, 2003, 13(5), 228–229
1-(Benzimidazol-2-yl)-1,2-dioxoalkane arylhydrazones and 2-phenylbenzimidazole
as the main products of the reactions of 1,2,3-triketone 2-arylhydrazones with
o-phenylenediamine
Ol’ga G. Khudina, Natal’ya V. Murashova, Yanina V. Burgart and Viktor I. Saloutin*
Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation.
Fax: +7 3432 74 5954; e-mail: saloutin@ios.uran.ru
10.1070/MC2003v013n05ABEH001788
The reactions of o-phenylenediamine with 1,2,3-triketone 2-arylhydrazones containing alkyl substituents result in the predominant
formation of 1-(benzimidazol-2-yl)-1,2-dioxoalkane arylhydrazones, whereas phenyl-substituted analogues afford 2-phenyl-
benzimidazole.
The formation of 1,5-benzodiazepine derivatives under mild
conditions is typical of the reactions of 1,3-diketones, including
monofluoroalkyl-containing compounds, with o-phenylene-
diamine.1 More severe reaction conditions, as well as the pres-
ence of a second fluoroalkyl substituent in the 1,3-diketone
molecule or the acyl group at the 2-position, are favourable for
the formation of 2-alkyl(aryl)benzimidazoles.2–4
In this work, we studied the interaction of 1,2,3-triketone
2-arylhydrazones 1a–h with o-phenylenediamine. We found
that compounds 1 do not react with the diamine under con-
ditions of formation of 1,5-benzodiazepines from unsubstituted
1,3-diketones. Under more severe conditions (on boiling in
o-xylene, toluene with the azeotropic distillation of water or
ethanol in the presence of catalytic amounts of acetic and hydro-
chloric acid), 2-substituted benzimidazoles 2a–f and 3a,b were
the main isolated products of these reactions. In this case, the
nature of the substituent at the 2-position of the benzimidazole
ring depends on the structures of starting 1,2,3-triketone 2-aryl-
hydrazones 1a–h. Thus, compounds 1a–f with alkyl (methyl,
butyl, and tert-butyl) substituents mainly form 1-(benzimidazol-
2-yl)-1,2-dioxoalkane arylhydrazones 2a–f,† whereas phenyl-
substituted 1,2,3-triketone 2-arylhydrazones 1g,h give only
2-phenylbenzimidazole 3a.
diamine. In the case of monofluoroalkyl-containing 1,3-di-
ketones, it results from the elimination of a ketone containing
the most electron-acceptor fluoroalkyl substituent. The produc-
tion of benzimidazoles 2 via path I was unexpected; it was not
†
New isolated compounds 2a–f, 4 were characterised by IR (Vaseline
oil), 19F NMR (75.0 MHz, C6F6) and 1H NMR (400 and 80 MHz, Me4Si)
spectroscopy and mass spectrometry (EI, 70 eV). Compound 2e was
additionally characterised by 13C NMR spectroscopy (100 MHz, Me4Si).
1-(Benzimidazol-2-yl)-1,2-dioxopropane 4-methoxyphenylhydrazone
2a (general procedure). A mixture of 1,2,3-triketone 2-arylhydrazone 1a
(235 mg, 1 mmol) and o-phenylenediamine (108 mg, 1 mmol) was dis-
solved in o-xylene (8 cm3) [or in toluene, 2e, or in ethanol in the presence
of acetic (0.1 cm3) and hydrochloric (0.1 cm3) acids, 2c]. The reaction
mixture was refluxed for 30 h and then concentrated to dryness. After
column chromatography on silica gel (100×250 µ) with chloroform as
an eluent, 193 mg (65%) of product 2a was obtained; mp 238–240 °C.
1H NMR ([2H6]DMSO/CCl4) d: 2.61 (s, 3H, Me), 3.81 (s, 3H, OMe),
6.97–7.73 (2m, 8H, 2C6H4), 12.44, 15.26 (2br. s, 2H, 2NH). IR (n/cm–1):
3310, 1580 (NH), 1630 (C=O), 1600, 1540, 1500 (C=N, C=C). MS, m/z:
309 (M+). Found (%): C, 65.99; H, 5.20; N, 18.05. Calc. for C17H16N4O2
(%): C, 66.22; H, 5.23; N, 18.17.
1-(Benzimidazol-2-yl)-1,2-dioxo-3,3,4,4-tetrafluorobutane 4-methyl-
phenylhydrazone 2b: after recrystallisation from benzene, 257 mg (68%)
1
was obtained, mp 201–202 °C. H NMR ([2H6]DMSO/CCl4) d: 2.38 (s,
It is likely that the initial step in the formation mechanism of
the reaction leading to benzimidazoles 2 and 3 are the same. We
propose that an amino group of o-phenylenediamine attacks the
alkyl or aryl substituted carbonyl group of 1,2,3-triketone 2-aryl-
hydrazone 1 to form intermediate diimine A (Scheme 1). Next,
the free amino group of intermediate A adds to the imine con-
taining the R2 substituent to form 2-substituted benzimidazoline
B, and not to the carbonyl group containing the R1 substituent
to give alternatively a 1,5-benzodiazepine. It is evident that this
direction of addition depends on steric hindrance produced by
the bulky arylhydrazone group. Intermediate benzimidazoline B
has two possibilities for aromatisation: path I by elimination of
a saturated hydrocarbon molecule R2H or path II by elimination
of a fluorinated 2-arylhydrazone-substituted ketone. In this case,
it is likely that the direction of aromatisation depends on thermo-
dynamic factors.
3H, Me), 6.82 [tt, 1H, H(CF2)2, 2JH–F 52.5 Hz, 3JH–F 5.7 Hz], 7.26–7.78
(2m, 8H, 2C6H4), 14.20 (br. s, 2H, 2NH). 19F NMR ([2H6]DMSO/CCl4)
d: 26.22 (dt, 2F, HCF2, 2JF–H 52.5 Hz, 3JF–F 8.0 Hz), 43.31 (m, 2F, CF2).
IR (n/cm–1): 3360, 1590 (NH), 1660 (C=O), 1615, 1550, 1500 (C=N,
C=C). Found (%): C, 57.07; H, 3.68; F, 20.23; N, 14.51. Calc. for
C18H14F4N4O (%): C, 57.15; H, 3.73; F, 20.09; N, 14.81.
1-(Benzimidazol-2-yl)-1,2-dioxo-3,3-difluoropropane 4-methoxyphenyl-
hydrazone 2c: after recrystallisation from 50% aqueous ethanol, 210 mg
(61%) was obtained, mp 220–222 °C. 1H NMR ([2H6]DMSO/CCl4) d:
3.83 (s, 3H, OMe), 7.22 (t, 1H, HCF2, JH–F 54.2 Hz), 7.00–7.76 (2m,
8H, 2C6H4), 14.03 (br. s, 2H, 2NH). 19F NMR ([2H6]DMSO/CCl4) d:
35.25 (d, 2F, HCF2, JF–H 54.2 Hz). IR (n/cm–1): 3330, 1595 (NH), 1665
(C=O), 1620, 1550, 1510 (C=N, C=C). MS, m/z: 345 (M+). Found (%):
C, 58.89; H, 4.37; F, 10.93; N, 16.45. Calc. for C17H14F2N4O2 (%): C,
59.30; H, 4.10; F, 11.03; N, 16.27.
1-(Benzimidazol-2-yl)-1,2-dioxo-3,3-difluoropropane 4-methylphenyl-
hydrazone 2d: after recrystallisation from benzene, 164 mg (50%) was
1
obtained, mp 220–221 °C. H NMR ([2H6]DMSO/CCl4) d: 2.37 (s, 3H,
1,2,3-Triketone 2-arylhydrazones contain alkyl substituents
primarily react via path I; in this case, 1-(benzimidazol-2-yl)-
1,2-dioxoalkane arylhydrazones 2a–f are formed, whereas
phenyl-containing analogues reacted via path II to result in
2-phenylbenzimidazole 3a. This was supported by the separa-
tion of 2-oxohexanal arylhydrazone 4† from the reaction mix-
ture of compound 1h (Scheme 1). It is likely that the reactions
of 1,2,3-triketone 2-arylhydrazones with alkyl substituents par-
tially proceed via path II. This is evident from the production
of 2-methylbenzimidazole 3b and arylhydrazone 4 in small
amounts in the reaction of 1,2,3-triketone 2-arylhydrazone 1e
and from medium yields (68–42%) of benzimidazoles 2a–f.
The structures of compounds 3a,b were supported by com-
paring their identity with authentic samples.5
Me), 7.22 (t, 1H, HCF2, JH–F 54.1 Hz), 7.25–7.76 (2m, 8H, 2C6H4), 14.23
(br. s, 2H, 2NH). 19F NMR ([2H6]DMSO/CCl4) d: 35.20 (d, 2F, HCF2,
JF–H 54.1 Hz). IR (n/cm–1): 3335, 1595 (NH), 1670 (C=O), 1620, 1560,
1510, 1470 (C=N, C=C). Found (%): C, 62.57; H, 4.37; F, 11.93; N,
17.08. Calc. for C17H14F2N4O (%): C, 62.19; H, 4.30; F, 11.57; N, 17.06.
1-(Benzimidazol-2-yl)-1,2-dioxo-3,3,4,4,5,5,6,6-octafluorohexane 4-methyl-
phenylhydrazone 2e: after recrystallisation from benzene, 201 mg (42%)
1
was obtained, mp 221–222 °C. H NMR ([2H6]DMSO/CCl4) d: 2.38 (s,
3H, Me), 6.90 [tt, 1H, H(CF2)4, 2JH–F 51.0 Hz, 3JH–F 5.6 Hz], 7.27–7.79
(2m, 8H, 2C6H4), 14.24 (br. s, 2H, 2NH). 13C NMR ([2H6]DMSO) d:
20.80 (C1), 115.49, 117.29, 121.61, 123.59, 130.15, 135.06, 135.14,
2
135.85 (C2–11), 141.19, 144.31 (C12,13), 177.16 (t, C14, JC–F 22.6 Hz),
107.84–114.72 (C15–18). 19F NMR ([2H6]DMSO/CCl4) d: 24.50 (dm, 2F,
HCF2, 2JF–H 51.0 Hz), 33.76 (m, 2F, CF2), 40.97 (m, 2F, CF2), 52.25 (m,
2F, CF2). IR (n/cm–1): 3380, 1585 (NH), 1645 (C=O), 1610, 1540, 1500,
1470 (C=N, C=C). Found (%): C, 50.01; H, 2.90; F, 31.67; N, 11.65.
Calc. for C20H14F8N4O (%): C, 50.22; H, 2.95; F, 31.77; N, 11.71.
The formation of 2-methyl(phenyl)benzimidazoles 3 via path
II is typical of the reactions of 1,3-diketones with o-phenylene-
– 228 –