Lithium Borohydride1

LiBH4

[16949-15-8]  · BH4Li  · Lithium Borohydride  · (MW 21.78)

(reducing agent for esters and lactones,1,2a,b acyl chlorides,2c epoxides,1 aldehydes and ketones;1,2a,b,d precursor of other borohydrides;1 catalyst for hydroborations3)

Physical Data: mp 284 °C (dec); d 0.666 g cm-3.

Solubility: sol ethers (3 g/100 mL Et2O, 25 g/100 mL THF),4 lower primary amines (MeNH2, EtNH2, i-PrNH2),5 diglyme6 (9 g/100 mL);4 sol (with reaction) alcohols7 (1.6 g/100 mL MeOH, 3 g/100 mL i-PrOH);4 solution in absolute EtOH shows no appreciable decomposition after 2-4 h at about 0 °C;7 solution in i-PrOH shows no decomposition after 24 h;4 sol (with slow decomposition) water.

Form Supplied in: off-white solid; 2.0 M solution in THF.

Analysis of Reagent Purity: hydrolysis with dilute acid and titration for boron;8 ethereal or THF solutions can be titrated with 2 N HCl-THF (1:1).4

Purification: recrystallization from Et2O; the purified material is pumped free of ether at 90-100 °C for 2 h.8

Handling, Storage, and Precautions: both solutions and (especially) the solid9 are flammable and must be stored under N2 in the absence of moisture; the solid is capable of creating a dust explosion; LiBH4 reacts with water and acids, generating flammable and/or explosive gas (H2 and borane), and is incompatible with strong oxidizing agents.

Reduction of Functional Groups.

Lithium borohydride is more reactive as a reducing agent than Sodium Borohydride and less reactive than Lithium Aluminum Hydride.1 In THF, LiBH4 readily reduces aldehydes and ketones to alcohols at room or even ice-bath temperature,9 whereas esters and lactones require higher temperatures and prolonged reaction times to give the corresponding alcohols and diols. Thus selective reductions are possible. Epoxides are reduced by LiBH4, while carboxylic acids, carboxylic acid salts, tertiary amides, nitriles, nitro compounds, alkenes, and halogeno derivatives do not usually react.1

The chief advantage of LiBH4 over LiAlH4 is its much greater chemoselectivity, while the chief advantage over NaBH4 is its higher solubility in ethereal solvents. The different reactivity of the two lithium hydrides (LiBH4 and LiAlH4) is essentially due to the different hardness of the two hydride-delivering anions, while the different reactivity of the two borohydrides (LiBH4 and NaBH4) is essentially due to the different Lewis acidity of the associated cation, rather than to differences in solubility.6,10

Lithium borohydride reactivity is greatest in media of low dielectric constant: increasing the polarity decreases reactivity.4 The order of reactivity is LiBH4 in Et2O > THF &AApprox; diglyme > 2-propanol; this trend is exactly reversed for Ca(BH4)2.

Several papers have dealt with the effects of solvent,4,6,11 concentration,10a added salt,6 and added cation complexing agents10 both on the reaction rate and the regiochemistry of LiBH4 reductions, regarding essentially ester reduction.

Since carbonyl compounds are rapidly reduced by LiBH4 alone, less attention has been devoted to this reaction. Nevertheless, it has been shown that the rate of the reduction of acetone in i-PrOH11 (k = 50.3 × 10-4 L mol-1 s-1) is not appreciably affected by the addition of Triethylamine, while addition of Lithium Chloride accelerated the reduction. The added lithium salt probably has a double effect: on one hand, it can modify the nature of the ionic cluster; on the other, it can activate the carbonyl group. In contrast, NaBH4 reductions are almost unaffected by added Sodium Iodide and accelerated by Et3N. Reaction rates for reduction of some aliphatic and aromatic ketones with borohydrides in various solvents have been reported.12

In the reduction of cyclic ketones, LiBH4 generally attacks more from the more hindered side than LiAlH4;13 stereochemical aspects of cyclic ketone reduction by complex borohydrides have been widely discussed in some reviews.14 In the reduction of conjugated cyclic enones1,10,13 LiBH4 usually gives more 1,4-attack than does LiAlH4. This tendency is enforced by the presence of a lithium-complexing agent, such as [2.1.1]cryptand: when lithium cation is removed from the reaction medium, the reaction rate of 1,2-attack is decreased more than that of 1,4-attack, probably because of different influence of Li+ on the carbonyl LUMO and on reducing agent HOMO levels, so that 1,4-attack becomes predominant.10b For example, cyclohexen-3-one is reduced to give predominantly the corresponding allylic alcohol by LiBH4 alone, while in the presence of [2.1.1]cryptand the saturated ketone and alcohol are largely predominant (eq 1). Results comparable to that reported in eq 1 have also been obtained using Tetra-n-butylammonium Borohydride in several aprotic solvents.15

Regio- and diastereoselective reductions of steroidal ketones have been achieved by using LiBH4.7,16a Stereoselective reduction of a polyfunctionalized ketone, intermediate in the synthesis of oleandomycin, was realised via LiBH4 reduction (THF-MeOH, -78 °C) of the dibutylboron aldolate derived from reaction of the ketone itself with dibutylmethoxyborane.16b

More studies have been devoted to the reduction of esters, regarding the solvent and possible additives. Different solvents can be used: Et2O, THF, diglyme, or i-PrOH, although in the latter case a large excess of LiBH4 is required to compensate the loss due to the side reaction with the solvent.5 A clean procedure to reduce esters in high yield using an essentially stoichiometric amount of LiBH4 in Et2O or THF has been reported.4 Under these reaction conditions, hindered esters, such as ethyl adamantanecarboxylate, and lactones are also readily reduced, while other functional groups, such as alkyl and aryl halides, nitro groups, ethers, and nitriles remain unaffected. Diesters have been reduced to the corresponding diols using LiBH4,4,17 while reduction of Ethyl Acetoacetate has been reported to give rise to some problems, due to the formation of a borate complex, from which the reduction product cannot be isolated.9

The reducing ability of LiBH4 has been found to be greatly enhanced in mixed solvents containing methanol, and to be dependent on the amount of added alcohol.18 Using the LiBH4-Et2O-MeOH (1 equiv with respect to LiBH4) reducing system, esters, lactones, and epoxides are selectively reduced, even at room temperature, with respect to nitro groups, aryl halides, primary amides, and carboxylic acids. By employing the LiBH4-diglyme (or THF)-MeOH (4 equiv with respect to LiBH4) systems, a further enhancement of reducing capabilities is observed: nitro compounds and nitriles are reduced to amines, and carboxylic acids are reduced to alcohols, while amides show different behaviors depending on substitution. Tertiary amides are reduced essentially to alcohols, through C-N bond fission, while primary amides are cleanly reduced to amines, via C-O bond fission. Secondary amides show different behavior depending on nitrogen substituent.

The chemoselective reduction of an ester moiety in the presence of a carboxylic acid, using LiBH4, or vice versa, using diborane, has been applied in the stereoselective synthesis of both (R)- and (S)-mevalonolactone.19a The chemoselective reduction of an ester with respect to an amide using LiBH4 in THF has been reported in carbohydrate chemistry.19b Sterically hindered acyloxazolidinones have been reduced to the corresponding primary alcohols using LiBH4 in Et2O containing water (1 equiv) in better yields than using LiBH4 or LiAlH4 alone.19c

An interesting stereoselective 1,4 reduction of an acetoxy unsaturated nitrile has been realized by using LiBH4 in THF, probably through the intermediate formation of an alkoxyhydride; the same reaction has been realized on a preparative scale using LiAlH4 in THF.20a Sparse reports on the reduction of other functional groups (carbazole derivatives of carboxylic acids to aldehydes,20b hydrazides to hydrazines,20c cyclic anhydrides to lactones,20d acyl chlorides to alcohols2b) using LiBH4 in various nonhydroxylic solvents have appeared.

Reactivity of LiBH4 towards n-octyl chloride has been found to be extremely low; Lithium Triethylborohydride is 104 times more efficient in carrying out the reduction to n-octane.21a Alkyl tosylates are almost inert towards LiBH4, while they are readily reduced by LiEt3BH.21b

Epoxides are smoothly reduced by LiBH4,18,22 with attack occurring mainly at the less hindered site and cis epoxides being reduced more rapidly than trans ones. 2,3-Epoxy alcohols and their derivatives can be regioselectively reduced to 1,2-diols by using a suspension of LiBH4 in hexane at ambient temperature;23 results are superior to that obtained using completely dissolved LiBH4 in THF or a Titanium Tetraisopropoxide-LiBH4 system (see below).

Addition of Lewis Acids.

In the effort to tune up the selectivity of lithium borohydride, several combinations of the reducing agent with a variety of Lewis acids have been assayed.

Addition of boranes or alkoxyboranes greatly enhances the reactivity of LiBH4 towards esters in Et2O or THF;24 a particularly high catalytic effect is shown by B-MeO-9-BBN and Trimethyl Borate. Many other additives that generate a borane species under the reaction conditions (e.g. LiEt3BH, LiEt3BOMe, Tri-n-butylborane) show a catalytic effect. These additives also exert a catalytic effect on epoxide reductions, but have little if any influence on the reduction of carboxylic acids, tertiary amides [which can be reduced by n-Bu4NBH4 or by NaBH4-Titanium(IV) Chloride (see under Sodium Borohydride)], nitriles, sulfur compounds, and pyridine. Borane-Tetrahydrofuran and Boron Trifluoride Etherate are ineffective as catalysts. Alkenes, although normally inert to the action of LiBH4, are hydroborated (see below) by this reagent in the presence of esters, with concomitant enhancement of the ester reduction rate: as a consequence, unsaturated esters are transformed into a mixture of regioisomeric diols.

Lithium borohydride combined with Chlorotrimethylsilane generates a more powerful reducing system.25 Amino acids can be reduced to amino alcohols, with retention of optical purity; primary, secondary, and tertiary amides, as well as nitriles, are reduced to amines, and sulfoxides to sulfides; a nitrostyrene derivative is reduced to the corresponding saturated amine, in better yield than with alternative reducing systems (LiAlH4 or catalytic hydrogenation). These reactions are believed to proceed through the formation of a borane-THF complex.

Lithium borohydride combined with Europium(III) Chloride in MeOH-Et2O has given the best result in regio- and diastereoselective reduction of a polyfunctionalized conjugated enone intermediate in the synthesis of palytoxin.26 Inferior results were obtained with other reducing systems.

Lithium borohydride combined with titanium tetraisopropoxide in THF, benzene, or CH2Cl2 reduces 2,3-epoxy alcohols regioselectively to 1,2-diols in high yield.27a,b Good 1,2 regioselectivity is shown also by Diisobutylaluminum Hydride (DIBAL) in benzene, while 1,3-diols can be regioselectively obtained by using Red-Al (Sodium Bis(2-methoxyethoxy)aluminum Hydride) in THF.27c,d The LiBH4-Ti(i-PrO)4 system is effective in syn diastereoselective reduction of b-hydroxy ketones to 1,3-diols,27e although other hydrides (LiAlH4, NaBH4) combined with different additives [Ti(i-PrO)4, Ti(OEt)4, TiCl4, LiI] show the same trend and often give better results.

The addition of titanium tetrachloride reverses the diastereoselectivity of the LiBH4 reduction of 3,3-dimethyl-2,4-pentanedione,28 so that meso-2,4-pentanediol is obtained as the main product.

Lithium borohydride (but also LiAlH4 and NaBH4) combined with boron trifluoride etherate in Et2O, THF, or THF-diglyme reduces cyclic lactones to cyclic ethers.29

Addition of Grignard Reagents.

Synthesis of secondary alcohols from esters can be realised by combining LiBH4 with Grignard reagents via formation of an intermediate ketone, which is reduced by LiBH4 much more rapidly than the ester.30a When 2-alkoxy esters are used, stereoselective formation of anti 1,2-diols is observed, especially when THF is used as solvent.30b The reversed diastereoselectivity is observed when DIBAL is added to the ester, with formation of an intermediate aldehyde, before adding the Grignard reagent.

Addition of Chiral Ligands.

N-Benzoylcysteine, a chiral ligand available in both enantiomeric forms, is highly effective in enantioselective LiBH4 reductions of alkyl aryl ketones in THF-t-BuOH (ee up to 92%).31a Analogous results are obtained using the dimer N,N-dibenzoylcystine,31b which also reduces a conjugated enone to the corresponding chiral allyl alcohol.31b The LiBH4-N,N-dibenzoylcystine system has also been used to enantioselectively reduce b-keto esters,31c b-chloro ketones31d (which are precursors of optically active oxetanes), acetylpyridines, and a- and b-amino ketones.31e

Other Reductions.

In an attempt to reduce the ester moiety of some functionalized 2-methylthiopyrimidines, it has been found that LiBH4 (and also LiAlH4) in THF reduces the heteroaromatic ring, leaving almost unaffected the ester and other functional groups, so that differently substituted 1,6-dihydroxypyrimidines can be obtained in good yields (eq 2).32 Differently functionalized pyrimidines are similarly reduced by LiBH4 in DMF. It should be emphasized that a tertiary amide like DMF can be a suitable solvent for LiBH4 (see above for discussion of amide reductions).

Alkyl- and arylhalostibines can be reduced to hydrides, having general formula RnSbH3 - n, both by LiBH4 and other complex hydrides (LiAlH4, NaBH4).2e

Hydroboration.

Lithium borohydride is an effective catalyst for the hydroboration of alkenes with Catecholborane at rt in THF.3 This method is superior to that employing Chlorotris(triphenylphosphine)rhodium(I) as catalyst, since trisubstituted and even tetrasubstituted ethylenes can also be almost quantitatively hydroborated. Other borohydrides (LiBEt3H in THF, NaBH4 in diglyme) were tested and found to be less effective as catalysts.

Preparation of Other Borohydrides.

Lithium borohydride has been used to synthesize other borohydrides,5 particularly aluminum borohydride (a volatile, liquid source of borohydride groups) through the metathesis between Aluminum Chloride and LiBH4 (eq 3). For this process, LiBH4 is superior to NaBH4, both for a more pronounced reactivity and for a more favorable equilibrium position, so that lower temperatures and a much smaller excess of AlCl3 are required.

Miscellaneous.

The addition of LiBH4 in the carbonylation of trialkylboranes not only has the effect of stopping the reaction after the transfer of only one alkyl group, but also enhances the rate of the uptake of Carbon Monoxide2f,33 (see also Potassium Triisopropoxyborohydride). Aldehydes or alcohols are obtained, depending on workup conditions (eq 4).

Lithium borohydride has been used in the degradation of peptides, in order to determine the terminal carboxylic groups.1f

Isotopically labelled lithium borohydrides, LiBD4 and LiBT4, have been used in reaction mechanism studies.2g,20a


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Luca Banfi, Enrica Narisano, & Renata Riva

Università di Genova, Italy



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