Isonitriles from primary amines

Selected examples of the synthesis of isonitriles from primary amines... 

The reaction product derived from isonitriles and primary amines in the presence of Pd(II)Cl2 reacts with silver oxide to give carbodiimides 163. ... 

Isonitrile synthesis from primary amines and dichlorocarbene (from chloroform) or dibromocarbene (see 1st edition). 

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 ... 

Dihalocarbenes produced under PTC conditions have been advantageously used in the classical isonitrile synthesis from primary amines, again giving higher yields than the classical procedure. Hydrazine affords diazomethane, amides are dehydrated to nitriles and sulfoxides are reduced to sulfides in high yields. Finally, alcohols are converted into halides (Table 17)... 

The question of the constitution of hydrocyanic acid has already been considered (p. 139). Here it need only be remarked that the isonitriles are converted by hydrolysis into primary amines and formic acid no carbon monoxide is produced, although from the formula this might be expected. The reason for this is to be sought in the fact that the first stage in the reaction consists in the addition of water to the two free valencies of the carbon atom. The reaction must therefore be formulated thus ... 

Although the extraction of primary amines from a basic medium with chloroform is an inadvisable procedure, on account of the formation of trace amounts of the pungent isonitriles, the specific synthesis of isonitriles by the two-phase reaction of primary amines with chloroform is unreliable. However, the application of the phase-transfer technique [e.g. 1 -5] for the controlled release of dichlorocarbene facilitates the synthesis of isonitriles in relatively high yields (Table 7.12). 

Formerly, isonitriles were perhaps best known to many chemists through the indescribably vile odor of volatile members of the series encountered during the Hofmann carbylamine test for primary amines. Over recent years, however, isonitriles have come into their own as versatile synthetic reagents. Several reliable preparative methods now allow ready access to this family of substances and their remarkable chemistry. Biological pathways to isonitriles are also known, the first such substance isolated being the antibiotic xanthocillin (141), isolated from Penicillium notatumP Isonitrile compounds are also isolated fairly frequently from marine sources. ... 

PA can also be obtained via the thiol-ene click reaction from a,ro-diene monomers bearing amide groups in the main backbone or as side moieties via the Ugi four-component reaction [36, 37]. In one such study [38], the authors used 10-undecenoic acid as carboxylic acid, 10-undecen-l-al as an aldehyde, and different primary amines and isonitriles to synthesise a,C0-diene monomers, and then applied them to polymerisation reactions. The main focus of this specific work was the ADMET mechanism, though thiol-ene photopolymerisation was also implemented to prepare linear aliphatic PA with Mn values of 3-9 kDa and Tg values of 1-10 °C. 

In a process reminiscent of isonitrile hydrolysis, dichlorocarbene as generated from CHCI3 reacts with HaS in the presence of primary or secondary amines to yield thioformamides (79 equation 37). If pressure is employed, CCI4 or CI3CCCI3 can also be used with the latter giving dithiooxamides (27), e.g. with BuNHa, 65% of BuNHCSCSNHBu. 24... 

Fig.1, Ugl reaction product and scaffold formation on solid-support, (a) The Ugi reaction comprises an oxo-component (aldehyde or ketone) (R1), a primary or secondary amine (R2), an isonitrile group (R3), and a carboxylic acid (R4), which are condensed to yield a single product (1) In a "one-pot" reaction, (b) The proposed solid-phase Ugi reaction comprises an aldehyde-tunctionalized matrix to which the other three solution-phase components are added to yield a single ligand scaffold (2) (reproduced from (17) with permission trom Elsevier), (c) Putative solid-phase Ugi reaction mechanism for affinity chromatography ligand formation on aldehyde-tunctionalized chromatography sorbent. Tbe diagram shows only one ligand per bead tor clarity. (Reproduced trom (16) with permission from the author).

Amines, carboxylic acids, and isonitriles. A wide range of primary/ secondary amines (95,398), carboxylic acids (2,158), and isonitriles (644) are commercially available from the Available Chemical Directory (ACD) as of September 2007 (Table 1). The compounds used for the Ugi reaction on the aldehyde activated agarose vary from case to case they must be dissolved in an appropriate buffer, either an aqueous solution or an organic solvent such as methanol. Table 2 presents the list of the different amines (A1-A8), carboxylic acids (C1-C6), and isonitrile (II) components used for the Ugi combinatorial library prepared in this work (see Note 4). 

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