Checked by Andrew B. Benowitz and Amos B. Smith, III.
1. Procedure
A.
Phenylthioacetic acid morpholide. A
100-mL, round-bottomed flask is charged with
24.0 g (0.2 mol) of acetophenone,
1 g of p-toluenesulfonic acid monohydrate,
36.0 g (0.41 mol) of morpholine, and
6.4 g (0.2 mol) of sulfur (Note
1). The flask is equipped with a
reflux condenser and is heated at reflux for 3 hr (Note
2). The resulting reddish-brown solution is poured into
100 mL of stirred hot methanol (55–60°C). The wall of the
beaker is scratched with a
glass rod for seeding. The beaker is sealed with aluminum foil and put into a
refrigerator for 6 hr (Note
3). The resulting crystalline product is filtered and washed twice with ice-cold
methanol (10 mL). The material (
22.2 g, mp
69–79°C, almost colorless) is recrystallized by adding
25 mL of methanol and 25 mL of water and heating at reflux, followed by slow addition of
methanol (about 58 mL) until complete solution is obtained. After the sides of the flask are scratched, the solution is cooled in a refrigerator for about 10 hr;
21.9 g (
49.5%) (Note
4) of the pure product is obtained, mp
77.5–79°C.
B.
3-Morpholino-2-phenylthioacrylic acid morpholide. A distillation apparatus (
250-mL, round-bottomed flask, distillation head,
thermometer, condenser and
receiver) equipped with a
magnetic stirrer is charged with
22.3 g (0.1 mol) of phenylthioacetic acid morpholide,
26.1 g (0.3 mol) of morpholine and
67 mL (0.4 mol) of triethyl orthoformate (Note
5). The flask is heated in a
heating bath (bath temperature

160°C) for 8 hr. During this time,
ethanol is distilled continuously from the reaction (about 18 mL). Further raising the temperature of the bath to 180°C gives rise to the distillation of excess
morpholine and
triethyl orthoformate (38 mL, bp 128–130°C) from the orange solution within 30 min (Note
6). The mixture is evaporated under reduced pressure (
rotary evaporator, bath temperature

80°C). The remaining crystalline material is dissolved in
30 mL of chloroform and
150 mL of hot methanol (about 60°C). The solution is allowed to cool to room temperature (Note
7) and is put into a freezer (−24°C) for 12 hr. The light yellow product is filtered and washed with
methanol (30 mL) followed by
diethyl ether (30 mL). After drying in the open air for 18 hr,
29.4 g (
92%) (Note
8) of pure material is obtained, mp
156–156.5°C (Note
9).
2. Notes
1. All chemicals were obtained from the Aldrich Chemical Company, Inc. It is advisable to distill
acetophenone and
morpholine. The
sulfur should be small particles and must not form lumps. Excess
morpholine is generally recommended in Willgerodt-Kindler reactions.
2. The reflux condenser should be connected by a
gas outlet and tubing directly to the hood pipe to prevent
hydrogen sulfide from entering the laboratory atmosphere.
3. If crystallization fails, a small amount of the solution is evaporated, cooled in an
ice/sodium chloride bath, and scratched with a glass rod. The resulting crystals are used to seed the main solution.
4. a) The reported yield
3 of
94% could not be achieved. The amount of
sulfur can be increased to 12.4 g (0.2 mol) giving a higher yield of
phenylthioacetic acid morpholide that contains some unreacted
sulfur and a yellow impurity (
2-morpholin-4-yl-1-phenyl-2-thioxoethanone) that is difficult to remove. b) Spectral data:
1H NMR (500 MHz, CDCl
3) δ: 3.37 (m, 2 H), 3.61 (m, 2 H), 3.72 (m, 2 H), 4.34 (s, 2 H), 4.34 (m, 2 H), 7.23 (m, 1 H), 7.31 (m, 4 H);
13C NMR (125 MHz, CDCl
3) δ: 50.06, 50.50, 50.70, 65.99, 66.21, 127.01, 127.01, 127.66, 128.84, 135.70, 199.91.
7. Crystallization of the pure product begins after slight cooling.
8. Additional product can be obtained by evaporating the combined mother liquor, adding
25 mL of methanol to the remaining oil, and cooling the resulting solution to −24°C.
9. The product consists of a mixture of E/Z isomers
4 in an approximate ratio of 15:85; R
f = 0.35 and 0.25 (0.25-mm Whatman precoated silica gel plate,
33% ethyl acetate in hexanes). Anal. Calcd for C
17H
22N
2O
2S: C, 64.12; H, 6.96; N, 8.80; S, 10.07, Found: C, 64.38; H, 6.99; N, 8.80; S, 10.18. IR (KBr) cm
−1: 1611, 1586, 1440, 1429, 1413, 1236, 1226, 1116; Z-isomer (major isomer);
13C NMR (75 MHz, CDCl
3) δ: 124.8, 128.5 (C2',C3'-C
6H
5), 125.3 (C4'-C
6H
5), 139.3 (C1'-C
6H
5), 112.6 (C2), 137.5 (C3), 198.9 (C1);
1H NMR (300 MHz, CDCl
3) δ: 6.07 (s, HC=C); E-isomer (minor isomer);
13C NMR (75 MHz, CDCl
3) δ: 126.4 (C4'-C
6H
5), 128.1, 129.9 (C2',C3'-C
6H
5), 138.3 (C1'-C
6H
5), 115.2 (C2), 147.4 (C3), 203.3 (C1).
10. The spectral data for the title compound are as follows:
1H NMR (500 MHz, CDCl
3) δ: 3.05 (m, 4 H), 3.71 (m, 4 H), 7.21 (dddd, 1 H), 7.35 (m, 2 H), 7.46 (s, 1 H), 7.50–7.53 (m, 2 H), 7.57 (ddd, 2 H), 7.65 (ddd, 2 H);
13C NMR (125 MHz, CDCl
3) δ: 51.79, 66.11, 126.21, 126.28, 127.29, 127.67, 128.13, 130.08, 130.31, 131.57, 135.51, 137.12, 138.64, 162.80, 185.84.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
3-Aminothioacrylic acid amides are versatile β-dicarbonyl derivatives that have found widespread use as C-C-C and C-C-C-S building blocks in the synthesis of heterocyclic and open chain products.
5,6 To date, 2-arylthioacrylmorpholides with mainly a 3-dimethylamino leaving group have been prepared by the Vilsmeier-Haack reaction of arylthioacetic acid amides with
DMF/POCl3.
7,8 This synthesis is not convenient since the resulting 3-dimethylaminothioacrylic acid morpholides must be isolated as hydroperchlorates, the yields are occasionally low, and in a number of cases (especially if other amino groups beside the morpholino or dimethylamino are found in the products, or if the aryl group is ortho-substituted) no stable crystalline material is obtained. With the present procedure,
9 a very reliable synthesis of 3-morpholinothioacrylic acid amides with a wide variety of 2-aryl substituents has been elaborated. Instead of
triethyl orthoformate/
morpholine, the non-commercially available
trismorpholinomethane10 can be used,
9 also enabling the synthesis of the 2-unsubstituted 3-morpholinothioacrylic acid morpholide. In addition to the well known Willgerodt-Kindler reaction,
11 the starting thioacetamides can also be obtained by other methods such as reaction of styrenes with
sulfur and amines,
12 and the reaction of arylthioacetic acid thiol ester with amines.
13 Furthermore the thioamide amino group of the synthesized 3-morpholinothioacrylic acid amides can also be monosubstituted. Through the use of
pyrrolidine, 3-pyrrolidinothioacrylic acid amides can be obtained. Generally the procedure is very simple and safe. Scale-up can be effected without incident and very pure products are obtained. Since the 3-morpholino substituent usually acts as a leaving group in further synthetic applications, the same reactivity is found as in the well investigated 2-aryl-3-dimethylaminothioacrylic acid morpholides.
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