Sodium borohydride with nitriles

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Nitriles are, with few exceptions, not reduced by NaBHa. SulfuratedNaBHa, prepared by the reaction of sodium borohydride with sulfur in THF, is somewhat more reactive than NaBHa, and reduces aromatic nitriles (but not aliphatic ones) to amines in refluxing THF. Further activation has been realized by using the Cobalt Boride system, (NaBHa-CoCD which appears to be one of the best methods for the reduction of nitriles to primary amines. More recently it has been found that Zirconium(IV) Chloride Et2SeBr2, CuSOa, Chlorotrimethylsilane, and l2 are also efficient activators for this transformation. The NaBHa-Et2SeBr2 reagent allows the selective reduction of nitriles in the presence of esters or nitro groups, which are readily reduced by NaBHa-CoCL. 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

The tricyclic benzothiazepinone 1 is reduced by ethanolic sodium borohydride to a tetrahydro compound, which is isolated as the sulfoxide 2, formed by air oxidation. Reaction of 1 with dichloroketene or various nitrile oxides results in cycloadducts.426... 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

If the perhydrooxazolo[3,2- ]pyridine now possesses a nitrile at C-5, the aminonitrile can be reduced with sodium borohydride as exemplified in Scheme 89 <1998T8783>. Another option is to generate an intermediate iminium ion and to further reduce it with zinc borohydride <1998T8783>. 

It was observed that a-amino oximes 511, when treated with sodium borohydride in boiling acetonitrile, produced the expected fragmentation products 513 in moderate to good yields (31-87%) (equation 225). The use of the hydride-induced fragmentation in cyclic oximes leads to amino nitrile compounds, as a result of the reduction of the immonium salt intermediates 512. Careful selected oxime structures showed that the reaction time increases when the stabihty of the immonium intermediate decreases, showing the importance of the mesomeric assistance. 

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>. 

An entirely different synthesis, due to Meyers and Libano, involves the acid-catalyzed condensation of a ditertiary glycol with an w-chloro-nitrile. The resulting w-chloroalkylpyrroline is reduced with aqueous sodium borohydride and cyclized by steam distillation under basic conditions.234 An example of this route is given in Scheme 24. 

According to Kobayashi et ul.,268 4-oxo- and 4-imino-4f f-pyrido[l,2-a]-pyrimidine-3-nitriles can be reduced to the 6,7,8,9-tetrahydro compounds with sodium borohydride. Reduction of the hydroiodide of 41 (R = H) with sodium borohydride or lithium aluminimum hydride, however, was unsuccessful.2... 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

In the simplest case, reaction of a primary monoamine via a two-fold Michael reaction with acrylonitrile (bis-cyanoethylation) led to the dinitrile (Fig. 1.1). Subsequent reduction of the two nitrile functions - by hydrogenation with sodium borohydride in the presence of cobalt(II) ions - afforded the corresponding terminal diamine. Repetition (iteration) of this synthetic sequence, consisting in Michael addition followed by reduction, provided the first - structurally variable - access to regularly branched, many-armed molecules. 

The von Braun Reaction with Dihydroatisine.—Indian researchers37 have reported a study of the von Braun reaction of dihydroatisine (29) and a mass spectral analysis of the resulting product, the N-nitrile (93). Reduction of atisinium chloride (94) with sodium borohydride gave dihydroatisine (29). The reaction of the latter with cyanogen bromide in anhydrous ether at room temperature for 24 hours gave (93) [m.pt 265 °C] in a yield of 86%. Acid hydrolysis of (93) with 10% HC1 afforded compound (95). 

Small Quantities. Wear eye protection, laboratory coat, and nitrile rubber gloves. In the fume hood, cautiously add small portions of sodium borohydride to a large volume of water such that the concentration of borohydride is less than 3%. Under a nitrogen atmosphere, add dilute acetic acid dropwise while stirring. When neutralization is complete, wash down drain with at least 50 times its volume of water.7... 

Nitriles having at least one hydrogen on the functional carbon, react with trimethylchlorosilane under electrochemical conditions to provide a mixture of silazanes and enamines of acylsilanes. These enamines have been suggested to be formed from the isomeric ketene imine form of the nitrile. They were obtained as a mixture of Z (major) and E isomers. Treatment of the silazane-enamine mixture with trimethylchloro-silane/methanol and sodium borohydride followed by neutralization of the salt gives the corresponding RSMA.191... 

Satoh, T., Suzuki, S., Suzuki, Y., Miyaji, Y., and Imai, Z., Reduction of organic compound with sodium borohydride-transition metal salt systems reduction of organic nitrile, nitro and amide compounds to primary amines, Tetrahedron Lett., 10, 4555 4558, 1969. 

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