1  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Ways to make esters Baeyer-Villiger oxidation

O

OO

mCPBA

Favorskii rearrangement

O

Br CO2EtNaOEt/EtOH

Mitsunobu  reaction R'OH+RCO2H

DEAD, PPh3 RCO2R'

N NCO2Et

EtO2C

Ph3P

N NCO2Et

EtO2C

Ph3P

O R

OH

N NH

CO2Et

EtO2C

Ph3P

ROH

RCO2+

R O

ORCO2R'O PPh3 +

HN N

H

CO2Et

EtO2C+

R O PPh3

Functional Group Transformations

29.7.13  

2  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Mitsunobu Reaction

R R1

OH

PPh3, DIADR2CO2H

R R1

O R2

O

N NCO2R

RO2CR = iPr, DIAD

Diisopropyl azodicarboxylateR = Et, DEAD

Diethyl azodicarboxylate

O

O

OBnO

?

O

O

OBnO

H+, H2O

HO

O

BnOOHO

PPh3, DEAD

Functional Group Transformations

R R1

OH PPh3DEAD

OHR R1

OPh

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3  

Functional Group Transformations Mitsunobu Reaction

Nitrogen nucleophile:

OBnOH

PPh3, DEAD

TsNHCH3

OBnNTsH3C

N

HN

O

PPh3

DEAD

OH

N

N

O

Intramolecular Mitsunobu Reaction:

HNHO

CO2EtCO2EtPh PPh3

DEAD NCO2Et

CO2EtPh

CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Weak Nitrogen nucleophile: O

BnO OBn

OHBnO

NH

R

PPh3, DEADO

BnO OBn

BnON

R

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4  

Functional Group Transformations Mitsunobu Reaction

CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Azides: ROH + PPh3 + DEAD HN3 PPh3 +RO

HN

HN CO2EtEtO2CRN3

RN3 + Ph3PO N N CO2EtEtO2CPPhO OPhO

H

O(PhO)2P N3 Can be used instead of HN3

N N CO2EtEtO2C

(PhO)2P N3

O

PPh3

N N CO2EtEtO2CPPhO OPhO

PPh3

OHR

N N CO2EtEtO2CPPhO OPhO

HR O PPh3 +

N N N

R N3 + PhP O

O(PhO)2P N3ROH + + PPh3 + DEAD

29.7.13  

5  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Activation of hydroxyl group

R OH

ClSO

Cl OSO

ClR

Cl

Functional Group Transformations

Preparation of alkyl halides:

R Cl + +SO2 Cl

Alkyl halides are involved in the formation of C−C bond by nucleophilic substitution

Inversion of configuration

But, if reaction is taking place in solvent like 1,4-dioxane

OSO

ClR

O

O

O O RCl

R Cl

Retention of configuration

Reaction with SOCl2

29.7.13  

6  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Activation of hydroxyl group

PCl

Cl

RO 2ROH POR

OR

RO

Functional Group Transformations

PCl

ClClROH

Reaction with Phosphorous halides

- HCl  

The reaction will stop at this stage if it is carried out in presence of an amine

POR

OR

RO H+

When amine is not present

POR

OR

OH

Cl

R2RCl+P

OHOH

OH

Inversion of configuration

Drawbacks: Not suitable for acid sensitive compounds Amines can not be used

OHOO

BrOO

?

R Cl PHOR

OR+O

29.7.13  

7  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Ph3P Br Br Br Ph3P Br+

R OH

R O PPh3

Br

- HBr

Activation of hydroxyl group Reaction with alkoxyphosphonium salts

R Br O PPh3

Formation of strong phosphoryl double bond is the driving force

HO

Ph3P

Br2Br

R OH PPh3+ R BrO

Br

Br

Br

Br+  

Bromide source

Functional Group Transformations

29.7.13  

8  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Cl CCl

ClCl

Ph3P R O PPh3ClCCl3 +

R OH

Cl3C CO

CCl3

PPh3R Cl

Activation of hydroxyl group PPh3/ CCl4

CCl3

R OH

Ph3P Cl

R ClHexachloroacetone can be used as chloride source

PPh3/ I2/ Imidazole N

NH

I2 R OHPPh3 R I

Functional Group Transformations

Ph3P I IPh3P I

RHO

-HI

ImidazoleROPPh3

I

R I

29.7.13  

9  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Functional Group Transformations Activation of hydroxyl group

Reaction with 2-Halo-3-alkylbenzoxazolium cation

O

NCl RHO

Addition

Elimination O

NOR

Cl

O

NO R Cl

Mitsunobu reaction

N NCO2Et

EtO2C

Ph3P

Me I

N NCO2Et

EtO2C

Ph3P

MeI+

OHR

N NCO2Et

EtO2C Me

HIR O PPh3R I

29.7.13  

10  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

HBr BrBrO BrBr

HBr

HBrOH

Br HO Br

HBr

H2O Br

BrBrBr

Activation of hydroxyl group Functional Group Transformations

Mild method OH MsCl

Py

OMs LiCl ClMsOLi

Some other methods

O

O

29.7.13  

11  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Functional Group Transformations Nitriles

Dehydration

RCONH2

Abnormal

BeckmannRearrangement

N

R

OHR CN

LAH

H 2/ Pd-C

RCH2NH2

H3O+ RCO2H

R'MgBrRCOR'

DIBAL-H

RCHO

RX + NaCN  

Alkylation

R'

R' CN

29.7.13  

12  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Functional Group Transformations Preparation of Nitriles

R X NaCN R CN R

O

NH2

P2O5 R CN

aldoxime

Beckmann rearrangenment can also occur

Reaction proceed faster in polar aprotic solvents

NHO

NH2O

H+N H

NO

H2O

N OH N OH2 N

NC

H+

tertiary carbocation

-H+

R

N

H

OHp-TsCl, Py

AcCl, PyR CN

29.7.13  

13  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

Functional Group Transformations Preparation of Nitriles

RCH2Br + KCN18-Crown-6

CH3CN83oC

RCH2CN

R CHOR

OH

CN

stable under mild acidic condition unstable under basic condition

OH-

R CHO + CN-

R CHOR

OTMS

CN

KCN

H+

TMSCN

ZnBr2

29.7.13  

14  CH-­‐423  Course  on  Organic  Synthesis;  Course  Instructor:  Krishna  P.  Kaliappan  

R CNR'MgBrH+/H2O

RO

R'

R CNLDAR'I R CN

R'

R CN

R CN

R CN

R CN

LAHor

H/Pd-C

R CH2NH2

partial hydrolysis

R

O

NH2

H3O+

RefluxR CO2H

SnCl2/HClDIBAL-H R

O

H

Stephen reaction

Utility of Nitriles

Functional Group Transformations

29.7.13