Ylids heterocyclics

Similar cycloadditions between thiirene dioxides and 1,3-dipoles generated in situ give heterocycles which result from either loss of sulfur dioxide or from the three-membered ring opening of the initially formed adduct (e.g. 174). Such cycloadditions with nitrilium imides (173a) and nitrile ylids (173b) are illustrated in equation 69175. 

Independent work by Schmid93 and by Padwa94 on the photochemistry of 2H-azirines has shown that irradiation of such systems leads in the first instance to the formation of nitrile ylids (nitrilium betaines). Subsequent 1,3-addition to a variety of dipolarophiles affords five-membered heterocycles. These additions take place in a stereospecific and regioselective manner thus, irradiation of the diphenyl-2f/-azirine 117 in the presence of dimethyl maleate leads to the formation of the two isomeric 1-pyrrolines... 

Heterocyclic carbanions stabilized by ylid formation, or by resonance that places the negative charge on a heteroatom, are specifically excluded. In addition, heterocyclic systems that do not depend on additional stabilization factors for their initial deprotonation, continued existence, or subsequent reaction with electrophilic substrates are discussed in less detail. 

X -phosphorins constitute a novel and very versatile class of heterocyclic compounds, the properties of which can be varied considerably by substituents at both the phosphorus and the ring C atoms. The ylid properties are fully suppressed by TT-electron delocalization over the entire ring. 

Nitrenes have a short lifetime (only several microseconds)86- 8 and undergo stabilization by the following reactions isomerization to imines, dimerization to azo compounds, hydrogen abstraction followed by ring closure to heterocyclic compounds, bimolecular insertion into C-H bonds to secondary amines, addition to solvent yielding ylids, and addition to unsaturated systems yielding heterocyclic compounds. Table 117-106 includes the reaction products and references for the different classes of nitrenes. 

I. Zugravescu, M. Petrovanu, N-Ylid Chemistry, McGraw-Hill, New York (1976), Chpt 2 (review) J Heterocyclic Chem 18 63 (1981)... 

Although there is no direct evidence for the postulated intermediate 3 in this example, there is evidence for the existence of analogous ylids in the aziridine series (see Section II, B), and in some reactions of pyridine-type heterocycles with DMAD intermediates corresponding to 3 have been trapped. The formation of intermediates similar to 3 is the commonest first stage in reactions of nitrogen-containing heterocycles with activated acetylenes. 

Syntheses of fused heterocycles by l,3 dipolar cycloaddition reactions to imidazole ylids have been described by several research groups. Boekelheide and Fedoruk150 quatemized the imidazoles 183 with phenacyl bromide, generated the corresponding ylids 184 and then added excess EP. The anticipated product (186) was apparently formed but was dehydrogenated to pyridoimidazole (185), which was isolated in 14% overall yield. 

Cyclic double ylids with aliphatic ring members occur solely as carbodiphosphoranes (24, 25). The related benzo-heterocycle exists as a 1,3-bis-ylid IQ, however, and is easily transformed into a cyclic diphosphonium-triple-ylid 1A (26). 

Heterocyclic nitrogen-derived ylids behaviors have been studied.373 For instance, pyridine derivatives lead exclusively to [2,3]-sigmatropic rearrangement (Sommelet-Hauser) products. 

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. 

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. 

A 1,3-dipole is a compound of the type a—Het—b that may undergo 1,3-dipolar cycloadditions with multiply bonded systems and can best be described with a zwitter-ionic all-octet Lewis structure ( Huisgen ylid ). An unsaturated system that undergoes 1,3-dipolar cycloadditions with 1,3-dipoles is called dipolarophile. Alkenes, alkynes, and their diverse hetero derivatives may react as dipolarophiles. Since there is a considerable variety of 1,3-dipoles—Table 12.2 shows a small selection—1,3-dipolar cycloadditions represent not only a general but also the most universal synthetic approach to five-membered heterocycles. 

Many annellated 3-nitropyrroles have been prepared by the reaction of ylids, generated from a variety of heterocycles, with nitromethane.1 The sequence of steps involves protonation of the ylid by nitromethane, addition of the anion CH2N02 to the iminium system, cyclization on the carbonyl, dehydration, and finally dehydrogenation. Thus, the isoquinolinium ylids 8 react with nitromethane in the presence of base to give 1-nitropyrrolo-[2,l-fl]isoquinolines (9) in about 20% yield (Scheme 4). A side reaction is the loss of nitrous acid from the intermediate, to give 10. 

An interesting class of elusive neutral species is heterocyclic ylids, as represented by the so-called Hammick intermediate that was postulated 65 years ago to explain the accelerated decarboxylation of 2-picolinic acid [146, 147]. An analogous dissociation takes place in ionized 2-picolinic acid in the gas-phase and was employed to generate the pyridine ion isomer 35+ (Scheme 13) [148]. Collisional neutralization of 35+ with A/,AT-dimethylaniline produced neutral ylid 35, which can also be represented as a singlet a-carbene (Scheme 13). Ylid 35 showed a survivor ion in the +NR+ mass spectrum, which was further char-... 

Other heterocyclic ylids have been generated in the gas-phase by collisional reduction of stable ylid cation-radicals using synthetic strategies similar to that described for 35+, e.g., imidazol-2-ylidene [149], thiazol-2-ylidene [150], pyrazine ylids [151], pyrimidine ylids [152], and pyridinium methylids [153]. 

However, the formation of ylids can be prevented by incorporation of P into heterocycles as in the following examples ... 

Alkenes, perfluoro-cycloadditions to benzyl azide, 60, 35 pyridine imines and ylids, 60, 36 Alkenes, perfluoro-, as heterocyclic precursors, 59, 10 Alkylation, free-radical, of 1,3-dimethyluracil, 55, 227 A-Alkylation, [ 1,2,4]triazolo[ 1,5-u)-pyrimidines, 57, 110 Alkynes, photocycloaddition to uracils, rearrangement with HCNO elimination, 55, 149 Alkynes, ethoxy-, cyclaoddition to hexafluoroacetone azine, 60, 32 Alkynes, perfluoro-, as heterocyclic precursors, 59, 10 Allenes... 

Michaet aflkfitfon of aromatic or heterocyclic aidehydes (via cyanohydrins) to aP-unsaturated systems. Also addition of aliphatic aldehydes catalyzed by thiazolhim ylids... 

Besides processes (1) and (2), the reader should be aware that nucleophilic attacks on alkynes are treated in other chapters of this book, dealing with rearrangements, cyclizations, polyacetylenes, cyclic acetylenes and perhaps others. A number of publications overlap with ours in different ways and at different levels -. They treat individual alkynes or families " , e.g. acetylene, diacetylenes , acetylene dicarboxylic esters haloacetylenes , alkynyl ethers and thioethers > ynamines , fluoro-alkynes ethynyl ketpnes , nitroalkynes , etc. synthetic targets, e.g. pyrazoles , if-l,2,3-triazoles , isothiazoles , indolizines S etc. reagents, e.g. nitrones , lithium aluminium hydride , heterocyclic A -oxides - , azomethine ylids - , tertiary phosphorus compounds , miscellaneous dipolar nucleophiles - , etc. The reader will appreciate that all of these constitute alternate entries into our subject. 

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). ... 

Recently several examples have been found of reactions involving thermal cleavage of the carbon-carbon bond of more heavily substituted aziridines. This reaction which takes place with particular facility with 2-aroyl-3-aryl aziridines and similar compounds containing polarised carbon-carbon bonds gives rise to azo-methine ylids which may often be trapped with dipolarophiles to give five mem-bered ring heterocycles in 1,3 dipolar additions... 

In the third article, Porter describes the chemistry of thiophenium salts and ylids, to which he has contributed extensively. The chemistry of 1,4-diazocines is presented by Perlmutter this article follows an earlier review by the same author on azocines in Volume 31 of Advances in Heterocyclic Chemistry. The final article of this volume, and the second contribution from Japan, is by Tsuge and Kanemasa and deals with recent advances in azomethine ylide chemistry. 

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