Azomethine yhdes cycloaddition

Further studies into the constmction of pyrrolo[l,2-a]indoles, however, revealed that the presence of a nitrile functionahty was not essential to the reaction (3). Subjecting precursor 13 to yhde formation by AgF (it should be noted that this was the only reagent to induce cycloaddition to any extent) in the presence of N-phenyhnaleimide surprisingly furnished adduct 14 in which the nitrile functionality was stiU intact. The reaction pathway was therefore assumed to proceed via initial formation of the silver bonded cation 15, which after desilyation generated the requisite silver bound azomethine yhde. Cycloaddition followed by sequential loss of silver and a hydrogen delivered the observed products. Replacement of the nitrile moiety with alternative functionalities also generated the expected products in good isolated yields (Scheme 3.4). 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

Treatment with amines of the type 279 generated the intermediate oxazolidinone 280, which underwent thermal decarboxylative formation of the azomethine yhde. Subsequent in situ intramolecular cycloaddition formed the products 281 and 282 in 63% yield and in a 1 1.2 ratio for n=l. Replacing toluene for acetonitrile, for n = 2, gave comparable yields and an improved ratio of 1 2.1 in favor of 281 (Scheme 3.93). 

The above azomethine ylide cycloadditions have been extended to an enantioselective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine yhdes derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Upon heating, aziridine 191 opened in the conrotatory manner to give azomethine yhdes 192 and/or 193, which underwent 1,3-dipolar cycloaddition reactions with alkenes and acetylenes. With styrene, for example, pyrrolidine 194 was formed exclusively in 81 % yield, and the regiochemistry of the cycloaddition was ascribed to control by the LUMO of the electron-deficient azomethine ylide. The cis relationship of the phenyl and benzoyl groups was attributed to secondary orbital interactions between them in the transition state. 

Bonini, B.F. Boschi, F. Franchini, M.C. Fochi, M. Fini, F. Mazzanti, A. Ricci, A. First 1,3-dipolar cycloaddition of azomethine yhdes with ( )-ethyl 3-fluoroacrylate regio- and stereoselective synthesis of enantiopure fluorinated prolines. Synlett 2006, 543-546. 

The Williams group published a three-component condensation reaction starting from oxindolidene acetate 158 which reacted with the azomethine yhde 161 formed in situ from the diphenylmorpholinone 160 and the isoprenoid aldehyde 159 (Scheme 32) [138-140]. The spiro compound 162 was obtained by 1,3-dipolar cycloaddition and converted further to the pentacyclic diketopiperazine 164. 

The cycloaddition of in sitM-generated azomethine yhdes with electron-deficient alkenes is a useful method for the generation of stereodefined, substituted pyrrolidines, and there has been some recent interest in the development of a catalytic asymmetric variant. While a variety of methods for the generation of azomethine ylides have been developed, treatment of an a-iminoester (8.200) with an amine base in the presence of metal salts is the process most commonly employed in the asymmetric variant, which generally uses an enantiomerically pure metal complex of copper, silver or zinc to give an N-metallated ylide (8.201) (Figure 8.6). ... 

Stabilized azomethine ylides can easily be formed using amino acids and their esters to generate an imine that is subsequently alkylated to generate an iminium ion. Decarboxylation or deprotonation then affords the reactive azomethine yhde. Coldham and coworkers examined the scope of this type of condensation—alkylation—cycloaddition cascade wherein the... 

There are also several examples of imidate-derived azomethine yhdes reported in the Hterature. For example, the Gin group described a clever use of these 1,3-dipoles in an approach to the azatricychc core of some stemofoline members of the stemona alkaloid family. The formation of the azomethine ylide 164 occurred upon exposure of pyrroUdine 163 to triflic anhydride and tetrabutylammonium triphenyldifluorosihcate (TBAT Scheme 35) (2008T3629). Cycloaddition of the resulting dipole across the pendant vinyl sulfide fiomished 165 in 71% yield. Enol triflate 165 was then reduced to give the saturated side chain in 166 in 89% yield by the action of Pd/C under an H.2 atmosphere. The enolate derived from 166 was treated with ethyl iodoa-cetate in the presence of hexamethylphosphoramide (HMPA) followed by... 

Pandey and coworkers developed an AgF-mediated route to azomethine yhdes starting from JV,A/-bis(trimethylsilylmethyl)alkyl amines and appHed this method of dipole formation toward a formal total synthesis of the Amar-yUidaceae class of alkaloids. Exposure of 176 to AgF effected a double desilylation and oxidation to furnish a transient azomethine yhde dipole (Scheme 37) (2011EJO4571). Cycloaddition of the dipole to the proximal enone fashioned tetracycle 177 in 56% yield. A base-mediated hydrolysis of the benzoyl ester occurred with concomitant epimerization, giving 178... 

In an approach to the stemofoUne class of alkaloids, the Martin group discovered an unusual set of conditions for generating azomethine yHdes. Oxidation of compound 186 under Swem conditions afforded a 5 1 mixture of 189 and 190 in 69% yield (Scheme 38) (2011TL2048). The formation of these two molecules can be easily rationalized via an intramolecular 1,3-dipolar cycloaddition of dipole 188, but the mechanism through which the azomethine ylide is formed under Swem conditions is not well understood. The authors proposed that the oxidized product 187a derived from 186 reacted with one of the electrophifrc species formed under the reaction... 

Even with considerable experimentation, the inability to easily remove the cyano group in structures 189 and 190 necessitated an alternate route to the key azomethine yUde intermediate. Ultimately, Martin and coworkers setded on the intramolecular reaction of the imino group in compound 191 with the critical carbenoid intermediate being obtained by a rhodium(II)-catalyzed decomposition of the diazo group in 191 so as to provide dipole 192 (Scheme 39) (2013T7592). Subsequent cycloaddition of the resulting azomethine yhde with the tethered alkene aflbrded 193 in 75% yield. Tricycle 193 was... 

Subsequently, the one-pot organocatalytic [C+NC+CC] coupling reaction between aldehydes 204, dialkyl-2-aminomalonate 205 and a,p-unsaturated aldehydes 28 was achieved with highly chemo-and enantioselectivity by Cordova, et al Scheme 3.66 [83]. The mechanism involved the 1,3-dipolar cycloaddition of azomethine yhde and chiral iminium intermediate, via re-facial and endo-addition to give the pyrroUdine derivatives. Later, the authors reported a similar approach to 5-hydroxypyrrolidme 208 from acylaminomalonates 207 and a,P-unsaturated aldehydes 28, Scheme 3.67 [84]. 

Coldham and coworkers developed a new method, which included an intramolecular [3 + 2] cycloaddition of azomethine yhde (198), to construct an ABC tricycUc intermediate (197) [99] (Scheme 17). The product (197) was further converted to an advanced ABCD tetracychc intermediate (195). An intermolecular version of this cycloaddition was reported by WUhams and Ahrendt who used a chiral azomethine yhde (205). A chiral AC spiro-cychc intermediate (203) was converted to an ACD tricychc intermediate (201) using RCM [100]. 

Incorporation of the indolizidine framework was then carried out by an azomethine yHde 1,3-dipolar cycloaddition using pipecoHc acid derivative... 

A. R. S. Babu, D. Gavaskar, R. Raghunathan, J. Organomet. Chem. 2013, 745-746, 409 16. An expedient ultrasonic assisted one-pot four component synthesis of novel ferrocene grafted pyrrohdine heterocycles via [3+ 2]-cycloaddition of azomethine yhdes. 

The same scheme is used to follow the Diels-Alder reaction of 3-styrylchro-mones [81] and intramolecular 1, 3-dipolar cycloaddition of azomethine yhdes [82]. The yield of the product was about 80% in 15 min of microwave irradiation. These reactions were foimd to take much longer time through conventional heating method. 

M. Komatsu, H. Okada, T. AkaM, Y. Oderaotoshi, S. Minakata, Generation and cycloaddition of polymer-supported azomethine yhde via a 1,2-silatropic shift of a-silylimines traceless synthesis of pyrrolidine derivatives. Org. Lett. 2002, 4, 3505-3508. 

Cabrera, S., Arrayds, R. G., Carretero, J. C. (2005). Highly enantioselective copper(I)-fesulphos-catalyzed 1,3-dipolar cycloaddition of azomethine yhdes. Journal of the American Chemical Society, 127, 16394-16395. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

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