112/28/10 1

Palladium-Catalyzed Cross-Couplings in Organic Synthesis

2010 Nobel Prize in Chemistry

Professor Sambasivarao Kotha

Department of Chemistry

IIT-Bombay 400 076

http/www.chem.iitb.ac.in/~srk

212/28/10 2

Richard F. Heck Ei-ichi Negishi Akira Suzuki

"palladium-catalyzed cross couplings in organic synthesis”

University of DelawareUSA

Purdue UniversityWest LafayetteIN, USA

Hokkaido UniversitySapporo, Japan

B 1931 B 1935 B 1930

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SiO

Si

HN

NO

NHN O

N

Cl

Cl

DVS-bis-BCM (electronic resin monomer)

Serotonin agonist Boscalid(fungiside)

Heck reaction

Negishicoupling

Suzukicoupling

Heck, Negishi and Suzuki coupling in synthesis of fine chemicals

4

Facts on the Nobel Prize in Chemistry

On 27 November 1895, Alfred Nobel signed his last will and testament, giving the largest share of his fortune to a series of prizes, the Nobel Prizes. As described in Nobel's will one part was dedicated to “ the person who shall have made the most important chemical discovery or improvement”.

http://nobelprize.org/nobel_prizes/chemistry/

5

Number of Nobel Prizes in Chemistry

102 Nobel Prizes in Chemistry have been awarded since 1901. It was not awarded on eight occasions: in 1916, 1917, 1919, 1924, 1933, 1940, 1941 and 1942.

Why were the Chemistry Prizes not awarded in those years? In the statutes of the Nobel Foundation it says: "If none of the works under consideration is found to be of the importance indicated in the first paragraph, the prize money shall be reserved until the following year. If, even then, the prize cannot be awarded, the amount shall be added to the Foundation's restricted funds." During World War I and II, fewer Nobel Prizes were awarded.

http://nobelprize.org/nobel_prizes/chemistry/

6

Number of shared and unshared Nobel Prizes in Chemistry

62 Chemistry Prizes have been given to 1 Laureate only.22 Chemistry Prizes have been shared by 2 Laureates.18 Chemistry Prizes have been shared between 3 Laureates

Why is that? In the statutes of the Nobel Foundation it says: "A prize amount may be equally divided between two works, each of which is considered to merit a prize. If a work that is being rewarded has been produced by two or three persons, the prize shall be awarded to them jointly. In no case may a prize amount be divided between more than three persons."

http://nobelprize.org/nobel_prizes/chemistry/

7

Youngest Chemistry Laureate

To date, the youngest Nobel Laureate in Chemistry is Frédéric Joliot, who was 35 years old when he was awarded the Chemistry Prize in 1935, together with his wife, Irène Joliot-Curie.

Oldest Chemistry Laureate

“in recognition of their synthesis of new radioactive elements”

The oldest Nobel Laureate in Chemistry to date is John B. Fenn, who was 85 years old when he was awarded the Chemistry Prize in 2002.

"for the development of methods for identification and structure analyses of biological macromolecules"

http://nobelprize.org/nobel_prizes/chemistry/

8

Multiple Nobel Laureates in Chemistry

Marie CuriePhysics 1903Chemistry 1911

Linus PaulingChemistry 1954Peace 1962

Frederick SangerChemistry 1958Chemistry 1980

Linus Pauling is the only person who have been awarded two unshared Nobel Prizes.

http://nobelprize.org/nobel_prizes/chemistry/

9

Family Nobel Laureates in Chemistry

The Curies were the most successful "Nobel Prize family”. The husband-and-wife partnership of Marie Curie and Pierre Curie were awarded the 1903 Nobel Prize in Physics. Marie Curie herself was awarded the Nobel Prize a second time, receiving the 1911 Nobel Prize in Chemistry. Marie and Pierre Curie's daughter, Irène Joliot-Curie, was awarded the 1935 Nobel Prize in Chemistry, together with her husband, Frédéric Joliot.

http://nobelprize.org/nobel_prizes/chemistry/

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ORGANIC SYNTHESIS

Target Oriented(Total Synthesis) Methods Oriented

NaturalProducts

DesignedMolecules

Reagents Catalysts SyntheticStrategies

SyntheticTactics

Material ScienceInterestingMolecules

BiologicallyInterestingMolecules

TheoreticallyInterestingMolecules

MedicallyInterestingMolecules

Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis, VCH, Weinheim, Germany, 1996.

Organic Reaction Vs Synthetic Method

R3 R2

R1

R4R6

R5

R7 EWG

R8 R9

R3

R4

R2R1

EWGR7

R8

R9

R5 R6

∆+

General approach to the solution of organic synthesis problems

CH4 + CO2 CH3COOH

CH4 + Br2 CH3Br + HBr

CH3Br + Mg CH3MgBr

CH3MgBr + CO2 CH3COOMgBr

CH3COOMgBr + HBr CH3COOH + MgBr2

1312/28/10 13

1412/28/10 14

Nobel Prize in Chemistry 2001

one half to William S. Knowles and Ryoji Noyori "for their work on chirally catalysed hydrogenation reactions" and the other half to K. Barry Sharpless "for his work on chirally catalysed oxidation reactions

William S. Knowles Ryoji Noyori K. Barry Sharpless

15

Boots route

H

Ac2O, HF

O

OH

Raney Nickel H2

CO and Pd

CO2H

Ibuprofen

Catalytic routeH

Ac2O, HFO

O

CO2Et

Cl

H

H

CO2Et NaOEt

O

H

H2O/H+

H

NOH

NH2O

H2O

NH2OH

Hoechst Celanese

1612/28/10 16

Commonly used Aryl-Aryl couplings methods

Ar Br

Ar MgCl

Ar ZnCl

Ar SnBu3

Ar B(OH)2

Ar Si(R')3

Ar' Br+

+

+

+

+

+

Ar' Br

Ar' Br

Ar' Br

Ar' Br

Ar' Br

Cu

Ni or Pd

Pd

Pd

Pd

Pd

Ar Ar'

Ar Ar'

Ar Ar'

Ar Ar'

Ar Ar'

Ar Ar'

Ullmann Coupling

Kumada Coupling

Negishi Coupling

Stille Coupling

Suzuki Coupling

Hiyama Coupling

1712/28/10 17

OMe

PhO2S SO2Ph

PdLn

MeO

PhO2SPhO2S

B. M. Trost and Y. Shi, J. Am. Chem. Soc., 1991, 113, 701Zipper-mode cascade

Zipper-mode cascade reaction with Pd

T. Sugihara, C. C. Coperet, Z. Owczarczyk, L. S. Harring, and E. Negishi, J. Am. Chem. Soc., 1994, 116, 7923

E

E

I

R

OH

E

E

O O

R

E = COOMe or COOEt

CO, basePdLn

66 %

1812/28/10 18

Ar Ar'

M(0)

Ar X

Ar-M-Ar'

Ar-M-X

Ar' M'

M = Ni, PdM' = Mg, Zn, Sn, Al

Catalytic cycle for cross-coupling reaction

Martin, A. R.; Yang, Y. Acta. Chim. Scand. 1993, 47, 221

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Relationship Between Some Fundamental Properties of Pd and Chemical Consequences

Fundamental Properties of Pd Consequences

Moderately large size Moderate stability of organopalladiums (Ni<Pd<Pt)

Strong preference for 0 and +2 oxidation states separately by a relatively narrow energy gap.

Relatively rare one-electron or radical process (e.g., relative to Ni).

Ready and reversible two-electron oxidation and reduction. (catalysis)

2012/28/10 20

X

X

> XAr > RCOX >C C X

C C X> ArX >> [alkyl] X

Functional Group Reactive Toward Pd

1. Alkyl halides lacking proximal π - or n-donar groups are relatively inert but included for comparison.

2. The X group and approximate reactive order are: I > OTf > Br >Cl > OZ > NZ2, CZ3, etc., where Z is any atom or group attached to O, N, and C.

3. Electron-poor aryl or vinyl halides react with Pd(0) complexes faster than electron rich halides.

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Electronegativity Values and Ionic Character

LiElement

EN

% Ionicity

Mg Ti Al Zn Cu

0.97

43

1.23 1.32 1.47 1.66 1.75

35 30 22 15 12

Element

EN

% Ionicity

Si Sn B C

1.74 1.72 2.01 2.50

12 11 6

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What is Suzuki Coupling reaction?

Recent application of the Suzuki-Miyaura cross-coupling reaction in organic synthesis

Kotha S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.(750 citations)

Most requested documents-chemistry and related scienceCAS Science Spotlight 2003 & 2004

http://www.cas.org/spotlight

Best review paper award 2005 : I. I. T., Bombay

X

R1

B(OH)2

R2

+R1 R2

X=I, Br, OTfz

Pd(0)

a) Miyaura, N.; Suzuki, A. JCS. Chem. Commun. 1979, 866b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437.c) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 513.

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Biologically important molecules with biaryl system

N

OMe

MeO

MeO

OMe

OMeImeluteine

N

O

OMe

Me

Eupolaramine

Natural products

Synthetic drugs

N

NN

NN

NCPh3

Cl

C4H9

Angiotensin (II) receptorAntagonist

N

F

NK-104HMG-CoA Reductase

Inhibitor

Polymers

X

X

X

X

X

X

XX

X

X

O OO O

HO OHHO OH

OHHOOHHO

2

Hyper Branched poly phenylene(Dendrimer)

Octapoly(p -Phenylene)Artif icial ion Channels

OO

CO2tBu

2412/28/10 24

Application of biaryl compounds

Angiotensin II receptor antagonists (treatment of hypertension)

NHNN

NN

NCl

OH

LosartanUS$ 1.3 bn pa (Ranbaxy 2007)

NHNN

NN

N

O

IrbesartanUS$2.1 bn (Sanofi-Aventis)

US$1.3 bn (BMS) 2008NHNN

NN OHO

O

ValsartanUS$881 m (Merck 2009)

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Choice of aryl halide:

X = I, MW = 204.01, Rs. 2560 per mol.X = Br, MW = 157.02, Rs. 183 per mol.X = Cl, MW = 112.56, Rs. 92 per mol.

X = I, 186.7 g per mol.X = Br, 139.7 g per mol.X = Cl, 95.3 g per mol.

X

ClMg

OMe+

[Pd]

OMe

+ MgClX

Choice of transmetallating reagent:

MgClBr (139.7 g/mol), when M = MgClZnClBr (180.6 g/mol), when M = ZnClMe3SnBr (243.6 g/mol), when M = SnMe3

B(OH)3 (61.8 g/mol) and NaBr (102.9 g/mol), when M = B(OH)2

Br

[M]

OMe+

[Pd]

OMe

+side product

Reaction efficiency: atom-economy

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Littke et al Angew. Chem. Int. Ed. Eng. 1998, 38, 3387

B(OH)2

R'

Pd2(dba)3 (1.5 mol%)

P(t-Bu)3 (3.6 mol%)dioxane, Cs2CO3

80-90 °C

Cl

+

R R R'

R = p -NH2= p -Me= p -COMe

R = p -CF3= p -OMe

(87-92%)

2727

S

NMe

Me

HOAc

Me IR2HB

Me

OTBS

MeOTPS

(MeO)2HC Me

Me

+

S

NMe

Me

HOAc

MeMe

Me

OTBS

OTPS

(MeO)2HC MeMe

Pd(DPPF)2Cs2CO3

Ph3AsH2O, DMF, rt

O

O

OOH

Me

Me

O

Me

OHMe

R

H

H

Me

S

NMe

R = Me epothilone BR = H epothelone A

steps

Synthesis of anticancer drugs

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Total synthesis of Michellamine B:

NH

HN

OH

OH OMe

MeOHOMe

Me

Me

Me

Me

MeHO

OH

OH

HN

Me

Me OBn

OBn

B(OH)2

OAc OMe

MeOAcOMe

Me

OTf

OTf

2

Suzuki

Pd(PPh3)4DME/H2O, Ba(OH)2

80 oC, 8h, 74%

Kelly et al Tetrahedon Lett. 1994, 35, 7621

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Synthesis of 4-arylindole-portion diazonamide

• A natural antitumor agent

• In 1999, Magnus et al reported synthesis of 4-arylindole portion of

the antitumor agent using SM coupling reaction in 76% yield

Chan, F.; Magnus, P.; McIver, G. E. Tetrahedron Lettt. 2000, 41, 835

B(OH)2

Me

64

OMeNO2Br Me

OMe

NO2

NH

(i)-(ii)

OMe

NH

Pd(PPh3)4, Na2CO3, EtOH/Toluene

(i) Me2NCH(OMe)2, DMF/111 °C/ 18h(ii) Raney Ni, NH2NH2/THF/H2O/MeOH/ 50 °C/3.5 h

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Roth et al. J. Org. Chem. 1991, 56, 3077.

General representation of Negishi reaction

ZnX X

+Pd(PPh3)4

R1 R2 R1 R2

31

O

3 stepsβ Ionone

OH

Vitamin A

85%

70%67%

> 98% pure

> 98% pure

(> 98% pure)

i.LDAii.ClPO(OEt)2iii.LDA (2.2 eq)

i) Me3Al, cat. Cl2ZrCp2ii) Br

TMS ZnCl2, Pd2(dba)3

iii) K2CO3, MeOHiv) nBuLi, (CH2O)n

Synthesis of Vitamin A

32

O

ONegishi Coupling

Xerulin: an inhibitor of cholesterol biosynthesis

33

Et Ph

(i)Ph2Zncat. Ni(acac)THF-NMP(ii) I2

88%

Ph I

PhEt

Ph

PhEt

O

NMe2H

Cl

O

NMe2H

Cl

BrZnCat. Pd2(dba)34PPh3

66% [Z > 99%]

(Z) Tamoxifen Hydrochloride

Z > 99%

Tamoxifen Hydrochloride: Drug to cure breast cancer

3434

X

+Pd(PPh3)4

R1 R2 R1

R2

General representation of Heck reaction

The greatest social impact of the Heck reaction has been its use in the coupling of alkynes to aryl halides; a reaction which was used to couple fluorescent dyes to DNA bases, allowing the automation of DNA sequencing and the elucidation of the human genome.

Name reactions for homologations Part-I Jie Jack Li. 2009, page No. 3.

3512/28/10 35

Heck coupling for the synthesis of pyrroles

S

I

NHBoc

Br CO2Et

K2CO3, DMF, rt, 2.5 h

S

Pd(OAc)2, PPh3

DMF, 65 oC, 24 h

S

I

N

Boc

CO2Et

72 % overall yield

N

Boc

CO2Et

S

NHBoc

ITBS

OH

TBS = t-BuMe2Si

+S

N

CH2OH

TBS

Boc Pd(OAc)2

Bu4NCl, DMFKOAc, 100 oC,

67%

3612/28/10 36

HN NMe

NMeTs

O

NBn

OTf

H

NMeNH

NMeTsO

BnN

OTfH

HN NMe

H

NMeNH H

BnN

NBn

O

O

NMeTs

NMeTs

+ meso isomer(21%)

(Pd(OAc)2(R)-tol-BINAp

PMP, MeCN80 °C

HN NMe

H

NMeNH H

BnN

NBn

MeN

NMe

H

H

Quadrigemine C

NMe

NH H

HN

MeN

NMe

HN

MeN

NH

Psycholeine

Antibacterial and Analgesicantagonist of the SRIF (somatostatin)receptor

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Our research topics

α-Amino AcidsAcc. Chem. Res. 2003, 342Synlett. 2010, 337

Suzuki-MetathesisChem. Asian J. 2009, 354

MetathesisIndian J. Chem. 2001,763Synlett 2007, 2767Chem. Soc. Rev. 2009, 2065

Suzuki CouplingTetrahedron 2002, 58, 9633Eur. J. Org. Chem. 2007, 1221

PolycyclicsTetrahedron 2001, 57, 625Tetrahedron 2008, 64, 10775Synthesis 2009, 165

Peptide ModificationsCurr. Med. Chem. 2005, 12, 849

[2+2+2] CycloadditionEur. J. Org. Chem. 2005, 4741

Chem. Rev 2011, 000Rongalite

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Proposed list of constrained analogues of phenylalanine (Phe) for modification by SM

reactionR

CO2P

NHAcCO2P

NHAcR

R

CO2PNHAcR

R

R

R CO2P

NHAc

CO2P

NHAc

CO2P

NHAc

NHAc

CO2P

NHAcPO2C

AcHN

CO2P

Phe (R = H)

Ind (R = H)

Atc (R = H)

Dbzg (R= H)

P = Protecting group

Kotha, S. Lahiri, K. Eur. J. Org. Chem. 2007, 1221

3912/28/10 39

R

R

R

RR

N

N

N

R

RR

R

R

O

O

O

O

O

OR

R

R

R

R

R

SO2

R

R

R

Several intricate molecular structures to demonstrate the utility of SM reaction

Kotha, S. Lahiri, K. Eur. J. Org. Chem. 2007, 1221

4012/28/10 40

I

I

NHAc

CO2Me +

B(OH)2

Me

Pd(0)

Na2CO3

THF/Toluene80oC

NHAc

CO2Me

Me

Me89%

I

I

NHAc

CO2Me Ar(OH)2

Pd(PPh3)4

Ar

Ar

NHAc

CO2Me

Kotha, S.; Ghosh, A. K. Synthesis 2004, 558.

Tetralin-based amino acid derivatives by the Suzuki-Miyaura cross-coupling

Coupling reactions from Kotha’s Group

4112/28/10 41

Suzuki Coupling and RCM method towards the synthesis of Benzoannulated products

Kotha, S.; Shah, V. R.; Mandal, K. Adv. Synth. Catal. 2007, 349, 1159-1172.

I

IR1

R2

R3

R1

R2

R3

R1

R2

R3

OB

O

CsF, Pd(PPh3)4,THF, reflux

Grubbs catalyst (3 mol%)

DCM, RT

a R1=NO2, R2=R3=H 90% 60%b R1=CO2Me, R2=R3=H 95% 86%c R1=CO2Et, R2=R3=H 92% 82%d R1=COCH3, R2=R3=H 89% 82%e R1=NO2, R2−R3= 71% 82%

aromatization

4212/28/10 42

I I

I

R R

R

+

B(OH)2

R

Pd(PPh3)4

aq Na2CO3

S

S

S

Br Br

Br

B(OH)2

R

+

Pd(PPh3)4

aq Na2CO3

S

S

S

R

R

R

R = CH3

R = OCH3

R = CHOR = COCH3

R = FR = CF3

R = 2-furylR = 2-thienyl

Eur. J. Org. Chem. 2004, 4003

4312/28/10 43

OH

OH

OH

OH

CHO

CHO

PCC

O

O

IndiumAllyl bromide

DCM, RT,75%

DMF, 15 min,74%

G-II,DCM, RT,33%

Suzuki

Synthesis of Cyclophanes

Kotha, S.; Mandal, K.; Arora, K. K.; Pedireddi, V. R. Adv. Synth. Catal. 2005, 347, 1215.

44

45

4612/28/10 46

NHCOLeuAlANHBoc

H

OMe

O

I

10

NHCOLeuAlANHBoc

H

OMe

O

Ar

a

11

Reagents and conditions: (a) ArB(OH)2, Pd(PPh3)4, Na2CO3, THF/ toluene (1:1)

.

Kotha, S.; Lahiri, K. Bioorg Med. Chem. Lett. 2001, 11, 2887.Kotha, S.; Lahiri, K. Biopolymers 2003, 69, 517.

Suzuki coupling in phenylalanine based peptides

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ChemCatChem 2010, 2, 243-245.

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Subject: many thanks for sending me a copy of your paperFrom: "Akira Suzuki" <asuzuki@eng.hokudai.ac.jp>Date: Tue, March 18, 2003 1:59 amTo: srk@chem.iitb.ac.in

Dear Professor Kotha:Thank you very much for sending me a copy of your review paper on Tetrahedron, which I have recently received through Kurashiki University of Science and Arts. At the end of March in 2002, I retired from the University, and returned to my home in Hokkaido. Of course I read the review article before. It is actually very fine. I am very much pleased to learn that you and your group are interested in our coupling reaction. Recently I have published a book, "Suzuki Coupling" from Aldrich early this year. I submitted the manuscript almost two years ago, but it took long time to be published. As I recognized that many chemists all over the world are interested in the reaction, I have decided to write the second book "Suzuki Coupling Part-2" and already started to write the manuscripts. So I hope you could have chance to read these books in near future. Best regards,Akira Suzuki

Ph. D students

1. Dr. E. Brahmachary2. Dr. N. S. Chary3. Dr. R. Sivakumar4. Dr. E. Manivannan5. Dr. S. Halder6. Dr. (Ms). K. Lahiri7. Dr. K. Mohanraja8. Dr. M. Behera9. Dr. A. Ghosh10. Dr. A. C. Deb11. Dr. D. Kasinath12. Dr. K. Mandal13. Dr. S. Banerjee14. Dr. K. Singh15. Dr. V. Shah16. Dr. (Ms). P. Khedkar17. Dr. M. K. Dipak18. Ms. A. Tiwari19. Ms. N. G. Krishanan20. Mr. S. Vittal21. Ms. S. Misra22. Mr. A. S. Chavan

23. Ms. D. Bansal24. Mr. M. P. Meshram25. Mr. G. Waghule26. Mr. M. Shirbhate27. Mr. R. Ali

1. Mr. S. A. Jothi2. Mr. G. Giridharan3. Ms. R. Deshpande 4. Ms. M. S. Subhashi5. Mr. S. R. Subbaiah6. Mr. A. Mehta7. Mr. C. Chatterjee8. Mr. AP. Suresh Babu9. Ms. S. Bhattacharjee10. Mr. P. Charkrabarty11. Mr. T. Kesharwani12. Mr. A. Singh 13. Mr. V. Rane 14. Mr. A. Pal 15. Mr. T.T. Rao16. Mr. M. Banik 17. Mr. R. K. Das 18. Mr. V. Shukla 19. Mr. U. Basu 20. Mr. K. Raju21. Ms. G. Rama

M. Sc. students

1. Dr. T. Ganesh2. Dr. R. Vinod. Kumar3. Dr. S. Kumar4. Dr. (Ms). K. Lahiri5. Dr. D. Nagaraju6. Dr. (Ms). P. Khedkar7. Dr. T. Niranjan

Post-doctoral students

Project/Summer students

1. Mr. S. M. Husian2. Mr. M. J. Rihan3. Ms. M. Sridevi4. Mr. A. Pradeesh5. Ms. B. V. Lakshmi

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