Reduction with zinc borohydride

The double bond in indole and its homologs and derivatives is reduced easily and selectively by catalytic hydrogenation over platinum oxide in ethanol and fluoroboric acid [456], by sodium borohydride [457], by sodium cyanoborohydride [457], by borane [458,459], by sodium in ammonia [460], by lithium [461] and by zinc [462]. Reduction with sodium borohydride in acetic acid can result in alkylation on nitrogen giving JV-ethylindoline [457]. 

Diastereoselective hydride addition is quite versatile, and it provides facile synthetic access to ( —)-pinidine (661), an alkaloid isolated from several species of Pinus, as well as its unnatural isomer (+ )-pinidine (660b). The unstable aldehyde 655, prepared in four steps from 624 [202], undergoes Grignard addition with 4-pentenylmagnesium bromide followed by Swem oxidation to afford ketone 656 in 90% yield for the two steps. Stereoselective hydride addition with L-Selectride provides the -yn-alcohol 657 (91 9), while zinc borohydride reduction provides almost exclusively the anri-alcohol 658 (>99 1) (Scheme 144). 

A rather different phenolic oxidation, that of the oxime (154) with thallium(III) trifluroacetate to give the isoxazole (155), followed by zinc borohydride reduction, has been used to give (156) which is a versatile intermediate for the synthesis of the sponge metabolites ( )-aerothionin (157a), ( )-homoaerothionin (157b), and ( )-aerophobin-1 (158). ... 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

Zinc borohydride has been found to effect very efficient reductive amination in the presence of silica. The amine and carbonyl compound are mixed with silica and the powder is then treated with a solution of Zn(BH4)2. Excellent yields are also obtained for unsaturated aldehydes and ketones.96... 

Kondo et al. (182,183) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54) with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with m-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2 -acetylpapaveraldine (129) (Section III,B,1). 

Nitration of 206 with a mixture of potassium nitrate and sulfuric acid yielded a mixture of dinitro derivative 240 and oxidation product 46. Heating 206 with sodium borohydride led to hydrolysis to 208 rather than to any reduction product. On the other hand, reduction with zinc in cold acetic acid provided dihydro derivative 241, whereas catalytic hydrogenation over palladium on carbon provided tetrahydro derivative 242 (Scheme 59) [90JCS(P 1) 1463]. 

TABLE 3-3. Asymmetric Acylation Using (2A,5A)-24 and Subsequent Stereoselective Reduction with Zinc Borohydride in THF at —78°C... 

The high-yield reductive methylation of numerous alkyl and arylamines and of dialkyl-and alkyl-arylamines with paraformaldehyde in the presence of zinc chloride and zinc borohydride has been reported (equation 52)151. 

Brimble and coworkers176 studied the asymmetric Diels-Alder reactions of cyclopentadiene with chiral naphthoquinones 272 bearing different chiral auxiliaries. The highest endo and facial selectivities were obtained using zinc dichloride as the Lewis acid catalyst and (—)-pantolactone as the chiral auxiliary. Thus, the reaction between cyclopentadiene and 272 afforded a 98 2 mixture of 273 and 274 (equation 76). The chiral auxiliary was removed easily by lithium borohydride reduction. 

The neutralization values were influenced by reduction with strong reducing agents, lithium aluminum hydride, sodium borohydride, and amalgamated zinc plus hydrochloric acid (35, 46). For the most part, the consumption of NajCOj and of NaOEt decreased in equivalent amounts. This is further confirmation of the assumption that lactones of the fluorescein type or of the lactol type are present. The reaction with sodium ethoxide was shown to be no true neutralization, that is, exchange of H+for Na+, at all, but an addition reaction w ith the formation of the sodium salt of a semi-acetal or ketal ... 

Refluxing of 9-fluorenone-l-carboxylic acid with zinc dust and copper sulfate in aqueous potassium hydroxide for 2.5 hours afforded 9-fluorenol-1-carboxylic acid in 94% yield [1004]. Reduction with sodium borohydride in aqueous methanol at 0-25° converted 5-ketopiperidine-2-carboxylic acid to /ra j-5-hydroxypiperidine-2-carboxylic acid in 54-61% yield [1005], On the other hand, reduction of V-benzyloxycarbonyl-5-ketopiperidine-2-carboxylic acid gave 89% yield of V-benzyloxycarbonyl-cis-5-hydroxypiperidine-2-car-boxylic acid under the same conditions [1005],... 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

Thiophenecarbaldehydes add smoothly to a,f3-unsaturated ketones and nitriles under cyanide ion catalysis to form y-diketones (366) and y-ketonitriles (367) respectively (76CB534). The 2,5-dicarbaldehyde gives the bis-adduct (368). The aldehydes undergo normal reduction to the hydroxymethylthiophenes by sodium borohydride. However, electrochemical reduction of the 2,5-dialdehyde on a mercury electrode at pH 1-3 gives the bimolecular reduction product (369) as a mixture of meso- and ( )-forms in the ratio 7 3. Reduction with zinc and acetic acid gives only the meso -form of (369) (75CR(C)(280)165>. 

Thioindoxyls are readily oxidized to thioindigo dyes.584 They may be reduced to benzo[6]thiophenes (Table XI) with zinc (Clemmensen reduction) or tin and acid (method a) (use of mossy zinc is preferred for the reduction of halothioindoxyls and also minimizes reduction of the thiophene ring),315 sodium borohydride (method b),222,424,432 or... 

Reduction by LiAlH4 of 2,3-dihydrothieno[3,2-6]thiophen-3-one (22) and its 2-methyl- and 2-ethyl-derivatives afforded the appropriate thienothiophene 2.21,25,28,29 Similarly, Gronowitz and co-workers48 used borohydride reduction of ketones 33 and 34 to prepare 2-methyl-thieno[3,2-6]thiophene (35). Attempts to reduce 2,3-dihydrothieno[3,2-6]thiophen-3-one (22)28 and 2,3-dihydro-4,6-dimethylthieno[3,4-6]-thiophen-3-one (87)T with zinc powder in acetic acid were unsuccessful. 

Numerous reducing agents were tried at this point unsuccessfully. For example, lithium aluminum hydride destroyed the substrate, whereas DIBAH or lithium borohydnde in THF and sodium borohydride in ethanol led to reduction of the quinoline system. On the other hand, both potassium borohydride (either with or without 18-crown-6) and zinc borohydride (with or without ethanol) produced no reaction at all. Lithium triethylborohydride resulted in de-methoxylation, and sodium borohydride in refluxing THF gave a 45% yield of diol 16 together with overreduced product. 

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