REDUCTIONS

Invaluable process
Can be used to remove functionality from a molecule
A versatile method for introducing stereocentres
Formally reduction is the gain of electrons but it is more easy to visualise it as the gain of
hydrogen (although this far from mechanistically correct)

Metal Hydrides
The most common metal hydrides are lithium aluminium hydride (LiAlH4) and sodium
borohydride (NaBH4)
There are differences mechanistically
In many cases the lithium cation is vital for reaction
number of repetitions
depends on sterics of
the carbonyl

lithium activates
carbonyl
Li
H2Al

H2Al

Li

H3Al

addition of a crown compound

can prevent reduction by
removing lithium

Al

O
R

R
R
4

each addition is slower

alkoxide electron-withdrawing
group so reduces reactivity of
hydride

In NaBH4 reactions cation is not important but solvent can be

not concerted
Solv
HH

R
Solv

H
R1

H
O

OH

Solv

H 3B

Solv

R1

multiple reductions occur

alkoxide makes hydride less reactive

Chemoselectivity
LiAlH4 very reactive, will reduce most carbonyl functionality
Care should be taken as it will react with acidic protons (RCO2H, RCH2OH, RCH2NH2)
NaBH4 much milder, can be used to selectivily reduce aldehydes, ketones and acid
chlorides in the presence of other functionality
Properties of both reagents can be altered by the addition of substituents
Some of these will be discussed below

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Lithium Aluminium Hydride LiAlH4

General
All carbonyl groups are reduced
Many other functional groups are reduced
Reaction with acidic protons generates H2:
3 LiAlH4 + 4 RCO2H

LiAl(OCH2R)4 + 2 LiAlO2 + 4 H2
Amides

Behave unpredictably (in my opinion)

hemiketal
or aminol

OH
R1

LiAlH4

R2

O
R1

H
N

R
R

N
R2

H3O

AlL3

R2

O
H

hydrolysis

R
H

R2
H2Al
R1

H
R1

N
R2

R2
H

Which path is followed is a result of sterics and electronics around the amine
Personally I have found it is also effected by solvent, temperature, day of the month
Enones
Another problematic functional group
H

1,4-addtion
R1

O
R2

1,2-addition

Al H

R1

O
R2

R1

OH
R2

Very dependant on the exact structure of the enone

Advisable to choose a different reagent

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Epoxides
O
R

R1

OH

LiAlH4

R1

R2

R2

Hydride normally delivered to the least hindered end

Epoxides are more readily reduced than esters
Epoxides are less readily reduced than aldehydes / ketones

1. LiAlH4, Et2O, rt
2. H3O+
95 %

O
O

OH
O

Nitriles
Transformation
R

C N

NH2

Postulated Mechanism
Li
N

AlH3

AlH3

N
R

quite franky a little bit

of a mystery where
the proton comes from
I would prefer lithium cation
being present until w/u

H
R

NH2

AlH2

N
H

AlH2
2

Nitriles are easily introduced to a molecule

Nitriles are useful in aiding CC formation by stabilising anions
Ph

Ph

K NC
pH 3.0

Ph
O

NC

LDA
Ph

H 2N

Ph
N

OH

LiAlH4

NC

Ph
N

Me
NC

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Nitro Group
Transformation
R

NO2

NH2

Example
O
MeO

NO2

NH4OAc

LiAlH4

NO2

Ar

Ar

NH2

Hydrogenolysis
Transformation
R

X = halide, sulfonate ester, good leaving group

Examples
Cl
C8H 17
C8H 17
N

Cl

selective protection
of least hindered
primary alcohol
OH

LiAlH4, reflux,
26 hrs 72 %

OH

OH

TsCl, Pyr

OH

OTs

LiAlH4

Ease of Reduction of Functional Groups with LiAlH4

RCHO

RCH2OH

RCHOR1

RCH2OHR1

RCOCl

RCH2OH

RCH CHR1
O

RCH2 CHR1

RCO2R1

RCH2OH + R1OH

RCO2H

RCH2OH

RCONR12

RCH2NR12 or (RCH2OH
+ HNR12)

RCN

RCH2NH2

Easiest

OH

Hardest

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Alkoxyaluminate Reducing Systems

By altering both the sterics and electronics of the substituents
on LiAlH4 it is possible to tune the reactivity of metal hydrides
The addition of alkoxides reduces the reactivity of the hydride
due to their electron-withdrawing properties
This enables chemoselective reactions
LiAlH(OEt)3
Reduces nitriles to aldehydes
H

LiAlH(OEt)3

CN

H3O

Al(OEt)3

iPr

LiAlH(OtBu)3
Will reduce ketones, aldehydes and acid chlorides but little else
Allows good selectivity
only ketone reduced
ester untouched

OH

LiAlH(OtBu)3
H
H

H
H

AcO

AcO

both ketones reduced

bromide untouched
O

OH

LiAlH(OtBu)3
O
Br

HO

Br

Sodium Bis(2-methoxyethoxy)aluminium Hydride (Red-Al)

O

H
Na

Al
H

O
O

Similar selectivity to LiAlH4

But more stable and soluble (so why it is sold as the
most viscous gum known to mankind is anyones
guess)
Can achieve 1,4-reductions in the presence of CuBr
Probably proceeds via the copper hydride
copper very
useful for
1,4-additions
O
O

Red-Al, CuBr
O

(CH2)4 OTHP

(CH2)4 OTHP

O
O
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Sodium Borohydride NaBH4

Much less powerful reducing reagent
Selective for aldehydes, ketones and acid chlorides
Does not touch epoxides, esters, acids and nitriles

OMe

O
TBSO

OTBS

OTBS O

CO2Me

NaBH4

lactone survives

OMe

O
TBSO

OTBS

OTBS O

CO2Me

ketone reduced

OH

ozonolysis cleaves
electron-rich double bond

reduce only aldehyde

and not ester

allows lactone
formation

OH

H3O

1. O3, MeOH
2. NaBH4

TMSO
H

TMSO2C

O
O

NaBH 4 can reduce imides but only as far as the aminol

Allows an elegant route to bicyclic alkaloids

NaBH4

SiMe3

OH

CF3CO2H

SiMe3

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Substituents on Boron
Super Hydride LiBHEt3
Addition of electron-donating groups (inductive effect) increases reducing power
One of the best reducing reagents
Especially good at hydrogenolysis (superior to LiAlH4)
Ph

Ph

1. MeSO2Cl, Et 3N
2. LiBHEt3

HO

K & LSelectride (K

or Li

BH(

)3)

Very reactive hydride donors due to inductive effect

Bulk makes them very good at diastereoselective reactions (substrate control)

existing stereocentres
control formation of new
stereocentre

tBu
Si

tBu

O
PMBO

Si

tBu

DMP
PMBO

OH

tBu

OMe

tBu
Si

tBu

L-Selectride
95 % 2 steps PMBO

OH

OMe

OMe

Sodium Cyanoborohydride NaBH3CN

Very unreactive therefore very selective
Will reduce iodides, bromides and tosylates in HMPA even in the presence of carbonyls
Ketones can be reduced BUT in acid media (ph 3-4)

H
O
H
O

NaBH3CN,
HPMA, 70C 1 hr
70 %

H
O
H

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Effect of Counterions / Additives

Changing the counter-cation can have a profound effect on the reactivity of NaBH4
Addition of LiBr, AlCl 3 or ZnCl2 results in more powerful reducing agent (due to higher ionic
potential)
Addition of CeCl3 (Luche Reduction) gives very selective 1,2-reduction of conjugated
aldehydes and ketones
O
N3

CO2Me

OH

NaBH4CeCl3
MeOH

N3

CO2Me

Two reasons:
Co-ordination of the carbonyl and cerium result in increased hardness and more +
character thus more reactive to "H"
Tethering effect "intramolecularises reaction"
Reaction is under kinetic control (irreversible)
H H
H

Ce
O

Use of Ni2+ or Co2+ results in a reversible complexation and a thermodynamically

controlled reaction which results in predominantly 1,4-reduction

Borane / Diborane B2H6

Very reactive
But also strong Lewis acid
Co-ordinates to electron-rich centres which alters its properties considerably
Complimentary to LiAlH4 (reverses much of its reactivity)
O

O
O

CO2H

BH3

OH
O

RCO2H

RCH2OH

RCOR1

CHOHR1

RCN

RCH2NH2

RCO2R1

RCH2OH + R1OH

RCOCl

inert

Easiest

Hardest

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Diisobutylaluminium Hydride DIBAL-H (iBu2 AlH)

Strong reducing agent
But frequently possible to use it to reduce only one "oxidation state"
Esters can be reduced to aldehydes
N

H
N
H H

DIBAL-H
-78C

76 %

N
H H

CO2Me
HO

N
H H

HO

HO

Lactones reduced to lactols

O

OH

DIBAL-H
-78C

Wittig
80 %

C5H 11
H
OTHP

HO

C5H 11

C5H 11

OTHP

THPO

H
OTHP

(CH2)3 CO2H

OTHP

OTHP

Nitriles to aldehydes
iBu 2Al

DIBAL-H

H3O+

H
O

O
O

MECHANISM FOR DIBAL-H REDUCTIONS

The mechanism of the DIBAL-H reduction different to that of other metal hydride reagents
Primarily because it is a Lewis acid. This means it needs to coordinate to a Lewis base first
before it is activated then it delivers the hydride intramolecularly
Unlike the other metal hydrides it is an electrophilic reagent
R
O

H
Al

R1

OR

Al

Al

H
R1

OR

O
R1
RO

AlR2
O
H

R1

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RCNRCH2NH2
RNO2RN2
RCH=CHRRCH2CH2R

LiAlH4

LiBEt3H

DIBAL-H

Hydrog.

RCO2HRCH2OH
RCONR2RCH2NR2

LiAlH(OMe)3

RCO2RRCH2OH / ROH

LiAlH(OtBu)3

Lactonediol
Epoxidealcohol

BH3

RCOClRCH2OH

NaBH4
RCHORCH2OH
RCORRCHOHR

/
/

/ /

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STEREOSELECTIVITY
The stereocontrol of carbonyl reduction is of great importance
A number of ways to control it
SUBSTRATE CONTROL
If the substrate contains a chiral centre -to the carbonyl
this can control the approach of the hydride
rotate until largest
substituent perpendicular to
carbonyl

O
Ph

Me

Me

view along bond

hydride attacks along Brghi-Dunitz angle

attacks passed smallest substituent

OH
Ph

OH

Me
H

R
H

FelkinAnh Model
nucleophile attacks carbonyl
passed smallest group

Represents transition state

M

large group always

perpendicular to carbonyl

smallest group eclipses

Burghi-Dnitz angle

Nuc

Note: the larger the hydride source the better the selectivity
Hence the usefulness of the Selectrides
CramChelation Control
If a heteroatom is present chelation is possible and the transition state conformation is
changed.
Predicted by Cramchelation model
chelation controls conformation
Li
OH
MeO
H
Ph

MeO O

Ph

LiAlH4

H
Ph
R

OMe
H

MeO
H

Ph

OH
R

nucelophile attacks past smallest substituent

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1,3-Stereochemical Induction
Very useful transfer of sterochemical information
Use inconjunction with stereoselective aldol reaction allows a powerful entry to 1,3-diols

O
N

TMSO

OTMS

N
Cu

Ph

OH

tBuO

OBn

tBuO

Ph

5 mol %, -90C
85 %

OBn

Me4NBH(OAc)3
OTES

OH

OH

tBuO
BnO

OBn

Diastereoselectivity achieved by internal delivery of the hydride

The borohydride reagent has a very poor counter-ion so rapidly co-ordinates to the oxygen
lone-pair
Acetate ligand readily displaced
substituents adopt
psuedo-equatorial
orientation

Mechanism

BnO

BnO

O
AcO

B H
OAc

HO
OtBu

OtBu
H

OH

OH

OH

tBuO
OBn

approach via Burghi-Dunitz angle

A powerful extension of this methodology allows the reversal of diastereoselectivity
Preco-ordination with a Lewis acid results in external hydride delivery
attack from the
least hindered face
H
O

OH

Bu3B, NaBH4
95 %

Bu

OH

B Bu

OH

largest substituents in
psuedo-equatorial conformation

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Chiral Auxiliary
Really a more specific example of substrate control
A chiral unit is introduced into a prochiral molecule to induce a diastereoselective reaction
The unit can then be removed at later stage to give an optically enhanced product
preferred conformation
has dipoles opposed

Tol
O

O
O

R
Tol

DIBAL-H
O
Tol

hydride approaches
from opposite side to
bulky toluene group

OH

R
O

DIBAL-H
ZnCl2

Tol

Ln
Zn

O
R

conformation
controlled by chelation

Tol

OH

Auxiliary removal
O

OH

Tol

OH

Li / NH3
C7H 15

C7H 15

reduce sulfoxide
O
Tol

OH

1. LiAlH4
2. Me3OBF4

C8H 17

O
Tol

OH

KOH

O
C8H 17

C8H 17

cation formation

Chiral Reagents
Sometimes substrate has no chiral centre and / or chiral auxiliary introduction / removal
incompatible with existing functionality
To overcome these short-comings chiral reagents introduced
largest substituent adopts
pseudo-equatorial
conformation

smallest group
has 1,3-interaction
RS
O
B

H
B O

+
RL

RS

OH

RL
RL

RS

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C8H 17

C8H 17
CO2Me

O
Li

Al

CO2Me

OEt
OH

Proposed transition state model

orientation of BINOL system
controls carbonyl approach

unsaturated group
is equatorial

O
H Al
O Li O O
Et

C8H 17

ethoxide forms bridge to allow

6-membered transition state

Chiral Catalysis
Ultimate goal is to generate enantiopure material from only a catalytic source of chirality
Possibly the most successful general catalyst for the reduction of ketones is the CBS
oxazaborolidines
stoichiometric reductant
catalytic
Ph

O
Br

Ph

OH

BH3THF

Br

B
Me

Mechanism
Ph

interaction of amine and borane

activates hydride source
increase Lewis acidity of endo boron
Ph

Ph

N B

Ph

N B

Me

BH3 Me

endo boron co-ordinates carbonyl

both activates carbonyl and
spatially arranges it
Ph

Ph
O

Ph

Me
B
O
B H
H2

O
RS

Ph

RL

Me
B

RS

O
H 2B H

RL

large substituent organised

away from oxazaborolidine
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