Protection and Deprotection of Carboxylic Acid

Presented by:-

Shivam Sharma

140602005

Dept. Of Pharmaceutical Science , Mcops, Manipal

Guided by:-

Dr. Alex Joseph

Associate Professor

Dept. Of Pharmaceutical Science , Mcops, Manipal 1

Contents

1. Introduction

2. Examples of protecting and deprotecting groups

3. General preparations of esters

4. General Cleavage of esters

5. Individual explanation

6. Reference

2

Why a Carboxylic Acid group be protected?

To mask the acidic proton so that it does not interfere with base -

catalyzed reactions

To prevent nucleophilic addition reactions

To improve the handling of the molecule

Example- To make the compound less water soluble ,

To improve its NMR characteristics

To make it more volatile so that it can be analyzed by gas

chromatography.3

2,2,2- Trifluro ethyl ester

Protecting and deprotecting group

4

General preparation of ester

1- Carboxylate

activation

2- Nucleophilic

displacement of

carboxylate

5

Example:-

1-

2-

R OH

O

+ R'OH R OR'

O

22-270 C , 0.1- 48 Hours

67-98 %

TMSCl

R C H C O 2 H

N H P G

+ R ' X R C H C O 2 R '

N H P G

N a H C O 3 , D M F

2 5 0 C , 2 4 H

9 0 - 9 5 %

3-

6

General cleavage of ester

1-

R OH

O

R OR'

O

TMSCl, NaI, CH3CN

Reflux, 5-35 H , 70-90%

2-R OH

O

R OR'

O

MgI2, Toluene

1-3 Days , 41-96%

+ R' I

3-

R OH

O

R OR'

O

Aq. NaOH, DMF ,HCl

15- 16min , 36-98%

7

Methyl ester

D e p r o t e c t i o n

P r o t e c t i o n

R O H

O

R O C H 3

OFormation:-

CH2 N2, Et2 O, RT, 90min, 92%

CH2 N2, MeOH, RT, 60min. 84%

MeOH, H2 SO4, 00 , 1 H, 50 , 18H, 98%

8

Cleavage:-

LiOH, CH3 OH, H2O, 50, 15H

AlBr3, Tetrahydrothiophene, RT, 62H, 98%

LiI, Pyr, Reflux, 91%

9

t- Butyl ester

Isobutylene, H2SO4, Et2O, 250 , 2- 24 H , 50-60%

T- BuOH , DMAP, Benzene, 200 C

Bu3PI2 , Et2O, HMPA, t- BuOH, 73%

Isobutylene, CH2Cl2, H3 PO4(P2O5), 780 C, 2 H

Formation:-

10

HCO2H, 200 , 3 H

CF3CO2H, CH2Cl2 , 250 , 1 H

Bromocatechol borane

TsOH, Benzene , Reflux 30 min, 76%

Cleavage:-

11

Allyl ester

Allyl bromide, Cs2Co3, DMF, 84%

Vinyl diazo methane, CH2 Cl2, 80-92%

Allyl alcohol , TsOH, Benzene , -H2O

Allyl bromide, NaHCO3, CH2Cl2 , 83%

Formation:-

R O H

O

R O

O

12

Papain, DTT, DMF

Pd(Ph3 P)4 , BnONH2, CH2Cl2 , 80%

Me2CuLi , Et2O, 1 h , 75- 85%

Cleavage:-

13

1,1-Dimethyl Allyl ester

Et2NH, DMF, 91%

CuI , KI, Cs2CO3 , DMF , 250 C

Formation:-

Cleavage:-

BCl3, CH2Cl2

Catalytic palladium

R O H

O

R O

O

C H 3H 3 C

1 - C H 3C H 3

C l

C u I , C a 2 C O 3

2 - H 2 , L i n d l a r C a t .

14

2,2,2-Trichloro ethyl ester

CCl3, CH2OH, DCC , Pyr

CCl3, CH2OH, TsOH, Toluene , Reflux

CCl3, CH2OCOCl, THF, Pyr, 60%

Formation:-

R O H

O

R O C H 2

O

C

C l 3

C l 3

C l 3

15

Benzyl ester

For Amino acids- DCC , DMAP, BnOH, 92%

BnBR, DBU , CH3CN, 75%

BnOCOCl, Et3N, DMAP, CH2Cl2, 30 min, 97%

Formation:-

16

BCl3, CH2Cl2, -10 , RT, 3 H , 90%

AlCl3 , Anisole, CH2Cl2 , CH3NO2, 00 – 250 C, 5 H, 80 -95%

Acidic alumina , microwave , 7 min, 90 %

Cleavage:-

17

Silyl ester

Trimethyl silyl ester

Formation:-

Cleavage:-

R O H

O

R O

O

S i ( C H 3 ) 3

Trimethyl silyl esters

Me3SiCl / Pyr , CH2Cl2 , 300C , 2H

MeC(OSiMe3) = NSiMe3, Dioxane , α- picoline,

6H , 80%

18

References

Protective groups in organic synthesis, third edition, theodora.W.Greene,

Peter G.M. Wuts

www.synarchive.com

www.organic-reaction.com/organic-synthesis/protecting-groups/

carboxylic-acid-protecting-groups/

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