Phosphonium ylides acylation

Since the pioneering work of H. J. Bestmann and coworkers in the 1960s, acylation of phosphonium ylides is a well known process for the preparation of P-ox-ophosphonium yhdes. The classical way (a) using acylating agents such as acyl chlorides and in situ transylidation is still useful (Scheme 4) [16,17]. 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Particularly interesting are the results obtained with the phosphonium ylides including an acyl rest derived from aminoacid if the N-H bond reactivity is blocked by an amide protection, the alkyne formation takes place [25,27], but if the N-H bond is not deactivated, an intramolecular cyclization occurs to give a new stabilized ylide [27,28]. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

In the reactions with phosphonio-a-methoxycarbonyl-alkanides, the products of type 261 derived from 1,3-cycloaddition can rearrange to the tautomeric lif-pyrazolo-triazole (87MI2). The reaction of 3-diazopyra-zoles and 3-diazoindazole with acyl-substituted phosphonium ylides led to pyrazolo-triazine and indazolo-triazine derivatives 266 instead of the expected triazole compounds (8IJHC675). In this case, the ylides, which can exist as phosphonium enolates, possess nucleophilic and electrophilic centers in a /8-relationship, giving [7 + 2] or [11 -I- 2]cycloaddition reactions. With dimethylsulfonio-a-aroyl-methanides, very complex, temperature-dependent mixtures were obtained, in some cases with sulfur retention (87MI3). 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

The reaction between a phosphonium ylidc derived from a fluorotrihalomcthane and an acetyl halide leads to the ylide acylation product 9 and the salt 10 by the Wittig reaction. This has been used to obtain alkenes 11 from acyl halides. ... 

Besides protons a series of heteroligands in the a-position of phosphonium ylides can also be substituted, giving rise to the formation of new alkylidenephosphoranes. Halogen atoms have been substituted by carbon groups (with lithium organyls or acyl chlorides) or another halogen. Reaction of a-lithiated ylides (see equation 35) or ylide anions with electrophiles may be considered as substitution of an alkali metal substituent at the ylide carbon atom. 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

Esters with one or two fluorines at the a-carbon are useful building blocks for construction of interesting and novel biologically active substrates. Alkylation of a-fluorocarboethoxy phosphonium ylides followed by hydrolysis of the resultant phosphonium salt with 5% aqueous sodium bicarbonate provides a useful preparative route to a-fluoroesters. Similarly, acylation/hydrolysis of either a-fluoro phosphonium ylides or a-fluorophosphonate anions gives a general route to 2-fluoro-3-oxo-esters. The a,a-difluoroesters can be prepared by Cu° catalyzed addition of iododifluoroacetates to olefins followed by reduction of the iodo addition adduct. Both terminal and internal olefins participate equally well in the addition reaction. 

In contrast to the straightforward facile acylation-hydrolysis reaction of the a-fluoro phosphonium ylide, the acylated product from the a-fluoro phosphonate carbanion is cleaved by base in two different ways. When R is a hydrocarbon group, such as CH3 or C5H5CH2, attack at the acyl carbon with bases, such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium silanoate is favored (Path II in equation 13) with resultant elimination of the a-fluorophosphonate anion. Less than 10% of the desired 2-fluoro-3-oxoester is observed. However, when R is a halofluoroalkyl group (CF3, CF2CI, C3F7), attack of the base (aqueous sodium bicarbonate) occurs only at phosphorus (Path I in equation 13) and the 2-fluoro-3-... 

Acyl carbene equivalents The moderately stabilized RCOCH=BPhj ylides are generated from the tetrafluoroborate salts. These ylides react with aldehydes to give a,p-epoxy ketones, in contrast to the stibonium, arsonium, and phosphonium ylides, which afford enones. The weaker Bi-0 bond disfavors decomposition of the adducts into enones and the bismuthine oxides. 

Addition reactions of (l-methoxyalkyl)triphenylphosphonium ylides, derived from the corresponding phosphonium salts (82) and n-BuLi, to aldehydes at — 78 °C followed by quenching the reaction mixture with aqueous NH4CI at the same temperature alforded a-hydroxyketones instead of the expected enol ethers.This is the first example of phosphonium ylides acting as an acyl anion equivalent. Flash vacuum pyrolysis (FVP) in a conventional flow system at 10 (84), prepared in a few steps... 

Many alkylidenephosphoranes can be transformed into new phosphonium ylides by reactions which take place in the side chain of a parent ylide, the a-C atom of the ylide group not being involved. Allylidenetriphenylphosphoranes react with a series of chloro compounds (alkyl chloioformates, acyl chlorides, 3-chloroacrylates, 2-chlorovinyl ketones, phosphorus chlorides) and other electrophilic compounds at the 7-C atom. Abstraction of a proton from the 7-position of the resulting phosphonium salts by a second mole of starting ylide (or proton migration) gives rise to the formation of -substituted derivatives of the original allylidenephosphoranes (equation 90). 

Fluonnated ylides have also been prepared in such a way that fluonne is incorporated at the carhon P to the carbamonic carbon Vanous fluoroalkyl iodides were heated with tnphenylphosphine in the absence of solvent to form the necessary phosphonium salts Direct deprotonation with butyUithium or hthium dusopropy-lamide did not lead to yhde formation, rather, deprotonation was accomparued by loss of fluonde ion Flowever deprotonation with hydrated potassium carbonate in thoxane was successful and resulted in fluoroolefin yields of45-S0% [59] (equation 54) P-Fluorinated ylides may also be prepared by the reaction of an isopropyli-denetnphenylphosphine yhde with a perfluoroalkanoyl anhydnde The intermediate acyl phosphonium salt can undergo further reaction with methylene tnphenylphosphorane and phenyUithium to form a new yhde, which can then be used in a Wittig olefination procedure [60] (equation 55) or can react with a nucleophile [6/j such as an acetyhde to form a fluonnated enyne [62] (equation 56)... 

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