Azomethine ylides, cycloaddition alkynes

Dipolar cycloaddition reaction of azomethine ylides to alkynes or alkenes followed by oxidation is one of the standard methods for the preparation of pyrroles.54 Recently, this strategy has been used for the preparation of pyrroles with CF3 or Me3Si groups at the (3-positions.55 Addition of azomethine ylides to nitroalkenes followed by elimination of HN02 with base gives pyrroles in 96% yield (Eq. 10.48).56... 

Scheme 6.186 Intramolecular azomethine ylide-alkene/alkyne [3+2] cycloadditions.

As a part of a program directed toward the synthesis of the potent topisomerase I inhibitors, the lamellarins (e.g., 153 and 154), Porco has reported the silver triflate-catalyzed tandem cycloisomerization-azomethine ylide cycloaddition of 155 (Scheme 2.42).75 The postulated mechanism of this intriguing and highly efficient process is shown in Scheme 2.43. Silver-catalyzed addition of the imine nitrogen to the alkyne results, on subsequent deprotonation, in the formation of an azomethine ylide 160. This ylide participates in [3+2] cycloaddition with the alkyne component leading to formation of a dehydropyrrole 161. Finally, oxidation by adventitious oxygen leads to formation of the product 162. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Other approaches including 1,3-dipolar cycloadditions of azomethine ylides or nitroxides to alkene or alkyne dipolarophiles have been applied to the synthesis of these ring systems. 

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). 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Reaction of 98 at 100 °C with alkenes or alkynes gives fused systems via 1,3-dipolar cycloaddition of a reactive azomethine ylide intermediate (see Section 2.04.6.1, Equation 7). For example, the reactions with phenylethyne and A-phenylmaleimide give the bicycle 99 and tricycle 100 products, respectively (Scheme 4). The reaction with A-phenylmaleimide shows second-order kinetics and first order with respect to 98 and the dipolarophile. However, surprisingly, in the absence of the dipolarophile, 98 does not lose CO2, but undergoes racemization. A mechanism for the process has been proposed and involves the initial formation of the ylide 101 and proton transfer to give ylide 102 which reacts with the dipolarophile. Selenopenams 103 have been synthesized by this method <1999JHC1365>. 

Treatment of the dihydroisoquinolinium salt 699 with Hiinig s base (/-PrzNEt) produces the corresponding azomethine ylide, which can undergo intramolecular cycloaddition with the tethered alkyne to afford the chro-meno[3,4- ]pyrrol-4(3//)-one 700 in high yield. Subsequent deprotection of the isopropyl protecting groups affords the marine natural product lamellarin K (Scheme 173) <1997CC2259>. 

The indazolines themselves may be regarded as masked azomethine ylides and therefore are susceptible to further [3 + 2] cycloaddition reactions (59JOC582). (V-Methyl-A -(2-perfluoropropenyl)trifluoroacetamide exists in a valence tautomeric equilibrium with a cyclic azomethine ylide, which can be trapped with various dipolarophiles. The [3 -I- 2] cycloadducts with alkynes rearomatize on cycloelimination of fluorophosgene to give trifluoromethyl-substituted pyrroles (89BAUI325) (Scheme 61). 

Application of azomethine ylides in dipolar cycloaddition reactions with alkenes provides a route to pyrrolidine derivatives, as illustrated by the generation of the intermediate 498, and its subsequent conversion to the target system 499 (Scheme 64) <1995TL9409>. The use of alkynes as dipolarophiles instead gives rise to 3-pyrrolines, which has been exploited in a route to indoloquinones <1997JOC4763>. 

Oxazoles have also been used to generate azomethine ylides in intramolecular [3+2] cycloadditions with alkynes <2000JA5401 1 he nucleophilic attack of cyanide ion on the oxazolinium salt 75 led to the formation of azomethine... 

Eliminations and cycloadditions. l,l-Dihalo-2-alkyl acetates U"e transformed into (Z)-alkenyl halides on treatment with Sml2. Azomethine ylides are generated from bis(tosylmethyl)amines RN(CH2Ts)2. Trapping of these 1,3-dipolar species with alkenes or alkynes furnishes pyrrolidines and 3-pyrrolines, respectively. ... 

Peri-, regio-, and stereoselectivity of cycloaddition reactions of substituted mesomeric betaines (106) have been studied with different alkynic and alkenic dipolarophiles. High periselectivity has been observed in cycloaddition with both series of dipolarophiles, with the dipolarophile adding exclusively across the 1,3-azomethine ylide dipole (106a). The formation of 2,2 -bipyrroles (108) could be explained by a rearrangement of initial bicyclic cycloadduct (107) <90JOC910>. All these reactions are shown in Scheme 18. 

Novikov, M.S. Khlebnikov, A.F. Sidorina, E.S. Kostikov, R.R. 1,3-Dipolar cycloaddition of azomethine ylides derived from imines and difluorocarbene to alkynes a new active Pb-mediated approach to 2-fluoropyrrole derivatives. J. Chem. Soc., Perkin Trans. 1 2000, 231-237. 

Treatment of 4-carboxythiazolidine with formaldehyde and methyl propargylate affords thi-azocine (52), apparently via intermediate formation of an azomethine ylide, which then undergoes (3 + 2] cycloaddition with the alkyne, followed by Michael addition to a second equivalent of alkyne and final rearrangement (Scheme 18) <87CC1296>. 

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