Synthesis Of Isocyanides

Until recently, isocyanides(RNC) were a relatively little studied class, not so much because of their renowned malodorous property, but rather because of the the lack of suitable general methods for their synthesis in quantity. The advent of such methods within the last 20 years, and its applications in the MCR, have resulted in the explosive development of isocyanides chemistry and the elevation of the isocyano group from a position of comparative obscurity to a place of prominence among functional groups.Cyanide ion, despite its ambident character, is alkylated preferentially at carbon by alkyl halides and sulphates to give mainly nitriles, isocyanides being formed in only minor amount. On the other hand, cyanide ion 'complexed' with a heavy metal such as silver or copper is alkylated preferentially at nitrogen, so that the reaction of silver cyanide or copper cyanide with an alkyl iodide affords an isocyanide complex convertible by reaction with potassium cyanide into the free isocyanide. However, yield in this method for the synthesis of isocyanides are generally low and at their best never exceed 55%.Another classic method for the synthesis of the isocyanides (the Hofmann carbylamine reaction) involves the reaction of a primary amine with chloroform in the presence of a strong base such as ethanolic potassium hydroxide or potassium t-butoxide in t-butanol. Isocyanide formation in this case can be envisaged as the result of initial attack by dichlorocarbene on the amine to give an intermediate convertible by sequential β-elimination and α- elimination into observed product. An analogous pathway to product is probably also involves in the formation of aryl isocyanides by the thermal reaction of arylamines with sodium trichloroacetate. In this classic form the carbylamine reaction lacks generality and even when successful does not give particularly good yields.N-monosubstituted formamides can be dehydrated to isocyanides using a variety of reagents (e.g. P₂O₅, PCl₃, SOCl₂, COCl₂, ArSO₂Cl, POCl₃) in the presence of a suitable base (e.g. dialkylamines, trialkylamines, pyridine, potassium t-butoxide). Thisprocedure, which frequently gives good yield comparatively, is the most generally applicable and widely used method for synthesis of isocyanides. Icocyanide formation under these is readily explained in terms of base-induced α-elimination in a intermediate formimidate. Phosgene in conjunction with triethylamine or pyridine is a particularly efficient reagent combination for laboratory work, converting N-monosubstituted formamides into isocyanides in high yield (70-95%). However, the hazards involved in handling phosgene make this procedure unsuitable for the routine large-scale synthesis of isocyanides and a convenient, though less efficient, reagent combination for the purpose is phosphorus oxychloride in the presence of triethylamine or pyridine. The dehydration of sulphonyl derivatives of N-alkylformamide using phosphorus oxychloride in the presence of triethylamine at 0-10℃ provides a useful method for the preparation on sulphonylmethyl isocyanides (e.g. TosMIC) valuable as synthetic intermediates. However, these methods are of limited practicallity since the elvated tempratures involved tend to result in subsequent isccyanide into nitrile rearrangement. On the other word, enhancing the stability of the isocyanide is the most important point in this reaction. It is one of the jumping-off places of this paper.