Pergamon Tetrahedron Letters 41 (2000) 1303–1305 TETRAHEDRON LETTERS Heterocyclic aldehydes as novel components in the boronic Mannich reaction Nathalie Schlienger, a,b Martin R. Bryce a,* and Thomas K. Hansen b,*,† a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK b Medicinal Chemistry Research, Novo Nordisk A/S, Novo Nordisk Park, 1760 Maaloev, Denmark Received 11 November 1999; accepted 7 December 1999 Abstract A range of heterocyclic aldehydes are shown for the first time to react in the boronic Mannich reaction to provide an expedient synthesis of new highly-functionalised small molecules. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: boron; boron compounds; Mannich reaction; heterocycles. Petasis et al. have recently introduced a protocol for the synthesis of amino acids in one step by a three- component boronic Mannich reaction (BMR) based on simply mixing an aryl or alkenyl boronic acid, an amine and an aldehyde at room temperature. 1–4 We have exploited this reaction in the syntheses of new 2-ketopiperazine 5 and 2-keto-1,4-diazepine derivatives 6 designed as conformationally constrained amino acid mimics. Examining the literature it appears that while the boronic acid component has been varied somewhat (e.g. including thienyl, furyl and benzo[b]furyl derivatives) 2,3 and several amines (especially secondary amines) 2–4 react, all reported successful examples of the BMR involve glyoxylic acid or an α-hydroxyaldehyde as the functionalised aldehyde component. 7 A key issue, therefore, was to establish if different structural variants of the aldehyde input could take part in the BMR. Herein, we report that a range of heterocyclic aldehydes react in this protocol providing the rapid, multi-component assembly of a series of novel highly-functionalised small molecules. We screened a range of heterocyclic aldehydes in conjunction with equimolar quantities of phenyl- alkenyl boronic acid 1 8 and morpholine as the amine input (Scheme 1). The reactions were carried out in DMF:CH 2 Cl 2 (4:6 v/v) at 50°C for 2 days. LCMS and 1 H NMR analysis of the crude product mixture established that products 2a–e were formed. It is notable that all of the aldehydes which gave the BMR product 2 possessed a heteroatom α to the aldehyde group. Both π-deficient (e.g. 2-pyridyl) and π-rich (e.g. 2-furyl) aldehydes reacted. In contrast, several other aldehydes both with and without * Corresponding authors. E-mail: m.r.bryce@durham.ac.uk (M. R. Bryce) † E-mail: tkha@novo.dk 0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)02273-X tetl 16201