Isocyanides reactions with radicals

A small library of highly functionalized pyrrolines 95 was synthesized by reaction of allylic and propargylic isocyanides 94 with thiols followed by radical cyclization (Scheme 33). The radical reaction was carried out using a radical initiator (AIBN) under flash heating microwave irradiation [67]. 

An example in which primary alkylamines are used as alkyl radical precursors for cyclization is reported in equation 5061, in which the initial transformation to isocyanide and subsequent reaction with (TMS SiH gave the desired products in 78% yield after workup. 

The same authors also reported a modified sequential reaction, replacing the isocyanide partner with an alkyne (Scheme 61) [172]. Varied functionalized TMS-protected -allylic alcohols could be prepared. In addition, the phenyltellurium group final transfer to vinyl radical 191 afforded vinyl telluride 189, which could be further elaborated. Once again, this reaction proved highly versatile, as basically all kind of carbonyl compounds were suitable (aromatic and aliphatic ketones and aldehydes). Electron-poor alkynes did not give the desired products. 

In a total synthesis of )-camptothecin 1579, which shows high potential in terms of anti-tumor and anti-retroviral activity, a new [4+1] radical annulation has been established, facilitated by the use of phenyl isocyanide 1574. With 1575, 1574 effects a cascade of free radical reactions via 1576-1578 forming two new ring systems, a quinoline and a pyrrolidine, in a one-pot-synthesis [1191, 1192]. An improved synthesis of camptothecin analogues, in which the alkyne moiety is protected by a TMS group, has been filed for a patent application [1193]. 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

Reaction (7.13) shows the simplest and most popular type of hex-5-en-l-yl radical cyclization mediated by (TMS)3SiH. Thus, a 50 mmol solution of 5-hexenyl bromide and silane in the reported conditions leads to a 24 1 ratio of cyclized vs uncyclized products [6]. Similar results were obtained by replacing the bromide with isocyanide [7]. 

Tris(trimethylsilyl)silane is found to be an efficient reducing agent for a variety of functional groups. In particular, the reduction of halides, chalcogen groups, thiono esters and isocyanides are the most common ones. The efficiency of these reactions is also supported by available kinetic data. The rate constants for the reaction of (TMS)3Si radicals with a variety of organic substrates are collected in Table 2. 

Imidoyl radicals are often prepared by the addition of carbon- or heteroatom-centred radicals to isocyanides, but can also be prepared by hydrogen atom abstraction from imines. This latter method has been adopted in a new annulation approach to quinoline synthesis. Thus, reaction of the imine 1 with phenylacetylene and di-isopropyl peroxydicarbonate in benzene at 60°C gave a mixture of the quinolines 2 and 3 in 65% yield (2 3 = 4.4). 

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