Me
Me
Me
H
95d
93d
91d
>95d
92
Cl
Cl
Cl
Cl
4g
4a
4b
4c
4d
4e
4f
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Et
Et
Pr
Ph
H
89
75
Me
Me
Me
Me
H
>95d
87d
95d
91d
81
4g
H
a All reactions were carried out at r.t. for 30 min.
b Calculated on the pure product obtained by extraction with CH2Cl2.
c After 5 h.
d Mixture of the two possible regioisomers.
© Georg Thieme Verlag Stuttgart · New York
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C. Delpivo et al.
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to reuse the residue aqueous solution for other synthetic CH2Cl2 followed by removal of the solvent. From the data
cycles.
reported in Table 3 it is possible to note that this method-
ology is very efficient. The lower yields obtained in some
cases (Table 3, entries 1–4, 6, 7) are probably due to the
volatility of these products that make the workup and their
recovery difficult.
Products 6c–f and 7c–f arising from asymmetric 1,2-di-
carbonyl compounds 4c–f were obtained as a mixture of
two regioisomers. In almost all cases, the reaction was re-
gioselective, even if only slightly. The relative isomeric
ratio (from 40:60 to 50:50 reported in the experimental Products 12c–e arising from asymmetric 1,2-dicarbonyl
section) has been calculated from the 1H NMR spectrum compounds 4c–e were obtained as a mixture of two regio-
based on some diagnostic signals ascribed to the different isomers. In these cases the 13C NMR spectra showed the
regioisomers, such as the singlet belonging to the methyl presence of a mixture of two regioisomers, but because of
1
group.
the overlapping of the signals in the H NMR spectra, it
was not possible to calculate the relative isomeric ratio,
except in the case of compound 12e (50:50 isomeric ratio,
see experimental section).
From the data reported in Table 1, it is possible to note that
this methodology was very efficient for the synthesis of
quinoxalines starting both from ketones and aldehydes. In
contrast, when the substituents R1 and R2 were both aro- It is important to note that when the 1,2-dicarbonyl com-
matics (4i, 4j) the yields were very low even after longer pounds 4f and 4g – reagents with at least one aldehyde
reaction times (Table 1, entries 9 and 10). This can be due group – were used, the expected 1,2-dihydropyrazines
to the fact that the starting aromatic dicarbonyl compound were not obtained.
is almost insoluble in water. In order to overcome this
To the best of our knowledge, in literature there are no
problem, the reaction was carried out in solvents, such as
specific syntheses of quinoxalines under such mild condi-
ethanol and dichloromethane, in which diaryl ketones are
tions, apart from a few articles39 in which water is used as
soluble. The results are summarized in Table 2.
reaction medium but under different conditions. Further-
more, this is the first time that the synthesis of 2,3-dihy-
dropyrazines has been performed in aqueous media
without any condensing agent or catalyst at room temper-
ature.
Table 2 Synthesis of Quinoxalines Using 1,2-Aryldiamines and 1,2-
Dicarbonyl Compounds Bearing Two Aryl Substituents in an Organic
Solvent
Entry Diamine Dicarbonyl Solvent
Product Yield (%)a
In conclusion, we have reported a very simple, efficient,
clean, and eco-friendly method for the synthesis of a se-
ries of quinoxaline and 2,3-dihyropyrazine derivatives
from 1,2-dicarbonyl compounds and 1,2-diamines in wa-
ter. The mild reaction conditions, such as room tempera-
ture and the absence of any condensing agents or catalyst,
make this methodology an alternative procedure to the
conventional acid- or base-catalyzed thermal processes.
This green protocol permits to obtain the products, which
are new compounds in some cases, in good to excellent
yields.
1
2
3
4
5
6
1
1
1
1
2
3
4i
4i
4j
4j
4i
4i
EtOH
CH2Cl2
EtOH
CH2Cl2
EtOH
EtOH
5i
5i
5j
5j
6i
7i
90b
70c
70d
40c
95b
89b
a Calculated based on the pure product collected by filtration.
b After 30 min at r.t.
c After 3 h at r.t.
d After 2 h at r.t.
All reagents are commercially available and 1,2-diaminocyclohex-
ane used was a racemic mixture of trans-isomers. 1H and 13C NMR
spectra were recorded on Varian Mercury 400 instrument operating
at 400 and 100.56 MHz, respectively. Chemical shifts are refer-
enced to the solvent (CDCl3, δ = 7.27 and δ = 77.2/77.0 for 1H and
13C NMR, respectively). Coupling constants (J) are given in Hz.
GC-MS analyses were performed on a gas chromatograph Agilent
6890 equipped with a 5% (phenyl)ethylpolysiloxane column (30 m
length, 0.250 mm i.d., 0.25 μm thickness), interfaced to a quadru-
pole mass detector Agilent 5973 N. Mass spectra were recorded by
at an ionization voltage of 70 eV in the EI mode. HRMS analyses
were performed on MAT95XP Thermo Finnigan. NMR spectral
data of known compounds 5a–j, 6a,b,f,g,i, 7a,b,f,g,i, 11a–e, 12a,
13a agree with those reported in the literature.37,40–58 For the NMR
spectra of new compounds see the Supporting Information.
As shown in Table 2, in these solvents, the yields of com-
pounds 5i and 5j (Table 2, entries 1–4) drastically in-
creased with respect to those obtained in water (Table 1,
entries 9 and 10). Given that between these two organic
solvents the better yields were obtained in ethanol, the lat-
ter was used in the preparation of 6i and 7i. In these cases
as well, the yields were very high.
Synthesis of 2,3-Dihydropyrazines
A series of 2,3-dihydropyrazines were obtained using ali-
phatic 1,2-diamines 8–10 and 1,2-dicarbonyl compounds
4a–e in water and at room temperature without any con-
densing agent or catalyst (Table 3).
The data of new compounds 6c,d, 7c,d, 12b–e and 13b–e are report-
ed together below with some spectral data of known compounds not
yet reported in the literature. In the cases in which a couple of regio-
1
isomers were obtained, the ratio and the H NMR signals assign-
The yields reported in Table 3 are obtained after extrac-
tion of the products from the crude reaction mixture with
ments are attributed only to the major or the minor isomer.
Synthesis 2013, 45, 1546–1552
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Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines
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Table 3 Synthesis of 2,3-Dihydropyrazines in Watera
O
R1
R3
N
R1
R2
R3
NH2
H2O
r.t.
+
O
R2
R4
N
R4
NH2
8–10
4a–e
11–13
Entry
Diamine
R3
R4
Dicarbonyl
R1
R2
Product
Yield (%)b
1
2
8
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
Me
Et
Me
Et
11a
11b
11c
11d
11e
12a
12b
12cc
12dc
12ec
13a
13b
13c
13d
13e
70
72
3
8
Me
Me
Me
Me
Et
Et
71
4
8
Pr
70
5
8
Ph
Me
Et
95
6
9
Me
80
7
9
Me
75
8
9
Me
Me
Me
Me
Me
Et
Et
87c
85c
85c
94
9
9
Me
Pr
10
11
12
13
14
15
9
Me
Ph
Me
Et
10d
10d
10d
10d
10d
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
90
Me
Me
Me
Et
>95
95
Pr
Ph
85
a All reactions were performed at r.t. for 30 min.
b Calculated based on the pure product obtained by extraction with CH2Cl2.
c Mixture of the two possible regioisomers.
d (±)-trans-1,2-Diaminocyclohexane.
Quinoxalines; General Procedure
HRMS: m/z calcd for C11H11ClN2: 206.06108; found: 206.06111.
A 50 mL round-bottomed flask was charged with a solution of the
appropriate 1,2-dicarbonyl compound 4 (3 mmol) in H2O (7 mL).
To this solution was added the respective 1,2-diamine 1–3 (3 mmol)
and the mixture was stirred at r.t. After 30 min, the crude mixture
was extracted with CH2Cl2 (3 × 10 mL). The combined organic lay-
ers were dried (MgSO4) and after filtration, the solvent was re-
moved to give the desired product (Tables 1 and 2).
6-Chloro-3-methyl-2-propylquinoxaline and 6-Chloro-2-meth-
yl-3-propylquinoxaline (6d/6′d)
The product mixture was obtained in a 60:40 ratio; yield: 613 mg
(93%); brown solid.
1H NMR (CDCl3): δ = 8.0 (d, J = 2.3 Hz, 1 H, major), 7.97 (d, J =
2.3 Hz, 1 H, minor), 7.93 (d, J = 8.9 Hz, 1 H, minor), 7.90 (d, J =
8.9 Hz, 1 H, major), 7.60 (dd, J = 8.9, 2.3 Hz, 2 H, minor + major),
2.969 (t, J = 7.78 Hz, 2 H, major), 2.966 (t, J = 7.79 Hz 2 H, minor),
2.76 (s, 3 H, minor), 2.75 (s, 3 H, major), 1.93–1.82 (m, 2 H, major
+ minor), 1.09 (t, J = 7.26 Hz, 6 H, minor + major).
In the cases 5i, 5j, 6i, and 7i, the reaction was carried out in the same
conditions but using EtOH as solvent, the final mixture was filtered
to afford pure products.
13C NMR (CDCl3): δ = 157.9, 157.2, 154.5, 153.7, 141.7, 141.4,
139.9, 139.5, 134.55, 134.5, 130.0, 129.9, 129.86, 129.7, 127.8,
127.5, 37.9 (2×), 23.0, 22.96, 21.5, 21.4, 14.31, 14.295.
MS (70 eV, EI): m/z (%) = 220 (M+, 5), 205, (20), 192 (100), 172
(8), 151 (9), 136 (4), 123 (3), 110 (11), 89 (3), 75 (17), 63 (3).
6-Chloro-2-ethyl-3-methylquinoxaline and 6-Chloro-3-ethyl-2-
methylquinoxaline (6c/6′c)
The product mixture was obtained in a 60:40 ratio; yield: 585 mg
(95%); brown solid.
1H NMR (CDCl3): δ = 8.01 (d, J = 2.28 Hz, 1 H, major), 7.96 (d, J =
2.28 Hz, 1 H, minor), 7.94 (d, J = 8.92 Hz, 1 H, minor), 7.90 (d, J =
8.95 Hz, 1 H, major), 7.60 (dd, J = 8.94, 2.30 Hz, 2 H, minor + ma-
jor), 3.02 (q, J = 7.37 Hz, 4 H, minor + major), 2.75 (s, 3 H, minor),
2.74 (s, 3 H, major), 1.41 (t, J = 7.37 Hz, 6 H, minor + major).
13C NMR (CDCl3): δ = 158.7, 158.0, 154.4, 153.6, 141.7, 141.4,
139.9, 139.5, 134.51, 134.47, 130.0, 129.9, 129.8, 129.7, 127.8,
127.5, 29.11, 29.09, 22.9, 22.8, 11.94, 11.99.
MS (70 eV, EI): m/z (%) = 206 (M+, 81), 178 (16), 164 (26), 151
HRMS: m/z calcd for C12H13ClN2: 220.07673: found: 220.07678.
6-Chloro-3-methyl-2-phenylquinoxaline and 6-Chloro-2-meth-
yl-3-phenylquinoxaline (6e/6′e)
The product mixture was obtained in a 55:45 ratio; yield: 693 mg
(91%); brown solid.
1H NMR (CDCl3) δ = 8.11 (d, J = 2.26 Hz, 1 H, minor), 8.06 (d, J =
2.25 Hz, 1 H, major), 8.05 (d, J = 9.22 Hz, 1 H, major), 7.99 (d, J =
(18), 137 (20), 110 (24), 89 (4), 75 (42), 50 (9).
© Georg Thieme Verlag Stuttgart · New York
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C. Delpivo et al.
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9.13 Hz, 1 H, minor), 7.71–7.62 (m, 6 H, major + minor), 7.53–7.48
(m, 6 H, major + minor), 2.781 (s, 3 H, major), 2.780 (s, 3 H, minor).
13C NMR (CDCl3): δ = 155.9, 155.2, 153.9, 153.0, 141.7, 141.5,
139.9, 139.7, 138.85, 138.79, 135.6, 135.1, 130.9, 130.7, 130.6,
130.4, 129.8, 129.4, 129.38, 129.1, 129.08, 128.8, 128.3, 127.5,
24.62, 24.58.
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and evaporated to afford
the desired product (Table 3). The 2,3-dihydropyrazine derivatives
are generally unstable and are gradually transformed into brown-
colored, strong-smelling compounds when they were allowed to
stand at r.t. The purity of the products was determined by 1H and 13
NMR spectroscopy and GC-MS.
C
MS (70 eV, EI): m/z (%) = 254 (59), 253 (100), 239 (3), 213 (11),
178 (18), 151 (19), 127 (4), 110 (18), 89 (5), 75 (31), 51 (9).
5,6-Diethyl-2-methyl-2,3-dihydropyrazine (12b)
Yield: 342 mg (75%); liquid.
HRMS: m/z calcd for C15H11ClN2: 254.06108; found: 254.06104.
1H NMR (CDCl3): δ = 3.64–3.57 (m, 1 H), 3.24–3.10 (m, 1 H),
2.80–2.60 (m, 1 H), 2.52–2.37 (m, 4 H), 1.24 (d, J = 6.93 Hz, 3 H),
1.10 (t, J = 7.47 Hz, 3 H), 1.09 (t, J = 7.45 Hz, 3 H).
13C NMR (CDCl3): δ = 162.8, 162.0, 51.0, 49.2, 28.1, 27.9, 18.6,
10.3, 9.8.
MS (70 eV, EI): m/z (%) = 152 (M+, 26), 137 (46), 123 (3), 109 (5),
96 (6), 82 (6), 68 (7), 56 (100).
2-Ethyl-3,6-dimethylquinoxaline and 3-Ethyl-2,6-dimethylqui-
noxaline (7c/7′c)
The product mixture was obtained in a 55:45 ratio; yield: 541 mg
(>95%); yellow solid.
1H NMR (CDCl3): δ = 7.89 (d, J = 8.57 Hz, 1 H, minor), 7.86 (d, J =
8.47 Hz, 1 H, major), 7.79 (br s, 1 H, major), 7.75 (br s, 1 H, minor),
7.49 (dd, J = 8.53 Hz, 1.76 Hz, 1 H, minor + major), 3.02 (q, J =
7.43 Hz, 4 H, minor + major), 2.743 (s, 3 H, minor), 2.740 (s, 3 H,
major), 2.56 (br s, 6 H, minor + major), 1.40 (t, J = 7.43 Hz, 6 H,
major + minor).
13C NMR (CDCl3): δ = 157.6, 156.8, 153.1, 152.2, 141.4, 141.2,
139.8, 139.5, 139.3, 139.2, 131.2, 131.1, 128.2 128.0, 127.7, 127.4,
29.2, 29.1, 22.9, 22.8, 21.93, 21.89, 12.3, 12.2.
HRMS: m/z calcd for C9H16N2: 152.13135; found: 152.13134.
6-Ethyl-2,5-dimethyl-2,3-dihydropyrazine and 5-Ethyl-2,6-di-
methyl-2,3-dihydropyrazine (12c/12′c)
Yield: 360 mg (87%); liquid.
1H NMR (CDCl3): δ = 3.65–3.48 (m, 2 H), 3.23–2.95 (m, 2 H),
2.81–2.63 (m, 2 H), 2.47–2.21 (m, 4 H), 2.02 (br s, 6 H), 1.20–1.10
(m, 6 H), 1.00 (br t, J = 7.26 Hz, 6 H); all signals of the two isomers
were overlapped.
MS (70 eV, EI): m/z (%) = 186 (M+, 100), 185 (98), 158 (18), 144
(20), 130 (5), 116 (12), 89 (56), 63 (19).
13C NMR (CDCl3): δ = 162.7 161.9, 159.2, 158.4, 51.24, 51.18,
HRMS: m/z calcd for C12H14N2: 186.11570; found: 186.11578.
49.4, 49.3, 28.7, 28.4, 22.8, 22.6, 19.0, 18.9, 10.3, 9.8.
MS (70 eV, EI): m/z (%) = 138 (M+, 48), 123 (54), 110 (5), 96 (9),
3,6-Dimethyl-2-propylquinoxaline and 2,6-Dimethyl-3-propyl-
quinoxaline (7d/7′d)
The product mixture was obtained in a 56:44 ratio; yield: 522 mg
(87%); yellow solid.
82 (11), 68 (19), 56 (100).
HRMS: m/z calcd for C8H14N2: 138.11570; found: 138.11578.
1H NMR (CDCl3): δ = 7.89 (d, J = 8.39 Hz, 1 H, minor), 7.87 (d, J =
8.49 Hz, 1 H, major), 7.79 (br s, 1 H, major), 7.75 (br s, 1 H, minor),
7.50 (dd, J = 8.45, 1.97 Hz, 1 H, major + minor), 2.97 (t, J = 7.71
Hz, 4 H, minor + major), 2.752 (s, 3 H, minor), 2.749 (s, 3 H, ma-
jor), 2.57 (s, 6 H, minor + major), 1.92–1.80 (m, 4 H, minor + ma-
jor), 1.08 (t, J = 7.37 Hz, 6 H, minor + major).
13C NMR (CDCl3): δ = 156.8, 156.0, 153.2, 152.3, 141.4, 141.1,
139.8, 139.4, 139.3, 139.2, 131.2, 131.1, 128.2, 127.9, 127.7, 127.4,
38.01, 37.97, 23.0, 22.9, 21.92, 21.89, 21.8, 21.7, 14.36, 14.34.
2,5-Dimethyl-6-propyl-2,3-dihydropyrazine and 2,6-Dimethyl-
5-propyl-2,3-dihydropyrazine (12d/12′d)
Yield: 388 mg (85%); liquid.
1H NMR (CDCl3): δ = 3.66–3.53 (m, 2 H), 3.26–3.07 (m, 2 H),
2.88–2.74 (m, 2 H), 2.42–2.32 (m, 4 H), 2.13 (d, J = 2.33 Hz, 6 H),
1.61–1.50 (m, 4 H), 1.27–1.20 (m, 6 H), 0.98–0.92 (m, 6 H); all sig-
nals of the two isomers were overlapped.
13C NMR (CDCl3): δ = 162.1, 161.2, 159.3, 158.5, 51.2, 51.1, 49.4,
MS (70 eV, EI): m/z (%) = 200 (M+, 5), 172 (100), 157 (7), 131 (6),
116 (4), 89 (19), 63 (6).
49.3, 37.6, 37.3, 22.8, 22.6, 19.7, 19.2, 18.9 (2×), 13.7 (2×).
MS (70 eV, EI): m/z (%) = 152 (M+, 34), 137 (54), 124 (43), 109
(21), 95 (11), 82 (9), 70 (100), 54 (17).
HRMS: m/z calcd for C13H16N2: 200.13135; found: 200.13126.
HRMS: m/z calcd for C9H16N2: 152.13135; found: 152.13137.
3,6-Dimethyl-2-phenylquinoxaline and 2,6-Dimethyl-3-phenyl-
quinoxaline (7e/7′e)
The product mixture was obtained in a 50:50 ratio; yield: 667 mg
(95%); yellow solid.
1H NMR (CDCl3): δ = 7.96 (d, J = 8.61 Hz, 1 H), 7.91 (d, J = 8.49
Hz, 1 H), 7.85 (br s, 1 H), 7.79 (br s, 1 H), 7.63–7.57 (m, 4 H), 7.51–
7.39 (m, 8 H), 2.72 (br s, 6 H, CH3), 2.54 (br s, 3 H, CH3), 2.53 (br
s, 3 H, CH3).
13C NMR (CDCl3): δ = 154.9, 154.1, 152.5, 151.6, 141.5, 141.2,
140.3, 139.9, 139.7, 139.6, 139.41, 139.38, 132.1, 131.6, 129.1,
129.06, 129.01, 128.7, 128.3, 128.0, 127.4, 24.5, 24.4, 22.1, 22.0.
2,5-Dimethyl-6-phenyl-2,3-dihydropyrazine and 2,6-Dimethyl-
5-phenyl-2,3-dihydropyrazine (12e/12′e)
The product mixture was obtained as two regioisomers in a relative
ratio 50:50; yield: 474 mg (85%); liquid.
1H NMR (CDCl3): δ = 7.43–7.36 (m, 4 H, mixt.), 7.36–7.28 (m, 6
H, mixt.), 3.81 (dd, J = 16.43, 5.25 Hz, 1 H), 3.72–3.63 (m, 1 H),
3.36–3.16 (m, 2 H), 2.99–2.83 (m, 2 H), 2.02 (d, J = 2.2 Hz, 3 H),
2.01 (dd, J = 2.36, 0.93 Hz, 3 H), 1.30 (d, J = 5.57 Hz, 3 H), 1.28 (d,
J = 5.34 Hz, 3 H).
13C NMR (CDCl3): δ = 161.8, 160.9, 158.7, 157.8, 137.7, 137.5,
129.5, 129.4, 128.4 (2×), 127.5, 127.24, 51.9, 51.3, 50.4, 49.7, 24.5,
24.3, 19.0, 18.9.
MS (70 eV, EI): m/z (%) = 233 (M+ + 1, 100), 192 (9), 165 (6), 131
(7), 117 (5), 103 (6), 89 (31), 63 (10).
MS (70 eV, EI): m/z (%) = 186 (M+, 54), 171 (11), 144 (6), 130 (11),
115 (26), 104 (100), 77 (25), 51 (12).
HRMS: m/z calcd for C16H14N2: 234.11570; found: 234.11563.
2,3-Dihydropyrazines; General Procedure
HRMS: m/z calcd for C12H14N2: 186.11570; found: 186.11565.
A 50 mL round-bottomed flask was charged with a solution of the
appropriate 1,2-dicarbonyl compound 4 (3 mmol) in H2O (7 mL).
To this solution was added the respective 1,2-diamine 8–10 (3
mmol) and the mixture was stirred at r.t. After 30 min, the crude
2,3-Diethyl–4a,5,6,7,8,8a-hexahydroquinoxaline (13b)
Yield: 518 mg (90%); yellow solid; mp 190 °C (dec.).
Synthesis 2013, 45, 1546–1552
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Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines
1551
1H NMR (CDCl3): δ = 2.30–2.15 (m, 2 H), 2.22 (q, J = 7.38 Hz, 4
H), 2.12–2.00 (m, 2 H), 1.63–1.51 (m, 2 H), 1.25–1.00 (m, 4 H),
0.87 (t, J = 7.38 Hz, 6 H).
13C NMR (CDCl3): δ = 162.5, 58.4, 33.1, 27.9, 25.1, 10.4.
MS (70 eV, EI): m/z (%) = 192 (M+, 64), 177 (60), 163 (49), 149
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HRMS: m/z calcd for C12H20N2: 192.16265; found: 192.16260.
2-Ethyl-3-methyl-4a,5,6,7,8,8a-hexahydroquinoxaline (13c)
Yield: 523 mg (>95%); yellow solid; mp 190 °C (dec.).
1H NMR (CDCl3): δ = 2.78 (dd, J = 12.92, 3.44 Hz, 1 H), 2.77–2.71
(m, 1 H), 2.27–2.19 (m, 2 H), 2.12 (dd, J = 12.86, 2.66 Hz, 1 H),
1.85–1.73 (m, 5 H), 1.43–1.29 (m, 3 H), 1.23–1.10 (m, 2 H), 0.83 (t,
J = 7.80 Hz, 3 H).
13C NMR (CDCl3): δ = 162.3, 158.6, 58.4, 58.3, 33.1, 33.0, 28.3,
25.1 (2×), 22.2, 10.2.
MS (70 eV, EI): m/z (%) = 178 (M+, 68), 163 (40), 149 (48), 135
(33), 121 (14), 109 (26), 95 (12), 82 (48), 67 (100), 54 (49).
HRMS: m/z calcd for C11H18N2: 178.14700; found: 178.14707.
2-Methyl-3-propyl-4a,5,6,7,8,8a-hexahydroquinoxaline (13d)
Yield: 547 mg (95%); yellow solid; mp 180.1–182.3 °C.
1H NMR (CDCl3): δ = 2.72 (dd, J = 13.02, 3.17 Hz, 1 H), 2.71–2.65
(m, 1 H), 2.21–2.13 (m, 2 H), 2.06 (dd, J = 13.17, 3.24 Hz, 1 H),
1.80–1.69 (m, 3 H), 1.69–1.60 (m, 2 H), 1.47–1.35 (m, 1 H), 1.35–
1.22 (m, 3 H), 1.18–1.06 (m, 2 H), 1.06–0.96 (m, 1 H), 0.83 (t, J =
7.11 Hz, 3 H).
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13C NMR (CDCl3): δ = 162.0, 159.0, 58.7, 58.6, 37.4, 33.33, 33.27,
25.4, 25.3, 22.6, 19.9, 13.7.
MS (70 eV, EI): m/z (%) = 192 (M+, 48), 177 (34), 163 (83), 149
(21), 136 (20), 121 (14), 109 (11), 95 (17), 82 (49), 67 (100), 54
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HRMS: m/z calcd for C12H20N2: 192.16265; found: 192.16270.
2-Methyl-3-phenyl-4a,5,6,7,8,8a-hexahydroquinoxaline (13e)
Yield: 576 mg (85%); yellow solid; mp 200 °C (dec.).
1H NMR (CDCl3): δ = 7.50–7.44 (m, 2 H), 7.44–7.36 (m, 3 H),
2.75–2.60 (m, 2 H), 2.48–2.28 (m, 2 H), 2.09 (s, 3 H), 1.92–1.78 (m,
2 H), 1.60–1.28 (m, 4 H).
13C NMR (CDCl3): δ = 161.3, 158.1, 137.4, 129.3, 128.3, 127.4,
59.3, 58.5, 33.3, 33.1, 25.3, 25.2, 24.1.
MS (70 eV, EI): m/z (%) = 226 (M+, 99), 211 (6), 184 (12), 172 (12),
156 (8), 130 (9), 115 (23), 104 (100), 82 (48), 67 (78), 54 (32).
HRMS: m/z calcd for C15H18N2: 226.14700; found: 226.14683.
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Acknowledgment
(21) (a) Ghosh, P.; Mandal, A. Adv. Appl. Sci. Res. 2011, 2, 255.
(b) Hasaninejad, A.; Reza, A.; Mohammadizadeh, M. R.;
Shekouhy, M. ARKIVOC 2008, (xiii), : 28. (c) Bhosale, R.
S.; Sarda, S. R.; Ardhapure, S. R.; Jadhav, W. N.; Bhusare,
S. R.; Pawar, R. P. Tetrahedron Lett. 2005, 46, 7183.
(22) Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W.
H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett. 2004, 45,
4873.
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Commun. 2003, 2286. (b) Kim, S. Y.; Park, K. H.; Chung, Y.
K. Chem. Commun. 2005, 1321.
This work was supported by Alma Mater Studiorum, Università di
Bologna (RFO funds) and MIUR (PRIN Project 2007: New fron-
tiers in the synthesis, reactions and applications of compounds con-
taining heteroatoms). Special thanks are due to Prof. Graziano
Baccolini for his technical support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1546–1552
© Georg Thieme Verlag Stuttgart · New York