Thiyl Radical Mediated Racemization of Benzylic Amines

Abstract

Thiyl radical mediated reversible H abstraction from the stereogenic center α to the nitrogen atom is a mild method to racemize benzylic amines. Owing to the sensitivity of atom‐transfer reactions to enthalpic effects, a knowledge of both the S–H and the α‐C–H bond dissociation energies is fundamental to select the thiol that is appropriate to abstract the hydrogen atom from a given amine. In the absence of experimental data, theoretical calculations supply a useful predictive tool. The experiments described here are helpful in delineating the optimal conditions that have to be fulfilled for the racemization to proceed in a reasonable time in the presence of either a stoichiometric or a catalytic amount of thiol. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Biocatalytic Routes to Optically Active Amines

“…[33] For an efficient reaction, the binding dissociation enthalpies of the thiol SÀH and amine a-CÀH bonds should match, so that neither the hydrogen abstraction nor the hydrogen transfer is too slow. [32] Thus, choosing the optimal thiol is crucial for efficient racemization. Especially for benzylic amines, oxidation and subsequent condensation reactions took place (Scheme 3 b).…”

“…[31] In DKR reactions, various benzylic and one aliphatic primary amine were resolved within three days at a catalyst loading of 4 mol %, furnishing 69-95 % product yields. Bertrand and co-workers investigated the radical-induced racemization of both benzylic [32] and aliphatic amines. [33] For an efficient reaction, the binding dissociation enthalpies of the thiol SÀH and amine a-CÀH bonds should match, so that neither the hydrogen abstraction nor the hydrogen transfer is too slow.…”

“…Especially for benzylic amines, oxidation and subsequent condensation reactions took place (Scheme 3 b). [32] Thus, choosing the optimal thiol is crucial for efficient racemization. Additionally, for application in an enzymatic DKR, the thiol must not inhibit the enzymatic reaction.…”

Metal‐Free Transformation of Phenols into Substituted Benzamides: A Highly Selective Radical 1,2‐O→C Transposition in O‐Aryl‐N‐phenylthiocarbamates

“…For example, although reversible radical abstraction of the a-hydrogen readily occurs in amines, no scission of C À N bonds is observed under these conditions. [6] Our computational study on the C À N radical fragmentation in a model thiocarbamate estimates a barrier of about 29 kcal mol À1 (Scheme 2 a), [7] which is 5-7 kcal mol À1 higher than that of the O-neophyl rearrangement in thiocarbonates. Encouraged by these results, we replaced the Oalkyl substituent with an N-alkyl moiety to investigate whether respective thiocarbamates will afford a more selective radical rearrangement (Scheme 2 b).…”

Nickel Nanoparticles as Racemization Catalysts for Primary Amines

“…In addition to redox catalysts, radicals can also be employed as racemization catalysts, and the use of thiyl radicals resulted in moderate to good yields in a multistep DKR. As opposed to the case of Pd, however, these radicals are only known to racemize aliphatic amines, due to significant side‐product formation when using benzylic amines, and quite large quantities of catalyst are required to perform the reaction (120 mol‐%) 18–21…”