Isocyanide reactions between

Reaction between isocyanides, acids, amines, and aldehydes or ketones (Ugi)... 

Oiganic synthesis 65 [OS 65] 4CC reaction between aldehyde, primary amine, acid and isocyanide... 

Oiganic synthesis [OS 66] Ugi reaction between aldehyde, secondary amine salt and isocyanide... 

Modern MCRs that involve isocyanides as starting materials are by far the most versatile reactions in terms of available scaffolds and numbers of accessible compounds. The oldest among these, the three-component Passerini MCR (P-3CR), involves the reaction between an aldehyde 9-1, an acid 9-2, and an isocyanide 9-3 to yield a-acyloxycarboxamides 9-6 in one step [8], The reaction mechanism has long been a point of debate, but a present-day generally accepted rational assumption for the observed products and byproducts is presented in Scheme 9.1. The reaction starts with the formation of adduct 9-4 by interaction of the carbonyl compound 9-1 and the acid 9-2. This is immediately followed by an addition of the oxygen of the carboxylic acid moiety to the carbon of the isocyanide 9-3 and addition of this carbon to the aldehyde group, as depicted in TS 9-5 to give 9-5. The final product 9-6 is... 

R = Bu , Pr, p-ClC H, or p-MeCeH4) have been isolated from the reaction between free isocyanide and a variety of Ir substrates. Studies of the oxidative addition reaction ... 

Group IV Donors. A new class of Pt complex of the formula [Pt(PPh3)2-(CNBu )] has been isolated from the reaction between [Pt(PPh3)2(C2H4)] and free isocyanide. Further treatment with CO gave [Pt(PPh3)2(CNBu )(CO)], and comparison of the v(NC) frequencies in these two new complexes suggests that CO is a more effective ji-acceptor than the isoelectronic isocyanide. Oxidative addition reactions were also reported. ... 

Reaction between aldehydes or ketones, zinc, and halo amides 6-41 Reaction of aldehydes with the conjugate base of formamide reaction of ketones with imines 6-67 Reaction between isocyanides, TiCI4 and aldehydes or ketones, followed by hydrolysis... 

In a competing reaction between bonded carbonyls and isocyanides with amines, amine attack on the carbonyl appears to be much more rapid than on the isocyanide. However, as the electron density on the metal, and hence on the carbonyl carbon increases the tendency to react with amines de-... 

Pyrane derivatives were obtained through a stereoselective isocyanide-based multicomponent reaction. The reaction between an isocyanide, a dialkyl acetylene-... 

Another approach to a-ketoamide peptide mimetics was employed by Xu et al. [33] for the preparation of a human cytomegalovirus protease inhibitor library. In this case the oxidizable -OH group, protected as formate, belonged to the starting isocyanides. Thus, the reaction between N-acylated a-amino acids, amines, aldehydes, and isocyanides 42 afforded the a-hydroxyamides 43 in modest yields. Cleavage of the O-formyl bond was accomplished during the reaction by employing two... 

The Passerini reaction between a-chloroketones, isocyanides, and carboxylic acids afforded a-acyloxy-jS-chlorocarboxamides 52, which, on treatment with an excess of powdered KOH in tetrahydrofuran, underwent O-deacylation followed by a Darzens-type O-alkylation to give the functionalized oxiranes 53. When carboxamides 52 were treated with an excess of CsF, with or without a phase-transfer catalyst, a different ring closure took place to afford 3-acyloxy-2-azetidinones 54 in high yields (Scheme 2.21) [46]. 

Another synthesis of the butenolide core was reported by the Domling group [54], The reaction between arylglyoxals, isocyanides, and a-diethylphosphonoalkanoic... 

An interesting route to indazolinones was reported by Tempest and co-workers [58]. The reaction between 2-fluoro-5-nitrobenzoic acid, aldehydes, isocyanides,... 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

Analogously, the reaction between phenylglyoxal, isobutylamine, n-butyl isocyanide, and benzoic acid afforded 3-oxo-3-phenylpropanoic amide 85 which was cy-clized to diphenylimidazol-5-carboxamide 86 in very high yield (Scheme 2.31) [60], The procedure was extended to solid-phase synthesis by employing resin-bound isocyanides. Wang resin was preferred to Rink resin because of its stability. The reaction of the resin-bound isocyanides 87 with supporting Ugi reagents afforded the... 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

Rossen et al. [71a] has reported a synthesis of piperazine 113, a key intermediate in the synthesis of the HIV protease inhibitor Crixivan . The reaction between a preformed imine 110, f-butyl isocyanide, and formic acid afforded the Ugi product 111, which was dehydrohalogenated with triethylamine and cyclized with KO Bu to the tetrahydropyrazine 112. Catalytic hydrogenation in the presence of Rh-BINAP (97% ee) and deformylation with aqueous hydrazine gave the target piperazine 113 (Scheme 2.40). 

The Ugi-4CR provides straightforward access to precursors of the pyrazine ring that are suitable for a Davidson cyclization [72], The reaction between arylglyoxals, amines, isocyanides, and benzoylformic acid in ether afforded adducts 114, which cyclized on treatment with an excess of ammonium acetate in acetic acid to give pyrazine carboxamides 115 (Scheme 2.41). 

Zhu et al. [103] reported a fadle access to biologically relevant macrocycles bearing an endo diaryl ether bond by means of a tandem Ugi-4CR/SNAr. The reaction between 3-hydroxyphenylacetic [or 3-(3-hydroxyphenyl)propionic] acid, aldehydes, amines, and isocyanide 197 gave the expected dipeptide derivatives 198 as a 1 1 mixture of diastereoisomers. The reaction gave high yields when performed in tri-... 

Early findings by Suzuki and co-workers [109] showed that the palladium-catalyzed iminocarbonylative cross-coupling reaction between 9-alkyl-9-BBN derivatives, t-butylisocyanide, and arylhalides gives access to alkyl aryl ketones 132 after hydrolysis of the corresponding ketimine intermediates 131. Presumably, the concentration of free isocyanide is kept to a minimum by its coordination with the borane. Formation of an iminoacylpalladium(II) halide 130 by insertion of isocyanide to the newly formed arylpalladium complex followed by a transmetallation step afford the ketimine intermediates 131 (Scheme 8.52). 

This three-component reaction between a carboxylic acid, a carbonyl compound such as a ketone or aldehyde, and an isocyanide, offers direct access to a-hydroxy carboxamides. 

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