Sodium Borohydride

NaBH4

[16940-66-2]  · BH4Na  · Sodium Borohydride  · (MW 37.84)

(reducing agent for aldehydes and ketones, and many other functional groups in the presence of additives1)

Physical Data: mp 400 °C; d 1.0740 g cm-3.

Solubility: sol H2O (stable at pH 14, rapidly decomposes at neutral or acidic pH); sol MeOH (13 g/100 mL)1b, and EtOH (3.16 g/100mL),1b but decomposes to borates; sol polyethylene glycol (PEG),2a sol and stable in i-PrOH (0.37 g/100 mL)3 and diglyme (5.15 g/100 mL);1b insol ether;1b slightly sol THF.1c

Form Supplied in: colorless solid in powder or pellets; supported on silica gel or on basic alumina; 0.5 M solution in diglyme; 2.0 M solution in triglyme; 12 wt % solution in 14 M aqueous NaOH. Typical impurities are sodium methoxide and sodium hydroxide.

Analysis of Reagent Purity: can be assessed by hydrogen evolution.4

Purification: crystallize from diglyme3 or isopropylamine.4

Handling, Storage, and Precautions: harmful if inhaled or absorbed through skin. It is decomposed rapidly and exothermically by water, especially if acid solutions are used. This decomposition forms toxic diborane gas and flammable/explosive hydrogen gas, and thus must be carried out under a hood. Solutions in DMF can undergo runaway thermal reactions, resulting in violent decompositions.5 The addition of supported noble metal catalysts to solutions of NaBH4 can result in ignition of liberated hydrogen gas.5

Reduction of Aldehydes and Ketones.

Sodium borohydride is a mild and chemoselective reducing agent for the carbonyl function. At 25 °C in hydroxylic solvents it rapidly reduces aldehydes and ketones, but it is essentially inert to other functional groups such as epoxides, esters, lactones, carboxylic acid salts, nitriles, and nitro groups. Acyl halides, of course, react with the solvent.1a The simplicity of use, the low cost, and the high chemoselectivity make it one of the best reagents for this reaction. Ethanol and methanol are usually employed as solvents, the former having the advantage of permitting reductions in homogeneous solutions with relatively little loss of reagent through the side reaction with the solvent.1a Aprotic solvents such as diglyme greatly decrease the reaction rates.1a On the other hand, NaBH4 in polyethylene glycol (PEG) shows a reactivity similar to that observed in EtOH.2a Although the full details of the mechanism of ketone reduction by NaBH4 remain to be established,6 it has been demonstrated that all four hydrogen atoms can be transferred. Moreover, the rate of reduction was shown to slightly increase when the hydrogens on boron are replaced by alkoxy groups.1a,c,d However, especially when NaBH4 is used in MeOH, an excess of reagent has to be used in order to circumvent the competitive borate formation by reaction with the solvent. Ketone reduction has been accelerated under phase-transfer conditions7 or in the presence of HMPA supported on a polystyrene-type resin.8

The isolation of products is usually accomplished by diluting the reaction mixture with water, making it slightly acidic to destroy any excess hydride, and then extracting the organic product from the aqueous solution containing boric acid and its salts.

Kinetic examination of the reduction of benzaldehyde and acetophenone in isopropyl alcohol indicated a rate ratio of 400:1.1a Thus it is in principle possible to reduce an aldehyde in the presence of a ketone.9a Best results (>95% chemoselectivity) have been obtained using a mixed solvent system (EtOH-CH2Cl2 3:7) and performing the reduction at -78 °C,9a or by employing an anionic exchange resin in borohydride form.10 This reagent can also discriminate between aromatic and aliphatic aldehydes. On the other hand, reduction of ketones in the presence of aldehydes can be performed by NaBH4-Cerium(III) Chloride. NaBH4 in MeOH-CH2Cl2 (1:1) at -78 °C reduces ketones in the presence of conjugated enones and aldehydes in the presence of conjugated enals.9

Conjugate Reductions.

NaBH4 usually tends to reduce a,b-unsaturated ketones in the 1,4-sense,1d affording mixtures of saturated alcohol and ketone. In alcoholic solvents, saturated b-alkoxy alcohols can be formed as byproducts via conjugate addition of the solvent.11 The selectivity is not always high. For example, while cyclopentenone is reduced only in the conjugate fashion, cyclohexenone affords a 59:41 ratio of allylic alcohol and saturated alcohol.1d Increasing steric hindrance on the enone increases 1,2-attack.11 Aldehydes undergo more 1,2-reduction than the corresponding ketones.1c,1d The use of pyridine as solvent may be advantageous in increasing the selectivity for 1,4-reduction, as exemplified (eq 1) by the reduction of (R)-carvone to dihydrocarveols and (in minor amounts) dihydrocarvone.12

Trialkyl borohydrides such as Lithium Tri-s-butylborohydride and Potassium Tri-s-butylborohydride are superior reagents for the chemoselective 1,4-reduction of enones. On the other hand, 1,2-reduction can be obtained by using NaBH4 in the mixed solvent MeOH-THF (1:9),13 or with NaBH4 in combination with CeCl3 or other lanthanide salts.14

NaBH4 in alcoholic solvents has been used for the conjugate reduction of a,b-unsaturated esters,15 including cinnamates and alkylidenemalonates, without affecting the alkoxycarbonyl group. Conjugate nitroalkenes have been reduced to the corresponding nitroalkanes.16 Saturated hydroxylamines are obtained by reducing nitroalkenes with the Borane-Tetrahydrofuran complex in the presence of catalytic amounts of NaBH4, or by using a combination of NaBH4 and Boron Trifluoride Etherate in 1:1.5 molar ratio.17 Extended reaction can lead also to the saturated amines.17

Reduction of Carboxylic Acid Derivatives.

The reduction of carboxylic esters1c,1d by NaBH4 is usually slow, but can be performed by the use of excess reagent in methanol or ethanol18 at room temperature or higher. The solvent must correspond to the ester group, since NaBH4 catalyzes ester interchange. This transformation can also be achieved at 65-80 °C in t-BuOH19 or polyethylene glycol.2b Although the slow rate and the need to use excess reagent makes other stronger complex hydrides such as Lithium Borohydride or Lithium Aluminum Hydride best suited for this reaction, in particular cases the use of NaBH4 allows interesting selectivity: see, for example, the reduction of eq 2,20 where the b-lactam remains unaffected, or of eq 3,21 where the epoxide and the cyano group do not react.

Borohydrides cannot be used for the reduction of a,b-unsaturated esters to allylic alcohols since the conjugate reduction is faster.18b The reactivity of NaBH4 toward esters has been enhanced with various additives. For example, the system NaBH4-CaCl2 (2:1) shows a reactivity similar to LiBH4.18b Esters have also been reduced with NaBH4-Zinc Chloride in the presence of a tertiary amine,22 or with NaBH4-Copper(II) Sulfate. The latter system reduces selectively aliphatic esters in the presence of aromatic esters of amides.23 Finally, esters have also been reduced with NaBH4-Iodine.24a In this case the reaction seems to proceed through diborane formation, and so it cannot be used for substrates containing an alkenic double bond. A related methodology, employing Borane-Dimethyl Sulfide in the presence of catalytic NaBH4,25 is particularly useful for the regioselective reduction of a-hydroxy esters, as exemplified by the conversion of (S)-diethyl malate into the vicinal diol (eq 4).

Lactones are only slowly reduced by NaBH4 in alcohol solvents at 25 °C, unless the carbonyl is flanked by an a-heteroatom functionality.1d Sugar lactones are reduced to the diol when the reduction is carried out in water at neutral pH, or to the lactol when the reaction is performed at lower (~3) pH.26 Thiol esters are more reactive and are reduced to primary alcohols with NaBH4 in EtOH, without reduction of ester substituents.27

Carboxylic acids are not reduced by NaBH4. The conversion into primary alcohols can be achieved by using NaBH4 in combination with powerful Lewis acids,1k,28 Sulfuric Acid,28 Catechol,24b Trifluoroacetic Acid,24b or I2.24a In these cases the actual reacting species is a borane, and thus hydroboration of double bonds present in the substrate can be a serious side reaction. Alternatively, the carboxylic acids can be transformed into activated derivatives,29 such as carboxymethyleneiminium salts29a or mixed anhydrides,29b followed by reduction with NaBH4 at low temperature. These methodologies tolerate the presence of double bonds, even if conjugated to the carboxyl.29a

Nitriles are, with few exceptions,21 not reduced by NaBH4.1k Sulfurated NaBH4,30 prepared by the reaction of sodium borohydride with sulfur in THF, is somewhat more reactive than NaBH4, and reduces aromatic nitriles (but not aliphatic ones) to amines in refluxing THF. Further activation has been realized by using the Cobalt Boride system, (NaBH4-CoCl2) 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,31 Et2SeBr2,32 CuSO4,23 Chlorotrimethylsilane,33 and I224a are also efficient activators for this transformation. The NaBH4-Et2SeBr2 reagent allows the selective reduction of nitriles in the presence of esters or nitro groups, which are readily reduced by NaBH4-CoCl2.

NaBH4 in alcoholic solvents does not reduce amides.1a,1c-d However, under more forcing conditions (NaBH4 in pyridine at reflux), reduction of tertiary amides to the corresponding amines can be achieved.32 Secondary amides are inert, while primary amides are dehydrated to give nitriles. Also, NaBH4-Et2SeBr2 is specific for tertiary amides.32 Reagent combinations which show enhanced reactivity, and which are thus employable for all three types of amides, are NaBH4-CoCl2, NaBH4 in the presence of strong acids34 (e.g. Methanesulfonic Acid or Titanium(IV) Chloride) in DMF or DME, NaBH4-Me3SiCl,33 and NaBH4-I2.24a

An indirect method for the reduction of amides to amines by NaBH4 (applicable only to tertiary amides) involves conversion into a Vilsmeier complex [(R2N=C(Cl)R)+Cl-], by treatment with Phosphorus Oxychloride, followed by its reduction.35 In a related methodology, primary or secondary (also cyclic) amides are first converted into ethyl imidates by the action of Triethyloxonium Tetrafluoroborate, and the latter reduced to amines with NaBH4 in EtOH or, better, with NaBH4-Tin(IV) Chloride in Et2O.36

In addition to the above-quoted methods, tertiary d-lactams have been reduced to the corresponding cyclic amines by dropwise addition of MeOH to the refluxing mixture of NaBH4 and substrate in t-BuOH,37 or by using trifluoroethanol as solvent.38 This reaction was applied during a synthesis of indolizidine alkaloid swainsonine for the reduction of lactam (1) to amine (2) (eq 5).38

Acyl chlorides can be reduced to primary alcohols by reduction in aprotic solvents such as PEG,2a or using NaBH4-Alumina in Et2O.39 More synthetically useful is the partial reduction to the aldehydic stage, which can be achieved by using a stoichiometric amount of the reagent at -70 °C in DMF-THF,40 with the system NaBH4-Cadmium Chloride-DMF,41 or with Bis(triphenylphosphine)copper(I) Borohydride.

Alternative methodologies for the indirect reduction of carboxylic derivatives employ as intermediates 2-substituted 1,3-benzoxathiolium tetrafluoborates (prepared from carboxylic acids, acyl chlorides, anhydrides, or esters)42 and dihydro-1,3-thiazines or dihydro-1,3-oxazines (best prepared from nitriles).43 These compounds are smoothly reduced by NaBH4, to give acetal-like adducts, easily transformable into the corresponding aldehydes by acidic hydrolysis. Conversion of primary amides into the N-acylpyrrole derivative by reaction with 1,4-dichloro-1,4-dimethoxybutane in the presence of a cationic exchange resin, followed by NaBH4 reduction, furnished the corresponding aldehydes.44

Cyclic anhydrides are reduced by NaBH4 to lactones in moderate to good yields. Hydride attack occurs principally at the carbonyl group adjacent to the more highly substituted carbon atom.45 Cyclic imides are more reactive than amides and can be reduced to the corresponding a-hydroxylactams by using methanolic or ethanolic NaBH4 in the presence of HCl as buffering agent.1c These products are important as precursors for N-acyliminium salts. The carbonyl adjacent to the most substituted carbon is usually preferentially reduced46 (see also Cobalt Boride). N-Alkylphthalimides may be reduced with NaBH4 in 2-propanol to give an open-chain hydroxy-amide which, upon treatment with AcOH, cyclizes to give phthalide (a lactone) and the free amine. This method represents a convenient procedure for releasing amines from phthalimides under nonbasic conditions.47

Reduction of C=N Double Bonds.

The C=N double bond of imines is generally less reactive than the carbonyl C=O toward reduction with complex hydrides. However, imines may be reduced by NaBH4 in alcoholic solvents under neutral conditions at temperatures ranging from 0 °C to that of the refluxing solvent.1c,1d,48 Protonation or complexation with a Lewis acid of the imino nitrogen dramatically increases the rate of reduction.1i Thus NaBH4 in AcOH (see Sodium Triacetoxyborohydride) or in other carboxylic acids is an efficient reagent for this transformation (although the reagent of choice is probably Sodium Cyanoborohydride). Imines are also reduced by Cobalt Boride, NaBH4-Nickel(II) Chloride, and NaBH4-ZrCl4.31 Imine formation, followed by in situ reduction, has been used as a method for synthesis of unsymmetrical secondary amines.48 Once again, Na(CN)BH3 represents the best reagent.1c,1d,48 However, this transformation was realized also with NaBH4,48,49 either by treating the amine with excess aqueous formaldehyde followed by NaBH4 in MeOH, or NaBH4-CF3CO2H, or through direct reaction of the amine with the NaBH4-carboxylic acid system. In the latter case, part of the acid is first reduced in situ to the aldehyde, which then forms an imine. The real reagent involved is NaB(OCOR)3H (see Sodium Triacetoxyborohydride). Reaction of an amine with glutaric aldehyde and NaBH4 in the presence of H2SO4 represents a good method for the synthesis of N-substituted piperidines.49c Like protonated imines, iminium salts are readily reduced by NaBH4 in alcoholic media.1c,50 N-Silylimines are more reactive than N-alkylimines. Thus a-amino esters can be obtained by reduction of N-silylimino esters.51 a,b-Unsaturated imines are reduced by NaBH4 in alcoholic solvents in the 1,2-mode to give allylic amines.52 Enamines are transformed into saturated amines by reduction with NaBH4 in alcoholic media.48,53

The reduction of oximes and oxime ethers is considerably more difficult and cannot be realized with NaBH4 alone. Effective reagent combinations for the reduction of oximes include sulfurated NaBH4,30 NaBH4-NiCl2, NaBH4-ZrCl4,31 NaBH4-MoO3,54 NaBH4-TiCl4,55 and NaBH4-Titanium(III) Chloride.56 In all cases the main product is the corresponding primary amine. NaBH4-ZrCl4 is efficient also for the reduction of oxime ethers. NaBH4-MoO3 reduces oximes without affecting double bonds, while NaBH4-NiCl2 reduces both functional groups. The reduction with NaBH4-TiCl3 in buffered (pH 7) aqueous media has been used for the chemoselective reduction of a-oximino esters to give a-amino esters (eq 6).56

NaBH4 reduces hydrazones only when they are N,N-dialkyl substituted. The reaction is slow and yields are not usually satisfactory.57 More synthetically useful is the reduction of N-p-tosylhydrazones to give hydrocarbons,1c,1d,58 which has been carried out with NaBH4 in refluxing MeOH, dioxane, or THF.58 Since N-p-tosylhydrazones are easily prepared from aldehydes or ketones, the overall sequence represents a mild method for carbonyl deoxygenation. a,b-Unsaturated tosylhydrazones show a different behavior yielding, in MeOH, the allylic (or benzylic) methyl ethers.58c The reduction of tosylhydrazones with NaBH4 is not compatible with ester groups, which are readily reduced under these conditions. More selective reagents for this reduction are NaBH(OAc)3 and NaCNBH3.

Reduction of Halides, Sulfonates, and Epoxides.

The reduction of alkyl halides or sulfonates by NaBH4 is not an easy reaction.1d It is best performed in polar aprotic solvents59 such as DMSO, sulfolane, HMPA, DMF, diglyme, or PEG (polyethylene glycol),2a at temperatures between 60 °C and 100 °C (unless for highly reactive substrates), or under phase-transfer conditions.60a The mechanism is believed to be SN2 (I > Br > Cl and primary > secondary). Although the more nucleophilic Lithium Triethylborohydride seems better suited for these reductions,59b the lower cost of NaBH4 and the higher chemoselectivity (for example esters, nitriles, and sulfones can survive)59a makes it a useful alternative. Also, some secondary and tertiary alkyl halides, capable of forming relatively stable carbocations, for example benzhydryl chloride, may be reduced by NaBH4. In this case the mechanism is different (via a carbocation) and the reaction is accelerated by water.59a,b Primary, secondary, and even aryl iodides and bromides1d have been reduced in good yields by NaBH4 under the catalysis of soluble polyethylene- or polystyrene-bound tin halides (PE-Sn(Bu)2Cl or PS-Sn(Bu)2Cl).61 Aryl bromides and iodides have also been reduced with NaBH4-Copper(I) Chloride in MeOH.62

NaBH4 reduces epoxides only sluggishly.1d Aryl-substituted and terminal epoxides can be reduced by slow addition of MeOH to a refluxing mixture of epoxide and NaBH4 in t-BuOH,63 or by NaBH4 in polyethylene glycol.2b The reaction is regioselective (attack takes place on the less substituted carbon), and chemoselective (nitriles, carboxylic acids, and nitro groups are left intact).63 The opposite regioselectivity was realized by the NaBH4-catalyzed reduction with diborane.64

Other Reductions.

Aromatic and aliphatic nitro compounds are not reduced to amines by NaBH4 in the absence of an activator.1d The NaBH4-NiCl2 system (see Nickel Boride) is a good reagent combination for this reaction, being effective also for primary and secondary aliphatic compounds. Other additives that permit NaBH4 reduction are SnCl2,65 Me3SiCl,33 CoCl2 (see Cobalt Boride), and MoO3 (only for aromatic compounds),66 Cu2+ salts (for aromatic and tertiary aliphatic),23,67 and Palladium on Carbon (good for both aromatic and aliphatic).68 Also, sulfurated NaBH430 is an effective and mild reducing agent for aromatic nitro groups. In the presence of catalytic selenium or tellurium, NaBH4 reduces nitroarenes to the corresponding N-arylhydroxylamines.69

The reduction of azides to amines proceeds in low yield under usual conditions, but it can be performed efficiently under phase-transfer conditions,60b using NaBH4 supported on an ion-exchange resin,70 or using a THF-MeOH mixed solvent (this last method is well suited only for aromatic azides).71

Tertiary alcohols or other carbinols capable of forming a stable carbocation have been deoxygenated by treatment with NaBH4 and CF3CO2H or NaBH4-CF3SO3H.72 Under the same conditions,72 or with NaBH4-Aluminum Chloride,73 diaryl ketones have also been deoxygenated.

Cyano groups a to a nitrogen atom can be replaced smoothly by hydrogen upon reaction with NaBH4.74 Since a-cyano derivatives of trisubstituted amines can be easily alkylated with electrophilic agents, the a-aminonitrile functionality can be used as a latent a-amino anion,74a as exemplified by eq 7 which shows the synthesis of ephedrine from a protected aminonitrile. The reduction, proceeding with concurrent benzoyl group removal, is only moderately stereoselective (77:23).

Primary amines have been deaminated in good yields through reduction of the corresponding bis(sulfonimides) with NaBH4 in HMPA at 150-175 °C.75 NaBH4 reduction of ozonides is rapid at -78 °C and allows the one-pot degradation of double bonds to alcohols1b (see also Ozone). The reduction of organomercury(II) halides (see also Mercury(II) Acetate) is an important step in the functionalization of double bonds via oxymercuration-or amidomercuration-reduction. This reduction, which proceeds through a radical mechanism, is not stereospecific, but it can be in some cases diastereoselective.76 In the presence of Rhodium(III) Chloride in EtOH, NaBH4 completely saturates arenes.77 NaBH4 has also been employed for the reduction of quinones,78 sulfoxides (in combination with Aluminum Iodide79 or Me3SiCl33), and sulfones (with Me3SiCl),33 although it does not appear to be the reagent of choice for these reductions. Finally, NaBH4 was used for the reduction of various heterocyclic systems (pyridines, pyridinium salts, indoles, benzofurans, oxazolines, and so on).1c,1d,48,80 The discussion of these reductions is beyond the scope of this article.

Diastereoselective Reductions.

NaBH4, like other small complex hydrides (LiBH4 and LiAlH4), shows an intrinsic preference for axial attack on cyclohexanones,1c,1d,81 as exemplified by the reduction of 4-t-butylcyclohexanone (eq 8).81a This preference, which is due to stereoelectronic reasons,82 can be counterbalanced by steric biases. For example, in 3,3,5-trimethylcyclohexanone, where a b-axial substituent is present, the stereoselectivity is nearly completely lost (eq 9).81a

Also, in 2-methylcyclopentanone81c the attack takes place from the more hindered side, forming the trans isomer (dr = 74:26). In norcamphor,81a both stereoelectronic and steric effects favor exo attack, forming the endo alcohol in 84:16 diastereoisomeric ratio. In camphor, however, the steric bias given by one of the two methyls on the bridge brings about an inversion of stereoselectivity toward the exo alcohol.81a

The stereoselectivity for equatorial alcohols has been enhanced by using the system NaBH4-Cerium(III) Chloride, which has an even higher propensity for attack from the more hindered side,83 or by precomplexing the ketone on Montmorillonite K10 clay.84 On the other hand, bulky trialkylborohydrides (see Lithium Tri-s-butylborohydride) are best suited for synthesis of the axial alcohol through attack from the less hindered face.

NaBH4 does not seem to be the best reagent for the stereoselective reduction of chiral unfunctionalized acyclic ketones. Bulky complex hydrides such as Li(s-Bu)3BH usually afford better results.1c,1d When a heteroatom is present in the a- or b-position, the stereochemical course of the reduction depends also on the possible intervention of a cyclic chelated transition state. Also, in this case other complex hydrides are often better suited for favoring chelation (see Zinc Borohydride). Nevertheless, cases are known85 where excellent degrees of stereoselection have been achieved with the simpler and less expensive NaBH4. Some examples are shown in eqs 10-15.

The stereoselective formation of anti adduct (4) in the reduction of ketone (3) was explained through the intervention of a chelate involving the methoxy group,85a although there is some debate on what the acidic species is that is coordinated (probably Na+). A chelated transition state is probably the cause of the stereoselective formation of anti product (6) from (5).85b Methylation of the NH group indeed provokes a decrease of stereoselection. On the other hand, when appropriate protecting groups that disfavor chelation are placed on the heteroatom, the reduction proceeds by way of the Felkin model where the heteroatomic substituent plays the role of large group, and syn adducts are formed preferentially. This is the case of a-dibenzylamino ketones (eqs 12 and 13)85c,d and of the a-silyloxy ketone of eq 14.85e Finally, the sulfonium salt of eq 15 gives, with exce llent stereocontrol, the anti alcohol.85f This result was explained by a transition state where the S+ and carbonyl oxygen are close due to a charge attraction.

The reduction of a diastereomeric mixture of enantiomerically pure b-keto sulfoxides (7) furnished one of the four possible isomers with good overall stereoselectivity (90%), when carried out under conditions which favor epimerization of the a chiral center (eq 16). This outcome derives from a chelation-controlled reduction (involving the sulfoxide oxygen) coupled with a kinetic resolution of the two diastereoisomers of (7).86

The reduction of cyclic imines and oximes follows a trend similar to that of corresponding ketones. However, the tendency for attack from the most hindered side is in these cases attenuated.1c,1d,57,87 In the case of oximes, while NaBH4-MoO3 attacks from the axial side, NaBH4-NiCl2 attacks from the equatorial side.88 An example of diastereoselective reduction of acyclic chiral imines is represented by the one-pot transformation of a-alkoxy or a,b-epoxynitriles into anti vicinal amino alcohols (eq 17) or epoxyamines. The outcome of these reductions was explained on the basis of a cyclic chelated transition state.89

Enantioselective Reductions.

NaBH4 has been employed with less success than LiAlH4 or BH3 in enantioselective ketone reductions.1d,90,91 Low to moderate ee values have been obtained in the asymmetric reduction of ketones with chiral phase-transfer catalysts, chiral crown ethers,91a b-cyclodextrin,91b and bovine serum albumin.91c On the other hand, good results have been realized in the reduction of propiophenone with NaBH4 in the presence of isobutyric acid and of diisopropylidene-D-glucofuranose (ee = 85%),91d or in the reduction of a-keto esters and b-keto esters with NaBH4-L-tartaric acid (ee &egt;86%).91e

Very high ee values have been obtained in the asymmetric conjugate reduction of a,b-unsaturated esters and amides with NaBH4 in the presence of a chiral semicorrin (a bidentate nitrogen ligand) cobalt catalyst.92 Good to excellent ee values were realized in the reduction of oxime ethers with NaBH4-ZrCl4 in the presence of a chiral 1,2-amino alcohol.93

Related Reagents.

Cerium(III) Chloride; Nickel Boride; Potassium Triisopropoxyborohydride; Sodium Cyanoborohydride; Sodium Triacetoxyborohydride.


1. (a) Brown, H. C.; Krishnamurthy, S. T 1979, 35, 567. (b) FF 1967, 1, 1049. (c) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH-Lavoisier: Paris, 1991. (d) COS 1991, 8, Chapters 1.1, 1.2, 1.7, 1.10, 1.11, 1.14, 2.1, 2.3, 3.3, 3.5, 4.1, 4.4, 4.7.
2. (a) Santaniello, E.; Fiecchi, A.; Manzocchi, A.; Ferraboschi, P. JOC 1983, 48, 3074. (b) Santaniello, E.; Ferraboschi, P.; Fiecchi, A.; Grisenti, P.; Manzocchi, A. JOC 1987, 52, 671.
3. Brown, H. C.; Mead, E. J.; Subba Rao, B. C. JACS 1955, 77, 6209.
4. Stockmayer, W. H.; Rice, D. W.; Stephenson, C. C. JACS 1955, 77, 1980.
5. The Sigma-Aldrich Library of Chemical Safety Data, Sigma-Aldrich: Milwaukee, 1988.
6. Wigfield, D. C. T 1979, 35, 449.
7. Bunton, C. A.; Robinson, L.; Stam, M. F. TL 1971, 121. Subba Rao, Y. V.; Choudary, B. M. SC 1992, 22, 2711.
8. Tomoi, M.; Hasegawa, T.; Ikeda, M.; Kakiuchi, H. BCJ 1979, 52, 1653.
9. (a) Ward, D. E.; Rhee, C. K. CJC 1989, 67, 1206. (b) Ward, D. E.; Rhee, C. K.; Zoghaib, W. M. TL 1988, 29, 517.
10. Yoon, N. M.; Park, K. B.; Gyoung, Y. S. TL 1983, 24, 5367.
11. Johnson, M. R.; Rickborn, B. JOC 1970, 35, 1041.
12. Raucher, S.; Hwang, K.-J. SC 1980, 10, 133.
13. Varma, R. S.; Kabalka, G. W. SC 1985, 15, 985.
14. Komiya, S.; Tsutsumi, O. BCJ 1987, 60, 3423.
15. Schauble, J. H.; Walter, G. J.; Morin, J. G. JOC 1974, 39, 755. Salomon, R. G.; Sachinvala, N. D.; Raychaudhuri, S. R.; Miller, D. B. JACS 1984, 106, 2211.
16. Hassner, A.; Heathcock, C. H. JOC 1964, 29, 1350.
17. Varma, R. S.; Kabalka, G. W. SC 1985, 15, 843.
18. (a) Olsson, T.; Stern, K.; Sundell, S. JOC 1988, 53, 2468. (b) Brown, H. C.; Narasimhan, S.; Choi, Y. M. JOC 1982, 47, 4702.
19. Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. BCJ 1984, 57, 1948.
20. Kawabata, T.; Minami, T.; Hiyama, T. JOC 1992, 57, 1864.
21. Mauger, J.; Robert, A. CC 1986, 395.
22. Yamakawa, T.; Masaki, M.; Nohira, H. BCJ 1991, 64, 2730.
23. Yoo, S.; Lee, S. SL 1990, 419.
24. (a) Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. T 1992, 48, 4623. (b) Suseela, Y.; Periasamy, M. T 1992, 48, 371.
25. Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. T 1992, 48, 4067.
26. Wolfrom, M. L.; Anno, K. JACS 1952, 74, 5583. Attwood, S. V.; Barrett, A. G. M. JCS(P1) 1984, 1315.
27. Liu, H.-J.; Bukownik, R. R.; Pednekar, P. R. SC 1981, 11, 599.
28. Abiko, A.; Masamune, S. TL 1992, 33, 5517.
29. (a) Fujisawa, T.; Mori, T.; Sato, T. CL 1983, 835. (b) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J. TL 1991, 32, 923.
30. Lalancette, J. M.; Freche, A.; Brindle, J. R.; Laliberté, M. S 1972, 526.
31. Itsuno, S.; Sakurai, Y.; Ito, K. S 1988, 995.
32. Akabori, S.; Takanohashi, Y. JCS(P1) 1991, 479.
33. Giannis, A.; Sandhoff, K. AG(E) 1989, 28, 218.
34. (a) Wann, S. R.; Thorsen, P. T.; Kreevoy, M. M. JOC 1981, 46, 2579. (b) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S. S 1980, 695.
35. Rahman, A.; Basha, A.; Waheed, N.; Ahmed, S. TL 1976, 219.
36. Tsuda, Y.; Sano, T.; Watanabe, H. S 1977, 652.
37. Mandal, S. B.; Giri, V. S.; Sabeena, M. S.; Pakrashi, S. C. JOC 1988, 53, 4236.
38. Setoi, H.; Takeno, H.; Hashimoto, M. JOC 1985, 50, 3948.
39. Santaniello, E.; Farachi, C.; Manzocchi, A. S 1979, 912.
40. Babler, J. H.; Invergo, B. J. TL 1981, 22, 11.
41. Entwistle, I. D.; Boehm, P.; Johnstone, R. A. W.; Telford, R. P. JCS(P1) 1980, 27.
42. Barbero, M.; Cadamuro, S.; Degani, I.; Fochi, R.; Gatti, A.; Regondi, V. S 1986, 1074.
43. Meyers A. I.; Nabeya, A.; Adickes, H. W.; Politzer, I. R.; Malone, G. R.; Kovelesky, A.; Nolan, R. L.; Portnoy, R. C. JOC 1973, 38, 36. Politzer, I. R.; Meyers, A. I. OSC 1988, 6, 905.
44. Lee, S. D.; Brook, M. A.; Chan, T. H. TL 1983, 24, 1569.
45. Takano, S.; Ogasawara, K. S 1974, 42.
46. Goto, T.; Konno, M.; Saito, M.; Sato, R. BCJ 1989, 62, 1205.
47. Osby, J. O.; Martin, M. G.; Ganem, B. TL 1984, 25, 2093.
48. Gribble, G. W.; Nutaitis, C. F. OPP 1985, 17, 317.
49. (a) Sondengam, B. L.; Hentchoya Hémo, J.; Charles, G. TL 1973, 261. (b) Gribble, G. W.; Nutaitis, C. F. S 1987, 709. (c) Verardo, G.; Giumanini, A. G.; Favret, G.; Strazzolini, P. S 1991, 447.
50. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P. JACS 1983, 105, 7754; Polniaszek, R. P.; Kaufman, C. R. JACS 1989, 111, 4859.
51. Matsuda, Y.; Tanimoto, S.; Okamoto, T.; Ali, S. M. JCS(P1) 1989, 279.
52. De Kimpe, N.; Stanoeva, E.; Verhé, R.; Schamp, N. S 1988, 587.
53. Borch, R. F.; Bernstein, M. D.; Durst, H. D. JACS 1971, 93, 2897.
54. Mundy, B. P.; Bjorklund, M. TL 1985, 26, 3899.
55. Spreitzer, H.; Buchbauer, G.; Püringer, C. T 1989, 45, 6999.
56. Hoffman, C.; Tanke, R. S.; Miller, M. J. JOC 1989, 54, 3750.
57. Walker, G. N.; Moore, M. A.; Weaver, B. N. JOC 1961, 26, 2740.
58. (a) Caglioti, L. OSC 1988, 6, 62. (b) Rosini, G.; Baccolini, G.; Cacchi, S. S 1975, 44. (c) Grandi, R.; Marchesini, A.; Pagnoni, U. M.; Trave, R. JOC 1976, 41, 1755.
59. (a) Hutchins, R. O.; Kandasamy, D.; Dux III, F.; Maryanoff, C. A.; Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro, J.; Puglis, J. JOC 1978, 43, 2259. (b) Krishnamurthy, S.; Brown, H. C. JOC 1980, 45, 849. (c) Kocienski, P.; Street, S. D. A. SC 1984, 14, 1087.
60. (a) Rolla, F. JOC 1981, 46, 3909. (b) Rolla, F. JOC 1982, 47, 4327.
61. Bergbreiter, D. E.; Walker, S. A. JOC 1989, 54, 5138.
62. Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. JOC 1989, 54, 5308.
63. Ookawa, A.; Hiratsuka, H.; Soai, K. BCJ 1987, 60, 1813.
64. Brown, H. C.; Yoon, N. M. JACS 1968, 90, 2686.
65. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. CPB 1981, 29, 1443.
66. Yanada, K.; Yanada, R.; Meguri, H. TL 1992, 33, 1463.
67. Cowan, J. A. TL 1986, 27, 1205.
68. Neilson, T.; Wood, H. C. S.; Wylie, A. G. JCS 1962, 371. Petrini, M.; Ballini, R.; Rosini, G. S 1987, 713.
69. Uchida, S.; Yanada, K.; Yamaguchi, H.; Meguri, H. CL 1986, 1069; CC 1986, 1655.
70. Kabalka, G. W.; Wadgaonkar, P. P.; Chatla, N. SC 1990, 20, 293.
71. Soai, K.; Yokoyama, S.; Ookawa, A. S 1987, 48.
72. Olah, G. A.; Wu, A.; Farooq, O. JOC 1988, 53, 5143.
73. Ono, A.; Suzuki, N.; Kamimura, J. S 1987, 736.
74. (a) Stork, G.; Jacobson, R. M.; Levitz, R. TL 1979, 771; (b) Santoyo-Gonzalez, F.; Hernandez-Mateo, F.; Vargas-Berenguel, A. TL 1991, 32, 1371.
75. Hutchins, R. O.; Cistone, F.; Goldsmith, B.; Heuman, P. JOC 1975, 40, 2018.
76. Gouzoules, F. H.; Whitney, R. A. JOC 1986, 51, 2024. Takahata, H.; Bandoh, H.; Hanayama, M.; Momose, T. TA 1992, 3, 607 and refs. therein.
77. Nishiki, M.; Miyataka, H.; Niino, Y.; Mitsuo, N.; Satoh, T. TL 1982, 23, 193.
78. Cho, H.; Harvey, R. G. JCS(P1) 1976, 836.
79. Babu, J. R.; Bhatt, M. V. TL 1986, 27, 1073.
80. COS 1991, 8, Chapters 3.6-3.8, pp 579-666.
81. (a) Boone, J. R.; Ashby, E. C. Top. Stereochem. 1979, 11, 53. (b) Ref. 6. (c) Caro, B.; Boyer, B.; Lamaty, G.; Jaouen, G. BSF(2) 1983, 281.
82. Wong, S. S.; Paddon-Row, M. N. CC 1990, 456 and refs. therein.
83. Krief, A.; Surleraux, D.; Ropson, N. TA 1993, 4, 289.
84. Sarkar, A.; Rao, B. R.; Konar, M. M. SC 1989, 19, 2313.
85. (a) Glass, R. S.; Deardorff, D. R.; Henegar, K. TL 1980, 21, 2467. (b) Maugras, I.; Poncet, J.; Jouin, P. T 1990, 46, 2807. (c) Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C. T 1988, 44, 3671. (d) Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Holdgrün, X. TA 1990, 1, 375. (e) Saito, S.; Harunari, T.; Shimamura, N.; Asahara, M.; Moriwake, T. SL 1992, 325. (f) Shimagaki, M.; Matsuzaki, Y.; Hori, I.; Nakata, T.; Oishi, T. TL 1984, 25, 4779. (g) Morizawa, Y.; Yasuda, A.; Uchida, K. TL 1986, 27, 1833. (h) Fujii, H.; Oshima, K.; Utimoto, K. CL 1992, 967. (i) Fujii, H.; Oshima, K.; Utimoto, K. TL 1991, 32, 6147. (j) Kobayashi, Y.; Uchiyama, H.; Kanbara, H.; Sato, F. JACS 1985, 107, 5541. (k) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. JACS 1992, 114, 5900. (l) Elliott, J.; Hall, D.; Warren, S. TL 1989, 30, 601.
86. Guanti, G.; Narisano, E.; Pero, F.; Banfi, L.; Scolastico, C. JCS(P1) 1984, 189.
87. Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. JOC 1983, 48, 3412.
88. Ipaktschi, J. CB 1984, 117, 856.
89. (a) Brussee, J.; Van der Gen, A. RTC 1991, 110, 25. (b) Urabe, H.; Aoyama, Y.; Sato, F. JOC 1992, 57, 5056 and refs. therein.
90. Brown, H. C.; Park, W. S.; Cho, B. T.; Ramachandran, P. V. JOC 1987, 52, 5406.
91. (a) Takahashi, I.; Odashima, K.; Koga, K. CPB 1985, 33, 3571. (b) Fornasier, R.; Reniero, F.; Scrimin, P.; Tonellato, U. JOC 1985, 50, 3209. (c) Utaka, M.; Watabu, H.; Takeda, A. JOC 1986, 51, 5423. (d) Hirao, A.; Itsuno, S.; Owa, M.; Nagami, S.; Mochizuki, H.; Zoorov, H. H. A.; Niakahama, S.; Yamazaki, N. JCS(P1) 1981, 900. (e) Yatagai, M.; Ohnuki, T. JCS(P1) 1990, 1826.
92. von Matt, P.; Pfaltz, A. TA 1991, 2, 691.
93. Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. JCS(P1) 1990, 1859.

Luca Banfi, Enrica Narisano & Renata Riva

Università di Genova, Italy



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.