Polymer-Bound 3-N,N-(Dimethylamino)-2-isocyanoacrylate for the Synthesis of Thiazoles via a Multicomponent Reaction

Abstract

The synthesis of resin-bound 3-N,N-(dimethylamino)-2-isocyanoacrylate is described. This bifunctional reagent can be used for the synthesis of thiazoles via a multicomponent reaction. Several examples are reported.

Key words

solid-phase synthesis - thiazole heterocycles - multicomponent reaction - combinatorial chemistry - isocyanide

References

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  Resin-bound 3-N,N-(dimethyl-amino)-2-isocyanoacrylate is available from Priaton, Bahnhofstrasse 9-15, 82327 Tutzing, Germany (www.priaton.de).

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11

Representative example:
Synthesis of 2-[1-(Acetylbenzylamino)-2-methyl-propyl]thiazole-4-carboxylic Acid
Benzylamine (0.11 mL, 1 mmol) and iso-butyraldehyde (0.092 mL, 1 mmol) were dissolved in a 1:1 mixture of absolute CH₂Cl₂-MeOH (2 mL). This mixture was stirred for 2 h followed by the addition of HMBA-resin bound 3-N,N-(dimethyl-amino)-2-isocyanoacrylate (500 mg, 0.19 mmol), thioacetic acid (0.071 mL, 1 mmol) and 2 mL of the above solvent mixture. After agitating for 16 h the resin was filtered off and washed with CH₂Cl₂ (3 ×) and MeOH (3 ×). The resin was dried under high vacuum. Cleavage was performed with LiOH (18 mg, 0.75 mmol) in water (2 mL) and THF (2 mL) for 16 h. Thereafter the resin was filtered off and washed with a THF-water mixture. The resulting solvent mixture was neutralized with 2 N HCl and evaporated to dryness. The crude product was purified by preparative HPLC (column Grom-Sil 120 ODS-5, 50 × 20 mm, 5 µm, flow 30 mL/min, gradient 30-100% A in 15 min, solvent A = MeOH + 0.5% HOAc, solvent B = water + 0.5% HOAc). Yield 35 mg (56%). ¹H NMR (400 MHz, CDCl₃): δ = 0.85 and 0.98 (dd, J = 6.3 Hz; 6 H), 2.10 (s, 3 H), 2.79-2.90 (m, 1 H), 4.57-4.80 (q, J = 17.2 Hz; 2 H), 5.37-5.48 (m, 1 H), 6.83 (d, J = 7.0 Hz, 2 H), 7.12-7.18 (m, 3 H), 8.07 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.4, 20.2, 22.4, 29.8, 125.8, 127.2, 127.9, 128.5, 128.9, 136.6, 145.6, 162.7, 168.5, 172.1.