Staudinger/aza-Wittig reaction to accessN^β-protected amino alkyl isothiocyanates

Abstract

A unified approach to access Nβ-protected amino alkyl isothiocyanates using Nβ-protected amino alkyl azides through a general strategy of Staudinger/aza-Wittig reaction is described. The type of protocol used to access isothiocyanates depends on the availability of precursors and also, especially in the amino acid chemistry, on the behavior of other labile groups towards the reagents used in the protocols; fortunately, we were not concerned about both these factors as precursor-azides were prepared easily by standard protocols, and the present protocol can pave the way for accessing title compounds without affecting Boc, Cbz and Fmoc protecting groups, and benzyl and tertiary butyl groups in the side chains. The present strategy eliminates the need for the use of amines to obtain title compounds and thus, this method is step-economical; additional advantages include retention of chirality, convenient handling and easy purification. A few hitherto unreported compounds were also prepared, and all final compounds were completely characterized by IR, mass, optical rotation, and 1H and 13C NMR studies.

Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones

“…These results not only lie in the wide scenario of the heterocyclic scaffolds obtainable through tandem Staudinger/aza-Wittig sequence [24,25,37,38,39,40,41], but the concurrent presence of reactive functionalities in the target compounds 5a – k ensures post-modifications in view of heterobicyclic structures. In fact, the tautomerism thionoamide/thioloimide permits the introduction of a further element of diversity at the sulfur atom producing imidazole derivatives suitable to be combined with the useful 1-amino-Boc protected group [42] directly installed by this approach, as for 5a , 5c – f, 5k .…”

“…We reasoned that the azidation process of the pertinent α-halohydrazone derivative followed by tandem Staudinger/aza-Wittig reaction with CS 2 could have been a successful route [24,25].…”

Synthesis of Isothiocyanates: An Update

“…28 Due to this reaction being performed under neutral conditions, it is able to accommodate the use of protecting groups (PG) such as fluorenylmethyloxycarbonyl chloride (Fmoc), tertbutyloxycarbonyl (Boc), and carboxybenzyl (Cbz). 27 The yields for this reaction in the preparation of N-protected aminoalkyl isothiocyanates are excellent at ≥83% and this was found to carry on to large-scale applications. 27 The general proposed mechanism for the reaction from the N-protected alkyl azides is shown in Scheme 18.…”

“…While there are a few methods that can be used to produce amino acid isothiocyanates, this synthesis faces challenges of potential racemization and overcoming the steric bulk of amino acid side chains. This methodology describes a way to produce N-protected aminoalkyl isothiocyanates from either N-protected amino acids or N-protected alkyl azides, 27 as shown in Scheme 17. Employing the tandem Staudinger/aza-Wittig reactions allows this to be possible, and it has also been successfully used to produce sugar isothiocyanates, 27 and aryl and alkyl isothiocyanates.…”

“…This methodology describes a way to produce N-protected aminoalkyl isothiocyanates from either N-protected amino acids or N-protected alkyl azides, 27 as shown in Scheme 17. Employing the tandem Staudinger/aza-Wittig reactions allows this to be possible, and it has also been successfully used to produce sugar isothiocyanates, 27 and aryl and alkyl isothiocyanates. 28 Due to this reaction being performed under neutral conditions, it is able to accommodate the use of protecting groups (PG) such as fluorenylmethyloxycarbonyl chloride (Fmoc), tertbutyloxycarbonyl (Boc), and carboxybenzyl (Cbz).…”