CHAN LAM COUPLING

S D Barman
Raiganj University
Department of Chemistry

1. CHAN LAM Coupling Presented By Subhankar Deb Barman M.Sc 3 rd Semester 1

2. INTRODUCTION The Chan–Lam coupling reaction–also known as the Chan–Evans–Lam coupling, is a cross-coupling reaction between an aryl boronic acid and an alcohol or an amine to form the corresponding secondary aryl ethers or aryl amines respectively. The Chan–Lam coupling is catalyzed in the presence of copper(II) salts and may be conducted in air at room temperature 2

3. Over the last two decades, palladium-catalyzed coupling reactions have become a staple reaction of the pharmaceutical industry, to the extent that processes to remove residual palladium from pharmaceutical products have become an active area of work. In 1998 Chan, Evans, and Lam reported the oxidative coupling of amines (and other nucleophiles) with arylboronic acids by copper salts . HISTORY BEHIND CHAN LAM COUPLING Patrick Y-S. Lam, PhD Blumberg Institute Distinguished Professor (Principal Investigator ) Dominic Chan Professor, Department of Chemistry,  The Chinese University of Hong Kong 3

4. RELATED REACTIONS Ullmann Reaction : This reactions include copper-catalyzed Nucleophilic Aromatic Substitution between various nucleophiles (e.g. substituted phenoxides) with aryl halides. 4

5. Buchwald-Hartwig Cross Coupling Reaction : Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudohalides (for example triflates) and primary or secondary amines. 5

6. GENERAL SCHEME OF CHAN LAM COUPLING 6

7. ADVANTAGE OF CHAN LAM COUPLING In comparison to the Ullmann–Goldberg reaction or Buchwald–Hartwig Reaction catalyzed by copper or palladium, CEL couplings proceed under much milder conditions, often amination at room temperature, and are thus more attractive for complicated and sensitive substrates. Room Temparature Reaction Weak Base Aerobic Reaction 7

8. PROPOSED GENERAL MECHANISM OF CHAN LAM COUPLING : 8

9. APPLICATIONS: 1 . Preparation of NH-containing heteroarenes Chan and Lam also discovered the arylboronic/cupric acetate arylation reaction as a powerful methodology for aryl or heteroaryl C-N bond cross-coupling to arylate a variety of standard NH-containing heteroarenes (2) to produce(3) 9

10. Reactions with three different arylboronic acids 1 having electron-de fi cient to electron-rich rings were attemptedusing heteroarenes , imidazole ( 4) , and pyrazole ( 5) . The yields of ( 6 ) and ( 7 ) were generally good, indicating that this reaction can tolerate arylboronic acids, which differ in electronic nature 10

11. C opper-promoted C-N bond cross-coupling of NH-containing substrate (9) with phenyltrimethylstannane (8) at room temperature with the addition of TBAF to form (10). Using aryl trialkyl stannanes as coupling partners can be valuable because of their availability, air and moisture stability, and compatibility with a variety of functional groups. 11

12. Arylboronic acids(1 ) were allowed to react with a limiting quantity of alkanethiol (12) (1 equiv) in the presence of copper(II) acetate and pyridine in anhydrous DMF to obtain alkyl sulfides (13) 2. Preparation of aryl/alkyl sulphide 12

13. A novel route to aryloxyamines (15) via thecopper-mediated cross-coupling of N-hydroxy phthalimide (14) and phenylboronic acids(1 ). 3. Preparation of aryloxyamines 13

14. The copper-promoted N-arylation of enantiomerically pure alpha- aminoesters ( 16) with p-tolylboronic acid( 1 ) and copper(II) acetate under mild conditions to form( 17) with little or no racemization at room temperature 4. Synthesis of alpha-aminoesters 14

15. A synthetic method for preparing novel phenoxyquinoline -4(1H )-one compounds ( 19) and ( 20) via cross-coupling of hydroxyquinoline -4(1H )-one ( 18) with a variety of phenylboronic acids (1 ) . The reaction is mediated by copper(II) acetate at room temperature in air and is tolerant of several functional groups on phenylboronic acids 5. Preparation of N aryloxyquinoline 15

16. The purine/pyrimidine substructure and the amino-substituted congeners are frequently occurring motifs in commercially available drugs. For example , aryl 2-aminopyrimidines have been used in treating diseases modulated by the adenosine receptor.The anti-HIV/HBV drugs, abacavir and penciclovir, and the anti-atherosclerotic agent,aronixil, are three aminopurine and aminopyrimidine drugs presently available in the market.Conventionally, nucleophilic aromatic substitution of electron-de fi cient halogenated purines/pyrimidines , such as( 21) , with suitable amines is used as a generalmethod for synthesizing amino-substituted purines/pyrimidine s( 22) . This is a medicinal application. 6. Symthesis of purine/pyrimidine based drug molecule 16

17. N-arylation of 5-methyl-2-methyl thiopyrimidin-4-amine ( 23 ) and of 4 -chloro-2-methylthiopyrimidin-6-amine (25) with arylboronic acids( 1 ) . N-Arylated pyrimidines ( 24) and ( 26) were obtained in moderate-to-good yields. 17

18. pyrrolic amine ,(27) is coupled with aryl boronic ester , (28), to afford product (29), which is then carried forward to the biologically active target(30). The nitrile group of (2) does not poison the Cu(OAc)2 used, and pyridine is the ligand used for the reaction. Though the reaction is characterized by a lengthy duration (three days), it was carried out at room temperature in ambient air. 8. Synthesis of biological active compound 18

19. 19 Conclusions: I have discussed a novel copper catalyst for an improved CHAN LAM protocol which is simple & rapid , can be performed at room temperature producing coupling product within a short time. The catalyst could be used very effectively for coupling reaction of amines, amides, & thiols with boronic acids to produce corresponding coupling products in high yield.

20. 20 1 . Kodepelly Sanjeeva Rao; Tian-Shung Wu (2012). "Chan-Lam coupling reactions: Further reading synthesis of heterocycles". Tetrahedron. 68: 7735–7754. doi:10.1016/j.tet.2012.06.015 . References 2 . Vantourout, J. C.; Miras, H. N.; IsidroLlobet, A.; Sproules, S.; Watson, A. J. B. (2017). "Spectroscopic Studies of the Chan–Lam Amination: A MechanismInspired Solution to Boronic Ester Reactivity". Journal of the American Chemical Society. 139: 4769–4779 . doi:10.1021/jacs.6b12800 .

21. 21 Acknowledgements : ▪ I would like to express my special thanks to Dr. Kinkar Biswas for giving me an opportunity to present this seminar on the topic and providing his able guidance. ▪ I also extend my gratitude to all other teachers Department of Chemistry , for providing me the necessary facilities. ▪ I would also like to thank my dear classmates for their support

22. 22 THANK YOU