Acids, hydroxy, reaction with

A few other aldehydes have been used in the reaction, either under normal or pseudo-physiological conditions. Of these, glycolalde-hyde, 5-hydroxypentanal, phenylacetaldehyde, and benzalde-hyde condense readily, but hydroxy and methoxy derivatives of these aromatic aldehydes give the product in poor yield,presumably due to their instability, as evidenced by their tendency to undergo self-condensation in acid solution. Reaction with phthaldehydic acids, such as opianic acid, proceeded readily, whereas reaction with chloral did not occur,... 

The a-bromo or a-chloro carboxylic acids 2 are versatile intermediates for further synthetic transformations. For example they can be converted into a-hydroxy carboxylic acids by reaction with water by reaction with cyanide a-cyanocarboxylic acids 7 are obtained, which can be further converted to... 

Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it ha.s a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocepha-losporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 5reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole) to produce, after deprotecting, ceftiofur (57) [18]. 

The 5-unsubstituted-l,2,3-triazol-4-ones (176, R = H) participate in electrophilic substitution reactions. Bromination in chloroform of anhydro-4-hydroxy-l,3-dimethyl-1,2,3-triazolium hydroxide (180) gave its 5-bromo derivative (182). The meso-ionic 3-aryl-1,2,3-triazol-4-ones (176, R = Me, R = Ar, R = H) gave 5-bromo derivatives (176, R = Me, R = Ar, R = Br) with bromine in acetic acid. Their reaction with sulphur monochloride gave the sulfide (189, X = S), and with thionyl chloride they gave the sulfoxide (189, X = SO). ... 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

There are several examples in the literature of activation of hydroxy compounds by various organophosphorus compounds. For example, in the presence of pyridine, ji-butyltriphenoxyphosphonium bromide (1) activates carboxylic acids towards reaction with amines or phenols to give, respectively, amides or esters (1). 

Halogen acids by reaction with water, H—OH, potassium, or sodium hydroxide, K—OH, Na—OH, or silver hydroxide, Ag—OH, yield hydroxy acids by replacing the halogen with hydroxyl. 

Methyl ketones are often directly prepared from carboxylic acids by reaction with methyllithium. Other simple alkyl ketones may also be prepared in the same fashion, making this a method that should be considered whenever these substrates are required. An important demonstration of this protocol was reported by Masamune and coworkers in their synthesis of chiral propionate surrogates (Scheme 13). The ethyl and cyclopropyl ketones are important starting materials for macrolide total synthesis and have been prepared on a large scale. The overall yield for the ethyl ketone is 65% using 3.5 equiv. of ethyllithium without protection of the hydroxy group. 

Before all these acetal-based protecting groups were introduced, the tetrahydropyranyl (THP) ether had found extensive use in organic synthesis. It can easily be synthesized from a variety of hydroxy-containing compounds like carbohydrates, amino acids, steroids and nucleotides by the acid-catalyzed reaction with dihydropyran. It is stable to bases, but the protection is removed through acidic hydrolysis with hydrochloric acid, toluenesulfonic acid or acidic ion-exchange resin (Scheme 27). In the case of acid sensitive substrates, e.g. containing an epoxide or a further acetal, pyridinium p-toluenesulfonate should be applied for particularly mild deprotection conditions. ... 

Selective acylation was also possible with four equivalents of an arylsulphonyl chloride or an aroyl chloride furnishing 76c " and 76d, in yields up to about 50%, while the regioselective acylation fails with aliphatic acid chlorides. Reaction with benzyloxycarbonyl chloride (EtsN, MeCN, RT), however, allowed the partial protection of four hydroxy groups to yield 76e. Compounds 76c-76e (interesting as building blocks for various self-assembled structures ) may be used for further derivatizations. 

Corey et al. [36] developed an efficient and mild lactonization method using 2-pyridinethiol ester. Slow addition of 2-pyridinethiol esters, prepared from to-hydroxy acids by reaction with 2,2 -dipyridyl disulfide and Ph3p or 2-fhiopyridyl chloroformate and EljN, to refluxing xylene under dilution conditions yielded... 

The substituted 2-hydroxybenzophenone, 2-(2-hydroxy-4-di-n-butylamino)-benzoylbenzoic acid underwent reaction with 4-methoxy-2-methyldiphenyl-amine in concentrated sulphuric acid at 10-1 during 20 hours followed by work-up in alkaline solution and a final treatment by refluxing in hot toluene for 2 hours to give 2-anilino-3-methyl-6-dibutylaminofluoran in 88% yield (ref.81). 

Reduction of a-keto acids. -Keto acids can be reduced selectively to -hydroxy acids by reaction with triethyl phosphite in acetonitrile overnight followed by alkaline hydrolysis. Four examples were reported, and yields ranged from 70 to 95%. A possible mechanism is shown in the formulation. ... 

HC(44/3)l>. The two most important methods are (i) conversion of thienyllithium to a thienyl-boronic acid by reaction with alkyl borate, followed by oxidation with H2O2, and (ii) reaction of thienylmagnesium derivatives with t-butylperbenzoate, followed by dealkylation of the /-butyl ethers with acid. The boronic acid method has been used for the synthesis of several pyridine-substituted hydroxy thiophenes <92ACS654>. 

Another method for the conversion of an alkene into an allylic alcohol, but with a shift in the position of the double bond, proceeds from the corresponding p-hydroxyselenide. The p-hydroxyselenide can be obtained from the epoxide by reaction with phenylselenide anion or directly from the alkene by addition of phenylselenenic acid, phenylselenenyl chloride in aqueous MeCN, or by acid-catalysed reaction with A-phenylseleno-phthalimide. The hydroxyselenide does not need to be isolated, but can be oxidized directly with tert-BuOOH to the unstable selenoxide, which spontaneously eliminates phenylselenenic acid to form the E-allylic alcohol. For example, 4-octene gave 5-octen -ol (6.15). Elimination takes place away from the hydroxy group to give the allylic alcohol no more than traces... 

Hydroxy-acids.—Optically active a-hydroxy-acids can be obtained from a/ -unsaturated acid chlorides by condensation with 5-proline followed by bromo-lactonization, debromination, and hydrolysis (Scheme 5). Optical yields are as high as 90%. a-Keto-acids can be reduced to a-hydroxy-acids by reaction with trialkyl phosphites followed by alkaline hydrolysis of the intermediate phos-phonate. Yields are said to be higher than those obtained by other methods using selective reduction (NaBH4 Raney nickel). 

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