Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions

Abstract

The reaction of organic azides with trivalent phosphorous compounds to afford the corresponding azaylides is known as the Staudinger reaction.1) This reaction proceeds via a primary imination adduct, phosphazide, which spontaneously decomposes into azaylide and nitrogen in most cases.2) The azaylide product can usually be isolated as a stable compound, which can be used to prepare various amines, imines, amides, isocyanates, isothiocyanates, 3,4) and so forth, 5) as a versatile synthetic intermediate. As for the isothiocyanate synthesis, a convenient one-pot procedure was reported by Tsuge et al. in 1984 as is to say the tandem Staudinger/azaWittig reaction.6,7) They used carbon disulfide (CS 2 ) as the co-solvent in the reaction of only (trimethylsilyl)methylazide with triphenylphosphine (PPh 3 ), 6) and the yield of the corresponding isothiocyanate was superior to that obtained from a stepwise method 8) in which CS 2 was added to the primary reaction mixture containing the azaylide product. Especially, the tandem method was recently utilized in a carbohydrate field in order to effectively obtain isothiocyanate-functionalized sugars.9-11) Herein, we investigated the substrate generality of the tandem and stepwise Staudinger/aza-Wittig reactions and their reaction mechanisms utilizing a 1 H-NMR analysis. Results and DiscussionOur first target was to prepare chloroethylisothiocyanate (3a), because 3a was an indispensable material for the synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1), useful for the pendant moiety of the oral carbapenem antibiotic L-084 (Chart 1).12) In recent years, the development of new antibiotics has attracted the attention in the clinical realm for the treatment of severe infectious diseases. L-084 is one of several promising candidates for oral administration and is now under clinical trials. During the course of our synthetic study of L-084, we established an efficient synthetic route for 1 from 2 and 3a, 13) but to the best of our knowledge, there was no application to prepare 3a without using the harmful and toxic thiophosgene. 14,15) Thus, we planned to develop an effective and harmless synthetic route for 3a in which scaleup production would be possible. Chloroethylisothiocyanate (3a) was initially prepared from the reaction of chloroethylazide (5a) 16) and PPh 3 followed by the aza-Wittig reaction with CS 2 , but 3a was obtained in only 16% yield from 5a due to the decomposition of the unstable intermediate 8a (Entry 1 in Table 1). As a result of the optimization of the reaction conditions, we found that the yield of 3a dramatically increased to 83% when CS 2 was used as the co-solvent in the reaction of 5a with Ph 3 P, compared to the above stepwise method.At this point, we investigated in detail the tandem Staudinger/aza-Wittig reactions (Method I) and the stepwise reactions (Method II), as shown in Table 1. Namely, several azides 5b-g were treated with Ph 3 P in a mixed solvent of CS 2 and CHCl 3 to afford the corresponding isothiocyanates in good yields except for th...

Structure–activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N′-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism

“…The dihydroxyation of 22 followed by selective pivaloylation provided 23 whose hydroxyl group was converted to the corresponding azide 24 . The azide 24 was then converted to the isothiocyanate 25 efficiently with carbon disulfide and triphenylphosphine; 18 the isothiocyanate 25 was coupled with the amines of the A-region 16 and 17 to afford the final compounds 26 and 27 .…”

Synthesis of Isothiocyanates: An Update

“…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). 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.…”

Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

“…[42] Reactions were performed in water in pressure vials under microwave (MW) conditions using sodium azide as as ource of azide anion. Subsequently produced crude azides 6-9 were subjected to consecutive Staudinger/aza-Wittig reaction [43][44][45][46][47][48] with triphenylphosphine and carbon disulfide to yield pure target (wisothiocyanatoalkyl)dimethylphosphine oxides 10-13 (n = 3-6) in low overall yields (10-27 %), after preparative thin-layer chromatography.T he synthesis of (2-isothiocyanatoethyl)dimethylphosphine oxide by this approachwas unsuccessful.…”