Zinc-Catalyzed Transacetalization of N,O-Acetals into N,N-Acetals with Benzotriazoles, Indazoles, and Azides

This paper is dedicated to Professor Barry M. Trost to celebrate his career on the occasion of 20 years of Science of Synthesis.

Abstract

N,O-Acetals obtained from β-oxidation of ynamides underwent transacetalization with benzotriazoles, leading to N,N-acetals. The Zn(OTf)₂ efficiently catalyzed the process, and the reaction is further accelerated in hexafluoroisopropanol, providing a single N1-regiosiomer. The transacetalization conditions developed could be extended to other N-donors, such as 1H-indazole and TMSN₃ to afford the corresponding N,N-acetals.

Key words

Zn catalysis - transacetalization - N,N-acetal - ynamide - benzotriazole

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• 12 Synthesis of 3 – Typical Procedure for 3a In a 4 mL vial, the N,O-acetal 1a (38.2 mg, 0.1 mmol), benzotriazole (2, 35.7 mg, 0.3 mmol), and Zn(OTf)₂ (3.6 mg, 0.01 mmol) were dissolved in hexafluoroisopropanol (HFIP, 1 mL). The reaction mixture was then heated to 60 °C for 9 h, when the reaction was judged to be complete (TLC). The mixture was concentrated to dryness, and the residue was purified by SiO₂ flash chromatography (EtOAc/n-hexane/CH₂Cl₂ = 1:15:5) to afford 3a (30 mg, 87%) as a white solid; mp 108–110 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 9.2 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 7.3 Hz, 2 H), 7.63 (t, J = 15.4 Hz, 1 H), 7.55 (t, J = 14.9 Hz, 1 H), 7,48 (t, J = 15.4 Hz, 1 H), 7.38 (t, J = 13.9 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 189.0, 145.8, 134.5, 133.5, 132.4, 129.1, 128.5, 125.0, 120.5, 109.7, 71.4, 38.9, 31.3. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₆N₄O₃S⁺: 344.0938; found: 344.0941.