Reagent-controlled regiodivergent intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and β-ketoamides

Abstract

Two regiodivergent approaches to intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and amides have been developed, controlled by the reagents employed. With the Brønsted base KOt-Bu and CBrCl₃ as radical initiator, benzo[d]imidazo[2,1-b]thiazoles are synthesized via attack at the α-carbon and keto carbon of the β-ketoester moiety. In contrast, switching to the Lewis acid catalyst, In(OTf)₃, results in the regioselective nucleophilic attack at both carbonyl groups forming benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones instead.

Keywords: cyclization; fused-ring systems; indium; radical; regiodivergent.

Scheme 1

Two different intermolecular cyclization pathways controlled by reagents used.

Scheme 2

Scope of reaction. Reaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), KOt-Bu (2 mmol), in 3 mL CBrCl₃/MeCN 1:9 (v/v) under reflux for 16 h.

Scheme 3

Scope of the reaction. Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), In(OTf)₃ (0.1 mmol), in 1.5 mL toluene at 100 °C for 16 h. ^a2 mL of 2-butanol/toluene 1:3 (v/v) used as solvent instead. ^bIsopentanol/toluene.

Scheme 4

Control experiments.

Figure 1

Proposed mechanism (benzo[d]imidazo[2,1-b]thiazoles).

Figure 2

Proposed mechanism (benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones).