Isonitrile cycloaddition

TosMIC reagents. For example, glyoxylic acid ethyl ester undergoes cycloaddition with (2-naphthyl) tosylmethyl isonitrile (17) to produce oxazole 18 in good yield. ... 

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 only examples dealing with [4 + 1] cycloadditions of alkylidenecyclo-propanes involve the additions of isonitriles to diacylmethylenecyclopropanes. 

An elegant method for the preparation of some cyclopropenone imines reported by Krebs118 is the (1 + 2) cycloaddition of isonitriles (as divalent carbon species) to activated triple bond of ynamines and certain cycloalkynes, e.g. ... 

Cycloadditions on a ruthenium(n) complex between 2 equiv. of phenylacetylene and various types of isonitriles were described for the first time by Singleton.367 3673 These transformations were shown to proceed through coordinatively unsaturated ruthenacycle intermediates to furnish the corresponding imino-2,5-diphenylcyclopentadiene complexes. 

Isonitrile complexes, having a similar electronic structure to carbonyl complexes, can also react with nucleophiles. Amino-substituted carbene complexes can be prepared in this way (Figure 2.6) [109-112]. Complexes of acceptor-substituted isonitriles can undergo 1,3-dipolar cycloaddition reactions with aldehydes, electron-poor olefins [113], isocyanates [114,115], carbon disulfide [115], etc., to yield heterocycloalkylidene complexes (Figure 2.6). 

Upon reaction of A -vinyliminophosphoranes (109) with aromatic isocyanates, vinylcarbodiimides (110) are formed, as shown in Scheme 47. Divi-nylcarbodiimides (111) can be obtained as side products (88CB271). With isonitriles the vinylcarbodiimides also afford pyrroles (112) via [4 + 1]-cycloaddition. Divinylcarbodiimide can also react via [4 -l- l]-cycloaddition with an isonitrile, whereupon an electrocyclic step of the initial diaza-1,3,5-trienes (113) follows. Finally, the pyrrolo[2,3-e]pyrazine 114 is obtained (88CB271). 

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

The formation of bicycles 88 occurred through the iminium intermediate 89, in the similar manner as Ugi-reaction. But in contrast to the four-component classical Ugi-reaction, the protonated Schiff base 89, containing both nucleophilic and electrophilic centers, undergoes [4+1] cycloaddition with isonitrile to the bicyclic adduct 90 followed by rearomatization via 1,3-H shift (Scheme 39). 

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]. 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

Other important pyrrole syntheses of this type are cycloadditions involving mesoionic oxazolium 5-oxides, azomethine ylides or isonitriles, e.g. (145 +146 — 147) or (148 +149 — 150). 

Reactions between 5-cyanotetrazole and transition metals, when performed in boiling acetone, lead to hydrolysis of the cyano group and formation of 5-carbamyl tetrazolate complexes (68). Complexes containing 1- or 5-substituted tetrazolate anions can also be obtained by 1,3-dipolar cycloaddition of organic isonitriles (RNC) (15) or nitriles (RCN) (61), respectively, to coordinated azide ligands [Eqs. (3) and (4)]. 

R CO-5-R-ttaH) tetrazoles, respectively (114). The azide Pd(N3)2-(PPh3)2 also undergoes 1,3-cycloaddition reactions with organic isonitriles (RNC) (15) and isothiocyanates (RNCS) (114) to afford the complexes 42 and 43 (M = Pd), respectively. N-l-Coordinated tetrazolate chelate complexes 44 and 45 are formed by treatment of... 

Interesting synthetic applications of the [4+4] and [4+4+4] cycloadditions are reported. A novel, short-step synthetic method of muscone (24) has been developed using complex 10 as a starting compound [7]. Insertion of allene to the Ni-carbon bond in 10 at low temperature gives the bis-7r-allylnickel 22. Then isonitrile is inserted to 22. When the reaction mixture is warmed, the 15-membered cyclic compound 23 is formed by reductive elimination, and conversion of 23 to muscone (24) is achieved by hydrolysis and subsequent hydrogenation in 43 % overall yield. 

The synthetic reactions of nucleophilic carbenes have been reviewed.11 Isonitriles, dimethoxycarbene, and NHCs are covered. The review focuses on the 1,3-dipolar cycloaddition reactions made possible when the nucleophilic carbene reacts with electrophiles such as dimethylacetylene dicarboxylate. Such reactions were also the subject of research papers during 2005 (see the section on nucleophilic and basic carbenes). 

Insertion into two P—C bonds and isonitrile cycloaddition occur with phosphorus tricyanide (240). 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

The azido hgand is particularly versatile as a leaving group, as the displacement is acid catalyzed. Coordinated azide ligands also have the potential to react via 1,3-dipolar cycloaddition with organic isonitriles or nitriles to give 1- or... 

Isomerization of enyne-isonitriles to enallene-isonitriles resulted in a formal [4 -F 1] cycloaddition to indenoquinolines <03OL3277>. Starting material is prepared in two steps. Application to other related systems resulted in low yields and/or exclusive formation of indoles. 

The isolation of cyclopentanecarboxylates from 1,3-diiodopropane and an acrylate in the presence of metallic copper and an alkyl isonitrile has been reported by Saegusa and coworkers (equation 39). The reaction is proposed to involve formation of a transient 3-iodopropylcopper-isonitrile complex (47) from the diiodopropane, which then adds to the unsaturated ester in a Michael fashion (equation 40). The nonconcertedness of this reaction results in stereoselective cycloaddition. For example, Iratfa diethyl ma-leate and fumarate produce the same cyclopentane adduct in identical yields (equation 41). The generality of this cycloaddition has not been explored. 

Ketenimine complexes can serve as three-atom components in [3 + 2] cycloadditions. The reaction of the tungsten complex (378) with cyclohexyl isonitrile and phenyl isocyanate produces the heterocyclic carbene complex (379), which is the result of the in situ trapping of a ketenimine complex with the isocyanate. Complexes of the type (379) can be oxidatively cleaved to give the previously inaccessible 5-ethoxyhydantoins. [3 + 2] Cycloadditions of this type have also been carried out with aldehydes. 

The reactions of alkenyl carbene complexes with isonitriles can produce a variety of products whose distribution is sensitive to the nature of the isonitrile. Reacting 3 equiv. of aryl isonitrile with the alkenyl complex (383) produces the dihydro- y-carbolinone (385). 74 The ketenimine in (384) is liberated with a second equivalent of the isonitrile, and the the third equivalent undergoes a formal [4 -i- 2] cycloaddition with the free ketenimine. With sterically encumbered isonitriles, the ketenimine is more rapidly liberated from the metal by a second isonitrile and 2 equiv. are required to drive the reaction to completion. Free ketenimines that are generated in this manner can be trapped via their [4 + 2] cycloadditions with maleic anhydride. 7 Primary and secondary alkyl isonitriles will react with alkenyl carbene complexes to give cycloadducts that can be converted to pyrroles or products that contain five-member ring carbo-cycles. 7 ... 

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