Carbonyl, addition acetate anion

This process has been coupled with meta addition of a carbonyl anion equivalent and the controlled exo addition of the incoming nucleophile to generate acorenone and acorenone B stereospecifically from [(o-methylanisole)Cr(CO)3] (63 Scheme 14).123 The first step is addition of a cyanohydrin acetal anion (64) to the less-hindered meta position in [(o-methylanisole)Cr(CO)3]. Addition of allylMgBr to the resulting ketone, anti-Markovnikov addition of HBr to the alkene, substitution for Br by CN, and coordina-... 

Hydroxide ion can react at two different sites of the B-keto ester. Abstraction of the acidic a-proton is more favorable but is reversible and does not lead to product. Addition of hydroxide ion to the carbonyl group, followed by irreversible elimination of ethyl acetate anion, accounts for the observed product. 

Addition of anionic nucleophiles to alkenes and to heteronuclear double bond systems (C=0, C=S) also lies within the scope of this Section. Chloride and cyanide ions are effieient initiators of the polymerization and copolymerization of acrylonitrile in dipolar non-HBD solvents, as reported by Parker [6], Even some 1,3-dipolar cycloaddition reactions leading to heterocyclic compounds are often better carried out in dipolar non-HBD solvents in order to increase rates and yields [311], The rate of alkaline hydrolysis of ethyl and 4-nitrophenyl acetate in dimethyl sulfoxide/water mixtures increases with increasing dimethyl sulfoxide concentration due to the increased activity of the hydroxide ion. This is presumably caused by its reduced solvation in the dipolar non-HBD solvent [312, 313]. Dimethyl sulfoxide greatly accelerates the formation of oximes from carbonyl compounds and hydroxylamine, as shown for substituted 9-oxofluorenes [314]. Nucleophilic attack on carbon disulfide by cyanide ion is possible only in A,A-dimethylformamide [315]. The fluoride ion, dissolved as tetraalkylammo-nium fluoride in dipolar difluoromethane, even reacts with carbon dioxide to yield the fluorocarbonate ion, F-C02 [840]. 

The search for endothelin antagonists as potential compounds for treating cardiovascular disease was noted in Chapter 5 (see atrasentan). A composed with a considerably simpler structure incorporates a pyrimidine ring in the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of the enolate from the acetate to the benzophenone carbonyl. The aUcoxide anion on the first-formed quaternary carbon then displaces chlorine on the acetate to leave behind the oxirane in the observed product (95). Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether-alcohol (96). Reaction of this with the pyrimidine (97) in the presence of base leads to displacement of the methanesulfonyl group by the aUcoxide from 96. Saponification of the ester group in that product gives the corresponding acid, ambrisentan (98). " ... 

Carbanions (and other anions) can undergo fragmentation reactions to produce a carbanion and a smaller molecule, usually carbon dioxide or a molecule containing a carbonyl group. Examples include the loss of carbon dioxide from the acetate anion (reaction 4.9), considered above. Other important examples include reactions of type (4.34), which are the reverse of addition reactions such as (4.20) and (4.30). 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Iodide and acetate salts increase the rate of reaction of Li [1] with CH3I at 25 °C in acetic acid. The effects of water, LiBF4, and other additives are also reported. Iodide salts also promote catalytic methanol carbonylation at low water concentrations. In the case of Lil promoter, lithium acetate is produced. The promotional effects of iodide and acetate on both the model and catalytic systems are rationalized in terms of iodide or acetate coordination to (1) to yield five-coordinate RhI anions as reactive intermediates for rate-determining reactions with CH3I.11... 

In addition to the polymeric rhodium catalysts previously discussed, monomeric rhodium systems prepared from [Rh(CO)2Cl]2 by addition of strong acid (HC1 or HBF4) and Nal in glacial acetic acid have also been shown to be active homogeneous shift catalysts (80). The active species is thought to be an anionic iodorhodium carbonyl species, dihydrogen being produced by the reduction of protons with concomitant oxidation of Rh(I) to Rh(III) [Eq. (18)], and carbon dioxide by nucleophilic attack of water on a Rh(III)-coordinated carbonyl [Eq. (19)]. 

Reactions 7 and 8 involve oxidation of rhodium(I) to rhodium(III). Reaction 8 can also be written as an oxidative addition of I2 (formed thermally from 2 HI) to the Rh(I) complex. Rhodium(III) iodide (for convenience written as an anionic carbonyl complex) may precipitate from the reaction medium. It has to be converted to rhodium(I) again. This is done in the acetic acid process by water and carbon monoxide. 

The iodide content of the catalyst formulation is the key to avoiding these problems of competing reactions and achieving maximum acetic acid selectivity. The addition of iodide ensures that any initially formed methanol (7) is rapidly (H) converted to the more electrophilic methyl iodide. However, further increases in the quantities of iodide beyond that needed for methanol conversion to methyl iodide may lead to a portion, or all, of the catalytic-ally active cobalt carbonyl reverting to catalytically inactive cobalt iodide species - e.g. the [Col4] anion identified in this work, or possibly the cationic [Co(MeOH) (CO) I species (9). 

Treatment of the reduced intermediate (23-6) with butyl hthium leads to the anion from the removal of a proton on the methylene group reaction of that with methyl acetate affords the methyl ketone (24-1), which contains two of the three required side chain carbon atoms. The additional carbon atom and the basic function are incorporated by means of a Mannich condensation. Thus, reaction of (24-1) with A-methylpiperazine and formaldehyde leads to the aminoketone (24-2). The carbonyl group is then reduced with sodium borohydride and the resulting alcohol is dehydrated by reaction with phosphoms oxychloride in pyridine. In this case, too, the Z isomer is responsible for most of the activity. This is isolated from the resulting mixture of olefins to afford thiothixene (24-3) [25]. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

The pathway by which the reactions are considered to occur involves attack of the enolate anion at the 1 0 bond of o-iodosyl benzoic acid followed by reductive elimination of o-iodobenzoic acid upon addition of methoxide to the carbonyl group. Ring opening of the epoxide thus formed yields the hydroxy dimethyl acetal ... 

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