Resin-Bound Isothiocyanates and Their Synthetic Equivalents as Intermediates for the Solid-Phase Synthesis of Substituted Thiophenes

Author:

Stephensen Henrik1,Zaragoza Florencio1

Affiliation:

1. Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark

Publisher

American Chemical Society (ACS)

Subject

Organic Chemistry

Reference7 articles.

1. Solid-phase organic reactions II: A review of the literature Nov 95–Nov 96

2. Solid-phase synthesis of substituted 3-aminothiophenes and 2-methylene-2,3-dihydrothiazoles

3. Typical procedure. Preparation of thiophene6h: To Wang-resin-bound 1,3-diamino-2,2-dimethylpropane10(0.60 g, approximately 0.6 mmol, swollen in 1,2-dichloroethane) were added 1,2-dichloroethane (5.2 mL), carbon disulfide (0.8 mL), and diisopropylethylamine (0.52 mL). After shaking for 45 min a solution of tosyl chloride (1.32 g, 6.91 mmol) in 1,2-dichloroethane (1.5 mL) was added, and shaking was continued for 15 h. After filtration and washing of the resin with dichloromethane (5 × 8.0 mL), a solution of methanesulfonylacetonitrile (0.72 g, 6.04 mmol) in DMF (6.0 mL) was added, followed by the addition of DBU (0.84 mL). The resulting mixture was shaken for 15 h, filtered and washed with DMF (5 × 8.0 mL). The resin was then treated with a solution of 4-phenylphenacyl bromide (1.65 g, 6.00 mmol) in DMF (6.0 mL) and acetic acid (0.3 mL) for 15 h. The mixture was filtered, and the resin was washed with DMF (5 × 8.0 mL) and then suspended in a mixture of DMF (7.0 mL) and DBU (1.6 mL). After shaking for 15 h the resin was extensively washed with DMF, dichloromethane, and methanol. Cleavage from the support was effected by treatment with 50% trifluoroacetic acid in dichloromethane (6.0 mL) for 1 h. Concentration of the filtrate yielded 273 mg (80%) of6h(trifluoroacetate) as an oil (85% pure by HPLC, 254 nm), which crystallized upon addition of methanol (2.0 mL). Filtration and drying yielded 82 mg (24%) of slightly yellow crystals, 93% pure by HPLC (254 nm). Mp 216−218 °C (2-propanol); IR (KBr) 3459, 3313, 1677, 1549 cm-1;1H NMR (300 MHz, DMSO-d6) 0.98 (s, 6H), 2.74 (s, 2H), 3.16 (s, 2H), 3.25 (s, 3H), 7.42 (t,J= 7.3 Hz, 1H), 7.52 (t,J= 7.3 Hz, 2H), 7.66−7.80 (m, 6H);13C NMR (75 MHz, DMSO-d6) 22.25, 35.10, 43.43, 46.02, 54.37, 92.82, 99.29, 126.69, 127.41, 127.94, 128.99, 139.07, 140.08, 141.89, 155.52, 165.93, 183.81. Anal. Calcd for C25H28F3N3O5S2(571.64):  C, 52.53; H, 4.94; N, 7.35. Found:  C, 52.60; H, 5.19; N, 7.13.

4. Substituierte 3,4-Diamino-thieno[2,3-b]pyrrole

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