Formic acid isonitriles

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 ... 

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

As the isonitriles are rapidly hydrolyzed to amines and formic acid, an extraction step with hydrochloric acid is normally sufficient in practice to remove these impurities from a desired nitrile product. 

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnCl2 as promoting Lewis acid, a-amino acid amides are obtained [13,45] with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19 1 in favor of the D-amino acid amides 30 (Scheme 20). 

In the aromatic series the direct conversion of acid amides into acid nitriles does not take place readily but the acid itself is made from the acid amide by the reverse process as indicated above, viz., by hydration to the ammonium salt of the acid, which then yields the acid. A related method, however, is used for preparing acids from anilides of formic acid. Aniline being an ammonia compound yields acid-amidelike products with aliphatic acids, e.g. acet anilide, CH3—CO—NH— CeHs (p. 556). Such a compound can not, however, lose water in the same way as the acid amide in the above reaction for the ammonia residue in an anilide contains only one hydrogen. Nevertheless anilides lose water but in a different way. In the case of the anilide of formic acid, i.e. formanilide, H—CO—NH—CeHs, the loss of water results in a compound in which the carbon and nitrogen remain linked to the benzene ring and an iso-cyanide or iso-nitrile is formed. The isonitrile is readily converted into the nitrile and the acid may then be obtained from that. 

Sulfonyl halides (e.g. benzenesulfonyl chloride) form adducts (11) with acid amides in an equilibrium reaction. From these adducts or via adducts of this type 0-sulfonated lactim ethers, isonitriles, adenine, nitriles, amidines, amidinium salts and formic acid esters were prepared. The adducts from DMF and chlorosulfonamides (12) can be used to prepare amidines or amidrazones. A/-Chlorosulfonylcarboxylic acid amides yield nitriles on treatment with DMF or other tertiary amides, presumably via an acid amide sulfonyl chloride complex (13 equation 3). ... 

In the isonitriles it is very probable that the carbon atom combined with the nitrogen atom is only bivalent C0H4. N=C . The isonitriles are isomeric with the acid-nitriles, e.g., C H4.C=N, benzo-nitrile. While the nitriles on saponification give acids, the isonitriles decompose into a primary amine and formic acid ... 

Polymer-bound isonitrile (423), obtained from TentaGel-NH2 through treatment of the resin with formic acid and acetic anhydride, followed by dehydration of the resulting formamide with tosyl chloride and pyridine, has been employed in the preparation of N-substituted amino add ester [349]. Thus, Ugi MCR, performed in the presence of an alcohol instead of the carboxylic component, gave rise to an imino-ether spedes (426). Several Lewis acids were tested in searching for optimal reaction conditions. Boron trifluoride etherate displayed the better yields in term of desired product of the Ugi-type reaction. Amino acid methyl esters (427) were thus obtained when using methanol as the alcohol component, after deavage from the resin of the intermediate imino-ethers by an acetone/water mixture (Scheme 87). 

The Ugi reaction is the synthesis of an a-amino acid amide by reaction of an aldehyde with an amine and an isonitrile in the presence of zinc chloride and formic acid. )3-D-Galactosylamine has been proposed as a chiral amine partner whose alcohol functions are protected by esterification with pivalate groups (reaction 8.7) (Kunz and Pfrengle 1988). The reaction is carried out in oxolane between -75 and -25°C. The diastereomeric mixture obtained corresponds to a d/l ratio close to 95 5. The pure D-isomer is obtained by recrystallization in heptane. It is known that the bond between a sugar molecule and nitrogen is easy to cleave in glycosylamines (see Section 3.6.2). 

In the laboratory, formic acid can be obtained by heating oxalic acid in anhydrous glycerol and extraction by steam distillation. Another preparation (which must be performed under a fume hood) is the acid hydrolysis of ethyl isonitrile (C2H5NC) using HCl solution. 

On hydrolysis with dilute acids isonitriles are converted to amines even in the cold. During the reaction formic acid is formed ... 

In many of its reactions hydrocyanic acid behaves as the nitrile of formic add H.CN. Many facts, in particular its great chemical and pharmacological similarity to the isonitriles >C = NR suggest another constitution, namely, that of carbimide >C =NH with bivalent carbon. The addition reactions of the nitriles (see above), which reactions are also characteristic of hydrocyanic acid, can equally well be explained on the basis of this second structural formula. In the nitrile form it is at the triple bond between carbon and nitrogen that addition takes place. In the methylene form this occurs at the two free valencies of the bivalent carbon atom, e.g. ... 

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