Cycloaddition of 4,5-dihydrooxazol-5-one derivatives to 4-methylbenzene-1,2-dithiol

Article abstract of DOI:10.1007/s11178-005-0291-y

Reactions of 4,5-dihydrooxazol-5-one derivatives with 4-methylbenzene-1,2- dithiol in the presence of triethylamine includes nucleophilic attack by the thiol group on the carbonyl carbon atom in the oxazole ring, followed by opening of the latter and recy

Full text of DOI:10.1007/s11178-005-0291-y

Russian Journal of Organic Chemistry, Vol. 41, No. 7, 2005, pp. 1046–1049. From Zhurnal Organicheskoi Khimii, Vol. 41, No. 7, 2005, pp. 1067–1070.
Original English Text Copyright © 2005 by Tikdari, Fozooni, Vazee, Hamidian.
Cycloaddition of 4,5-Dihydrooxazol-5-one Derivatives
to 4-Methylbenzene-1,2-dithiol*
A. M. Tikdari, S. Fozooni, H. Vazee, and H. Hamidian
Shahid Bahonar University of Kerman, Kerman, Iran
fax: +98(341)3222033; e-mail: amomeni@mail.uk.ac.ir
Received March 30, 2004
Abstract—Reactions of 4,5-dihydrooxazol-5-one derivatives with 4-methylbenzene-1,2-dithiol in the presence
of triethylamine includes nucleophilic attack by the thiol group on the carbonyl carbon atom in the oxazole
ring, followed by opening of the latter and recyclization to 1,4-benzodithiine derivatives.
In the recent years, a considerable impetus was
given to study of dihydrooxazolone derivatives, specif-
ically 4,5-dihydrooxazol-5-ones which are key inter-
mediate products in the synthesis of drugs, e.g.,
levothyroxine, anticancer agents, D-penicillamine, and
fungicides [1–2]. In addition, these compounds are
used in the preparation of metal-selective electrodes, in
particular those selective for transition metals [3–4].
4,5-Dihydrooxazolones exhibit specific reactivity
toward nucleophiles. Some their reactions involve
cleavage of the O–C5 bond, while other reactions fol-
low a substitution mechanism [5-–6].
isomer II predominates in the product mixture, and it
can readily be isolated by crystallization.
When the reaction of 4,5-dihydrooxazol-5-ones Ia–
Id with 4-methylbenzene-1,2-dithiol in the presence of
triethylamine was performed at elevated temperature
(120–130°C) initially formed product II or III under-
went intramolecular cyclization leading to 1,4-benzo-
dithiine derivatives IV or V, respectively. As in
the previous case, the major isomer (IVa–IVd) was
isolated from the reaction mixture.
EXPERIMENTAL
The present communication reports on reactions
of a series of 4-methylidene-4,5-dihydrooxazol-5-ones
Ia–Id with 4-methylbenzene-1,2-dithiol, which result
in formation of new compounds. Initial oxazolones
Ia, Ib, and Id were synthesized by condensation of
N-benzoylaminoacetic acid with the corresponding
carbonyl compounds in acetic anhydride in the pres-
ence of anhydrous sodium acetate. Compound Ic was
obtained by reaction of 2-phenyl-4,5-dihydrooxazol-
5-one with p-chlorobenzaldehyde. The reactions of
oxazolones Ia–Id with 4-methylbenzene-1,2-dithiol
were carried out in dry benzene in the presence of tri-
ethylamine. These mild conditions were sufficient to
ensure cleavage of the C5–O bond in the oxazole ring
via nucleophilic attack by the thiol group on the
carbonyl carbon atom in I [7–8]. Taking into account
the presence of two thiol groups in the nucleophile
molecule, formation of two regioisomeric products II
and III might be expected (Scheme 1). Insofar as the
electron density on the thiol sulfur atom in the para
position with respect to the methyl group is greater,
The melting points were determined on a Gallen-
kamp melting point apparatus and are uncorrected. The
mass spectra were recorded on a Shimadzu QP 1100
EX mass spectrometer. The IR spectra were obtained
on an Amatson 1000 FT-IR spectrophotometer. The
NMR spectra were measured on a Bruker DRX-500
Avance instrument using tetramethylsilane as internal
reference.
4-(1-Methylethylidene)-2-phenyl-4,5-dihydro-
oxazol-5-one (Ia) [9]. A mixture of 2.4 g (26 mmol)
of anhydrous sodium acetate, 4.8 g (26 mmol) of
N-benzoylaminoacetic acid, 9.0 g (77 mmol) of acetic
anhydride, and 12.0 g (0.2 mol) of freshly distilled
acetone was heated under shaking until a pinkish solu-
tion was obtained (6 h). The solution was poured into
water, and the precipitate was filtered off, washed with
a solution of NaHCO3 to remove acetic anhydride, and
recrystallized from 96% ethanol. Yield 1.8 g (33%),
colorless crystals, mp 99–100°C.
(E,Z)-2-Phenyl-4-propylidene-4,5-dihydrooxa-
zol-5-one (Ib) [10]. A mixture of 3.3 g (36 mmol) of
* The original article was submitted in English.
1070-4280/05/4107-1046 © 2005 Pleiades Publishing, Inc.

CYCLOADDITION OF 4,5-DIHYDROOXAZOL-5-ONE DERIVATIVES
1047
Scheme 1.
R1
R2
NaOAc
N
PhCONHCH2COOH
+
R1R2C=O
Ph
O
O
O
Ia–Id
R1
R2
O
R1
R2
O
SH
Me
O
SH
SH
Et3N, room temp.
S
S
Me
Ia–Id
+
+
Ph
N
Ph
N
H
H
Me
HS
IIa–IId
IIIa–IIId
SH
NHCOPh
NHCOPh
SH
Me
S
S
Et3N, 120–130°C
Ia–Id
+
+
CHR1R2
O
CHR1R2
O
S
Me
S
Me
IVa–IVd
Va–Vd
I–V, R1 = R2 = Me (a); R1 = H, R2 = Et (b), R2 = 4-ClC6H4 (c), R2 = 2-furyl (d).
anhydrous sodium acetate, 7.2 g (40 mmol) of N-ben-
zoylaminoacetic acid, 20 ml of acetic anhydride, and
25 ml of propionaldehyde was heated under shaking
until an orange solution was obtained (45 min). The
mixture was cooled and poured onto crushed ice, and
the precipitate was filtered off, washed with water, and
treated with 70% aqueous ethanol. The precipitate was
filtered off and recrystallized from 50% aqueous etha-
nol. Yield 4.0 g (46%), colorless needles, mp 81–83°C.
S-(4-Methyl-2-sulfanylphenyl) 2-benzoylamino-
3-methyl-2-butenethioate (IIa). A mixture of 0.2 g
(1 mmol) of oxazole (Ia), 0.16 g (1 mmol) of
4-methylbenzene-1,2-dithiol, and 0.2 g of triethyl-
amine was stirred for 1 h at room temperature. It was
then dissolved in 10 ml of hot 96% ethanol, the
solution was cooled, and the precipitate was filtered
off and recrystallized from 96% ethanol. Yield 0.2 g
(57%), mp 145–146°C. IR spectrum (KBr), ν, cm–1:
3329 (N–H), 1716 (C=O), 1641 (C=O). 1H NMR spec-
trum (CDCl3), δ, ppm: 1.38 s (6H, CH3), 2.40 s (3H,
CH3), 4.10 m (1H, SH), 5.88 m (1H, NH), 7.2–7.7 m
(8H, Harom). 13C NMR spectrum (CDCl3), δC, ppm:
21.6, 28.7, 55.7, 61.2, 127.1–141.5, 166.7, 199.8. Mass
spectrum, m/z (Irel, %): 357 [M]+ (33), 202 (100),
105 (10), 154 (12), 77 (100). Found, %: C 64.01;
H 5.47; N 4.11. C19H19NO2S2. Calculated, %: C 63.83;
H 5.36; N 3.92.
(E,Z)-4-(4-Chlorobenzylidene)-2-phenyl-4,5-
dihydrooxazol-5-one (Ic) [9]. A mixture of 1.61 g
(0.01 mol) of 2-phenyl-4,5-dihydrooxazol-5-one and
1.36 g (0.01 mol) of p-chlorobenzaldehyde was heated
for 5 min on a water bath. The mixture was poured
onto crushed ice, and the precipitate was filtered off
and washed with 96% ethanol. Yield 1.84 g (65%),
pale yellow crystals, mp 191–192°C.
(E,Z)-4-(2-Furylmethylidene)-2-phenyl-4,5-
dihydrooxazol-5-one (Id) [11]. A mixture of 6.2 g
(0.065 mol) of 2-furaldehyde, 4.9 g (27 mmol) of
N-benzoylaminoacetic acid, 2.5 g (27 mmol) of anhy-
drous sodium acetate, and 9.0 g (77 mmol) of acetic
anhydride was heated for 30 min at 80°C. The mixture
was poured onto crushed ice, and the precipitate was
filtered off, washed with cold water, dried, and recrys-
tallized from 96% ethanol. Yield 13.2 g (85%), yellow
needles, mp 170–171°C.
S-(4-Methyl-2-sulfanylphenyl) (E,Z)-2-benzoyl-
amino-2-pentenethioate (IIb). Oxazole Ib, 0.2 g
(1 mmol), was dissolved in 20 ml of dry benzene, and
0.16 g (1 mmol) of 4-methylbenzene-1,2-dithiol and
0.2 g of triethylamine were added. The mixture was
stirred for 30 min at room temperature, and the pre-
cipitate was filtered off, washed with dry benzene, and
recrystallized from dry benzene. Yield 0.27 g (76%),
colorless crystals, mp 189–190°C. IR spectrum (KBr),
ν, cm–1: 3303 (N–H), 1697 (C=O), 1642 (C=O).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

TIKDARI et al.
1048
1H NMR spectrum (CDCl3), δ, ppm: 1.4 t (3H, CH3),
2.10–2.22 m (2H, CH2), 2.4 s (3H, CH3), 3.96 m (1H,
SH), 5.03 m (1H, NH), 6.99–7.75 m (9H, Harom, =CH).
13C NMR spectrum (CDCl3), δC, ppm: 11.50, 21.10,
25.3, 57.3, 59.40, 127.12–141.49, 166.79, 200.84.
Mass spectrum, m/z (Irel, %): 357 [M]+ (35), 202 (10),
154 (14), 105 (100), 77 (100). Found, %: C 63.67;
H 5.00; N 3.84. C19H19NO2S2. Calculated, %: C 63.83;
H 5.36; N 3.92.
the residue was crystallized from ethanol and purified
by column chromatography. Yield 39%, colorless crys-
tals, mp 107–108°C. IR spectrum (KBr), ν, cm–1: 3339
1
(N–H), 1742 (C=O), l612 (C=O). H NMR spectrum
(CDCl3), δ, ppm: 1.2 s (6H, CH3), 2.12 s (3H, CH3),
3.18 m (1H, CH), 5.57 m (1H, NH), 6.88–7.7 m (8H,
Harom). 13C NMR spectrum (CDCl3), δC, ppm: 20.4,
20.7, 33.8, 102.9, 130.8–144.4, 170.1, 192.7. (10), 202
(60), 77 (100). Found, %: C 63.66; H 5.50; N 3.76.
C19H19NO2S2. Calculated, %: C 63.83; H 5.36; N 3.92.
S-(4-Methyl-2-sulfanylphenyl) (E,Z)-2-benzoyl-
amino-3-(4-chlorophenyl)-2-propenethioate (IIc).
Oxazole Ic, 0.29 g (1 mmol), was dissolved in 20 ml of
dry benzene, and 0.16 g (1 mmol) of 4-methylbenzene-
1,2-dithiol and 0.2 g of triethylamine were added. The
mixture was stirred for 25 min at room temperature,
and the precipitate was filtered off, washed with dry
benzene, and recrystallized from dry benzene. Yield
0.35 g (81%), colorless crystals, mp 184–185°C. IR
spectrum (KBr), ν, cm–1: 3280 (N–H), 1691 (C=O),
N-(7-Methyl-3-oxo-2-propyl-2,3-dihydro-1,4-
benzodithiin-2-yl)benzamide (IVb). A mixture of
0.4 g (2 mmol) of oxazole Ib, 0.32 g (2 mmol) of
4-methylbenzene-1,2-dithiol, and 0.4 g of triethyl-
amine was stirred for 1 h at 120–130°C. It was then
dissolved in chloroform, the solvent was removed, and
the residue was crystallized from ethanol and purified
by column chromatography. Yield 40%, colorless crys-
tals, mp 109–110°C. IR spectrum (KBr), ν, cm–1: 3315
1
1
1641 (C=O). H NMR spectrum (CDCl3), δ, ppm:
(NH), 1722 (C=O), 1600 (C=O). H NMR spectrum
2.41 s (3H, CH3), 4.35 m (1H, SH), 5.7 m (1H, NH),
7.0–7.7 m (13H, Harom, =CH). 13C NMR spectrum
(CDCl3), δC, ppm: 21.1, 21.3, 55.8, 57.3, 57.5, 126.9–
142.1, 166.6, 200.5. Mass spectrum, m/z (Irel, %): 439
[M]+ (10), 105 (30), 77 (100). Found, %: C 62.91;
H 4.03; N 3.24. C23H18ClNO2S2. Calculated, %:
C 62.79; H 4.12; N 3.18.
(CDCl3), δ, ppm: 1.01 t (3H, CH3), 2.03–2.34 m
(4H, CH2), 2.41 s (3H,CH3), 5.12 s (1H, NH), 6.77–
7.95 m (8H, Harom). 13C NMR spectrum (CDCl3), δC,
ppm: 11.2, 20.1, 22.9, 42.3, 100.1, 129.9–142.2, 164.8,
196.9. Mass spectrum, m/z (Irel, %): 357 [M]+ (25), 202
(10), 105 (10), 77 (100). Found, %: C 64.11; H 5.45;
N 4.18. C19H19NO2S2. Calculated, %: C 63.83; H 5.36;
N 3.92.
S-(4-Methyl-2-sulfanylphenyl) (E,Z)-2-benzoyl-
amino-3-(2-furyl)-2-propenethioate (IId). A mixture
of 0.24 g (1 mmol) of oxazole Id, 0.16 g (1 mmol) of
4-methylbenzene-1,2-dithiol, and 0.2 ml of triethyl-
amine in 20 ml of dry benzene was stirred for 1 h at
room temperature. The precipitate was filtered off,
washed with cold benzene, and recrystallized from
96% ethanol. Yield 0.18 g (46%), colorless crystals,
mp 207°C (decomp.). IR spectrum (KBr), ν, cm–1:
3354 (N–H), 1691 (C=O), 1641 (C=O). 1H NMR spec-
trum (CDCl3), δ, ppm: 2.44 s (3H, CH3); 3.85 m (1H,
SH); 5.59 m (1H, NH); 6.06 s, 6.23 s, 6.71 s (3H,
furyl), 7.2–7.6 m (9H, Harom, =CH). 13C NMR spec-
trum (CDCl3), δC, ppm: 21.2, 50.4, 56.8, 107.0, 110,5,
127.0–142.6, 151.5, 166.3, 199.4. Mass spectrum, m/z
(Irel, %): 395 [M]+ (15), 245 (100), 105 (70), 77 (20).
Found, %: C 63.92%; H 4.46; N 3.69. C21H17NO3S2.
Calculated, %: C 63.77; H 4.33; N 3.54.
N-[2-(4-Chlorophenyl)-7-methyl-3-oxo-2,3-dihy-
dro-1,4-benzodithiin-2-yl]benzamide (IVc). A mix-
ture of 0.32 g (2 mmol) of oxazole Ic, 0.32 g (2 mmol)
of 4-methylbenzene-1,2-dithiol, and 0.4 g of triethyl-
amine was stirred for 1 h at 120–130°C. It was then
dissolved in chloroform, the solvent was removed, and
the residue was crystallized from ethanol and purified
by column chromatography. Yield 31%, colorless crys-
tals, mp 112–113°C. IR spectrum (KBr), ν, cm–1: 3292
1
(N–H), 1719 (C=O), 1608 (C=O). H NMR spectrum
(CDCl3), δ, ppm: 2.39 s (3H, CH3), 3.71 s (2H, CH2),
13
6.91–7.77 m (12H, Harom), 5.57 s (1H, NH). C NMR
spectrum (CDCl3), δC, ppm: 20.1, 39.3, 109.1, 125.9–
146.6, 168.9, 198.5. Mass spectrum, m/z (Irel, %): 439
[M]+ (15), 105 (20), 77 (100). Found, %: C 62.55;
H 3.96; N 3.20. C23H18ClNO2S2. Calculated, %:
C 62.79; H 4.12; N 3.18.
N-(2-Isopropyl-7-methyl-3-oxo-2,3-dihydro-1,4-
benzodithiin-2-yl)benzamide (IVa). A mixture of
0.4 g (2 mmol) of oxazole Ia, 0.32 g (2 mmol) of
4-methylbenzene-1,2-dithiol, and 0.4 g of triethyl-
amine was stirred for 1 h at 120–130°C. It was then
dissolved in chloroform, the solvent was removed, and
N-[2-(2-Furyl)-7-methyl-3-oxo-2,3-dihydro-1,4-
benzodithiin-2-yl]benzamide (IVd). A mixture of
0.48 g (2 mmol) of oxazole Id, 0.32 g (2 mmol) of
4-methylbenzene-1,2-dithiol, and 0.4 g of triethyl-
amine was stirred for 1 h at 120–130°C. It was then
dissolved in chloroform, the solvent was removed, and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

CYCLOADDITION OF 4,5-DIHYDROOXAZOL-5-ONE DERIVATIVES
1049
3. Mashhadizadeh, M.H., Momeni, A., and Razavi, R.,
Anal. Chim. Acta, 2002, vol. 462, p. 245.
4. Mashhadizadeh, M.H. and Momeni, A., Talanta, 2003,
the residue was crystallized from ethanol and purified
by column chromatography. Yield 35%, colorless crys-
tals, mp 113–114°C. IR spectrum (KBr), ν, cm–1: 3367
1
vol. 59, p. 47.
(N–H), 1732 (C=O), 1633 (C=O). H NMR spectrum
5. Tikdari, A.M., Tripathy, P.K., and Mukerjee, A.K.,
Chem. Ind., 1986, vol. 23, p. 825.
6. Just, G., Chuny, B.Y., Kim, S., Rosebery, G., and
Rossy, P., Can. J. Chem., 1976, vol. 54, p. 208.
7. Tikdari, A.M., Hamidian, H., and Razee, S., Phos-
phorus, Sulfur, Silicon, 2002, vol. 177, p. 2821.
8. Tikdari, A.M. and Fozooni, S., Heterocycl. Commun.,
2003, vol. 9, no. 5, p. 473.
(CDCl3), δ, ppm: 2.21 s (3H, CH3), 3.46–3.63 m (2H,
CH2), 5.72 m (1H, NH), 6.07–7.00 m (3H, furyl), 7.2–
7.92 m (8H, Harom). 13C NMR spectrum (CDCl3), δC,
ppm: 21.9, 40.1, 105.6, 124.9–143.2, 155.9, 161.8,
197.3. Mass spectrum, m/z (Irel, %): 395 [M]+ (10), 245
(55), 77 (100). Found, %: C 63.58; H 4.17; N 3.66.
C21H17NO3S2. Calculated, %: C 63.77; H 4.33; N 3.54.
9. Crawford, M. and Little, W.T., J. Chem. Soc., 1959,
p. 729.
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