Arylation benzoic acids

Carboxylic Acids and Derivatives.—A convenient synthesis of o-alkyl-, o-alkenyl-, and o-aryl-benzoic acids utilises nucleophilic aromatic substitution of o-methoxyaryl-oxazolines (Scheme 11). The oxazolines (92) are converted into the acids (93) by organometallic replacement of the methoxy-group, and... 

Aryl- or alkenylpalladium comple.xcs can be generated in situ by the trans-metallation of the aryl- or alkenylmercury compounds 386 or 389 with Pd(Il) (see Section 6). These species react with 1,3-cydohexadiene via the formation of the TT-allylpalladium intermediate 387, which is attacked intramolecularlv by the amide or carboxylate group, and the 1,2-difunctionalization takes place to give 388 and 390[322]. Similarly, the ort/trt-thallation of benzoic acid followed by transmetallation with Pd(II) forms the arylpalladium complex, which reacts with butadiene to afford the isocoumarin 391, achieving the 1,2-difunctionalization of butadiene[323]. 

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]. 

Because cyano groups may be hydrolyzed to carboxylic acids (Section 20 19) the Sand meyer preparation of aryl nitriles is a key step m the conversion of arylammes to sub stituted benzoic acids In the example just cited the o methylbenzomtnle that was formed was subsequently subiected to acid catalyzed hydrolysis and gave o methylbenzoic acid in 80-89% yield... 

Contains Halogen.—Halogen compounds may be n/ly/em aryl or add haUdc tQ ha/oyru aethylene bromide, btomoben/ene, benzoyl cbloiide, oi rhloio-benzoic acid). 

Phenyl radicals can be generated by the thermal decomposition of lead tctrabcnzoate, phenyl iodosobenzoate, and diphenyliodonium hydroxide,- - and by the electrolysis of benzoic acid.- These methods have been employed in the arylation of aromatic compounds, including heterocycles. A method of promise which has not been applied to the arylation of heterocycles is the formation of aryl radicals by the photolysis of aromatic iodides at 2537... 

This last result bears also on the mode of conversion of the adduct to the final substitution product. As written in Eq. (10), a hydrogen atom is eliminated from the adduct, but it is more likely that it is abstracted from the adduct by a second radical. In dilute solutions of the radical-producing species, this second radical may be the adduct itself, as in Eq. (12) but when more concentrated solutions of dibenzoyl peroxide are employed, the hydrogen atom is removed by a benzoyloxy radical, for in the arylation of deuterated aromatic compounds the deuterium lost from the aromatic nucleus appears as deuterated benzoic acid, Eq. (13).The over-all reaction for the phenylation of benzene by dibenzoyl peroxide may therefore be written as in Eq, (14). 

The electron-donating hydroxy substituent is necessary in order to facilitate the migration of the aryl group otherwise a substituted benzoic acid would be obtained as reaction product. 

Even in Ugi reactions of chiral 4,5-dihydro-3//-pyrrole derivatives with aryloxy substituents vicinal to the cWo-cyclic imino group, a low stereoselectivity was found with either chiral or achiral isocyanides and benzoic acid leading to substituted 2-aminoearbonyl-3-aryl-oxy-1 -benzoylpyrrolid ine derivatives82. 

In contrast to 2,3-dioxygenases, the related ipso/ortho oxygenation of aryl carbox-ylates has received considerable less attention and has hardly been utilized by the synthetic community, so far. Biooxidation of benzoic acid and P-naphthalene carboxylate provide access to corresponding 1,2-dihydroxylated dihydroaryl compounds in excellent stereoselectivity (Scheme 9.35), analogous to TDO- and NDO-mediated ortho/meta oxygenations. Whole-cell-mediated biotransformations were performed with mutant strains of Rahtonia and Pseudomonas and enable access to preparative quantities in >5 gl titers [261,262]. 

The Arndt-Eistert method is useful for making aryl-acetic acids from benzoic acids. How would you carryout this conversion ... 

The aerobic reduction of aryl and alkyl carboxylates to the corresponding aldehydes. The reaction involves formation of an acyl-AMP intermediate by reaction of the carboxylic acid with ATP NADPH then reduces this to the aldehyde (Li and Rosazza 1998 He et al. 2004). The oxidoreductase from Nocardia sp. is able to accept a range of substituted benzoic acids, naphthoic acids, and a few heterocyclic carboxylic acids (Li and Rosazza 1997). 

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]. 

The cell is suitable for the manufacture of (i) metal alkoxides, (ii) thiolates, (iii) carboxylates, (iv) hydroxides, (v) organometallics and chemicals such as diphenylacetic acid, (vi) ortho- and para-trifluoromethyl-benzoic acid, (vii) aryl-... 

Pararosaniline, after being formed from parafuchsin with sodium hydroxide, is fused at 175°C with aniline and/or m-toluidine, for instance in the presence of catalytic amounts of benzoic acid, and thus arylated. 

Nickel(O) triphenylphosphine can be used to couple aryl halides and alkenes to synthesize substituted olefins [149], 1,2-bis[(di-2-propylphosphino)benzene]nick-el(0) can be used to couple aryl halides [150], and l,2-bis[(diphenylphos-phino)ethane]nickel(0) can be used to prepare benzoic acid from bromobenzene in the presence of carbon dioxide [151]. 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

Insertion of aUcynes into aromatic C-H bonds has been achieved by iridium complexes. Shibata and coworkers found that the cationic complex [Ir(COD)2]BF4 catalyzes the hydroarylation of internal alkynes with aryl ketones in the presence of BINAP (24) [111]. The reaction selectively produces ort/to-substituted alkenated-aryl products. Styrene and norbomene were also found to undergo hydroarylation under similar condition. [Cp IrCl2]2 catalyzes aromatization of benzoic acid with two equivalents of internal alkyne to form naphthalene derivatives via decarboxylation in the presence of Ag2C03 as an oxidant (25) [112]. 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

The chemistry of aryl groups attached to the 7r-deficient heterocycles is unexceptional and much as might be expected. Thus, electrophilic substitution of phenylpyridines occurs exclusively in the phenyl ring. 4-Phenylpyridine gives mononitration products in the ratio o m p, 20 33 47 (68JCS(B)862, 71JCS(B)712). The oxidation of phenylpyridines can lead to either a pyridinecarboxylic acid or benzoic acid. 

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