Azomethine yhdes

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. 

Tominaga and coworkers have reported the formadon of indoLmne by the reacdon of azomethine yhde v/ith Tnitro-2-phenylthioethylene fEq 10 86 ... 

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,... 

In some cases 0-substituted oximes reacted with azomethine ylides. Thus, reaction of 0-substituted oxime (NC)2C=NOTs 139 with azomethine yhde derived from aziridine 140 afforded imidazoline 141 in 44% yield (equation 61). Addition of lithium derivative of silylated alkyne to oxime ethers 142 leads to 4-ethynyl-Af-hydroxy-2-imidazolines 143 in 49-72% yields (equation 62) . 

Possibly, the most common protocols used in the generation of azomethine ylides are those based on the in situ, fluorine-mediated desilyation of cyanoami-nosilanes developed by Padwa et al. (2). Typically, treatment of precursor 1 with AgF, in the presence of dimethyl acetylenedicarboxylate (DMAD), led to the formation of the intermediate cycloadduct 2, which was subjected to immediate DDQ oxidation to give pyrrole 3. The mechanistic rationale invokes fluoride-mediated desilyation to form the intermediate anion 4, which then undergoes loss of cyanide furnishing the corresponding azomethine yhde (Scheme 3.1). 

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). 

During extensive studies, the Katritzky group utilized benzotriazole chemistry as an azomethine yhde synthetic equivalent. Initial studies, with the simple bis substituted hydroxylamine (51) had furnished a wide range of cycloadducts, from... 

Roussi et al. (23) studied the deprotonation of tertiary amine N-oxides to generate azomethine yhdes. Typically, treatment of 87 with lithium diisopropyla-mide (LDA) in the presence of a suitable dipolarophUe led to the subsequent formation of the adducts shown (Scheme 3.23). In most cases, material yield is high, although the protocol suffers from formation of isomers for some dipolarophiles. 

Amino acids can be used as azomethine yhde precursors, although the stereo-genic center is by necessity lost and require reaction with chiral dipolarophiles to circumvent the problem of absence of stereocontrol. Harwood et al. (57) demonstrated that the chirality of the original amino acid could be preserved by derivatization to give back not only the original stereocenter, but further stereoinduction. 

Similar products could be generated via azomethine yhdes derived by a formal 1,2-H shift from the precusor imine, rather than by the decarboxylative approach outlined above (82,83). For example (83), condensation of aldehyde 272 with the requisite amino ester 273 led to the intermediate ylide, which dehvered adducts 274 and 275 in a 1.2 1 ratio in 75% yield. Grigg has once again applied this protocol to the synthesis of a wide range of complex molecular frameworks (276... 

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. 

The azomethine yhde derived from 79 has also been used in reactions with chiral ( )-y-alkoxy-a,p-unsaturated esters 80 (Scheme 12.27). The corresponding tetra-substituted pyrrolidines 81 were obtained with complete regiocontrol in fair to excellent de (125). 

Azomethine yhdes have also been subjected to reactions with 165 (Scheme 12.52). Gamer and Ho (288) developed the reaction of the photogenerated azomethine ylide 173 with 165 for the synthesis of quinocarcin. The reaction gave 174 with complete endo/exo selectivity and with more than 90% de. Other types of azomethine ylides have also been used in reactions with 165 and its derivatives (289,290). 

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. 

M.A. Marx, A.-L. Grillot, C.T. Louer, K.A. Beaver and P.A. Bartlett, Synthetic design for combinatorial chemistry. Solution and polymer-supported synthesis of polycyclic lactams by intramolecular cyclization of azomethine yhdes,... 

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. 

Novikov, M.S. Khlebnikov, A.F. Shevchenko, M. A facile carbene route to 2-fluoro-2-pyrrolines via fluorinated azomethine yhdes. J. Fluorine Chem. 2003, 123, 177-181. 

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 azomethine ylides described above all bear an ester or other electron-withdrawing group in order to promote yhde formation. Non-stabihzed azomethine ylides are less common, but can be produced, for example by decarboxylation or desilylation. The parent azomethine yhde 233 can be conveniently prepared by desilylation of an a-amino-silane, in which a leaving group (alkoxide, cyanide, benzotriazole, etc.) is present at an a position (3.147). Formation of the non-stabilized ylide 233 in the presence of an alkene or alkyne dipolarophile leads to the 2,5-unsubstituted pyrrolidine or dihydropyrrole product. 

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). ... 

Zhang and coworkers screened a variety of phosphine ligands in the silver-catalysed cyclo addition of the azomethine yhde generated from aryl imines such as (8.202) with dimethyl maleate (8.203), and discovered that the highest ees are achieved with the bis-ferrocinyl amide phosphine (8.204). ° During Zhang s studies it was shown that silver complexes with BINAP are poor catalysts in the addition with dimethyl maleate, however Sansano and coworkers have discovered... 

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... 

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