Reductions 37 RSPHRH Na, Li  NH3 O

S Na, NH3(l) R NH R' R NH2

Na, NH3 R2 N Ts  R 2 NH 2.9. Reduction by hyride transfer-reagent:

REACTIVITY OF HYDRIDE DONAR REDUCING AGENTS Iminium Acyl Aldehyde Ester Amide Caboxylic ion chloride or ketone salt Hydride Donar More Reactive  Least Reactive LiAlH4 Amine Alcohol Alcohol Alcohol Amine Alcohol Red Al  Alcohol Alcohol Alcohol Amine Alcohol

LiAlH (Ot-Bu4)3  Aldehyde Alcohol Alcohol Aldehyde  NaBH4 Amine  Alcohol Alcohol   NaBH3CN Amine     

B2H6   Alcohol  Amine Alcohol AlH3  Alcohol Alcohol Alcohol Amine Alcohol Disiamylborane   Alcohol  Aldehyde  DIBAL   Alcohol Aldehyde Aldehyde Alcohol

2.9.1. Lithium aluminium hydride (LiAlH4) Most reductions of carbonyl compounds are done with reagents that transfer a hydride from boron or aluminium. Sodium borohydride is a mild reducing reagent that rapidly reduce aldehyde and ketones but not esters. Lithium aluminium is strongly donor reagent and it rapidly reduce ester acids, nitriles, amides as well as aldehyde and ketones. Neither sodium borohydride nor lithium aluminium hydride reacts with isolated carbon- carbon double bonds. There reagents are nucleophilic and as such they normally attack polarized multiple bond such as C=O, CN by transfer of hydride ion to the more positive atom. Lithium aluminium hydride is a more powerful reducing agent than sodium borohydride and reduces most of commonly encountered organic functional group.

O O O AlH3 O O O H H Al 2 3 AlH2 AlH H H O + OH H3O O

4 Al 38 Reductions Common Functional Groups, reduced by LAH

Functional groups Reduction product

RCHO  R CH2OH R R C O  CH OH R R O  R CH2OH + R'OH R C OR' O  RCH OH R C OH 2 O  R CH NHR' R C NHR' 2 O

 R CH2NR'2 or RCH(OH)NR'2 RCHO + R'2(NH) R C NR'2

 R CH2 NH2 or R C NH RCHO R C N H R C N OH  H2 H R C NH2

ArNO2  Ar NH NH Ar or Ar N N Ar

R CH2 Br  R CH3 O

R CH O S Ar 2  R CH3 O

O OH

R C CH 2  C CH3 H R H Aldehye, ketone, esters, carboxylic acids and lactones can all be reduced smoothly to corresponding alcohols under mild conditions. Carboxylic amides are converted into amines or aldehydes.

OH CHO

O N LiAlH4 O N THF, 0ºC O O

Ph Ph LiAlH4 THF, heat OH H2N COOH H2N Reductions 39

LiAlH4 N O N Et2O, 20ºC Me Me

OMe OMe Reduction of  -aryl-,  unsaturated carbonyl compounds with lithium aluminium hydride, where the car- bon-carbon double bond is often reduced as well as the carbonyl group. LiAlH4 CHO Ph Et2O, 35ºC Ph OH LiAlH4, Et2O CHO Ph –10ºC Ph OH or NaBH4, or AlH3 or DIBAL-H Cyclic organoaluminium compound is formed.

H* O R-OH* Ph Al Ph Ph OH 1º alcohol (saturated)

Reduction of propargylic alcohols R C  C  CH2 OH with lithium aluminium hydride to give trans alk- enes.

LiAlH4 CH2 OH R C C CH2OH R OH O O OH (i) LiAlH HO 4 NaBH4 CO Et CO2Et + O O 2 OH (ii) H3O EtOH CO2Et Reduction of amide to amine by Lithium Aluminium Hydride:

O Li AlH3 NR2 Li O AlH3 O H AlH3 R CH2 NR2 H AlH3 R NR2 R H Amine R NR R NR H 2 H 2

O O AlH3 Li O

+ LiAlH4 H3O NMe2 NMe2 H THF, 0ºC H 40 Reductions

Stereoselectivity and chemoselectivity of LiAlH4:

O H OH HO H LiAlH 4 + Me Me Me Me Me Me H H H 72 : 28

H2 Al O O O OH H LiAlH H AlH H HO Ph 4 3 Ph Ph Ph + Me H Me Me Me H H H HO HO HO Ratio 20 : 80

Mixture of product is obtaind, unhindered ketones react with LiAlH4, equatorial alcohols is the predominant

product. When hindered ketones reacts with LiAlH4 axial alcohol will be major product. OH O LiAlH 4 OH +

Ratio 90 : 10

OH O LiAlH4 OH +

LiAlH4 45 : 55

s LiBH( Bu)3 <1 : >99

Alternative reagent can provide high selectivity. Dissolving metal reductions (Li, NH3). Provides the thermody- namically more favourable equatorial alcohols almost exclusively from either two cyclic ketones.

O R HO R R LAH epoxidation HO HO

LiAlH 4 NaBH4CN OH O SN2 OH Reductions 41

2.9.2. Sodium Borohydride (NaBH4) :

[NaBH4/EtOH/25ºC]

Common Functional Groups, reduced by NaBH4

Functional groups Reduction product

RCHO  R CH2OH R R C O  CH OH R R O

 R CH2NHR' R C NHR' O

 R CH2NR'2 or RCH(OH)NR'2 RCHO + R'2(NH) R C NR'2

R C N OH  H2 H R C NH2

R–COCl  R–CH2NH2

RCOOCOCl  RCH2OH  RNH R N N N 2

O OH

R C CH 2  C CH3 H R H Sodium borohydride is a very selective reducing agent and reduce aldehyde and ketone to alcohols. Sodium borohydrides is a comparatively weak reducing agent. Because boron hydrogen has more covalent character than lithium hydrogen. It does not react or slow react in the case of ester or cyclic ester functional group.

NaBH4 is a chemoselective reagent for carbonyl compound in the presence of esters (cyclic or acyclic) and amide functional group. It is prepared by the reaction of sodium hydride and trimethyl borate. 250ºC 4NaH B OMe3  NaBH4  3MeONa

NaBH4 is insoluble in ether but soluble in alcohol and water. So, it is used in hydroxylic solvent like alcohol, isopropanol etc. Reducing properties of sodium borohydride are substantially modified in the presence of metal salt, perticularly in the presence of cerium (III) chloride. Sodium borohydride reduces ,  unsaturated ketone with extremely high selective, such that 1, 2, not 1, 4 reduction occurs to gives allylic alcohols. O OH OH

NaBH 4 + MeOH

no CeCl3 59 : 41

CeCl3.7H2O 99 : 1 42 Reductions Sodium borohydride is a nucleophile that you have seen reducing simple aldehyde and ketone to alcohols. But it will also do conjugate addition reaction, which of the alternatives actually takes place depends on the reac-

tivity of the C O group.

NaBH4 usually react with ,  unsaturated aldehyde to give alcohols by direct addition to the carbonyl group. CHO NaBH4, EtOH OH Ph Ph O OH

NaBH4, EtOH

Mechanism:

O O O O OH

H OEt H BH3 H OEt

H BH3 Luche reduction:

OH O Ce3+

NaBH4, EtOH

CeCl3 : Hard Lewis acid model salt

For ester and other less reactive carbonyl compounds, conjugate addition takes place because NaBH4 does not reduce ester or amide. O O

NaBH MeO 4 MeO MeOH Ph Ph ,  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. More reactive aldehdye group is protected as the hydrate, which is stablised by complexation with cerium ion and is generated during isolation of the prod- uct.

O OH

NaBH4, CeCl3.7H2O EtOH, –15ºC CHO

CHO Reductions 43

O OH H NaBH4, CeCl3.7H2O

EtOH, H2O, –15ºC CHO CHO

NaBH4 is more chemoselective than LiAlH4. At room temperature in ethanol it readily reduce aldehyde and ketone but it does not generally attack esters or amide O OH

NaBH4 CO2Et CO2Et EtOH Stereoselectivity:

O NaBH4 H i-BuOH OH

H3C CH3 H3C CH3 H3C CH3

H3C H3C H3C NaBH4 + H OH 14% 86% O OH H

O CH2SO2Ph OH CH2SO2Ph O CH3

+

H H H  NaBH4 20 : 80 NaBH4.CeCl3 95:5

OH OH OH 1 1 R' Zn(BH4)2 R R 2 R2 + R2 R ether, 0ºC O OH OH anti syn (Major) (Minor) Chemoselectivity: Reduction of carboxylic ester in the presence of carboxylic amide is possible using sodium borohyride and calcium chloride. O

C NH2 NaBH4/CaCl2 NH2 Et O C HO C O O 44 Reductions

O OH

H NaBH4 EtO EtOH EtO

O O

2.9.3. Lithium tri-t-butoxyaluminium hydride (lithium hydridotri-t-butoxyaluminate) t [LiAlH(O Bu)3]: t Common Functional Groups, reduced by [LiAlH(O Bu)3]

Functional groups Reduction product

R R C O  C O Cl H O  R CH2OH + R'OH R C OR'

O  R CH NHR' R C NHR' 2 R C N OH  H2 H R C NH2

RCOOCOCl  RCH2OH

R C N  RCH2NH2

O OH

R C CH 2  C CH3 H R H

t [LiAlH(O Bu)3] is prepared by the action of three equivalent of tert-butyl alcohol on lithium aluminium hydride. Lithium tri-t-butoxyaluminium hydride is a much milder reducing agent than lithium aluminium hydride. Alde- hyde and ketones are reduced normally to alcohols, carboxylic ester and epoxides react only slowly and halides, nitriles and nitro group are not reduced.

O O O

O O O OHC t HO LiAlH(O Bu)3 Amberlite resin O MeO C THF, –10ºC PhH 2 MeO C 2 O O O O

t LiAlH(O Bu)3 reduce carboxylic acid, acid chloride and di-alkylamides into aldehyde. Reductions 45

COCl CHO t LiAlH(O Bu)3 –78ºC NC NC t LiAlH(O Bu)3 reduce tertiary amide into aldehyde.

(i) LiAlH(OEt)3 CONMe2 + CHO (ii) H3O NMe2 LAH (excess) LAH R CH2 NH2

R C N H O+ LiAlH(OEt)3 3 R C N [Al(OEt)3] R CHO H 2.9.4. Mixed lithium aluminium hydride-aluminium chloride reagent:

3LiAlH4 AlCl 3  3LiCl  LiAlH 3

LiAlH4 AlCl 3  LiCl  2AlH 2 Cl (LiAlH3–ALANE)

LiAlH4 3AlCl 3  LiCl  4AlHCl 2

The general effect of the addition of AlCl3 is to lower the reducing power of LiAlH4.

OH LiAlH4 LiAlH4-AlCl3 OH CO2Et Butanol (1:1) Et2O Br Br O OH mixed hydride

O mixed hydride Ar Ar Ar Ar mixed hydride

O OH LiAlH -AlCl (3:1) Ph NMe2 4 3 Ph NMe2

Et2O O 46 Reductions 2.9.5. Diisobutylaluminium hydride (DIBAL-H):

[DIBAL-H or DIBAL or iBu2AlH]

Common Functional Groups, reduced by [DIBAL-H or DIBAL or iBu2AlH]

Functional groups Reduction product

R-CHO  R-CH2OH R R O  CH OH R R R C O  R-CHO Cl O

C  R-CHO R OR O O

C C  R-CHO R O R O R C N  R-CHO R R R R C N  R–CH2–NH–R H  R-CHO R N N N

R C N  RCH2NH2 O R CH CH3  R OH

O  R CH2OH + R'OH R C OR'

DIBAL reduce esters and ketone into alcohols. DIBAL on reduction of nitriles gives amines and epoxides are cleaved to alcohols. At low temperature, esters and lactones are reduced directly to aldehydes (or lactols); nitriles and carboxylic amide gives amines which are readily converted into aldehydes by hydrolysis. O O DIBAL-H O OH PhMe, –78ºC Reductions 47

CO2Me CHO O DIBAL-H O DCM, –78ºC MeO MeO

H H CN CHO DIBAL-H hexane, –70ºC

DIBAL reduce the ,  -unsaturated carbonyl compound to allylic alcohols Boc Boc DIBAL-H Ph N Ph N OH CO2Et PhMe, –78ºC  unsaturated ester Note: DIBAL reduce to alkyne cis alkene

R R DIBAL-H R C C R H H C H 4 9 C4H9 iBu AlH (i) I2, THF C H C C H 2 4 9 (ii) H O+ i 3 Al Bu2 I Mechanism:

iBu AliBu Al i O Al 2 Bu2 O O H O O DIBAL H O+ C 3 C R H R O Et R O Et R OEt R OEt H H stable at –78º unreactive towards further reaction

C4H9 C4H9 + H iBu2AlH H3O C4H9 C C H i H Al Bu2 H H Cis Alkene Reduction of Nitrile: CN CHO (a) iBu2AlH hexane, –78ºC + (b) H , H2O 48 Reductions

O O HO H

O O H (a) iBu2AlH Et2O, –78ºC (b) H+, H2O OH Summary : At ordinary temperature DIBAL reduce Ester and ketone  Alcohol

Nitrile  Amine

Epoxide  Alcohol

Lactone  Lactols

Carboxylic acid  Imine

Alkyne  cis-alkene

2.9.6. Sodium cyanoborohydride (NaBH3CN) and Sodium triacetoxyborohydride

(NaBH(OAc)3) :

Common Functional Groups, reduced by (NaBH(OAc)3) and (NaBH3CN) Functional groups Reduction product

R-CHO  R-CH2OH R R O  CH OH R R O

C  R-CHO R Cl R N  C R CH2 NH R R Cl  R-NH R N N N 2 O  CH3–CH2–OH

Sodium cyanoborohydride is more selective reducing agent than sodium borohydride because of electron- withdrawing effect of the cyano group. Aldehye and ketone are unaffected by sodium cyanoborohydride in neutral solution but they are readily reduce to corresponding alcohol at pH = 3-4 by way of protonated carbonyl group. NaBH CN Aldehyde and ketone 3 No reaction Neutral condition

pH (3-4) Alcohol O DO NaBD3CN D D2O Reductions 49 Iminium groups are more easily reduced than carbonyl group in acid solution. Reductive amination of aldehyde or ketones by way of the immunium salt formed from the carbonyl compound. A primary or secondary amine, typically at pH > 5 at this pH carbonyl group uneffected.

NaBH3CN NH ' RCHO + HNR'2 R NH2 R 2

Ph Ph

N N N , CHCl2, Ti(OiPr)4 H H H then NaBH3, MeOH O N N N Bn Bn

Me H N N CH2O (37% in water)

F F

O O H2N Ph O NH NaBH(OAc) , ClCH CH Cl, O 3 2 2 O Ph AcOH Eschweiler-Clark reaction:

O

H O H O R–NH2 N R NH R HCOOH H H H

Note: Sodium triacetoxyborohydride (NaBH(OAc)3: Reduce aldehyde selectivity in the prescence of ketones. However, ,  hydroxy ketones are reduced with this reagent and stereoselectively gives anti-diol product. The reagent tetramethyl ammonium

triacetoxyborohydride, Me4NBH(OAc)3 has shown excellent selectively for this transformation. Exchange of one of the acetoxy groups for alcohol is thought to proceed stereoselective intramolecular transfer of hydride.

OH O OH OH Me4NBH4(OAc)3 CO CH CH CH Ph CO CH CH CH Ph 2 2 2 2 MeCN, AcOH, –40ºC 2 2 2 2 anti: syn, 95:5

Reduction of tosylhydrazone of aliphatic carbonyl group (in acidic modify): Carbonyl compound into corresonding hydrocarbons involves reduction of the derived toluene-p- sulfonyl (tosyl) hydrazones with sodium cyanoborohydride in acidic dimethylformamide (DMF). The reaction is specific for aliphatic carbonyl compound, aromatic compound are normally unaffected. 50 Reductions

O

H H

P-TsNHNH , TsOH H 2 H O DMF, Solfolane than O NaBH3CN, 100ºC H H O O

Reduction of ,  unsaturated carbonyl compound with tosylhydrazone followed by the migration of double bond.

AcO AcO P-TsNHNH2-AcOH

O than NaBH3CN, 70ºC

Mechanism:

Na BH2CN H H H O N N N Ts N + H2NNH-Ts Ts H

N N H

O

(i) NH2NHTs (ii) NaBH3CN DMF, heat stereoselective for trans-alkene

Note: Zn(BH4)2 is a perticularly effective agent for the reductive amination of ,  unsaturated aldehyde and ketone.

CHO HC NNHTs CH3

H2NNHTs NaBH3CN DMF, heat

* Selective formation of primary amine uses the rhodium (III) complex RhCp Cl2  as a catalyst and ammo-  2

nium formate HCOONH4  , which acts as the source of the ammonia and the hydride. Reductions 51

O NH2

HCOONH4

0.1 mol% (RhCp*Cl2)2, MeOH, 70ºC Cp*   Pentamethylcyclopentadienyl anion Note: Sodium triacetoxy borohydride can reduce aldehyde selectively in the presence of ketones.

Summary: NaBH3 CN alcohol Aldehyde and ketone acidic medium

EtNH2, NaBH3CN O NHEt

H P-TsNHNH2, TsOH O DMF H O

+ H2NNH-Ts

O O

H NaBH(OAc)3 C H2C O OH

2.9.7. Borane and its derivatives: Table: Functional groups reduced by borane Functional Group Reduction Product

RCOOH RCH2OH

B RHC CHR R R

RCHO RCH2OH

R2C = O RCH(OH)R

R C N RCH2NH2

RCONR2 RCH2NR2

RCO2COR RCH2OH O

R CH2 OH R H

RCO2 R ' RCH2 OH R 'OH (slow rate of reaction) RCOCl No reaction

RNO2 No reaction