Protection and deprotection carboxylic of carboxylic acid functional group

1. Protection and Deprotection
of Carboxylic Acid
Guided by:-
Presented by:-
Dr. Alex Joseph
Shivam Sharma
Associate Professor
140602005
Dept. Of Pharmaceutical Science ,
Dept. Of Pharmaceutical Science ,
Mcops, Manipal Mcops, Manipal
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2. 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
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3. 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.
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4. 2,2,2- Trifluro ethyl ester
Protecting and deprotecting group
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5. General preparation of ester
1- Carboxylate
activation
2- Nucleophilic
displacement of
carboxylate
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6. Example:-
1-
2-
O
R OH
O
TMSCl
+ R'OH R OR'
22-270 C , 0.1- 48 Hours
67-98 %
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-
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7. General cleavage of ester
1-
O
R OH
O
R OR'
TMSCl, NaI, CH3CN
Reflux, 5-35 H , 70-90%
2-
O
R OH
O
R OR'
MgI2, Toluene
1-3 Days , 41-96%
+ R' I
3-
O
R OH
O
R OR'
Aq. NaOH, DMF ,HCl
15- 16min , 36-98%
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8. Methyl ester
Formation:- O
P r o t e c t i o n
D e p r o t e c t i o n
O
R O H
R O C H 3
 CH2 N2, Et2 O, RT, 90min, 92%
 CH2 N2, MeOH, RT, 60min. 84%
 MeOH, H2 SO4, 00 , 1 H, 50 , 18H, 98%
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9. Cleavage:-
 LiOH, CH3 OH, H2O, 50, 15H
 AlBr3, Tetrahydrothiophene, RT, 62H, 98%
 LiI, Pyr, Reflux, 91%
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10. t- Butyl ester
Formation:-
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
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11. Cleavage:-
 HCO2H, 200 , 3 H
CF3CO2H, CH2Cl2 , 250 , 1 H
Bromocatechol borane
TsOH, Benzene , Reflux 30 min, 76%
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12. Allyl ester
Formation:-
O
R O H
Allyl bromide, Cs2Co3, DMF, 84%
R O
Vinyl diazo methane, CH2 Cl2, 80-92%
Allyl alcohol , TsOH, Benzene , -H2O
Allyl bromide, NaHCO3, CH2Cl2 , 83%
O
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13. Cleavage:-
 Papain, DTT, DMF
 Pd(Ph3 P)4 , BnONH2, CH2Cl2 , 80%
 Me2CuLi , Et2O, 1 h , 75- 85%
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14. 1,1-Dimethyl Allyl ester
O
R O H
 Et2NH, DMF, 91%
O
 CuI , KI, Cs2CO3 , DMF , 250 C
Formation:-
Cleavage:-
 BCl3, CH2Cl2
 Catalytic palladium
R O
C H 3
H 3 C
1 - C H 3
C 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 .
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15. 2,2,2-Trichloro ethyl ester
Formation:-
O
R O H
CCl3, CH2OH, DCC , Pyr
CCl3, CH2OH, TsOH, Toluene , Reflux
CCl3, CH2OCOCl, THF, Pyr, 60%
O
R O C H 2
C
C l 3
C l 3
C l 3
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16. Benzyl ester
Formation:-
 For Amino acids- DCC , DMAP, BnOH, 92%
 BnBR, DBU , CH3CN, 75%
 BnOCOCl, Et3N, DMAP, CH2Cl2, 30 min, 97%
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17. Cleavage:-
 BCl3, CH2Cl2, -10 , RT, 3 H , 90%
 AlCl3 , Anisole, CH2Cl2 , CH3NO2, 00 – 250 C, 5 H, 80 -95%
 Acidic alumina , microwave , 7 min, 90 %
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18. Silyl ester
Trimethyl silyl ester
Formation:-
Cleavage:-
O
R O H
O
R O
S i ( C H 3 ) 3
 Me3SiCl / Pyr , CH2Cl2 , 300C , 2H
 MeC(OSiMe3) = NSiMe3, Dioxane , α- picoline,
6H , 80%
 Trimethyl silyl esters
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19. 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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