Conversion with Isothiasyanate inCPME (2016)

The Optimization study has revealed the feasibility of this method,

 

and among the solvents tested cyclopentyl methyl ether (CPME)27

 

proved to be the ideal one (Scheme 7).

This procedure is widely applicable

to a set of different combinations of isothiocyanates and

organolithiums commercially available, giving the expected

analytically pure thioamides in excellent yields after simple

recrystallization from the same solvent.

Because of the wide
access to functionalized organolithiums via deprotonation or
lithium halogen exchange techniques,28 we were delighted in
expanding the protocol to the straightforward synthesis of
complex thioamides including highly sterically demanding
structures.

It is important to note that by transmetalating the
lithium carbanion to a Gilman reagent (R2CuLi)29 it is possible
to chemoselectively obtain a functionalized thioamide bearing
an ester group, thus directing the addition of the organometallic
species exclusively at the isothiocyanate moiety.


No racemization takes place upon the addition of various
organolithium reagents to optically active isothiocyanates
(Scheme 8), in agreement with the results observed in the
cases of less basic (di)halocarbenoids and isocyanates.


More
importantly, the formation of enantiopure reagents such as
lithiated N-Boc-pyrrolidine30 or Hoppe’s carbamate,31 through
the deprotonation in the presence of chiral ligands (−)- or
(+)-sparteine affords the corresponding thioamides with (almost)
full retention of stereochemistry and in excellent diastereomeric
ratio.


As expected, by switching from one enantiomer of sparteine
to the other, it is possible to obtain both asymmetric forms of a
given thioamide with comparable optical purity.