CHAPTER 1

KEIlUC1'ION OF 'THE OKGANlC COMPOIJNIEi IJSING

L.ITIIIIIM ALUMINUM IIYDRlll!i: I\ Kli'JlliW

CHAPTER 1

REDUCTION OF THE ORGANIC COMPOUNDS USING

LITHIUM ALUMINIUM HYDRIDE : A REVIEW

1.1. Introduction

Prior to the hydride era, various non hydridic procedures were devel-

oped for the reduction of organic functioniil groups. They include the cata-

lytic hydrogenation for nitriles, Meerwein-l'onndorf-Verley reaction for al-

dehydes a n d ketones, Bouveault and Blanc procedure for esters. But non

hydridic methods require high temperature and long reaction time.

The discovery of metal hydrides dramatically changed the situation.

Indeed, numerous major applications in various phases of chemical research

have appeared for the hydrides and a r e still continuing to appear. These

reducing agents include both nucleophilic and electrophilic reagents. The

most common commercially available nucleophilic metal hydrides are lithium

aluminium hydride, lithium boro hydride and sodium boro hydride.

Lithium aluminium hydride* (LAH) was synthesized1 in 1945 by the

reaction of lithium hydride and anhydrous aluminium chloride in ether so-

lution.

4LiH + AICI, LiAIH, + 3LiCl

* Although the systematic name is lithium tetrahydroaluminate, the name lithiu~r~ alurninirirn

hydride is retained as it is more familiar in this name.

The invention of LAH brought abou t a revolutionary change in the

procedure for the reduction of functional groups in organic molecules. It is

a n exceedingly powerful reagent capable of reducing practically all organic

functional groups.

The attractive features of lithium aluminium hydride as a reagent are

the following. (I) I t can be easily prepared from commercially available lithium

hydride (2) it is indefinitely stable at room temperature (3) it is ether soluble

(4) as compared w i t h o ther reducing agents, except hydrogen, i t has a

favourable reducing capacity to mass ratio (5) the reductions occur a t room

temperature (6) no unusual equipment is needed.

The thermal decomposition of LAH sets at about 120°C, is rapid a t

150°C and complete at 220°C in accordance wi th the equation

LiAIH, -> LiH + A1 + 1.5 13,

It reacts readly wi th water and other compounds containing activc

hydrogen atoms and must be used under anhydrous conditions. The impor-

tance of LAH has been changed from that of a laboratory reagent to a w ~ d e l y

used reducing agent in organic chemistry and pharmaceutical industries. The

L first review on the reduction using LAH appeared in 1948. I t was followed

by many The latest review o n the reductions using LAH was in

6 1995 by Peter .

1.2. Functional groups reduced by LAH

Almost all polar functional groups have been reduced by lithium alu-

minium hydride. Important functional groups reduced by LiAlH,, t h r ~ r prod-

ucts and molar ratio are given in table 1.1.

Functional Groups

Table 1 . 1

List of iunct~onal groups reducrd by 1,AII

Aldehyde

Carboxylic acid

Ester

Anhydride

.4cid chloride

Ketone

Epoxide

Lactone

Quinone

Amide-unsubsti tuted

Amide-monosubstituted

Amide-disubstituted

Lactam

Nitrile

Nitro (aliphatic)

Nitro (aryl)

Hydroxyl amine

Azoxy

Anil

Diazo

Nitroso

products

primary alcohol

prlrnary alcohol

prrmary rilcohol

prlmary alcohol

p r ~ m a r y alcohol

secondary alcohol

dlcohol

dl01

hydroquinone

primary amine

secondary amine

tertiary amine

aldehydes

cyclic amine

primary amine

imine or aldehyde

aminr

azo compound

anline

azo compound

amine

arnine

mole of LA11 required

0.25

0.75

0.5

Alkyl halide hydrocarbon 0.25

Disulphide thiol 0.5

Sulphoxide thioether 0.5

Sulphonyl chloride thiol 0.5

Sulphone sulphide 0.75

Since LAH is not soluble without resic!ues, it is a d v ~ ~ n t ~ ~ g r o u s to pl'lcc

the soiutions of the hydride in the reaction flask a n d add [ h e reactants r r

their solutions from dropping funnel (Direct technique). In the in\.erbi: ie'ii-

niquc a solution of the hydride is added to the solution of the compound to

be reduced. This avoids excess LAII. When sparingly soluble compounds

have to be reduced, they may be introduced into the reaction flask by the

extraction in a soxhlet apparatus.

1. 3. Reduction of aldehydes and their derivatives

Carbonyl group seldom offers any great d ~ i f ~ c u l t y to r e d u c t ~ o n uslng

LAH and the proiiucts, alcohols, were o b t a ~ n e d 111 good y ~ e l d .

The reduction of nldehycies using LAII af iordid primary nlc:>hols n~xii

i t is very diificult to reduce the iridehyde group ulanc w h e n o t !~t , r i u n c t i t > r ~ ~ ~ l

groups are also present. In the reciuctioii of an aldeilyde corlto~ning a iio~:i,ir

bond, both the doubli: bond and aldehyilc group werr r e i l ~ : s ~ i i . C:.i,tonrili.it!li\.iii.

primary alcohols on reduction using LAII. But 9 -an t l~ ru ldehyde was re-

8 duced in TI-LI: to afford 1,2-di(9-anthryl)ethane, by the coupling o i the nor-

mal reduction product, 9-~11thrylc:1rbinol, fo!!owed by L7-elimir-tntion and hy-

drogenat ion . 9-Phenanthraldehyde(1.1) gave 9-hydroxyniethyl phenwn-

threne(l.2) and 1,2-di(9-phenant!.:.l)ethanol(l.3) respectively in 5841 and

17% yield.

L A H reduces9 b o t h t h e d o u b l e bond a n d a l ~ i e h y e l e g r o u p o i

c innamaldehyde (1.4) forming 3-phenylpropan-1-01 (1.5) w h e n it is acided

directly. I t is possible to reduce only the aldehyde group by L N I , when the

inverse technique is applied. The addi t ion of the reagent to a n ether solu-

tion of the compound a t -10°C afforded 9096 cinnamyl alcohol (1.6). Alanes

produced from lithium aluminium hydride and aluminium chloride were found

effective1' in the reduction of cinnamalclel~yde to cinnamyl alcolrol

LA11 1 A11 C,II,CH,CII,CH,OH +- C,HSCH=CH.Cf10 A+ CnF~,CtI=CH.CII,O1l D ~ r e c t Inverse

1.3 - 1 O°C

1 . 5 1.6

9 FIochstein a n d Brown suggested the orgi inoaluminiun~ conipounci ('I .7)

as the intermediate in the reduction of i~lclehydes a n d ketones i l s i n ~ LATI.

11 The presence of a similar intermediate was estnbiislri.ii by the, re i luc t ion

follo~veci the hydrolysis using DCI-D,O 0i3,3-bi~(m~thylthio)-l-phtrnyl~~1~open-

0

1 1 SCH, /"-/ : ,-.\ ,,,# ,$\\ Lnn (--? /k - Ll,l,,l, /SCH3 - s c H 3 /-

i" -

5; /,= \>:<.I'

% \ \ \ S C H , H EI D

H

12 Carbonyl compounds that show steric hindrance in their re'lctions

with other nucleophilic reagents, behave normally towards LAII. One of

the applications of this reduction is the identificittion and charnctcrizaLio~~

of the sterically hindered carbonyl eroup. Although the normal rc~iuction of

carbonyl group results in the formation of alcohol, there are soriie recordeci

examples of the reduction of >CO group to -CI-I,- . Conover and Tarbell 13

have observed that the reduction of N,N-dimethyl-par~inobenzrildehyde (1.10)

in excess LAI-I resulted mainly in the replacement of the oxygen of the car-

bony1 group by hydrogen to give N,N-dimethyl-paminotoluenc (1.11).

CHO I

1-1

14 Acetals of aldehydes are stablc to LA11 . T l ~ ~ r c t o r i ~ , whl 'n I! is < I ? -

sired to reduce other functional groups without reducing aldehyde group,

blocking of the latter may be accomplished by acetal formation. Thus ac-

etoacetic ester is converted into 4-hydroxy-2-butano~xe by the reduction of

the corresponding diethyl acetal with LA11 followed by acid hydrolysis of

the acetal group. 2-Telrahydrofuranyl a n d 2-tetruhydropyranyl '~lkyl ethers

being acetals are not reduced15 by LAH. Even though LAI-I is not capable

of the reduction of acetals, occurs in presence ofAlC1, or ZrC1,.

Thus butyraldehyde diethyl acetal o n reduction1' using LAH-AICI, gave

butylethyl ether. Imines and oxinies are derivatives of aldehydes. Bun~gardner

reported17 the reduction of N-cyclopropyl benzaldimine (1.12) to benzylpropyl

amine(1.13).

Aliioximes yielded anlines when reduced using LAI-I. Benzaldoxime

yielded18 benzyl amine on reduction using IAH, but nldoximes on reduc-

tion'' using LAH in hexamethylphosphoramide (IIMPA) afforded the cor-

responding nitriles or aldehydes.

L"&I reduces aromatic aldehydes toalkanes2' when they are converted

to y t o l u e n e sulphonyl hydrazoncs. (Scheme 1.1)

Scheme 1.1

2-Alkylamino tetrahydropyrans may be considered as derivatives of

aldehyde. These compounds were reduced2' to amino alcohols. Thus 2-(N-

Piperidyl) tetrahydropyran (1.14) was reduced to 5-piperidino-1-pe1,tanol

(1-15).

1.4. Reduction of Ketones and their derivalivcs

Aliphatic as well a s aromatic ketones were reduced 7122'23 to st:con~<-

ary alcohols. 'The reduction products of ketones depend on the sc,lvent 24

action and steric effect of the solvent. I n the case of mono and dioxygenated

ethers the size of the carbon residue at tached to the oxygen is a directing

factor of the stereochemical outcome. I n the reduction of unsymmetrical

open chain ketone using LAE1,the main product arises by the attack of the

hydride anion o n the less hindered side of the carbonyl group. Thus the

reduction of camphor (1.16) gave mainly exo isoborneol (1.17)

where as norcamphor (1.18) afforded the endo a l c o h 0 1 ~ ~ ' ~ ~ ( 1 . 1 9 ) .

Me Me Mc Me

LA13 +

27 Certain tetra aryl pinacolones were reported to undergo facile re-

ductive cleavage to triaryl methanes and benzylic alcohols when treated with

lithium aluminium hydride in pyridine. This supported the rolr uf pyridine

as a Lewis base which co-ordinates a lunl in iun~ hydride a n d allows the par-

t icipat ion of unassocia ted a lkox ides in the react ion scheme. T h u s

benzopinacolone (1.20) had been cleaved to triphenyl methane (1.21) and

benzyl alcohol in 72% yield.

i I Pyridine ' \ \ i/ ;! 2

R = alkyl group + C,EI,CH,OI1

In the case of dicarbonyl compouniis, jrbc-nzoquinc)nt~ anil ~ t n t l l l . ~ q ~ ~ -

inone, the products were respectively hydroijuinone and anthrahycl~~oquinonr

when they were treated with LA11 in etherz8. The y ~ e l ~ l o f the produl .1~ iv'is

29 about 7096. Similarly Johns and co-workers reported the r t d u c t i o : ~ o i 2,2 ' -

dinitrobenzophenone into his(o-nitrophcnyl) in 24% yield when i t 1s treatci!

with I.AZ1.

The reduction of a n unsaturated ketone to a saturated alcohol i v a s

reported by Krishnamurthy et a130. Generally, such ketones were converted

into unsaturated a l c o h 0 1 ~ ~ ' ~ ~ w h e n a solution of the hydride was added to

the solution of Lhe compound. Thus 4-phenyl-3-butenone (1.22) gave 4-phenyl-

3-butenol (1.23) o n reduction using LAH~' .

/ CH3 /CH3

'OH

Ether

Ashby ef a ~ ~ ~ ' ~ ~ r e ~ o r t e d the reduction of a,i) double bond in enones

by LAII in 'I'I~E at 0°C in presence of cuprous iodide. Thus the enone ?,2,6,6-

tetramethyl-trans-4-heptei-i-3-one (1.24) yielded the saturated ketone (1.25)

and the carbonyl group reduced product 1.26. t Bu

Similarly, 3-niethylpent-3-en-2-one (1.27) w n s t o 3-mc~thyl-

2-pentanone (1.28). The active species was believed to be H:AII and a s i x

membered cyclic transition state was proposed

1 LAH I cycH, - CII- COCY

CqCH = LOCH > CuI

3

Lutz and c o - w o r k e r ~ ~ ~ reported that 1 , 2 - d i m e ~ i t y l ~ r o p e n o n e (1.29)

was reduced to the en01 (1.30) by 1,4 reduction. The en01 produced was

persistent and isolable.

/ COC,H,, L A H ,-

'gH1l- c A

/ CH3 'qH1~- ,C9H,?

I I C CH2 \

Schlenk reported36 the preference of the reduction 01' thr cilrL.ony1 g r o u p

to hydrogenolysis of carbon-halogen bond in halogenated ketones. Thus 1,3-

dichloroacetone afforded 1,3dichloropropanol in 77% yield. a-Cliloro ketones

were reduced 37'38 to chlorohydins using LAH, where as the reduction of

a ~ ~ l o i n s ~ ~ " in ether solution led to the corresponding glycols in good yield.LAH

reduced a-amino ketones to amino-alcohols40' Lukes et a1 4'1reported the re-

duction of a ketoamide to amino alcohol where both keto and amide groups

were reduced. o-Azidoacetophenone a n d o-diazoacetophenone 42,43 were

reduced to 2-amino-1-phenylethanol by LAH.

Analogous to aldehydes, keto group can be protected44 from th:-je-;__, ~.

duction by the conversion to ketals. The diethyl ketal o i ethyl-jrocetyl bcn-

zoate (1.31) was reduccd using I A N to djethylkctol of pace tp i bcnzyl al-

cohol (1.32). COOC,IH, CI3,OI~i 1 i

The keto group was recovered by the hydrolysis with alcoholic hy-

drochloric acid. Barton reported45 the selective conversion of steroidal ke-

tones into metal enolates, which is a convenient means of protecting such

functions during the reduction using LAH. The major complication in the

use of metal enolates as protecting groups is the tendency of enolized a,P-

unsaturated ketones to undergo protonation a t the a-carbon atom to give

the unconjugated ketone.

Like aldoximes, ketoximes also yield primary amines o n redliction us-

ing LAI-I. Thus cyclohexanone oxinie (1.33) nil'ordcii cycl.1hexyii1r1lin~~(l.34)

in more than 70% yield on redustion18 using t.A1~1 i n TIIT:.

hTOIl El NII, ?\, A LAH I I_' x.. 1 Et,O.Reflux. 30 min I

\.,/'.

a,p-Unsaturated ketoximes yielded unsatura ted anlines, sa tura ted

arnines and sometimes aziridines 46147. However, in presence of hexamethyl

phosphornmide, ketoximes give back the ketones instead of the normal

48 product,amine, when they are treated wi th LA13 .

Diary1 ketones and alkyl aryl ketones were reduced to the hydrocar-

bons by the reduction49 using LA13 in presence of AICI,. Benzophcnone was

converted to diphenylrnethane in 92% yield even under the niildcst condi-

tion, but acetophenone afforded only 25% ethylbenzene. The presence of

activating groups in ketones facilitate hydrogenolysis. Thus j.-N,Nclirnethyl

aminoncetophenone (1.35) was reduced to f ) - d i m e t h y l i i n ~ i n o c l I i y l L ~ ~ ~ i i z e ~ i e

(1.36) in 84% yield.

COCH, C71HS I I -

An interesting type of reduction of ketones to alkenes using LAH in

presence of TiC1, to alkenes was reported by ~ l e m i n ~ ~ ' . The reduction of

2,4-dimethyl-3-pentanone (1.37) gave 2,5-diniethyl-3,4-di(isopropy1)hex-3-

ene (1.38)

Unsymmetrical ketones introduce the problem of stereochemicttl speci-

ficity, owing to the appearance of a new asymmetric carbon atom due to the

conversion to a secondary alcohol during the reduction using LAII. I n the

reduction of several keto steroids both epimeric alcohols were produced.

Unsaturated ketones o n reduction30 using lithium tris (t-butoxy) alu-

i/ minium hydride gave saturated alcohols. Diarylketones were rcduceil by

LAH in pyridine to secondary alcohols. LAH in pyridine is o t special i n t e r -

est because of its ability to reduce aryl ketones more rapidly5lthan aliphatic

ketones. Reduction of ketones in the solid Lii\lF14-hydrocarbon two phase

system in the presence of phase transfer cnt:l!ysts was rcporti:d by Gc:v~~r:;y.~n

et a1 ". Alane produced by the reaction of LAI~I and aluminium chloride in

53 ether cleaves the carbon-oxygen bond in cyclic monothioketals (1.39) de-

rived from ketones and mercaptoethanol to P-hydroxyethy l sulphides (1.40).

Hojo et reported that lithium aluminium hydride o n silica gel is a

good reagent for the reduction of carbonyl compounds. The difference in

the reactivity between ketones a n d esters was made use of in the selective

reduction of keto group in keto esters. LAH-SiO, could r e d u ~ e ~ ~ c o r n ~ o u n d s

bearing keto and nitro functional groups to nitro alcohol in fairly good yield.

56a Lithium trimethoxy aluniinohydride (LTMAH) was reported to have a

greater selectivity than lithiunialuminiuni hydride in their reactloll with ketone.

This is due to the greater steric effect of the reducing species[AlI-I(OCM,),]-

The LAH reduction of 3,3,5-trimethylcyclohexanone (1.41) produced a cis/

trans ratio of 20:79 where as in the r e c ~ u c t i o n ~ ~ ~ using LTMAII the ratio

was changed tol:24. Similarly the reduction56c of isopinocnmpl~one (1.42)

afforded 89% of the endo alcohol, while CTMAEI produced 98% endo alco-

hol.

1.5. Reduction of carboxylic acids and their derivatives

1.5.1. Acids

The r e d u c t i o ~ ~ of carboxylic acids is somewhat difficult than the re-

duction of their derivatives. Because of the presence of acidic hydrogen in

the carboxylic acids, excess quantity of the reagent is to be used. Very often,

acids have very low solubility in ether a n d therefore need long reaction pe-

riod. They are extracted in ether using soxhlet extrnctor. Thus poducarpic

acid (1.43) was reduced57 to podocarpinol (1.44) in 4.6% yield in two hours

and only to 56% yield in 96 hrs.

Triphenyl ncetic acid was not reduced a t all at ordinary conditions in

ether whereas sebacic acid was reduced to 1 , 1 0 d e ~ a n e d i o l ~ ~ . Furnaric acid

(1.45) afforded59 trans-2-butene-1,4-diol (1.46) in 78% yield.

H \ H

C LAFI C A

\ /Ci1201i

I I I I

FIOOC 1-IC)H2C 1-1

However, cinnamic acid (1.47) on reduction using LAH afforded 3-

phenyl-1-propanol (1.5). In this case both the double bond and the carboxyl

group were reduced. This was the report58 in which LAH reduction of

acyclic a,P-unsaturated carbonyl compounds resulted in the reduction of

carbon-carbon double bond in addition to the expected carbonyl reduction.

Acetylenic acids in which the triple bond is in cortjugation with car-

boxyl group were found to be reduced59 to oleiinic alcohols in good yield.

Acetylene dicarboxylic acid gave trans2-butene-1,4-di,sl in 84 % when re-

duced using LAII at room temperature. Kent et a160 repnrtecl the reduction

of glyceric acid to glyceraldehyde by the conversion of the protected aldonic

ester into N-methyl-N-phenylamide followed by the treatment with LAH.

Kayser and Morand reported6'the reduction of unsymmetrical dicar-

boxylic acids to lactones. Thus 2,2-dimethyl succinic acid a n d 2,2-diphinyl

succinic acid were reduced to the respective Iactones in good yields. Amino

acids were r e d ~ c e d ~ ~ ~ ~ ~ t o amino alcohols. The hydrazide of 2,2-diphenyl-3-

hydroxypropanoic acid was reduced64 using LAH in N-ethyl morpholine at

100°C to 3-amino2,2-diphenylpropanol.

Nystrom reported6' the reduction o f 3 - b r o m o ~ r o ~ a n o i c acid at low teni-

peratures using LA11 in ether to 3-broniopropnol by inverse tcclinique. 1;~-

placement of one of the iodine atoms took place when ? , - l - ,5- t r i io i l~~b(~n~.~>i i '

acid(1.48) was reduced wi th LAH a n d the product was 3,5-cliiodobenzyl

alcohol6' (1.49).

COOH

LAH --

1

1 . 4 8 1 . 4 9

Very recently ,Perale= reported67 that there was difference in the prod-

ucts when 1-bromo-2,2-diphenylcyclopropanecarboxylic acid was reduced

with lithium aluminium hydride under strictly anaerobic conditions and loosely

aerobic conditions.

One carbonyl group of the methyl hydrocell adipati. (1.50) wri:; pro-

tected f rom reduction by the conversion of the compound lo ?-os.izoline.

In the reduction of camphoric acid Noyce and ~ e n n e y ~ ~ dicl not observe an);

selectivity. It was reported69that a carboxyl group could be masked against

LAH reduction if it was converted to 2-oxazolines. The oxazoline (1.51) on

reduction followed by hydrolysis gave ethyl 6-hydroxyhexanoate (1.52).

1.5.2. Acid chlorides

The reduction of acid chlorides using LAH is easier than that of the

acid. Even though triphenyl acetic acid was not reduced b); LAII, triphenyl

acetyl chloride (1.53) was readily reduced70 to the alcohol (1.54) uni ler

usual conditions.

Addition of acid chlorides to a solution of LA11 afforded alcohols from

aliphatic, aromatic a n d unsaturated acyl chlorides. N y s t r o n ~ and Brown

reported7 excellent yields of i~lcohols by the reduction or benzoyl, palrnitoyl,

1-caproyI, trimethyl-acetyl, sym-o-phthaloyl a n d sorboyl c l t l o r ~ d r s . ? ? -

Uichloroethanol in 60% yield was obtained by the reduction Ld iiicl-ilori~tlcctyi

71 chloride with LAI-I . Halogen free alcohols w c r r cl isa o!,!aineLi !-v t ! i c 1.: -

duction of halogenated acid ch1oridc:j6'. ~ - ~ ' K O I ~ I L ~ ~ ~ : ~ ~ ~ ~ ~ : , L I ~ ; ~ ~ ~ c j ~ ~ ! ~ > r ! ~ l c ! !vas

reduced using LAH in presence of A1CI3 to get higher yields oi 3-t,ronio-

propanol than the reduction with LAN alone. . 1.5.3. Acid anhydrides and lactones

Anhydrides yield alcohols on reduclion using LAI-I. Benzoic anhy-

dride afforded benzyl alcohol whcn reduced7 using LAEI in ether. Cyclic

anhydrides were reduced to diols. Thus phthalic anhydride afforded 87%

phthalyl alcohol. Bloomficld et a l 72 observeci the reduction of such anhy-

73 drides at very low temperatures giving lackones. Kayser and Morand re-

duced several anhydrides with both lithium alunlinium hydride and sodium

b o r o h y d r ~ d e . They found that the site of r e d u c t ~ o n was consistentl>- the

same and the yield of lactones was comparable. Further, there was a iteii-

nite preference for the reduction a t the more electron rich ci~rt,onyl fui ic-

tion. The ring system to which the anhydride wits attached grriitly influ-

enced the site of the hydride reduction. 3-Hitrophthalic a11hyciridc(l.55)

was reduced73 to a mixture of 4-nitrophthaliile (1.56) and 7 - n i t r o ~ h t h a l i d e

(1 -57).

Arth reported74a the reduction of lactoncs to cyclic hcn~iiiceials ot' H I -

. . dehydes. The reduction was done a t -10°C in rciluxing ?'I[I:. l h u s y-vol-

erolactone (1.58) gave 2-hydroxy -5- n ie thy l t e t r ahydrof~~ran (1.59) and a-

methyl-6-caprolactone yielded 3,6-dimethyl-2-hydruxy tetrahydropyran.

1.5.4. Esters

Lithium aluminium hydridr is a very I>o\verful reagent and often con-

verts esters to alcohols. Under forcing condilions, the reduction may be car-

riecl beyond the stage of prirnary alcol-iol to the stage of hydrocarbon but

this behaviour has not been encountered under normal conclitions of opern-

tion where reagent-ester ratio is 3:?. A solution of the cster i n diethyl ether

o r TIIF is added to a solution of the reagent. The reaction is exothermic a ~ i d

is completed usually within one hour. Aron3;ltic esters require lower ten?-

74 b peratures and longer tinics. The reduction product of esters is alclehycle

only in cases where the reduction is done at lower temperature. Zaltharin

75 and co-workers reported the reduction of methylhexunoate (1.60) to hexanill

(1.61) along with 1-hexanol (1.62).

76 a,P-Unsaturated esters were reduced to a,p-unsaturated alcohols

by LAH by inverse technique a t low tempernture. But if the reduction is

done in hydrocarbons as solvents, even high temperature and prolonged

reaction time cannot d o any harm. The reduction of methyl cinnamate in

benzene using equimolar amount of L N I and ester a t 60°C within a reac-

tion time of 14.5 bows afforded more than 70% cinnamyl alcohol. But such

es ters in ~ v h i c h the d o u b l e bond is i n conjugat ion w i t h the r ing

77 afforded saturated alcohols with excess LAH. Reiluction of methyl phenylpr-

opiolate with half a mole LhII in ether at -78°C for 5 minutes phenylpr-

opargyl alcohol in quantitative yield. But the reduction of thc same wilh

0.75 mol LAH at 20°C afforded rnns cinnamyl alcohc>l after 15 minutes.

During the studies o n the reactions of triphenylgerniyl lithium witl.1

ketones Cilman and Gerow reported7' the reduction o i methyl triphenylger-

manecarboxy la te ( l .63) w i t h LA13 w h i c h a f fo rded t r ipheny lhydroxy-

methylgermane (1.64)

C6H5 I

C6H5

LAH c , ~ ~ G e - C O O h f e -----+ c &&e-CH,OH

I 0 ~ 1 C6H5 C,N,

In the reduction of halogenated esters to halogenilted iilcohols, the

halogens are dehalogenated if precautions are not taken8'. Thus ethyl 2-

fluoro-3-l~ydroxypropanoate Tvas dcfluorinateci when it was r c ~ l u c c d ~ v i c h

LAII. T11e carbon-halogen bond is often inert to the mixed hydride reagents.

Thus methyl 3-brornopropanoate (1.65)was convertedfi5 into 3-bromopropanol

(1.66) in 72-90% yield by LAH in presence of AIC1, a t low temperature. I t is

to be noted that LAH in presence of AIC13 retards or prevents the reduction

of the halogen whereas LAIJ alone facilitates the reduction of the halot;en.

Fruer reported8' the reduction of n~ethyl 4-methyl-4-nitropentonoale

using LAN to 4-methyl-4-nitropentnnol at -35°C wiLh 76% yielLi ancl n~ethyl

4,4-dinittopimelate afforded 4,4-dinitro-1,7-hepta1lcdiol in 56% y~elcl.

82 The selective reduction of one of the ester groups i n es1el.s 31' cl i -

carboxylic acids is not possible i f two ester groups are of comparable reiic-

tivity. Thus diethyl sebacate furnished only the diol and the unchanged es-

ter. But selectivity could be achieved in the reduction of dimethyl cis-?-me-

82 thy l -2 -ca rboxycyc lohexaneace tn t e . 3 - M e t h y l n ~ e r c a p t o p r o p n n o i c ac id

83 trimethyl orthoester(l.67)was reduced to 3-methylmercapto propionaldehyde

dimethylacetal (1.68) in 97% yield when refluxed with LAI~1 for 411 in a mixture

of benzene and ether.

An interesting selective reduction8*of the ester group wus obsrrved iin

the reduction of 3-carbethoxy-4-ketoquinolizidine (1.69) which affbrcied 4-

ketoquinolizidine (1.70).

c N 9 c 0 0 c 2 E 1 5

L A H ,

I I 0 I I

0

The reduction of optically active esters, in which the u-carbon a tom is

65 asymmetric as in the esters of nminoacids, occurs ivitliout 1.acemization .

Therefore the reduct ion of es ters has been ut i l ized u s a means of

r e c o ~ e r i n ~ ~ ~ ~ ~ ~ t h e alkory component, where ordinary hydrolytic proceilures

S 8 might cause undesired raceniization of the alcohol. 1-Iowever, Eliel ri'ported

a case in which the ester functional group is hydrolysed to acid in presence

of LAH. Thus 3-hydroxyphthalic acid was isolated when 1-methyl-3-acetoxy

hydrogen phthalate was reduced using LAN.

1.5.5. Amides, Imides and Lactones

The reduction of amides using LAH led either to amines or to alde-

hydes depending on the ~ o n d i t i o n s ~ ~ . A detailed examination has been done

o n the conditions lending to the formation of aldehydes and amines from

anudes by LAH. The report was that by adding the aniide to the reducing

agent the amine was the main product while a l d c i ~ y d e resulted from N,N-

dialkylamides, if LAH was added to an ether solution of the aniide a t low

temperature using 0.25 moi of reducing agent per mole of amide. But mono

\ut>st~tuted a ln i~ l r s did n o t v i r l ~ i a l t i . , i y i % s , i c.clui.tiun of unsuhsiituted rimidt.s

procetds by f h e initial d c h y d r a t i , , ~ ~ o i tht. itrnide ti, form a n i t r ~ l e ~ ~ . Thr

reduction o f the substituted amid<.s to an1ii:es proct-eds by an initial redur-

tion to a fi,:.nxnal amino alcohol de:rivativr, followed by elimination and sub-

s~-quen t rt.iluclion of th t . rc.:iirltin;: inlint. C I I . i n>~n~ur ; i salt 90.94 l i i i l a t ~ o n o i

90 ~,rnincs 8 . ; I-(,st ac ron ip l~she~ i by .~d.lin;: 2n millilitrt,r of water for n g ram r l

I~tIiir.ini ai iniinium hy~1r i . I~ . follo.c\,:~ h j 11 n i ~ l l ~ l ~ t r e s L>f 15% aquet,us s o ~ i ~ u i - ~ ,

hydroxide solution. This method90 is preferred hecause other methods result

in obstinutc: emulsions.

, In tli<x re~iuct ion o i amidcs ~rs ing LATI i l i i substituent o n nitrogen is a

95 in1ajor facl,,r which conti..>ls thr rrsulLs. 1:xc : ,ptions were rrportr,ii 28,85

n

ihc r e d u c l ~ c r of diethyl benzamicie and ethyl ,:,paraginatr using I.AIl. Tb,.

products were respectively benzyl illc<.)hol anil 2-aminohutane- l , - I -d~,>l . ?,

i~~~nzc1i~.!i1~I~~h0nox).-5,1.~~Iihy~iri~iri..1~~1l (1.71i ( . : t i t iv. i.onqiJrrecI a s c i ! , i r I ~ ~ . t i t ~ t c . c i

%.It, ,tniicie. i t 1ra.i reported t g , uniirrg;, reductive, l.s>ssen rearrangement to givv

i . ; ,N'-~lini<thvl e t h y l e n e . ~ ~ a m i n e ( l .72).

' r i n I I : I , I :omp>uncl: like. pyrrolc ~.irer(.

9 0 47 .11so redu<.ec, to alcohols. . \ n i i l<.restlnj; irciuctivr c.ycli,ation 1s shown

In the synthesis o i the yohinlbinr skeleton (1.74) from (1.73).

98 Reduction of cyclic ureas generally affords aminals. The reductive

cleavage of C-N bond was also observed 99-101 with trisubtituted cyclic ureas.

1,3-Dimethyl-2-imidazolindinone (1.75) was reduced to the corresponding

cyclic aminal (1 -76) in 58% yield

N,N-DimethyI-;~-nitrobenzi~n'iidc o n reductionT0' svith [.A11 aiiorcied

quantitative yield of dimethyl-;>-an~inobenzylun~ine ilnci N-n1elhyi-5-ph?nyl-

5-oxopentanamidc furnisiicd 5-mcthylan1ino-1-phci-r~l~~entanol~ '~. 1,:v..n thi>~!~;h

the reduction of the tertiary amides using excess L N I produced tertiary aillines,

the controlled reduction led to aldehydes103. Thus Wittig et a1 lo' obtained a

series of unsaturated aldehydes. For example, C,H,(CI-I =CII)nCI-I@(n=1,2,1

and5) was obtained by the partinl reduction of the corresponding N-acylcarbazoles

using LAII. The structure of the arnide influences the yield of aldehyde.

~ - ~ c ~ ~ a z i r i d i n e unusually affordedlo5 the a ldehyde in excellent yield. The

conversion of aryl amides to the corresponding aldehydes proceeded more

readily than the aliphatic derivatives. Thus benzaldehyde w a s obtained

from N-n~ethylbenzanil ide in 60% yield in contrast to the 25% yield, real-

ized for n-butyraldchyclc.

Newman et a1 92isolated nitrile as an intermediate in the reduction of

amides using LAI-I. He suggested that the reduction of armides to primary

arnines proceeds via a base induced dehydration of amide to nitrile, followed

by the reduction of the nitrile to anline. This was rationalized by taki i l ,~ into

consideration of the fact that LAI-I was a very strong base9'. When triisopropyl

amide was subjected to reduction using LAH triisopropyl acetonitrile was

obtained in about 60% yield. It was reportedlo2that amidcs containing nitro

105-107 group were reduced to diamino compounds by alnne. The reduction

of amides is made easier by using modified LA13 such as di and triethoxy

alumino hydride.

Dunet and c o - ~ o r k e r s ~ ~ ~ observed a 5% yield of isoindoline when

phthalimide was reduced using LAH. N-meti-tylglutnriniicle (1.77) was also

reducedlo9 to N-methylpiperidine (1.78) under tlhe same conditions.

In some cases the reduction o f arnides using L A H afforded nitriles

along with arnines. The reduclion of lactams to amines resembles closely to

the reduction of amides. 5,5-Dimethyl-2-pyrrolidone(l.79)with 3 mol LAI-I

in THF gave 2,2-dimethyl pyrrolidine110(1.80) in 67-7996 yield.

1.5.6. Nitriles

The complete reduction of a nitrile to amine is very slow and requires

higher temperature. The reduction operations are to be conilucted in an at-

mosphere of nitrogen. Equimolar mixture of LAII and substrate in ether a t

28,111 refluxing temperature afforded 40-90% primary amines from cyanides

Unsaturated nitriles were converted into unsaturated amines112. New a n d

~ o - w o r k e r s ~ ' ~ isolated a primary amine(1.82) in 78% yield when 1,2-dicyano-

2-(4-methylpheny1)-propane (1.81) was reduced using LAII.

CI-I, CH, I 1

1-Cyclohexenylacetonitrile w a s reduced''' using LA11 to ? - ( I -

cyclo1iexenyl)ethylamine. Thus the p,y-unsoturi~te~i nitrile was converted t(,

the corresponding unsaturated amine. LAII hns been used ndt only to re-

duce simple nitriles but also to reduce cyanohydrins to p-hydroxy primary

amines. It is also used to reduce2' acyl cyanides to P-hydroxynnlines.

Burger and co-workers'14 succeeded in getting primary amino alcohols

from acyl cyanides. Thus benzoyl cyanide and p-chlorobenzoyl cyanide were

converted into 2-amino-1-phenylethanol a n d 2-amino-1-(p-chlorophenyl)

ethanol respectively in about 409b yield. Mousseron et a1 o b s e r ~ e d " ~ t h e re-

duction of 1-cyanocyclohexene a t -15°C to cyclohexane carboxaldehyde and

a t room temperature to aminomethylcyclohexane. a-Chloronitriles on re-

duction116 using LAfI afforded aziridine. The reduction of a-aminonitriles

depends on the s i ~ b s t i t u e n t s " ~ on the u-carbon atom. Generally, ~ v l i e n the

a-carbon is mono substituted reaction proceeds through path A and when i t

is disubstituted, path B is preferred ( Scheme 1.2)

Scheme 1.2

a-Aminonitriles prepared from benzaldehyde, substituted t,enzalde-

hyde or furfural yielded (2-amino)-2-arylethyl anlines. It was observed 117

that the nitriles derived from indole-3-aldehyde (1.83) on reduction resulted

in the displacement of the n i t r i le g roup w i t h the format ion of 3-amino-

methylindole (1.84). It was recorded by S n ~ i t h a n d ~ o g e r s " ~ that cyclopro-

pylcyanide was reduced even a t -70°C by LAH to give the corresponding

alcohol.

<R\

LAH A

'Wj CH- N.-,

r5-d -'-.J'\N/.

H

During the studies on the catalytic activity of silica, Flojo a n d co-work-

ersS5 have observed that carboxy esters as well as ketones bettrine cyan':

group were converted into corresponding cyano alcohols by LA11 in prcs-

ence of SiO, in ether. LAH in presence of excess o f alcohol f o r n ~ s lithium

trialkoxyaluminium hydrides which are better reducing agents than LAI-I

for the conversion of nitriles to aldehydes 119,120

1.6. Keduction of Nitro, Nitroso, azo and azido groups

1.6.1. Nitro compounds

Nitro con~pounds are less facile in the reduction reaction of 1.AI.l when

compared with carbonyl compounds. Extreme care should be taken to con-

duct the reduction of nitro con~pounds . The reduction should be carried out

under nitrogen atmosphere as there is evidence that the intermediate prod-

ucts are oxygen sensitive. A conlplicated sequence121aof reactions is involved

in the reduction of aromatic nitrogroup. (Scheme 1.3)

Scheme 1.3

iiliphatic nitro compounds afford primary arnines on LAI-I reduction.

It has been shown 121b that the reduction of tertiary alkyl nitro compounds

is complicated by the rearrangement of the intermediate hydroxyl amine de-

rivative.

It was reporteds1 that aliphatic nitroesters were reduced to the cor-

responding nitro alcohols. The reduction1'' products of unsaturated nitro

compounds depended upon the quantity of the reagent used.

Aromatic nitro compounds on reduction 28'123-125 using LAM furnished

azo compounds. Nitrobenzene on reduction'26 with LAH at 25°C afforded

84% of azobenzene and small quantities of azoxyhenzene. Anomalous re-

ductions 123-127 of aromatic nitro c o n ~ p o u n d s by I.AI-I were also reported.

When 2,6-di(methoxy carbonyl methyl)-nitrobenzene (1.85) was reducecl using

LAH, corresponding amino alcohol (1.86) was formed.

LAH .. E the1

Corbett et a1 12' reported the reduction of halogeno-nitro con~pounds

leadlng to azoxy compounds. Thus 2-bromonitrobenzene was converted Into

azoxy benzene whereas 2-bromo-5-methoxynitrobenzene afforded 3,3'-dimeth-

oxyazobenzene. I-Bromo-2-nitronaphthalene (1.87) gave good yields of 2,2'-

azonaphthalene (1.88). But the reduction of 1-nitronaphthalene did not pro-

duce identifiable products.

Reduction of the halogenonitroarenes with excess LAH resulted in the

formation of azo compounds with or without halogen. When less amount of

LAHwas used, azoxy compounds were isolated. ~ t t e r n ~ t s ~ ~ ~ f o r the prepartion

11H-dibenzolr, f1[1,2]diazepin-11-one by I.AH reduction of 2,2'-dinitro-

benzophenone met wi th failure.

1.6.2. Nitroso, azo and azido compounds

Hanna et a1 130reported the reduction of N-nitrosamines to disubsti-

tuted unsym-hydrazines. Generally, in such reductions the more polar ni-

trogen-oxygen bond is reduced preferentially to the nitrogen-nitrogen bond.

N-nitroso-N-methylaniline (1.89) gave 77% N-methyl-N-phenylhydrazine

(1.90). Similarly, N-nitrosodimethylamine was reduced13' to N,N-diniethyl-

hydrazine.

LAH can reduce azobenzene to hydrazobenzene only with consider-

able difficulty. It was observed by 0lahI3* that such reduction needed large

excess of the reagent, higher temperature a n d prolonged reaction time. But

the addition of small amount of transition metal halides as catalyst had re-

markable effect on the reduction of azobenzene to liydrazobenzent.. 4,4'-

Dichloroazobenzene was reduced to the corresponding hydrazo hcnzcnr in

90% yield. ~ a k a ~ i m a l ~ ~ o b s e r v e d that the reaction of N-nitrosamidcs xvith

LAH resulted mainly in the attack of LAH at the carbonyl group to give

aldehyde a n d the diazotate ion as the primary products. The reduction of

N-nitroso-N-benzylbenzamide (1.91) using LAH gave benzyl alcohol (1.92)

and phenyldiazomethane(l.93). Phenyldiazomethane was formed from the

diazotate ion by the loss of hydroxide ion.

LAH + - C 6 H 5 c H > ~ ~ ~ _ CP,CH,OH + C& CH-N-N C6H,C0 -60° C

58 % 14%

I t w a s reported 42'43that a -d iazoace tophenone a n d w-azidoaceto-

phenone were reduced to 2-amino-1-phenylethanol. P-Azidoethylbenzene

was reduced134 to P-aminoethylbenzene a n d a - i o d o a z i d e ( l . 9 4 ) to alk-

e n e ~ ' ~ ~ ( 1 . 9 5 ) .

@i*La~*n)@L,, I N3 , / c = b ~ 7 - - ."

H ,i" ': -,,-,,

1 . 9 5 , 1 . 9 4 i 1 . . i '; , . .

.--- ., ..-,-*& 1.7. Reduction of halogen substituted compounds

Generally, halogen substituted compounds are dehalogenated in pres-

ence of LAH. For example, alkyl halides undergo dehalogenation in pres-

ence of LAH. The selective of a halogen is possible if the

reactivities of halogens are different. The reactivity order of halogens was

found to be I > Br > C1 > F. Thus alkyl fluorides are generally not reduced.

137,138 2-Chlorooctane afforded octane in 73% yield, when the reduction IV il s

done in THF at room temperature.

I, 3-Dichloroalkanes were found to be reduced using LAH in dioxane

to give hydrocarbons as major products . T h u s 2-benzyl-2-methyl-1, 3-

dichloropropane (1.96) was reducedT3' to 2-benzyl-2-methyl propane (1.97).

Besides small amount of cyclopropane was also isolated.

Allylic halogens were more reactive than vinylic halogens towards

reduction using LAH, as shown by Hatch and c o - w o r k e r ~ ' ~ ~ . The reduc-

tion of 2-fluoro-1,1,3-trichloro-1-propene afforded 2-fluoro-1,l-dichloro-1-

propene. There are cases of replacement of vinylic halogens 141,142 also.

2,3,3,4,4-Pentafluorocyclobutene (1.98) o n reduction using LAH a t O°C af-

forded 23% 3,3,4,4-tetrafluorocyclobutene (1.99).

LAH

F Ether F F F 1: r:

Benzylic halogens were found more reactive than aromatic ones. Iodo

and bromo arenes can be easily reduced143 using LAH, but the fluoroarenes

are quite ~ n r e a c t i v e ~ ~ ~ ~ ~ ~ ~ u n l e s s they are polyfluorinated. Thus 3-iodochlo-

robenzene when reduced with LAIS in THF afforded chlorobenzene.

Amines were found resistant to L A H reduction while halogenated

amines undergo dehalogenation reactions. Thus 2-aminotrifluoro-methyl-

146 benzene was defluorinated to give 2-aminotoluenr in quantitative yield.

The electron releasing effect of the amino group helps the replacrment of

halogens. In the cases of halogenated ketones, acids and acid chlorides the

halogen atom is either replaced by hydrogen or retained during reaction with

However, i n the reduction of halogenated esters, the halogens

80 were dehalogenated, if precautions were not taken .

1.7.1.Reduction of halogeno compounds in presence of catalysts

First row transition metal halides are found very effective catalysts 147

in the reduction using LAH to remove halogens f rom organic molecules.

LAH alone is not effective in the reduction of bromobenzene and bromoc-

yclohexane a t room tempera tu re . But these c o m p o u n d s a r e easi ly

dehalogenated in hydrocarbon solvents in presence of transition metal chlo-

rides. It was found that LiAIH,-NiCl, was the most effective reagent in such

reductions. It was reported65that in the presence of AICI, the power of LAH

for dehalogenation is decreased or prevented. Thus no evidence of reduction

was found when iodomethyl benzene and 9-bromofluorene were treated sepa-

rately with LAH in presence of A1C13. In contrast to this, iodomethylbenzene

was converted into toluene in 86% yield and 9-bromofluorene (1.100) to a

148 mixture of fluorene (1.101) a n d difluorene (1.102) by LAH .

Haloalkanes and arenes were reported5' to be reduced using 1.Al-I In

the solid LAH-hydrocarbon two phase system, in the presence of phase t rans l ; :~ .

catalyst, crown ethers. Bromohexane and bromobenzene were respectively

reduced in 22% and 23% yield using LAI-I when 15-crown-5 was used as

the catalyst a t 80°C during three hours. The con~plex formed in this reac-

t ion has a planar structure a n d hence the participation of LAI-I in these

reductions can be explained in the same way as in ether solution.

1.8. Reduction of alcohols and phenols

The reduction of saturated alcohols to the hydrocarbons using L A H

is very rare. LAH reacts with alcohols a n d forms alkoxy alumino hydrides

which a re found very useful a s stereo selective reducing agents for other

organic functional groups. Lithium trimethoxy, diethoxy, triethoxy and tri(tert-

butoxy) aluminohydrides are examples 1491150f151, I t is interesting to note

that the reduction of 9-(hydroxymethyl) anthracene (1.103) a n d 1,2-di(9-

anthryl) ethanol (1.104) to 1,2-di(9-anthryl)ethane(l.l05)in 59 and 65% yield

8 respectively .

ore^^^^ reported a method for the replacement of an allylic hydroxyl

group by hydrogen without the saturation of the doub l~ : bond . .l-llc : ~ l ~ ~ ~ ~ l l o l

was treated with a pyridine-suphur trioxide complex and the intermediate

formed was reduced with LAH. The results obtained b). Ll'ong anii Groy 15'

showed that the reduction of a n allylic alcohol is a stereospecific process

and likely proceeded through the cyclic organoaluminium intermediate (2.7).

Grant et a/154 reported the reduction of the triple bond of propargylic

alcohols to a trans olefinic compound using LAH. This has received atten-

tion because of the synthetic utility of the organoaluminium intermediate

formed. The triple bond in the propargylic type acetylenic alcohols was se-

lectively reduced to a double bond by LAH 155'156. The double bond of cinnamyl

alcohol was hydrogenated by I .AH~ in 92% yield in ether to give 3-phenyl-

propanol .

When bromohydrins were reduced157 using LAH in presence of ?.iC12,

alkenes were produced nonstereospecifically. Erythro and thrro 5-bromo-6-

decanols gave 80:20 a n d 70:30 mixtures of trans and cis-5-decene respec-

tively. Allylic and benzylic alcohols were reductively coupled 157,158 by LAH

in presence of TiC1,. Thus 1,3-diphenyl-1,3-propanediol (1.106) undergoes

reduct ive coup l ing to f o r m cis a n d trans 1 ,2 -d ipheny l cyc lopropanes

(1.107,l.lO8)1,3-diphenyl-l-propano1 (l.l09),trans 1,3-diphenylpropene

(1.110) a n d 1,3-diphenylpropane (1.111).

H C6H5 C,H5 C,H5 1.108

1.107 LAH

OH OH Tic4

In presence of A1C1, alcohols were hydrogenolysed159 w i t h LAI-I.

Brewster et al 160reported the reduction of allylic alcohol to alkenes by

chloroalanes produced from LAI-I a n d A1C1,. Cer ta in alcohols were con-

verted to the hydrocarbon-stage by the r e d u ~ t i o n ~ ~ u s i n g LAN in presence

of AlC1,. Tr iphenyl carbinol w a s reduced to t r ipheny l m e t h a n e whi le

benzhydrol-a secondary aryl alcohol-furnished diphenyl methane. Benzyl

alcohol-a primary aryl alcohol-resisted the reduction.

Phenols when refluxed with LAH resulted i n hydrogenolysis of phe-

nolic hydroxyl group161a. But, because the reaction requires very high tem-

perature, all other functional groups present, if any, in the molecule will be

reduced. LAI-I was reported 161b

Lo form diaryloxyalkoxy hydridcs with ?,a-

di-tert-butylphenol which was used as sterco selective reducing agent for

cyclohexanones.

1.9. Reduction of epoxides

The reductive cleavageT6* of the epoxide ring to give monohydric

alcohols is important in steroid chemistry. Unsymmetrical epoxides con-

163 taining primary and a secondary oxide linkage undergoes preferential rup-

ture of the primary linkage forming secondary alcohols. However, among

secondary and tertiary linkages, the preference of rupture is secondary link-

age. The regiospecificity of reduction of epoxides to alcohols is interesting.

LAI-I approaches the oxide from the less hindered side, yielding the more

substituted trans For example 1,2-dirnethyl-1,2-e~~oxycyc1ohcxi~ne

(1.112) furnished 74% trans -1,Z-d~methylcyclohexane-1-01 (1.113). l 'lschcnkr

et a1 165areported the r e d u c t ~ o n of a.p-epoxyketones to epoxy ,~ lcohols

LAH

\,'

1.10. Reduction of hydrocarbons and heterocycles

1.10.1. Hydrocarbons

Although LAN is a very powerful reducing agent, it is interesting to

note that i t reduces only a few number of unsaturated bonds 81165b. This en-

ables us to use LAH for reducing functional groups containing carbon-car-

bon double bonds. One of the most interesting reaction of LA13 with hydro-

8 . carbons is the reduction uf 1,2-di(9-anthryl)ethane(l.l05) to 9-methylan-

thracene in 24% yield .

1,2-Ui(9-anthry1)ethene was reduced8 by LA13 in tetrahydrofuran a t

65°C to 1, 2-di(9-anthryl)ethane(1.105) in 78% yield. It was reported that

acenaphthylene (1.114) w a s reduced166 to acenaphthene (1.115) i n 97%

yield.

LAH

Carbitol . 1 2O0C

There are several compounds in which the reduction ol a polar I'unc-

tional group is accompanied by the complete or partial reduction oi an un-

saturated bond in the a , P position. Among aliphatic conipounds the reciuc-

tion of unsaturated bond was observed in the case of allylic alcohol, undl--r

9 forcing conditions . Further I-(1'-cyc1ohexenyl)-1-bntyn-?-ol was reduced 155

to the corresponding diene, 2-pentyne. Besides pentane in 98% yield was

also isolated when the reduction was done in toluene. Alkanes were aisd

produced when alkvnes were reduced wi th LAH in presence of transition

metals. Partial reduction of alkynes afforded trans alkenes. 3-Hexyne o n

167 reduction gave trans-2-hexene in 9791 yield .

In 1976, Sato 168'169 found that the hydroalumination reaction wi th

LAH proceded at room temperature in the presence of a catalytic quantity

of titanium or zirconium compounds. 1-Hexene was reduced to hexane. Simi-

larly 4-vinylcyclohexene was reduced to 4-ethylcyclohexene.

It was found that hydroalumination of alkenes followed by treatment

with halogen or N-halosuccinimide afforded haloalknnes. Thus 3-chloromethyl-

quinuclidine(l . l l7)was obtained from 3-methylei~equinuclidine169 (1.116).

Reduction of the double bond has been observed in the case of ally1 alcohol

under forcing conditions.

CH,C1

LAH > =I,

1 . 1 1 6

i:, 1.117

1.10.2. Heterocycles

Although it is not common, heterocyclic ring systems are sonietiincs

reduced by LAH . Bohlmann reported'170 the reduction of benz im~~loza lc to

2,3-dihydrobenzimidazole a n d quinoxaline to 1,2,3,4-trtral~ydroquinoxnline.

In several successful reductions of functional groups in pyridine derivatives,

the pyridine ring remains intact . However, pyr id ine itself is slowly at-

tacked 1711172. Halogens in the a and y positions to the nitrogen atom of the

heterocycles are distinctly more r e a c t i ~ e l ~ ~ t h a n those in the position to-

w a r d s nucleophilic reagents. Quaternary iodides in the quinol ine and

isoquinoline series a re readily reduced174. The products a re N-alkyldi-

hydroquinolines or the analogous dihydroisoquinolines. In the reduction of

P-chlorotetrafluoropyridine, the fluorine atom in the y-position was replaced 175

by hydrogen on reduction using LAH. N-Nitrosopiperidine was reduced 130

in 75% yield by LAH in ether to N,N-pentamethylenc hydrazine. Phenazine

(1.118) was partially reduced by LAH to 9,lO-dihydrophe~lazine (1.119) in

90% yield.

1.118 1.119

1.11. Reduction of Sulphur Co~npounds

Alkyl thiocyanates and arylthiocyanates on reduction with lithium alu-

minium h y d r ~ d e afforded mercaptans and throphcno' respectrvely whereas

each mole of d ~ s u l ~ h l c i e was reduced 176f177 to two moles of thiols. Bordxvcll

et a1 17'reported the reduc t~on of sulfones to sulphiilcs. Sulphenyl t hlorriit,

( 1 . 2 0 ) sulphinic acid (1.121) and sulphinyl chlo~.icles (1.122) \verp r t3 -

d ~ c e d l ~ ~ to disulphides (1.123).

Field and c o - ~ o r k e r s l ~ ~ reported the reduction of chlorides of sulphonic

acids by lithium aluminium hydride. The addit ion of thc chloride to the

refluxing ether solution of the reagent gave thiols whereas the inverse tech-

nique a t -20°C afforded sulphinic acids.

Esters of sulphonic acids were reduced176 by LAH which often led to

mixtures of hydrocarbons and alcohols. c ronyn lS0 reported the reduction

of thioamides to amines by desulphurization.

Desulphurization of aliphatic and aromatic sulphides by LAH in pres-

ence of cupric chloride was reported by ~ u k a i ~ a r n a l ~ ' a n d co-workers in

1973. A neat example of the use of LAH is the reductionlS2 of methane

sulphonylester( 1.124) to the saturated alcohol (1.125).

1 .12 S o l v e n t s used in the reduction using I . A H

LA13 is soluble in a variety of ethereal solvents like diethyl ether, THF,

rnonoglyme, d ig lyn~e and triglyme. The approximate s o l u b i ~ i t i e s ~ ~ ~ o f the

hydride a t 25OC are given in table 1.2

Table 1 . 2

Solubility of LA11 in various solvents

Solvent Solubility in g in lOOg solvent

Diethyl ether

TI-IF

Diglyme

Di-n-butyl ether

Dioxane

Ethyl butyl e the r w a s used a s the so lven t in the reduc t ions of

s ~ l ~ h o n e s l ~ ~ . Dioxane is not a good solvent l o r L.413 and has been used

rarely. Moreover, the isolation of products is con~plicated by its miscibility

with water. pyridineZ7 has been shown to be a n excellent solvent for the

LAH reduction of aromatic ketones. With pyridine LAH forms 1,2 a n d 1,4-

dihydropyridine derivatives (1.126,1.127) which no longer contains metal

hydrogen bonds.

Carbitol, N-ethylmorpholine and no11 polar solvents such a s benzene,

toluene, n-hexane, heptane were also used as solvents 64,166,164,1S5 .Triethyl

amineZ4 and anisole were also used as solvents in the reduction of N-subski-

tuted 1-benzoyl-1-phenylmethanimines. Diethyl carbitol , rnethylal and me-

thylene chloride were also found as useful solvents 186a-c. Toluene was the

solvent in the reduction of 2-pentyne. Wang reported4' the ability of HMI'A

as the medium in the reduction of oximes. I t was reported that the reduc-

tion of 9-anthraldehyde using LAH in ether afforded 9-hydroxymethyl an-

thracene and in TIIF afforded 1,2-di(9-anthry1)ethme. The difference in

the products in the two solvents was accounted with the difference in the

solubility of the con~plex of 9-hydroxymethylanthracene in ether and THF.

147 THF was not found completely inert towards L A H ' ~ ~ ~ . Ashby et n l sug-

gested that the difference between LiAlH, in tetrahydrofuran and LiAlH, in

diethyl ether was d u e to the difference in the solvation of Li+AIM,- in these

two solvents. A mixture of ether and benzene was used in the r e d i l c t ~ o ~ ~ 83

of ortho esters to acetals.

The effect of the solvent o n the stereo selectivity of LA13 reduction of

1,2 iminoketones was studied by Alcaide and c o - ~ o r k e r s ~ ~ . The results are

based on the generally accepted feature of LAH reduction of carbonyl com-

pounds, that the electrophilic activation187 of the carbonyl group by the cationic

lithium takes place by the replacement of a molecule of solvent co-ordinated

to the cation. The ability of solvation and steric size of the solvent are found

responsible for the observed results. No systematic study has bee11 done on

the effect of solvent on the reducing power of lithium aluminium hydr i~ le .

1 . 1 3 Mechanism o f the reduction using LAl-I

The mechanism of the reduction of various functional groilps using

LAH is different and also not clear. how eve^-, among all functisnalities, the

mechanism of the reduction of aldehydes and ketones is somewhat known.

X-ray observations188a on the crystalline borohydride point towards a polar

structure consisting of lithium ions and tetrahedral borohydride ions. LA13

is possibly somewhat less polar than the borohydride but i t is reasonable to

suppose that in ether solutions it exists largely as ionic aggregates of strongly

solvated lithium ions (1.128) and aluminohydride anions188b, AIH;.

1 . 1 2 8

The simplest assumption is that hydride furnished by the ~lissociation

of the complex hydride functions as a nucleophilic reagent. Nearly all the

normal reduction reactions involved the polarisation of a covalent multiple

bond by a strongly electronegative a tom followed by the addit ion of a hy-

dride ion to the electron deficient carbon atom by a n S N ~ displacement.

h4olecular orbital picture of the t~ucleophilic addition to the carbonyl group

According to the molecular orbitc~l picture 73'169 the most f i~vourablr

mechanism for electrophilic and nucleophlic addit ion to the carbonyl iunc-

tion involves the association of a cation with the oxygen a tom of the carbo-

nyl function which enhances the addit ion of a n~cl<~lphile to the lowest un-

occupied molecular orbital and specifically to the carbon a tom of the carbo-

nyl group. The maximum overlap in the transition state would suggest a n

initial approach perpendicular to the molecular plane but the polarity of the

n~olecule favours a greater separation between nucleophile a n d the oxygen

atom. ~ a l d w i n l ~ O extended these results a n d according to Baldwin approxi-

mation, the approach vector of the hydride on a carbonyl function is shifted

from the symmetric position in space away from the oxygen atom.

It has been reportedi12 that in the reaction of lilhium a l u n ~ i n i u l ~ l hy-

dride wi th carbonyl compounds, the removal of Li* cation with the appro-

printe crown ether brought no reaction within a reasonable reiiction time

before hydrolysiu. Concurrent or prior association of the c,irbonyl oxygen

with Li* cation followed by hydride trnnsier has been suggested by Ashby 191

and co-workers. Pierre and 1-1nnde1'~' have proposed that the cr~tion inter-

venes in a catalytic fashion and that stereo selection is fixed fronph the first

step in the mechanism, namely the association of the cation with the carbo-

nyl oxygen atom.

The mechanism of the reduction of carbonyl compound is thus accepted

to involve the following steps. (1) Association of the cntion with the oxygen

atom of the carbonyl group. This is a fast step in which the solvent separates

ion pair far apart. (2) Approach of the A H 4 - nucleophile from above or be-

low the molecular plane to the carbonyl end at a n angle wider than Y O o and

as close as possible to 110'. (3) Passage through the transition state. (4) For-

mation of the products.

From the results of the reductions of cyclic anhydrides it has been rc-

ported73 that there is a definite preference for the reduction to occur at the

more electron rich carbonyl function. The Li' cation preferentially associ-

ates with the carbonyl group bearings the most basic, isolated nonbonding

electrons on its oxygen atom followed by addit ion of hydride ion to the car-

bon end of the activated carbonyl function. The course of reaction is gov-

erned by electronic effects which induce difference in electron availability

o n the two carbonyl groups. The following facts cause difference in electron

availability. (1) Conjugation with aromatic systems results in delocalisation

of electrons which weakens the carbonyl dipole. (2) Presence of tertiary car-

bon alpha to one of the carbonyl functionality. (3) Presence of phenyl or nl-

tro groups which withdraw electrons or alkyl groups &hat release electrons

on the carbon to the carbonyl group. I t was also pointed ou t earlier that

under conditions of overpowering steric crowding the course of the reaction

might be reversed. The mechanism of the reduction of LA13 can be illus-

trated by taking the reduction of ketones as a n example (Scherl~e 1.4).

56a,149,151 than Each successive transfe:. of hydride ion becomes slower

the preceding one because of the electron withdrawing inductive eifect of

the alkoxy group that tends to oppose the loss of hydride ion. The selectiv-

149- ity of the modified reagents like LiAIH (OR), is based on this principle

l5'. The mechanism of the reduction of acid chlorides is slightly different.

The acid chloride is firt converted to the aldehyde. The aldehyde is further

reduced to primary alcohols. Useful modification of the properties of LA13

is also achieved by the addition of aluminium chloride in various propor-

tions. The general effect of the addition of aluminium chloride is to lower

the reducing power of LAH. The replacement of aluminium chloride by the

bromide or iodide is found not advantageous. Reagents prepared from LAH

and copper salts have also been used to bring about some selective reduc-

tions like the reduction of open chain conjugated enones to the saturated

ketones.

Tomoatsu et al 193suggested S N ~ ' mechanism for the reduction of some

allylic substrates. Recent studies194 on the mechanism of LAH revealed that

single electron transfer (SET) mechanism is operating in some cases.

1.14. Decomposition of LAH-substrate complex

Normal decomposition of the compound-LAH complex is done using

7 water or ethanol. It is followed by either NaOH or acid. The unreacted hy-

dride is decomposed by the addition of ethyl acetate i f the decomposition prod-

uct, ethanol, does not interfere. But Kumar and c o - ~ o r k e r s l ~ ~ reported facile

acylation and trans esterification by ethyl acetate. Use of ethyl acetate yielded

excIusively the acetate of the desired alcohol. Many compounds containing

active hydrogen decompose the reagent with the liberation of hydrogen.

This review illustrates the powerful reducing action of LAH on wide

variety of functionalities. The reaction proceeds with extreme rapidity and

virtually no side reactions are observed. The reduction products are only

slightly influenced by solvents. The reactions generally proceed by hydride

ion transfer by S N ~ displacement. Addit ion of catalytic quantities of alu-

minium chloride1', silica gel and transition metal halides have found effect

o n the reducing power of LAH. The mode of addit ion of the reagent has also

9 shown to have effect in isolated cases. LAH has also been s h o ~ v n ~ ~ t o act a s

a strong base in certain reactions.

Although LAH was widely used for the reduction of functional groups

only a few compounds with more than one functional group was investi-

gated. Besides, it has been noticed that in some reduction reactions LAH

selectivly reduces certain functional groups. Therefore an extensive work is

necessary to unravel this possibility.