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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

HECK REACTION, SUZUKI COUPLING & SHARPLESS

EPOXIDATION

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Contents1. Coupling reaction2. What are C-C

coupling reactions?3. Main features of

cross coupling4. Important coupling

reactions5. Heck reaction

6. Suzuki coupling7. Sharpless

epoxidation

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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

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• 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

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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

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Main featuresCommon 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. Kitching

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Important coupling reactions

https://en.wikipedia.org/wiki/Coupling_reaction

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HECK REACTION

 unsaturated halide alkene  substituted alkene

• 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

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REACTION MECHANISM

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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 stepv. 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 stepvii. 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 2013

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APPLICATIONSA. 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

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Suzuki coupling

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.

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REACTION MECHANISM

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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

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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

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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 reactionhttps://en.wikipedia.org/wiki/Epoxide#cite_ref-UllmannEpoxides_1-0

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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

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Peracids for epoxidation of C=C Double Bonds

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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

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References 1.  New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor)

20142. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the

2010 Nobel Prize Dr. Carin C. C. Johansson Seechurn, Dr. Matthew O. Kitching3. https://en.wikipedia.org/wiki/Coupling_reaction4. Organic chemistry. 2nd edition, David R. Klein, wiley publication house , December

20135. 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

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