· dibal-h ph-me the reagent has also found use for the reduction of alkynes to cis-alkenes sodium...

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Reduction ( Metal Hydride ) -Part-I

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Metal Hydride as Reducing Agents

Lithium aluminium hydride (LAH)

Lithium aluminium hydride is one of the strongest reducing agents used in organic chemistry, it is commercially available. It is nucleophilic in nature and normally attacks polarized multiple bonds such as C=O and CN bonds and do not usually reduce isolated carbon–carbon double or triple bonds. Mechanism for the reduction of carbonyl group by metal hydride

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Lithium aluminium hydride is powerful reducing agent than sodium borohydride and reduces most of the commonly encountered organic functional groups


Functional groups reduced by Lithium Aluminium Hydride

It reacts readily with water and other compounds that contain active hydrogen atoms and must be used under anhydrous conditions in a non-hydroxylic solvent; diethyl ether and THF are commonly employed. Lithium aluminium hydride has found widespread use for the reduction of carbonyl compounds. Aldehydes, ketones, esters, carboxylic acids and lactones can all be reduced smoothly to the corresponding alcohols under mild conditions. Carboxylic amides are converted into amines or aldehydes, depending on the conditions and on the type of N–substitution.

LiAlH4

THF, 0 °C

98 %


LiAlH4

THF, Heat

100 %

LiAlH4

Ether, 20°C

75 %

An exception to the general rule that carbon–carbon double bonds are not attacked by hydride reducing agents is found in the reduction of aryl α, β unsaturated carbonyl compounds with lithium aluminium hydride, where the carbon–carbon double bond is often reduced with the carbonyl group.

LiAlH4

Ether, 35°C

LiAlH4

Ether, -10°C

or NaBH4

With ketones that are conformationally locked, it is normally straightforward

to predict which is the less-hindered side of the carbonyl group and with LAH

more stable equatorial alcohol predominates, whereas with more hindered

ketone LAH gives mixture of equatorial and axial alcohol. However one can

selectively obtained less stable axial alcohol from hindered ketones using bulky

hydride reagents likel-selectride[LiBH(sBu)3]or lithium hydrido-tri-tert-

butoxyaluminate [LiAlH(OtBu)3].


LiAlH4

90 10

LiAlH445 55

LiBH(sBu)31 99

Treatment of carboxylic amides, nitriles, imines or nitro compounds with lithium aluminium hydride provides amine products. Reductive opening of epoxides proceeds with SN2 substitution by hydride ion to form a new C H bond with overall inversion of configuration at the carbon atom attacked. Epoxides can therefore be reduced to alcohols. With unsymmetrical epoxides, reaction takes place at the less-substituted carbon atom to give the more substituted alcohol product. In the presence of a Lewis acid, however, the direction of ring-opening may be reversed. Thus, reduction of the epoxide with sodium cyanoborohydride in the presence of boron trifluoride etherate gives cis-2-methylcyclohexanol by backside attack of hydride on the epoxide–Lewis acid complex. The direction of ring-opening is now dictated by the formation of the more-stable carbocation intermediate.

LiAlH4 NaBH3CN

BF3.OEt

Primary and secondary alkyl halides are reductively cleaved to the corresponding hydrocarbons with lithium aluminium hydride or lithium triethyl borohydride.


LiAlH4

Tertiary halides react only slowly and give mostly alkenes. Aryl iodides and bromides may also be reduced to the hydrocarbons with lithium aluminium hydride under more vigorous conditions. Sulfonate esters of primary and secondary alcohols are also readily reduced with lithium aluminium hydride and this reaction can be employed in synthesis for the replacement of a hydroxyl group by a hydrogen atom

LiAlH4Ts-Cl

Pyridine

Ts-Tosyl group

Sodium borohydride (NaBH4) Sodium borohydride is less reactive than lithium aluminium hydride and is therefore more chemoselective in its action. It reacts only slowly with water and most alcohols at room temperature and reductions with this reagent are often effective in alcoholic solution. At room temperature in ethanol it readily reduces aldehydes and ketones but it does not generally attack esters or amides and it is normally possible to reduce aldehydes and ketones selectively with sodium borohydride in the presence of a variety of other functional groups. For example, ethyl acetoacetate, which contains both an ester and a ketone functional group, on reduction with sodium borohydride gives ethyl 3-hydroxybutanoate, the product from selective reduction of only the keto group. In contrast, the more reactive lithium aluminium hydride gives 1,3-butanediol, by reduction of both carbonyl groups. To effect selective reduction of the ester, the keto group must be protected as its acetal, and the ester reduced with lithium aluminium hydride. Mild acid hydrolysis then regenerates the ketone to give the keto-alcohol.


LiAlH4

LiAlH4

NaBH4

EtOH

Ether

H+

H+

The reducing properties of sodium borohydride are substantially modified in the presence of metal salts, and particularly useful in this respect are lanthanide salts. In the presence of cerium (III) chloride, for example, sodium borohydride reduces α,β-unsaturated ketones with extremely high selectivity, such that only 1, 2 reduction occurs without 1, 4 reduction to give allylic alcohols.

NaBH4

59 41

MeOH

no CeCl3

CeCl3.7H2O 99 1 Sodium borohydride–CeCl3 (Luche reduction) can discriminate between different ketone and aldehyde groups, effecting the selective reduction of the less-reactive carbonyl group. For example, α, β-unsaturated ketones are reduced selectively in the presence of saturated ketones or aldehydes. Ketones can be sometimes be reduced in the presence of an aldehyde.


It is believed that, under the reaction conditions, the more-reactive aldehyde group is protected as the hydrate, which is stabilized by complexation with the cerium ion, and is regenerated during isolation of the product.

NaBH4

EtOH,-15°C

CeCl3.7H2O

64 %

Although lithium aluminium hydride is used most commonly for the reduction of carboxylic esters, sodium borohydride can provide some useful selectivity and its reactivity is enhanced in the presence of metal salts. For example, reduction of carboxylic esters in the presence of carboxylic amides is possible using sodium borohydride and calcium chloride or lithium chloride. The use of solid-supported reagents is gaining in popularity, mostly because of their ease of use and the ability to purify the product by simple filtration rather than column chromatography.

CH2Cl2,MeOH

room temp

Lithium tri-t-butoxyaluminium hydride (LiAlH(OtBu)3

Lithium tri-t-butoxyaluminium hydride (lithium hydridotri-t-butoxyaluminate), is readily prepared by action of three equivalents of tert-butyl alcohol on lithium aluminium hydride. Lithium tri-t-butoxyaluminium hydride is a much milder reducing agent than lithium aluminium hydride. Thus, although aldehydes and ketones are reduced normally to alcohols, carboxylic esters and epoxides react only slowly and halides, nitriles and nitro groups are not attacked. Aldehydes and ketones can therefore be selectively reduced in the presence of these groups.


One of the most useful applications of these reagents is in the preparation of aldehydes from carboxylic acids by partial reduction of the acid chlorides or dialkylamides in the presence of other functional groups.

LiAlH(OtBu)3

-78°C 80 %

Reduction of tertiary amides with excess of lithium aluminium hydride gives the corresponding amines in good yield. With the less-active lithium triethoxyaluminium hydride LiAlH(OEt)3 reaction stops at the N,O-acetal stage and hydrolysis gives the corresponding aldehyde (7.75). Similarly, reduction of a nitrile with lithium triethoxyaluminium gives the aldehyde

LiAlH(OtBu)3

H3O+

The reagent diisobutylaluminium hydride (DIBAL-H) is also effective for reduction of nitriles to aldehydes.

Aluminium hydride (Alane-AlH3)

A useful modification of the properties of lithium aluminium hydride is achieved by addition of aluminium chloride in various proportions. This serves to release mixed chloride–hydrides of aluminium. The most popular of these is aluminium hydride AlH3, sometimes referred to as Alane.

Alane are less reactive than LAH and remains inert to the carbon–halogen bond.

LiAlH(OtBu)3

H3O+


Alpha, Beta unsaturated amines are selectively reduced with Alane to give allyl

amines.

LiAlH4-AlCl3(3:1)

Ether

95 %

Diisobutylaluminium hydride (DIBAL-H)

Diisobutylaluminium hydride (DIBAL-H or DIBAL, iBu2AlH) is a very useful derivative of aluminium hydride and is available commercially as a solution in a variety of solvents. At ordinary temperatures, esters and ketones are reduced to alcohols, nitriles give amines and epoxides are cleaved to alcohols. However, it is particularly useful for the preparation of aldehydes. At low temperatures, esters and lactones are reduced directly to aldehydes (or lactols); nitriles and carboxylic amides give imines which are readily converted into the aldehydes by hydrolysis The lack of further reduction of the aldehyde lies in the relative stability of the intermediate hemiacetal (or imine salt), which hydrolyses to the aldehyde only upon work-up.

DIBAL-H

hexane,-78°C

DIBAL-H

Ph-Me,-78°C

DIBAL-H

CH2Cl2,-78°C

Diisobutylaluminium hydride has found considerable use for the selective 1, 2- reduction of alpha, beta-unsaturated carbonyl compounds to allylic alcohols.


DIBAL-H

Ph-Me

The reagent has also found use for the reduction of alkynes to cis-alkenes

Sodium cyanoborohydride and sodium triacetoxyborohydride A number of reagents derived from sodium borohydride by replacement of one or more of the hydrogen atoms by other groups allow more-selective reduction than with sodium borohydride itself. Among the most useful are sodium cyanoborohydride and sodium triacetoxyborohydride. Sodium cyanoborohydride is a weaker and more-selective reducing agent than sodium borohydride because of the electron-withdrawing effect of the cyano group. It is stable in acid to pH = 3 and can be used to do reductions in the presence of functional groups that are sensitive to the more-basic conditions of reduction with sodium borohydride. Aldehydes and ketones are unaffected by sodium cyanoborohydride in neutral solution, but they are readily reduced to the corresponding alcohol at pH = 3 to 4 by protonation of carbonyl group. Iminium groups are more easily reduced than carbonyl groups in acid solution and this has been exploited in a method for reductive amination of aldehydes and ketones by way of the iminium salts formed from the carbonyl compounds and a primary or secondary amine, typically at pH > 5 at this pH the carbonyl compounds themselves are unaffected. Sometimes yield can be improved by addition of titanium (IV) salts such as Ti(Oi-Pr).


NaBH3CN

CH2O,(37% in H2O)

NaBH3CN, MeCN

Benzyl amine

NaBH3(OAc)3

DCE,AcOH

Reductive amination with formaldehyde and sodium cyanoborohydride provides a convenient method for methylation of a secondary amine (or dimethylation of a Luche reduction Luche reduction (primary amine). Reductive amination of an aldehyde or ketone with ammonia or a primary amine can sometimes be problematic, as the product amine can undergo further reductive amination with the starting carbonyl compound. β-hydroxy-ketones are reduced with tetramethylammonium triacetoxyborohydride. The reduction occurs stereo selectively to give predominantly the anti-diol product. Exchange of one of the acetoxy groups for the alcohol is thought to precedes stereo selective intramolecular transfer of hydride.

Me4BH(OAc)3

MeCN,AcOH

Anti:Syn= 95:5

Carbonyl compounds can be converted into the corresponding hydrocarbons via reduction of the derived toluene-p-sulfonyl (tosyl) hydrazones with sodium cyanoborohydride in acidic dimethylformamide (DMF). The reaction is limited to aliphatic carbonyl compounds; aromatic compounds are normally unaffected. The tosyl hydrazones need not be isolated but can be prepared and reduced in situ.


p-TsNH2NH2

DMF,Sulfolane

then NaBH3CN

With α, β unsaturated carbonyl compounds, reduction of the tosyl hydrazone is accompanied by migration of the double bond. The mechanism for this reaction involves reduction of the iminium ion to the tosylhydrazine 1, elimination of p-toluenesulfinic acid and subsequent [1,5]-sigmatropic shift of hydrogen, with loss of nitrogen, to the arranged alkene.

p-TsNH2NH2

then NaBH3CN

-TsH

· dibal-h ph-me the reagent has also found use for the reduction of alkynes to cis-alkenes sodium...

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