Synthesis of benzimidazolone derivatives based on 2-acylcyclohexane-1,3- diones alkoximes

Article abstract of DOI:10.1134/S1070428008070130

2-(1-Alkoxyiminoalkyl)cyclohexane-1,3-diones undergo at heating Beckmann rearrangement to give 6,7-dihydro-1,3-benzoxazol-4(5H)-one derivatives that under treatment with amines in acid medium are converted into 1,5,6,7-tetrahydro-4H-benzimidazol-4-ones. I

Full text of DOI:10.1134/S1070428008070130

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 7, pp. 1024−1030. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © D.B. Rubinov, T.A. Zheldakova, I.L. Rubinova, F.A. Lakhvich, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 7, pp. 1034−1040.
Synthesis of Benzimidazolone Derivatives
Based on 2-Acylcyclohexane-1,3-diones Alkoximes
D. B. Rubinov, T. A. Zheldakova, I. L. Rubinova, and F. A. Lakhvich
Insitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, 220141 Belarus
e-mail: rubinov@iboch.bas-net.by
Received November 1, 2007
Abstract—2-(1-Alkoxyiminoalkyl)cyclohexane-1,3-diones undergo at heating Beckmann rearrangement to give
6,7-dihydro-1,3-benzoxazol-4(5H)-one derivatives that under treatment with amines in acid medium are converted
into 1,5,6,7-tetrahydro-4H-benzimidazol-4-ones. In reaction of 6,7-dihydro-1,3-benzoxazol-4(5H)-ones with
O-ethylhydroxylamine 4-ethoxyimino derivatives were obtained that treated with hydrochloric acid formed the
corresponding N-ethoxybenzimidazolones.
DOI: 10.1134/S1070428008070130
Ethers of oxime derivatives (alkoximes) of cyclo-
hexane β-triketones I are the active reagents of the
present-day graminicide herbicides of cyclohexoximes
series like alloxidim (Ia), sethoxydim (Ib), traloxydim
(Ic) etc. [1–3]. Owing to the structural likeness to natural
substances containing some kind of β-tricarbonyl system
[4, 5] this pesticide group possesses a valuable complex
of properties: They are characterized by low consump-
tion, selectivity of action, they are nontoxic, do not
possess oncogenic, mutagenic, teratogenic, and other
undesirable properties [6]. Unlike graminicides from the
series of alkoxyphenoxypropionic acids derivatives [3]
the cyclohexoximes suffer very fast degradation in soil
giving nontoxic decomposition products that after several
weeks are no more detectable in soil, and their residual
content in the cultivated plants is many factors of ten
smaller than those of the other classes of herbicides.
The above aspects arose our interest to the synthesis
and the study of properties of new benzoxazolones
derivatives with a goal of their conversion into
benzimidazoles in order to obtain new substances with a
potential biological, in particular, pesticide, action.
We showed formerly [8] that alkoxyiminodiketones
easily underwent Beckmann rearrangement providing
benzoxazolones. In this study the reaction was investig-
ated by an example of oximes Ia–Ie. On boiling these
compounds for 24 h in ethanol substances Ib–Ie were
converted into the corresponding benzoxazolones IIa–
IId, and the unsymmetrical alkoximine Ia yielded a mix-
ture of isomers Ie and III in a ratio 2:1 (see the scheme).
Spectral characteristics and elemental composition of
compounds obtained were consistent with the assumed
structures. In the 1H and 13C NMR spectra of 5-ethylthio-
propyl-substituted benzoxazolone IIa containing chiral
centers at C6 and C2'' most atoms gave rise to a double
set of signals proving the presence of a diastereomers
mixture.
In the course of storage and natural metabolism of
oximes I form benzoxazolones II [7] that also are
obtained as side products in the synthesis of oximes [8].
The benzoxazole moiety proper is also a biophore and is
included into a considerable number of insecticide,
fungicidal, and other pesticide preparations [1, 2], and
also in drugs [9]. Benzoxazoles are often found alongside
benzimidazoles in naturally occurring substances [10,
11], therefore both classes of compounds are the subject
of an extensive research by synthetic chemists [12, 13]
and pharmacologists [14, 15].
By reaction of benzoxazolones IIa–IId with amines
(p-anisidine, benzylamine, phenethylamine or
methylamine) in the presence of trifluoroacetic acid we
obtained 60–80% yields the corresponding
benzimidazolones IVa–IVj.
The reaction of 5-methoxycarbonyl-substituted
benzoxazolone IIe and its isomer 7-methoxycarbonyl-
substituted derivative III with benzylamine in both cases
1024

SYNTHESIS OF BENZIMIDAZOLONE DERIVATIVES
1025
Scheme.
OR5
R4
O
N
O
O
O
R3
R3
R3
N
N
4
4
3a
7a
R6NH2
CF3CO2H
3a
7a
5
6
3
5
6
3
D
2
R4
2
R4
R2
R1
R2
R1
R2
R1
1
1
7
7
O
N
R6
IIa_IIe
Ia_Ie
IVa_IVj, IVn, IVo
HCl
O
O
EtONH2
conc. HCl
.
NH2 HCl
N
O
HCl
R2
R1
C3H7
OEt
N
O
N
CO2CH3
VIa, VIb
O
R4
R2
R1
III
NH2
O
O
Va, Vb
VII
I, R1 = R2 = CH3, R3 = CO2CH3, R4 = C3H7, R5 = CH2CH=CH2 (a); R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = R5 = C3H7
(b); R1 = R3 = H, R2 = 2,4,6-(CH3)3Ph, R4 = R5 = C2H5 (c); R1 = R2 = CH3, R3 = H, R4 = R5 = C2H5 (d); R1 = R3 = H, R2 =
CH2CH(SC2H5)CH3, R4 = R5 = C2H5 (e); II, R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = C2H5 (a); R1 = R3 = H, R2 =
2,4,6-(CH3)3Ph, R4 = C2H5 (b); R1 = R2 = CH3, R3 = H, R4 = C2H5 (c); R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = C3H7
(d); R1 = R2 = CH3, R3 = CO2CH3, R4 = C3H7 (e); IV, R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = C3H7, R6 = CH2Ph (a);
R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = C3H7, R6 = 4-CH3OPh (b); R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 =
C2H5, R6 = CH2Ph (c); R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 = C2H5, R6 = 4-CH3OPh (d); R1 = R2 = CH3, R3 = H,
R4 = C2H5, R6 = CH2Ph (e); R1 = R2 = CH3, R3 = H, R4 =C2H5, R6 = 4-CH3OPh (f); R1 = R3 = H, R2 = 2,4,6-(CH3)3Ph, R4 =
C2H5, R6 = CH2Ph (g); R1 = R3 = H, R2 = 2,4,6-(CH3)3Ph, R4 = C2H5, R6 = 4-CH3OPh (h); R1 = R3 = H, R2 = 2,4,6-
(CH3)3Ph, R4 = C2H5, R6 = CH2CH2Ph (i); R1 = R3 = H, R2 = 2,4,6-(CH3)3Ph, R4 = C2H5, R6 = CH3 (j); R1 = R3 = H, R2 =
2,4,6-(CH3)3Ph, R4 = C2H5, R6 = OC2H5 (n); R1 = R3 = H, R2 = CH2CH(SC2H5)CH3, R4 =C3H7, R6 = OC2H5 (o); V, R1 = H,
R2 = 2,4,6-(CH3)3Ph, R4 = C2H5 (a); R1 = H, R2 = CH2CH(SC2H5)CH3, R4 = C3H7 (b); VI, R1 = R2 = CH3 (a); R1 = H,
R2 = 2,4,6-(CH3)3Ph (b).
O
2'''
O
3a
N
O
1'''
2''
4
7
1'''
5
6
1'
3a
N
O
4
2
7a
S
*
5
6
2'
1'
3''
4''
2
1''
6''
7a
*
2'
7
3'
2''
3''
1''
2'''
3'''
5''
IIa
IIb
O
O
O
H3CO2C
N
N
H3CO2C
N
C3H7
C3H7
C3H7
CH2Ph
N
N
N
CO2CH3
OCH3
OCH3
IVl
IVk
IVm
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

RUBINOV et al.
1026
resulted in the formation of the same benzimidazolone
IVk, and the reaction of compounds IIe and III with p-
anisidine gave the same mixture of regioisomeric
products IVl and IVm in a ratio ~2:1. These facts show
that at the opening of the oxazole ring first a nucleophilic
attack occurs at C2 atom of the benzoxazole followed by
a cyclization both at atoms C4 and C7a. The structure of
obtained benzimidazolones IV was unambiguously
confirmed by the sum of data of IR, 1H NMR, mass
spectra, and elemental analyses reported in
EXPERIMENTAL.
prolonged boiling in toluene in the presence of trifluoro-
acetic or concn. hydrochloric acid without isolation of
intermediately formed derivatives Va and Vb.
On treating benzoxazolone IIc with concn. hydro-
chloric acid the opening of the oxazole ring occurred
with the formation of aminodiketone hydrochloride VIa
identical in physicochemical and spectral characteristics
to the previously described compound [16]. Under the
same conditions 7-methoxycarbonyl-substituted
benzoxazolone III alongside the opening the oxazole ring
suffered decarboxylation; as a result the isolated product
was identical to salt VIa. Same as mentioned in [16] we
failed to isolate from salt VIa the compound with a free
amino group due to its instability. However from
6-mesityl-substituted benzoxazolone IIb after the open-
ing of the oxazole ring by concn. hydrochloric acid and
treating obtained salt VIb with sodium hydroxide we
prepared aminodiketone VII that unlike such compounds
described in the literature proved to be relatively stable
and was characterized by IR and 1H NMR spectra.
Boiling benzoxazolones IIa–IId with an ethanol
solution of O-ethylhydroxylamine resulted in the
oximation of the carbonyl group of the ring leading to
the formation of the corresponding O-ethyloximes Va–
Vc.At heating with concn. hydrochloric acid compounds
Va and Vb converted in N-ethoxy-substituted benzimid-
azolones IVn and IVo. N-Ethoxy-substituted benzimid-
azolones IVn and IVo were also obtained directly from
benzoxazolones IIb and IIc in one stage process by
O
O
O
O
R4
R4
4
4
N
N
4
N
O
N
R4
..
R4
.
6
NHR6
.
7a
7a
NHR
7a
O
O
OH
R6
H2N
R6
The described reaction of benzoxazolones with
amines can serve an efficient and simple procedure for
preparation of N-substituted benzimidazolones.
boiled for 24 h (TLC monitoring). The reaction mixture
was evaporated in a vacuum, the residue was subjected
to chromatography on silica gel, eluent petroleum ether–
ethyl acetate.
2-Ethyl-6-[2-(ethylsulfanyl)propyl]-6,7-dihydro-
1,3-benzoxazol-4(5H)-one (IIa). Yield 1.91 g (68%).
Oily substance. IR spectrum, cm–1: 1700, 1620, 1590.
1H NMR spectrum, δ, ppm (diastereomers mixture 1:1):
0.99 t and 1.00 t (3H, CH3CH2CH2, J 7.4 Hz), 1.25 t and
1.26 t (3H, CH3CH2S, J 7.4 Hz), 1.31 d and 1.32 d (3H,
CH3CHS, J 6.6 Hz), 1.61–1.74 m (2H, CH2CHS), 1.82
m (2H, CH3CH2CH2), 2.33 m (1H, 6-CHA), 2.55 q and
2.56 q (2H, CH3CHS, J 7.4 Hz), 2.61 m,(1H, C4HA), 2.65
m (1H, C6HB), 2.68 m (1H, C5H), 2.76 t (2H,
CH3CH2CH2, J 7.4 Hz), 2.83 m (1H, SCH), 3.07 m (1H,
C4HB). 13C NMR spectrum, δ, ppm: 13.67 (C3'), 14.81
and 14.83 (C2'’’), 20.15 (C2'), 21.98 and 22.20 (C3'’), 23.73
and 24.18 (C1'’’), 27.98 and 28.67 (C7), 29.95 (C1'), 33.16
and 33.26 (C6), 36.60 and 36.94 (C2'’), 42.39 and 42.68
(C1'’), 43.89 and 44.46 (C5), 134.13 (C3a), 163.28 (C7a),
165.35 (C2), 190.55 (C4). Mass spectrum, m/z: [M]+ 281,
[M + 1]+ 282, [M + 2]+ 283. Found, %: C 64.15; H 8.11;
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer UR-
20 from samples of solid compounds pelletized with KBr,
1
from oily substances, in thin film. H and 13C NMR
spectra were registered on a spectrometer BrukerAvance
500 at operating frequencies 500 (1H) and 125 MHz (13C)
from solutions in deuterochloroform (or, if indicated, in
DMSO-d6), reference TMS. Mass spectra were measured
on MKh-1320 instrument. Melting points were
determined on a Bo¸tius heating block. The reaction
progress was monitored and the homogeneity of
compounds was checked by TLC on Kieselgel 60 F254
plates (Merck), the spots were visualized under UV
irradiation followed by spraying with iron(III) chloride
solution. For column chromatography silica gel Kieselgel
60 (Fluka) was used.
Benzoxazolones IIa–IIe. A solution of 10 mmol of
alkoxyiminodiketone Ia–Ie in 50 ml of ethanol was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SYNTHESIS OF BENZIMIDAZOLONE DERIVATIVES
1027
Benzimidazolones IVa–IVe. To a solution of 1.0–
1.5 mmol of benzoxazolone IIa–IIe, or III in 20 ml of
toluene was added 1.1 equiv of amine and 1.1 equiv of
trifluoroacetic acid. The reaction mixture was boiled for
2–3 h (with benzylamine and O-ethyloxime for 24 h);
the reaction completion was monitored by TLC. On
completion of the reaction toluene was removed on a
rotary evaporator. The residue was dissolved in 20 ml
chloro-form, washed with 20 ml of water, the water layer
was separated, and products were extracted into
chloroform (3×10 ml). Combined extracts were dried
with anhydrous sodium sulfate, the solvent was removed
on a rotary evaporator. The residue was subjected to
column chromatography on silica gel, eluent chloroform–
ethanol.
N 4.97; S 11.56. C15H23NO2S. Calculated, %: C 64.02;
H 8.24; N 4.98; S 11.39. M 281.42.
6-(Mesityl)-2-ethyl-6,7-dihydro-1,3-benzoxazol-
4(5H)-one (IIb). Yield 2.69 g (95%), mp 117–119°C
(from petroleum ether). IR spectrum, cm–1: 1700, 1615,
1
1595. H NMR spectrum, δ, ppm: 1.39 t (3H, CH3CH2,
J 7.6 Hz), 2.27 s (3H, 4'-CH3Ph), 2.33 br.s and 2.44 br.s
[6H, 2',6'-(CH3)2Ph], 2.66 d.d (1H, C6HA, J1 17.0,
J2 4.3 Hz), 2.84 q (2H, CH3CH2, J 7.6 Hz), 2.97 d.d (1H,
C4HA, J1 17.8, J2 5.7 Hz), 3.22 d.d (1H, C6HB, J1 17.0,
J2 14.1 Hz), 3.44 d.d (1H, C4HB, J1 17.8, J2 12.1 Hz),
4.06 m (1H, C5H), 6.89 s (2Harom). 13C NMR spectrum,
δ, ppm: 10.96 (C2'), 20.65 (C2'’’), 21.35 br (C1'’’), 21.69
(C1'), 22.22 br (C3'’’), 26.33 (C7), 35.84 (C5), 41.70 (C6),
129.84 br (C3'’), 131.57 br (C5'’’), 134.02 (C3a), 134.24
(C1'’), 136.22 br (C2'’), 136.73 (C4'’), 163.48 (C7a), 166.39
(C2), 191.00 (C4). Found, %: C 76.51; H 7.33; N 4.87.
[M]+ 283. C18H21NO2. Calculated, %: C 76.29; H 7.47;
N 4.94. M 283.37.
1-Benzyl-2-propyl-6-[2-(ethylsulfanyl)propyl]-
1,5,6,7-tetrahydro-4H-benzimidazol-4-one (IVa).
Yield 61%. Oily substance. IR spectrum, cm–1: 1675,
1540. 1H NMR spectrum (DMSO-d6), δ, ppm: 0.94 t
and 0.95 t (3H, CH3CH2CH2, J 7.4 Hz), 1.14–1.27 m
(6H, CH3CH2CHS, CH3CH2S), 1.52–1.66 m (2H,
CHCH2S), 1.76 m (2H, CH3CH2CH2), 2.27–2.36 m (2H,
C5HA, C7HA), 2.46 q and 2.51 q (CH3CH2S), 2.56–2.82
m (6H, C5HB, C6H, C7HB, SCH, CH3CH2CH2), 5.03–
5.14 m (2H, CH2Ph), 6.96 d (2Harom, J 7.4 Hz), 7.30–
7.40 m (3Harom). Mass spectrum, m/z: [M]+ 370, [M +
1]+ 371. Found, %: C 71.48; H 8.21; N 7.67; S 8.55.
C22H30N2OS. Calculated, %: C 71.31; H 8.16; N 7.56; S
8.65. M 370.56.
6,6-Dimethyl-2-ethyl-6,7-dihydro-1,3-benzoxazol-
4(5H)-one (IIc). Yield 1.56 g (81%). Oily substance. IR
spectrum, cm–1: 1695, 1615, 1590. 1H NMR spectrum,
δ, ppm: 1.15 s (6H, CH3CCH3), 1.34 t (3H, CH3CH2,
J 7.7 Hz), 2.34 s (2H, CH2), 2.76–2.82 m (4H, 2CH2),
2.98 s (2H, CH2). Found, %: C 68.53; H 7.91; N 7.17.
[M]+ 193. C11H15NO2. Calculated, %: C 68.37; H 7.82;
N 7.25. M 193.25.
2-Ethyl-6-[2-(ethylsulfanyl)propyl]-6,7-dihydro-
1,3-benzoxazol-4(5H)-one (IId). Yield 1.74 g (65%).
Oily substance. IR spectrum, cm–1: 1695, 1616, 1588.
1H NMR spectrum, δ, ppm: 1.23 t and 1.25 t (3H,
CH3CH2S, J 7.4 Hz), 1.30 and 1.31 d (3H, CH3CHS,
J 6.6 Hz), 1.35 t (3H, CH3CH2C, J 7.6 Hz), 1.60–1.70 m
(2H, CH2CHS), 2.31 m (1H, C6HA), 2.54 q and 2.55 q
(2H, CH3CHS, J 7.4 Hz), 2.60 m (1H, C4HA), 2.63 m
(1H, C6HB), 2.68 m (1H, C5H), 2.72 m (2H, CH3CH2C),
2.83 m (1H, SCH), 3.06 m (1H, C4HB). Mass spectrum,
m/z: [M]+ 267, [M + 1]+ 268, [M + 2]+ 269. Found, %:
C 62.73; H 8.01; N 5.07; S 11.76. C14H21NO2S.
Calculated, %: C 62.89; H 7.92; N 5.24; S 11.99. M 267.39.
1-[4-(Methoxy)phenyl]-2-propyl-6-[2-(ethyl-
sulfanyl)propyl]-1,5,6,7-tetrahydro-4H-benzimid-
azol-4-one (IVb). Yield 68%. Oily substance. IR
spectrum, cm–1: 1675, 1525. 1H NMR spectrum, δ, ppm:
0.90 t (3H, CH3CH2CH2, J 7.4 Hz), 1.17 t and 1.20 t
(3H, CH3CH2S, J 7.4 Hz), 1.22 d and 1.23 d (CH3CHS,
J 6.6 Hz), 1.50–1.66 m (4H, CH3CH2CH2, CHCH2S),
2.18–2.26 m (1H, C5HA), 2.30–2.38 m (1H, C7HA), 2.40–
2.58 m (7H, C5HB, C6H, C7HB, CH3CH2S, CH3CH2CH2),
2.74 m (1H, CHS), 3.87 C (3H, OCH3), 7.04 d (2Harom
,
J 8.5 Hz), 7.24 d (3Harom, J 8.5 Hz). Mass spectrum, m/z:
[M]+ 386, [M + 1]+ 387. Found, %: C 68.47; H 7.71;
N 7.35; S 8.25. C22H30N2O2S. Calculated, %: C 68.36;
H 7.82; N 7.25; S 8.30. M 386.56.
From allyloxyiminodiketone Ia was obtained a mix-
ture of methyl 6,6-dimethyl-2-propyl-4-oxo-4,5,6,7-
tetrahydro-1,3-benzoxazole-5-carboxylate (IIe) and its
regioisomer, methyl 6,6-dimethyl-2-propyl-4-oxo-
4,5,6,7-tetrahydro-1,3-benzoxazole-7-carboxylate
(III) in a ratio 2:1. Overall yield 1.90 g (72%). The
compounds were isolated in individual state by column
chromatography; they were identical by physicochemical
characteristics to substances described in [8] .
1-Benzyl-2-ethyl-6-[2-(ethylsulfanyl)propyl]-
1,5,6,7-tetrahydro-4H-benzimidazol-4-one (IVc).
Yield 58%. Oily substance. IR spectrum, cm–1: 1680,
1545. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.14–
1.25 m (9H, CH3CH2, CH3CH2S, CH3CH), 1.51–1.60 m
(2H, CHCH2S), 2.16–2.24 m (1H, C5HA), 2.31–2.53 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

RUBINOV et al.
1028
(5H, C5HB, C6H, C7HA, CH3CH2S), 2.60 m (2H,
CCH2CH3), 2.72 m and 2.80 m (1H, SCH), 2.87 m (1H,
C7HB), 5.16 C (2H, CH2Ph), 7.01 d (2Harom, J 7.4 Hz),
7.24–7.35 m (3Harom). Mass spectrum, m/z: [M]+ 356,
[M + 1]+ 357. Found, %: C 71.81; H 8.05; N 7.77; S 8.85.
C21H28N2OS. Calculated, %: C 70.75; H 7.92; N 7.86;
S 8.99. M 356.53.
(2Harom, J 7.0 Hz), 7.29–7.36 m (3Harom). Found, %:
C 80.81; H 7.61; N 7.67. [M]+ 372. C25H28N2O.
Calculated, %: C 80.61; H 7.58; N 7.52. M 372.51.
1-[(4-Methoxy)phenyl]-6-mesityl-2-ethyl-1,5,6,7-
tetrahydro-4H-benzimidazol-4-one (IVh). Yield 78%,
mp 218–220°C (from ethyl acetate). IR spectrum, cm–1:
1
1700, 1525. H NMR spectrum, δ, ppm: 1.26 s (3H,
CH3CH2, J 7.6 Hz), 2.22 s (3H, CH3Ph), 2.23 br.s (3H,
CH3), 2.41 br.s (3H, CH3), 2.51 d.d (1H, C7HA, J1 17.4,
J2 5.3 Hz), 2.66 d.d (1H, C7HA, J1 17.0, J2 4.2 Hz),
2.81 m (2H, CH3CH2), 3.15 d.d (1H, C5HB, J1 17.4,
J2 12.2 Hz), 3.29 d.d (1H, C7HB, J1 17.0, J2 14.3 Hz),
3.87 s (1H, OCH3), 4.03 s (1H, C6H), 6.83 s (2Harom),
7.04 d (2Harom, J 8.9 Hz), 7.23 d (2Harom, J 8.9 Hz). Found,
%: C 77.38; H 7.31; N 7.17. [M]+ 388. C25H28N2O2.
Calculated, %: C 77.29; H 7.26; N 7.21. M 388.51.
1-[4-(Methoxy)phenyl]-2-ethyl-6-[2-(ethyl-
sulfanyl)propyl]-1,5,6,7-tetrahydro-4H-benzimid-
azol-4-one (IVd). Yield 63%, mp 90–91°C (from a mix-
ture ether–hexane). IR spectrum, cm–1: 1700, 1525.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.15–1.25 m
(9H, CH3CH2, CH3CH2S, CH3CH), 1.56 m (2H,
CHCH2S), 2.20–2.28 m (1H, C5HA), 2.32–2.42 m (1H,
C7HA), 2.42–2.58 m (7H, C5HΒ, C6H, C7HΒ, CH3CH2S,
CH3CH2C), 2.75 m (1H, CHS), 3.87 s (3H, OCH3), 7.05
d (2Harom, J 8.9 Hz), 7.29 d (3Harom, J 8.9 Hz). Mass
spectrum, m/z: [M]+ 372, [M + 1]+ 373. Found, %: C 67.66;
H 7.65; N 7.57; S 8.65. C21H28N2O2S. Calculated, %:
C 67.71; H 7.58; N 7.52; S 8.61. M 372.53.
6-Mesityl-1-phenethyl-2-ethyl-1,5,6,7-tetrahydro-
4H-benzimidazol-4-one (IVi). Yield 70%, mp 201–
203°C (from ethyl acetate). IR spectrum, cm–1: 1680,
1
1545. H NMR spectrum, δ, ppm: 1.27 t (3H, CH3CH2,
J 7.5 Hz), 2.16 s (3H, CH3Ph), 2.17 d.d (1H, C5HA,
J1 16.6, J2 4.2 Hz), 2.20 br.s and 2.24 C (6H, 2CH3Ph),
2.43 d.d (1H, C7HA, J1 16.6, J2 5.4 Hz), 2.56 q
(2H, CH3CH2, J 7.5 Hz), 2.64 d.d (1H, C5HB, J1 16.6,
J2 12.3 Hz), 2.86–2.94 m (3H, C7HB, PhCH2CH2N),
3.66 m (1H, C6H), 4.05 m (PhCH2CH2N), 6.69 s (2Harom),
6.96 d (2Harom, J 6.5 Hz), 7.15–7.21 m (3Harom). Found,
%: C 80.88; H 7.83; N 7.47. [M]+ 386. C26H30N2O.
Calculated, %: C 80.79; H 7.82; N 7.25. M 386.54.
1-Benzyl-6,6-dimethyl-2-ethyl-1,5,6,7-tetrahydro-
4H-benzimidazol-4-one (IVe). Yield 60%. Oily sub-
stance. IR spectrum, cm–1: 1680, 1540. 1H NMR spec-
trum, δ, ppm: 1.09 s (6H, CH3CCH3), 1.24 t (3H, CH3CH2,
J 7.4 Hz), 2.27 s (2H, C5H2), 2.56 s (2H, C7H2), 2.59 q
(2H, CH3CH2, J 7.4 Hz), 5.14 s (2H, CH2Ph), 6.97 d
(2Harom, J 7.4 Hz), 7.23–7.34 m (3Harom). Found, %:
C 76.68; H 7.91; N 9.97. [M]+ 282. C18H22N2O.
Calculated, %: C 76.56; H 7.85; N 9.92. M 282.39.
1-Methyl-2-ethyl-6-[2-(ethylsulfanyl)propyl]-
1,5,6,7-tetrahydro-4H-benzimidazol-4-one (IVj).
Yield 48%, mp 232–236°C (from ethyl acetate). IR
6,6-Dimethyl-1-[(4-methoxy)phenyl]-2-ethyl-
1,5,6,7-tetrahydro-4H-benzimidazol-4-one (IVf).
Yield 72%, mp 142–143°C (from toluene). IR spectrum,
1
spectrum, cm–1: 1665, 1550. H NMR spectrum, δ, ppm:
1
cm–1: 1680, 1520. H NMR spectrum, δ, ppm: 1.09 s
1.39 t (3H, CH3CH2, J 7.5 Hz), 2.27 C (3H, CH3), 2.31 br.s
and 2.46 br.s (6H, 2CH3), 2.58 d.d (1H, C5HA, J1 16.6,
J2 4.2 Hz), 2.75 q (2H, CH3CH2, J 7.5 Hz), 2.78 d.d (1H,
C7HA, J1 16.6, J2 5.5 Hz), 3.20–3.32 m (2H, C5HB, C7HB),
3.49 C (3H, CH3N), 4.04 m (1H, C6H), 6.88 C (2Harom).
Mass spectrum, m/z: [M]+ 296, [M + 1]+ 297, [M + 2]+
298. Found, %: C 77.09; H 8.30; N 9.37. C19H24N2O.
Calculated, %: C 76.99; H 8.16; N 9.45. M 296.41.
(6H, CH3CCH3), 1.19 t (3H, CH3CH2, J 7.5 Hz), 2.29 s
(2H, C5H2), 2.42 s (2H, C7H2), 2.52 q (2H, CH3CH2,
J 7.5 Hz), 3.87 s (3H, CH3O), 7.05 d and 7.23 d (4Harom
,
J 8.8 Hz). Found, %: C 72.64; H 7.57; N 9.29. [M]+ 298.
C18H22N2O2. Calculated, %: C 72.46; H 7.43; N 9.39.
M 298.39.
1-Benzyl-6-mesityl-2-ethyl-1,5,6,7-tetrahydro-4H-
benzimidazol-4-one (IVg). Yield 66%. Oily substance.
Methyl 1-benzyl-6,6-dimethyl-4-oxo-2-propyl-
4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylate
(IVk). Yield 64%, mp 181–183°C (from toluene). IR
spectrum, cm–1: 1740, 1685, 1535. 1H NMR spectrum,
δ, ppm: 0.94 t (3H, CH3CH2, J 7.4 Hz), 1.09 s and 1.11 s
(6H, CH3CCH3), 1.80 m (2H, CH3CH2), 2.23 d (1H,
C7HA, J 16.7 Hz),2.58 m (2H, CH3CH2CH2), 3.09 d (1H,
C7HΒ, J 16.7 Hz), 3.38 s (1H, C5H), 3.43 s (3H, OCH3),
1
IR spectrum, cm–1: 1680, 1540. H NMR spectrum, δ,
ppm: 1.35 s (3H, CH3CH2, J 7.5 Hz), 2.22 br.s and
2.23 s (6H, 2CH3Ph), 2.36 br.s (3H, CH3Ph), 2.58–
2.68 m (2H, C5HA, C7HA), 2.71 q (2H, CH3CH2, J 7.5 Hz),
3.12 d.d (1H, C5HB, J1 16.7, J2 12.2 Hz), 3.24 d.d (1H,
C7HB, J1 16.8, J2 14.1 Hz), 3.99 m (1H, C6H), 5.04 d and
5.09 d (2H, CH2Ph, J 16.7 Hz), 6.83 s (2Harom), 6.95 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SYNTHESIS OF BENZIMIDAZOLONE DERIVATIVES
1029
5.08 d and 5.13 d (2H, PhCH2N, J 17.1 Hz), 6.87 d
(2Harom, J 7.1 Hz), 7.29–7.36 m (3Harom). Mass spectrum,
m/z: [M]+ 354, [M + 1]+ 355. Found, %: C 71.08; H 7.56;
N 8.08. C21H26N2O3. Calculated, %: C 71.16; H 7.39;
N 7.90. M 354.45.
chromatography on silica gel, eluent petroleum ether–
ethyl acetate. Yield 0.49 g (42%), oily substance. IR
1
spectrum, cm–1: 1740, 1660, 1590. H NMR spectrum
(DMSO-d6), δ, ppm (diastereomers mixture 1:1): 1.01 t
and 1.02 t (3H, CH3CH2CH2, J 7.4 Hz), 1.23 t and 1.24 t
(3H, CH3CH2S, J 7.4 Hz), 1.26–1.31 m (6H, CH3CHS,
CH3CH2O), 1.51–1.67 m (2H, CH2CHS), 1.78 m (2H,
CH3CH2CH2), 2.01 m (1H, C6HA), 2.26 m (1H, C5H),
2.38 m (1H, C4HA), 2.51 q and 2.52 q (2H, CH3CH2S,
J 7.4 Hz), 2.68 t (2H, CH3CH2CH2, J 7.4 Hz), 2.82 m
(1H, SCH), 2.86 m (1H, C6HΒ), 3.01 m (1H, C4HΒ),
4.09 m and 4.20 m (2H, CH3CH2O). Mass spectrum, m/z:
[M]+ 324, [M + 1]+ 325, [M + 2]+ 326. Found, %: C 63.11;
H 8.73; N 8.59, S 9.99. C17H28N2O2S. Calculated, %:
C 62.93; H 8.70; N 8.63, S 9.88. M 324.48.
Methyl 6,6-dimethyl-1-[4-(methoxy)-phenyl]-4-
oxo-2-propyl-4,5,6,7-tetrahydro-1H-benzimidazole-5-
carboxylate (IVl). Yield 54%, mp 200–202°C (from
1
toluene). IR spectrum, cm–1: 1745, 1690, 1525. H NMR
spectrum, δ, ppm: 0.87 t (3H, CH3CH2, J 7.4 Hz), 1.13 s
and 1.16 s (6H, CH3CCH3), 1.64–1.72 m (2H, CH3CH2),
2.19 d (1H, C7HA, J 16.7 Hz), 2.51 m (2H, CH3CH2CH2),
2.99 d (1H, C7HΒ, J 16.7 Hz), 3.32 s (1H, C5H), 3.70 s
(3H, OCH3), 3.89 s (3H, PhOCH3), 7.03 d (2Harom, J 8.9
Hz), 7.16 d (2Harom, J 8.9 Hz). Found, %: C 68.22; H
7.06; N 7.40. [M]+ 370. C21H26N2O4. Calculated, %: C
68.09; H 7.07; N 7.56. M 370.45.
6-Mesityl-2-ethyl-1-ethoxy-1,5,6,7-tetrahydro-4H-
benzimidazol-4-one (IVn). A mixture of 0.2 g (0.63
mmol) of benzoxazole Va and 3 ml of concn. HCl was
heated for 30 min hill the disappearance of the initial
compound (TLC monitoring). The mixture was diluted
with 10 ml of water and extracted with chloroform (2×10
ml). The combined extracts were washed with water,
dried with sodium sulfate, and evaporated on a rotary
evaporator. The residue was crystallized from ethyl
acetate. Yield 0.17 g (86%), crystalline substance, mp
Methyl 6,6-dimethyl-1-[4-(methoxy)-phenyl]-4-
oxo-2-propyl-4,5,6,7-tetrahydro-1H-benzimidazole-7-
carboxylate (IVm). Yield 28%. Oily substance. IR
1
spectrum, cm–1: 1745, 1700, 1525. H NMR spectrum,
δ, ppm: 0.87 t (3H, CH3CH2, J 7.4 Hz), 1.10 s and 1.17 s
(6H, CH3CCH3), 1.64–1.72 m (2H, CH3CH2), 2.27 d (1H,
C5HA, J 16.5 Hz), 2.43 m (2H, CH3CH2CH2), 2.93 d
(1H, C5HΒ, J 16.5 Hz), 3.28 s (1H, C7H), 3.55 s (3H,
OCH3), 3.88 s (3H, PhOCH3), 7.00 br.s and 7.13 br.s
(4Harom). Found, %: C 68.02; H 7.19; N 7.65. [M]+ 370.
C21H26N2O4. Calculated, %: C 68.09; H 7.07; N 7.56.
M 370.45.
1
136–138°C. IR spectrum, cm–1: 1690, 1550. H NMR
spectrum, δ, ppm: 1.39 t (3H, CH3CH2, J 7.5 Hz), 1.40 t
(3H, CH3CH2O, J 7.0 Hz), 2.27 s (3H, CH3), 2.32 s (3H,
CH3), 2.47 s (3H, CH3), 2.60 d.d (1H, C7HA, J1 16.9, J2
4.1 Hz), 2.80 q (2H, CH3CH2, J 7.5 Hz), 2.92 d.d (1H,
C5HA, J1 16.6, J2 5.4 Hz), 3.20–3.38 m (2H, C5HΒ, C7HΒ),
4.03 m (1H, C6H), 4.21 q (2H, CH3CH2O, J 7.05 Hz),
6.90 s (2Harom). Found, %: C 73.48; H 7.98; N 8.47. [M]+
326. C20H26N2O2. Calculated, %: C 73.59; H 8.03; N
8.58. M 326.44.
6-Mesityl-2-ethyl-6,7-dihydro-1,3-benzoxazol-
4(5H)-one O-ethyloxime (Va). In 20 ml of ethanol was
dissolved 1 g (3.6 mmol)of benzoxazolone IIb, and 0.27
g (4.4 mmol) of O-ethylhydroxylamine was added. The
mixture was heated at reflux for 24 h. The solvent was
removed on a rotary evaporator, and the residue was
crystallized from toluene. Yield 1 g (90%), crystalline
substance, mp 112–114°C. IR spectrum, cm–1: 1660,
1630, 1590. 1H NMR spectrum, δ, ppm: 1.30 t (3H,
CH3CH2O, J 7.0 Hz), 1.40 t (3H, CH3CH2C, J 7.6 Hz),
2.31 s [3H, 4'-(CH3)Ph], 2.36 br.s and 2.47 br.s [6H, 2',6'-
(CH3)2Ph], 2.80–2.90 m (2H, C4HA, C6HA), 2.87 q (2H,
CH3CH2C, J 7.6 Hz), 3.25–3.33 m (2H, C4HB, C6HB),
3.77 m (1H, C5H), 4.25–4.31 m (2H, CH3CH2O), 6.92 s
(2Harom). Found, %: C 73.47; H 8.14; N 8.69. [M]+ 326.
C20H26N2O2. Calculated, %: C 73.59; H 8.03; N 8.58.
M 326.44.
2-Ethyl-1-ethoxy-6-[2-(ethylsulfanyl)propyl]-
1,5,6,7-tetrahydro-4H-benzimidazol-4-one (IVo) was
similarly obtained from benzoxazole Vb and purified by
column chromatography on silica gel, eluent chloroform–
ethanol. Yield 59%. Oily substance. IR spectrum, cm–1:
1
1685, 1550. H NMR spectrum, δ, ppm: 1.00 m (3H,
CH3CH2CH2, J 7.4 Hz), 1.25 t and 1.26 t (3H, CH3CH2S,
J 7.4 Hz), 1.30 d and 1.31 d (3H, CH3CHS, J 6.7 Hz),
1.37 t (3H, CH3CH2O, J 7.0 Hz), 1.57 m and 1.70 m
(2H, CH2CHS), 1.78 m (2H, CH3CH2CH2), 2.20–2.29
m (1H, C7HA), 2.38–2.48 m (2H, C5HA, C6H), 2.56 m
(2H, CH3CH2S), 2.56–2.64 m (1H, C7HΒ), 2.78 t (2H,
CH3CH2CH2, J 7.4 Hz), 2.84–2.97 m (2H, C5HΒ, SCH),
4.23 q (2H, CH3CH2O, J 7.0 Hz). Mass spectrum, m/z:
2-Propyl-6-[2-(ethylsulfanyl)propyl]-6,7-dihydro-
1,3-benzoxazol-4(5H)-one O-ethyloxime (Vb) was
obtained like compound Va and purified by column
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

RUBINOV et al.
1030
[M]+ 324, [M + 1]+ 325, [M + 2]+ 326. Found, %: C 63.09;
H 8.82; S 9.80. C17H28N2O2S. Calculated, %: C 62.93;
H 8.70; S 9.88. M 324.49.
N 5.68. [M]+ 245. C15H19NO2. Calculated, %: C 73.44;
H 7.81; N 5.71. M 245.32.
REFERENCES
2-Amino-5,5-dimethylcyclohexane-1,3-dione
hydrochloride (VIa). In 5 ml of concn. HCl was boiled
1 g (5.18 mmol) of benzoxazolone IIc for 30 min, the
reaction mixture was evaporated on a rotary evaporator
till syrup-like residue, 15 ml of water was added thereto,
the separated crystals were filtered off, washed with water
on the filter, then with chloroform, and dried in a vacuum.
Yield 0.87 g (88%), yellowish-brown crystals, mp 125°C
(decomp.). IR spectrum, cm–1: 1680, 1630, 1570. 1H NMR
spectrum, δ, ppm: 1.08 s (6H, CH3CCH3), 2.44 br.s (4H,
2CH2), 9.15 br.s (1H, OH enol). Salt VIa was also
obtained by this procedure from benzoxazolone III (yield
85%).
1. Mel’nikov, N.N., Novozhilov, K.V., and Belan, S.R.,
Pestitsidy i regulyatory rosta rastenii (Pesticides and
Growth Regulators), Moscow: Khimiya, 1995, 576 p.
2. Belan, S.R., Grapov, A.F., and Mel’nikova, G.M., Novye
pestitsidy. Spravochnik (New Pesticides, Handbook),
Moscow, 2001, 196 p.
3. Baskakov, Yu.A., Zh. Vsesoyuz. Khim. Obshch., 1988,
vol. 33, p. 631.
4. Rubinov, D.B., Rubinova, I.L., and Akhrem, A.A., Khim
Polim. Soedin., 1995, p. 635.
5. Lakhvich, F.A. and Khlebnikova, T.S., Vesti Akad. Nauk
BSSR, Ser. Khim., 1996, no. 4, p. 101.
2-Amino-5-mesitylcyclohexane-1,3-dione hydro-
chloride (VIb) was obtained likewise from benzoxazo-
lone IIb. Yield 0.85 g (85%), mp 240°C (decomp.). IR
spectrum, cm–1: 1650, 1570, 1500. 1H NMR spectrum,
δ, ppm: 2.18 s (3H, CH3), 2.33 s (6H, 2CH3), 2.54 br.d
(2H, CH2, J 17.0 Hz), 3.10 d.d (2H, CH2, J1 17.0,
J1 13.6 Hz), 3.74 m (1H, C5H), 6.83 s (2H, C6H2),
9.10 br.s (1H, OH enol).
6. Lakhvich, F.A., Rubinov, D.B., and Rubinova, I.L.,
Zemledelie, zashchita rastenii (Agriculture and Plant
Protection), 2006, no. 4, p. 33.
7. US: Environmental Protection Agency, Federa, Register,
1998, vol. 63, no. 241, 69194.
8. Lakhvich, F.A., Rubinov, D.B., Rubinova, I.L., Zh. Org.
Khim., 1990, vol. 26, p. 306.
9. Vinsovai, J., Ceska a Slovenska Farmacie, 2003, vol. 52,
p. 282.
2-Amino-5-mesitylcyclohexane-1,3-dione (VII). To
a solution of 0.28 g (1 mmol) of salt VIb in 10 ml of
methanol was added an equimolar quantity of NaOH in
water, methanol was distilled off in a vacuum, the residue
was diluted with water, the reaction product was extracted
into ethyl acetate, the organic extracts were dried with
sodium sulfate, evaporated on a rotary evaporator, and
the residue was dried in a vacuum. Yield 0.23 g (92%).
Colorless crystals, mp 150°C (decomp.). IR spectrum,
10. Lewis, J.R., Nat. Prod. Rep., 2000, vol. 17, p. 57.
11. Lewis, J.R., Nat. Prod. Rep., 2001, vol. 18, p. 95.
12. Moskvichev, Yu.A., Gerasimova, N.P., Pashinin, A.N.,
Korikov, P.V., Nozhnin, N.A., Alov, E.M., and Kozlo-
va, O.S., Khim. Geterotsikl. Soedin., 2001, p. 1268.
13. DeLuca, M.R. and Kerwin, S.M., Tetrahedron Lett., 1997,
vol. 38, p. 199.
14. Paramashivappa, R., Phani, Kumar, P., Subba, Rao, P.V.,
Srinivasa, and Rao, A., Bioorg. Med. Chem. Lett., 2003,
vol. 13, p. 657.
15. Iwao, E., Yamamoto, K., Yokoyama, Y., Hirayama, F., and
Haga, K., J. Infect. Chemother., 2004, vol. 10, p. 90.
16. Aren, A.K. and Bite, D.V., Izv. Akad. Nauk Latv. SSR, Ser.
Khim., 1971, p. 246.
1
cm–1: 1620, 1510. H NMR spectrum, δ, ppm: 2.04 d.d
(1H, C6HA, J1 16.7, J1 4.5 Hz), 2.14 s (3H, CH3), 2.17 m
(1H, C6HΒ), 2.27 br.s (6H, 2CH3), 2.34 m (1H, C4HA),
2.79 d.d (1H, C4HΒ, J1 15.9, J1 13.8 Hz), 3.62 m (1H,
C5H), 6.76 s (2H, C6H2). Found, %: C 73.58; H 7.71;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008