Reactions of an Isonitrile

Insertion Reactions into Element-Nitrogen and Heavier Group VB Bonds 11.4.3. Geminal (or 1,1-) Addition of an Amide 11.4.3.1. Insertion Reactions of an Isonitrile... 

Second, if we consider computational docking as a suitable option to complement experimental screening, the major advantage is the very large number of potential ligands that can be evaluated. For example, if we consider a simple chemical reaction such a the four-component Ugi-reaction [16], a reaction of an isonitrile Ri—NC, an aldehyde, R2—CHO, an amine R3—NH2 and a carboxylic acid R4—COOH, the use of 100 isonitriles, 1000 aldehydes, 1000 amines and 1000 carboxylic acids allows for the formation of 10 Ugi-Products - at least in theory. 

Scheme 10.2 Stabilization of the isoimide intermediate 5 generated by the reaction of an isonitrile with a carboxylic acid...

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

The best results in the imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the appropriate amines. Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

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-... 

Rhodium-catalyzed reactions of diynes and an isonitrile give rise to iminocyclopentadienes (Equation (68)).421 Portionwise addition of the isonitrile (5 x0.2equiv.) was found to increase the yield. The reaction may proceed through formation of metallacyclopentadienes followed by insertion of an isonitrile molecule. 

The reaction of alkoxy(aryl)carbene iron complexes with two equivalents of an isonitrile leads to the formation of azetidin-2-ylidene complexes [197]. For other reactions of Fischer-type carbene complexes with isonitriles see [198]. 

Mechanisms of the manifold reactions of a-dialkylamino alkyllithium intermediates R(Me2N)CLiNu, formed when tertiary amides (RCONMc2) react with PhMc2SiLi followed by a second lithium reagent NuLi, have been discussed. The formation of diverse products following 1 1 insertion of an isonitrile RNC into the Li-C bond of LiCH(SiMc3)2 has been discussed. ... 

The problem of to what extent and how the reactivity of the isonitrile ligand is altered by coordination to a metal has an important bearing on the function of transition metals as homogeneous catalysts. It is also of interest from the standpoint of energy transfer in vivo, to determine whether or not there is any correlation between the reactivities of isonitrile complexes and their conductivities. In this paper we summarize some recent work on the syntheses and reactions of iron isonitrile complexes. 

Synthesis of cyclopropanes. Cyclopropanes can be synthesized in fair yield by the reaction of an olefin with an a-chloro compound catalyzed by coppcr(I) oxide t-butyl isonitrile. 

As outlined in Scheme 8, a synthesis of l,6aA -dithia-6-azapentalenes 94a-d from dithioles 93a-d and isonitriles is an example of utilization of the HCl formed in a catalytic amount from phosphoryl chloride and moisture in the air. The liberated acid and isonitrile produce the reactive electrophilic species 97 that reacts with the dithiole giving rise to the intermediate, cycloaddition product 96, which then leads to final product via release of HCl. An alternative mechanism was also considered, implying that the a-addition reaction of the isonitrile to the dithiolylium halide 95, obtained by protonation of 1,2-dithiole 93, gives rise to the intermediate salt and then to the final product <1997HAC479>. 

The reaction has also been carried out under alkaline conditions, with hydroxide in aqueous dioxane. The mechanism here involves nucleophilic attack by hydroxide at the carbon atom. An intramolecular addition of an alkyne (in an ortho alky-nyl phenyl isonitrile) to the carbon of an isonitrile occurred with heating in methanol to give quinoline derivatives. ... 

Passerini reaction. Formation of 2-acyloxy amides on treatment of an isonitrile with a carboxylic acid and an aldehyde or ketone. 

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). 

The IBX-mediated oxidative Ugi-type multicomponent reaction of tetrahydroisoquinoUne with isocyanides and carboxylic acids affords the nitrogen- and carbon-functionalized tetrahydroisoquinolines 867 in good to excellent yields [1184]. Likewise, the three-component Passerini reaction of an alcohol, carboxylic acid and an isonitrile in the presence of IBX affords the corresponding a-acyloxy carboxamides 868 in generally high yields (Scheme 3.347) [1185]. 

The versatility of our reaction planning algorithms is demonstrated in our third example. The design of an isonitrile preparation method exemplifies the fact that reactions can be designed for specific purposes. 

This category consists of 5 conceivable basic reactions (see Figure 4). However only two of them comply with an isonitrile substructure. Introducing the suitable elements and substituents into these two basic reactions yields three possible specific reactions for an isonitrile synthesis. 

Our historical account would be incomplete without a few words about the surprisingly original four center condensation (4CC) method of Ivar Ugi [60]. The reaction of an acylamino acid, or peptide with an amine, an aldehyde and an isonitrile leads to a peptide derivative... 

After a series of control experiments carried out excluding the effect of the Br0nsted acidity of the capsule and the involvement of the OH functional groups of the resorcin[4]arene, the effect of the cavity on the catalytic supramo-lecular hydration reaction was confirmed. In order to further substantiate this hypothesis, experiments were carried out repeating the hydration reactions of several isonitriles in the presence of the capsule and with an excess of tetraeth-ylammonium as competitive guest, observing in all cases a marked decrease of the formation of the corresponding formamides. 

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