Sodium cyanoborohydride indole

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]. 

Addition of methyllithium to the lactone 1219, followed by reduction with sodium borohydride in refluxing ethanol, afforded, almost quantitatively, ellipticine (228). Reaction of the compound 1219 with the lithio derivative of formaldehyde diethylmercaptal, and reduction with sodium borohydride in refluxing ethanol, led to the mercaptal 1221. Cleavage of the mercaptal 1221 with bis(trifluoroacetoxy) iodobenzene [Phl(OCOCF3)2] in aqueous acetonitrile gave the 11-formyl derivative, which was reduced with sodium cyanoborohydride (NaBHsCN) to 12-hydroxyellipticine (232) (710,711) (Scheme 5.202). The same group also reported the synthesis of further pyiido[4,3-fc]carbazole derivatives by condensation of 2-substituted indoles with 3-acetylpyridine (712). 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Indolines are produced in good yield from 1-benzenesulfonylindoles by reduction with sodium cyanoborohydride in TFA at 0°C (Equation 5) (89TL6833). If acyl groups are present at C-2 or C-3 in the substrate, they are reduced to alkyl groups. Indole is also reduced to 2,3-dihydroindole by sodium cyanoborohydride and acetic acid or triethylamineborane and hydrochloric acid. An alternative method for preparing indolines involves treatment of indoles with formic acid (or a mixture of formic acid and ammonium formate) and a palladium catalyst (82S785). Reduction of the heterocyclic ring under acidic conditions probably involves initial 3-protonation followed by reaction with hydride ion. 

One of the starting materials, the bromoindolinemesylate 183 was obtained from the commercially available 5-hydroxyindole by mesylation followed by successive treatment of the resulting indole derivative with sodium cyanoborohydride and bromine. Coupling of 183 with the known boronic acid 184 in the presence of zero valent palladium complex led directly to the lactam 185, the intermediate carbinolamine 186 formed initially in the reaction suffering facile aerial oxidation during work-up. On reduction with sodium (2-methoxyethoxy)aluminium-hydride, the amide 185 yielded the aminophenol 187 which on chromatography underwent oxidative aromatisation to 182 in 54% yield. 

The observation that enamines may be reduced by NBH in acetic acid/ THF ° and sodium cyanoborohydride coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205) in high yield. //-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of l-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline (207) via an intermeuiate 3,2 dimer (206). ... 

As well as ebumamine (282), the -oxide of 1,2-dehydroaspidosper-midine (281) gave a new product on reaction with triphenylphosphine and acetic acid (167). The compound showed a molecular ion at m/e 296 analyzing for C19H24N2O. The UV spectrum was that of an -acylindoline and the IR spectrum indicated a lactam (rmax 1680 cm-1). The product was unaffected by catalytic hydrogenation or by sodium cyanoborohydride reduction. In aqueous hydrochloric acid for 2 hr at 90°, the product was transformed into an -acylindole which was assigned structure 291. The parent compound for these transformations was therefore 292. Lithium aluminum hydride reduction of 292 gave the diamine 293, which afforded the indole 294 on treatment with acid. 

The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic ergoline synthons from 5-methoxy-lH-indole-4-carboxaldehyde has been described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to l,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds which show specificity for serotonin and dopamine receptors. 

A Pummerer rearrangement cyclization was next achieved hy treating indole 242 with trifluoroacetic anhydride in dichloromethane. The indole-nine product was then reduced with sodium cyanoborohydride and desulfurized with Raney nickel to furnish lactam 243. It is interesting to note that in contrast to the Pummerer cychzation of the acetamide 242, which undergoes cyclization to the indole 3-position as shown, photocyclization of... 

At this juncture, the stereochemistry of the amine-substituted carbon required inversion to the correct configuration of the natural product. Toward this end, lactone 354 was treated with tetramethylguanidine and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) under an air atmosphere in THE. These conditions led to oxidation to yield enamine 355, which was subsequendy reduced with sodium cyanoborohydride to complete the epimerization process. These conditions were also sufficiently hydridic to reduce the ketone carbonyl. Heating in ethyl acetate then led to cycHza-tion to yield lactam 356. Oxidation using IBX next provided ketone 357, which was employed as a coupling partner for 2-iodoanihne in the key indolization step (Scheme 51). 

Reduction of the heterocyclic ring is readily achieved under acidic conditions formerly, metal-acid combinations were used, but now much milder conditions employ relatively acid-stable metal hydrides such as sodium cyanoborohydride. Triethylsilane in trifluoroacetic acid is another convenient combination 2,3-disubstituted indoles give cis indolines by this method. Such reductions proceed by hydride attack on the p-protonated indole - the 3//-indolium cation. Catalytic reduction of indole, again in acid solution, produces indoline initially, further slower reduction completing the saturation. ... 

Hydrolysis of the nitrile 199 gave 2-trifluoromethylindole-3-acetic acid 201 in moderate yield [60], A partial reduction of the nitrile group in 199 provided indole-3-acetaldehyde 202 in 51 % yield. The latter was used for the synthesis of the 2-trifluoromethylated analogue of oxypertine (an antipsychotic used in the treatment of schizophrenia) 203 upon treatment with IV-phenylpiperazine and sodium cyanoborohydride [64]. 

Reduction of the indole double bond using sodium cyanoborohydride in glacial acetic acid. The use of sodium borohydride leads to reduction and N-alkylation. 

---