Reactions Involving Isonitriles

This appears to be favored by the reaction involving isonitriles given in Section I,B,e. 

Finally, a novel three-component radical cascade reaction involving isonitriles has just been published [6]. In this paper, aromatic disulfides, alkynes, and isonitriles have been reported to react under photolytic conditions to afford -arylthio-substituted acrylamides 49 or acrylonitriles 50 in fair yields as mixtures of the E and Z geometric isomers (Scheme 21). The procedure entails addition of a sulfanyl radical to the alkyne followed by attack of the resulting vinyl radical on the isonitrile. A fast reaction, for example, scavenging by a nitro-derivative (route a) or f-fragmentation (route b), is necessary in order to trap the final imidoyl radical, since addition of vinyl radicals to isonitriles seems to be a reversible process. The reaction provides very easy access to potentially useful poly-functionalized alkenes through a very selective tandem addition sequence. 

REACTIONS INVOLVING ISONITRILES 11.4.1 Diastereoselective Passer ini Reaction... 

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

These reactions involve the addition across the C=N bond in isonitriles by the O-H or N-H bonds of alcohols or amines to form carbenes. The general reactions may be represented as Eqs. (7) and (8) ... 

With Aralkyl- or Wacylpyridinium salts, the addition of isonitriles takes place efficiently when a carboxamido group is present in the 3-position. The outcome of the reaction involves the stabilization of the nitrilium intermediates by the amide, which suffers a mild dehydration providing 3-cyano-4-carbamoyl-l,4-dihydropyridines. This method also works with the corresponding Wacylquinolinium and Wacylisoquinolinium salts (Equation 58) <2006OL5789, 2004JOC3550>. 

A synthesis of a set of 2-pyridylpyrroles has been described, involving annulation of 1,3-dicarbonyl compounds with 2-(aminomethyl)pyridine under acidic conditions, as illustrated by the construction of compound 437 (Equation 121) <20020L435>. Likewise, pyrroles have also been obtained from reactions between 1,3-diaryl-l,3-dicarbonyl compounds and imines or oximes promoted by the TiCU/Zn-system <2004SL2239>. Yet another approach involves rhodium-catalyzed reactions of isonitriles with 1,3-dicarbonyl synthons, which enables for instance preparation of fluorinated pyrroles <20010L421>. 

Good yields and purities were obtained for the two examples shown. Ugi reaction using solid-supported benzenesulfonamide, prepared by coupHng 4-carbox-ybenzenesulfonamide onto Rink resin, has also been described. The sulfonamide took the place of the amino component in the classical Ugi MCR. An extension of this Ugi reaction involving a support-bound amine, furfural, and an isonitrile and an acrylic acid was used by Schreiber [307] to generate support-bound dipeptides capable of performing intramolecular Diels-Alder reactions (see Section 4.5.9). 

In another example of multi-component reactions involving Diels-Alder cycloadducts, Zhu and coworkers found that a mixture of an amine, an aldehyde, and isonitrile 141 led to oxazole 142 when the reaction was carried out in the presence of a mild acid catalyst (Scheme 26) (02JA2560). Further reaction of 142 with a variety of a, 3-unsaturated acid chlorides produced Diels-Alder substrates 143 that underwent cyclization to give bridged ethers 144. Ring opening with concomitant loss of morpholine afforded 145 that rapidly tautomerized to give 146 in 32-75% yield. 

Aminopyridines can be used in other ways copper-catalysed interaction with diazo-ketones and three-component reactions involving an isonitrile and an aldehyde also give imidazo[l,2-a]pyridines such condensations can be promoted using an ionic liquid" or scandium triflate with microwave heating." In the former route, 2-substituted products result and from the latter, 3-aminoimidazo[l,2-a]pyridines are formed. 

Murahashi described a new pyrrole synthesis involving a rhodium complex-catalyzed reaction of isonitriles (e.g., 3) with 13-dicarbonyl compounds 4 to afford the pyrroles 5 <01OL421>. This process is believed to proceed by chemoselective activation of the a-C-H bond of the isonitrile even in the presence of the more acidic dicarbonyl derivative. 

Initially, Passerini proposed that the reaction involved an addition of carboxylic acid to carbonyl compound, giving acyloxy hemiacetal, which then reacted with isonitrile to form the final product. However, current views about this reaction favor the following consecutive processes the protonation of the carbonyl compound from carboxylic acid, followed by the attack of isonitrile to give a nitrilium ion, the nucleophilic addition of carboxylate, acyl group transfer, and the final amide tautomerization. A general mechanism for this reaction is shown here. ... 

The number of molecules that participate as reactants in an elementary reaction defines the molecularity of the reaction. If a single molecule is involved, the reaction is unimolecular. The rearrangement of meth)d isonitrile is a unimolecular process. Elementary reactions involving the collision of two reactant molecules are bimolecular. The reaction between NO and O3 is bimolecular. Elementary reactions involving the simultaneous collision of three molecules are termolecular. Termolecular reactions are far less probable than unimolecular or bimolecular processes and are rarely encountered. The chance that four or more molecules will collide simultaneously with any regularity is even more remote consequently, such collisions are never proposed as part of a reaction mechanism. 

T3506). Similarly, 2-halobenzaldehydes, isonitriles, amines, and propar-gylic acids underwent Ugi reaction, then copper(I)-catalyzed alkyne—azide 1,3-dipolar cycloaddition, and then intramolecular Ullmann-type triazole N-arylation to afford triazolo-flised benzodiazepines such as 136 (13EJ01223). Similar reactions involving a post-Ugi lactamization or a post-Ugi intramolecular imination process delivered benzo-l,4-diazepin-2,5-dione derivatives or 4,5-dihydro-3H-l,4-benzodiazepine derivatives (13ACO202,13T9056). 

Scandium catalysts were often used in combinatorial organic synthesis. For library production of a-amino amidines, multicomponent reactions involving aldehydes, amines, and isonitriles (3CC Ugi condensation) were developed using Sc(OTf)3 as catalyst (Scheme 12.28). A set of amino amidines was synthesized by this method in good to excellent yields [63]. 

Migratory Insertion Reactions Involving CO, CO2 or Isonitriles. DF calculations on the reaction of CO with Cp2ZrMc2 show that CO binds laterally and... 

Many novel cluster compounds have now been prepared in this way, including mixed metal clusters. Further routes involve the oxidative fusion of dicarbon metallacarborane anions to give dimetal tetracarbon clusters such as (103) and (104) O (jjg insertion of isonitriles into inetallaborane clusters to give monocarbon meiallacarboranes such as (105) and the reaction of small ii/t/o-carboranes with alane adducts such as Et3NAlH3 to give the commo species (106) ... 

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). 

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