Selected Applications of Ylides in Synthesis

The addition of two equivalents of an acylmethylenetriphenylphosphorane to the hydroximoyl chlorides (61) results in a transylidation reaction, leading to the forma- 

Vaultier, R. Danion-Bougot, D. Danion, J, Hanielin, and R, Carrie, Bull, Sac. chim. France, 1976, 1537. 

Pteridines have been prepared by the treatment of the nitroso-uracil (62) with phenacylidenetriphenylphosphorane.  

The addition of amines to propadienyltriphenylphosphonium bromide gives salts (63), which exist in either the enamine or imine form. The application of these salts 

General.—A synthesis of /S-unsaturated aldehydes uses the ylide from the salt (63) followed by hydrolysis of the resulting acetals. Vinyloxazines (65), 

Among other interesting phosphoranes used successfully in olefin synthesis are (66) and those derived from the salts (67), (68), (69), (70), (71), and (72) together with analogues of (72) prepared using other dienes.  

The stilbene obtained from the salt (73) and the aldehyde (74) in methanol was predominantly trans whereas it was predominantly cis when the reaction was carried out in DMF.  

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Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

The perfluoroacetamide catalysts, rhodium(II) trifluoroacetamidate [Rh2(tfm)4] and rhodium(II) perfluorobutyramidate [Rh2(pfbm)4], are interesting hybrid molecules that combine the features of the amidate and perfluorinated ligands. In early studies, these catalysts were shown to prefer insertion over cycloaddition [30]. They also demonstrated a preference for oxindole formation via aromatic C-H insertion [31], even over other potential reactions [86]. In still another example, rhodium(II) perfluorobutyramidate showed a preference for aromatic C-H insertion over pyridinium ylide formation, in the synthesis of an indole nucleus [32]. Despite this demonstrated propensity for aromatic insertion, the perfluorobutyramidate was shown to be an efficient catalyst for the generation of isomtinchnones [33]. The chemoselectivity of this catalyst was further demonstrated in the cycloaddition with ethyl vinyl ethers [87] and its application to diversity-oriented synthesis [88]. However, it was demonstrated that while diazo imides do form isomtinchnones under these conditions, the selectivity was completely reversed from that observed with rhodium(II) acetate [89, 90]. 

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). 

The last comprehensive survey of this area dates back to 1984, when the two-volume set edited by Padwa, 1,3-Dipolar Cycloaddition Chemistry, appeared. Since then, substantial gains in the synthetic aspects of this chemistry have dominated the area, including both methodology development and a body of creative and conceptually new applications of these [3+ 2]-cycloadditions in organic synthesis. The focus of this volume centers on the utility of this cycloaddition reaction in synthesis, and deals primarily with information that has appeared in the literature since 1984. Consequently, only a selected number of dipoles are reviewed, with a major emphasis on synthetic applications. Both carbonyl ylides and nitronates, important members of the 1,3-dipole family that were not reviewed previously, are now included. Discussion of the theoretical, mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have been kept to a minimum, but references to important new work in these areas are given throughout the 12 chapters. 

In contrast to considerations of 50 years ago, today carbene and nitrene chemistries are integral to synthetic design and applications. Always a unique methodology for the synthesis of cyclopropane and cyclopropene compounds, applications of carbene chemistry have been extended with notable success to insertion reactions, aromatic cycloaddition and substitution, and ylide generation and reactions. And metathesis is in the lexicon of everyone planning the synthesis of an organic compound. Intramolecular reactions now extend to ring sizes well beyond 20, and insertion reactions can be effectively and selectively implemented even for intermolecular processes. 

Thiazolylium quaternary salts show great reactivity toward nucleophiles. The unsubstituted 2-position of thiazolylium and benzothiazolylium cations is exceptionally reactive and its hydrogen atom is removed by bases affording an ylide which is particularly stabilized by the adjacent sulfur atom. This stabilization is for a large part responsible for the natural selection of thiazolylium, among other azolyliums, as the active part of vitamin Bi. 2-Alkylthiazolylium and benzothiazolylium quaternary salts are transformed by bases into exceptionally reactive anhydro bases which have wide application in synthesis. 

Aggarwal VK, Winn CL. Catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds scope, selectivity, and applications in synthesis. Acc. Chem. Res. 2004 37 611-620. Li A-H, Dai L-X, Aggarwal VK. Asymmetric ylide reactions epoxidation, cyclopropanation, aziridination, olefination, and rearrangement. Chem. Rev. 1997 97 2341-2372. 

The majority of published work on aza-ylides concerns their applications in synthesis, and here we report a selection of contributions from this area. The Staudinger reaction is a popular route to aza-ylides and has been used to prepare a series of perfluoroalkyl-tagged aza-Wittig reagents, e.g., (68), which were generated in situ (Scheme 22), and utilised in the synthesis of 3//-quinazolidine-4-ones in a fluorous biphasic system. A method for the preparation of aza-polycyclic compounds derived from pyrrolidine, indolizidine and indole has... 

Selected Applications in Synthesis 4.1 Carotenoids, Retenoids and Pheromones.- Classical Wittig methods involving the ylide (146) and the dialdehyde (147) have been used to synthesize (148), a diastereoisomer of decaprenoxanthin.88 The retinonitrile (150) has been prepared as a mixture of four geometric isomers by phosphonate-based olefination of the 1-cis, 9-cis-Ci5-aldehyde (149). It was possible to separate the four isomers of (150) and reduce each of them to the corresponding retinal. 

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

Comparable cis/trans selectivities and similar conformational effects on them were studied in ring enlargements of cyclic sulfonium ylides. ° Rearrangements of sulfur ylides performed in repetition were used for stepwise ring expansion 5- 8—> 11- —> 14- - 17-membered. ° Synthesis applications of... 

Scope, selectivity, and applications in the synthesis of catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds 04ACR611. 

Similar to carbonyl ylides, azomethine ylides are normally generated as transient species in situ, and a number of protocols have been established so far [22]. Among them, the transition-metal-mediated procedures have enj oyed great privileges in terms of milder reaction conditions, better selectivities, and broad functional group tolerance. This part focuses on the recent development of transition-metal-mediated in situ generation of (metal-containing) azomethine ylides as well as their applications for the synthesis of aromatic compounds. 

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