Isonitriles condensations with

Rikimaru K, Yanagisawa A, Kan T, Fukuyama T (2004) A versatile synthesis of a-amino acid derivatives via the ugi four-component condensation with a novel convertible isonitrile. Synlett 1 41-44... 

A further strategy used to prepare amides on insoluble supports is based on the Ugi reaction (Figure 13.8). Simple mixing of an amine, an aldehyde, an acid, and an isonitrile can lead to the formation of a-amino acid amides. The mechanism of this remarkable reaction is outlined in Figure 13.8. Sometimes, the amine is first condensed with the aldehyde to form an imine, which is then combined with the acid and the isonitrile. 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

Syntheses using four-component condensation with isonitriles 82AG826. 

The conversion of isothiocyanates to isonitriles on polymer-supported [l,3,2]oxa-phospholidine under microwave conditions has been intensively studied [114]. Commercial Merrifield resin was treated with aminoethanol and the resulting precursor was condensed with bis(diethylamino)phosphine in anhydrous toluene to generate the desired polymer-supported reagent. When using the novel solid-... 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

The contribution of the carbene-like structure to isonitrile molecules renders them electrophilic as evidenced by condensation with active methylene compounds (36a) and phenols (36b). 

The synthesis of hydrastine (61) by Falck and Manna demonstrate that the amide product of the Passerini reaction could be used in a subsequent Bischler-Napieralski reaction as a method to produce isoquinolines. In their report, carboxybenzaldehyde derivative 62 was condensed with isonitrile 63 in 71% yield to provide amide 64. Cyclization (POCI3/CH3CN), reduction of the dihydroisoquinoline (Adam s catalyst/H2), and reductive alkylation with formaldehyde gave a diastereomeric mixture of a- and p-hydrastines in 58% overall yield from Passerini product 64. 

Carbonyl protection and deprotection is also important. Yoshihisa Kobayashi of the University of California, San Diego has devised (/. Org. Chem. 2007, 72, 3913) the isonitrile 15. Usually, the product 16 after Ugi condensation would he very difficult to hydrolyze. In the case of 16, mild acid effected cyclization to the acyl indole 17, which was easy to hydrolyze. In a different approach, Francesco Naso of the Universita di Bari has shown (Chem. Commun. 2007, 3756) that acid chlorides such as 18 condensed with 19 to give the furan 20. Such fiirans are easily oxidized, liberating the starting acid. 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Another method for preparing pyrrole rings is by Ugi-type three-component condensation (Scheme 6.184). In the protocol published by Tye and Whittaker [345], levulinic acid was reacted with two different isonitriles and four amine building blocks (1.5 equivalents) to provide a set of eight pyrrole derivatives. While the previously published protocol at room temperature required a reaction time of up to 48 h and provided only moderate product yields, the microwave method (100 °C, 30 min) optimized by a Design of Experiments (DoE) approach (see Section 5.3.4), led to high yields of the desired lactams for most of the examples studied. 

For this purpose, perfluorooctanesulfonyl-tagged benzaldehydes were reacted with 1.1 equivalents of a 2-aminopyridine (or 2-aminopyrazine), 1.2 equivalents of an isonitrile, and a catalytic amount of scandium(III) triflate [Sc(OTf)3] under micro-wave irradiation in a mixture of dichloromethane and methanol (Scheme 7.85). A ramp time of 2 min was employed to achieve the pre-set temperature, and then the reaction mixture was maintained at the final temperature for a further 10 min. The fluorous tag constitutes a multifunctional tool in this reaction, protecting the phenol in the condensation step, being the phase tag for purification, and serving as an acti-... 

Pinen—3a-ol, 53, 17 fcrans-Pinocarveol, 53, 17 Pivalaldehyde, by condensation of tert-butylmagnesium bromide with 1,1,3, 3-tetra-methylbutyl isonitrile, 51, 38... 

Benzaldehyde, by condensation of phenyllithium with 1,1,3,3-tetra-methylbutyl isonitrile, 51,38 by reduction of benzonitrile with Raney nickel alloy, 51,22 BENZALDEHYDE, 3,4,5-TRIMETH-OXY-, 51,8... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

A further method for preparing hydantoins is the N-alkylation of other hydantoins with reactive alkyl halides in the presence of strong bases [154]. Hydantoinimines have been synthesized from polystyrene-bound isonitriles by an Ugi-type multicomponent condensation (Entry 15, Table 15.13). 

Condensation of an MSMA isonitrile with an aroylfluoride gives a salt which undergoes loss of trimethylsilyl fluoride to form a nitrile ylid. This transient species reacts with DMAD to form 2-aroyl pyrrole in high yield.162 Substitution of acyl chloride for acyl fluoride in the reaction affords only poor yields of adducts.465... 

Isonitriles also react with CpWCl(CF3C=CCF3)2 and CpMo-(CF3C=CCF3)2CF3 to form C5 rings (98). Condensation of the two alkynes with RNC to form Tj4-cyclopentadienimines [Eq. (64)] mimics the CO... 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

In Ugi s four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [5, 6] a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, 5f. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-... 

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