Azomethine ylides stereoselective cycloadditions

Pandey, G., Bagul, T.D., Sahoo, A.K. (1998) [3 -E 2] Cycloaddition of Non stabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analognes. Journal of Organic Chemistry, 63, 760-768. 

Dipolar cycloaddition reaction of benzo(A)thiophene-l,1-dioxide 282 with nonstabilized azomethine ylides gave high overall yield of new pyrrolo derivatives 5 and 6 with low stereoselectivity (Scheme 50) <2006TL5139>. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted azomethine ylides have been conducted under microwave irradiation. Oritani reported that a mixture of the aldehyde 137 and N-methyl- or N-benzylglycine ethyl ester (138) on the surface of silica gel, irradiated under microwaves for 15 min, generated azomethine ylides 139 that subsequently underwent in situ intramolecular cycloadditions to afford the corresponding tricyclic compounds 140 in 79 and 81% yield, respectively (Scheme 9.42) [93],... 

Cycloaddition (13,326).2 The azomethine ylide (a) generated with LDA from trimethylamine oxide adds stereoselectively to the dihydronaphthalenes 1 to provide the benzisoindoiines 2, of use as a-adrenergic agents in therapy. 

The above-mentioned complexes are the sole iridium derivatives applied to DCR, and the cycloaddition of nitrones to enals or methacrylonitrile, the unique process studied. We think that iridium-based catalysts are underrepresented in 1,3-dipolar cycloaddition chemistry. For example, no iridium (1) systems have been developed to this end. It can be anticipated that the (bidentate ligand)lr(l) fragment could be active (and stereoselective if chiral bidentate ligands are used) in DCR such as those involving azomethine ylides. 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

However, the highly stereoselective nature of the dipole intermediate, which was observed in the preceding cases, did not translate to azomethine ylide cycloadditions of 113 and 114, both of which formed mixtures of products derived from endo... 

N-Unsubstituted azomethine ylides may be generated thermally (79), and the N-metalated, 2-azaallyl anion versions may be generated by action of nonmetalhc bases such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) on certain imines (80). Although they are assumed to show similar chemical properties, these two species usually show different reaction patterns, as shown in Scheme 11.7, where the regio-and stereoselectivities of the cycloadditions are quite different (24,78-80). Metala-tion of (alkylideneamino)acetonitriles can be performed with metallic bases other than LDA. Thus, butyllithium, ethylmagnesium bromide, and magnesium bromide-diisopropylamide are also effective (78). The N-magnesioazomethine... 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

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. 

A chiral enone derived from carbohydrates, 131, undergoes a stereoselective [3+2] cycloaddition reaction with azomethine ylides to afford pyranopyrrolidines in good yields. The cycloaddition reaction is highly regio- and stereoselective (Equation 64) <2005SL587>. 

In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

The efficient desilylation from amine radical cation in media favouring SSIP formation has also been used [104] for the sequential double desilylation reaction of amine 110 to generate azomethine ylide 111 which upon cycloaddition with a different dipolarophile gives a stereoselective pyrrolidine ring system 112 as depicted in Scheme 20. 

Pandey, G., Laha, J.K., and Lakshmaiah, G. 2002. Stereoselective construction of X-azabicyclo[ i.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine. Tetrahedron 58, 3525-3534. 

With trifluoromethyl-substituted azomethine ylides, generated in situ by the ring opening of CAV-2-bcnzoyl-l -methyl-3-(trifluoromcthyl)aziridine (2)124 or by protonation of trifluoro-methylated thioamidinium salts, 25 1,3-dipolar cycloadditions with both electron-deficient and electron-rich alkenes can be achieved rcgiosclcctively. However, stereoselectivity depends on both the ylide configuration and electronic interactions. 

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