Lithium Tri-s-butylborohydride1


[38721-52-7]  · C12H28BLi  · Lithium Tri-s-butylborohydride  · (MW 190.15)

(reducing agent for various functional groups;2 selective reducing agent;3-6 stereoselective reducing agent for ketones7,8 and other functional groups;5,9,10 regioselective reducing agent for cyclic anhydrides;11 used for conjugate addition and alkylation of a,b-unsaturated esters or ketones12 and for Michael-initiated ring closure reactions;13 reduces (2-arylprop-1-en-3-yl)trimethylammonium iodides to 2-arylpropenes;14 hydroborates substituted styrenes;15 reacts with carbon monoxide in the presence of free trialkylborane16)

Alternate Name: L-Selectride®.

Physical Data: not isolated; prepared and used in solution.

Solubility: solubility limits have not been established. The reagent is normally used as a 1.0 M solution in THF or Et2O. Use of a solution in toluene is reported and one method of preparation results in a THF-pentane solvent mixture.

Form Supplied in: 1.0 M solution in THF (L-Selectride®).

Analysis of Reagent Purity: solutions of pure reagent exhibit doublets (J &AApprox; 70 Hz) centered in the range d -6.3 to d -6.7 in the 11B NMR spectrum.17-20 Concentration of hydride is determined by hydrolysis of aliquots and measurement of the hydrogen evolved or by quenching aliquots in excess 1-iodooctane and analysis of the octane formed by GLC.17 Concentration of boron is verified by oxidizing aliquots using alkaline hydrogen peroxide and analyzing the 2-butanol formed by GLC.21

Preparative Methods: direct reaction of tri-s-butylborane with LiH is not suitable, proceeding only to about 10% completion after 24 h in refluxing THF.17 The preferred methods are reaction of the organoborane with Lithium Aluminum Hydride in the presence of 1,4-Diazabicyclo[2.2.2]octane18 or with t-Butyllithium.19 Reaction with lithium trimethoxyaluminum hydride is effective but leads to byproducts not easily separated from the reagent.20

Handling, Storage, and Precautions: solutions are air- and water-sensitive and should be handled in a well-ventilated hood under an inert atmosphere using appropriate techniques.22 Potentially pyrophoric s-Bu3B is a byproduct of reductions; thus standard organoborane oxidation21 is recommended as part of the workup.

Functional Group Reductions.

Alkanes are formed from primary and some secondary alkyl halides via SN2 processes with potential chemoselectivity based on relative ease of displacement (I > Br > Cl).2a The corresponding reaction for tosylates has not been investigated thoroughly.2b Dealkylation of quaternary ammonium halides yields the corresponding amines, demethylation being strongly favored.2c Rates and regioselectivities for reduction of various epoxides have been determined.2d Reduction of conjugated nitroalkenes gives nitroalkanes2e or ketones,2f depending on the workup used (eq 1).

Certain g-keto esters undergo reduction-lactonization2g which, in some cases, is followed by reduction of the g-lactones to the g-lactols (eq 2).2h Some esters of D2-isoxazolinylcarboxylates are reduced to the corresponding primary alcohols (no yields given).2i

The reagent is ineffective compared to t-butylmagnesium chloride as a hydride source for a hydrozirconation procedure.2j

Selective Reductions.

Ketones are reduced selectively in the presence of other functional groups: carboxylic acids;3a esters,3b -n including g-lactones3j,k and 1,3-dioxolan-4-ones;3e amides,4 including benzenesulfonamides4a,b and 2-acetyl b-lactams;4f,g and internal epoxides.31 An enamine is reduced selectively in the presence of a sulfoxide.5

Diastereospecific 1,2-reduction of a conjugated enone occurs in the case of 2b-t-butyldimethylsilyloxycyperone (eq 3).6a The corresponding 2a-silyloxy diastereomer requires LiAlH4 for reduction, also yielding the 3b-ol. A conjugated enone undergoes 1,2-reduction while a lactone (both functions in the same 14-membered ring) remains untouched (see below).12o

Amides are reduced to aldehydes in the presence of other readily reducible functional groups by first treating with ethyl trifluoromethanesulfonate (EtOTf) or MeOTf in CH2Cl2, removing the solvent, dissolving the residue in THF, and treating with L-Selectride (eq 4).6b In all cases, some unreacted starting material is recovered. K-Selectride® (Potassium Tri-s-butylborohydride) gives a lower yield; other hydrides give byproducts.

A keto aldehyde is reduced selectively (eq 5).6c The resulting hydroxy ketone is in equilibrium with its cyclic hemiacetal.

Stereoselective Reductions.

The synthetic use that first brought attention to L-Selectride was the diastereoselective reduction of alkyl-substituted cyclic ketones to alcohols.20 Numerous applications for cyclic7,11m and acyclic8,23c ketones have now been reported, including various ketocarboxylate3 and ketonamide4 systems.

Various theoretical models are used to rationalize observed diastereoselectivity.23 In simple cases, the bulk of the reagent appears to dictate that hydride approach from the less sterically hindered face of the carbonyl (eq 6).20 However, complexation effects, including those of heteroatoms,7b crown ethers,3i,8u and cryptands,8u may reverse the direction of approach. It is also observed that varying the coordinating ability of the solvent influences the ratio of diastereomers.3e

In most cases, imines can be reduced stereoselectively to amines (eq 7).9a-e However, some 2-substituted imines resist reduction and require using the more reactive Lithium Triethylborohydride. Enamino sulfoxides are also stereoselectively reduced to amines.5 Chiral b-imino sulfoxides are reduced stereoselectively but in poor yield.9f Reduction of a tartarimide gives >99% stereoselection in the formation of the corresponding hydroxylactam (eq 8).10

Regioselective Reduction of Cyclic Anhydrides.

Various succinic and phthalic anhydrides are reduced to lactones.11 With certain exceptions (eq 9),11d reduction occurs preferentially at the less hindered carbonyl function. A mechanistic interpretation of the results has been proposed.11d,e

Reduction of Enones and Enoates.

Following the first reported stereoselective reduction of an acyclic enone to an allylic alcohol,12a a reasonably systematic study using K- and L-Selectride was conducted.12b With certain exceptions, results for the latter are comparable to those for the former:

  • 1)whereas one equivalent of K-Selectride gives exclusively 1,2-addition with 3,5-dimethyl-2-cyclohexenone, L-Selectride gives a 1:1 mixture of 1,2- and 1,4-addition products;
  • 2)in reductive alkylation of enones use of L- rather than K-Selectride leads to higher yields of monoalkylated products;
  • 3)while attempted reduction of a,b-unsaturated esters with K-Selectride leads to Claisen condensation products, slowly adding a mixture of ester and t-butyl alcohol to a THF solution of L-Selectride at -70 °C gives the saturated ester cleanly.

    Replacing t-butyl alcohol with various electrophiles in the procedure of (3) allows reductive alkylation, although Claisen condensation product also forms if the enoate lacks a- or b-substitution.

    Other reports confirm that stereoselective 1,2-reduction is likely with both acyclic enones12c,d and b-substituted cyclic enones.12e-g However, in one case, treating the latter first with Methylaluminum Bis(2,6-di-t-butyl-4-methylphenoxide) followed by L-Selectride (2 equiv, -78 °C, 30 min) gives the 1,4-reduction product in quantitative yield.12g Terminal acyclic enones undergo 1,4-reduction with predominant formation of the s-trans enolate, the exact ratio s-trans:s-cis depending on the relative bulk of R and R (eq 10).12h Systems with extended conjugation, such as a phenyldienone, resist conjugate addition and undergo stereoselective 1,2-reduction.12i Unlike simpler substrates, a complex methyl enoate is reduced to the corresponding allylic alcohol.12j

    Cyclic enones without b-substituents often undergo 1,4-reduction,12k-m which may be followed by alkylation;12k,m,n the alkylation may be stereoselective.12k,m In some cases, mixtures of 1,2- and 1,4-reduction products are obtained,12o,p in contrast to 1,2-reduction only for K-Selectride.12o Vinyl triflates may be produced from enones if 1,4-reduction is facile.12q In the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone, a conjugated cyclic dienone is reduced to the conjugated enone.12r

    a,b-Alkynic esters tend toward nearly exclusive 1,2-reduction with formation of propargylic alcohols.12b Likewise, a,b-alkynic ketones yield only propargylic alcohols.8e,f

    Michael Initiated Ring Closure (MIRC) Reactions.

    Formation of five- and six-membered rings results from treatment of o-alkylidenemalonates with L-Selectride, but better yields are realized with nucleophiles other than hydride.13a A MIMIRC procedure using 2-cyclohexenone and Vinyltriphenylphosphonium Bromide (VTB) is highly successful (eq 11).13b The 1-t-butyl 9-methyl diester of (E,E)-(S)-2,4-dimethyl-2,7-nonadienedioic acid is converted to a cyclohexane diester as a single stereoisomer (eq 12).13c

    Reduction of (2-Arylprop-1-en-3-yl)trimethylammonium Iodides.

    Treatment of [2-(4-methoxyphenyl)prop-1-en-3-yl]trimethylammonium iodide with L-Selectride results in addition of hydride with displacement of Me3N, giving 2-(4-methoxyphenyl)propene in virtually quantitative yield (eq 13).14 This reaction may be applicable for derivatives containing a wide variety of aryl groups.

    Hydroboration of Styrenes.

    This reaction is quantitative with Lithium Triethylborohydride but proceeds to the extent of less than 40% with L-Selectride, polymerization of styrene being the predominant result.15

    Reaction with Carbon Monoxide.

    Carbonylation of LiBH-(s-Bu)3 followed by treatment with refluxing aqueous NaOH gives 2-methyl-1-butanol.16a Since LiBH(s-Bu)3 is an intermediate in hydride-induced carbonylation of s-Bu3B using LiAlH(OMe)3,16b,20 different workup procedures yield 2-methylbutanal16c or 3,5-dimethyl-4-heptanol.16d

    Related Reagents.

    Lithium Aluminum Hydride; Lithium Triethylborohydride; Lithium Trisiamylborohydride; Potassium Tri-s-butylborohydride.

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    John L. Hubbard

    Marshall University, Huntington, WV, USA

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