Isocyanides, synthesis from formamides

Appel s dehydration reagent can be successfully applied to the synthesis of isocyanides 1515 from formamides 1513 [987, 1224]. The dehydration reaction with triphenylphosphine/tetrachloromethane proceeds smoothly and furnishes generally good yields of 89-91% for alkyl, ben2ylic, and aryl isocyanides 1515 [1224]. 

Useful application of Tf20 as dehydrating reagent is accounted by the synthesis of isocyanides from formamides and vinylfor-mamides (eq 43). ... 

An approach to the synthesis of indoles 1573 employing a free-radical cycliza-tion of aryl isocyanides bearing pendant alkynes 1572 in a cascade-type reaction has recently been described [1190]. Isocyanide 1572 is prepared in 82% yield from formamide 1571 by dehydration with phosphoryl chloride at 0 °C within 15 min. 

Polymeric reagents bearing an isocyanide group 1654 cannot be prepared easily. A patent application New functionalized polymeric reagents with an isonitrile moiety for solution and solid-phase synthesis details syntheses of such isocyanides 1654 from the corresponding formamides according to an Appel reaction with tiiphenylphos-phane/tetrachloromethane and triethylamine [1228]. 

Dehydration.. Synthesis of isocyanides from formamides (eq 6) is the only example of a dehydration reaction reported for triphosgene to date. ... 

This reaction was first reported by Hofmann in 1868. It is the synthesis of isonitriles (also known as isocyanides) from primary amines and chloroform in the presence of alkali and is known as the Hofmann isonitrile synthesis, Hofmann carbylamine reaction, or Hofmann carbylamine synthesis. This reaction has been used to test the presence of primary amines from the order of isocyanides. Alternatively, the isonitriles can be prepared by means of the treatment of formamide of primary amines with toluenesulfonyl chloride" or phosphorus oxychloride (POCls)." Currently, the isonitriles have gained much attention in organic synthesis because of their application as versatile building blocks for heterocycles and in multicomponent reactions to generate combinatorial libraries, such as that in the Passerini reaction and Ugi reaction ... 

The synthesis of an imidazole C-nucleoside linked through C-4, namely 2-carbamoyl-4-(2 -deoxy-j5-D-ribofuranosyl)imidazole 1586, was achieved by way of a nine-step reaction sequence starting from 2-deoxy-3,5-di-0-p-tolyl-D-erythro-pentofuranosyl chloride. The isocyanide intermediate 1585 was obtained by dehydration of the corresponding formamide 1584 with phosphoryl chloride, affording the imidazole 1586 in a good yield of 86% based on formamide 1584. Substituted imidazole nucleotides play a vital role in purine biosynthesis, and some of them... 

The formation of the chiral formamidine 1658 from octahydroisoquinoline 1656 and the isocyanide 1657 derived from valinol tert-butyl ester gives an intermediate with high chirality-inducing potential, which, through further reaction steps, allows an asymmetric synthesis of (+)-morphinane with high enantiomeric purity (>98% ee in the decisive asymmetric reaction step) [1229]. The isocyanide 1657 is obtained in 85% yield by dehydration of the corresponding formamide with thionyl chloride. 

A total synthesis of the sesquiterpenoids (-)-axamide-4 1663 and (—)-axisonitrile-4 1664, affording both natural products, has been accomplished in eleven steps [1233]. From the view of a chemist, it is remarkable that both the isocyanide and its chemical precursor molecule formamide are naturally occurring. The transformation of (—)-axamide-4 into (—)-axisonitrile-4 is carried out with p-tosyl chloride in 94% yield. 

Oxomethylenebis-(3/f+-imidazolium) bis(methanesulphonate) (21) is a new and versatile non-basic dehydrating agent for the synthesis of a variety of base-sensitive isocyanides from the corresponding formamides in particular, for... 

Nitrophenyl Isocyanide Although o-nhrophenyl isocyanide (ONPIC, Iz) was known for quite a while, Hahn and coworkers have recently reported the first synthesis of ONPIC [88] as a ligand in metal complexation. It can be readily synthesized from commercially available o-nitroaniline 6x via formamide 81 formation followed by dehydration (Scheme 7.75). 

Cyclohexyl Isocyanide Several methods are available for the synthesis of cyclohexyl isocyanide. However, it can be readily prepared from the corresponding formamide in the presence of POCI3 or cyanuric chloride [98]. It is a colorless liquid having an offensive odor. Although cyclohexyl isocyanide (Izc) has been known for several years and commercially available, traditionally it has been used as a NCIC in MCRs. Recently, Yan and coworkers have reported that Izc can be used as a CIC in the presence of TFA in methanol under MWI. They employed this methodology for their fluorous synthesis of 1,4-BDZs 270 (Scheme 7.85), which can be further modified via the Suzuki coupling to obtain 272 [99]. Deprotection of cyclohexylamine has also been observed in the presence of Lewis acids [96]. 

---