Hydride Reducing Agents

General Mechanism: ! ! !

• reduction of aldehydes & ketones

• reduction of carboxylic acids & derivatives

R R'

O MHnR R'

O

H

H3O+

R R'

OH

H

MHn-1

H

R X

O MHnR X

O

H

H3O+

R H

O

H

MHn-1

R H

O

R H

OH

H

ML3

H H

Aluminum Hydrides

1. Lithium Aluminum Hydride (LiAlH4) ! ! • general

LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)H

3 ROH

H Al HH

H

Li O

k1(fast)

H Al HO

H

HO

k2H Al O

O

H

H

H

O

k3

O

k4(slow)

H Al OO

O

H

H

H

O Al OO

O

H

H

H

H

k1 > k2 > k3 > k4

Aluminum Hydrides

1. Lithium Aluminum Hydride (LiAlH4) ! ! !

• reactivity

• examples

- highly reactive, non-selective reducing agent - use with caution! Highly flammable solid! - one equivalent of LiAlH4 delivers 4 equivalents of hydride; still typically used in excess - reduces carboxylic acids, esters, lactones, acid chlorides, anhydrides, aldehydes, ketones to give alcohols - reduces amides, lactams, nitriles, azides, aryl nitro groups to give amines - other reactive FG include: epoxides, alkyl halides, propargyl alcohols, etc.

O

N Me

O

OMeO

H

H LiAlH4THF70%

OH

N Me

OMeO

H

H

Aluminum Hydrides

1. Lithium Aluminum Hydride (LiAlH4) ! ! !

OTIPSOO

OH

OO

OBz

OTIPS1. LiAlH4, THF, rt2. PhCOCl, Et3N, DMAP

90%

O

O

O

H

CO2Me

O

O

HO

H

OH

LiAlH4THF, 65°C

98%

• examples

CO2H

OMeO2CMeO2C

O

H

OH

H

HO

OH

OH

LiAlH4THF, reflux

72%

Aluminum Hydrides

2. Trialkoxyaluminum hydrides: LiAl(OtBu)3H , LiAl(OMe)3H !

- LiAl(OtBu)3H can also be used to reduce acid chlorides to aldehydes

• reactivity

• examples

- much less reactive than LiAlH4

- hindered, will reduce only most reactive FG (aldehydes, ketones, acid chlorides)

O O

O

O

Li(OtBu)3AlHEt2O, 0°C

O OH

O

O

OO

OHC

EtO2C

Li(OtBu)3AlHTHF, -10°C

O

OO

EtO2C O

Amberlite IR-20benzene, 80°C

HOO

O

O

O

O

Aluminum Hydrides

3. Sodium Bis(2-Methoxyethoxy)aluminum Hydride (Red-Al, Vitride, SMEAH)

• reactivity

• examples

- similar reactivity to LiAlH4 - moisture sensitive, but not pyrophoric; thermally stable to 200°C

S

TBSO O S

S

TBSO OH SRedAltoluene, -78°C

80%

BnO OHOBnO OH BnO OH+

OH

OH

Red-AlDIBALLiAlH4 1 : 1

150 : 11 : 13

HAlO

H O OMe

OMeNa

Aluminum Hydrides

4. Diisobutylaluminum Hydride (DIBAL, DIBAL-H)

• reactivity

• examples

- strong reducing agent, but bulky sometimes see selectivity - reduces aldehydes, ketones, esters, epoxides to alcohol; lactones to lactols

- pyrophoric liquid, typically purchased in solution

PMBO N MeO

OMe

TBSODIBALTHF PMBO H

OTBSO

89%

TBSO OEt

ODIBAL

hexanes, -78°C91%

TBSO H

O

TBSOOTBS

CO2MeDIBAL

CH2Cl2, -78°C TBSOOTBS

OH93%

AlH

Aluminum Hydrides

Epoxide Opening: Red-Al vs. DIBAL

Red-Al

BnO OHOBnO OH BnO OH+

OH

OH

Red-AlDIBAL

150 : 11 : 13

DIBAL

Boron Hydrides

1. Sodium Borohydride (NaBH4)

• general

- requires activation:

OH O R'

BH

H HH

δ+

MeOHEtOHiPrOHtBuOH

30 minslow

stable

half life of NaBH4 at 25°C

H B HH

H

NaH B H

OR

HH B OR

OR

HH B OR

OR

OR

k1 k2 k3RO B OR

OR

OR

k4

k1 = k2 = k3 = k4

Boron Hydrides

1. Sodium Borohydride (NaBH4)

• reactivity

• examples

- selective reducing agent - reduces aldehydes and ketones to alcohols; imines to amines - carboxylic acids, esters, lactones, epoxides, nitiriles and nitro groups do not react

OOPiv

IONaBH4MeOH

99%O

OPiv

IHO

O

O

SS

NaBH4EtOH-CH2Cl2

HO

O

SS

Boron Hydrides

2. Lithium Borohydride (LiBH4)

• reactivity

• examples

- reduces aldehydes, ketones, esters, lactones, epoxides - does not react with carboxylic acids, amides, nitriles, etc. - can attenuate reactivity by choice of solvent: in ether > THF > 2-propanol - reacts violently with water

FO2N

HN N

HOTBS

O

O CO2Me LiBH4MeOH-THF-Et2O

FO2N

HN N

HOTBS

O

O OH

83%

MeO2C CO2H

MeHO LiBH4

81% CO2H

MeHO

HO

Boron Hydrides

3. Sodium Borhydride / CeCl3: Luche Reduction

• reactivity

• examples

- selectively reduces α,β-unsaturated carbonyl compounds to allylic alcohols - also good for readily enolizable ketones

N N

OMeO2C

H

HNaBH4, CeCl3MeCN-MeOH

78%

N N

OHMeO2C

H

HH H

O OH OH

+

NaBH4NaBH4, CeCl3

51 : 49>99 : 1

Boron Hydrides

4. Borane (BH3)

• reactivity

• examples

- very selective: CO2H ≈ CHO > ketone >> CO2R ≈ CN - also reacts with alkenes and alkynes

O O

HO2CBH3•SMe2

THF O O

HO

Boron Hydrides

5. Sodium Cyanoborohydride (NaCNBH3)

• reactivity

• examples

- very mild reducing agent; less reactive than NaBH4 - stable in aqueous solution at pH >3

CO2Me

NH2

ONaCNBH3, H2C=O

MeCN-H2O

96%

CO2Me

N

O

Me Me

O

OtBu

OAc

MeO2C

O

TsNHNH2EtOH

NaCNBH3O

OtBu

OAc

MeO2C

NTsN

O

OtBu

OAc

MeO2C

OTsNHNH2NaCNBH3

79%

!

Boron Hydrides

5. Sodium Cyanoborohydride (NaCNBH3)

• hydrazone mechanisms

!

Boron Hydrides

6. Lithium Triethylborohydride (LiEt3BH): Super Hydride

• reactivity

• examples

- very powerful reducing agent stronger than LiAlH4 - excellent reagent for reduction of sulfonates & epoxides

BnO

OH

OTsLiEt3BHTHF BnO

OH92%

HO H

O

LiEt3BHTHF

HO H

OH

Br

H

LiEt3BDTHF H

D

Boron Hydrides

7. Lithium or Potassium Tri-s-butylborohydride (Li(sBu)3BH, K(sBu)3BH): L/K-Selectride

• reactivity

• examples

- bulky reducing agents - reduce aldehyde & ketones, but not carboxylic acid derivatives

M+ HB3

O

CO2E

t

O

O

O

CO2E

t

HO

OLi(sBu)3BHTHF, -78°C

OK(sBu)3BHTHF, -78°C

O

NO

BPSO

O R

O

K(sBu)3BHTHF, -78°C

NO

BPSO

O R

OH

Boron Hydrides

8. Zinc Borohydride ( Zn[BH4]2 )

• reactivity

• examples

- prep (in ether): NaBH4 + ZnCl2 Zn(BH4)2 - ether solution of Zn(BH4)2 is neutral good for base sensitive compounds

OBnO Zn(BH4)2

ether OBnOH

Boron Hydrides

9. Sodium Triacetoxyborohydride ( NaBH(OAc)3 )

• reactivity

• examples

- also known with tetraalkylammonium counterions Me4NBH(OAc)3 - selective reduction of aldehydes in presence of ketones - hydroxyl directed reduction of ketones

CHO

OMe4NBH(OAc)3benzene, reflux

77%

OOH

HO Ph

OHO Ph

OHMe4NBH(OAc)3benzene, reflux

Silyl Hydrides

1. Triethylsilane / Wilkinson’s Catalyst (Et3SiH / (Ph3P)3RhCl)

• reactivity

• examples

- selective 1,4-reduction of enones

O Et3SiH(Ph3P)3RhCl

OSEt3 H3O+ O

Other Reductions of Carbonyls

1. Meerwein-Pondorf-Verely Reduction (MPV)

- reverse of Openauer oxidation - equilibrium determined by choice of solvent

R R'

O

R R'

OHH

OH

Al(OiPr)3

O

Al(OiPr)3

Other Reductions of Carbonyls

2. Clemmensen Reduction

3. Wolff-Kishner Reduction

4. Raney-Nickel

H2NNH, KOtBuEtOH, refluxN

N

NN

O

PhCl

H

CHO

91%N

N

NN

O

PhCl

H

CH3

MeO

O

CO2HZn(Hg)HCl

MeO

CO2H

68%

S S

N

EtNi(Ra)

iPrOH, 70°C N

Et

78%N

EtO

HS SH

BF3•OEt281%