New method for the preparation of N,N-dimethyl-(thioacetamides) from 4-substituted 1,2,3-thiadiazoles

Full text of DOI:10.1134/S1070428007120226

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1870–1873. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © D.A. Androsov, M.L. Petrov, A.A. Shchipalkin, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 12,
pp. 1863–1865.
SHORT
COMMUNICATIONS
New Method for the Preparation of N,N-Dimethyl-
(thioacetamides) from 4-Substituted 1,2,3-Thiadiazoles
D. A. Androsov, M. L. Petrov, and A. A. Shchipalkin
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: mlpetrov@lti-gti.ru
Received May 18, 2007
DOI: 10.1134/S1070428007120226
N,N-Dialkylethanethioamides are obtained via de-
composition of 4-substituted 1,2,3-thiadiazoles by the
action of strong bases in the presence of secondary
amines [1]. This procedure seems to be applicable for
the preparation of the corresponding N,N-dimethyl-
amides. We propose to use dimethylformamide instead
of dimethylamine (which is inconvenient to handle
with due to its low boiling point, 7.4°C) in the syn-
thesis of N,N-dimethylethanethioamides from 4-substi-
tuted 1,2,3-thiadiazoles.
(Ig) [7], and (4-methoxyphenyl)-1,2,3-thiadiazole (IIIh)
from 4-methoxyacetophenone (Ih) [5]. Likewise,
2-fluoroacetophenone (If) was converted into ethoxy-
carbonylhydrazone IIf, and the latter was treated with
thionyl chloride to obtain previously unknown
4-(2-fluorophenyl)-1,2,3-thiadiazole (IIIf) (Scheme 1).
1,2,3-Thiadiazoles IIIa–IIIh readily undergo de-
composition with liberation of nitrogen by the action
of such a strong base as sodium methoxide. The sub-
sequent treatment of the reaction mixture with excess
DMF gives the corresponding N,N-dimethylethane-
thioamides Va–Vh (Scheme 2). Using 4-(2-fluoro-
phenyl)-1,2,3-thiadiazole (IIIf) as an example we
showed that the reaction involves intermediate forma-
tion of methyl (2-fluorophenyl)ethanethioate (IVf).
The structure of compounds Va–Vh was proved by
1H and 13C NMR spectroscopy and mass spectrometry,
as well as by comparison with published data.
Initial 4-substituted 1,2,3-thiadiazoles are readily
accessible according to Hurd and Mori [2]. Following
this procedure we synthesized 4-tert-butyl-1,2,3-thiadi-
azole (IIIa) from pinacolone (Ia) [3], 4-(1-adamantyl-
1,2,3-thiadiazole) (IIIb) from 1-adamantyl methyl
ketone (Ib) [4], 4-phenyl-1,2,3-thiadiazole (IIIc) from
acetophenone (Ic) [2], 4-(4-chlorophenyl)-1,2,3-thia-
diazole (IIId) from 4-chloroacetophenone (Id) [5],
4-(4-bromophenyl)-1,2,3-thiadiazole (IIIe) from
4-bromoacetophenone (Ie) [6], (4-methylphenyl)-
1,2,3-thiadiazole (IIIg) from 4-methylacetophenone
Scheme 2.
S
MeONa, MeOH
IIIa–IIIh
R
S
–N2
OMe
IVa–IVh
Scheme 1.
O
NNHCOOEt
H2NNHCOOEt
HCONMe2
R
Me
Ia–Ih
R
N
Me
R
NMe2
Va–Vh
IIa–IIh
R
For R, see legend to Scheme 1.
SOCl2
N
S
Ethyl 2-[1-(2-fluorophenyl)ethylidene]hydrazine-
1-carboxylate (IIf). A mixture of 1 g (7.25 mmol) of
2-fluoroacetophenone (If), 0.8 g (7.69 mmol) of ethyl
hydrazinecarboxylate, 7 ml of propan-2-ol, and one
IIIa–IIIh
R = t-Bu (a), 1-Ad (b), Ph (c), 4-ClC6H4 (d), 4-BrC6H4 (e),
2-FC6H4 (f), 4-MeC6H4 (g), 4-MeOC6H4 (h).
1870

NEW METHOD FOR THE PREPARATION OF N,N-DIMETHYL(THIOACETAMIDES)
1871
drop of glacial acetic acid was heated for 20 min under
reflux. The mixture was then kept for 8 h, and the
precipitate was filtered off and dried. The product was
chromatographically pure and was used in further
syntheses without additional purification. Yield 1.3 g
(83%), fine colorless prisms, mp 111°C (from propan-
chloroform (5×10 ml). The extract was dried over
sodium sulfate, the solvent was distilled off, and the
residue was purified by column chromatography on
silica gel L (40–100 μm) using carbon tetrachloride as
eluent. A light yellow fraction was collected. Yield
0.25 g (70%), oily substance with a sharp odor, Rf 0.51
1
1
2-ol), Rf 0.17 (chloroform). H NMR spectrum
(chloroform). H NMR spectrum (DMSO-d6), δ, ppm:
4.29 s (OCH3), 4.65 s (CH2), 6.78–7.31 m (C6H4).
Mass spectrum, m/z (Irel, %): 184 (26) [M]+, 152 (7)
[M – S]+, 139 (15) [M – CHS]+, 109 (93) [FC6H4CH2]+,
83 (27), 75 (100) [CSOCH3]+, 47 (15). Found, %:
C 58.86, 58.92; H 5.05, 5.17. C9H9FOS. Calculated,
%: C 58.68; H 4.92. M 184.23.
(DMSO-d6), δ, ppm: 1.24 t (CH3CH2), 2.19 d
(CH3C=N, JHF = 2.5 Hz), 4.16 q (OCH2), 7.19–7.26 m
(3-H, 4-H), 7.41–7.43 m (5-H), 7.50 d.t (6-H, JHF
=
7.7 Hz), 10.19 s (NH). 13C NMR spectrum (DMSO-d6),
δC, ppm: 14.92 (CH3CH2), 17.64/17.70 (CH3C=N),
60.95 (CH2), 116.18/116.47 (C3), 124.68/124.72 (C5),
127.77/127.94 (C1), 130.08/130.12 (C6), 130.93/131.05
(C4), 147.24 (C=N), 154.51 (C=O), 158.53/161.81
(C2). Mass spectrum, m/z (Irel, %): 224 (74) [M]+, 151
[M – CO2Et]+, 136 (100) [M – NHCO2Et]+, 121 (55),
110 (67), 90 (24), 83 (38), 75 (58), 57 (29). Found, %:
C 58.72, 58.89; H 5.52, 5.79. C11H13FN2O2. Calculat-
ed, %: C 58.92; H 5.84. M 224.23.
N,N,3,3-Tetramethylbutanethioamide (Va). Thia-
diazole IIIa, 1 g (7 mmol), was added to a solution of
sodium methoxide prepared from 5 ml of anhydrous
methanol and 0.207 g (9 mmol) of metallic sodium.
The mixture was heated for 1 h under reflux, 5 ml of
anhydrous dimethylformamide was added, methanol
was distilled off, 50 ml of water was added to the
residue, and the mixture was extracted with ethyl ace-
tate (3×10 ml). The extract was dried over anhydrous
sodium sulfate, the drying agent was filtered off, the
filtrate was treated with silica gel on heating under
reflux, the solvent was distilled off under reduced pres-
sure, and the precipitate was recrystallized from 10 ml
of cyclohexane. Yield 0.45 g (40%), colorless crystals,
mp 38–39°C (from cyclohexane); published data [8]:
mp 38.5–40°C. The product was chromatographically
pure in the systems chloroform–hexane (1:1) and ethyl
4-(2-Fluorophenyl)-1,2,3-thiadiazole (IIIf). A flask
equipped with a magnetic stirrer, reflux condenser, and
a gas-outlet tube (connected to a system for absorption
of liberated hydrogen chloride) was charged with
1.23 g (5.49 mmol) of hydrazone IIf, 15 ml of freshly
distilled thionyl chloride was added on cooling to 0°C,
and the mixture was stirred for 0.5 h at 50°C. When
vigorous gas evolution ceased, the mixture was stirred
for 1.5 h at 70°C and cooled to 20–25°C, and excess
thionyl chloride was distilled off under reduced pres-
sure. The residue was washed with water and dried.
Yield 0.846 g (86%), light yellow prisms, mp 32–33°C,
1
acetate–hexane (1:10). H NMR spectrum (CDCl3), δ,
ppm: 1.03 m (CH3), 2.86 s (CH2), 3.28 s and 3.44 s
(NCH3). 13C NMR spectrum (CDCl3), δC, ppm: 29.97
(CH3), 32.51 [C(CH3)3], 42.86 and 44.39 (NCH3),
201.81 (C=S). Found, %: C 60.46, 60.57; H 10.61,
10.88. C8H17NS. Calculated, %: C 60.32; H 10.76.
1
Rf 0.78 (chloroform). H NMR spectrum (DMSO-d6),
δ, ppm: 7.21–7.45 m (3-H, 4-H, 5-H), 8.48 d.t (6-H,
JHF = 7.4 Hz), 8.92 d (5′-H, JHF = 1.1 Hz). 13C NMR
spectrum (DMSO-d6), δC, ppm: 116.08/116.47 (C3),
118.86/118.97 (C1), 124.90/124.94 (C5′), 130.23/130.27
(C5), 130.76/130.88 (C6), 133.51/133.70 (C4),
156.29/156.34 (C4′), 158.03/161.36 (C2). Mass spec-
trum, m/z (Irel, %): 180 (18) [M]+, 132 (19) [M – CS]+,
120 (22) [M – N2 – S]+, 108 (43) [o-C6H4CHF]+, 107
(51) [o-C6H4CF]+, 93 (16), 75 (15), 69 (22). Found, %:
C 53.17, 53.49; H 2.98, 3.11. C8H5FN2S. Calculated,
%: C 53.32; H 2.80. M 180.20.
2-(1-Adamantyl)-N,N-dimethylethanethioamide
(Vb) was synthesized in a similar way from 0.4 g
(1.8 mmol) of thiadiazole IIIb using 0.12 g (5.4 mmol)
of sodium, 10 ml of anhydrous methanol, and 10 ml of
anhydrous DMF. After removal of methanol, the mix-
ture was diluted with 30 ml of water, and the precip-
itate was filtered off, dried, and recrystallized from
15 ml of methanol. Yield 0.2 g (47%), colorless needles,
mp 155–157°C (from methanol), Rf 0.5 (chloroform).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.66 m (CH2,
Ad), 1.95 m (CH, Ad), 2.72 s (CH2CS), 3.33 s and
3.39 s (NCH3). 13C NMR spectrum (DMSO-d6), δC,
ppm: 28.24 (CH, Ad), 34.33 (C1, Ad), 36.36 (CH2, Ad),
42.38 (CH2, Ad), 43.05 and 44.04 (NCH3), 55.31
Methyl 2-(2-fluorophenyl)ethanethioate (IVf).
Thiadiazole IIIf, 0.35 g (1.94 mmol), was added to
a solution of sodium methoxide prepared from 20 ml
of anhydrous methanol and 0.134 g (5.8 mmol) of
metallic sodium. The mixture was heated for 4 h,
cooled, poured into 30 ml of water, and extracted with
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ANDROSOV et al.
1872
(CH2), 199.15 (C=S). Mass spectrum, m/z (Irel, %): 237
(43) [M]+, 236 (78) [M – H]+, 204 (19) [M – H – S]+,
135 (48) [Ad]+, 102 (17) [M – Ad]+, 88 (73)
[S=CN(CH3)2]+, 79 (68), 70 (63), 55 (61), 41 (100).
Found, %: C 70.55, 69.76; H 9.84, 9.97. C14H23NS.
Calculated, %: C 70.83; H 9.76. M 237.40.
(Irel, %): 259 (48) [M]+, 226 (14) [M – SH]+, 171 (25)
[BrC6H4CH2]+, 134 (31) [M – Br – S=CN(CH3)2]+, 88
(100) [S=CN(CH3)2]+, 73 (39), 70 (66). Found, %:
C 46.78, 46.81; H 4.33, 4.61. C10H12BrNS. Calculated,
%: C 46.52; H 4.68. M 358.18.
2-(2-Fluorophenyl)-N,N-dimethylethanethio-
amide (Vf) was synthesized in a similar way from
0.32 g (1.78 mmol) of thiadiazole IIIf using 0.114 g
(4.95 mmol) of sodium and 20 ml of anhydrous
methanol. The mixture was heated for 2 h under reflux,
5 ml of anhydrous DMF was added, methanol was
distilled off, and the mixture was heated for 2 h under
reflux, poured into 50 ml of water, and extracted with
chloroform (3×10 ml). The extract was dried over
sodium sulfate, the solvent was distilled off, and the
residue was purified by column chromatography on
silica gel L (40–100 μm) using carbon tetrachloride
and chloroform as eluent. A light yellow fraction was
collected. Yield 0.25 g (86%), light yellow rhombic
N,N-Dimethyl-2-phenylethanethioamide (Vc)
was synthesized in a similar way from 1 g (6.2 mmol)
of thiadiazole IIIc using 0.285 g (12.4 mmol) of
sodium, 30 ml of anhydrous methanol, and 10 ml of
anhydrous DMF. After removal of methanol, the mix-
ture was poured into 100 ml of water, and the precip-
itate was filtered off, washed with water (5×20 ml),
and dried. Yield 0.85 g (77%), orange crystals,
mp 81°C (from benzene or petroleum ether); published
1
data [9]: mp 79–80°C; Rf 0.58 (chloroform). H NMR
spectrum (CDCl3), δ, ppm: 3.19 s and 3.49 s (NCH3),
4.31 (CH2), 7.32 m (C6H5). 13C NMR spectrum
(CDCl3), δC, ppm: 42.27 and 44.80 (NCH3), 50.92
(CH2), 126.93 (C4), 128.06 (C2, C6), 128.79 (C3, C5),
135.65 (C1), 200.60 (C=S). Found, %: C 70.23, 70.31;
H 7.44, 7.63. C10H13NS. Calculated, %: C 66.99; H 7.31.
1
plates, mp 32–34°C, Rf 0.43 (chloroform). H NMR
spectrum (DMSO-d6), δ, ppm: 3.19 s and 3.46 s
(NCH3), 4.21 (CH2), 6.68–7.42 m (C6H4). 13C NMR
spectrum (DMSO-d6), δC, ppm: 42.01 and 42.67
(NCH3), 44.77 (CH2), 115. 09/115. 28 (C3),
123.02/123.14 (C1), 124.42 (C5), 128.70/128.76 (C4),
129.80/129.83 (C6), 159.07/161.03 (C2), 199.76 (C=S).
Found, %: C 60.57, 60.82; H 6.31, 6.43. C10H12FNS.
Calculated, %: C 60.88; H 6.13.
2-(4-Chlorophenyl)-N,N-dimethylethanethio-
amide (Vd) was synthesized in a similar way from 1 g
(5.1 mmol) of thiadiazole IIId using 0.24 g
(10.2 mmol) of sodium. Yield 0.85 g (78%), orange–
brown crystals, mp 74°C (from methanol); published
1
data [10]: mp 73–74°C; Rf 0.4 (chloroform). H NMR
spectrum (DMSO-d6), δ, ppm: 3.17 s and 3.46 s
(NCH3), 4.22 (CH2), 7.25 m (C6H4). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 42.24 and 44.82 (NCH3),
49.58 (CH2), 128.87 (C3, C5), 129.55 (C2, C6), 132.76
(C4), 134.20 (C1), 200.00 (C=S). Mass spectrum, m/z
(Irel, %): 213 (60) [M]+, 180 (25) [M – SH]+, 165 (30)
[M – SH – CH3]+, 134 (24) [M – Cl – S=CN(CH3)2]+,
125 (54) [ClC6H4CH2]+, 88 (100) [S=CN(CH3)2]+, 73
(51), 70 (66). Found, %: C 55.93, 56.07; H 5.42, 5.64.
C10H12ClNS. Calculated, %: C 56.20; H 5.66. M 213.72.
N,N-Dimethyl-2-(4-methylphenyl)ethanethio-
amide (Vg) was synthesized in a similar way from 1 g
(5.7 mmol) of thiadiazole IIIg using 0.23 g
(10.1 mmol) of sodium. Yield 0.8 g (73%), light brown
needles, mp 72°C (from methanol); published data
1
[11]: mp 72°C; Rf 0.32 (chloroform). H NMR spec-
trum (DMSO-d6), δ, ppm: 2.30 s (CH3), 3.18 s and
3.46 s (NCH3), 4.24 (CH2), 7.10 d (2-H, 6-H), 7.20 d
(3-H, 5-H). 13C NMR spectrum (DMSO-d6), δC, ppm:
21.03 (CH3), 42.24 and 44.80 (NCH3), 50.52 (CH2),
127.98 (C3, C5), 129.43 (C2, C6), 132.57 (C4), 136.50
(C1), 200.90 (C=S). Found, %: C 68.45, 68.63; H 7.51,
7.81. C11H15NS. Calculated, %: C 68.35; H 7.82.
2-(4-Bromophenyl)-N,N-dimethylethanethio-
amide (Ve) was synthesized in a similar way from 1 g
(4.15 mmol) of thiadiazole IIIe using 0.19 g
(8.3 mmol) of sodium. Yield 0.85 g (78%), light
orange needles, mp 69–70°C (from methanol), Rf 0.38
2-(4-Methoxyphenyl)-N,N-dimethylethanethio-
amide (Vh) was synthesized in a similar way from 1 g
(5.2 mmol) of thiadiazole IIIh using 0.24 g
(10.4 mmol) of sodium. Yield 0.85 g (78%), yellow
needles, mp 79°C (from methanol); published data
1
(chloroform). H NMR spectrum (DMSO-d6), δ, ppm:
3.16 s and 3.44 s (NCH3), 4.19 (CH2), 7.18 d (2-H,
6-H), 7.40 d (3-H, 5-H). 13C NMR spectrum
(DMSO-d6), δC, ppm: 42.27 and 44.82 (NCH3), 50.01
(CH2), 120.82 (C4), 129.94 (C3, C5), 131.81 (C2, C6),
134.74 (C1), 199.85 (C=S). Mass spectrum, m/z
1
[10, 11]: mp 75–76°C; Rf 0.27 (chloroform). H NMR
spectrum (DMSO-d6), δ, ppm: 3.18 s and 3.46 s
(NCH3), 3.76 s (CH3O), 4.21 (CH2), 6.85 d (2-H, 6-H),
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NEW METHOD FOR THE PREPARATION OF N,N-DIMETHYL(THIOACETAMIDES)
1873
7.23 d (3-H, 5-H). 13C NMR spectrum (DMSO-d6), δC,
REFERENCES
ppm: 41.92 and 44.58 (NCH3), 49.80 (CH2), 55.04
(CH3O), 113.92 (C3, C5), 127.44 (C1), 128.93 (C2, C6),
158.28 (C4), 200.91 (C=S). Mass spectrum, m/z
(Irel, %): 209 (61) [M ]+, 164 (38) [M – NH(CH3)2]+,
121 (90) [M – S=CN(CH3)2]+, 88 (100) [S=CN(CH3)2]+,
78 (59), 70 (65), 51 (35). Found, %: C 62.87, 63.05;
H 7.43, 7.56. C11H15NOS. Calculated, %: C 63.12;
H 7.22. M 209.31.
1. Malek-Yazdi, F. and Yalpani, M., Synthesis, 1977,
p. 328.
2. Hurd, C.D. and Mori, R.I., J. Am. Chem. Soc., 1955,
vol. 77, p. 5359.
3. Seybold, G. and Heibl, C., Chem. Ber., 1977, vol. 110,
p. 1225.
4. Petrov, M.L., Shchipalkin, A.A., and Kuznetsov, V.A.,
Russ. J. Org. Chem., 2007, vol. 43, p. 630.
5. Raap, R. and Micetich, R.G., Can. J. Chem., 1968,
vol. 46, p. 1057.
6. Petrova, L.L., Trufanova, L.V., Petrov, M.L., Abra-
mov, M.A., Zmitrovich, N.I., and Terent’eva, N.A.,
Khim. Farm. Zh., 1994, vol. 28, no. 1, p. 19.
The melting points were determined on a Boetius
1
13
melting point apparatus. The H and C NMR spectra
were measured on Bruker Avance (300 and 75 MHz,
respectively) and Bruker AMX-400 instruments (400
and 100 MHz) relative to the residual proton (1H) and
carbon signals (13C) of deuterated solvents. The mass
spectra (electron impact, 70 eV) were obtained on
a Kratos MS 890 mass spectrometer with direct sample
admission into the ion source (ion source temperature
200°C). The progress of reactions was monitored by
TLC on Silufol UV-254 plates; spots were visualized
under UV light or by treatment with iodine vapor. All
solvents used in this work were purified and dehydrat-
ed according to standard procedures.
7. Zmitrovich, N.I., Petrov, M.L., and Petrov, A.A.,
Zh. Org. Khim., 1991, vol. 27, p. 1394.
8. Schuijl, P.J.W. and Brandsma, L., Recl. Trav. Chim.
Pays–Bas, 1968, vol. 87, p. 38.
9. Bobylev, V.A., Petrov, M.L., and Petrov, A.A., Zh. Org.
Khim., 1982, vol. 18, p. 274.
10. Ogura, K., Ito, Y., and Tsuchihashi, G., Synthesis, 1980,
p. 736.
11. Schroth, W. and Andersch, J., Synthesis, 1989, p. 202.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007