OXIDATION OF C–H BONDS Allylic Oxidation Reagent:

SeO2

Transformation:

R R OH • a series of General Mechanism sigmatropic rearrangements

H O hydrolysis OH O R O R Se Se Se R OH R O OH

• SeO2 toxic and hard to remove from product • Catalytic variant developed using TBHP as stoichiometric co-oxidant • Problem of side-reactions especially if alkene in ring • Reaction also functions with other reagents such as PDC

Guidelines for Predicting Product 1. Hydroxylation occurs a to the most substituted end of alkene 2. Order of oxidation is CH2>CH3>CH 3. If alkene in ring, oxidation will occur in ring if possible (but Bredt's rule applies) 4. Rearrangement products can and will (more often than not) be formed • wrong Use in Synthesis stereochemistry

O HO O O O H H

O SeO2, O OH HCOOH OH O 50% O

O • selective by guideline 1 O • selective by guideline 2 O O

O CO2Et

O SeO2 75 %

AcO AcO H H • guideline 2 Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 32 Related reaction: Formation of Dicarbonyl Compounds Transformation: O O SeO2 / H2O 72 % Ph Ph CHO

Mechanism

OH OH O Se SeO2 + H2O Se O O H O OH R H R

O O O O R Se R H OH Use in Synthesis

NH NH

SeO2 CHO N N H H O O O O

• note epimierisation

N O N OH

N O N H H O O O

What have we learnt? • The position a -to a double bond can be oxidised • A set of guidelines allow some degree of predictablilty to this reaction • The reaction proceeds via a series of sigmatropic rearrangements • A related reaction results in the synthesis of dicarbonyl compounds

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 33 Oxidation of Activated C–H Bonds -Hydroxylations Reagent: Davis' Oxaziridine O SO2Ph Ph N Oxodiperoxymolybdenum(pyridine)- (hexamethylphosphoric triamide) MoOPh O O Mo O O O pyr HMPA

Transformation: O O R R OH General Mechanism Oxaziridine Ph OH R R 1 1 R O O NSO2Ph R SO2Ph O Ph N R O M R1 NSO Ph O Ph 2

MoOPh

OH O R 1 R O R1 R R1 O O R Mo O O O O O O O O M Mo pyr HMPA M O O O Mo O pyr HMPA O pyr HMPA

Use in Synthesis

CH OBn CH OBn O 2 O 2 H 1. LDA OH 2. Davis' oxaziridine O O H 70 % H OMe OMe

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 34 Use in Synthesis

OTBS OTBS 1. KHMDS 2. Davis' oxaziridine O O O H 83 % H O OBn OH OBn

CHO O OHC OH O

O 1. LDA O 2. MoOPh

H H

O O HO

1. LDA 2. MoOPh H O O O O

• Chiral oxaziridines can be prepared allowing reagent control asymmetric reactions

O O NaHMDS Ph Ph Ph e.e. = 94.5 % Ph OH

N S O O2 Reaction with other Stabilised Anions

H H

tBuOK TolSO2 Davis' O oxaziridine O O

H

TolSO2 O O

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 35 Reaction with other Stabilised Anions

O O N O LDA Nef-like Reaction MoOPh

LDA base MoOPh CN HO CN O

Li OH OSEM OSEM OSEM

N BuLi N Davis' N N N oxaziridine N 22% SEMO SEMO SEMO Li OH

• Use of oxaziridines preferable to MoOPh (results & toxicity) but this is substrate dependant

What have we learnt? • You can readily introduce hydroxyl group a -to functionality • Reaction can be achieved asymmetrically • Reaction can be used to oxidatively cleave functionality

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 36 Miscellaneous C–H Oxidations • Some recent developments in C–H oxidation • Katsuki has used Mn-salen complexes to perform enantioselective C–H oxidations

H OH R R 0.02 eqiv. cat., X = O, NP X PhIO, –30˚C, X yield = 41-61 % e.e. = 82-90 % R C H Cl R 6 5 H

N N Mn O O PhPh

Oxidation of Unactivated C–H Bonds Dioxirane Strikes Back • Dioxiranes are amazingly reactive (sometimes)

H O OH O

H H • Can be quite slow so more reactive dioxiranes have been developed: F3C O O O 18 min., –20˚C 98%

F3C O OH O HO 20 equiv., DCM / OH H2O, –20˚C HO 74 %

Possible Mechanism

H O H OH O O O + + R R O R R R R R R R Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 37 MISCELLANEOUS OXIDATIONS Ozonolysis

Reagent:

O3, DMS or PPh3 or LiAlH4

Transformation:

R R O

R R R R

General Mechanism

R R R O R O O O O O O R O R O O R R O O ozonide • Ozonide then has to be broken down (they can be isolated but not advisable)

Decomposaition with DMS, PPh3 or H2 Pd / C R O O PPh3 + O=PPh3 or (DMSO) O R R O

Reductive Decomposaition with LiAlH4, NaBH4

• Quite shockingly this gives the alcohol

Oxidative Decomposition with peracids or hydroperoxides

R O O H2O2 O R OH R O

Selectivity

• More electron-rich alkenes react faster • Enol ethers give esters on ozonolysis

OMe OMe O , DMS 3 O

CHO

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 38 Use in Synthesis

O NSO2Ar NHNH2 Fischer CO2Et indole OMe + N OMe H N MeO Ac H OMe OMe OMe

• lactam formation • attacks and isomerisation electron-rich O3, AcOH alkene N NSO2Ar NSO2Ar

CO Et H 2 HCl CO2Et N H H N CO2Me N CO2Me Ac H CO Me O O 2 H O

• Alternatively… The Lemieux–Johnson Reagent Reagent:

OsO4, NaIO4

Transformation:

R R O

R R R R

General Mechanism • Use catalytic quantities of osmium which is reoxidises by the periodate • Dihydroxylation as before (vide supra) • NaIO4 cleaves the diol… • proton transfer

O R OH O OH R O O O R O O I O I I O O O O R OH O R O R R OH H2O

What have we learnt? • Alkenes can be oxidatively cleaved in a number of ways

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 39 Baeyer-Villiger Oxidation Reagent:

RCO3H

Transformation:

O O R1 R R1 R O

General Mechanism

O OH O H O R R1 R R1 R3 O H

H O O R 1 R1 O R R O 3 O R CO2H R3 O

Migratory aptitude • Unsymmetric ketones have a choice of which substituent will migrate • Normally most nucleophilic group / group that can stabilise d+ charge best migrates t-alkyl > cyclohexyl » secondary alkyl » benzyl > vinylic > primary alkyl > methyl • Reason…

H O • migration is concerted R O d+ • during migration 2 e– spread over 3 atoms R1 O \ any group stabilising the electron defficiency will be favoured R3 O

• As the migration is concerted (bonds broken and formed at same time) it occurs with retension of stereochemistry

EtO2C EtO2C CF CO H OAc 3 3 OAc NaH2PO4 DCM O O 85 % O OAc OAc

• retension of stereochemistry

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 40 • The methyl group has a very poor migratory aptitude, consequently the Baeyer-Villiger reaction is an excellent way to make acetates • Acetates are readily cleaved, therefore the Baeyer-Villiger is equivalent to: O R OH R Use in Synthesis • Problem: if alkenes are present a possible competative reaction is epoxidation • Conditions: under acidic conditions Bayer-Villiger favoured • Conditions: mCPBA + inert solvent at low temperature encourages epoxidation

MeO MeO MeO O O O

(COCl)2 tBu Bu3N tBu tBu

H NBu3 • forms C • forms acid Cl ketene CO2H O chloride O • HCl generated on ketene formation Baeyer-Villiger H MeO O O O

Ph3CO3H tBu tBu H tBu H H O H O H O H O

O HO HHO O O H O tBu O OH H O O Catalytic Asymmetric Baeyer-Villiger

O O H H O , tBuCHO H O H 2 Yield = 62 % e.e. = 91 % H O H 97SL1151 O2N tBu N

O Cu 2 tBu

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 41 Tamao-Fleming Oxidation Reagent:

KF, KHCO3, H2O2 or EX / RCO3H / base

Transformation:

SiR2X OH

General Mechanism

OH X Si Si O OH X Si O O X

X = heteroatom or H • concerted migration so retension of stereochemistry Use in Synthesis • Silyl groups relatively unreactive • C–Si bond only easily broken when carbon functionality allows it eg:

Me Si X 3

• Silyl group very useful - can be thought of as super-proton - it activates double bonds, encourages substitution rather than addition, controls regio- and stereochemistry (97CR2063) Tamao Oxidation

SiR2X OH KF, KHCO3, H2O2

Fleming Oxidation • More useful silyl groups BUT harsher conditions

PhSiMe2 SiMe2X OH EX RCO3H, + 2+ E = H , Hg , Br2 base

O O O 1. BF3 O O 2. H2O2, O NaHCO , KF 1. BuLi 3

2. SiPh2Cu C5H11 C5H11 C5H11 H H BzO BzO BzO H OCONHPh SiPh2R OH

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 42 Wacker-Type Oxidations Reagent:

O

PdCl2(cat), or CuCl, O2

O Transformation: O R R General Mechanism

PdCl2Ln R OH Pd(2)Cl2Ln OH2 R PdClLn R

PdClLn R b-elimination

O OH

O O R R +

Pd(2)Ln Pd(0)Ln PdHClLn

HCl HO OH • re-oxidises palladium Use in Synthesis

O CO2Me OMe OTBS

• allows these 2 stereocentres 20 mol% to be set-up via the reliable PdCl2, CuCl, Brown or Roush crotylation O2, H2O / DMF 85 %

O CO2Me O OMe OTBS

• Problems: alkene isomerisation chlorination (especially if CuCl2 used) regiochemistry acid sensitivity of molecule as HCl produced

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 43 Modifications to the Wacker Reaction Smith's Modifications

O standard Wacker + considerable acetonide hydrolysis O O 57 % O O

• HCl destroying product • Replace CuCl with Cu(OAc)2 - no HCl generated only the weaker AcOH - allows catalytic copper to be used making work-up easier • Yield increased to 86 % Oxo-mercurial Variant

PhSO2 PhSO2 O 1. THF:H2O, Hg(OAc)2 2. THF, PdCl2, CuCl2 N Bu N Bu Bn 70 % Bn • Proceeds via oxo-mercuriation then transmetallation • Standard Wacker resulted in a maximum yield of 45 %

Intramolecular Wacker-Type Oxidation

H H H H 10% PdCl , 2 H HO 3 CuCl2, O OH PdCl PdLn

CO, MeOH

O

CO2Me Asymmetric Intramolecular Variant

10 mol% cat., MeOH O OH 90-97 % e.e.

O R R1 N N R1 R

O

Pd(O2CCF3)2

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 44