FUNCTIONAL GROUP INTERCONVERSIONS ALCOHOLS & THE CARBONYL GROUP INTRODUCTION • So far we have discussed methods for the formation of the carbon skeleton • In a large number of these reactions we found that either the starting material or the product contained an alcohol or a carbonyl group • Due to the importance of these two groups we will take a very brief look at them both ALCOHOL OXIDATION • Alcohols can readily be oxidised to the carbonyl moiety • This is an incredibly important reaction as we have seen that the carbonyl group is one of the cornerstones of C–C bond formation (organometallics, neutral nucleophiles, aldol, Julia, Peterson & Wittig reactions)

R1 = H

OH O O

R R1 R R1 R OH

• Primary (R1 = H) alcohols – normally more reactive than seconary alcohols on steric grounds • Need to be able to control oxidation of primary alcohols so only obtain aldehyde or acid • Large number of reagents – all have their advantages and disadvantages • Look at some of the more common... fragmentation common to most oxidations (as Chromium (VI) Oxidants you shall see) General Mechanism Cr(VI) Cr(IV) O OH2 proton O H O H Cr O Cr O –H2O transfer Cr HO OH Cr O O R O O O HO R HO H O R

• This fragmentation mechanism is common to most oxidations regardless of the nature of the reagent "Overoxidation" formation of carboxylic acids • Invariably achieved in the prescence of H2O and proceeds via the hydrate

O O O H O OH Cr O 2 O O Cr OH O O R H R H OH R OH R H OH Jones Oxidation H2SO4, CrO3, acetone OH O OH O

R H R OH R R1 R R1 • Harsh, acidic conditions limit use of this method

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 1 Pyridinium Chlorochromate (PCC)

Cl must avoid water Cr O O N O H OH O OH O

R H R H R R1 R R1 • Less acidic than Jones reagent (although still acidic)

Pyridinium Dichromate (PDC) O O O Cr O Cr O O O N H 2 • Even milder than PCC and has useful selectivity O PDC OH PDC O R H DCM R H DMF R OH

Other Oxidants Manganese Dioxide MnO2 • Mild reagent • Very selective – only oxidises allylic, benzylic or propargylic alcohols

HO HO

MnO2 only oxidises activated alcohol OH O

Activated Dimethylsulfoxide (DMSO) Oxidations DMSO, activator & base

• Possibly the most widely used group of oxidants • Huge number of variants depending on the nature of the activator or the base • The most common is the Swern Oxidation

DMSO activator

OH 1. Me2S(O), (COCl)2, DCM O 2. Et3N

• Mild (especially with wide choice of reagents) • Overoxidation never a problem • 1,2-Diols are not cleaved (see below)

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 2 Mechanism O O Cl O O S Cl S Cl S S Cl O O O R O Cl H common intermediate to all activated DMSO oxidations O S O S H R O R H R H base: H

• Please note the similarity between this mechanism and the Cr(VI) mechanism Cleavage of 1,2-Diols • Many metal based oxidising agents will cleave 1,2-diols • This can be synthetically useful reaction • When it is desired NaIO4 or Pb(OAc)4 normally used HO OH NaIO4 O O

1 R R1 R R

O O I proton transfer O O

O OH O O O O O I proton transfer I O OH O O

R R1 R R1

From Nicolaou's synthesis of amphoteronolide B OH 1. (COCl)2, DMSO; then Et3N BnO BnO CO2Me O 2. Ph3P=CH2CO2Me O

CARBONYL REDUCTION • Alcohols prevalent throughout pharmacologically interesting molecules • A versatile method of introducing them is via carbonyl reduction • Again not going into great detail just give you an overview of some of the more common lithium activates Lithium Aluminium Hydride (LiAlH or LAH) carbonyl 4

Al Li H3Al Li H3Al O O O H3Al O H R R H R 1 H H 1 R d+ R group 3 so R1 R1 R Lewis acid 4 number of repetitions depends on sterics of the carbonyl • Each addition is slower • Alkoxide electron-withdrawing group so reduces reactivity of hydride

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 3 • Reduces most carbonyl functionality • Little or no selectivity • By altering the substituents on aluminium the reactivity can be tuned • Bulky and electron withdrawing groups (alkoxides) reduce activity and make reagent more selective

Sodium Borohydride (NaBH4)

• Considerably milder than LiAlH4 • Selectively reduces aldehydes and ketones in the presence of esters only ketone will LiAlH4 would react with NaBH4 reduce both O O OH O still reducing agent OR OR but alkoxide reduces reactivity

H3B H R R

O H OEt OH EtOBH3 O 1 1 H Et R R

• Not saying this is concerted (all occuring at once) • Altering substituents on boron changes behaviour • Add electron donating groups (alkyl) and increase the reactivity

NaBH4 vs LiAlH4 NaBH4

O O O O O

> 1 > 1 > 1 > R H R R R OR R NR 2 R OH

LiAlH4 Diisobutylaluminium hydride (DIBAL) • A good, strong reducing agent • Different mechanism to the two previous metal-hydrides • Aluminium centre is a Lewis acid and needs to coordinate to a Lewis base to activate hydride • DIBAL = electrophilic reducing agent (e– rich carbonyls) – • NaBH4 & LiAlH4 = nucleophilic reducing agent (e poor carbonyls) coordination intramolecular activates hydride R delivery R AlR2 O Al O H OH O H 1 Al R R1 R R R 1 H H R R1 R • Advantage of DIBAL is that reduction of esters can be stopped at alcohol or aldehyde

stable at low temperature AlR2 OH 2 x DIBAL O 1 x DIBAL O H O

R H R OR1 -78 ˚C R H R H R1O

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 4 From Corey's synthesis of the prostaglandins O OH OH O O H H H 1 x DIBAL CHO H H -78 ˚C H RO R RO R RO R

Borane (BH3) • Like DIBAL, borane is an electrophilic reducing agent (e– rich carbonyls first)

• As a result reactivity is complete reverse of LiAlH4 & NaBH4

O O O O O

1 1 1 R H R R R OR R NR 2 R OH LiAlH4 ✓ ✓ ✓ ✓ ✗ /✓

NaBH4 ✓ ✓ ✗ ✗ ✗

BH3 ✗ /✓ ✗ /✓ ✗ /✓ ✓ ✓

Oxidation and Reduction • The importance of these two operations is highlighted by the vast number of methods for excuting both. You need to be aware that there are many examples reagents and catalysts that can perform both diastereo and enantioselective reductions. There are also a number of reagents that can perform selective oxidations via either kinetic resolution or desymmetrisations.

FUNCTIONAL GROUP INTERCONVERSION: ACETAL FORMATION • Last transformation for todays lecture combines alcohol and aldehyde / ketone • You should have already met this...

Oxygen nucleophilies • Add to carbonyls BUT they are also good leaving groups so reaction reversible • Normally use large excess of nucleophile to drive reaction to completion • Can stop at half way stage to form hemiacetals

O MeOH, H MeO OMe

H2O, H

• Reversibility of reaction useful as it means acetals can used as carbonyl protecting group

O O OMe O OMe OH O OH MeOH R-MgBr H2O H MeO R H R OMe MeO OMe R R

acetal inert aldehyde would be regenerate aldehyde attacked by Grignard Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 5 • It should be noted that if your compound is a diol it too can be protected as an acetal

O OH OH O O O O

R OMe H R OMe

Mechanism H H H OH OH O O

O O H Me Me O Me hemiacetal protonation increases polarisation of H carbonyl considerably provides another resonance form

OH2 OMe H Me MeO OMe O O Me O Me acetal O Me H water a good leaving group (stable, a lot of it Nitrogen Nucleophiles about)

O R R H RNH2 N N +

– H2O imine enamine

Mechanism proton transfer O HNRR' O NHRR' H2O NRR'

loss of proton to neutralise charge

R R' R R' N N base H

enamine iminium

• Primary amines generally give imines • Secondary amines generally give neutral enamines via the charged iminum species • You have seen the use of enamines as enolate equivalents already

What have we learnt? • A number of selective reagents for both oxidation and reduction • Acetal formation is reversible • As a result acetals make good protecting groups • O, N and S nucelophiles can be used to form acetals

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis 6