Stabilized carbon nucleophiles

Treatment of y-nitro alcohols with diethyl azodicarboxylate DEAD and triphenylphos-phine affords nitrocyclopropanes with inversion of configuration at the a-carbon via the intramolecular Mitsunobu reaction involving carbon nucleophiles stabilized by the nitro group (equation 16)28. The reaction works best with nitro compounds (pA"a < 17) and is not applicable to the sulfonyl derivatives (pATa 25). 

The use of carbon nucleophiles stabilized by SR groups has been a feature of sulphur chemistry for many years now, and this year has seen additional uses for these versatile reagents. Thus the carbanion CH(SPh)2 adds in a 1,2-manner to 2-methylacrolein giving the allyl alcohol (175), which is then converted to the activated diene (176) by standard methodology. The latter has been used in studies towards the total synthesis of the Rubradirin antibiotics. The related anion ArC(SPh)2 also adds to a,/3-unsaturated systems however, in the case of lactone (177) conjugate addition is observed. If the initial ion from (177) is trapped with benzylic bromides then frans-butyrolactones (178) are obtained in good yield. ... 

Interestingly, the allylation of a stabilized carbon nucleophile has been found to be reversible. Complete isomerization of dimethyl methylmalonate, involving bis-allylic C—C bond cleavage, from a secondary carbon 38 to a primary carbon 39 was observed by treatment with a Pd catalyst for 24 h. The C—C bond cleavage of a monoaliylic system proceeds slowly[40]. 

For trisubstituted olefins, the nucleophile attacks predominantly at the less substituted end of the allyl moiety, e.g. to afford a 78 22 mixture of 13 and 14 (equation 7). Both the oxidative addition of palladium(O) and the subsequent nucleophilic attack occur with inversion of configuration to give the product of net retention7. The synthesis of the sex pheromone 15 of the Monarch butterfly has been accomplished by using bis[bis(l,2-diphenylphosphinoethane)]palladium as a catalyst as outlined in equation 87. A substitution of an allyl sulfone 16 by a stabilized carbon nucleophile, such as an alkynyl or vinyl system, proceeds regioselectively in the presence of a Lewis acid (equation 9)8. The... 

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

The Wittig and Related Reactions of Phosphorus-Stabilized Carbon Nucleophiles... 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

Highly stabilized phosphorus ylides are prepared from acetylenic esters, a carbon-based nucleophile, and triphenylphosphine in aqueous media.40 In acetone-water (2 1) solvent, the reaction proceeds via the conjugate addition of triphenylphosphine to dialkyl acetylenedicarboxy-lates the resulting vinyl triphenylphosphonium salts undergo Michael addition reaction with a carbon-nucleophile to give the corresponding highly stabilized phosphorus ylides. 

The preparation of 5-chloro-l,2,4-thiadiazol-2-ium chlorides 95 by treatment of formimidoyl isothiocyanates 94 with a twofold excess of methanesulfenyl chloride has been reported in an unusual variation of a type C synthesis. These salts show interesting chemical behavior toward several nitrogen and carbon nucleophiles. The nature of the N-substituent determines the stability of the salt 95. When the substitutent on nitrogen is /-butyl, the salt 95 decomposes readily in solution to give the 5-chloro-l,2,4-thiadiazole 96 (Scheme 10) <2003HAC95>. 

Alkoxycarbenium ions are important reactive intermediates in modem organic synthesis.28 It should be noted that other names such as oxonium ions, oxocarbenium ions, and carboxonium ions have also been used for carbocations stabilized by an adjacent oxygen atom and that we often draw structures having a carbon-oxygen double bond for this type of cations.2 Alkoxycarbenium ions are often generated from the corresponding acetals by treatment with Lewis acids in the presence of carbon nucleophiles. This type of reaction serves as efficient methods for carbon-carbon bond formation. 

The first examples of iridium-catalyzed allylic substitution [1] occurred between stabilized carbon nucleophiles and both alkyl- and aryl-substituted allylic alcohol derivatives with exceptional selectivity for the branched substitution product. 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

Hard carbon nucleophiles that do not contain stabilizing electron-withdrawing substituents have been shown to react with allylic carbonates only recently in the... 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

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