Isocyanides cycloaddition

Similar to the above reactions is the isocyanide cycloaddition which leads to the regio-specific synthesis of ethyl 5-aminoimidazole-4-carboxylates (104,105 Scheme 59). 

Pyrroles and their Benzo Derivatives Synthesis Table 2 Pyrroles by isocyanide cycloadditions. 

A series of 3-imino-2-aryl-l-azetines has been prepared by cycloaddition of nitrile ylides to isocyanides. Thus generation of the nitrile ylides (215) in the presence of cyclohexyl isocyanide gives the 3-cycIohexyIimino-2-aryI-l-azetines (205). Similar 1-azetines are formed by interception of nitrile ylides with a-methylbenzyl isocyanide (72AG(E)47) cf. Section 5.09.4.2.2). 

Aumann et al. showed that 1,2,4-tridonor-substituted naphthalenes, such as 126, are accessible from 3-donor-substituted propenylidenecarbene complexes 124 containing a (Z)-positioned 3-phenyl substituent and isocyanide (Scheme 26). These transformations constitute formal [5+1] cycloadditions [39, 89, 90]. Since isocyanides are strongly coordinating ligands on chromium, at least... 

The reaction of alkoxyarylcarbene complexes with alkynes mainly affords Dotz benzannulated [3C+2S+1C0] cycloadducts. However, uncommon reaction pathways of some alkoxyarylcarbene complexes in their reaction with alkynes leading to indene derivatives in a formal [3C+2S] cycloaddition process have been reported. For example, the reaction of methoxy(2,6-dimethylphenyl)chromium carbene complex with 1,2-diphenylacetylene at 100 °C gives rise to an unusual indene derivative where a sigmatropic 1,5-methyl shift is observed [60]. Moreover, a related (4-hydroxy-2,6-dimethylphenyl)carbene complex reacts in benzene at 100 °C with 3-hexyne to produce an indene derivative. However, the expected Dotz cycloadduct is obtained when the solvent is changed to acetonitrile [61] (Scheme 19). Also, Dotz et al. have shown that the introduction of an isocyanide ligand into the coordination sphere of the metal induces the preferential formation of indene derivatives [62]. 

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). 

Cycloaddition Reactions with Mesityl Azide, Diphenyldiazomethane, Isocyanides, and Benzonitrile... 

This silylene formation from 27 under mild conditions permits the synthesis of a variety of interesting carbo- and heterocycles, most of which are new types of compounds. The results are summarized in Schemes 5 and 6. The reactions with benzene and naphthalene represent the first examples of [2+1] cycloadditions of a silylene with aromatic C=C double bonds.59 623 The reactions with carbon disulfide and isocyanide (Scheme 6) are also of great interest because of their unusual reaction patterns.62b... 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

Besides isocyanides, Nair and coworkers also used carbenes to add to alkynes such as DMAD (9-90) leading to 1,3-dipoles, which can be trapped in a formal 1,3-dipolar cycloaddition (Scheme 9.21) [61]. Thus, the dimethoxycarbene 9-99, generated in situ through thermolysis of 9-98, reacts with DMAD (9-90) to give the dipole 9-100, which adds to an aldehyde 9-97 or a ketone. As the final product, dihydrofurans 9-101 are obtained in good yields. 

The application of the one-pot Ugi four-component reaction by stirring a mixture of the aldehyde 486, benzyl amine 487, isocyanide 479, and acrylic acid 385 in methanol at room temperature for 36 h afforded the triene 488 as a 74 26 mixture of amine rotational isomers in 80% combined yield. The triene 488 on heating in DMSO at 120 °C for 12 h underwent cycloaddition to give the tricyclic compound 489 as a single diastereomer in 98% yield (Scheme 111). 

The unstable 2-cyclopropylidene-l,3-cycloalkanediones 34a,c,d were trapped in situ by isocyanides 391 to give [4 + 1] cycloadducts under mild reactions conditions to afford 3-spirocyclopropane furans or pyrroles (Table 32) [95]. In the case of 34a, the primary cycloaddition products 392 and 394 decomposed very easily to give the stable pyrrolidindiones 393 and 395, respectively, as a single stereoisomer, upon addition of methanol (entries 1-2). Compounds 34c and 34d gave the expected adducts in moderate to good yields (Table 32, entries 3-7). 

Type Ilbd pyrrole syntheses fall into three general categories (1) Hinsberg-type (2) azomethine ylide cycloadditions and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594,06TL3755>. 

The formation of a diverse array of five-membered ring heterocycles via the cycloaddition of isocyanides with furan- or pyrrole-based enones was reported. The reaction mechanism is discussed and an example is shown below <06OL3975>. 

Intramolecular nitrile oxide cycloaddition. The conjugate addition of t-butyl isocyanide to a nitroalkene can generate a nitrile oxide, which can be trapped intramolecularly by a double bond to form an isoxazoline. 

For arylsulfonyl methyl isocyanides (3), [3 + 2] cycloadditions with aldehydes yielding 4,5-disubstituted oxazoles (N) have been reported [115]. The cycloaddition takes place in the same manner as with the use of isocyano esters (A, = H) ... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

The initial success with early transition metals, such as zirconium and titanium, reported by the Buchwald group, included an indirect cycloaddition between an enyne and isocyanides. The first protocol that used [Gp2Ti(PMc3)2] or Ni(GOD) together with triphenylphosphine failed to cyclize the enynes under the pressure of GO, but provided the cyclic imines with trialkylsilyl isocyanides, and bicyclic enones were obtained by hydrolysis of the resultant imine products (Equation (9)). ... 

Isocyanides, which are better candidates to react with dienes in a 1,4-fashion, were shown to cycloadd to 1-azadienes. Thus, the formation of isoindole derivative 15 as the major product (ca. 28% yield), upon treatment of benzoquinone 13 with two equivalents of p-tolyl isocyanide [81AG(E)982] was reported the reaction involves the insertion of the isocyanide carbon atom into the C—H bond of 13 leading to the 1-azadiene derivative 14, which in turn undergoes a [4 + 1] cycloaddition with a second isocyanide molecule (Scheme 4). 

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