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

12/28/10 1 "palladium-catalyzed cross couplings in organic synthesis”

Richard F. Heck Ei-ichi Negishi Akira Suzuki

University of Delaware Purdue University Hokkaido University USA West Lafayette Sapporo, Japan IN, USA B 1931 B 1935 B 1930

12/28/10 2 Heck, Negishi and Suzuki coupling in synthesis of fine chemicals

Heck reaction

O Si Si

DVS-bis-BCM (electronic resin monomer)

N O N Negishi Cl coupling N Cl HN O

HN Suzuki coupling Serotonin agonist Boscalid 12/28/10 (fungiside) 3 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/ 4 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/ 5 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/ 6 Youngest Chemistry Laureate

“in recognition of their synthesis of new radioactive elements” 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

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

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. 7 http://nobelprize.org/nobel_prizes/chemistry/ Multiple Nobel Laureates in Chemistry

Marie Curie Linus Pauling Frederick Sanger Physics 1903 Chemistry 1954 Chemistry 1958 Chemistry 1911 Peace 1962 Chemistry 1980

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

http://nobelprize.org/nobel_prizes/chemistry/ 8 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.

9 http://nobelprize.org/nobel_prizes/chemistry/ 12/28/10 10 ORGANIC SYNTHESIS

Target Oriented Methods Oriented (Total Synthesis)

Natural Designed Reagents Catalysts Synthetic Synthetic Products Molecules Strategies Tactics

Material Science Biologically Theoretically Medically Interesting Interesting Interesting Interesting Molecules Molecules Molecules Molecules 12/28/10 11 Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis, VCH, Weinheim, Germany, 1996. Organic Reaction Vs Synthetic Method

R1 R1 R2 R EWG R7 R 7 ∆ R3 3 R EWG 2 + R6 R9 R R8 R9 R4 4 R8 R5 R6 R5

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 12/28/10 13 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

12/28/10 14 Catalytic route Boots route Hoechst Celanese H

Ac2O, HF H O

Ac O, HF 2 H

O Cl CO2Et NaOEt H O

CO2Et

Raney Nickel + H2O/H H2

OH O H

NH2OH

CO and Pd N OH H

H2O CO2H H2O N Ibuprofen 15 Commonly used Aryl-Aryl couplings methods

Cu Ar Br + Ar' Br Ar Ar' Ullmann Coupling

Ar MgCl + Ar' Br Ni or Pd Ar Ar' Kumada Coupling

Pd Ar ZnCl + Ar' Br Ar Ar' Negishi Coupling Pd Ar SnBu3 + Ar' Br Ar Ar' Stille Coupling Pd Ar B(OH)2 + Ar' Br Ar Ar' Suzuki Coupling Pd Ar Ar' Hiyama Coupling Ar Si(R')3 + Ar' Br

12/28/10 16 Zipper-mode cascade reaction with Pd

OH O O

R CO, base R PdLn E E E E I

E = COOMe or COOEt 66 %

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

OMe MeO

PdLn

PhO2S PhO2S PhO2S SO2Ph

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

12/28/10 17 Catalytic cycle for cross-coupling reaction

Ar Ar' Ar X M(0)

M = Ni, Pd Ar-M-X M' = Mg, Zn, Sn, Al

Ar' M' Ar-M-Ar'

Martin, A. R.; Yang, Y. Acta. Chim. Scand. 1993, 47, 221 12/28/10 18 Relationship Between Some Fundamental Properties of Pd and Chemical Consequences

Fundamental Properties of Pd Consequences

Moderately large size Moderate stability of organopalladiums (Ni

Strong preference for 0 and +2 Relatively rare one-electron or oxidation states separately by a radical process (e.g., relative to relatively narrow energy gap. Ni). Ready and reversible two-electron oxidation and reduction. (catalysis)

12/28/10 19 Functional Group Reactive Toward Pd

C C X X > > Ar X RCOX > > ArX >> [alkyl] X C C X

X

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.

12/28/10 20 Electronegativity Values and Ionic Character

Element Li Mg Ti Al Zn Cu EN 0.97 1.23 1.32 1.47 1.66 1.75 % Ionicity 43 35 30 22 15 12

Element Si Sn B C EN 1.74 1.72 2.01 2.50 % Ionicity 12 11 6

12/28/10 21 What is Suzuki Coupling reaction?

X B(OH)2

Pd(0) + R 1 R2 R1 R2

X=I, Br, OTfz

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

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 science CAS Science Spotlight 2003 & 2004 http://www.cas.org/spotlight

Best review paper award 2005 : I. I. T., Bombay 12/28/10 22 Biologically important molecules with biaryl system

Natural products Polymers OMe O X X MeO

N N Me Hyper Branched poly phenylene MeO X X (Dendrimer) X OMe OMe

OMe X Imeluteine Eupolaramine X Synthetic drugs X HO OH HO OH Cl F HO N HO OH OH CPh3 X X N N N C4H9 O O O O N N O O

CO2tBu 2 N Octapoly(p-Phenylene) Angiotensin (II) receptor NK-104 Artificial ion Channels Antagonist HMG-CoA Reductase Inhibitor

12/28/10 23 Application of biaryl compounds

Cl N OH N N N N O N NH N N N N NH

Losartan US$ 1.3 bn pa (Ranbaxy 2007) HO Irbesartan O N N N US$2.1 bn (Sanofi-Aventis) O N NH US$1.3 bn (BMS) 2008

Valsartan US$881 m (Merck 2009)

12/28/10 24 Angiotensin II receptor antagonists (treatment of hypertension) Reaction efficiency: atom-economy Choice of aryl halide:

ClMg [Pd] + MgClX + OMe X OMe X = I, MW = 204.01, Rs. 2560 per X = I, 186.7 g per mol. mol. X = Br, 139.7 g per mol. X = Br, MW = 157.02, Rs. 183 per X = Cl, 95.3 g per mol. mol. X = Cl, MWChoice = 112.56, of transmetallating Rs. 92 per mol. reagent: [M] [Pd] +side product + Br OMe OMe MgClBr (139.7 g/mol), when M = MgCl ZnClBr (180.6 g/mol), when M = ZnCl

Me3SnBr (243.6 g/mol), when M = SnMe3

12/28/10 B(OH)3 (61.8 g/mol) and NaBr (102.9 g/mol), 25

when M = B(OH)2 Cl B(OH)2

Pd2(dba)3 (1.5 mol%) + P(t-Bu)3 (3.6 mol%) R R' dioxane, Cs2CO3 R R' 80-90 °C

R = p-NH2 R = p-CF3 (87-92%) = p-Me = p-OMe = p-COMe

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

12/28/10 26 Synthesis of anticancer drugs

S Me N Me H (MeO)2HC OAc Me Me Me + OTPS

Pd(DPPF)2 R2HB OTBS Cs2CO3 Me I Me

Ph3As H2O, DMF, rt S S Me Me N N H H O O OAc Me H OH Me O steps Me (MeO)2HC Me Me Me R Me Me O Me OTPS OH Me OTBS Me R = Me epothilone B R = H epothelone A 27 Total synthesis of Michellamine B:

Me OH Me OBn

HN HN 2 Me OH Me OBn Suzuki Me B(OH)2 OH OMe OTf OMe OH Me Me OAc OMe HO Me OMe OAc NH Me OH Me OTf Pd(PPh3)4 DME/H2O, Ba(OH)2 80 oC, 8h, 74% 12/28/10 28 Kelly et al Tetrahedon Lett. 1994, 35, 7621 Synthesis of 4-arylindole-portion diazonamide

Me B(OH) Me Br NO2 2 OMe NO2 (i)-(ii) NH Pd(PPh ) , Na CO , 3 4 2 3 OMe OMe EtOH/Toluene 64 N H

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

• 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

12/28/10 Chan, F.; Magnus, P.; McIver, G. E. Tetrahedron Lettt. 2000, 29 41, 835 General representation of Negishi reaction

ZnX X

Pd(PPh3)4 +

R R 1 2 R1 R2

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

12/28/10 30 Synthesis of Vitamin A

i.LDA ii.ClPO(OEt)2 O iii.LDA (2.2 eq)

3 steps 85% β Ionone

i) Me3Al, cat. Cl2ZrCp2 ii) TMS ZnCl , Pd (dba) > 98% pure Br 2 2 3 iii) K2CO3, MeOH iv) nBuLi, (CH2O)n

67% > 98% pure 70%

OH

Vitamin A (> 98% pure)

31 O

Negishi Coupling O

Xerulin: an inhibitor of cholesterol biosynthesis

32 Tamoxifen Hydrochloride: Drug to cure breast cancer

(i)Ph2Zn cat. Ni(acac) THF-NMP Ph I (ii) I Et Ph 2 88% Et Ph Z > 99% O

NMe2H Cl

Cat. Pd2(dba)3 BrZn 4PPh3

O

NMe2H Cl Ph

Et Ph 66% [Z > 99%]

(Z) Tamoxifen Hydrochloride 33 General representation of Heck reaction

X

Pd(PPh3)4 + R2 R R 1 2 R1

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. 34 Heck coupling for the synthesis of pyrroles

CO2Et I I Br CO2Et

S NHBoc S N K2CO3, DMF, rt, 2.5 h Boc

Pd(OAc)2, PPh3 DMF, 65 oC, 24 h 72 % overall yield

CO2Et

S N Boc

Pd(OAc)2 NHBoc Boc OH Bu4NCl, DMF KOAc, 100 oC, N + TBS S I 67% S TBS TBS = t-BuMe2Si CH2OH 12/28/10 35 NMeTs Bn O N NMeTs O H H H H N N NMe NBn NMe (Pd(OAc)2 OTf (R)-tol-BINAp + meso isomer (21%) PMP, MeCN 80 °C NMe NMe OTf N Bn N H N H H H NMeTs O N O NMeTs Bn

Me N Bn H Me NH N N

H H H MeN N N NMe

HN NMe NMe N H H N N NMe H H Me N Bn H

Psycholeine Quadrigemine C

antagonist of the SRIF (somatostatin) Antibacterial and Analgesic 12/28/10 receptor 36 Our research topics

Suzuki Coupling Peptide Modifications Tetrahedron 2002, 58, 9633 Curr. Med. Chem. 2005, 12, 849 Eur. J. Org. Chem. 2007, 1221 Metathesis Indian J. Chem. 2001,763 Rongalite α-Amino Acids Synlett 2007, 2767 Chem. Rev 2011, 000 Acc. Chem. Res. 2003, 342 Chem. Soc. Rev. 2009, 2065 Synlett. 2010, 337 Suzuki-Metathesis Chem. Asian J. 2009, 354 Polycyclics Tetrahedron 2001, 57, 625 [2+2+2] Cycloaddition Tetrahedron 2008, 64, 10775 Eur. J. Org. Chem. 2005, 4741 Synthesis 2009, 165

12/28/10 37 Proposed list of constrained analogues of phenylalanine (Phe) for modification by SM R reaction

R NHAc R NHAc CO2P NHAc R R CO2P Ind (R = H) CO2P Dbzg (R Phe (R = H) = H)

NHAc NHAc NHAc R CO2P CO2P CO2P

R Atc (R = H)

CO2P NHAc AcHN CO P 2 PO2C NHAc P = Protecting group

12/28/10 38 Kotha, S. Lahiri, K. Eur. J. Org. Chem. 2007, 1221 Several intricate molecular structures to demonstrate the utility of SM reaction R R

R

N N

N R R R R R

R R O R O O R

SO2 R O O R R O

R

R R

12/28/10 39 R Kotha, S. Lahiri, K. Eur. J. Org. Chem. 2007, 1221 Coupling reactions from Kotha’s Group

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

I NHAc Ar NHAc Ar(OH) CO2Me 2 CO2Me

I Pd(PPh3)4 Ar

Me B(OH)2 NHAc I NHAc Pd(0) CO2Me CO2Me + Na2CO3 I THF/Toluene Me 80oC Me 89%

Kotha, S.; Ghosh, A. K. Synthesis 2004, 558. 12/28/10 40 Suzuki Coupling and RCM method towards the synthesis of Benzoannulated products

O R3 R3 R3 B Grubbs O R R2 I R2 catalyst (3 mol%) 2 CsF, DCM, RT R1 I Pd(PPh ) , R1 R1 3 4 aromatization THF, reflux

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%

Kotha, S.; Shah, V. R.; Mandal, K. Adv. Synth. Catal. 2007, 349, 1159-1172. 12/28/10 41 R R

I I B(OH)2

Pd(PPh3)4 + aq Na2CO3

R

R = CH3 I R = OCH3 R = CHO R = COCH3 R = F R R R = CF3 R = 2-furyl R = 2-thienyl

Br Br S S B(OH)2 R Pd(PPh3)4 S S + aq Na2CO3

R S S

Br

12/28/10 42 R Eur. J. Org. Chem. 2004, 4003 Synthesis of Cyclophanes

Suzuki

CHO Indium Allyl bromide OH

DMF, 15 min, OH CHO 74%

G-II, DCM, RT, 33%

O OH

PCC DCM, RT, 75% O OH

12/28/10Kotha, S.; Mandal, K.; Arora, K. K.; Pedireddi, V. R. Adv. Synth. Catal. 2005, 347, 1215. 43 44 45 Suzuki coupling in phenylalanine based peptides

I Ar

a O O H H OMe OMe NHCOLeuAlANHBoc NHCOLeuAlANHBoc 10 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.

12/28/10 46

ChemCatChem 2010, 2, 243-245.

12/28/10 47 12/28/10 48 12/28/10 49 12/28/10 50 12/28/10 51 12/28/10 52 Subject: many thanks for sending me a copy of your paper From: "Akira Suzuki" Date: Tue, March 18, 2003 1:59 am To: [email protected]

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 M. Sc. students 1. Dr. E. Brahmachary 23. Ms. D. Bansal 1. Mr. S. A. Jothi 2. Dr. N. S. Chary 24. Mr. M. P. Meshram 2. Mr. G. Giridharan 3. Dr. R. Sivakumar 25. Mr. G. Waghule 3. Ms. R. Deshpande 4. Dr. E. Manivannan 26. Mr. M. Shirbhate 4. Ms. M. S. Subhashi 5. Dr. S. Halder 27. Mr. R. Ali 5. Mr. S. R. Subbaiah 6. Dr. (Ms). K. Lahiri 6. Mr. A. Mehta 7. Dr. K. Mohanraja Post-doctoral students 7. Mr. C. Chatterjee 8. Dr. M. Behera 1. Dr. T. Ganesh 8. Mr. AP. Suresh Babu 9. Dr. A. Ghosh 2. Dr. R. Vinod. Kumar 9. Ms. S. Bhattacharjee 10. Dr. A. C. Deb 3. Dr. S. Kumar 10. Mr. P. Charkrabarty 11. Dr. D. Kasinath 4. Dr. (Ms). K. Lahiri 11. Mr. T. Kesharwani 12. Dr. K. Mandal 5. Dr. D. Nagaraju 12. Mr. A. Singh 13. Dr. S. Banerjee 6. Dr. (Ms). P. Khedkar 13. Mr. V. Rane 14. Dr. K. Singh 7. Dr. T. Niranjan 14. Mr. A. Pal 15. Dr. V. Shah 15. Mr. T.T. Rao 16. Dr. (Ms). P. Khedkar Project/Summer students 16. Mr. M. Banik 17. Dr. M. K. Dipak 1. Mr. S. M. Husian 17. Mr. R. K. Das 18. Ms. A. Tiwari 2. Mr. M. J. Rihan 18. Mr. V. Shukla 19. Ms. N. G. Krishanan 3. Ms. M. Sridevi 19. Mr. U. Basu 20. Mr. S. Vittal 4. Mr. A. Pradeesh 20. Mr. K. Raju 21. Ms. S. Misra 5. Ms. B. V. Lakshmi 21. Ms. G. Rama 22. Mr. A. S. Chavan

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