Synthesis of 2,3-diphenylquinoxaline 1-oxides by oxidative cyclization of benzil α-arylimino oximes

Article abstract of DOI:10.1055/s-1998-2216

The title compounds-3a-h were synthesized by condensation of (E)-benzil monoxime 2 with the appropriate substituted aniline, 1 followed by oxidative cyclization to the corresponding 2,3-diphenylquinoxaline 1-oxides 4a-h using lead tetraacetate.

Full text of DOI:10.1055/s-1998-2216

SYNTHESIS
December 1998
1769
Synthesis of 2,3-Diphenylquinoxaline 1-Oxides by Oxidative Cyclization
of Benzil α-Arylimino Oximes
A. J. Maroulis, K. C. Domzaridou, C. P. Hadjiantoniou-Maroulis*l
Department of Chemistry, Aristotle University of Thessaloniki, P.O.B. 103, GR-540 06 Thessaloniki, Greece
Fax: 03031-997679; E-Mail: comm@chem.auth.gr
Received 27 April 1998
Abstract: The title compounds 3a–h were synthesized by con-
Quinoxaline 1-oxides are usually prepared from the par-
ent heterocycle by use of oxidants such as peracetic acid,
3-chloroperoxybenzoic acid, permaleic acid, etc.8 Exclud-
ing the unusual, albeit existent, danger of an explosion,1
the main disadvantages of the procedure involving the ox-
idation of the parent heterocycle are the lack of regiose-
lectivity in those cases where nonsymmetric substrates are
used, and the frequent isolation of mixtures of mono- and
di-N-oxides.2, 8
densation of (E)-benzil monoxime 2 with the appropriate substi-
tuted aniline, followed by oxidative cyclization to the
1
corresponding 2,3-diphenylquinoxaline 1-oxides 4a–h using lead
tetraacetate.
Key words: oxidative cyclization, benzil α-arylimino oximes,
2,3-diphenylquinoxaline 1-oxides
Quinoxaline N-oxides have been the subject of intensive
research in the last few decades.1–3 A good deal of this
work was designed to obtain biologically active com-
pounds since both the N-oxides and the corresponding
quinoxalines, which are generally obtained by deoxygen-
ation of the N-oxides, are widely used as antiinfectives,
bacteriocides, insect repellents, herbicides, etc.1, 2 Howev-
er, a considerable part of the published work is also of
synthetic value, since it is well known that the heterocy-
clic N-oxides in general permit functional group and
structure modifications which are difficult or impossible
to perform when procedures not involving them are fol-
lowed.1, 4
Contrary to this in our procedure the milder oxidant lead
tetraacetate was used in the place of peracids and the
mono-N-oxides 4 were the only products of the reaction.
Moreover, with the exception of the oxidative cyclization
of m-substituted α-arylimino oxime 3a where a small
amount (6%) of a second isomer 4e' was isolated (Table),
in all cases the outcome of the reaction was a single prod-
uct in fair to good yields.
The condensation of the substituted anilines 1 with the
(E)-benzil monoxime was achieved in aqueous ethanol.
The composition of the solvent mixture (vide infra) was
established after tedious attempts to avoid the oiling out
of the resulting reaction mixtures. The only examples in
the literature for the synthesis of benzil α-arylimino
oximes 3 are those describing the synthesis of 3a.9, 10
The variable yields obtained for 3 (28–75%) are shown
in the Table.
The synthesis and oxidation of α-arylimino oximes 3 to
the title quinoxaline 1-oxides 4 is part of our effort to syn-
thesize and oxidatively cyclize mixed heteroallylic deriv-
atives of dicarbonyl compounds such as α-hydroxyimino
aroylhydrazones of biacetyl,5 arylhydrazones of biacetyl
benzoylhydrazones,6 and mono- and bisarylhydrazones of
α-hydroxyimino β-diketones.7
1
With the exception of 3c, for which both H NMR and
13C NMR spectra suggest the existence of two isomers,
all α-imino oximes 3 exist in one form. Most likely and
in agreement with previous studies,10, 11 the imine moi-
ety exists in the Z-configuration. Z-configuration is as-
sumed by the oximino group as evidenced by the large
downfield shift (from δ = ca. 7.9 to ca. 11.5) of the oxime
proton on going from chloroform-d to dimethyl sulfox-
ide-d6.12 Only compound 3c shows two OH resonances
in dimethyl sulfoxide-d6 (δ = 12.20 and 11.60) and there-
fore must exist in both the Z,Z and the Z-imine, E-oxime
configuration.
Treatment of the α-imino oximes 3 with lead tetraacetate
gives the corresponding quinoxaline N-oxides 4 in yields
ranging from 16 to 71% as shown in the Table.
It seems likely, from a mechanistic point of view, that the
oximino group in 3 is first oxidized to the nitroso acetate13
5 which is further cyclized, in an entropy favored electro-
philic cyclization, to the intermediate 6. The latter, after
loss of acetic acid, is converted to the quinoxaline N-oxide
4 (Scheme 2).
Scheme 1

SYNTHESIS
Papers
Table. Benzil α-Arylimino Oximes 3a–h and 2,3-Diphenylquinoxaline 1-Oxides 4a-h Prepared
1770
Com- R1
pound
R2
R3
Yield mp (°C)
(%)
Molecular
Formulaa
or Lit. mp
(°C)
IR (Nujol)
MS (70 eV)
m/z
1H NMR
13C NMR
(CDCl3/
DMSO-d6)
δ c
ν (cm-1)
(CDCl3/TMS)b
δ, J (Hz)
3a
H
H
H
75
210–211
(EtOH)
2119, 10
–
300 (M+, 35), 6.87–7.02 (m, 3 H, Ar),
283 (3), 270 7.10–7.32 (m, 5 H, Ar),
(12), 268 (8), 7.36–7.6 (m, 5 H, Ar),
180 (100), 103 7.64 (s, 1 H, OH), 7.65
(13), 77 (42)
(dd, 2 H, J = 8, J = 2.5, 2'-
H, 6'-H)
3b
H
OMe
H
H
H
H
54
205–206
(EtOH/H2O) (330.4)
C21H18N2O2
3140,1609, 330 (M+, 42), 3.72 (s, 3 H, OMe), 6.72 161.6,
1505,1202, 313 (17), 300 (d, 2 H, J = 8.2, 3-H, 5-H), 152.9
943
(30), 210 (100), 6.95 (d, 2 H, J = 8.2, 2-H,
105 (54), 91 6-H), 7.17–7.32 (m, 4 H,
(82), 77 (81)
Ar), 7.37–7.52 (m, 4 H,
Ar), 7.83 (s, 1 H, OH),
7.95 (d, 2 H, J = 7.3, 2'-H,
6'-H)
3c
3d
3e
OMe
H
28
72
64
194.5–195.5
(EtOH)
C21H18N2O2
(330.4)
3140,1590, 330 (M+, 28), 3.63 (s, 3 H, OMe), 6.44– 162.0,
1145, 965,
690
313 (55), 299 6.57 (m, 3 H, 1-H, 4-H, 6- 153.1,
(61), 210 (100), H), 7.05 (t, 1 H, J = 7.7, 5- 151.8
105 (86), 92 H), 7.18–7.33 (m, 4 H,
(78), 77 (96)
Ar), 7.37–7.54 (m, 4 H,
Ar), 7.77 (s, 1 H, OH),
7.96 (d, 2 H, J = 7.0, 2'-H,
6'-H)
H
Me
194–196
(EtOH/H2O) (314.4)
C21H18N2O
3150,1610, 314 (M+, 26), 2.22 (s, 3 H, Me), 6.85 (d, 161.7,
1205, 954,
770
225 (50), 194 2 H, J = 8.1, 3-H, 5-H), 152.4
(55), 115 (81), 6.95 (d, 2 H, J = 8.1, 2-H,
105 (91), 91 6-H), 7.18–7.31 (m, 3 H,
(100), 77 (84)
Ar), 7.37–7.53 (m, 5 H,
Ar), 7.95 (dd, 2 H, J = 7.0,
J = 2.0, 2'-H, 6'-H), 8.14
(s, 1 H, OH)
Me
H
188.5–190
(EtOH/H2O)
C21H18N2O
(314.4)
3150, 1610, 314 (M+, 10), 2.19 (s, 3 H, Me), 6.72 (s, 161.8,
968, 770,
690
287 (9), 225 1 H, 2-H), 6.71 (d, 1 H, J 152.2
(22), 194 (32), = 8.1, 4-H), 6.80 (d, 1 H, J
105 (100), 91 = 8.1, 6-H), 7.03 (t, 1 H, J
(30), 77 (88)
= 8.1, 5-H), 7.18–7.32 (m,
4 H, Ar), 7.37–7.54 (m, 4
H, Ar), 7.85 (s, 1 H, OH),
7.86 (d, 2 H, J = 7.3, 2'-H,
6'-H)
3f
H
Cl
H
H
H
46
43
199–200
(EtOH/H2O) (334.8)
C20H15ClN2O 3150, 1610, 334 (M+, 65), 6.85 (d, 2 H, J = 8.7, 3-H, 163.1,
1200, 1018, 303 (5), 269 5-H), 7.11 (d, 2 H, J = 8.7, 151.9
698
(10), 216 (29), 2-H, 6-H), 7.18–7.33 (m,
214 (100), 111 4 H, Ar), 7.35–7.54 (m, 4
(11), 103 (9)
H, Ar), 7.69 (s, 1 H, OH),
7.94 (dd, 2 H, J = 7.6, J =
1.9, 2'-H, 6'-H)
3g
Cl
193–196
(EtOH/H2O) (334.8)
C20H15ClN2O 3145,1580, 334 (M+, 27), 6.75 (d, 1 H, J = 7.9, 4-H), 163.6,
963, 768,
685
298 (11), 214 6.92 (s, 1 H, 2-H), 6.94 (d, 151.7
(59), 190 (83), 1 H, J = 7.9, 6-H), 7.06 (t,
118 (85), 105 1 H, J = 7.9, 5-H), 7.16–
(100), 77 (85)
7.65 (m, 6 H, Ar), 7.89–
8.05 (m, 4 H, Ar), 8.41 (s,
1 H, OH)

SYNTHESIS
December 1998
1771
Table. (continued)
Com- R1
pound
R2
R3
H
Yield mp (°C)
(%)
Molecular
Formulaa
or Lit. mp
(°C)
IR (Nujol)
MS (70 eV)
m/z
1H NMR
13C NMR
(CDCl3/
DMSO-d6)
δ c
ν (cm-1)
(CDCl3/TMS)b
δ, J (Hz)
3h
Me
Me
66
232–234
(EtOH)
C22H20N2O
(328.4)
3120, 1582, 328 (M+, 62), 3.30 (s, 6 H, 3-Me, 4-Me), 161.9,
939, 766, 310 (53), 297 6.71 (dd, 1 H, J = 7.8, J = 153.0
682
(57), 282 (63), 1.9, β-H), 6.77 (d, 1 H, J =
207 (100), 105 1.9, 2-H), 6.89 (d, 1 H, J =
(87), 77 (91)
7.8, 5-H), 7.15–7.28 (m, 3
H, Ar), 7.35–7.53 (m, 5 H,
Ar), 7.87 (dd, 2 H, J = 7.8,
J = 1.6, 2'-H, 6'-H), 11.59
(s, 1 H, OH)
4a
4b
H
H
H
H
H
48
27
205–206
(EtOH)
20715
298 (M+, 41),
281 (100), 269
(23), 179 (24),
140 (27), 103
(16), 77 (77)
OMe
227–228
(EtOH)
C21H16N2O2
(328.4)
1612, 1238, 328 (M+, 44), 4.01 (s, 3 H, MeO), 7.19–
1015, 945, 311 (58), 268 7.54 (m, 11 H, Ar), 7.47
821
(20), 240 (15) (dd, 1 H, J = 2.2, J = 8.8,
149 (14), 106 6-H), 7.97 (d, 1 H, J = 2.2,
(27), 91 (67)
8-H), 8.8 (d, 1 H, J = 8.0,
5-H)
4c
OMe
H
H
71
250–252
(EtOH)
C21H16N2O2
(328.4)
1570, 1337, 328 (M+, 39), 3.98 (s, 3 H, MeO), 7.18–
1010, 845, 327 (90), 310 7.43 (m, 11 H, Ar), 7.48
692
(100),
298 (d, 1 H, J = 2.2, 5-H), 8.53
(56), 267 (39), (d, 1 H, J = 9.5, 8-H)
155 (29), 106
(57)
4d
4e
4e'
4f
H
Me
H
H
64
51
6
203–204.5
(EtOH)
C21H16N2O
(312.4)
1340, 1195, 312 (M+, 87), 2.63 (s, 3 H, 7-Me), 7.19–
945, 821, 295 (100), 283 7.47 (m, 10 H, Ar), 7.66
745
(53), 269 (25), (d, 1 H, J = 7.9, 6-H), 8.08
148 (44), 89 (d, 1 H, J = 7.9, 5-H), 8.43
(71), 77 (47)
(s, 1 H, 8-H)
Me
H
H
180–182
(EtOH)
C21H16N2O16 1330, 955, 312 (M+, 75), 2.59 (s, 3 H, 6-Me), 7.18–
(312.4)
830, 775, 295 (100), 283 7.46 (m, 10 H, Ar), 7.56
700
(64), 269 (27), (d, 1 H; J = 8.4, 7-H), 7.95
147 (48), 89 (s, 1 H, 5-H) 8.51 (d, 1 H,
(74), 77 (59)
J = 8.4, 8-H)
H
Me
H
201–203
(EtOH)
C21H16N2O
(312.4)
1330, 1270, 312 (M+, 87), 3.10 (s, 3 H, 8-Me), 7.10–
910, 761, 295 (96), 165 7.57 (m, 11 H, Ar), 7.63 (t,
696
(67), 147 (59), 1 H, J = 8.4, 6-H), 8.1 (d,
105 (100), 89 1 H, J = 8.4, 5-H)
(80), 77 (96)
H
Cl
H
66
41
48
210–211
(EtOH)
C20H13ClN2O 1342, 1165, 332 (M+, 61), 7.22–7.47 (m, 10 H, Ar),
(332.8) 1090, 945, 315 (100), 303 7.77 (dd, 1 H, J = 2.2, J =
705
(30), 178 (25), 8.8, 6-H), 8.12 (d, 1 H, J =
157 (23), 151 8.8, 5-H), 8.64 (d, 1 H, J =
(27), 77 (41)
2.2, 8-H)
4g
4h
Cl
Me
H
156–157
(EtOH)
C20H13ClN2O 1562, 1340, 332 (M+, 85), 7.21–7.41 (m, 10 H, Ar),
(332.8)
945, 760, 315 (100), 303 7.66 (dd, 1 H, J = 2.2, J =
690
(54), 178 (45), 8.8, 7-H), 8.17 (d, 1 H, J =
157 (39), 151 2.2, 5-H), 8.56 (d, 1 H, J =
(35), 77 (59)
8.8, 8-H)
Me
H
244–245
(EtOH)
C22H18N2O
(326.4)
1310, 1170, 326 (M+, 67), 2.51 (s, 3 H, 6-Me), 2.53
941, 750, 325 (91), 308 (s, 3 H, 7-Me), 7.18–7.43
700
(100), 296 (76), (m, 10 H, Ar), 7.93 (s, 1
154 (79), 103 H, 5-H), 8.38 (s, 1 H, 8-H)
(75), 77 (77)
a Satisfactory microanalyses obtained: C ± 0.38, H ± 0.12, N ± 0.23.
b Except for compound 3h which was run in CDCl3/DMSO-d6.
c The first entry corresponds to the signal of C=N and the second to that of C=NOH.

SYNTHESIS
Papers
1772
of the oxidant was monitored throughout the experiment by the use of
KI/starch paper and maintained, if necessary, by the addition of extra
amounts of Pb(OAc)4. When all the starting material was consumed
(ca. 1 h) the mixture was filtered and the filtrate was extracted succes-
sively with 0.4 M aq Na2S2O3 (40 mL) and saturated Na2CO3
(40 mL). The CH2Cl2 solution was dried (Na2SO4) and evaporated
under reduced pressure and the residue was column chromatographed
(low pressure, silica gel, mixtures of petroleum ether/EtOAc of in-
creasing polarity). The quinoxaline 1-oxides 4 thus isolated were fur-
ther purified, when required by recrystallization (EtOH). Isolated
yields after purification are recorded in the Table.
Scheme 2
(1) Porter, A. E. A. Comprehensive Heterocyclic Chemistry; Kat-
ritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol.
3, pp 157–196.
(2) Cheeseman, G. W. H.; Werstiuk, E. S. G. Adv. Heterocycl.
Chem. 1978, 22, 367.
(3) Albini, A.; Pietra, S. Heterocyclic N-Oxides; CRC: Boca Raton,
FL, 1991; p 187.
(4) Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocyclic
N-Oxides; Academic Press: London, 1971.
(5) Theocharis, A. B.; Maroulis, A. J.; Hadjiantoniou-Maroulis, C.
P.; Alexandrou, N. E. J. Chem. Soc., Perkin Trans. 1 1989, 619.
(6) Hadjiantoniou-Maroulis, C. P.; Maroulis, A. J.; Terzis, A.;
Mentzafos, D. J. Org. Chem. 1992, 57, 2252.
(7) Hadjiantoniou-Maroulis, C. P.; Ikonomou, V.; Parisopoulou, E.
J. Heterocycl. Chem. 1996, 33, 655.
Mps were determined using a Kofler hot-stage apparatus and are un-
corrected. IR were recorded for Nujol mulls on a Perkin–Elmer 297
or 257 spectrophotometer calibrated with the 1602 cm–1 absorption of
polystyrene. The 1H NMR and 13C NMR spectra were recorded on a
Bruker AM300 instrument and the chemical shifts are reported as δ
values with units of ppm. 1H NMR spectra are referenced to TMS as
an internal standard and 13C NMR spectra are referenced to CDCl3 at
δ = 77.00 or DMSO-d6 at δ = 40.00. The MS were recorded from a
VG Tritech TS-250 spectrometer at 70 eV and elemental microanal-
yses were performed on a Perkin–Elmer 240 B analyzer. All reactions
were monitored by TLC carried out on pre-coated 0.25 mm Merk sil-
ica gel 60 F254 plates, and the spots were visualized under UV light.
Separations were accomplished by column chromatography on Merk
silica gel (230–400 mesh) at low pressure. All organic solvents were
purified and dried according to established procedures.14
(8) Ref 1, p 168.
(9) Auwers, K.; Siegfeld, M. Ber. Dtsch. Chem. Ges. 1893, 26, 795.
(10) Armesto, D.; Horspool, W. M.; Apoita, M.; Gallego, M. G.; Ra-
mos, A. Synthesis 1989, 448.
(11) Garcia Ruano, J. L.; Henao, M. A.; Molina, D.; Perez-Ossorio,
R.; Plumet, J. Tetrahedron Lett. 1979, 3123.
Synthesis of α-Arylimino Oximes 3; General Procedure:
A solution of (E)-benzil monoxime (2) (6.75 g, 30 mmol) and substi-
tuted aniline 1 (66 mmol) in EtOH (20 mL) and water (10 mL), to
which glacial HOAc (2.5 mL) was added, was refluxed for 4–12 h.
The crystals which separated after gradual cooling to r.t. were filtered
off and the solution was refluxed and cooled until all the starting mon-
oxime was consumed. Further purification of the product 3 was per-
formed by recrystallization (EtOH or EtOH/H2O). The isolated yields
are shown in the Table.
Haro, R.; Perez-Ossorio, R.; Plumet, J.; Garcia Ruano, J. L.;
Pascual Rigau, C. J. An. Quim. 1979, 75, 165; Chem. Abstr.
1979, 91, 38805.
(12) Kleinspehn, G. G.; Jung, J. A.; Studniarz, S. A. J. Org. Chem.
1967, 32, 460.
(13) Butler, R. N. Chem. Rev. 1984, 84, 249.
(14) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon: Oxford, 1966.
(15) Landquist, J. K.; Stacey, G. J. J. Chem. Soc. 1953, 2822.
(16) Rosum, Y. S.; Lisovskaya, N. N. Zh. Obsch. Khim. 1959, 29,
228; Chem. Abstr. 1959, 53, 21990i.
Oxidation of α-Arylimino Oximes 3, to 2,3-Diphenylquinoxaline
1-Oxides 4; General Procedure:
To a stirred solution of 3 (1.0 mmol) in CH2Cl2 (20 mL) was added
Pb(OAc)4 (1.2 mmol) dissolved in CH2Cl2 (20 mL). The slight excess