Protection and deprotection of carboxylic acid

Protection and deprotection carboxylic of carboxylic acid functional group

1. 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

2. Contents Introduction Examples of protecting and deprotecting groups General preparations of esters General Cleavage of esters Individual explanation Reference 2

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. 3

4. 2,2,2- Trifluro ethyl ester Protecting and deprotecting group 4

5. General preparation of ester 1- Carboxylate activation 2- Nucleophilic displacement of carboxylate 5

6. Example:- 1- 2- 3- 6

7. General cleavage of ester 1- 2 - 3- 7

8. Methyl ester Formation:- CH 2 N 2, Et 2 O, RT, 90min, 92% CH 2 N 2, MeOH, RT, 60min. 84% MeOH, H 2 SO 4, , 1 H, 5 , 18H, 98% 8

9. Cleavage:- LiOH, CH 3 OH, H 2 O, 5 0, 15H AlBr 3, Tetrahydrothiophene, RT, 62H, 98% LiI, Pyr, Reflux, 91% 9

10. t - Butyl ester Isobutylene, H 2­ SO 4, Et 2 O, 25 , 2- 24 H , 50-60% T- BuOH , DMAP, Benzene, 20 C Bu 3 PI 2 , Et 2 O, HMPA, t- BuOH, 73% Isobutylene, CH 2 Cl 2, H 3 PO 4 (P 2 O 5 ), 78 C, 2 H Formation:- 10

11. HCO 2 H, 20 , 3 H CF 3 CO 2 H, CH 2 Cl 2 , 25 , 1 H Bromocatechol borane TsOH, Benzene , Reflux 30 min, 76% Cleavage:- 11

12. Allyl ester Allyl bromide, Cs 2 Co 3, DMF, 84% Vinyl diazo methane, CH 2 Cl 2, 80-92% Allyl alcohol , TsOH, Benzene , -H 2 O Allyl bromide, NaHCO 3, CH 2 Cl 2 , 83% Formation:- 12

13. Papain, DTT, DMF Pd(Ph 3 P) 4 , BnONH 2, CH 2 Cl 2 , 80% Me 2 CuLi , Et 2 O, 1 h , 75- 85% Cleavage:- 13

14. 1,1-Dimethyl Allyl ester Et 2 NH, DMF, 91% CuI , KI, Cs 2 CO3 , DMF , 25 C Formation:- Cleavage:- BCl 3, CH 2 Cl 2 Catalytic palladium 14

15. 2,2,2-Trichloro ethyl ester CCl 3, CH 2 OH, DCC , Pyr CCl 3, CH 2 OH , TsOH, Toluene , Reflux CCl 3, CH 2 OCOCl, THF, Pyr, 60% Formation:- 15

16. Benzyl ester For Amino acids- DCC , DMAP, BnOH, 92% BnBR, DBU , CH 3 CN , 75% BnOCOCl, Et 3 N, DMAP, CH 2 Cl 2, 30 min, 97% Formation:- 16

17. BCl 3, CH 2 Cl 2, -10 , RT, 3 H , 90% AlCl 3 , Anisole, CH 2 Cl 2 , CH 3 NO 2, – 25 C, 5 H, 80 -95% Acidic alumina , microwave , 7 min, 90 % Cleavage:- 17

18. Silyl ester Trimethyl silyl ester Formation:- Cleavage:- Trimethyl silyl esters Me 3 SiCl / Pyr , CH 2 Cl 2 , 30 C , 2H MeC(OSiMe 3 ) = NSiMe 3, ­ Dioxane , α- picoline, 6H , 80% 18

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/ 19