Sodium Borohydride - an overview (2023)

Sodium borohydride, a representative borohydride reagent, behaves as an effective source of nucleophilic hydride in an aprotic polar solvent, such as DMSO, sulfolane, HMPA, DMF or diglyme, and is used for the reduction of alkyl halides.^93,94 As shown in Table 3, primary and secondary iodides, bromides and chlorides are converted to hydrocarbons at temperatures between 25 and 100°C using sodium borohydride. Vicinal dihalides, such as 1,2-dibromooctane, are smoothly converted to the corresponding saturated hydrocarbons, in contrast to the reductions using LiAlH₄ or low-valent metal salts, which predominantly afford alkenes.

Sodium borohydride reduction offers a significant advantage in synthetic applications. The method allows the reductive removal of halides selectively without affecting other functional groups, such as ester, carboxylic acid, nitrile and sulfone. A typical chemoselective dehalogenation is illustrated in Scheme 19.⁹⁵

Some alkyl halides (primary I, Br, Cl and secondary Br) are reduced by NaBH₄ under phase-transfer conditions, as shown in equation (4).⁹⁶ This reaction is carried out by the addition of a concentrated aqueous solution of NaBH₄ to a stirred solution of substrate and catalyst in a suitable solvent, such as toluene. Yields are nearly quantitative in most cases, although an excess of sodium borohydride is required.

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Sodium borohydride and lithium aluminum hydride have only moderate stereoselectivity. The anions tend to attack sterically hindered compounds from the least sterically hindered side. For example, reduction of bicyclo[2.2.1]heptan-2-one yields a mixture of two alcohols in which the endo compound predominates. The exo face of the carbonyl group is more open to attack by the nucleophilic hydride reagent, and as a result the endo alcohol is the major product.

Sodium borohydride, a common reagent for this purpose, was used to reduce the symmetrical dicarbonyl compound (21) to afford the hemiacetal in a high yield (Equation (11)) <64T2181>. In a similar manner the hemiacetals (22) and (23) were prepared by reduction of dicarbonyl precursors with sodium borohydride <89JOC91> and aluminum triisopropoxide <51JA1668>, respectively. An attempt to use LAH for this type of reduction resulted in the formation of diols rather than hemiacetals <74H(2)177>. Enzymatic reduction of dicarbonyl compounds was used to prepare a hemiacetal from the dialdehyde (Equation (12)). Besides selective reduction of the enal carbonyl, stereospecific hydroxylation also occurred in the saturated ring <80JCS(P1)2535, 83JCS(P1)1579>.

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Sodium borohydride is very efficient at reducing an acid chloride to the primary alcohol and has been used quite extensively. The advantages over the aluminum hydrides are that NaBH₄ is readily available, easy to handle, and has a good degree of functional group tolerance (esters, lactones, amides, nitriles, etc.; see Scheme 5 for some examples). A plethora of variations including NaBH₄–TiCl₄,³⁴ NaBH₄–alumina,³⁵ Zn(BH₄)₂·TMEDA,³⁶ and Bu₄NBH₄³⁷ have also been reported, though these are infrequently applied in the literature. The advantage of these modifications stems more from their solubility in other nonalcoholic solvents, for example, the more popular of these, Bu₄NBH₄, can be used in dichloromethane. Nevertheless sodium borohydride has itself been used in THF (Scheme 5). Lastly, it should be mentioned that borane and its derivatives react very slowly with acid chlorides and are therefore not generally used to achieve this transformation.

Sodium borohydride reduces disulfides to thiols, which can then be used to reduce nitro groups. Based on the redox properties of 1,2-dithiolane, lipoamide (17) was used for the selective reduction of monosubstituted nitrobenzenes to the corresponding anilines.⁸¹ Lipoamide (17) can also be immobilized on hydrophilic polymers such as polyvinylamine, polyethyleneimine and chitosan.⁸² These polymeric reducing catalysts can be recycled and are easy to separate from the reaction mixture. The system has been used to reduce nitroarenes to anilines.⁸³

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Sodium borohydride can also be used to couple dinitrobenzenes.⁸⁴ 1,3-Dinitrobenzene (19) and 1,3,5-trinitrobenzene (21) produce diphenylamine derivatives in reactions that are of preparative value when the nitro compound is present in excess (Scheme 3). The method involves the addition of a suspension of sodium borohydride in methanolic sodium hydroxide to a solution of the nitro compound in refluxing methanol. Under these conditions, no reduction to dinitrocyclohexenes is observed.^85,86 Coupling products are not obtained from 1,2,4-trinitrobenzene, even though two of the nitro groups have a meta relationship. 1,4-Dinitrobenzene (23) undergoes reductive coupling to yield 4,4′-dinitroazobenzene (24).

Curiously, 1,2-dinitrobenzene (25) couples with the loss of one nitro group; however, the product is a diphenylhydroxylamine derivative (26) rather than a diphenylamine (equation 16). Nitroso compounds can also be reduced to amines in good yields using diborane (equation 17).⁸⁷

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Sodium borohydride (NaBH₄) was first prepared by Schlesinger and Brown in 1943,^27,28 but experimental details were not reported until the 1950s.²⁹ Sodium borohydride was first prepared by reaction of sodium hydride (NaH) with trimethylborate, B(OMe)₃.³⁰

$4\mathrm{N}\mathrm{a}\mathrm{H}+\mathrm{B}{\left(\mathrm{O}\mathrm{M}\mathrm{e}\right)}_3\to {\mathrm{NaBH}}_4+3{\mathrm{M}\mathrm{e}\mathrm{O}}^{-}{\mathrm{N}\mathrm{a}}^{+}$

Sodium borohydride is a relatively selective reducing agent. Ethanolic solutions of sodium borohydride reduce aldehydes and ketones in the presence of epoxides, esters, lactones, acids, nitriles, or nitro groups.^27,33 Reduction of aldehydes is straightforward. In Shao and coworker's³⁴ synthesis of limaspermidine, reduction of the aldehyde moiety in 5 gave alcohol 6 in 95% yield. In general, sodium borohydride is an excellent reagent for the reduction of ketones or aldehydes in the presence of esters,³⁵ hydroxyl groups that are α to the carbonyl,³⁶ a carbohydrate residue,³⁷ or halogens in the α-position.³⁸ Aryl ketones³⁹ or aryl aldehydes⁴⁰ are also easily reduced.

Sodium borohydride reduces ozonides (Section 6.7.2) to an alcohol.⁴² An example is the ozonolysis of 9 where borohydride reduction gave alcohol 10 in 94% yield in a synthesis of (−)-cytoxazone by Jung and coworkers.⁴³

Sodium borohydride can be used for the reduction of enamines, imines, or iminium salts, and such reductions are particularly useful in alkaloid and amino acid syntheses. In a synthesis of amphorogynine C, Mann and coworkers⁴⁴ reduced the imine unit in 11 to the amine (12) by reaction with NaBH₄, and immediate protection with Boc anhydride gave 13 in 85% overall yield. Enamines can also be reduced to give the corresponding amine.⁴⁵

An important variation is called reductive amination, in which an aldehyde or ketone is mixed with an amine in the presence of sodium borohydride, generating the corresponding N-alkyl amine. Miranda and Gómez-Prado⁴⁶ employed reductive amination in a synthesis of hericerin, where the reaction of aldehyde 14 and benzylamine, followed by in situ treatment with sodium borohydride, yielded 15 in >82%. In a related reaction, sodium borohydride reduces iminium salts to the amine,⁴⁷ and pyridinium salts can also be reduced.⁴⁸

Anhydrides are related to lactones as imides are related to lactams. Partial reduction of an anhydride to a hydroxy-lactone is difficult, but reduction (with ring opening) to a hydroxy acid is facile. Subsequent ring closure can generate a lactone when NaBH₄ is used to reduce cyclic anhydrides that have less than six carbon atoms in the ring. An example is the reduction of anhydride 19 in DMF, to give lactone 21 in 55% yield.⁵² Norbornyl systems usually react via the exo-face, as discussed in Section 7.9.6, which accounts for the selectivity of this reduction. In this particular example, reduction of the exo-carbonyl gave alcohol 20, which spontaneously closed to the lactone (21) in the presence of the carboxyl group.

The functional group transforms for this section follows:

Sodium borohydride trisulfide (NaBH₂S₃) converts aldehydes, ketones, or epoxides into symmetrical disulfides <1995COFGT(2)113>. The instability of the reagent, which decomposes rapidly in the presence of oxygen or atmospheric moisture, places limitations on its use. Firouzabadi and co-workers have reported the preparation of stable sulfurated calcium and barium borohydrides [Ca(BH₂S₃)₂ and Ba(BH₂S₃)₂] and investigated their reactivity as reducing reagents <2000PS(159)99, 2000PS(166)83>. With regard to disulfide formation from epoxides, the reactivity and regioselectivity of both reagents is higher than that of NaBH₂S₃. Substituted epoxides are opened from the less hindered side of the ring and in good yield (Scheme 120).

Sodium borohydride has been widely used to reduce organomercurials to produce the corresponding hydrocarbons. The mechanism involving the reduction of the organomercurials with sodium borohydride is believed to be a free radical process as shown in Scheme 17 <1976JA5973, 1984TL5239, B-1985MI006, 1991COS(8)850>.

Reduction of exo- and endo-norbornylmercury(II) bromide with sodium borodeuteride provides exo-[2-D]norbornane as the major product (Equation (162)) <1970JA6611>. Other examples of this phenomenon can be found in the literature <1981JOC563>.

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The diastereoselectivity in metal hydride demercuration of α-mercury(II) carbonyl compounds depends on the nature of the solvent, the amount of hydride used, the mode of addition, the nature of the hydride source, and the ligand on mercury (Equation (163)) <1986JOC2024>.

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A frequent problem associated with the reductive demercuration of organomercurial compounds is deoxymercuration, which would result in the isolation of alkenes. This is often minimized by using alkaline borohydride (Equation (164)) <1984T2317, 1966JA993, 1983TL4923, 1997T2835, 2001T9915>. Alkaline borohydride in the demercuration of peroxymercurials has also been accomplished (Equation (165)) <1992CC428, 1992CC926, 1992T3835, 1993T2729>.

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Phase-transfer reagents are sometimes used to avoid deoxymercuration and other side reactions (Equation (166)) <1986CC855, 1979S891, 1984JOC2838>.

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Reductive demercurations using an excess of sodium borohydride in DMF without sodium hydroxide have been reported to give good results (Equation (167)) <1997JOC5267>. However, it seems that it is not a general method for the reduction of CHg bonds.

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Zinc borohydride has been successfully used for reductive demercuration to give desired product as a milder reducing agent compared to alkaline borohydride, which resulted in the isolation of the starting alkenes used prior to mercury addition (Equation (168)) <1992SC3013>.

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A number of demercurations also use tributyltin hydride (Equation (169)) <2002AG(E)2144, 2001TA597, 2001OL2567, 1996JOC2109, 1984T2317, 1983JA6882>, or triphenyltin hydride <1984JA8313, 1996CAR69>, but complete removal of tin residues can be difficult. As with sodium borohydride, there is also a problem with competitive deoxymercuration when tin hydrides are used <1984T2317>. The presence of sodium acetate prevents this problem if triphenyltin hydride is employed (Equation (170)) <1984JA8313, 1996CAR69>.

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LAH has been used as the reducing agent in demercuration (Equation (171)) <1999JOC101, 1983JA6882, 1986JA2094, 1997JOC4653>. Methylmercurio derivatives RHgMe are stable toward a number of hydrides (NaBH₄, LiAl(OBu^t)₃H, l-selectride, or superhydride) and the halomercurio functionality can be regenerated by treatment with HgCl₂ or HgBr₂. Alternatively, LAH gave the fully reduced product (Scheme 18) <1999JOC101>.

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The reduction of organomercury(II) halides with LAH has been investigated and the findings suggest an electron-transfer mechanism involving attack of the alkyl radical on the metal hydride (Scheme 19) <1983TL1411>.