Betaine ylides

The normal preference for (Z) alkenes in reactions of non-stabilized phos-phoranes can be reversed by employing the Schlosser modification of the Wittig reaction (Scheme 6).19 Here, equilibration of the initially formed erythro and threo betaine intermediates is achieved by reaction with additional strong base, usually an alkyl lithium. The resulting betaine ylide then gives the (E) alkene on treatment with a proton source followed by potassium tert-butoxide. 

This reaction has been further modified by intercepting the betaine ylide with electrophiles other than a proton to give trisubstituted alkenes in which the electrophile is introduced at what was the phosphorane a-carbon. This reaction is referred to as the a-substitution plus carbonyl olefination via P-oxodphosphorus ylides (SCOOPY) reaction.20... 

Schlosser, M., Coffinet, D. a-SubstItutlon plus carbonyl olefinatlon via P-oxido phosphorus ylides (SCOOPY) reactions. Stereoselectivity of allyl alcohol synthesis via betaine ylides. Synthesis 1971, 380-381. 

Wang, Q., Deredas, D., Huynh, C., Schlosser, M. Sequestered alkyllithiums why phenyllithium alone is suitable for betaine-ylide generation. Chem.— Ear. J. 2003, 9, 570-574. 

Die aus Yliden 34 und Alddiyden 333 entstehenden Betaine 368 lass sich vorzugsweise bei tiefen Temperaturen mit Li-Organylen umsetzen. Dabei entstehen die sogenannten. .Betain-ylide" 24) u. a. durch die beiden Grenzforraeln 369a und 369b zu beschreiben sind ... 

In this context, one may also pay attention to the so-called "betaine-ylides" that act as key intermediates in stereocontrolled Wittig olefination reactions. They are generated from the ordinary adducts obtained by the combination of a phosphine ylide and an aldehyde in the presence of lithium bromide (or another soluble lithium salt). When the P-betaines are a-deprotonated with phenyllithium, the stereocenter at the phosphorus-adjacent carbon atom becomes configurationally mobile. In this way, erythro/threo mixtures can spontaneously convert into virtually pure /Areo-betaine ylides (p-lithiooxy ylides, P-oxido ylides). Reprotonation and subsequent elimination of triphenylphosphine oxide affords trans olefins, whereas a-substitution by electrophiles other than acids leads to branched alkenes exhibiting a well-defined stereochemistry "("three-dimensional"" Wittig reaction or SCOOPY method). ... 

Accumulating evidence makes it increasingly clear that there is no single dominant Wittig transition state geometry and, therefore, no simple scheme to explain cis/trans selec-tivities. The conventional betaine pathway may not occur at all, the stabilized ylides, e,g., PhsP—CH —C02Et, can be ( )- or (Z)-selective, depending on the solvent and substrate (E. Vedejs, 1988 A, B, 1990). 

Azole iV-oxides, iV-imides and iV-ylides are formally betaines derived from iV-hydroxy-, iV-amino- and iV-alkyl-azolium compounds. Whereas iV-oxides (Section 4.02.3.12.6) are usually stable as such, in most cases theiV-imides (Section 4.02.3.12.5) andiV-ylides (Section 4.02.3.12.3) are found as salts which deprotonate readily only if the exocyclic nitrogen or carbon atom carries strongly electron-withdrawing groups. 

Tnfluoromethyl-substUuted 1,3-dipoles of the propargyl-allenyl type and trifluoromethyl-substituted nitrilium betaines. Tnfluoromethyl- [164, 765] and bis(trifluoromethy])-substituted [166, 167] nitrile ylides have been generated by different methods and trapped with various dipolarophiles to yield [3+2] [768] and [3+1] cycloadducts [769], respectively... 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

In the Wittig reaction, a phosphorus ylide, R2C—P(C6H03, also called a phosphoreme and sometimes written in the resonance form R2C=P(C6H5)3, adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine. (An ylide—pronounced ill-id—is a neutral, dipolar compound with adjacent plus and minus charges. A betaine—pronounced bay-ta-een—is a neutral, dipolar compound with nonadjacent charges.)... 

There are four main factors that affect the enantioselectivity of sulfur ylide-mediated reactions i) the lone-pair selectivity of the sulfonium salt formation, ii) the conformation of the resulting ylide, iii) the face selectivity of the ylide, and iv) betaine reversibility. 

The fourth factor becomes an issue when anti betaine formation is reversible or partially reversible. This can occur with more hindered or more stable ylides. In these cases the enantiodifferentiating step becomes either the bond rotation or the ring-closure step (Scheme 1.12), and as a result the observed enantioselectivities are generally lower (Entry 5, Table 1.5 the electron-deficient aromatic ylide gives lower enantioselectivity). However the use of protic solvents (Entry 6, Table 1.5) or lithium salts has been shown to reduce reversibility in betaine formation and can result in increased enantioselectivities in these cases [13]. Although protic solvents give low yields and so are not practically useful, lithium salts do not suffer this drawback. [18]... 

As the formation of betaines from amide-stabilized ylides is known to be reversible (in contrast with aryl- or semistabilized ylides, which can exhibit irreversible anti betaine formation see Section 1.2.1.3), the enantiodifferentiating step cannot be the C-C bond-forming step. B3LYP calculations of the individual steps along the reaction pathway have shown that in this instance ring-closure has the highest barrier and is most likely to be the enantiodifferentiating step of the reaction (Scheme 1.16) [25]. 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

D. Miscellaneous.—Low yields of the spirophosphoranes (34) were obtained on heating the phosphorane (32) with the aziridines (33). Stable phosphoranes have been obtained from phenanthraquinone mono-imine (35) and trialkyl phosphites, and from 2-chlorotropone (36) and ylides. In the latter reaction cyanomethylenetriphenylphosphorane gave instead the betaine (37). 

Carbonyls. The stereochemistry of the Wittig olefin synthesis has been reviewed. /i-a/u-Stereoselective olefin synthesis via /3-oxido-ylides is possible only in the presence of soluble lithium salts. Protonation of jS-oxido-ylides prepared from salt-free ylides leads to mixtures of erythro-and r/jr o-betaines and hence to mixtures of cis- and rm/i5-olefins. 

The formation of the naphthalene (73) from the bis-ylide (72) and diethyl ketomalonate involves an unusual olefin synthesis on the carbonyl of an ester group. The methylene-pyrans (75) were formed when the diethyl malonates (74) were refluxed with j3-keto-ylides in xylene or decalin. Possible intermediates are the ketens (76) and the allenes (77). Addition of ylide to the allenes gives the betaines (78) which form methylene-pyrans either directly or via acetylenes as shown. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

In agreement with the behavior of ylides 427/441 the pyridinium imine betaines 446 gave rise to the formation of oxazinones 447 on interaction with diphenyl cyclopro-penone274 or its thio analogue275 ... 

The (3 + 3) cycloaddition principle has been extended to the heterocyclic betaines 448 representing aza analogues of ylides 427. The betaines 448 combined with diphenyl cyclopropenone and its thione268 to yield the condensed heteroaromatic systems 449 ... 

Addition of benzotriazole to l-phenyl-2-aroylacetylenes gives a,/3-unsaturated ketones 221 in high yields. By treatment with dimethylsulfonium ylide, ketones 221 are converted to epoxides 222, Opening of the oxirane ring and electrophilic attack of the obtained tertiary carbocation on N-2 of the benzotriazole system leads to betaines 223 that consecutively eliminate formaldehyde to give triazapentalenes 224 (Scheme 28) <2004ARK(iii)109>. 

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