Tandem Thioacylation‐Intramolecular Hydrosulfenylation of Propargyl Amines – Rapid Access to 2‐Aminothiazolidines

Abstract

An investigation directed towards the preparation of α‐substituted propargyl thioureas from the corresponding propargylamine resulted in a tandem thioacylation/anti‐hydrosulfenylation and the formation of the corresponding thiazolidine in excellent (46–98 %) yields rather than the anticipated thiourea. Initial interpretation of this outcome was formulated in terms of the highly substituted nature of the α‐carbon of these amines resulting in steric acceleration, however, even simple propargylamines engage in this chemistry. In light of these observations, it was determined subsequently that the formation of the thiourea is quite rapid, but cyclization occurred during chromatographic purification and is in fact facilitated by silica gel. Control reactions and monitoring the progress of the reaction by NMR spectroscopy clearly indicate that the cyclization is relatively slow until either purification or the introduction of silica gel results in cyclization. Subsequently, it was found that even the parent system afforded the thiazolidine when the reaction was conducted on silica gel. Overall, the reaction is tolerant of a variety of substitution patterns, internal and terminal alkynes and isothiocyanates providing rapid access to 2‐aminothiazolidines.

Enantiomeric Separation of New Chiral Azole Compounds

“…A degassed solution of toluene containing N -phenylmaleimide or ethyl glyoxylate reacted with the corresponding oxazoline [ 5 ] and thiazoline [ 6 ] methylidenes was heated at reflux overnight and resulted in an ene reaction providing twelve new chiral azole compounds. The detailed processes and reactions are presented elsewhere [ 24 ].…”

“…Exposure of XVI to either N -phenylmaleimide or ethyl glyoxylate delivered the corresponding ene adducts I-V in modest to good yields [ 24 ]. The thiazoline derivatives XVII were prepared in analogous fashion through a one-step thio acylation/hydroamination sequence [ 6 , 7 ] and then subjected to ene reactions with N -phenylmaleimide and ethyl glyoxylate, which afforded the corresponding adducts in generally good yields.…”

“…The copper-catalyzed hydroamination of propargyl imidates was recently proposed as an efficient way to obtain alkyl-or aryl-substituted dihydrooxazoles providing interesting intermediates for further elaboration [ 5 ]. Recent investigations from our laboratory have focused on the synthesis and reactivity of “pre-aromatic” heterocycles derived from propargylic systems [ 6 , 7 ]. A subsequent reaction with these methylidene compounds can take advantage of aromatization as a driving force.…”

Development of a Telescoped Flow Process for the Safe and Effective Generation of Propargylic Amines

“…Such a process was expected to yield valuable heterocyclic derivatives via intermediate thiourea adducts 12 that would cyclize in an acid-catalyzed reaction cascade. This sequence is interesting as it allows direct access to either thiazoline or thiazole derivatives 13 or 14 as reported in the literature [33,34,35,36,37]. We were specifically interested in selectively generating thiazoline species as these provide an exocyclic alkene that can serve as a handle for accessing highly functionalized derivatives (Figure 1).…”

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line

“…While, in our earlier work, silica gel was investigated and shown to promote fast cyclization of thioureas formed in situ from propargyl amines and isothiocyanates. Therefore, we have focused on developing this interesting one-pot chemistry further to access bio-active thiazolidine-based structures easily [ 36 ]. In 2019, our group published the synthesis of a novel group of thiazolidines using this procedure, some of which were prone to oxidation at C4 upon extended exposure to the ambient atmosphere producing thiazolidinones ( Scheme 1 ) [ 13 ].…”