“Palladium-catalyzed reactions: a revolutionary impact in Medicinal

Chemistry”

Scuola di dottorato in scienze e tecnologie della chimica e dei

materiali

Corso di Scienze Farmaceutiche, alimentari e cosmetologiche

Andrea Desogus, PhD

PALLADIUM (Pd)

From “Pallas” (asteroid / goddess)

PALLADIUM

Isolation in 1803, by dissolution of Platinum in HNO3 and H2SO4

1805 - Recognition of the discovery by the English Royal Society of Chemistry

WILLIAM HYDE WOLLASTON

1766 - 1828

PALLADIUMPROPERTIES

atomic number 46

atomic weight 106.42

phisical state at r.t. solid

melting point 1554.9 °C

Boiling point 2963 °C

density 12.023

Electronic configuration [Kr]4d10

Oxidation states 0, +1,+2,+3,+4,+5,+6

Common isotopes: Pd-102, Pd-104, Pd-105, Pd-106, Pd-108, Pd-110

COMMON USES

Catalytic converter for cars

Jewelry

Electronics

Hydrogen storage

Dentistry

Organic synthesis

PALLADIUM

Pd-catalyzed Hydrogenation of alkenes

•Two hydrogen atoms added across the double bond

•Thermodynamically favorable reaction

•Pd catalyst cleaves H2 into 2H, attaching them on its surface together with the alkene syn addiction

Hydrogenator

The Pt group

PALLADIUM

Pt group

Very reactive and very useful in catalysis

“18 rule” 3d10 4s2 4p6 e.c. of Kr and Xe

They strongly want to reach 18 external e-

Pd: 10 e-

Pd in coupling reactions

Wide interest in C-C,C-N, C-O bonds formation

Palladium complexes are catalysts: they can switch oxydation state and lower the activation energy

Pd complexes are coupled with a ligand, usually a phosphine

Pd(0)

•Good nucleophilic

•Good Base

•Reductant

Pd(II)

•Good electrophilic

•Good reactivity with electron-rich olefines

•Good reactivity with Lewis bases

•Oxydant

Palladium complex species

Types of Pd catalysts

•Pd precursors

Used with a suitable ligand

•1° generation catalysts

PPh3 as ligand

Palladium Acetate

Pd2(dba)3

• 2 nd generation catalysts

Bidentate phosphine

palladium complexes

Types of Pd catalysts

Pd(dppf)Cl2 Pd(dppb)Cl2

• 3 rd generation catalysts

Pd(I) dimerTriaryl phosphite based palladacycle

New catalysts

Types of Pd catalysts

Buchwald 2012

Enantioselective asymmetric SMR

Synthesis of tri-ortho-substituted biaryls

RT synthesis of tetra-ortho-substuted biaryls

Zwitterion, RT SMR for sterically hindred substrates

Evolution of Phosphine ligands

dppf

Nobel Prize in chemistry 2010

“Palladium-catalyzed cross couplings in organic synthesis”

Akira Suzuki Richard Heck Ei-ichi Negishi

Palladium-catalyzed cross-couplings

Mild reaction conditions

Thermally stable reagents

Inert to water and oxygen

Chemoselective

Low toxicity of reagents, ligands and catalysts

ADVANTAGES

Important reactions in Palladium-catalyzed cross-couplings• Oxydative addition / Reductive elimination

• β–hydride elimination

• Transmetalation

β

α

HECK CROSS-COUPLING

1972

HECK CROSS-COUPLINGArylation or alkylation of olefines

•Not cataylitic arylation of olefines (1968)

•Organopalladium generation through RHgX and Pd(II) salt.

•Cataylitic with CuCl2 as reoxidant of Pd(0) to the Pd salt.

HECK CROSS-COUPLINGImportant modification (1972)

•Fitton’s discovery: aryl halides react with Pd(0) to give arylpalladium halides

•The organopalladium complex RPdX is generated from an organohalide, RX, and Pd(0)

Oxidative addition

Standard protocol

HECK CROSS-COUPLINGArylation or alkylation of olefines

•Organohalide RX

•Alkene

•Pd catalyst

•Ligand (usually with PPh3)

HECK CROSS-COUPLINGOxidative addition

Migratory insertion

β-hydride eliminationOlefine decomplexation

Reductive elimination

NEGISHI CROSS-COUPLING1977

NEGISHI CROSS-COUPLING

C-C coupling with organometallic species

•First studies: organozirconium and organoalluminium compounds as coupling partners good results

•Attempt with even less reactive species: organozinc compounds

Superior yields Very mild Highly selective

NEGISHI CROSS-COUPLING

Coupling of aryl or alkyl compounds

•Organozinc

•Organohalide

•Pd catalyst

•Ligand (usually PPh3)

NEGISHI CROSS-COUPLING

Oxidative addition

Transmetalation

Reductive elimination

SUZUKI CROSS-COUPLING1979

SUZUKI CROSS-COUPLINGCoupling of aryl and alkyl compounds with organoboronates

•Organoboron compounds in the presence of a base can be used as coupling partners in palladium-catalyzed cross coupling with vinyl and aryl halides

•Organoboron compounds: stable, weak nucleophils, chemoselective (wide range of functional groups), not toxic, not reactive

•Study with Miyaura: also named Suzuki-Miyaura reaction (SMR)

SUZUKI CROSS-COUPLINGBoronic acids or esters

Base

NaOH, NaHCO3, K2CO3, Et3N, Cs2CO3, NaOEt, CsF

Base activation of organoboron reagents as boronate intermediates facilitated the transfer of the organic group from boron to palladium

transmetalation

SUZUKI CROSS-COUPLINGCoupling of aryl and alkyl compounds

•Organohalide

•Boronic acid or ester

•Base

•Pd catalyst

•Ligand (usually PPh3)

SUZUKI CROSS-COUPLING

Oxidative addition

Transmetalation(rate limit step)

Reductive elimination

Other Pd Cross-couplings

Sonogashira Reaction

•Ethinylation

•Double cycle:

oPalladium cycle oCopper cycle with base Transmetalation

Inert atmosphere!

Other Pd Cross-couplingsStille Reaction

•Base not needed

•Use of Stannanes, compounds with Sn 4+ and 3 alkyl groups

•Difficult to couple an alkyl no selectivity

•Not Green: organo-tin compounds are TOXIC

Tributyltin chloride Hexamethylditin

Other Pd Cross-couplingsBuchwald-Hartwig amination

•C-N bond between aromatic carbon and amine

•Very difficult with traditional methods: stressed conditions

Cross-Coupling Applicationsin Medicinal Chemistry

Drug synthesis

Natural products synthesis

Industrial applications

Chemical transformation in living organisms

Heck coupling in Taxol® synthesis

Paclitaxel (Taxol®) BMS

Heck coupling in morphine synthesis

Morphine

Negishi coupling in Pumiliotoxin A synthesis

Pumiliotoxin A(toxic alkaloid)

Other applications of Negishi coupling

Hennoxazole Aantiviral

Negishi coupling

5-HT1A agonist(Eli Lilly,1997)

Negishi coupling

Suzuki coupling in (+)-dynemicin A synthesis

(+)-dynemicin A(antitumor agent)

Other applications of Suzuki coupling

Boscalid(fungicide)

Dragamacidin F antiviral

Suzuki coupling

Suzuki coupling

Suzuki nano-coupling in cells

•Pd-catalyzed reactions in living organisms: biocompatibility

•Palladium-meditated cell-surface labeling

•SMR with cell penetrating Pd[0]-nanocatalyst Pd(OAc)2(ADHP)2

•Coupling between a modified pore protein with a fluorescent boronic acid on a surface of E. coli

Pore proteinSpicer et al. J. Am. Chem. Soc. 2012, 134, 800

…Some personal experience…

Attempt of a Heck coupling

Possible reasons:

•Chlorine si the worst leaving atom (I>Br>Cl)

•Not a real alkene (N and X whitdraw e-)

…Some personal experience…

General procedure of a Suzuki coupling

R= H, CH3, F, Cl, acetyl, indolyl

Tintori et al. J. Med. Chem. 2015, 58, 347

CONCLUSIONS Palladium is the most versatile and ubiquitous metal in modern

organic synthesis.

Its use as catalyst has allowed the discovery of new reaction, most of them worthy the Nobel Prize.

Heck, Negishi and Suzuki cross-couplings, together with other Pd catalyzed reactions, are frequently used in drug synthesis. Thanks to them, new useful active compounds have been discovered.

The study of Pd complexes is still in progress, so new reaction, impossible to perform so far, could appear in the future.

THANKS FOR YOUR ATTENTION