Cycloaddition of azomethine ylides with

Scheme 10.10 1,3-Dipolar cycloadditions of azomethine ylides with maleimides in the...

In addition to cydocondensation reactions of the Paal-Knorr type, cycloaddition processes play a prominent role in the construction of pyrrole rings. Thus, 1,3-dipo-lar cycloadditions of azomethine ylides with alkene dipolarophiles are very important in the preparation of pyrroles. The group of de la Hoz has studied the micro-wave-induced thermal isomerization of imines, derived from a-aminoesters, to azomethine ylides (Scheme 6.185) [346]. In the presence of equimolar amounts of /i-nitrostyrenes, three isomeric pyrrolidines (nitroproline esters) were obtained under solvent-free conditions in 81-86% yield within 10-15 min at 110-120 °C through a [3+2] cycloaddition process. Interestingly, using classical heating in an oil bath (toluene reflux, 24 h), only two of the three isomers were observed. 

Only a few examples of the [3 + 2] cycloaddition of thiocarbonyl ylides with C=N compounds have been reported so far. By comparison with aldehydes, imines are poor dipolarophiles. For example, Al-benzylidene methylamine and adamanta-nethione (5)-methylide (52) produce 1,3-thiazolidine (129) in only 13% yield (163). An alternative and efficient approach to 1,3-thiazohdines involves the [3 + 2] cycloaddition of azomethine ylides with thiocarbonyl compounds [cf. (169)]. 

The stereochemistry of 1,3-dipolar cycloadditions of azomethine ylides with alkenes is more complex. In this reaction, up to four new chiral centers can be formed and up to eight different diastereomers may be obtained (Scheme 12.4). There are three different types of diastereoselectivity to be considered, of which the two are connected. First, the relative geometry of the terminal substituents of the azomethine ylide determine whether the products have 2,5-cis or 2,5-trans conformation. Most frequently the azomethine ylide exists in one preferred configuration or it shifts between two different forms. The addition process can proceed in either an endo or an exo fashion, but the possible ( ,Z) interconversion of the azomethine ylide confuses these terms to some extent. The endo-isomers obtained from the ( , )-azomethine ylide are identical to the exo-isomers obtained from the (Z,Z)-isomer. Finally, the azomethine ylide can add to either face of the alkene, which is described as diastereofacial selectivity if one or both of the substrates are chiral or as enantioselectivity if the substrates are achiral. 

Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2//-pyrroles with moderate to good yields.68 The Pt(II)-or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3-dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4C104-Taniaphos with nearly complete exo- selectivity and enantioselec-tivities up to 85% ee.10 The 3 + 2-cycloaddition of benzol/>]thiophene 1,1-dioxide... 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

There are some examples known for the cycloaddition of azomethine ylides with nonactivated olefins such as aryl-substituted olefins, strained olefins, acyclic or cyclic olefins, and electron-rich olefins. Stabilized ylide 79 (R = H, R = Et, R = Me), bearing an ester moiety as the only C substituent, can be successfully trapped with styrene when generated by the deprotonation route (Section II,D) from ethyl sarcocinate and paraformaldehyde under reflux in toluene, to give 194 as a mixture of two regioisomers (86CL973). 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

Scheme 5.17 Mechanism for copper(l)-zeolite catalysed cycloaddition of azomethine ylide with activated alkyne ...

The first chiral thiourea-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes 210 was reported by Gong, et. al., Scheme 3.68 [85], This reaction afforded highly substituted pyrrolidines 212 with high diastereo-selectivities and moderate enantioselectivities. 

The 1,3-dipolar cycloadditions of azomethine ylides with aldehydes readily produced high yields of oxazolidines, which hydrolysed to anti a-amino-y -hydroxy esters." Non-stabilized azomethine ylides with isotonic anhydrides produced oxa-zolidine intermediates, which were converted into l,3-benzodiazepin-5-ones via ringopening-decarboxylation-ring-closing reaction cascades." ... 

Cycloadditions of Azomethine Ylides with Electron-Deficient Alkenes... 

In 2010, Carretero and co-workers described the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ( )-p-phenylsulfonylenones (Scheme 1) [9]. In the presence of chiral Cu(I)-SEGPHOS catalysts, high reactivity, selectivity, and broad substrate scope were observed. Interestingly, a reversal firom endo- to exo-diastereoselectivity occurred when SEGPHOS or DTBM-SEGPHOS was employed as the ligand, respectively. This work expanded the scope of [3+2]... 

Scheme 2 Asymmetric [3+2] cycloaddition of azomethine ylides with cyclic enones and dimethyl maleate...

In 2011, Wang and co-workers successfully realized the catalytic asymmetric [3+2] cycloaddition of azomethine ylides with fra 5-4,4,4-trifluorocrotonate (Scheme 3) [12]. The Cu(MeCN)4BF4/TF-BiphamPhos catalytic system exhibited excellent performance in catalyzing this reaction, affording trifluoromethylated pyrrolidines in high yield with excellent diastereo- and enantioselectivity. Highly efficient epimerization of the kinetically favored c/Kfo-cycloadducts obtained from cis-A,A,A-... 

Scheme 3 Asymmetric [3-1-2] cycloaddition of azomethine ylides with trani-4,4,4-trifluoro-crotonate and methyl a-fluoroacrylate...

Wang and co-workers also developed the first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with readily accessible Morita-Baylis-Hillman adduct as the dipolarophUe catalyzed by Cu(l)/TF-BiphamPhos complex, which provides a facile access to a new kind of highly substituted pyrrolidine derivatives bearing a unique quaternary and two tertiary stereogenic centers in excellent diastereoselectivity and up to 97% ee (Scheme 6) [16]. Recently, the asymmetric [3+2] cycloaddition employing dimethyl itaconate and 2-methyleneglutarate as dipolarophiles was also realized with this catalytic system (Scheme 6) [17]. 

Guo and co-workers reported a highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with p-nucleobase-substituted acrylates as dipolarophiles using 1 mol% of a chiral Cu(I) complex, which provides the first rapid and divergent access to various enantioenriched azacyclic nucleoside analogues in high yields with excellent exo-selectivities and enantioselectivities (Scheme 8) [19]. In addition, other p-heteroarylacrylates such as pyrimidine-, benzimidazole-, imidazole-, benzotriazole-, and indole-substituted acrylates are also suitable... 

Most recently, Carretero and co-workers described the first example of the Cu (I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acyclic activated 1,3-dienes (Scheme 13) [25], This cycloadditiOTi occurs selectively at the terminal C=C bmid of the dienes, and the exo-adducts could be obtained with high diastereocOTitrol and excellent enantioselectivity. 

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