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Abstract
Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.
Highlights
Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species
Essentially all studies on the Curtius rearrangement convert carboxylic acids into amines and amine derivatives such as carbamates, amides, and ureas (e.g., 3a−d), overlooking opportunities for new directions. This Note reports the realization of an interrupted Curtius rearrangement process rendering a set of new products such as γ-amino ketones and unsaturated pyrrolidines from Boc-protected proline derivatives
Generation and subsequent trapping of the intermediate isocyanate 5 were thereby anticipated to afford a selection of versatile α-amino pyrrolidine species 6 as novel and potentially useful amine building blocks (Scheme 2)
Summary
In view of the synthetic versatility of the 1,4-disubstitution pattern observed in this unexpected product and the desire to evaluate the generality of this process, a small selection of NBoc-protected proline derivatives were subjected to these reaction conditions Their syntheses were readily accomplished by lithiation of N-Boc proline methyl ester (10, 0.5 M in toluene, 1.0 equiv) with LiHMDS (1.0 M in THF, 1.1 equiv) as a base at −78 °C, followed by trapping the resulting carbanion with various electrophiles bearing alkyl and benzyl appendages (Scheme 3). For a reaction on a 2 mmol scale, a solution containing substrate acid 4 (1 M, toluene, 2 mmol, 1.0 equiv) and NEt3 (2 mml, 1.0 equiv) was prepared and pumped using a Vaportec E-series flow reactor at a flow rate of 0.25 mL/min.
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