The Mitsunobu reaction and Mannich reaction

MITSUNOBU& MANNICH REACTION, NAME REACTION, ORGANIC CHEMISTRY, PHARMACEUTICAL CHEMISTRY, M.PHARM, PHARMACY, CHEMISTRY

1. SEMINAR ON ADVANCED ORGANIC CHEMISTRY-I Presented to – Dr. Pratap Chandra Acharya Assistant Professor, Department of Pharmacy Prepared by: Samima Nasrin Rahman Enrollment Number: 230624011 M.Pharm 1 st Semester 1

2. THE MITSUNOBU REACTION 2

3. Definition: The Mitsunobu reaction is a widely used and versatile method for the dehydrative oxidation–reduction condensation of an acid/ pronucleophile usually with a primary or secondary alcohol that requires the combination of a reducing phosphine reagent together with an oxidizing azo reagent. INTRODUCTION

4. SALIENT FEATURES Generally highly stereoselective . Occurs with inversion of the stereochemical configuration of the alcohol starting material. Acid/ pronucleophile : Carboxylic acids, phenols, imides, sulfonamides , and other compounds . Preparation of functional groups: Esters, aryl ethers, cyclic ethers, carbon–carbon and carbon–nitrogen bonds etc . Byproducts formed: Diethyl hydrazinedicarboxylate (DEAD-H2) from DEAD & triphenylphosphine oxide (TPPO) from TPP. 4

5. BASIC REACTION 5

6. REACTION MECHANISM STEP 1: STEP 2: 6

7. STEP 3: 7

8. STEP 4: 8 9 10 Ester

9. SYNTHETIC APPLICATIONS 9 Esterification: The Mitsunobu reaction was used to synthesize a series of esters. Amide Formation: A research team used the Mitsunobu reaction to synthesize a library of amides. Mitsunobu Inversion: The Mitsunobu reaction is widely used for the inversion of stereochemistry. Synthesis of various drugs: Quinine , colchicine, morphine , stigmatellin , oseltamivir , and strychnine etc. Mitsunobu Reaction with Phthalimide : Synthesis of phthalimide derivatives .

10. THE MANNICH REACTION 10

11. INTRODUCTION In organic chemistry, the Mannich reaction is a three-component organic reaction. The three components are: An enolizable ketone Formaldehyde Primary amine/Secondary amine /Ammonia BASIC REACTION 11

12. The Reaction : Amino alkylation of an acidic proton next to a carbonyl (C=O) functional group by formaldehyde (H−CHO) and a primary or secondary amine (−NH 2 ) or ammonia (NH 3 ). The final product is a β- amino-carbonyl compound also known as a Mannich base . Reactions between aldimines and α- methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. 12

13. REACTION MECHANISM Formation of Iminium ion: This iminium ion is formed due to nucleophiic addition of amine to formaldehyde and subsequent loss of water molecule. 13

14. Due to acidic conditions, the enolizable carbonyl compound is converted to enol form . The enol form now attacks the iminium ion at positively charged carbon adjacent to nitrogen to give finally a β – aminocarbonyl compound . β 14 ‘ R”

15. SYNTHETIC APPLICATIONS 15

16. Synthesis of antimalarial hybrid compounds by Mannich reaction. 16

17. 17 Synthesis of antibacterial Mannich - β -amino ketone derivatives.

18. Synthesis of Triazolino-3-thione Mannich derivatives . 18

19. 19 Synthesis of Novobiocin Mannich derivatives having antitubercular activity.

20. REFERENCES But TY, Toy PH. The Mitsunobu reaction: origin, mechanism, improvements, and applications. Chemistry–An Asian Journal. 2007 Nov 5;2(11): 1340-55. Mitsunobu Reaction (synarchive.com ) Mitsunobu Reaction: A Comprehensive Guide for Organic Synthesis Enthusiasts - (lambdageeks.com ) Subramaniapillai SG. Mannich reaction: A versatile and convenient approach to bioactive skeletons. Journal of Chemical Sciences. 2013 May;125:467-82 . 20

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