Synthesis of fused quinoxalines

Article abstract of DOI:10.1070/MC2002v012n02ABEH001560

The intramolecular cyclization of NH and N-alkyl quaternary salts of 2-quinoxaline-2-carboxaldehyde hydrazones affords pyrazolo-[3,4-b]quinoxalines in good yields.

Full text of DOI:10.1070/MC2002v012n02ABEH001560

Mendeleev Commun., 2002, 12(2), 68–70
Synthesis of fused quinoxalines
a
a
b
a
Michail G. Ponizovsky, Artem M. Boguslavsky, Mikhail I. Kodess, Valery N. Charushin* and
Oleg N. Chupakhin
b
a
Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.
Fax: +7 3432 74 5191; e-mail: charushin@prm.uran.ru
b
Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation
1
0.1070/MC2002v012n02ABEH001560
The intramolecular cyclization of NH and N-alkyl quaternary salts of 2-quinoxaline-2-carboxaldehyde hydrazones affords pyrazolo-
3,4-b]quinoxalines in good yields.
[
The idea to use tandem nucleophilic addition reactions at two
neighbouring C=N bonds of an azine ring for construction of
condensed aza heterocycles has been successfully applied to pyra-
zines and their aza and benzo analogues. Indeed, the ortho-
cyclization of 1-alkyl-1,4-diazinium salts with bifunctional nucleo-
philes is an efficient synthetic approach to condensed pyrazines,
quinoxalines, pyrido[2,3-b]pyrazines and pteridines in which the
Hydrazones 1a–g prepared according to standard procedures†
were subjected to N-alkylation with methyl iodide. It was expected
that both nitrogen atoms of the pyrazine ring, N-1 and N-4,
might be alkylated with methyl iodide. Indeed, the quaterniza-
tion of quinoxaline-2-carboxaldehyde N,N-dimethylhydrazone
1a (a model compound incapable of a further intramolecular
cyclization) gave a mixture of two quaternary salts 2a and 3a in
1
–5
‡
pyrazine ring is fused with five- and six-membered heterocycles
†
Scheme 1).1
,2
A common synthetic procedure for quinoxalin-2-carboxaldehyde hydra-
(
zones 1a–g. A solution of 1.0 g (6.2 mmol) of quinoxaline-2-carboxalde-
hyde in 15 ml of ethanol was added gradually to a solution of 6.2 mmol
of hydrazine (or hydrazine hydrochloride) in 10 ml of water for 3–5 min
with stirring at 60–70 °C. After stirring for additional 3–5 min, the reac-
tion mixture was cooled to room temperature to give a hydrazone pre-
cipitate, which was filtered off and recrystallised.
H
N
H
H
N
X
Y
HX
HY
N
R
N
R
1
2
1
a: 66% (from water), mp 78–79 °C. H NMR ([ H ]DMSO) d: 3.18
6
(
(
(
s, 6H, NMe ), 7.33 (s, 1H, CH=N), 7.6–7.8 (m, 2H, H-6, H-7), 7.9–8.0
2
1
3
2
m, 2H, H-5, H-8), 9.28 (s, 1H, H-3). C NMR ([ H ]DMSO) d: 41.90
Scheme 1
6
1
3
1
qq, Me, JC,H 137.0 Hz, JC,Me 3.03 Hz), 126.95 (dm, CH=N, JC,H
1
66.0 Hz), 127.94, 128.51, 129.66 (m, C-5, C-6, C-7, C-8), 140.09 (ddd,
Another approach to condensed aza heterocycles is based on
3
3
2
C-4a, J
10.6 Hz, J
10.3 Hz, J
5.4 Hz), 141.37 (dd, C-8a,
a nucleophilic reaction at the C=N bond of an azine ring in
combination with a nucleophilic attack at the exo-cyclic electro-
philic centre (Scheme 2). This approach was illustrated by the
reaction of 6-carbonyl-substituted 1,2,4-triazines with hydrazines.6
In this paper, we report on a new methodology for the synthesis
of fused quinoxalines from quinoxaline-2-carboxaldehyde.
C,CH
C,CH
C,CH
3
2
1
3
JC,CH 9.0 Hz, J
5.8 Hz), 142.56 (dd, C-3, J
185.0 Hz, J
C,CH
C,H C,CH
2
2
3
.5 Hz), 153.33 (dd, C-2, J
9.4 Hz, J
6.2 Hz). Found (%): C, 51.9;
C,CH
C,CH
H, 4.2; N, 30.0. Calc. for C H N (%): C, 51.95; H, 3.89; N, 30.28.
11
12
4
1
2
1
b: 75% (from aqueous ethanol), mp 210–212 °C. H NMR ([ H ]DMSO)
6
d: 6.85–7.35 (m, 5H, Ph), 7.70–7.90 (m, 2H, H-6, H-7), 7.90–8.10 (m,
2
H, H-5, H-8), 8.01 (s, 1H, CH=N), 9.51 (s, 1H, H-3), 11.91 (s, 1H, NH).
1
3
2
1
C NMR ([ H ]DMSO) d: 112.78 (d, C-3', JC,H 160.6 Hz), 120.32
6
1
3
(
dm, C-5', J
160.7 Hz, J
7.4 Hz), 128.36, 128.74, 128.94 and
N
N
E
N
N
E
C,H
C,CH
HX
HY
130.14 (C-5, C-6, C-7, C-8), 129.13 (ddd, C-4', 1J
158.9 Hz, 3J
X
C,H
C,CH
2
1
3
8
.0 Hz, J
1.7 Hz), 134.38 (dd, CH=N, J 166.4 Hz, J
3.7 Hz),
C,CH
C,H
C,CH
Y
140.64 (ddd, C-4a, 3J
9.4, 2J
5.8 Hz, 3J
5.8 Hz), 141.37
C,CH-3
8.7 Hz, J
C,CH-6
C,CH-5
3
2
1
(
dd, C-8a, J
5.7 Hz), 142.90 (dd, C-3, J 186.3 Hz,
C,CH-7
C,CH-8 C,H
Scheme 2
3
2
2
JC,CH 4.0 Hz), 143.91 (m, C-1'), 149.68 (dd, C-2, J
9.4 Hz, J
C,CH
C,CH
6
7
.6 Hz). Found (%): C, 72.5; H, 4.7; N, 22.5. Calc. for C H N (%): C,
1
5
12
4
Attempts to perform a cyclization reaction between quinoxa-
line-2-carboxaldehyde and hydrazines without activation of the
quinoxaline moiety were unsuccessful. We also failed to obtain
N-alkyl quaternary salts by reacting quinoxaline-2-carboxalde-
hyde with methyl iodide or triethyloxonium tetrafluoroborate
2.56; H, 4.87; N, 22.57.
1
2
1c: 75% (from aqueous ethanol), mp 220–221 °C. H NMR ([ H ]DMSO)
6
d: 2.37 (s, 3H, Me), 7.04–7.22 (m, 4H, p-C H ), 7.60–7.81 (m, 2H, H-6,
6
4
H-7), 7.88–8.01 (m, 2H, H-5, H-8), 7.92 (s, 1H, CH=N), 9.45 (s, 1H,
H-3), 11.09 (s, 1H, NH). Found (%): C, 73.5; H, 5.1; N, 21.1. Calc. for
C H N (%): C, 73.26; H, 5.38; N, 21.36.
(
the Meerwein reagent). Therefore, it was suggested to obtain
fused quinoxalines in two steps: (i) condensation of quinoxaline-
-carboxaldehyde with hydrazines resulting in corresponding
1
6
14
4
1d: 87% (from acetic acid), mp 338–340 °C. 1H NMR ([2H ]DMSO)
6
2
d: 3.30–4.60 (br. s, 1H, COOH), 7.30 (d, 2H, H-2', H-6'), 7.72–7.87 (m,
2H, H-6, H-7), 7.80 (d, 2H, H-3', H-5'), 7.98–8.11 (m, 2H, H-5, H-8),
8
6
1
hydrazones 1a–g; (ii) quarternization of quinoxalines 1a–g with
methyl iodide followed by an intramolecular nucleophilic attack
of NH of the side-chain hydrazone moiety at the activated C=N
bond of the pyrazinium cation (Scheme 3).
.10 (s, 1H, CH=N), 9.50 (s, 1H, H-3), 11.5 (s, 1H, NH). Found (%): C,
5.8; H, 4.1; N, 19.1. Calc. for C H N O (%): C, 65.70; H, 4.14; N,
16 12
4
2
9.17.
e: 63% (from acetic acid), mp 255–256 °C. H NMR ([ H ]DMSO)
1
2
1
6
d: 7.35 (d, 2H, H-2', H-6'), 7.76–7.89 (m, 2H, H-6, H-7), 8.00–8.12 (m,
N
N
COH
N
CH
N
NHR
2
1
H, H-5, H-8), 8.16 (d, 2H, H-3', H-5'), 8.20 (s, 1H, CH=N), 9.50 (s,
H, H-3), 11.80 (s, 1H, NH). Found (%): C, 61.3; H, 3.7; N, 23.7. Calc.
NH –NHR
2
N
a–g
for C15H11N5O2 (%): C, 61.43; H, 3.78; N, 23.88.
1
2
1
f: 70% (from aqueous ethanol), mp 96–98 °C. H NMR ([ H ]DMSO)
1
6
d: 3.00 (d, 3H, NMe), 7.40 (s, 1H, H-3), 7.58–7.75 (m, 2H, H-6, H-7),
.81–8.99 (m, 2H, H-5, H-8), 8.40 (d, 1H, NH), 9.20 (s, 1H, CH=N).
MeI
7
Found (%): C, 64.8; H, 5.2; N, 29.6. Calc. for C H N (%): C, 64.50;
1
0
10
4
N
COH
N
CH
N
NHR
H, 5.41; N, 30.09.
1
2
1g: 72% (from aqueous ethanol), mp 91–92 °C. H NMR ([ H ]DMSO)
6
d: 4.50 (d, 2H, CH Ph), 7.20–7.40 (m, 5H, Ph), 7.60 (s, 1H, H-3), 7.65–
2
N
R
N
7
9
.79 (m, 2H, H-6, H-7), 7.87–8.02 (m, 2H, H-5, H-8), 8.90 (t, 1H, NH),
.20 (s, 1H, CH=N). Found (%): C, 73.1; H, 5.4; N, 20.9. Calc. for
C H N (%): C, 73.26; H, 5.38; N, 21.36.
Me
I
Scheme 3
16 14
4
–
68 –

Mendeleev Commun., 2002, 12(2), 68–70
NMe2
H
N
N
N
N
N
N
MeI
N
R1
1a
NMe2
1b–e
N
Me
N
N
H
N
NMe2
N
N
N
N
Me
N
R1
2a
3a
N
Scheme 4
Me
1
2b–e
the ratio 4:1 ( H NMR data).
The quaternization of quinoxalines 1b,c with methyl iodide
in DMSO proceeds more selectively to result in the formation
of N -quaternary salts 2b,c. Salts 2b,c undergo a spontaneous
N
N
N
N
(
4)
H
N
N
N
N
intramolecular nucleophilic attack leading to σ -adducts 4a,b
followed by their oxidation into pyrazolo[3,4-b]quinoxalines 5b,c.
This two-step reaction can be regarded as intramolecular nucleo-
H
[O]
H
Me
Me
H
7
philic substitution of hydrogen (S ). Indeed, the elimination of
N
hydrogen is facilitated by atmospheric oxygen, as it takes place
R1
R1
in many other S NH reactions. In case of phenylhydrazones 1d,e
7
4
b,c
5b,c
bearing electron-withdrawing groups (COOH, NO ) at the para-
2
1
1
position, the nucleophilic character of NH of the hydrazone
b R = H
d R = COOH
e R = NO2
moiety is insufficient to cause the S NH process; therefore, only
1
1
c R = Me
the N -methylation reaction takes place affording quaternary salts
4
Scheme 5
2
d,e (Scheme 5).
Evidence for the structure of pyrazoloquinoxalines 5b,c is
nitrogen, while the phenyl group is not coplanar with the tri-
cyclic system due to hindrance caused by the N-methyl substi-
tuent (Figure 1).¶
In N-alkyl-substituted quinoxalin-2-carboxaldehyde hydrazones
f,g the nucleophilic character of NH is enhanced, and the intra-
1
13
§
provided by H and C NMR data. The X-ray diffraction analy-
sis of compound 5b revealed that the pyrazoloquinoxaline sys-
tem is planar and the methyl group is attached to the quaternary
1
‡
molecular reaction can be carried out on reflux in aqueous
ethanol in the presence of a few drops of sulfuric acid to afford
Quaternization of quinoxalin-2-carboxaldehyde phenylhydrazones 1a–e
with methyl iodide. A solution of the corresponding quinoxalin-2-car-
boxaldehyde phenylhydrazone (2 mmol) in 2 ml of DMSO and 2 ml of
methyl iodide was heated in water bath at 40–50 °C and refluxed for 3 h.
The precipitate obtained after cooling the reaction mixture to room tem-
perature was filtered off, washed with diethyl ether, dried in air and
recrystallised to give either quinoxalinium salts 2d,e or pyrazolo[3,4-b]-
quinoxalinium salts 5b,c. Attempts to isolate individual salts 2a and 3a
derived from quaternization of quinoxaline 1a with methyl iodide by
recrystallization were unsuccessful.
C(5)
C(4)
N(2)
C(7)
C(8)
C(6)
C(3)
N(4)
C(9)
C(1)
C(2)
N(1)
1
2
N(3)
2
d: 65% (from AcOH–DMSO), mp 360–362 °C. H NMR ([ H ]DMSO)
6
C(10)
C(15)
+
d: 4.0 (br. s, 1H, COOH), 4.70 (s, 3H, N Me), 7.48 (d, 2H) and 7.93 (d,
C(16)
2
1
1
H, p-C H ), 8.11–8.59 (m, 4H, H-5, H-6, H-7, H-8), 8.23 (s, 1H, CH=N),
6 4
0.0 (s, 1H, H-3), 11.98 (s, 1H, NH). Found (%): C, 46.7; H, 3.4; N,
2.6. Calc. for C H N O I (%): C, 47.02; H, 3.47; N, 12.90.
C(11)
1
7
15
4
2
C(14)
1
2
2
e: 67% (from AcOH–DMSO), mp 314–315 °C. H NMR ([ H ]DMSO)
6
+
d: 4.79 (s, 3H, N Me) 7.56 (d, 2H, H-2', H-6'), 8.16–8.28 (m, 2H, H-3',
H-5'), 8.16–8.59 (m, 4H, H-5, H-6, H-7, H-8), 8.31 (s, 1H, CH=N), 10.13
C(12)
C(13)
13
2
(s, 1H, H-2), 12.26 (s, 1H, NH). C NMR ([ H ]DMSO) d: 45.60 (dd,
6
+
1
146.1 Hz, 3
1
N Me,
1
J
J
4.6 Hz), 113.25 (ddd, C-2', C-6', JC,H
C,CH
C,H
3
2
66.4 Hz, JC,CH 5.7 Hz, JC,CH 2.4 Hz), 119.53, 133.79, 134.03 and
36.79 (C-5, C-6, C-7, C-8), 125.83 (dd, C-3', C-5', JC,H 167.6 Hz,
Figure 1 Molecular structure of pyrazolo[3,4-b]quinoxalinium iodide 5b.
1
1
3
1
¶
JC,CH 4.6 Hz), 129.73 (m, C-8a), 130.15 (dd, CH=N, J
171.3 Hz,
Crystallographic data for 5b: crystals of C H N I are monoclinic at
293 K, space group Cc, a = 6.689(3), b = 33.689(15), c = 7.224(3) Å,
b = 112.416(10)°, V = 1504.9(12) Å , Z = 4, M = 389.21, d = 1.713 g cm ,
C,H
16 13
4
3
1
2
JC,CH 5.1 Hz), 141.16 (dm, C-2, J 197.7 Hz), 140.73 (tt, C-4', J
C,H
C,H
3
3
–3
9
.6 Hz, J
3.4 Hz), 144.01 (m, C-4a), 148.82 (m, C-1'), 151.46 (dd,
C,CH
7.5 Hz, J
calc
3
2
–1
C-3, J
4.3 Hz). Found (%): C, 44.1; H, 3.3; N, 16,4.
m(MoKα) = 2.126 cm , F(000) = 760. Intensities of 3863 reflections were
C,CH
C,CH
Calc. for C H N O I (%): C, 44.16; H, 3.24; N, 16.09.
measured with a Smart 1000 CCD diffractometer at 293 K [l(MoKα) =
1
6
14
5
2
§
1
2
5
b: 62% (from water), mp 206–208 °C. H NMR ([ H ]DMSO) d: 4.19
= 0.71072 Å, w-scans, 2q < 62°], and 2476 independent reflections (R =
6
int
+
(
s, 3H, N Me), 7.70–7.88 (m, 5H, Ph), 8.20–8.78 (m, 4H, H-5, H-6, H-7,
= 0.0260) were used in further refinement. The absorption correction
was carried out semiempirically from equivalents. The structure was
solved by the heavy atom method and refined by the full-matrix least-
13
2
+
H-8), 9.61 (s, 1H, CH=N). C NMR ([ H ]DMSO) d: 38.65 (q, N Me,
6
1
JC,H 146.3 Hz), 117.77, 130.32, 132.59 and 137.83 (C-5, C-6, C-7, C-8),
1
2
1
27.86 (dm, J 166.1, C-2', C-6'), 129.7 (m, C-8a), 130.06 (ddd, C-3',
squares technique against F in the anisotropic-isotropic approximation.
C,H
1
3
2
C-5', J
165.4 Hz, J
6.1 Hz, J 3.1 Hz), 131.26 (dm, C-4',
The positions of the hydrogen atoms were calculated geometrically and
refined in a ridding model. The refinement converged to wR = 0.0899
and GOF = 0.984 for all independent reflections [R = 0.0395 was calcu-
lated against F for 1912 observed reflections with I > 2s(I)]. All
calculations were performed using SHELXTL PLUS 5.0. Atomic coor-
dinates, bond lengths, bond angles and thermal parameters have been
deposited at the Cambridge Crystallographic Data Centre (CCDC). For
details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2002. Any
request to the CCDC for data should quote the full literature citation and
the reference number 1135/106.
C,H
C,CH
C,CH
1
3
JC,H 163.5 Hz, J
7.2 Hz), 132.97 (m, C-9a), 137.59 (m, C-1'), 140.31
C,CH
2
2
dd, C-4a, J
C,CH
3
1
(
5.4 Hz, J
9.7 Hz), 140.34 (d, C-3, J 204.8 Hz),
C,CH
C,H
1
2
1
45.79 (d, C-3a, J
11.0 Hz). Found (%): C, 49.4; H, 3.4; N, 14.2.
C,CH
Calc. for C H N I (%): C, 49.38; H, 3.62; N, 14.20.
1
6
14
4
1
2
5
c: 71% (from water), mp 304–305 °C. H NMR ([ H ]DMSO) d: 1.83–
6
+
1
.92 (m, 3H, MePh), 4.18 (s, 3H, N Me), 7.58 (d, 2H), and 7.74 (d, 2H,
p-C H ), 8.17–8.78 (m, 4H, H-5, H-6, H-7, H-8), 9.6 (s, 1H, CH=N).
6
4
Found (%): C, 50.8; H, 3.5; N, 14.0. Calc. for C H N I (%): C, 50.77;
H, 3.76; N, 13.93.
17
15
4
–
69 –

Mendeleev Commun., 2002, 12(2), 68–70
Although several approaches to the synthesis of pyrazolo-
NHR
NHR
8–10
N
N
[3,4-b]quinoxalines have been described in the literature,
we
H+
N
N
believe that the above two-steps procedure involving condensa-
tion of the carbonyl group ring with hydrazines (to introduce a
nucleophilic fragment into a side-chain of pyrazines) followed
by intramolecular S NH reaction at the activated C=N bond is a
promising methodology for the synthesis of fused 1,4-diazines.
N
N
H
1
f R = Me
1
g R = CH Ph
2
N
[
O]
This work was supported by the US Civilian Research and
Development Foundation (award no. REC-005) and the Russian
Foundation for Basic Research (grant no. 01-03-96456a).
N
R
N
N
6
6
a R = Me
b R = CH Ph
References
2
1
2
3
4
5
6
7
8
9
V. N. Charushin, O. N. Chupakhin and H. C. van der Plas, Adv. Heterocycl.
Chem., 1988, 43, 301.
V. N. Charushin, G. A. Mokrushina, G. M. Petrova, G. G. Alexandrov
and O. N. Chupakhin, Mendeleev Commun., 1998, 133.
V. N. Charushin, S. G. Alexeev, O. N. Chupakhin and H. C. van der Plas,
Adv. Heterocycl. Chem., 1989, 46, 73.
O. N. Chupakhin, B. V. Rudakov, S. G. Alexeev and V. N. Charushin,
Heterocycles, 1992, 33, 931.
O. N. Chupakhin, G. L. Rusinov, D. G. Beresnev, V. N. Charushin and
H. Neunhoeffer, J. Heterocycl. Chem., 2001, 38, 901.
A. Rykowski, M. Mojzych and Z. Karczmarzyk, Heterocycles, 2000,
53.
Scheme 6
pyrazolo[3,4-b]quinoxalines 6a,b in good yields (Scheme 6).††
In this case, the pyrazine ring is activated by N-protonation;
indeed, no reaction was observed without an acid.
†
†
Intramolecular cyclization of quinoxalin-2-carboxaldehyde alkylhydra-
zones 1f,g into pyrazolo[3,4-b]quinoxalines 6a,b. A few drops of sulfuric
acid were added to a solution of quinoxalin-2-carboxaldehyde alkylhydra-
zone (2 mmol) in 10 ml of ethanol and 10 ml of water to adjust pH 2,
and the reaction mixture was refluxed for 4 h. The precipitate obtained
after cooling and neutralization of the reaction mixture was filtered off
and recrystallised to give pyrazolo[3,4-b]quinoxalines 6a,b.
a: 75% (from aqueous ethanol), mp 129–130 °C. H NMR ([ H ]DMSO)
d: 4.18 (s, 3H, NHMe), 7.80 (tm, 2H), 7.91 (tm, 2H, H-6, H-7), 8.11 and
.20 (2dd, 2×2H, H-5, H-8), 8.66 (s, 1H, CH=N). C NMR ([ H ]DMSO)
d: 33.76 (q, Me, J 140.4 Hz), 127.55, 128.05, 129.65 and 130.64 (C-5,
O. N. Chupakhin, V. N. Charushin and H. C. van der Plas, Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press, New York, 1994.
P. Madhavan Pillai and P. Ramabhadran, Indian J. Chem., 1986, 25B,
1
2
6
6
901.
1
3
2
M. von Saltza, J. D. Dutcher, J. Reid and O. Wintersteiner, J. Org.
Chem., 1963, 28, 999.
8
6
1
C,H
1
1
10 G. Henseke and C. Bauer, Chem. Ber., 1959, 92, 509.
C-6, C-7, C-8), 132.71 (d, C-3, J 197.0 Hz), 136.34 (d, C-3a, J
9.88 Hz, JC,CH 5.52 Hz, JC,CH
.23 Hz), 140.61 (dd, C-8a, J 10.11 Hz, J
C,H
C,H
2
2
1
1
0.11 Hz), 140.33 (ddd, C-4a, 1J
C,H
1
2
5.52 Hz), 141.45 (m,
C,CH
C,H
C-9a). Found (%): C, 65.3; H, 4.5; N, 30.4. Calc. for C H N (%): C,
10
8
4
6
5.21; H, 4.38; N, 30.42.
1
2
6b: 80% (from aqueous ethanol), mp 113–114 °C. H NMR ([ H ]DMSO)
6
d: 5.80 (s, 2H, CH Ph), 7.25–7.35 (m, 5H, Ph), 7.80–8.00 (m, 2H, H-6,
2
H-7), 8.15–8.31 (m, 2H, H-5, H-8), 8.82 (s, 1H, CH=N). Found (%): C,
7
3.7; H, 4.3; N, 21.2. Calc. for C H N (%): C, 73.83; H, 4.65; N, 21.52.
16 12 4
Received: 28th January 2002; Com. 02/1886
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