An Investigation of Imidazole and Oxazole Syntheses Using Aryl-Substituted TosMIC Reagents¹

Abstract

This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable regiochemistry. Employing chiral amines and aldehydes, particularly those derived from alpha-amino acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH(4)OH as the amine component in conjunction with a variety of aldehydes delivers 4, 5-disubstituted imidazoles in moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes is described.

Microwave‐Promoted Rhodium‐Catalyzed Arylation of Heterocycles through CH Bond Activation

“…Dihydroquinazoline, which contains a non-aromatic heterocycle, provided 2-phenylquinazoline as observed previously. [6] Bis(aryl) imidazoles, a highly important class of bioactive compounds, [15] were also highly effective arylation substrates. The observed substrate scope is fully consistent with our mechanistic understanding based on N-heterocyclic carbene/rhodium complexes as intermediates in CÀC bond formation.…”

Discovery Of Pyrroloimidazoles As Agents Stimulating Neurite Outgrowth

“…1,4,5-substituted imidazoles are accessible in a highly functionalized manner, by simply reacting (un-) substituted TOSMICs, aldehydes and primary amines in the presence of a suitable base under mild conditions. The compatibility of this reaction with unprotected functional groups is particulary noteworthy and reported in literature [11]. For example amino acids, amino alcohols, NH 4 OH, diamines, allyl amine and disulfide diamines can react as amine component.…”

Five‐Membered Heterocycles: 1,3‐Azoles

“…As we have previously seen for the synthesis of imidazoles, TosMIC (23) is also a useful reagent for the synthesis of oxazoles [45]. Aldehydes condense, in presence of a base, with TosMIC to afford 4,5-disubstituted oxazolines that eliminate toluenesulfinic acid to yield 5-monosubstituted oxazoles, as already outlined for the imidazole series.…”

“…The related reaction of ethyl glyoxylate or glyoxylic acid with primary amines or ammonia and aryl substituted TosMIC reagents 23 [44] is a versatile method for the synthesis of imidazole-5-carboxylates substituted at C4 (e.g., 29, Figure 10.4) [45]. The TosMIC chemistry can be extended utilizing an aldehyde as a partner (Scheme 10.10) [46].…”