Rearrangements involving isocyanides

Platinum(I) isocyanide complexes are formed when Na2PtCl4 reacts with methyl isocyanide, and the product isolated by addition of AgPF6 (equation 116). The structure has two square planar platinums linked by a Pt—Pt bond, with the two Pt(CNMe)3 units perpendicular. The NMR spectrum shows that intramolecular rearrangements occur involving the tetrahedral deformation of one Pt center followed by rotation about the Pt—Pt bond.353 354... 

In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

The mechanism is believed to involve a prior formation of an imine by condensation of the amine with the aldehyde, followed by addition of the carboxylic acid oxygen and the imino carbon across the isocyanide carbon the resulting acylated isoamide rearranges by acyl transfer to generate the final product. 

In 1960, Hellmann and Opitz l realized that the majority of the previously discussed named reactions and other related processes are all a-aminoalkylations of nucleophilic compounds of sufficiently weak acids, corresponding to MCRs of type I, or they have secondary reactions of type II that are followed by the formation of heterocycles [the Hell-mann-Opitz three-component reaction (HO-3CR),t Scheme 2]. In 1921, Passerinih 47] jjj. troduced his three-component reaction (P-3CR), which involves the reaction of a carboxylic acid 7, a carbonyl compound 1, and an isocyanide 10, to form (via rearrangement of the first-formed product 11) an a-carboxy-substituted alkanamide 12 (Scheme 2). This was the first example of a MCR of type II that involved an isocyanide. 

The U-4CR converts carbonyl compounds 1, amines 2, a great variety of acid components 3 and isocyanides 13 into their ra-adducts 15, which then rearrange into different types of product 18 (Schemes 4.2 and 4.11) [6], The U-4CRs can form products which are structurally more different than those of other chemical reactions, mainly due to the different types of acid components involved 3 [8,10,72,73]. 

Preparation of cyanides.1 An attractive route to cyanides involves as the first step dehydration of alkylformamides with phosgene-tricthylamine (1,857) or phosphoryl chloride-diisopropylamine (13,249) to form isocyanidcs followed by isocyanidc-cyanide rearrangement. This rearrangement traditionally was conducted in the gas phase, but proceeds in almost quantitative yield when carried out by flash pyrolysis at 600°. This route to cyanides is attractive because allyl isocyanides rearrange without allylic rearrangement. Moreover, optically active carboxylic acids can be obtained from optically active amines without raccmization. 

The first examples of the 1,3-oxazete system (44) have been prepared by the sequence shown in Scheme 8. The first stable 4-imino-l,2-oxazetidines (45) have been obtained from [3 + 1] cycloaddition of isocyanides to N-neopent-ylidene-t-butylamine AT-oxide. Their chemistry is dominated by O—N bond cleavage for example, acid brings about rearrangement to amino-acid derivatives, and, in the presence of tetrahydroisoquinoline, cyclo-reversion to give imine and isocyanate can be detected. An unstable 1,3-oxazetidine is involved in the reaction of the imine (46) with the aldehyde (47) to give the imine (48). ... 

Moreover, on the basis of the abovementioned nucleophilic character of the BF anion, which readily fluorinates our metal centres, as indicated by our studies, and the recognition, by others [28b], of the involvement of aminocarbyne intermediates in the proton-induced reductive coupling of isocyanides, we are investigating the possibility of rearrangement (or reformulation)of compounds (7 ), derived from the protonation, by HBF, of the parent diisocyanide species, to the bis(methylamino)ace-tylene-f luoro complexes trans-[MF(n -MeHNCECNHMe) (dppe)2] [BF4] or related compounds [28c]. 

A new multi-component Ugi-Smiles coupling reaction of heteroaromatic phenols (pyridines and pyrimidines) 151 with carbonyl compounds 152, amines 153 and isocyanides 154 involves a Smiles rearrangement to form a library of heterocyclic scaffolds 155. The first Ugi-Smiles conversion of thiols 156 was also performed. The reaction of 156 with a carbonyl compound, an amine and an isocyanide afforded the desired product 157 at 80 °C. 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

Phenylketene generated by photochemical Wolff rearrangement in the presence of an acid anhydride and an isocyanate gives a 3-component reaction forming acrylamides 194, in a process involving ketene reaction with the isocyanide and then acylation by the carboxylic add (Eqn (4.123)). ... 

Ugi multi-component reactions of an amine, aldehyde, carboxylic acid and isocyanide (or the three-component variant with preformed imines) involve a Mumm rearrangement of an imidate in the final step, often considered the stereoselective step. However, experimental and computational evidence for kinetic control has now been reported in Ugi reactions of a o-pentose-derived pyrroline (52). The selective step is the formation of the imidate by the addition of isocyanide to the intermediate iminium ion, with the conformation of the latter determined by its substitution pattern. 

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