Aliphatic isocyanides synthesis

The present procedure is the best way of preparing aliphatic isocyanides boiling above ethyl isocyanide. It has been applied to the synthesis of the following isocyanides 6 isopropyl (38%), -butyl (61%), te -butyl (68%), and benzyl (56%). In preparing isopropyl isocyanide or teri-butyl isocyanide, the petroleum ether should be of boiling point 30-35°, as otherwise it is difficult to separate these low-boiling isocyanides in the indicated yield, and,... 

Among the features of Volume 41 is the smallest-scale synthesis yet published in Organic Syntheses, namely, the preparation of 0.0005 mole of cholestanyl methyl ether by a generally useful methylation procedure that employs diazomethane and fluoboric acid (p. 9). Two preparations of isocyanides by dehydration of formamides are included. One of these, illustrated by cyclohexyl isocyanide (p. 13), is most suitable for aliphatic isocyanides while the other, illustrated by o-tolyl isocyanide (p. 101), is most suitable for aromatic isocyanides. 

A new isocyanide synthesis involves simply heating a monosubstituted aliphatic or aromatic formamlde (readily prepared at 0 from the amine and phenylformate ) in CHCI3 or CH2CI2 with triphenylphosphlne, CCI4 and Et3N. ... 

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

Arndtsen and co-workers developed an isocyanide-mediated three-component synthesis ofthe polysubstituted pyrroles 97, wherein an acyclic imine was activated in situ by acylation [54]. Thus, reaction of an imine, an acyl chloride, an alkyne, and an isocyanide in the presence of PrNEt2 afforded 97 in good to excellent yields (Scheme 5.29). A complex reaction sequence involving formation ofthe N-acyliminium by [4 + 1] followed by [3 + 2] cycloadditions and a retro-cycloaddition was proposed to account the formation of 97. The isocyanide participated actively in this reaction sequence however, it was not incorporated in the final adduct since it was lost as isocyanate by a retro-D-A reaction. The aliphatic imine was shown to be an appropriate substrate, at least in one case, leading to the corresponding pyrrole (R2 = isopropyl) in 72% yield. Azenes participated in this reaction in a similar manner. Thus, the isoquinoline 94 was converted to the benzo-fused pyrrole 98 in 50% yield. 

On heating (150 °C, 10 h) [Fe(CNMe)6]Cl2 is converted to a mixture of cis- and trans-[FeCl2(CNMe)4]. Somewhat surprisingly, [H4Fe(CN)j] reacts with aliphatic alcohols to form [Fe(CN)2(CNR)4] and other complexes. Intermediate species formed during this reaction can polymerize with the evolution of hydrogen cyanide. Addition of HCN displaces isocyanide, however, and so constitutes a catalytic cycle for the synthesis of RNC from HCN and ROH. 

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