Carboxy compounds, acylation with

Alkylation of ll-mercaptopyrido[l,2-h]cinnolin-6-ium hydroxide inner salts (e.g., 41) with ethyl bromoacetate gave ll-(ethoxycarbonylmethyl(thio derivatives 64 (R = H), which could be hydrolyzed to the ll-(carboxy-methyl)thio derivative or back to the starting compound 41 (74JHC125). Hydrolysis of the ll-bis(methoxycarbonyl)methylene 66 (R = H), and 2-cyano derivatives of 17 (R = H) in boiling HCl afforded 11-methyl and 2-carboxylic acid derivatives, respectively (74JHC125). The 2-nitro derivative of 17 (R = H) was reduced to the 2-amino derivative over Pd/C with NaBH4 in aqueous methanol, and the 2-amino group was acylated with acetic anhydride at 100°C. 

A route to /3-methyl-tetrahydroberberines has been developed from the hydra-stinine derivative (72), which can be acylated with the dimethoxyhomophthalic anhydride (73) to give acid (74). Reduction of this with lithium aluminium hydride followed by further reduction of the toluene-p-sulphonyl ester of the resulting hydroxymethyl compound yields the 13-methyl compound.91 An essentially similar synthesis of oxoberberines bearing a carboxy-group at C-13, of general type (74), has been reported by other workers.92... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

L-f/ireo-glycerol-l-yl)-pyrazoline-5-one (49) when its solution in alkali was acidified with acetic acid (50). The reaction was further extended to other bis(arylhydrazones) (51), The structure of the phenyl analogue (49) was established by oxidation to the known 3-carboxy-l-phenyl-4-phenylazopyrazolin-5-one (50). Later, on the basis of NMR data (39), the structure of this group of compounds was formulated as the hydra-zones (51). Acylation of 51 aflForded the tri-O-acylated derivatives (51), while periodate oxidation of 51 gave 3-formyl-l-aryl-4,5-pyrazoledione-... 

In spite of the routine nature of the chemistry involved in N-acylation (Equation (4.2)), Schotten-Baumann acylation requires an acid chloride as reagent, a compound that can react with the carboxy group as well. The mystification that the consequences of this caused at the time (1962) - since dipeptides and oligopeptides were being formed in this way - actually had a constructive outcome, since the mixed anhydride procedure of peptide-bond formation (Chapter 7) was developed by the workers who unravelled the course of events (Equation (4.2)). 

Manganese(III) can oxidize carbonyl compounds and nitroalkanes to carboxy-methyl and nitromethyl radicals [186]. With Mn(III) as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [186, 187). Further Mn(III)-mediated anodic additions of 1,3-dicarbonyl and l-keto-3-nitroalkyl compounds to alkenes and alkynes are reported in [110, 111, 188). Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(III)-mediated oxidation of acetic acid acetic anhydride in the presence of butadiene [189]. Also the nitromethylation of benzene can be performed in 78% yield with Mn(III) as electrocatalyst [190]. A N03 radical, generated by oxidation of a nitrate anion, can induce the 1,4-addition of aldehydes to activated olefins. NOj abstracts a hydrogen from the aldehyde to form an acyl radical, which undergoes addition to the olefin to afford a 1,4-diketone in 34-58% yield [191]. 

The stereospecificity of the interactions of several spin-labelled substrates with cyclohexa- and cyclohepta-amyloses, as models for chymotrypsin, has been studied. Complexes of the cycloamyloses with 2,2,6,6-tetramethyl-4-oxy-pyridyl-1-oxide in aqueous solution were examined by e.s.r. spectroscopy the nitroxide function moved to a relatively hydrophobic environment on binding to cyclohepta-amylose, and lost some freedom of rotation on binding to both cycloamyloses. The dissociation constant for the cyclohexa-amylose complex of the nitroxide is greater than that for the cyclohepta-amylose complex, consistent with measurements made on molecular models. In the hydrolysis of the asymmetric compound 3-carboxy-2,2,5,5-tetramethylpyrrolidyl-l-oxide 3-nitro-phenyl ester, catalysed by cyclohexa-amylose, enantiomeric specificity was observed in the acylation step but not in formation of the Michaelis complex , or on hydrolysis of the acylated cycloamylose intermediate. No differences were found in the e.s.r. spectra of solutions of the trapped acylcyclohexa-amylose intermediates derived from ( + )- and ( )-forms of the asymmetric nitroxide. The nitroxide function is less free to rotate in the acylcycloamylose intermediate than in the Michaelis complex and is not included in the cycloamylose cavity. 

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