Azomethine ylides, alkenyl cycloadditions

The mesoionic heterocycles called munchnones function as cyclic azomethine ylides in cycloaddition reactions.63 The alkenyl moiety can be attached at carbon or at nitrogen. 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

Intramolecular cycloaddition can be carried out on a variety of alkynyl azomethine ylides analogous to reactions of the alkenyl azomethine ylides. There is also one report of cyclization with an allene. 

Intramolecular azomethine ylide cycloaddition to the C—O double bond of an aldehyde was reported in 197369 and cycloaddition to the C—C double bond was first reported in 1975.70 Competition between 1,1- and 1,3-cycloaddition is observed in intramolecular reactions, although intermolecular reactions give only 1,3-cycloaddition. Photolysis of 2//-azirines is one generation method of nitrile ylides applicable to intramolecular cycloaddition.70 Another method involves the base-catalyzed 1,3-elimination of hydrogen halide from alkenyl imidoyl halides. Still other procedures involve thermolytic and photolytic cycloreversions of oxazolinones and dihydrooxazaphospholes. 

Table VIII summarizes the cycloaddition reactions of azomethine ylides with maleimides and maleic anhydrides. The upper part of the table involves endo-selective cycloadditions and the lower part nonselective reactions. Endo selectivity is closely related to the substitution pattern of the azomethine ylides used. The azomethine ylides that show high endo selectivity to these cyclic olefins bear an ylide-stabilizing substituent of the carbonyl or cyano type (EWG) at one carbon and an aryl, heteroaryl, acyl, or 1-alkenyl substituent (R ) at the other. These key substituents must be present for high endo selectivity, although the substituent (R) on the ylide nitrogen is equally important.

Selectivity in cycloadditions to maleates is mentioned first. The stereoselective cycloadducts produced in maleate cycloadditions are all 2,3-cis-pyrrolidines, indicating that the aryl or 1-alkenyl substituents as R are overlapping with one of the maleate esters in the transition state. More azomethine ylides show high stereoselectivity to dimethyl maleate than to dimethyl fumarate. Thus, there are several azomethine ylide 1,3-dipoles in Table IX that show high stereoselectivity to maleate but poor to fumarate. The N-unsubstituted azomethine ylides RCH=NH —CH COOR, derived from the imines of a-amino esters, are highly endo selective to maleimides, but poor in stereoselectivity to dimethyl maleate on the contrary, the N-substituted derivatives RCH=NR —CH COOR are nonstereoselective to maleimides, but exclusively stereoselective to the maleate. 

In a single example of an /V-alkenyl/azomethine ylide cycloaddition, a mixture of bridged stereoisomeric l-azabicyclo[2.2.1]heptanes was obtained279. C-Alkenyl-substituted azomethine ylides afford fused products, generally with a preference for cis fusion. 

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. ... 

Addition of an aldehyde to an alkenyl-amine can provide the required alkenyl-azomethine ylide (such as 225) for intramolecular cycloaddition. An alternative is the addition of an amine to an alkenyl-aldehyde. Thus, addition of A(-methyl glycine ethyl ester to the aldehyde 227 gave the intermediate azomethine ylide 228 and hence the cycloadduct 229 (S.MS). ... 

P3Troles are formed when acetylenes undergo cycloadditions with N-acylamino acids in the presence of EDC. An iV-alkenyl-munchnone azomethine ylide is generated in situ and is trapped by the dipolaraphile. Loss of CO2 yields the pyrrole (eq 10). 

A chiral selenophosphoramide catalyst was employed for the intramolecular cyclization of an alkenyl sulfonamide to achieve the enantioselective formation of N-heterocycles including an azepane derivative via a mechanism proposed to include formation of a three-membered sulfur-containing ring (14JA8915). A [4 + 3]-cycloaddition reaction of methyl coumalate 12 with an azomethine ylide, formed from imine esters 13 yielded functionalized azepine derivatives 14 (14OL4508). 

Kathiravan and Raghxmathan reported the synthesis of pyrrole-fused polycyclic heterocycles via intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides derived from pyrrole-2-carbaldehyde 28 and secondary amino acids in IL [BM1M][BF4]. The methodology involved the synthesis of N-alkenyl carboxaldehyde from 28 followed by freafment with sarcosine in [BM1M][BF4] as reaction medium at 85-95 C for about 3h to afford pyrrolo-pyrrolidines 29 in good yield (Scheme 3). The same reaction when carried out in organic solvents such as toluene, methanol, and acetonitrile, the reactions observed were slow, giving product in low yield [80]. 

Azomethine ylide 26 reacts with (—)-8-phenylmenthyl derivatives of Fischer alkenyl carbene complex 25 to afford 2-pyrrolidinone derivative 27 with high regioselectivity and diastereoselectivity (Scheme 5.7) [16]. A total synthesis of the anti-inflammatory and antidepressant drug (+)-roli-pram is achieved via the stereoselective [3+2] cycloaddition as a key reaction. 

SCHEME 5.7 [3+2] Cycloaddition of Fischer alkenyl carbene complex 25 with azomethine ylide 26. 

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