Halides benzylic, carboxylation

Complexes of other metals are also capable of catalyzing useful carbonylation reactions under phase transfer conditions. For example, certain palladium(o) catalysts, like Co2(C0)g, can catalyze the carbonylation of benzylic halides to carboxylic acids. When applied to vinylic dibromides, unsaturated diacids or diynes were obtained, using Pd(diphos)2[diphos l,2-bis(diphenylphosphino)ethane] as the metal catalyst, benzyltriethylammonium chloride as the phase transfer agent, and t-amyl alcohol or benzene as the organic phase(18),... 

The phase-transfer method has also been employed for the carbonylation of benzylic halides to carboxylic acids.477 The palladium(O) complexes [Pd(PPh3)4] (103), [Pd(diphos)2] (104) and [Pd(DBA)2] (105 DBA = dibenzylideneacetone) were used as catalysts. With (103) and (104) the carboxylic acid was the major product. Complex (105) gave little or none of the acid, the toluene and bibenzyl derivatives corresponding to the benzyl halide used being formed. Benzyl esters of the carboxylic acid were sometimes present as minor products. The reaction has been adapted to provide a new synthesis of anthranilic acid derivatives (equation 106).478 Tri-n-butylamine was used to neutralize the HBr formed. 

Other organometallic reagents can be used to convert alkyl halides to carboxylic acid derivatives. Benzylic halides were converted to carboxylic esters with CO in the presence of a rhodium complex, ether a borate ester B(OR )3,... 

MeO , OH , or EtO and methyl fluoride, anisole, and 4-fluoroanisole on the gas-phase 5 2 reactions between dimethylmethylphosphonate and methylformate and HOO versus HO , MeO , or EtO in an attempt to discover the origin of the O -effect on the Sf 2 reaction of carbanions with 4-substituted benzyl chlorides in liquid ammonia " on the solvolysis reaction and the 2 reaction between phenoxide ions, and both neutral and negatively charged amines and 4-substituted benzyl chlorides in liquid ammonia on the ionization rates (the step) of the 5" 1 reactions of many substituted trityl halides and carboxylates in aqueous acetone and in aqueous and pure acetonitrile in the presence of piperidine on the ionization rates ( i) of the 5 reactions of various diarylmethyl chlorides in the presence of piperidine, pyridine, or PPh3 in several dipolar aprotic solvents on the solvolyses of X,Y-substituted benzhydryl acetates in various aqueous MeOH and EtOH solutions and on the dispersions observed in Grunwald-Winstein correlations of 5 solvolyses of substrates with substituents containing adjacent tt-electrons. ... 

Allyl halides are probably the most common allylic reagents used. Palladium complexes with not only simple 77 -allylic moieties, but also cyclic derivatives, t/ -benzyls, 77 -allylic complexes derived from morphine alkaloids, and trialkyltin-subtituted T/ -allyls have been synthesized by oxidative addition of appropriate halides. Allyl carboxylates, especially acetates, are also common. When combined with other fimctionalities in the substrate, they lead to functionalized T/ -allylic Pd complexes. Examples of ester-substituted T/ -allyls obtained by reaction of the corresponding allylic trifluoroacetates 88 have been reported. Palladium complexes that bear an 7 -allyl with a pendant 2-pySiMc2-, where the py group coordinates to Pd, have been prepared from the corresponding allylic acetates 89. Allyl carbonates are also commonly used both in the stoichiometric preparation of -allylic complexes and in catalytic reactions that proceed through Pd -allylic intermediates. ... 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

Reagents that provide UV adsorptive derivatives of carboxylic acids are fairly numerous. The preparation of the simple benzyl esters by reacting the carboxylic ion with alkyl halides or diazo compounds has been unsuccessful due to their having unacceptable toxicity. The... 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0")2 ] by treatment with a strong base such as LDA. The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH2COOH and RR"CHCOOH. This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 458),... 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

If one of the species is anionic and we need to transport it to the organic phase, then a phase-transfer catalyst may be employed. Consider the example of benzyl penicillin where the reaction between phenyl acetic acid and the penicillin carboxylate ion, with penicillin amidase as a catalyst, is relevant, and which at pH 4.5 - 5.0 is shifted in the desired direction. Here a catalyst like tetrabutylammonium halide works, and with chloroform as a solvent 60% yield can be realized in contrast to a yield of only 5 - 10 % in water. 

The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Since each of these nucleophiles can also act as a base, reaction conditions are selected to favor substitution over elimination. Usually, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformation is not used extensively for synthesis. The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good yield. This can be a useful synthetic transformation because benzyl halides are available either by side chain halogenation or by the chloromethylation reaction (Section 11.1.3). 

Route A 1- is very convenient for the substitution of OH groups by bromide or iodide. The reaction conditions are relatively mild (acetonitrile, room temperature, and reflux for 1—3 h, neutral medium). The activating halide (methyl iodide, ally or benzyl bromide) is added in excess (5 equivalents) or in large excess (10 equivalents) when the resultant halide is nearly as reactive as the activating halide. The imidazolium-iV-carboxylates are the important intermediates, which undergo a displacement reaction to give the halides,... 

Hydroxycarbonylation and alkoxycarbonylation of alkenes catalyzed by metal catalyst have been studied for the synthesis of acids, esters, and related derivatives. Palladium systems in particular have been popular and their use in hydroxycarbonylation and alkoxycarbonylation reactions has been reviewed.625,626 The catalysts were mainly designed for the carbonylation of alkenes in the presence of alcohols in order to prepare carboxylic esters, but they also work well for synthesizing carboxylic acids or anhydrides.137 627 They have also been used as catalysts in many other carbonyl-based processes that are of interest to industry. The hydroxycarbonylation of butadiene, the dicarboxylation of alkenes, the carbonylation of alkenes, the carbonylation of benzyl- and aryl-halide compounds, and oxidative carbonylations have been reviewed.6 8 The Pd-catalyzed hydroxycarbonylation of alkenes has attracted considerable interest in recent years as a way of obtaining carboxylic acids. In general, in acidic media, palladium salts in the presence of mono- or bidentate phosphines afford a mixture of linear and branched acids (see Scheme 9). 

The electrochemistry of cobalt-salen complexes in the presence of alkyl halides has been studied thoroughly.252,263-266 The reaction mechanism is similar to that for the nickel complexes, with the intermediate formation of an alkylcobalt(III) complex. Co -salen reacts with 1,8-diiodo-octane to afford an alkyl-bridged bis[Co" (salen)] complex.267 Electrosynthetic applications of the cobalt-salen catalyst are homo- and heterocoupling reactions with mixtures of alkylchlorides and bromides,268 conversion of benzal chloride to stilbene with the intermediate formation of l,2-dichloro-l,2-diphenylethane,269 reductive coupling of bromoalkanes with an activated alkenes,270 or carboxylation of benzylic and allylic chlorides by C02.271,272 Efficient electroreduc-tive dimerization of benzyl bromide to bibenzyl is catalyzed by the dicobalt complex (15).273 The proposed mechanism involves an intermediate bis[alkylcobalt(III)] complex. 

Cobaloxime(I) generated by the electrochemical reductions of cobaloxime(III), the most simple model of vitamin Bi2, has been shown to catalyze radical cyclization of bromoacetals.307 Cobalt(I) species electrogenerated from [ConTPP] also catalyze the reductive cleavage of alkyl halides. This catalyst is much less stable than vitamin Bi2 derivatives.296 It has, however, been applied in the carboxylation of benzyl chloride and butyl halides with C02.308 Heterogeneous catalysis of organohalides reduction has also been studied at cobalt porphyrin-film modified electrodes,275,3 9-311 which have potential application in the electrochemical sensing of pollutants. 

It has been shown that reaction of carboxylic acids with benzyl halides, which does not occur when heated conventionally, could be performed efficiently under the action of MW irradiation in the presence of a quaternary ammonium salt as a catalyst (Eq. 3) [15]. Typical results are given in Tab. 5.3. 

Racemic fra .s-A--benzyl-2.5-bis-(ethoxycarbonyl)pyrrolidine has been resolved via its dicarboxylic acid, followed by subsequent transformation to offer (2R,5R)-21 or (25,5S -21. The absolute configuration of the alkylated carboxylic acids indicates that the approach of alkyl halides is directed to one of the diastereotopic faces of the enolate thus formed. In the following case, the approached face is the 57-face of the (Z)-enolate. By employing the chiral auxiliary (2R,5R)-21 or its enantiomer (25.55)-21. the (/ )- or (S)-form of carboxylic acids can be obtained with considerably high enantioselectivity (Table 2-4). 

Method A The finely powdered potassium salt of the carboxylic acid (11 mmol) is added to the alkylating agent [ 11 mmol for RX 5.5 mmol for X(CH2) X, 20 mmol with allylic and benzylic halides] and Aliquat or TBA-Br (0.1 mmol). The mixture is shaken vigorously for 15 min and then allowed to stand (see Table 3.9). The mixture is diluted with Et20 (60 ml), filtered through Florisil, and evaporated to yield the ester. 

In spite of the general lack of detailed understanding of mechanism, the procedure is superior to that using the cobalt catalyst both in the overall yields and in the specificity of the reaction to produce only mono-carbonylation products. Prolonged reaction times may lead, however, to the formation of benzyl esters of the acids, as a result of a catalysed reaction of the halide with the carboxylate anion. 

Cobalt(lll)(salen) catalyses the carboxylation of benzyl chlorides and allyl chlorides but not of halobenzenes [246], PdCl2(PPh3)2 catalyses the carboxylation of aryl halides, P-bromostyrene and allyl acetates [247]. 

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