One-Pot Conversion of Benzyl Alcohols to N-Protected Anilines and Alkyl Alcohols to Carbamoyl Azides

One-pot, scalable procedures converting benzylic or aliphatic alcohols to various N-functionalized amines are reported in 38-83 % overall yields. These multi-step conversions are relatively economic and involve the oxidative formation of acid chloride intermediates and the Curtius rearrangement of acyl azides. Notable aspects of economy include: (1) the use of a relatively green solvent (chlorobenzene) that tolerates both ionic and radical reactions, without the need for rigorously dry or O2-free conditions; (2) the use of minimal amounts of trichloroisocyanuric acid (TCCA) as a cheap and green chlorinating agent to oxidize the alcohol starting materials and then transform the aldehyde intermediates to acid chlorides under photoirradiation for azide addition; (3) the efficient capture of isocyanate intermediates by alcohol or azide nucleophiles providing N-protected anilines or N-protected alkylamines, respectively, the latter of which was employed in the synthesis of an anti-dementia drug, memantine hydrochloride, over two purification steps. Without the need for wasteful solvent-swaps and work-up operations, an optimized scalable sequence of reactions (up to 83 %) to replace the hydroxymethyl group of primary alcohols (R=substituted phenyl or alkyl) with valuable nitrogen functionality has been developed in an economical and green fashion.image