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 Al Li Al H 2 H3Al d+ O O O H2Al Od– R R d– H d+ H H R H R 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 H3B O Solv H R 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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 45 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 R1 R2 H O R1 3 + N R H O R2 O AlL3 H R O • hydrolysis 1 LiAlH R 4 R1 N R N R 2 H R R2

H2Al H 1 1 R R 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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 46 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 95 % O

Nitriles Transformation

R C N R NH2 Postulated Mechanism

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

H • I would prefer lithium cation 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 K NC N O N O NC N O pH 3.0

LDA

Ph Ph Ph I Me N OH LiAlH4 NC N O O H2N NC N

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 47 Nitro Group

Transformation

R NO2 R NH2 Example

O NO NO NH MeO 2 NH4OAc 2 LiAlH4 2 + Ar Ar

Hydrogenolysis

Transformation

R X R X = halide, sulfonate ester, good leaving group

Examples Cl

C8H17 O C8H17 LiAlH , reflux, N N O 4 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

1 1 RCHOR RCH2OHR

RCOCl RCH2OH

1 1 RCH CHR RCH2 CHR O OH

1 1 RCO2R RCH2OH + R OH

RCO2H RCH2OH

1 1 RCH2NR 2 or (RCH2OH RCONR 2 1 + HNR 2)

RCº N RCH2NH2 Hardest Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 48 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 Red-Al, CuBr O O O (CH2)4OTHP (CH2)4OTHP

O O Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 49 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

O

• 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

• NaBH4 can reduce imides but only as far as the aminol • Allows an elegant route to bicyclic alkaloids

O O O OH N NaBH4 N CF3CO2H O N

SiMe3 SiMe3

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 50 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, Et3N 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 O H H HPMA, 70˚C 1 hr H H 70 % O O I

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 51 Effect of Counterions / Additives

• Changing the counter-cation can have a profound effect on the reactivity of NaBH4 • Addition of LiBr, AlCl3 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 MeOH N3 CO2Me N3 CO2Me

• Two reasons: Co-ordination of the carbonyl and cerium result in increased hardness and more d+ 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

1 1 RCO2R RCH2OH + R OH

RCOCl inert Hardest

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 52 Diisobutylaluminium Hydride DIBAL-H (iBu2AlH) • 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)3CO2H -78˚C 80 %

C5H11 C5H11 C5H11 THPO H H H OTHP OTHP OTHP OTHP OTHP

• Nitriles to aldehydes

iBu2Al O N N

+ H DIBAL-H H H O O 3 O O

O O O H 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 R O O H Al O Al Al O H R1 OR H R1 H R1 H RO R1 OR

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 53 3 3 4 4 H Bu) t 3 3 OMe) O BH LiAlH NaBH LiBEt Hydrog. DIBAL-H LiAlH( LiAlH( ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ RCHO® RCH OH 2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ RCOR’® RCHOHR’ ✓ ✗ ✓ ✓ ✓ ✓ ✓ ✓ RCOCl® RCH OH 2 ✗ ✓ ✓ ✓ ✓ ✓ ✓ Lactone® diol ✓ / ✗ ✗ ✓ ✓ ✓ ✓ ✓ ✓ Epoxide® alcohol ✓ / ✗ ✗ ✓ ✓ ✓ ✓ ✓ RCO R’® RCH OH / R’OH ✓ / ✗ ✓ / ✗ 2 2 ✗ ✓ ✗ ✓ ✓ ✗ ✓ ✗ RCO H® RCH OH 2 2 ✗ ✓ ✗ ✓ ✓ ✓ ✓ ✓ RCONR’ ® RCH NR’ 2 2 2 ✗ ✓ ✗ ✓ ✓ ✓ ✓ RCº N® RCH NH ✓ / ✗ 2 2 ✗ ✗ ✗ ✓ ✓ ✗ ✓ ✓ RNO ® RN 2 2 ✗ ✓ ✗ ✗ ✗ ✓ ✗ ✓ RCH=CHR’® RCH2CH2R’

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 54 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 a -to the carbonyl this can control the approach of the hydride • rotate until largest substituent perpendicular to carbonyl

O O Me O

Ph º Me H H H R R • view along bond

• hydride attacks along Bürghi-Dunitz angle • attacks passed smallest substituent OH OH Me Ph º H R

Felkin–Anh Model H • 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 º H Ph R H R H Ph R Ph H R H • nucelophile attacks past smallest substituent

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 55 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 º 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 Bu B, NaBH 3 4 B 95 % O Bu H O

• largest substituents in psuedo-equatorial conformation

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 56 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 bulky toluene group Tol R Ln Zn O O O OH DIBAL-H ZnCl S S 2 Tol R Tol R • conformation H controlled by chelation

• Auxiliary removal

O OH OH Li / NH3 S Tol C7H15 C7H15

• reduce sulfoxide OH O OH H O KOH O 1. LiAlH4 S 2. Me OBF S C8H17 Tol C8H17 3 4 Tol C8H17

• 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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 57 C8H17 C8H17 O H CO2Me + Al CO2Me O OEt O Li OH

• Proposed transition state model • orientation of BINOL system • unsaturated group controls carbonyl approach is equatorial R O

H Al Li • ethoxide forms bridge to allow C8H17 O O O Et 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 • catalytic • stoichiometric reductant

Ph O Ph OH Br BH •THF Br + O 3 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 H2B H H H 2 RL RL

• large substituent organised away from oxazaborolidine Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 58