Imidic esters, reduction

Alternatively, the imide-acid chloride is reacted with methanol to give the imide ester which, after borohydride reduction and triethylsilane/trifluoroacetic acid treatment, furnishes the bicyclic lactam 6 as a racemate. The latter is acylated with either propanoyl chloride or 3-phcnylpropanoyl chloride and the resulting amides 7 deprotonated and alkylated with (bro-momethyljbenzene or iodomethane, respectively, to give the major alkylation products 8 with d.r. >98 2 and in 65% yield3. 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

Imidic esters are easily hydrolyzed in aqueous solution, but some are stable enough for a polarographic investigation in a cold solution. Reduction at a lead cathode in cold 1 M sulfuric acid of ethyl benzimidate gave benzylamine in 76% yield [43]. The reduction can probably be described by ... 

Amidines of aliphatic acids are generally not reducible in buffered solution. Some amidines derived from aromatic acids are reducible at very negative potentials and only in a narrow pH interval from slightly acid to alkaline solution. The reduction is similar to that of imidic esters [Eq. (10)], and yields the amine [44]. 

Dimethylamino-l-phenylphthalazine can in acid solution be reduced in a four-electron reaction to 2-(l -amino-1 -phenylmethyl)-A/, A/ -dimethylbenzamidine [310], which at higher pH forms l-phenyl-3-iminoisoindoline, which can be reduced to 1-phenylisoindoline (LII) in a four-electron reduction. From the reduction corresponding to the first wave of 4-methoxy-l-phenylphthalazine, the cyclic imidic ester 3-methoxy-l-phenylisoindole can be isolated it may be further reduced to LII. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Alcohols can also be generated by hydride reduction of esters of support-bound alcohols or thiols [396,655,656], or by reduction of resin-bound imides (Table 3.35). Similarly, the reaction of esters of support-bound alcohols or thiols with Grignard or... 

The unsaturated lactam ester 62 was also employed in a modified synthesis of ( )-lycorine (1) (109). In the event, O-ethylation of 62 with excess Meerwein reagent followed by reduction of the resulting imidate 77 with either sodium borohydride/stannic chloride dietherate (111) or sodium borohydride/stannous chloride gave an intermediate secondary amine, which cyclized on heating in methanol containing K2C03 to provide the lactam 78 (Scheme 5). When 78 was... 

Plants. In soya beans and maize, the major metabolite is 2-chloro-4-fluoro-5-(4-hydroxy-1, 2-cyclohexane-dicarboximido) phenoxyacetic acid formed by reduction of the tetrahydrophthaloyl double bond and hydroxylation other metabolic pathways include cleavage of the ester, and cleavage of the imide linkage... 

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