The document summarizes the Chan-Lam coupling reaction, which is a copper-catalyzed coupling between an aryl boronic acid and an alcohol or amine to form secondary aryl ethers or aryl amines. It provides the history of the reaction and compares it to related palladium-catalyzed reactions. The document then discusses the proposed mechanism and provides several applications of the Chan-Lam coupling reaction in synthesizing drug molecules, heteroarenes, aminoesters, and other compounds. In conclusion, the author discusses developing an improved Chan-Lam protocol using a novel copper catalyst that is simple, rapid, and produces products at room temperature in a short time.

1. Presented By
Subhankar Deb Barman
M.Sc 3rd 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:
Coordination
A to B
Oxidation
B to C
Reductive
elimination
C to D
Complexation
D to E
Transmetalation
E to A
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 acids1having
electron-deficient 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.  Copper-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-deficient
halogenated purines/pyrimidines, such as(21), with suitable amines is used as a
generalmethod for synthesizing amino-substituted purines/pyrimidines(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