Benzoic acid arylation, aryl chlorides

Another method that has been developed for benzoic acid arylation by aryl iodides involves use of a combination of catalytic palladium acetate with stoichiometric silver acetate in acetic acid (Scheme 14) [61], This method is tolerant of chloride and bromide substitution and most likely proceeds through a Pd(II)-Pd(IV) coupling cycle. Moderately electron-poor to electron-rich benzoic acids are reactive,... 

Aryl chlorides are widely used for C-C bond creation under Pd(0)-Pd(II) catalytic cycle conditions [62], As a consequence, use of cheaper ArCl in benzoic acid arylation should also be possible if appropriate ligands are used and catalytic cycle for the arylation is changed from Pd(II)-Pd(IV) to a Pd(0)-Pd(II) couple. The method involves use of catalytic palladium acetate in combination with butyl-di-1-adamantylphosphine ligand, cesium carbonate base, and an aryl chloride coupling partner [61]. Benzoic acids of any electronic properties are reactive (Scheme 15). Electron-poor benzoic acids react well, and it is possible to couple them with both electron-poor and electron-rich aryl chlorides. Both electron-poor and electron-rich aryl chlorides can be coupled with electron-rich benzoic acids. However, the combination of an electron-rich aryl chloride with an electron-rich benzoic acid is occasionally problematic due to product decarboxylation or aryl halide hydrodehalogenation. The nitro group is compatible with the reaction conditions, as is the ester group. 

Scheme 15 Benzoic acid arylation by aryl chlorides...

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored on TentaGel has been achieved [174]. An environmentally friendly Suzuki cross-coupling reaction has been developed that uses polyethylene glycol (PEG) as the reaction medium and palladium chloride as a catalyst [175]. A solventless Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as a base [176], This approach has been extended to Sonogashira coupling reaction wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenylphosphine and cuprous iodide (Scheme 6.52) [177]. 

Aryl vinyl sulfides and sulfoxidesArylsulfenyl chlorides add to trimethyl vinyl-silane in CH2CI2 at -78 - 20° to form 2-chloro-l-(trimethylsilyl)ethyl aryl sulfides in 90-95% yield. These adducts are converted into aryl vinyl sulfides in high yield by KF-2H20 DMSO at 70 100°. The sulfides, as expected, can be oxidized to the corresponding sulfoxides by m-chlo roper benzoic acid in CH2C12 at 20". 

Mesylates are used for Ni-catalysed reactions. Arenediazodium salts 2 are very reactive pseudohalides undergoing facile oxidative addition to Pd(0). They are more easily available than aryl iodides or triflates. Also, acyl (aroyl) halides 4 and aroyl anhydrides 5 behave as pseudohalides after decarbonylation under certain conditions. Sulfonyl chlorides 6 react with evolution of SO2. Allylic halides are reactive, but their reactions via 7t-allyl complexes are treated in Chapter 4. Based on the reactions of those pseudohalides, several benzene derivatives such as aniline, phenol, benzoic acid and benzenesulfonic acid can be used for the reaction, in addition to phenyl halides. In Scheme 3.1, reactions of benzene as a parent ring compound are summarized. Needless to say, the reactions can be extended to various aromatic compounds including heteroaromatic compounds whenever their halides and pseudohalides are available. 

A traceless solid-phase synthetic strategy has been developed. For example, a solid-phase Suzuki coupling of the Reissert intermediate 30 to 31 has been reported. The process consists of three steps (a) Solid-phase Reissert formation by the reaction of polymer-supported benzoic acid chloride resin with an isoquinoline, followed by reaction with TMSCN to afford the aryl bromide of Reissert 30, (b) Suzuki coupling of the solid-phase Reissert 30 with phenylboronic acid to provide the coupling product, and (c) subsequent treatment of the coupling product with aqueous KOH to produce 31 (86 % overall yield based on the starting bromide) (Eq. (62)) [99]. 

Acetylenes react with arenetellurolates to form aryl vinyl tellurides. The vinyl groups in vinyl aryl telluriums are converted to vinyl carboxylic acids by carbon monoxide in the presence of stoichiometric amounts of palladium dichloride1 or diacetate2 4. The yield and the product distribution is influenced by the reaction time, the CO pressure, the presence or absence of lithium chloride or triethyl amine, and the concentration of palladium salt. Diphenyl tellurium was converted to benzoic acid1,3. Hexyl phenyl tellurium formed only benzoic acid and no heptanoic acid1. 

On the other hand, in the case of benzoyl fluoride, the reaction is very slow and does not lead to the ultimate formation of a tertiary alcohol, but of the product 24 of the esterification of benzoic acid by the tertiary alcohol.Benzoyl chlorides react with perfluoroalkyl iodides in the presence of tris(diethylamino)phosphane in a nonpolar solvent to give the corresponding polyfluoroalkyl aryl ketones 25 via substitution of the chlorine. 

In an unusual variation, an aryl compound bearing a tertiary alcohol substituent (ArCMeaOH) reacted with aryl halides and a palladium catalyst to give the biar-yl." Benzoyl chloride was coupled to styrene to form PhCH=CHPh using a rhodium catalyst." Benzoic acid was coupled to styrene to give the same type of product using a palladium catalyst and a diacyl peroxide." " ... 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

The second approach involved the appropriately substituted benzoic acid and conversion to the acid chloride. Subsequently, the acid chloride is treated with 0,N-dimethylhydroxylamine hydrochloride ). This methoxymethylbenzamide is treated with an alkylmagnesium halide to give the alkyl aryl methanone. These ketones were purified by distillation. 

Under ligandless conditions PdCl2 catalyzed the hydrogenolysis of several 4-substituted aryl chlorides in alkaline aqueous solutions using NaH2P02 as reductant (Scheme 3.40) [275]. In case of certain ortho-substituted substrates, such as 2-chlorophenolate and 2-chloroaniline, strong chelation in the intermediate palladacycle completely inhibited the reaction. On the other hand, in case of 2-chlorobenzoic acid addition of iodide led to 86 % yield of benzoic acid. 

Reduction of ArCOOH and derivatives.2 Aryl carboxylic acids can be reduced to ArO-UOH by Sml2 (excess) in the presence of an acid, particularly phosphoric acid (85%). In contrast pyridinccarboxylic acids are reduced to the corresponding methylpyridine in 43-48% yield. Benzoic anhydride and benzoyl chloride are also reduced to benzyl alcohol, but in lower yield. Benzonitrilc is reduced under the same conditions to benzylamine in 99% yield. This behavior is characteristic for aryl nitriles. 

The ortho-arylation of benzoic adds with aryl chlorides affords biphenylcarbox-ylic acids 45 in a general way (Scheme 11.15) [45], the best results being obtained when using bulky n-butyl-di-l-adaman1ylphosphine. The corresponding reaction of aryl iodides was carried out with Pd(OAc)2 as catalyst, AgOAc, and acetic add... 

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