The Reactivity of (Z)-5-Acetyl-3-aryl-2,3-dihydro-2-[(thioacyl)methylene]-1,3,4-thiadiazoles
FULL PAPER
1
125 W Philips, high-pressure mercury vapor lamp, in a preparative
photochemical reactor equipped with a Pyrex double-walled im-
mersion well for water-cooling of the lamp.
as a red solid; m.p. 125 °C; the H NMR spectrum, which shows
a multiplet at δ ϭ 7.43 ppm, is identical to that exhibited by the
sample obtained by independent synthesis.[5] MS: m/z ϭ 266. The
organic phase was worked up according to the usual procedure; the
first product that eluted was 14 (26%), obtained as an orange oil
that solidified when treated with hexane. 1H NMR: δ ϭ 7.58 (d,
J ϭ 10.07 Hz, 2 H), 7.32 (m, 5 H), 7.15 (d, J ϭ 2.13 Hz, 1 H), 7.00
(d, J ϭ 7.63 Hz, 2 H), 6.79 (t, J ϭ 7.47 Hz, 1 H), 6.68 (d, J ϭ 1.53
Hz, 1 H), 5.68 (s, NH) ppm. 13C NMR: δ ϭ 129.4, 128.85, 127.7,
152.53, 120.02, 118.8, 115.8, 106.1 ppm. The second product that
eluted was 15, which was isolated as a red oil. 1H NMR: δ ϭ 10.76
(s, NH), 7.49 (m, 10 H), 6.50 (s, 1 H), 4.36 (q, J ϭ 6.8 Hz, 2 H),
1.49 (t, J ϭ 6.8 Hz, 3 H) ppm. MS: m/z ϭ 283.
Reaction of 1,3,4-Thiadiazoles with Sodium Alkoxides. General Pro-
cedure: The 1,3,4-thiadiazoles 1aϪe and 6a,b (1 mol) were added
to a solution prepared by dissolving sodium (1.3 mol) in MeOH or
EtOH. The solution was heated under reflux, then poured in water
and exhaustively extracted with CH2Cl2. The combined organic ex-
tracts were dried (Na2SO4) and the solvents evaporated to dryness
to give a residue that was usually column-chromatographed on sil-
ica gel (eluent: CH2Cl2).
Reaction of 1a with MeONa: The reaction was complete within
25 min. The first product eluted was 2 (25% yield), obtained as a
Reaction of 16 with NaH: EtOAc (2 mL) and NaH (0.108 g, 60%
suspension) were added to a solution of 16 (0.5 g) in DMF
(10 mL). The solution was heated under reflux for 10 min, and then
stirred at room temp. for 16 h. The solvent was evaporated under
reduced pressure and then the residue was diluted with H2O and
extracted exhaustively with CH2Cl2. The combined organic extracts
were dried (Na2SO4) and the solvents evaporated to dryness to give
a residue that was triturated with diisopropyl ether to give 16 as
a yellow solid, which was collected by filtration. The filtrate was
chromatographed on silica gel (CHCl3) to give a yellow oil that,
after treatment with hexane, provided 17 (0.07 g, 11.4%) as a solid;
1
pale pink solid, which was triturated with hexane; m.p. 75 °C. H
NMR: δ ϭ 7.23 (d, J ϭ 7.7 Hz, 2 H), 6.95 (t, J ϭ 7.93 Hz, 2 H),
6.84 (t, J ϭ 7.3 Hz, 1 H), 6.60 (s, 1 H), 6.47 (s, 1 H), 4.61 (s, NH),
2.44 (s, 3 H) ppm. 13C NMR: δ ϭ 144.6, 140.6, 139.3, 129.3, 121.2,
119.7, 115.5, 104.02, 15.7 ppm. MS: m/z ϭ 189. C11H11NS (189.3):
calcd. C 70.84, H 5.82, N 7.41; found C 70.91, H 5.82, N 7.47. The
second product eluted was 3a, obtained as a red oil. 1H NMR: δ ϭ
11.1 (s, NH), 7.27 (m, 5 H), 6.10 (s, 1 H), 3.94 (s, 3 H), 2.66 (s, 3
H) ppm. The third product eluted was further purified by chroma-
tography to give 4 as a yellow solid that was crystallized from diiso-
1
propyl ether/benzene (95:5); m.p. 134 °C. H NMR: δ ϭ 7.13 (m,
1
m.p. 90 °C. H NMR: δ ϭ 7.61 (m, 2 H), 7.31 (m, 8 H), 7.07 (t,
11 H), 3.80 (s, 3 H), 3.06 and 3.43 (2 d, J ϭ 14.5 Hz, 2 H), 1.96 (s,
3 H), 1.46 (s, 3 H) ppm. 13C NMR: δ ϭ 191.7, 158.1, 147.4, 141.7,
138.7, 129.5, 129.2, 128.8, 128.4, 126.85, 123.3, 121.3, 67.6, 53.1,
37.3, 27.1, 22.0 ppm.
J ϭ 7 Hz, 1 H), 4.36 (q, J ϭ 7.5 Hz, 2 H), 1.37 (t, J ϭ 7.5 Hz, 3
H) ppm. MS: m/z ϭ 323. C19H17NO2S (323.3): calcd. C 70.56, H
5.30, N 4.33; found C 70.98, H 5.26, N 4.33.
Reaction of 6a with MeONa: The reaction was complete within 8 h.
Reaction of 1a with EtONa: The reaction was complete within
40 min. The first product eluted was 2 (24%); analytical and spec-
troscopic data are identical to those exhibited by the sample ob-
tained in the reaction of 1a with MeONa. The second product
eluted was rechromatographed to give 3b as an orange oil: 1H
NMR: δ ϭ 15.18 (s, NH), 7.12 (m, 5 H), 6.09 (s, 1 H), 4.06 (q, 2
H), 2.61 (s, 3 H), 1.46 (t, 3 H) ppm.
The crude reaction product was triturated with hexane to give
1
methyl 7a (32.9%); m.p. Ͼ 210 °C. H NMR: δ ϭ 7.31 (m, 5 H),
7.07 (m, 3 H), 6.77 (d, J ϭ 8 Hz, 2 H), 3.79 (s, 3 H), 3.5 (s, 2 H)
ppm. 13C NMR: δ ϭ 161.7, 148.5, 135.8, 129.0, 128.9, 128.4, 126.6,
123.0, 121.4, 53.5, 36.04 ppm. MS: m/z ϭ 225.
Reaction of 6b with MeONa: The reaction was complete within 4 h.
The crude reaction product was triturated with hexane to give 7b
(30.2%); m.p. 72 °C. 1H NMR: δ ϭ 7.30 (m, 8 H), 7.16 (d,
4 H), 7.08 (t, 1 H), 6.78 (d, 2 H), 5.14 (s, 1 H), 3.87 (s, 3 H) ppm.
MS: m/z ϭ 301. C21H19NO (301.4): calcd. C 83.69, H 6.35, N 4.65;
found C 83.71, H 6.32, N 4.50.
Reaction of 1c with MeONa: The reaction mixture was heated un-
der reflux for 10 min and then stirred at room temp. for 2 h. Com-
pounds 3a and 4 were isolated by column chromatography and
their analytical and spectroscopic data are identical to those ob-
tained in the reaction of 1a with MeONa.
Preparation of [1,2-13C]Acetamide: A mixture of [1,2-13C]acetic acid
having 5% isotopic abundance (8.15 g) and urea (7.25 g) was heated
at 200 °C on an oil bath. Heating was continued until gas evolution
stopped, and then the mixture was distilled to give the title com-
pound (b.p. 200 °C, 5.70 g, 71%). 13C NMR: δ ϭ 173.2 (s ϩ d, J ϭ
130 Hz, CϭO), 22.6 (s ϩ d, J ϭ 130 Hz, CH3).
Reaction of 1d with EtONa: The reaction was complete within
25 min. The first product eluted was 10 (26%), obtained as a pale
yellow solid that was crystallized from hexane; m.p. 104 °C. 1H
NMR: δ ϭ 7.03 (d, J ϭ 9 Hz, 2 H), 6.87 (d, J ϭ 9 Hz, 2 H), 6.55
(s, 1 H), 6.39 (s, 1 H), 5.52 (s, NH), 2.44 (s, 3 H), 2.27 (s, 3 H)
ppm. MS: m/z ϭ 203. C12H13NS (203.3): calcd. C 70.90, H 6.45,
N 6.89; found C 70.92, H 6.50, N 7.02. The second product eluted
was 11, obtained as a brown solid that was triturated with hexane.
1H NMR: δ ϭ 15.10 (s, NH), 7.28 (d, J ϭ 4.8 Hz, 2 H), 7.13 (d,
J ϭ 4.8 Hz, 2 H), 6.05 (s, 1 H), 4.24 (q, J ϭ 4 Hz, 2 H), 2.61 (s, 3
H), 2.31 (s, 3 H), 1.42 (t, J ϭ 4 Hz, 3 H) ppm. MS: m/z ϭ 235.
Preparation of [1,2-13C]Thioacetamide: A mixture of [1,2-13C]acet-
amide having 5% isotopic abundance (5.65 g), P2S5 (4.40 g) and
K2S (9.50 g) in toluene was heated at 75Ϫ80 °C with stirring for
1 h, and then the toluene was decanted. This sequence was repeated
seven times. The reaction solvents were evaporated to dryness to
give a residue that was added to the white solid that had precipi-
tated from toluene, and then this mixture was chromatographed on
silica gel (CH2Cl2/EtOAc, 7:3). The last fractions gave [1,2-
13C]thioacetamide (1.27 g, 17.6%). 13C NMR: δ ϭ 206.9 (s ϩ d,
J ϭ 160 Hz, CϭS), 33.0 (s ϩ d, J ϭ 160 Hz, CH3) ppm.
1
The third product eluted was 12, obtained as a red oil. H NMR:
δ ϭ 6.95 (m, 6 H), 6.55 (d, J ϭ 8.9 Hz, 2 H), 4.21 (q, J ϭ 5.8 Hz,
2 H), 3.02 and 3.40 (2 d, J ϭ 14.7 Hz, 2 H), 2.31 and 2.37 (2 s, 6
H), 1.95 (s, 3 H), 1.45 (s, 3 H), 1.31 (t, J ϭ 5.8 Hz, 3 H) ppm. MS:
m/z ϭ 424.
Reaction of 1e with EtONa: The reaction was complete within
15 min. The aqueous layer was treated with 10% HCl solution; a Preparation of (Z)-[2,1Ј,2Ј,3Ј-13C]-5-Acetyl-2,3-dihydro-3-phenyl-2-
yellow solid precipitated, which was dissolved in CH2Cl2, dried
[(thioacetyl)methylene]-1,3,4-thiadiazole (1a*): 1-Chloro-1-(phenyl-
(Na2SO4) and the solvents were evaporated to dryness to give 16
hydrazono)-2-propanone (1.10 g) was added to a solution of [1,2-
Eur. J. Org. Chem. 2003, 2480Ϫ2487
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2485