Azomethine ylids generation

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... 

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... 

The third area of interest has been the emergence of use of silylmethylamino derivatives as precursors to 1,3-dipolar, non-stabilized azomethine ylids. The ability of the a-aminosilanes to generate the azomethine ylids in the presence of the dipolarophile attracted the attention of organic chemists (See Section VII). 

A large variety of silylmethylamino derivatives have been shown to be excellent starting materials for the in situ generation of non-stabilized azomethine ylids. Combined with a number of electron-deficient olefinic or acetylenic molecules that have been recognized as good dipolarophiles, ready access to diversely substituted five-membered ring nitrogen heterocycles has consequently been opened. 

This acid, used in catalytic amounts, easily generates azomethine ylids (this route is sometimes referred to as Achiwa s procedure ). Excellent to complete regioselectivity has been established when both ylid and ethylenic dipolarophile are dissymmetrical, but stereochemical control is not so strong. From these data, ab initio calculations have been made and frontier molecular orbital theory used to explain the origin of these selectivities.390... 

Among these groups (siloxy, amino, benzotriazolyl, thiolate, cyanide) the methoxy group has been the subject of a large number of studies. To generate the azomethine ylid, essentialy three reagents have been utilized silyl triflate (or iodide), trifluoroacetic acid and lithium fluoride (sometime combined with sonication). Thermal rearrangement has also proven to be efficient. 

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... 

Excellent yields are also obtained in spiro-adducts formed by the condensation of azomethine ylid thus generated, with 3-arylidene-flavanone derivatives at room temperature in the presence of trifluomethylacetic acid in toluene. These molecules are both flavonoids and spiro compounds, two classes of naturally occurring substances which exhibit biological activities 419... 

It was noted that using either the a- or a/-methylated precursor leads to the same mixture of the cycloaddition products. This demonstrates that the same azomethine ylid is generated as the common intermediate.64... 

Three techniques have been utilized to promote generation of an azomethine ylid from bis(trimethylsilmethyl)amines photochemistry, chemistry with silver fluoride and electrochemistry. 

Azomethine ylids can be generated photochemically by irradiating N-protected bis(trimethylsilylmethyl)amines in the presence of a sensitizer (1,4-dicyano-naphthalene, DCN ) in methanol as the solvent. The ylid reacted with a series of dipolarophiles to give adducts in moderate to good yields.446,447... 

Imidates, generated from secondary amides, are treated with trimethylsilyhnethyl triflate to give an azomethine ylid which reacts with electron-poor alkenes and acetylenes, yielding A2-pyrroline and pyrrole derivatives.54 Similar transformations are conducted from thioamides (vide infra). 

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. 

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. 

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 quaternization of a j8-carboline, followed by the generation of an azomethine ylid, enables cycloaddition of diethyl acetylenedicarboxylate to yield the fused pyrrole product (357) (Scheme 115) <89TL3423>. Similar systems, namely the pyrrolo[2,l-a]isoquinolines, have been formed by an intramolecular electrophilic substitution on the 2-aryl ring of a suitably substituted pyrrole (358) (Equation (104)) <93JCS(Pi)276i>. 

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