Dynamic kinetic resolution of amines involving biocatalysis and in situ free radical mediated racemization.

[reaction: see text] The association of lipase-catalyzed enzymatic resolution with in situ racemization mediated with the thiyl radical enables the dynamic kinetic resolution of non-benzylic amines. It leads to (R)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (S)-enantiomers.

Thiyl radical mediated racemization of nonactivated aliphatic amines.

The racemization of nonactivated aliphatic amines has been mediated with alkanethiols and with methyl thioglycolate in the presence of AIBN. The process involves reversible H-abstraction at the chiral center, in a position alpha relative to nitrogen, by thiyl radical. The knowledge of the reaction enthalpy is critical to select the appropriate thiol. In the absence of experimental values, theoretical calculations of the alpha-C-H BDEs and the S-H BDE provide a useful guide.

Thiyl radical-mediated cleavage of allylic C-N bonds: scope, limitations, and theoretical support to the mechanism.

Thiols mediate the radical isomerization of allylic amines into enamines. The reaction results in the cleavage of the allylic C-N bond, after treatment with aqueous HCl. The mechanism involves the abstraction of an allylic hydrogen alpha to nitrogen by thiyl radical, followed by a return hydrogen transfer from the thiol to the carbon gamma to nitrogen in the intermediate allylic radical. The scope and limitations of the reaction with respect to the nature of the thiol, to the structure of the allylic chain, and to the nature of the substituents at nitrogen were investigated. The experimental results were interpreted on the ground of DFT calculations of the C-Halpha BDE in the starting allylic amines, and of the C-Hgamma BDE in the resulting enamines. The efficiency of the initial hydrogen transfer is the first requirement for the reaction to proceed. A balance must be found between the S-H BDE and the two above-mentioned C-H BDEs. The incidence of stereoelectronic factors was analyzed through NBO calculations performed on the optimized geometries of the starting allylic amines. Additional calculations of the transition structures and subsequent tracing of the reaction profiles were performed for the abstraction of Halpha from both the allyl and the prenyl derivatives by p-TolS(*). The latter allowed us to estimate the rate constant for the abstraction of hydrogen by thiyl radical from an N-prenylamine and an N-allylamine.

Tandem radical and non-radical reactions mediated with thiols--a new method of cleavage of allylic amines.

Thiyl radical promotes the isomerisation of allylic amines into enamines via two consecutive hydrogen atom abstraction steps, and the subsequent polar addition of the corresponding thiol to the enamine results in the cleavage of the C-N bond via a thioaminal intermediate: this reaction provides a mild, metal-free methodology for the deprotection of allylated primary and secondary amines.