Cycloaddition with azomethine ylids

Finally, enantiomerically pure sulfinimines have also been used as precursors of chiral imidazolidines by 1,3-dipolar cycloaddition with azomethine ylids [181]. Reactions of different arylsulfinimines 245 with dipoles 246 are highly stereoselective, mainly affording diastereoisomer 247 (absolute configuration unequivocally established by X-ray studies), which was readily transformed into vicinal diamine 248 (Scheme 111). 

Whereas cycloaddition of azomethine ylids were usually conducted with careful exclusion of water, it was recently shown that the cydoaddition in water-tetra-hydrofuran solution of stabilized ylids derived from ethyl sarcosinate with several dipolarophiles can occur in excellent yields [53]. 

Some cycloadditions to azirines have been reviewed by Anderson and Hassner.27 Schmid et al. 28 photolyzed the arylazirine 1 in benzene in the presence of 2 equivalents of DM AD and obtained 40% of the pyrrole 3, a compound prepared previously by Huisgen et al.29 30 from oxazolones and sydnones with DMAD. Padwa and his co-workers have investigated the scope of these photoinduced cycloadditions to arylazirines. Irradiation of 1 in pentane for 3 hours in the presence of DMAD gave 95% of (3)31 the azomethine ylid 2 was postulated as an intermediate. 

The azomethine ylid 53, generated thermally from the aziridine 52, underwent cycloaddition in near quantitative yield. With DMAD, only one product is possible with EP the sole product was 54, and EPP gave 54 and 55 in 80 20 ratio. This latter result indicates that steric effects are important with the phenylpropiolic ester.52 Nitrones (57) add to benzylideneacenaphthenone (56) forming the spiroisoxazolidines (58), which lose aldehyde fragments on heating or photolysis to give the... 

Polymer-supported azomethine ylids generated from a-silylimines through a 1,2-silatropic shift, are shown to be versatile reagents suitable for the synthesis of libraries of pyrrolidine derivatives after 1,3-dipolar cycloaddition with a series of dipolarophiles. Effectively substituents R1, R2 and dipolarophiles A=B and A=B can be chosen to get the desired adduct.146... 

It has been demonstrated that TMS iodide (in combination with cesium fluoride) or TMS triflate in various solvents (THF, MeCN, HMPA) are excellent reagents to promote the generation of azomethine ylids from A-methoxymethyl-A-(trimethylsilylmethyl)aIkyl-amines and their cycloaddition to electron deficient alkenes with yields ranging from moderate to nearly quantitative. The geometry of the double bond in the alkene is preserved in the cycloadduct.410... 

The first study consisted of labelling one of the reactive carbon centers with deuterium. Thus, cycloaddition with a dissymmetric dipolarophile led to a 1 1 mixture of two deuterated pyrrolidines, indicative of the ambivalence.411 412 In the second study, 13C was used to label one of the carbons a- to nitrogen, and once again a 1 1 mixture of labeled pyrrolidines was obtained.413 These results demonstrate that free resonance of an unstabilized azomethine ylid occurs during the reaction. 

Lithium fluoride is able to promote the formation of azomethine ylids from /V-benzyl-/V-(met hox y met hy I)tri met h y I s i I y I met h y I am i ne. The reaction with methyl fumarate and maleate gives quantitative yields of trans and cis /V-benzyl-3,4-dicarbomethoxypyrro-lidines. Thus, the geometry of the alkenes is preserved during the cycloaddition reaction. These results are identical to those obtained using Achiwa s procedure (see Section VII.D.2). 

The benzotriazolyl group is a good leaving group. This feature was exploited in the use of benzotriazolylmethyl-aminomethyltrimethylsilane as a precursor of an azomethine ylid. At reflux in toluene, benzotriazolyltrimethylsilane was eliminated and formation of the ylid underwent quantitative [l,3]dipolar cycloaddition with diethyl fumarate, for example, giving a frans-3,4-dicarboethoxy pyrrolidine derivative exclusively. Other examples were reported as well.442... 

Silver fluoride also provides access to the azomethine ylid from /V-methoxymethyl-/V-(trimethylsilylmethyl)benzylamine, with the intermediate being trapped with classical dipolarophiles. No internal cycloaddition occurs when a non-activated ethylenic moiety... 

Like imidates, thioimidates were shown to be the precursors of azomethine ylids which lead to the formation of pyrroline and pyrrole derivatives through cycloaddition with dipolarophiles.454... 

The covalent assembly of functional Jt-systems is a general synthetic principle and in some cases they can even be achieved in a multi-component fashion. One of the most impressive examples is the very elegant access to covalently linked donor-fullerene arrangements by 1,3-dipolar cycloadditions with in situ-generated azomethine ylids [59]. However, here only the multi-component de novo synthesis of the chromophore structures will be considered. The major developments have been achieved in condensation-based and cross-coupling strategies. 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

Cycloaddition to pyrrolidines. The reaction of diethyl aminomalonate with formaldehyde can generate an azomethine ylid (a - b) which cycloadds to 1,2-dipolarophiles to form pyrrolidines. 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

The products are azomethine ylids, and can be trapped by [3+21 cycloaddition reactions with dipolarophiles (look back at Chapter 35). 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. There is no endo mle for 1,3-dipolar cycloadditions like that for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the reactions of C,/V-diphenylnitrone—both regioisomers 6.238 and 6.239 (R=C02Et) from the reaction with ethyl acrylate are mixtures of exo and endo isomers, only a little in favour of the exo product. Similarly, the reactions of methyl crotonate with nitrones favour the exo product 6.242 over the endo 6.243. In contrast, other reactions are endo selective, as in the cycloaddition 6.244 of an azomethine ylid to dimethyl maleate giving largely the endo adduct 6.245. 

Q ,/i-Unsaturated complexes undergo a number of facile cycloaddition reactions to produce more elaborate complexes. For example, cycloadditions using diazoalkanes, nitrileimines, alkylnitrones, azomethine ylids (see Ylide), and imines are feasible. For example, reaction of the chiral carbene (9) with trimethylsilyldia-zometathane gave the heterocyclic-substituted carbene (10) (Scheme 15). ... 

The mesomeric betaine (100) underwent 1,3-dipolar cycloaddition, with DMAD in toluene at 100°C, to give a mixture of two products (101) and (102). Compound (101) was formed by initial 1,3-dipolar cycloaddition of DMAD to the azomethine ylid fragment of (100) to yield a tricyclic intermediate which fragmented to (101). Compound (102) was formed via ring opening of (100) to a ketene intermediate which underwent a hetero Diels-Alder reaction with DMAD to give (102) <92JCS(P1)2789>. 

Due to the presence of these resonance forms in azomethine ylids, reaction with alkenes often leads to mixtures of regioisomeric cycloadducts. Resonance stabilizing substituents are usually employed to enhance the regioselectivity. Intramolecular reactions usually favor only one mode of addition. An example of an intermolecular reaction is taken from Williams synthesis of spirotryprostatin B,372 in which 5,6-diphenylmor-pholin-2-one (473) reacted with the aldehyde shown to give a mixture of ( )- and (Z)-azomethine ylids (474). This product was generated in situ with oxindole 475, and [3-i-2]-cycloaddition product 476 was obtained in 82% yield. 

Intramolecular versions of the reaction are not only possible but are quite useful. One illustration is Pandey s treatment of bis(trimethylsilylamine) 477 with AgF to generate azomethine ylid 478. 23 in the presence of the conjugated ester unit, cycloaddition gave a 61% yield of the azatricyclo product 479. 

Mesoionic thiazoles such as (69) can be considered to be potential precursors in basic media of cyclic azomethine ylids. These mesoionic thiazoles can be generated from 5-(tert-butylamino)thiazolium chlorides (68). They can undergo 1,3-dipolar cycloaddition reactions with carbon disulphide. The initial cycloadducts (70) and (71) rapidly eliminate tert-butyl isothiocyanate at room temperature to give the thiazolium-... 

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). ... 

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