Azomethine acyclic

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

Husson and co-workers (84) investigated the 1,3-dipolar cycloaddition of acyclic chiral azomethine ylides derived from (—)-Af-cyanomethyl-4-phenyl-l,3-oxazoli-dine with electron-deficient alkenes, and in some cases de >95% were obtained. 

Another approach employing chiral acyclic azomethine ylides was published in two recent papers by Alcaide et al. (85,86). The azomethine ylide-silver complex (51) was formed in situ by reaction of the formyl-substituted chiral azetidinone (50) with glycine (or alanine) in the presence of AgOTf and a base (Scheme 12.18). Azomethine ylides formed in this manner were subjected to reaction with various electron-deficient alkenes. One example of this is the reaction with nitrostyrene, as illustrated in Scheme 12.18 (86). The reaction is proposed to proceed via a two step tandem Michael-Henry process in which the products 52a and 52b are isolated in a... 

Chiral exocyclic alkenes such as 112, also having the chiral center two bonds away from the reacting alkene moiety, have been used in highly diastereoselective reactions with azomethine ylides, and have been used as the key reaction for the asymmetric synthesis of (5)-(—)-cucurbitine (Scheme 12.37) (169). The aryl sulfone 113 was used in a 1,3-dipolar cycloaddition reaction with acyclic nitrones. In 113, the chiral center is located four bonds apart from alkene, and as a result, only moderate diastereoselectivities of 36-56% de were obtained in these reactions (170). 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Cycloaddition of thiazolium azomethine ylides with dialkyl acetylenedicarboxylates 61 provides another approach to pyrrolo[2,1 -bjthiazoles 64 <070L4099>. Quatemization of 2-methylthiothiazole with trimethylsilylmethyl trifluoromethanesulfonate (TMSChkOTf) and subsequent fluoride-induced desilylation of the resulting (trimethylsilyl)methylammonium salt generate the acyclic azomethine ylide 62. This ylide readily participates in 1,3-dipolar cycloadditions with acetylene derivatives 61 to give adducts 63, which undergo spontaneous elimination of methylmercaptan to give the A-fuse cl thiazoles 64. ... 

The reduction of phthalazinones is apparently the only observed example of a reduction of a protonated compound containing > C=N—N < in which the C=N double bond proves to be easier to reduce than the N-N bond. The differences in reduction potential between the azomethine double bond and the nitrogen-nitrogen bond are not great in acyclic compounds and the presence of a phenyl group fused to the heterocyclic ring may alter several parameters. The phenyl group acts as a nonreducible, nondisplaceable unsaturated center, and its presence may influence the orientation of the molecule and the adsorption of the compound at the electrode. 

The attacks of heterocyclic A -oxides, e.g. of pyridine, quinoline, isoquinoline, phenanthridine, etc., on activated alkynes (RC CR R = R = COOMe R = Ph, R = COOEt R = Ph, R = CN) pose similar problems . An acyclic intermediate has been postulated but is rarely detected. Some of the possibilities are illustrated in equation (126) . If the open intermediate is formed, then the paths to the ylid and the 2-substituted quinoline in equation (126) seem simple enough, but several possible mechanisms can lead to the 3-substituted products . Other workers regard the reaction of the nitrone (or azomethine oxide) with alkyne as simple cycloadditions - which yield 2,3-dihydro-l,2-oxazoles since these are often unstable, only decomposition products may be found (equation 127). The construction of the indolizine skeleton initiated by a similar process has been reviewed (equation 128). ... 

As early as 1965, the first example of the the carbon-carbon bond cleavage of an aziridine generating an azomethine ylide 1,3-dipole was reported by Heine and Peavy (65TL3123). This also offers the first generation of acyclic azomethine ylides by the aziridine route. Thus, 1,2,3-triphenylaziridine, with its stereochemistry unspecified, was heated under reflux in toluene in the presence of diethyl acetylenedicarboxylate. The azomethine ylide (1) generated was captured by the acetylene to give a quantitative yield of diethyl l,2,5-triphenyl-3-pyrroline-3,4-dicarboxylate. 

The first evidence for the existence of acyclic N-unsubstituted azomethine ylides as tautomers of imines was reported by Grigg (77CC125 78CC109). When the imines of a-amino esters are heated in benzene or toluene in the presence of a variety of dipolarophiles, pyrrolidine- or 3-pyrroline-2-carboxylates are isolated in high yields. These heterocycles correspond to the products produced by the 1,3-dipolar cycloadditions of N-unsubstituted azomethine ylides, indicating the thermal equilibrium between the imine esters... 

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). 

Typical acyclic olefins of symmetrically substituted types are the esters of maleic and fumaric acids. Though maleimides and maleates are both symmetrical cis-olefins, these two exhibit quite different stereoselectivity in cycloadditions to azomethine ylides. There are relatively limited examples known for the stereoselective cycloadditions of azomethine ylides to symmetrical acyclic olefins. These stereoselective cycloadditions are listed in Table IX, and nonstereoselective reactions in Table X. 

The azomethine ylides that exhibit high stereoselectivity to symmetrical acyclic olefins are again ester- or cyano-stabilized types, and also N-unsubstituted or N-metallated types. The only exception is the N-substituted ylides with a general formula ArCH=N R"—CH COOR, whose poor endo selectivity to maleimides has been discussed above. 

The chemistry of azomethine ylide 1,3-dipoles, especially that of acyclic azomethine ylides, has completely changed since 1978. Methods of generating azomethine ylides, which were seriously limited before then to the aziridine route (Section II,A) and the deprotonation route (Section II,D), have been much extended. New methods, such as the desilylation route (Section II,B), the tautomerization route (Section II,C), the decarboxylation route (Section II,E), the N-oxide route (Section II,F), and the N-metallation route (Section II,G), are now known and the types of azomethine ylides available have been widely expanded. 

A reduction route similar to that of phenylhydrazones [229] seems to be rather general for azomethine derivatives of hydrazine [229] as it s followed by cyclic and acylic phenylhydrazones, semicarbazones, azines, cyclic hydrazones, and acylated cyclic and acyclic hydrazones [231] under pro tic conditions in DMF, acylated hydrazones of aromatic aldehydes are reduced with saturation of the C=N bond and cleavage of the N-N bond at a more negative potential [232]. The suggestion that the cleavage of the N-N bond precedes the saturation of the azomethine bond is also an essential part of the interpretation of many of the ring contractions of heterocyclic compounds (Chapter 18). 

Synthetic and biological interest in highly functionalized acyclic and cyclic amines has contributed to the wealth of experimental methodology developed for the addition of carbanions to the caibon-mtrogen double bond of imines/imine derivatives (azomethines). While a variety of practical methods exist for the enantio- and stereo-selective syntheses of substituted alcohols from aldehyde and ketone precursors, related imine additions have inherent structural limitations. Nonetheless imines, by virtue of nitrogen substitution, add a synthetic dimension not available to ketones. In addition, improved procedures for the preparation and activation of imines/imine derivatives have increased the scope of the imine addition reaction. 

There is no doubt that the field of asymmetric induction occupies a very important place in modem synthetic methodology. Elegant protocols designed to cany out dipolar cycloadditions have been developed and important advances in the theoretical description of these processes have taken place as a consequence (vide infra) Diastereoselective cycloadditions have been carried out between optically active nitrile oxides, nitrones,azomethine ylides and achiral dipolarophiles, and between optically active dipolarophiles and achiral nitrile oxides and achiral nitrones. The products have b n put to good use, either by translating the cycloaddition diastereoselectivity to the construction of useful optically active acyclic intermediates, or in Ae total synthesis of natural products (vide infra) ... 

Numerous cycloadditions of azomethine ylides to symmetrically substituted cyclic, as well as cis- and trans-acyclic dipolarophiles are known13. (Further examples from the literature can be found in references 398-408.)... 

With acyclic symmetrically substituted alkenes, cycloadditions to ester- orcyano-stabilized iV-unsubstituted or iV-metalated azomethine ylides also show high endo selectivity, e.g., maleate esters undergo more stereoselective addition than their fumarate analogs, with a marked preference for 2,3-rfs-substituted pyrrolidines211 1 227 -221 256. 

Generally speaking, piperideines and pyrrolines exist predominantly in the imine form and not in the tautomeric enamine form A -alkyl analogues have no alternative but to exist as enamines. These cyclic imines are resistant to hydrolytic fission of the C = N bond, in strong contrast with acyclic imines, but nonetheless they are very susceptible to nucleophilic addition at the azomethine carbon. An example of this is that both piperideine and pyrroline exist as trimers formed by the nucleophilic addition of nitrogen of one molecule to the azomethine carbon of a second molecule, etc. 

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