Experimental

Experimental

4-Cyano-3-methyl-but-3-enoic acid ethyl ester [18,19]

A mixture of ethyl acetoacetate (130.0g, 1.0 mol), toluene (150 mL), cyanoacetic acid (90.0g, 1.06 mol), ammonium acetate (16.0 g, 0.2 mol) and acetic acid (30 mL) was refluxed until no additional water was formed on azeotropic removal (8 h). Volatiles were removed in vacuo and the residue was partitioned between water and methylene chloride (400 mL). The organic phase was dried (Na₂SO₄), evaporated, and the crude product fractionated using a 30 cm Vigreux column to yield 106.5g (69.6%) of the product with b.p.₁₀ 110-118°C (Ref. 14a: b.p.₁₁ 114°C). According to ¹H-NMR, the eluted product fraction also contained isomeric 4-cyano-3-methyl-but-2-enoic acid ethyl ester. This product fraction was used for the preparation of 1a [20] via ethyl 2-amino-4-methyl-thiophene-5-carboxylate hydrochloride[21].

General procedure for the conversion of thieno [2,3-d]-1,2,3-thiadiazoles (1) to thieno [2,3-d]-1,3-dithiol-2-thiones (2) using the Matryoshka-autoclave.

A 50-mL Teflon autoclave was charged with 1 (140-840 mg) and carbon sulfide (30 mL). This Teflon autoclave was inserted into a 2L steel autoclave and 100-200 mL carbon disulfide was added. The closed steel autoclave was heated for the time and temperature indicated in Table 1, developing a pressure of 35-40 bar. The reaction temperature was measured inside the steel autoclave using a thermocouple attached to a digital voltmeter as well as a strip chart recorder via an analog/digital interface. Following the prescribed reaction time, the cooled autoclaves were opened, the contents of the Teflon autoclave were evaporated to dryness with recovery of the carbon disulfide. The residue was purified by flash column chromatography using methylene chloride/petroleum ether (b.p. 40-60°C) 1:1 as eluant.

Table 1: Thermolysis of Thieno [2,3-d]-1,2,3-thiadiazoles

Run	Starting Mat.	R1	R2	Scale (mg)	Temp. (°C)	Time (h)	Product (yield, %)	m.p. (°C)
1	1a	H	H	750	210-220	7	2a (37)	127-130 (toluene)
2	1a	H	H	240	230-240	8	2a(67)	127-130
3	1b	Cl	H	140	260-270	9	2b(10)(a)	210-215 (LC)
4	1c	CH₃	H	140	235-245	9	2c(77)(b)
5	1d	C₆H₅	H	150	240-267	9	3d(35)	223-224
6	1d	C₆H₅	H	150	210-220	7	2d(80)	175-177
7	1d	C₆H₅	H	840	210-230	6	2d(80)	175-177
8	1e	4-F-C₆H₄	H	140	230-240	9	2e(10)	156-158
9	1f	C₆H₅	CN	610	210-220	9	2f(18); 3f(36)	191-192 302-305
10	1g	COOC₂H₅	CH3	8550	207-218	7	2g(29)(c)	169-170
11	1g	COOC₂H₅	CH3	3500	225-232	6	2g(54)	169-170

(a) Yield based on 64 mg starting material recovered. (b) Yield of crude product. (c) Yield based on 3.4 g starting material recovered.

Click for: Table 2: Physical Properties of Compounds 2 and 3

To a solution of 2d (160 mg, 6.0 mmol) in dry toluene (20 mL), borane-dimethylsulfide (200 mg, 26 mal) was added and the reaction kept at 80-90°C until a TLC showed complete consumption of the starting material (30 min). The cooled reaction mixture was hydrolyzed with dry MeOH and evaporated to dryness. The addition of MeOH and evaporation was repeated 3 times until the flame test for boron was negative. The crude product did not show any ¹H-NMR signals in the region of 4.5 ppm, indicative of the S-CH₂-S moiety of the expected dithioacetal 5. Alkylation using an excess of MeI and 20% Na₂CO₃ gave, after extraction and Kugelrohr-distillation (0.2 mbar/110°C), 126 mg (72%) of 4b which crystallized: m.p. 36-68°C. ¹H-NMR (CDCl₃) d 2.43 (s, 1H, SCH₃), 2.49 (s, 1H, SCH₃), 7.10 (s, 1H, H-4), 7.25-7.60 (m, 5H, arom.); MS m/z 252 (M⁺, 92), 237, 203, 173, 160, 145, 121, 102, 91, 77.

Ethyl 2-Methylthio-6-methylthieno [2,3-d]-1,3-dithiole-5-carboxylate (7a) and Ethyl 2-Ethoxy-2-methylthio-6-methylthieno [2,3-d]-1,3-dithiole-5-carboxylate (7b)

1g [21](0.32 g, 1.16 mal) was stirred with freshly distilled dimethyl sulfate (4 mL) at 90-100°C under N₂ until it was dissolved (30 min.). The cooled solution was treated with tetrafluoroboric acid (54%, 0.4 mL), followed by ether (20 mL) to give 0.41g (93%) of crude 6. The yellow salt was dissolved in a 1:1 mixture of THF and MeCN (20 mL). NaBH₄ (0.2 g, 5.3 mal) was added, resulting in a colorless solution that was stirred for 1 h. The solvents were evaporated and the residue was partitioned between CH₂Cl₂/H₂O. The organic layer was dried (Na₂SO₄) and evaporated to yield 7a (0.25 g, 74%) as colorless crystals, m.p. 71-74°C (from petrol ether/EtOAc). ¹H-NMR (CDCl₃) d 1.35 (3H, t, O-CH₂CH₃), 2.26 (s, 3H, C-CH₃), 2.47 (s, 3H, S-CH₃), 4.30 (q, 2H, O-CH₂), 6.50 (s, 1H, H-2). Anal. for C₁₀H₁₂O₂S₂: Calcd: C, 41.07; H, 4.14; S, 343.85. Found: C, 41.27; H, 3.86; S, 43.64.

When EtOH was used instead of THF/MeCN as the solvent [10], after work-up and column chromatography on silica using petrol ether (b.p. 40-60°C)/t-BuOMe (99:1), a mixture of 7a and 7b was obtained. 7b eluted first and was characterized by its ¹H-NMR: (CDCl₃) d 1.32 (3H, t, O-CH₂CH₃), 1.41 (3H, t, O-CH₂CH₃), 2.43 (s, 3H, C-CH₃), 2.47 (s, 3H, S.CH₃), 3.75 (q, 2H, O-CH₂), 4.30 (q, 2H, O-CH₂). The second fraction was identical by ¹H-NMR and HPLC with 7a prepared using THF/MeCN.