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
• lithium activates depends on sterics of
carbonyl the carbonyl
Li H
H H2Al Li H3Al Al
δ+ O O O
H2Al O δ–
R R
δ– H δ+ H
R H
R H
R
R R R
4

• addition of a crown compound

• each addition is slower
can prevent reduction by
• alkoxide electron-withdrawing
removing lithium
group so reduces reactivity of
hydride
• In NaBH4 reactions cation is not important but solvent can be
• not concerted
Solv O H
R HH H
Solv O H O H B O Solv OH
R1 H R
H 3B O Solv
H
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

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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 H
or aminol N
OH R 1 R2
H3O +
R1 R
N
H O
R2
O AlL3 H R
O • hydrolysis
1
R LiAlH4
N R R1 R
N
H
R2
R2

H2Al H
R1
R1 R N R
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 H
• 1,4-addtion • 1,2-addition
H Al H

R1 O R1 O R1 OH

R2 R R2 R R2 R H

• Very dependant on the exact structure of the enone

• Advisable to choose a different reagent

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 Epoxides
O R1 H OH
LiAlH4
R1
R R2 R 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 OH
O
2. H3O+
O O
95 %

Nitriles
Transformation
R C N R NH2

Postulated Mechanism

Li
H AlH3 H
N AlH3
N N AlH2
C H
R R
R 2
• quite franky a little bit
of a mystery where
the proton comes from

• I would prefer lithium cation H

H
being present until w/u N AlH2
R NH2 H
R
2

• Nitriles are easily introduced to a molecule

• Nitriles are useful in aiding C–C formation by stabilising anions

Ph Ph Ph

O K NC O O
N N NC N
pH 3.0

LDA
Ph Ph Ph
OH I Me
N LiAlH4 NC N O O
H 2N NC N

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

47
 Nitro Group

Transformation

R NO2 R NH2

Example
O
MeO NO2 NH4OAc NO2 LiAlH4 NH2
+ Ar Ar

Hydrogenolysis

Transformation

R X R

X = halide, sulfonate ester, good leaving group

Examples
Cl

C8H 17
C8H 17 N O
O LiAlH4, reflux,
N
26 hrs 72 %
Cl
O O
• selective protection O O
of least hindered
primary alcohol

OH OH OH OTs OH
TsCl, Pyr LiAlH4

Ease of Reduction of Functional Groups with LiAlH4

RCHO RCH2OH Easiest

RCHOR1 RCH2OHR1

RCOCl RCH2OH

RCH CHR1 RCH2 CHR1

O OH
RCO2R1 RCH2OH + R1OH

RCO2H RCH2OH

RCH2NR12 or (RCH2OH
RCONR12
+ HNR12)

RC≡N RCH2NH2 Hardest

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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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 O
LiAlH(OEt)3 H3O
CN N Al(OEt)3
iPr H

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

LiAlH(OtBu)3
H H

H H H H
AcO AcO

• both ketones reduced

• bromide untouched
O OH

LiAlH(OtBu)3

O HO
H H
Br Br

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

H O
O
Na Al
O
H 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 O (CH2)4 OTHP

O O
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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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

O
OMe
O OTBS

TBSO O O O O OTBS O
CO2Me

• lactone survives NaBH4

O
OMe
O OTBS

TBSO O O O O OTBS O
CO2Me

• ketone reduced
OH

• ozonolysis cleaves • reduce only aldehyde

electron-rich double bond and not ester • allows lactone
formation
OH

1. O3, MeOH H3O O

TMSO 2. NaBH4
O
H H H
TMSO2C

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

• Allows an elegant route to bicyclic alkaloids

O N O NaBH4 O N OH CF3CO2H
O N

SiMe3 SiMe3

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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

HO 1. MeSO2Cl, Et 3N
2. LiBHEt3

K & L–Selectride (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 tBu tBu
O O O
Si Si Si
tBu tBu tBu
O O O
DMP L-Selectride
PMBO PMBO 95 % 2 steps PMBO
OH O OH

N O N O N O
OMe 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)

O O

H H
NaBH3CN,
O HPMA, 70˚C 1 hr O
H H H H
70 %
O O
I

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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 OH
NaBH4•CeCl3
N3 CO2Me MeOH N3 CO2Me

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

H H
H
B
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 H O H
BH3 OH
CO2H
O O O O

RCO2H RCH2OH Easiest

RCOR1 CHOHR1

RCN RCH2NH2

RCO2R1 RCH2OH + R1OH

RCOCl inert Hardest

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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 N N
DIBAL-H
H -78˚C H 76 % H H
N N N
H H H H H H
CO2Me
HO O HO HO O

• Lactones reduced to lactols

O OH
HO
DIBAL-H Wittig H
O O (CH2)3 CO2H
-78˚C 80 %
C5H 11
C5H 11 C5H 11
THPO H
H H OTHP
OTHP OTHP OTHP OTHP

• Nitriles to aldehydes

iBu 2Al O
N N

H
O
DIBAL-H H H3O+
O
O
O O
H O
H
H
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 AlR2
O H R O O
Al
Al Al O H
R1 OR H R1 H R1 H
RO
R1 OR

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 LiAlH(OtBu)3

LiAlH(OMe)3

DIBAL-H

Hydrog.
LiBEt3H
NaBH4

LiAlH4
BH3
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
RCHO→RCH2OH
RCOR’→RCHOHR’ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
✓ ✗ ✓ ✓ ✓ ✓ ✓ ✓
RCOCl→RCH2OH
Lactone→diol ✗ ✓ ✓/✗ ✓ ✓ ✓ ✓ ✓
Epoxide→alcohol ✗ ✓ ✓/✗ ✓ ✓ ✓ ✓ ✓
✗ ✓/✗ ✓/✗ ✓ ✓ ✓ ✓ ✓
RCO2R’→RCH2OH / R’OH
✗ ✓ ✗ ✓ ✓ ✗ ✓ ✗
RCO2H→RCH2OH
✗ ✓ ✗ ✓ ✓ ✓ ✓ ✓
RCONR’2→RCH2NR’2
RC≡N→RCH2NH2 ✗ ✓ ✗ ✓ ✓ ✓/✗ ✓ ✓
RNO2→RN2 ✗ ✗ ✗ ✓ ✓ ✗ ✓ ✓
✗ ✓ ✗ ✗ ✗ ✓ ✗ ✓
RCH=CHR’→RCH2CH2R’

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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 α-to the carbonyl
this can control the approach of the hydride
• rotate until largest
substituent perpendicular to
carbonyl

O
O Me

≡
O

Ph
Me
H H H R
R
• view along bond

• hydride attacks along Bürghi-Dunitz angle

• attacks passed smallest substituent
OH

≡
OH Me

Ph
H R
H
Felkin–Anh Model
• nucleophile attacks carbonyl
• Represents transition state
passed smallest group

O
M

• large group always

L
• smallest group eclipses perpendicular to carbonyl
Burghi-Dünitz angle Nuc S
R

•Note: the larger the hydride source the better the selectivity
• Hence the usefulness of the Selectrides
Cram–Chelation Control
• If a heteroatom is present chelation is possible and the transition state conformation is
changed.
• Predicted by Cram–chelation model
• chelation controls conformation
Li
OH
MeO O

≡
MeO O Ph OMe MeO OH
LiAlH4
H R H R
Ph H R H Ph
Ph H
R H
• nucelophile attacks past smallest substituent
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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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 O
N
N Cu N
O O OH
TMSO OTMS O Ph Ph
+ OBn tBuO
tBuO
5 mol %, -90˚C OBn
85 %
Me4NBH(OAc)3

OTES
O OH OH

tBuO
BnO
O O 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
Mechanism
• substituents adopt
psuedo-equatorial
orientation

≡
BnO BnO O OH OH
O HO
AcO
B H
OtBu H OtBu tBuO
H H
OAc O O OH O 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 H Bu OH OH
Bu3B, NaBH4
O B Bu
95 % H
O

• largest substituents in
psuedo-equatorial conformation

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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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 OH
S
O R S
DIBAL-H Tol R
H
O O • hydride approaches
from opposite side to
S
Tol R Ln bulky toluene group
Zn
O O O OH
DIBAL-H
ZnCl2 S S
Tol R Tol R
• conformation H
controlled by chelation

• Auxiliary removal

O OH OH
Li / NH3
S
Tol C7H 15 C7H 15

• reduce sulfoxide
O OH H OH
1. LiAlH4 O KOH O
S 2. Me3OBF4
Tol C8H 17 S C8H 17
Tol 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

• smallest group pseudo-equatorial
has 1,3-interaction conformation
RS

O H RL OH
B +
B O
RL RS RL RS

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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C8H 17 C8H 17
CO2Me O H CO2Me
+ Al
O OEt
O Li OH

• Proposed transition state model

• orientation of BINOL system
• unsaturated group controls carbonyl approach
is equatorial
R O

H Al • ethoxide forms bridge to allow

C8H 17 O Li O O 6-membered transition state
Et

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
• catalytic • stoichiometric reductant

Ph
O Ph OH
Br BH3•THF Br
+ O
N
B
Me

• interaction of amine and borane

Mechanism activates hydride source
• increase Lewis acidity of endo boron
Ph Ph
Ph Ph

O O
N B N B

Me BH3 Me

• endo boron co-ordinates carbonyl

• both activates carbonyl and
spatially arranges it

Ph Ph

O Me O Me
B B
N RS N RS
Ph O Ph O
B H H 2B H
H2
RL RL

• large substituent organised

away from oxazaborolidine
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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