i. The document presents information on three important coupling reactions: the Heck reaction, Suzuki coupling, and Sharpless epoxidation. ii. The Heck reaction forms carbon-carbon bonds between an alkene and an unsaturated halide. The Suzuki coupling couples an organoboron compound with a halide using palladium catalysis. The Sharpless epoxidation reaction produces chiral epoxides from allylic alcohols in high enantiomeric excess. iii. Examples of applications are given for drug synthesis using these reactions.

1. Presented by,
Vishal.D.Patil,
Pharmaceutical chemistry
Dept,
Roll no-523
Guide:-Prof. M. S.
Phoujdar,
Dept-Pharmaceutical
chemistry
SINHGAD COLLEGE OF PHARMACY, VADGOAN, PUNE-41
Vishal.D.Patil
1
HECK REACTION, SUZUKI
COUPLING & SHARPLESS
EPOXIDATION

2. Contents
1. Coupling reaction
2. What are C-C
coupling reactions?
3. Main features of
cross coupling
4. Important coupling
reactions
5. Heck reaction
6. Suzuki coupling
7. Sharpless
epoxidation
Vishal.D.Patil 2

3. Coupling Reactions
• Coupling reactions occur between
organometallic with organic halide with the
help of metal containing catalyst
• Coupling reactions can be divided into two
main classes, cross couplings in which two
different molecules react to form one new
molecule Vishal.D.Patil 3

4. • The other type of coupling is homocoupling,
in this reaction two similar molecules coupling
together to form a new molecule
New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor)
2014 Vishal.D.Patil 4

5. What are C-C cross coupling reactions?
• The C-C bond formation between an organic
electrophile (RX) and a nucleophile
(Organometallic R’M or R’-C=C) in the
presence of a transition metal catalyst, usually
Pd (even Cu, Ni, Fe etc are also used)
Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel
Prize Dr. Carin C. C. Johansson Seechurn, Dr. Matthew O. Kitching
Vishal.D.Patil 5

6. Main features
Common metal used in this field is Pd, in
addition to Zn, Ni, Cu, B, and Sn
Most of coupling reactions are air and water
sensitive??
But, some coupling reactions can be carried
out in aqueous solutions
Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel
Prize Dr. Carin C. C. Johansson Seechurn, Dr. Matthew O. KitchingVishal.D.Patil 6

7. Important coupling reactions
https://en.wikipedia.org/wiki/Coupling_reaction
Vishal.D.Patil 7

8. HECK REACTION
unsaturated halide alkene substituted alkene
Vishal.D.Patil 8
• This reaction was the first example of a carbon-carbon
bond-forming reaction that followed a Pd(0)/Pd(II)
catalytic cycle, the same catalytic cycle that is seen in
other Pd(0)-catalyzed cross-coupling reactions

9. REACTION MECHANISM
Vishal.D.Patil 9

10. i. The catalytic cycle for the Heck reaction involves a series of
transformations around the palladium catalyst. The
palladium(0) compound required in this cycle is generally
prepared in situ from a palladium(II) precursor
ii. Step A is an oxidative addition in which palladium inserts
itself in the aryl to bromide bond
iii. Palladium then forms a π complex with the alkene (3)
iv. In step B the alkene inserts itself in the palladium - carbon
bond in a syn addition step
v. Step C is a beta-hydride elimination step with the formation
of a new palladium - alkene π complex (5)
vi. This complex is destroyed in the next step
vii. The palladium(0) compound is regenerated by reductive
elimination of the palladium(II) compound by potassium
carbonate in the final step, D
Organic chemistry. 2nd edition, David R. Klein, wiley publication house ,
December 2013Vishal.D.Patil 10

11. APPLICATIONS
A. Alverine , a smooth muscle relaxant used for the treatment of
gastrointestinal disorders such as diverticulitis and irritable
bowel syndrome, was prepared from N,N-
diallylacetamide by means of a double Heck-Matsuda
reaction/hydrogenation
P Prediger, Allan R d Silva,C Roque, D Correia,Construction of 3-arylpropylamines
using Heck arylations. The total synthesis of cinacalcet hydrochloride, alverine, and
tolpropamine, Tetrahedron, 70(20), PP:-3333-3341
Vishal.D.Patil 11

12. Suzuki coupling
Vishal.D.Patil 12
The general scheme for the Suzuki reaction is shown
below where a carbon-carbon single bond is formed by
coupling an organoboron species (R1-BY2) with
a halide (R2-X) using a palladium catalyst and a base.

13. REACTION MECHANISM
Vishal.D.Patil 13

14. i. The first step is the oxidative addition of palladium to
the halide 2 to form the organopalladium species 3
ii. Reaction with base gives intermediate 4, which
via transmetalation with the boron-ate complex 6, forms
the organopalladium species 8
iii. Reductive elimination of the desired product 9 restores the
original palladium catalyst 1 which completes the catalytic
cycle
iv. The Suzuki coupling takes place in the presence of a base
and for a long time the role of the base was never fully
understood
Organic chemistry. 2nd edition, David R. Klein, wiley publication house ,
December 2013
Vishal.D.Patil 14

15. Application
• The Suzuki coupling has been frequently used in syntheses of
complex compounds.The Suzuki coupling has been used on
a citronellal derivative for the synthesis of caparratriene, a
natural product that is highly active against leukemia
• Scaled up reactions have been carried out in the synthesis of a
number of important biological compounds such as CI-1034
which used a triflate and boronic acid coupling partners which
was run on an 80 kilogram scale with a 95% yield
Junjia Liu, Stephen D. Lotesta, and Erik J. Sorensen, A Concise Synthesis of the
Molecular Framework of Pleuromutilin, Chem Commun (Camb). 2011 Feb 7; 47(5):
1500–1502 Vishal.D.Patil 15

16. Epoxidation
• Some oxidation reactions of alkenes give cyclic
ethers in which both carbons of a double bond
become bonded to the same oxygen atom. These
products are called epoxides or oxiranes
Epoxidation reaction
https://en.wikipedia.org/wiki/Epoxide#cite_ref-UllmannEpoxides_1-0
Vishal.D.Patil 16

17. Sharpless epoxidation
• The Sharpless epoxidation reaction is
an enantioselective chemical reaction to prepare 2,3-
epoxyalcohols from primary and secondary allylic alcohols
• The stereochemistry of the resulting epoxide is determined by the
diastereomer of the chiral tartrate diester used in the reaction
• The oxidizing agent is tert-butyl hydroperoxide
• Enantioselectivity is achieved by a catalyst formed from titanium
tetra(isopropoxide) and diethyl tartrate
Vishal.D.Patil 17

18. Peracids for epoxidation of C=C
Double Bonds
Vishal.D.Patil 18

19. Applications
(S,S)-reboxetine succinate
S.T.Hayes*, G.Assaf, G.Checksfield, C.Cheung, D.Critcher, L.Harris, R.Howard, S.Mathew, C.Regius,
G.Scotney, and A.Scott, Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the
Cheapest Commercial Chemistry for Manufacture, Org. Process Res. Dev., 2011, 15 (6), pp 1305–1314
• The development of a (S,S)-reboxetine succinate, used for
the treatment of fibromylagia
Vishal.D.Patil 19

20. References
1. New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor)
2014
2. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the
2010 Nobel Prize Dr. Carin C. C. Johansson Seechurn, Dr. Matthew O. Kitching
3. https://en.wikipedia.org/wiki/Coupling_reaction
4. Organic chemistry. 2nd edition, David R. Klein, wiley publication house , December
2013
5. P Prediger, Allan R d Silva,C Roque, D Correia,Construction of 3-arylpropylamines
using Heck arylations. The total synthesis of cinacalcet hydrochloride, alverine, and
tolpropamine, Tetrahedron, 70(20), PP:-3333-3341
6. Junjia Liu, Stephen D. Lotesta, and Erik J. Sorensen, A Concise Synthesis of the
Molecular Framework of Pleuromutilin, Chem Commun (Camb). 2011 Feb 7;
47(5): 1500–1502
7. S.T.Hayes*, G.Assaf, G.Checksfield, C.Cheung, D.Critcher, L.Harris, R.Howard, S.
Mathew, C.Regius, G.Scotney, and A.Scott, Commercial Synthesis of (S,S)-
Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for
Manufacture, Org. Process Res. Dev., 2011, 15 (6), pp 1305–1314
Vishal.D.Patil 20

21. Vishal.D.Patil 21