Pd(0)-Catalyzed C(sp3)-H Activation for the Synthesis of Natural Products and Cyclopropanes

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Pd(0)-Catalyzed C(sp

³

)-H Activation for the Synthesis of Natural Products and Cyclopropanes

Inauguraldissertation

zur

Erlangung der Würde eines Doktors der Philosophie vorgelegt der

Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel

von

Pierre Thesmar

BASEL, 2021

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel https://edoc.unibas.ch

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Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von

Prof. Dr. Olivier Baudoin Prof. Dr. Konrad Tiefenbacher Prof. Dr. Erick Carreira

Basel, 13/10/2020

Prof. Dr. Martin Spiess

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A Jacques et Marie-Thérèse.

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Acknowledgements

I would like to thank Prof. Dr. Olivier Baudoin for allowing me to perform my PhD within his research group. In particular, I thank him for allowing me to work on several fascinating projects, and giving me a great freedom to carry these out. Thank you a lot for this great mentorship, the experience and knowledge acquired during this time in your research lab is invaluable.

I warmly thank Konrad Tiefenbacher for co-supervising me during these four years (thank you for all the fruitful discussions), Prof Dr. Erick Carreira for accepting to co-examinate this thesis and Prof. Dr. Daniel Häussinger for chairing this PhD defense.

Thanks to the Baudoin team, past and present. Merci à Ronan pour m’avoir souvent guidé au début de ma thèse et ses conseils avisés. Big thanks as well to Antonin, Stefania, Nadja, Tavarichs Oleks and Anton, Kevin, Rafael, Shu-Shu, Takeru-san, Yann, David and my students/visiting students Brian, Phillip and Alessio.

Special thanks to all the members of the African Lab tribe: Ronan, Oleks, Brian, Alessio, Marc and Anton.

Un grand merci à Rodolphe « l’Oracle », Ronan, Antonin et Nina pour la relecture de cette thèse.

Thanks to all the staff of the University of Basel.

Merci à tous mes amis de Basel/Huningue/Saint-Louis !

Merci à tous les autres, disséminés aux quatre coins de la France et même ailleurs, qui m’ont fait l’honneur de venir me rendre visite à Basel-city.

Merci à ma famille, qui malgré la distance et mes visites qui se sont fait plus rares ces dernières années, m’ont toujours soutenu. Merci Papa, Maman, Victor et Maxime.

Merci Nina. Avoir eu la chance de te rencontrer est l’un des plus beaux cadeaux que le destin

m’ait jamais fait. Merci de m’avoir toujours soutenu, en particulier ces derniers mois. Mais

surtout merci pour tout le reste.

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Abstract

C-H bonds are ubiquitous in organic substances. That is why, over the past decades, the transition metal-catalyzed intramolecular activation of unactivated C-H bonds has emerged as a powerful tool for synthetic chemists. In particular, selective activation and functionalization of C-H bonds allows a straightforward access to high molecular complexity in an atom- and step-economical fashion and without the need from extensive functionalization of the starting materials.

Our research group being specialized in this particular field, my PhD thesis has been focused on the application of Pd(0)/Pd(II) catalyzed C(sp

³

)-H activation methods for the total synthesis of complex natural products, along with the development of new methodologies using this approach.

In the first part of this thesis, we report the enantioselective, scalable and divergent total synthesis of two complex dithiodiketodipiperazine natural products (–)-epicoccin G and (–)- rostratin A using a double Pd(0)-catalyzed C(sp

³

)-H activation strategy.

In the second part of this thesis, we present a new synthetic method to access cyclopropanes using remote functionalization of distal C-H bonds. Overall, taking advantage of the Pd-1,4 shift reactivity, cyclopropanation reaction was performed from intramolecular double C(sp

³

)- H activation on gem-dialkyl groups, which has been considered for long as an elusive transformation.

Keywords: C-H functionalization, C(sp³

)-H activation, organometallic catalysis, palladium, natural products, total synthesis, dithiodiketopiperazines, (–)-epicoccin G, (–)-rostratin A, 1,4- Pd shift, distal functionalization, cyclopropanes.

Pierre Thesmar

Prof. Dr. Olivier Baudoin group Department of Chemistry University of Basel St. Johanns-Ring 19

CH-4056 Basel, Switzerland

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Published works during this PhD

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp³)–H Activation Strategy,

Pierre Thesmar, Seemon Coomar, Alessandro Prescimone, Daniel Häussinger, Dennis Gillingham, Olivier Baudoin, Chemistry A European

Journal, 2020, doi: 10.1002/chem.202003683

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups Through Double C-H Activation, Antonin Clemenceau, Pierre Thesmar, Maxime Giquel, Alexandre Le Flohic, and

Olivier Baudoin, Journal of the American Chemical Society, 2020, 142, 36, 15355-15361

Efficient and Divergent Total Synthesis of (−)-Epicoccin G and (−)-Rostratin A Enabled by Double C(sp³)–H Activation, Pierre Thesmar and Olivier Baudoin, Journal of the American Chemical Society, 2019, 141, 40, 15779-15783

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Abbreviations:

Ac: Acetyl

Ac

2

O: Acetic anhydride AcOH: Acetic acid Ar: Aryl

BCB: Benzocyclobutene

BDE: Bond Dissociation Energy Cat.: Catalytic

CDC: Cross dehydrogenative coupling CMD: Concerted Metalation Deprotonation Cy: Cyclohexyl

Cyp: Cyclopentyl

d.r.: Diastereoisomeric ratio dba: Dibenzylideneacetone DCE: 1,2-dichloroethane DCM: Dichloromethane

DFT: Density functional theory DHIQ: 3,4-dihydroisoquinoline DHB: Dihydrobenzofuran

DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobutylaluminum hydride DKP: Diketopiperazine

DMAP: N,N-dimethylaminopyridine

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DMF: Dimethylformamide

DMSO: Dimethylsulfoxide

dppm: 1,1-Bis(diphenylphosphino)methane DTP: Dithiodiketopiperazine

e.r.: Enantiomeric ratio equiv.: Equivalent Et: Ethyl

FG: Functional group

FGT: Functional group transformation

F-TOTP: Tri(5-fluoro-2-methylphenyl)phosphine HAT: Hydrogen atom transfer

HIV: Human immunodeficiency virus HFIP: Hexafluoroisopropanol

HPLC: High pressure liquid chromatography IAC: Intramolecular acylal cyclisation IC

50

: Half maximal inhibitory concentration KIE: Kinetic isotopic effect

L: Ligand

LAH : Lithium aluminum hydride MS: Molecular sieves

MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide NBE: norbornene

NBS: N-bromosuccinimide

n-Bu: 1-Butyl

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Nf: Nonaflyl

NHCs: N-heterocyclic carbenes NMO: N-methyl morpholine N-oxide NMR: Nuclear magnetic resonance

ORTEP: Oak Ridge Thermal Ellipsoid Plot Ph: Phenyl

Piv: Pivaloyl

pKa: Acid dissociation constant (logarithmic scale) PPh

3

: Triphenylphosphine

PtBu

3

: Tri-tert-butylphosphine Py: Pyridine

RT: Room temperature SM: Starting material T: Temperature

TADDOL: α,α,α',α'-Tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol TBS: tert-Butyldimethylsilyl

TBAC: Tetrabutylammonium chloride TDG4: 2-hydroxynicotinaldehyde Tf: Triflyl

TFA: Trifluoroacetic acid

TFAA: Trifluoroacetic anhydride

TFE: 2,2,2-trifluoroethanol

TIPS: Triisopropylsilyl

THF: Tetrahydrofuran

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TMB: Trimethoxybenzyl

TMEDA: Tetramethylethylene diamine

s: Tosyl

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Part I: Introduction and bibliographic part

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1 Generality on organic chemistry

“Chemistry means the difference between poverty and starvation and the abundant life.”

—Robert Brent, First Mayor of Washington, D.C.

These powerful words summarize well the importance that chemistry has taken in our society, from basic cooking to elaborated polymers. In particular, organic chemistry, even if used unconsciously by humanity since millennials, was formally considered as a science since the synthesis of urea from potassium cyanate and ammonium sulfate by Friedrich Wöhler in 1828.

¹

This event disproved the previously established doctrine of vitalism, which stated that organic materials could not be synthesized form inorganic compounds.

²

Organic chemistry discovery allowed the rise of the pharmaceutical industry in the late 19

^th

century, and not so long after polymers, plastics and petroleum industries along with early academic research in this field.

³

In almost 200 years since its discovery, modern synthetic chemistry made great progress, as an

ultimate goal the efficient assembly of easily available building blocks in an efficient and

concise way, to produce complex targets of interest. This was mainly achieved by classical

approach consisting in transforming pre-existing functional groups into the desired chemical

functions (Scheme 1, a). This classical approach, used by chemists to build and functionalize

organic compounds, and then access chemical diversity through functional-group

interconversion, witnessed impressive advances. Nowadays, a cleverly designed synthetic

route can solve many regio-, chemo- and enantioselectivity issues. However, in a context of

green chemistry and atom-economy, synthetic chemists were keen to pioneer new synthetic

processes to answer the need of modern organic synthesis.

⁴

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Scheme 1: Different approaches to access desired functionality

Over the past decades, transition-metal catalyzed cross-couplings and related reactions, have

witnessed an impressive development, considerably extending the synthetic organic chemistry

toolbox. In particular, palladium-catalyzed cross-coupling and related reactions, as for instance

the Heck reaction or the Buchwald-Hartwig reaction, currently rank among the most useful and

widely used tools for synthetic chemists. Indeed, this new and efficient way to form carbon-

carbon and carbon-heteroatom bonds allowed a much easier access to sought-after molecular

complexity, in a concise and selective fashion (Scheme 1, b).

⁵

Today palladium-catalyzed

cross-coupling reactions can be considered as a comparatively mature technology and are used

routinely both in academia and industry.

⁶

Firstly described in the 1970’s, their development

grew exponentially after the full realization of their synthetic usefulness in the 1990’s by the

discovery of the drastic activity enhancement exhibited by palladium complexes with strongly

α-donating and bulky donating ligands. This statement is clearly demonstrated by the growing

interest in this field in modern literature (Figure 1). Finally, the Nobel Prize in Chemistry was

attributed in 2010 to Heck, Negishi and Suzuki, due to the success and popularity of this

research field, as well as the continuously growing literature in this area.

⁷

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Figure 1: Number of publications and patents related to named metal-catalyzed cross-coupling reaction

Most palladium-catalyzed cross-coupling reactions follow the same core mechanism, although some important differences can be noticed. The general mechanism for this family of reaction can be well exemplified by the Suzuki-Miyaura or Negishi cross-coupling. It is initiated by an oxidative addition of a carbon-halide/pseudohalide bond into Pd(0) complex, generating an electrophilic Pd(II) organometallic species. This electrophilic complex then undergoes transmetallation with a nucleophilic organoboronic or organozinc compound. The resulting Pd(II) complex, upon reductive elimination, affords the desired cross-coupled product.(Scheme 2)

Scheme 2: General mechanism for Suzuki-Miyaura and Negishi cross-couplings

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The usefulness of this kind of method has been proved via numerous applications.

⁸

However, the necessity to pre-functionalize the starting material in addition with the generation of stoichiometric waste prompted synthetic chemists to design greener and more efficient alternatives such as C-H activation.

Unactivated sp

²

and sp

³

carbon-hydrogen bonds being ubiquitous in organic compounds, the most efficient and concise imaginable synthetic approach toward the construction of complex organic frameworks would be the direct and selective functionalization of these particular bonds (Scheme 1, c).

⁹

However, despite being the most atom-economical possible strategy, the intrinsic low reactivity of C-H bonds combined with selectivity issues for the functionalization of complex structures makes this approach challenging.

2 C(sp

³

)-H functionalization

Whereas transition-metal catalyzed C(sp

²

)-H activation methods have been widely developed in the past three decades,

¹⁰

reports of C(sp

³

)-H bond functionalization are much less common.

Indeed, alkyl C(sp

³

)-H bonds are known to be particularly challenging to cleave because of their poor reactivity, rationalized by their high energy (90 to 100 kcal/mol), low acidity (pKa

= 45-60) and unreactive molecular orbitals.

¹¹

However, even if they are hard to activate compared to other bonds, C(sp

³

)-H bonds can be cleaved using extremely active species such as super-acids along with some radicals and carbenes.

¹²

Recently, synthetic chemists started to employ transition-metal catalysis to functionalize such C-H bond using milder conditions.

¹³

Following initial reports from Corey and co-workers

¹⁴

in 1958 and later Shilov in C(sp

³

)-H halogenation,

¹⁵

Woodward in C-H amination,

¹⁶

Scott and DeCicco in C-H insertion

¹⁷

and Bergman in iridium-catalyzed C(sp

³

)- H activation,

¹⁸

palladium-catalyzed C(sp

³

)-H activation emerged as a powerful tool for this kind of transformation.

3 Directed C(sp

³

)-H activation

Regioselectivity in C-H activation reactions has been a major challenge in the early era of investigation in this field. This important issue had been progressively solved by two distinct approaches to direct the metal positioning and thus the subsequent C-H activation.

The first strategy takes advantage of the presence of a coordinating group on the

substrate. Notably, the strong -donor or -acceptor nature of several heteroatoms such

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as nitrogen, sulfur or phosphorus-containing moieties confer them with some potent directing group ability. In the specific case of palladium, these various directing groups give the ability to form, after the desired directed C(sp

³

)-H activation, a stable 5 or 6- membered palladacycle.

¹⁹

Formation of these various palladacycles is generally favorized both thermodynamically and kinetically. Overall, this approach gives excellent regioselectivity and yields along with milder reaction conditions in comparison with other C(sp

³

)-H activation methods. However, a common downside of this approach is the often necessary thorough optimization of the directing moiety structure of the substrate. A directing group with inadequate coordinating properties will indeed not provide any reactivity. Furthermore, the coordinating directing group, if not present in the desired final target, should be able to be cleaved easily, which often adds one or several steps, and decreases the efficiency of the synthesis (Scheme 3, a).

Scheme 3: Non-covalent- and oxidative addition-directed C(sp³)-H activation

On the other hand, another useful way to trigger a selective C-H activation is to perform an oxidative addition of a carbon-leaving group bond into palladium, the most commonly used leaving groups being halides (Cl, Br and I) as well as pseudo-halides (OTf, ONf). These leaving groups act as efficient traceless directing groups. In this case, the metal forms a covalent bond with the substrate (Scheme 3, b).

The next section will briefly discuss C(sp

³

)-H activation directed by strongly coordinating

auxiliaries. Then, since the Baudoin research group mainly focuses on the oxidative addition

approach for subsequent C(sp

³

)-H activation, the next examples/chapters will be devoted to

this specific area.

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4 Palladium-catalyzed C(sp

³

)-H activation

4.1 Palladium-catalyzed C(sp

³

)-H activation directed by coordinating directing groups

Many recent developments in Pd-catalyzed C-H activation reaction use substrates containing one or several functional groups able to pre-coordinate efficiently palladium catalysts via coordination and position it for the cleavage of a proximate C-H bond.

“Cyclometallation” reactions, as introduced by Trofimenko almost fifty years ago,

²⁰

involve the cleavage of C(sp

²

) or C(sp

³

)-H bonds via late transition-metals, forming defined [M-R]

species. This kind of complexes appeared in the literature as early as the 1960’s.

²¹

These reactions are usually inner-sphere processes and proceed via various mechanistic pathways, greatly depending on the reactions conditions, but classically involving oxidative addition, electrophilic activation, concerted metalation/deprotonation (CMD), and σ-bond metathesis.

²²

Organopalladium compounds are valuable intermediates, being able to undergo a myriad of transformations. This kind of reactions has been widely studied to finally provide some synthetically useful processes. Numerous cyclopalladation reactions were described featuring C(sp

²

)-H activation,

²³

however reported cases of unactivated aliphatic C(sp

³

)-H activation remain scarce.

An early report from Shaw and co-workers was described in 1978, featuring the palladation of oximes, using a stoichiometric amount of Na

2

PdCl

4

and sodium acetate as a base, which effectively activates a C(sp

³

)-H bond from the tert-butyl group, yielding the chloride-bridged dimer palladacycle 1.1 from oxime 1.2.

²⁴

It was readily followed by other examples using other nitrogenous auxiliaries such as N,N-dimethylamine

²⁵

and pyridine, as depicted in Scheme 4, where 6-membered palladacycle 1.4 was isolated by Hiraki and co-workers.

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Scheme 4: 5- and 6-membered palladacycles arising from C(sp³)-H activation

The defined complex 1.2 previously synthesized by Shaw proved to be synthetically useful by

Baldwin in 1985, which succeeded in functionalizing the previously formed C(sp

³

)-Pd bond

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(Scheme 5).

²⁸

Indeed, chlorination of this complex followed by subsequent hydride reduction furnished chloride

1.5 in 64% yield. Reduction with sodium cyanoborodeuteride was also

effective and provided β-deuterated oxime 1.6 in 41% yield. To note, direct oxidation of the dimer

1.2 under various conditions failed, but was successful when performed on the

monomeric pyridine complex 1.7 using oxidation/reduction sequence with lead tetraacetate and subsequent sodium borohydride reduction, finally providing acetate 1.8 in quantitative yield.

Scheme 5: Shaw’s palladacycle derivatisation

This approach greatly evolved in the last decades, and this strategy is today widely used with palladium in catalytic amount, thanks to the extensive reports of Sanford, Daugulis and many others in this field.

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Recently, reports of this approach, directed by “common” functional groups, were described. For instance, Yu and co-workers recently developed a direct γ-C(sp

³

)- H arylation of free primary amines, allowing the arylation of both methyl and methylene C(sp

³

)-H bonds in good yield. For this reaction, they used 2-hydroxynicotinaldehyde (TDG4) as a catalytic transient directing group.

³⁰

(scheme 6)

Scheme 6: C(sp³)-H arylation of primary amines using catalytic transient directing groups

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4.2 Intramolecular C(sp

³

)-H activation directed by carbon-halogen bonds In 1992, Dyker published a seminal report on a new domino coupling reaction, aimed toward the synthesis of polycyclic systems via Pd(0)-catalyzed intramolecular activation of C(sp

³

)-H of methoxy groups from 2-iodoanisole derivates (scheme 7).

³¹

Scheme 7: Dyker synthesis of substituted 6H-dibenzo[b,d]pyrans

This methodology was later extended to the activation of more inert methyl moieties from tert- butyl group (Scheme 8).

³²

In both cases, the reaction is directed by oxidative addition and allowed the formation of substituted dibenzopyrans by trimerization of three iodoaryl precursors and benzocyclobutenes (BCB), this time with an external aryl-bromide reagent.

Scheme 8: Synthesis of substituted 1,2-dihydrocyclobutabenzenes

Pursuing his effort toward more useful C(sp

³

)-H activation, Dyker took advantage of the

palladacycle intermediate 1.15 and 1.19 which were intercepted with various bromoalkenes to

yield valuable indenes

³¹

and benzofurans

³³

(Scheme 9).

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Scheme 9: palladacycle intermediates interception

These seminal reports represent overall an important milestone in the development of intramolecular palladium-catalyzed C(sp

³

)-H activation for the synthesis of small and medium- sized fused ring in organic chemistry. However, this methodology was able to form various fused products and undergo aryl-coupling simultaneously, demonstrating a certain lack of control in these reaction conditions, likely explained by the absence of ligand used in this report. Apart from that, this work represented a formidable proof-of-concept for the burgeoning field of the palladium-catalyzed C(sp

³

)-H activation. Indeed, Dyker demonstrated that valuable products could be obtained in a concise and efficient manner, opening the way for many upcoming innovations in this field, along with numerous great applications in natural product synthesis.

³⁴

4.3 Early improvements using phosphine-type ligands

In 2003, Baudoin and co-workers reported the first example of Pd(0)/ligand-catalyzed intramolecular C(sp

³

)-H activation of aryl bromides.

³⁵

The use of an appropriate phosphine- type ligand was unprecedented and had many advantages, in particular shutting down the secondary oxidative addition, which efficiently prevented the formation of undesired oligomeric products, as observed in previous reports from Dyker. This methodology was proved to be divergent, depending on the benzylic gem-dialkyl substitution on the substrate.

Indeed, using the same catalytic system consisting of Pd(OAc)

2

, potassium carbonate and

sterically hindered tri-o-tolylphosphine (TOPT) ligand , two distinct classes of products could

be obtained from aryl bromide precursors 1.21. On one hand, benzocyclobutenes (BCB) 1.23

could be accessed using this methodology. On the other, if no methyl groups were present on

the substrate, methylene C(sp

³

)-H activation was observed, furnishing after β-hydride

elimination mixtures of regioisomeric olefins 1.22 (Scheme 10).

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Scheme 10: C(sp³)-H activation for BCB and olefins synthesis : early report from Baudoin

Reaction conditions were then optimized for each distinct product type, and it was discovered that both steric and electronic properties of the ligand had a great influence on the reaction outcome. For instance, use of the electron-deficient triarylphosphine ligand F-TOTP (tri(5- fluoro-2-methylphenyl)phosphine) allowed a decrease in temperature needed for the reaction generating olefins to proceed (from 150 °C to 100 °C), along with a notably superior selectivity for disubstituted/internals olefins (Scheme 11).

³⁶

BCB synthesis was also considerably improved by the use of the bulky ligand P(t-Bu)

3

, allowing greater efficiency and extension of the scope to aryl chloride.

³⁷

Overall, this study demonstrates the importance of phosphine ligands and their design in such Pd-catalyzed transformations.

Scheme 11: Divergent synthesis of olefins and BCB by Baudoin

4.4 Mechanistic investigations

In a context of growing field in diverse metal-catalyzed C(sp

²

)-H activation, in particular for

aryl-aryl coupling, it was important to unravel the mechanism of such reactions. Indeed, several

mechanisms had been postulated to explain this particular reactivity, such as carbopalladation

(similarly to Heck-type reaction), electrophilic aromatic substitution or σ-bond metathesis.

³⁸

All of these postulates were refuted by extensive experimental and computational studies by

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Davies/Macgregor

^39,40

and Echavarren/Maseras.

⁴¹

They proposed the concerted metalation deprotonation (CMD) mechanism as a viable explanation for the C(sp

²

)-H bond cleavage in such reactions.

⁴²

Later, the groups of Fagnou

⁴³

and Baudoin

³⁷

proved that the same CMD mechanism occurs in C(sp

³

)-H bond activation. The commonly accepted catalytic cycle for such transformation is then depicted in Figure 2. The active catalytic species Pd(0) is sometimes formed in-situ via Pd(II) reduction with phosphine ligand (L). The carbon-halide/pseudohalide bond of

1.24

undergoes oxidative addition with the liganded palladium species and the newly form complex undergoes fast ligand exchange with a carboxylate or carbonate to form the electrophilic Pd(II) species 1.25. Then, the C(sp

³

)-H step occurs via CMD mechanism, which allow the formation of a 5-membered (1.26) or 6-membered (1.27) palladacycles. Of note, the presence of a quaternary benzylic carbon and bulky substituents R

¹

and R

²

was observed to greatly favor the formation of this key palladacycle by Thorpe-Ingold effect. These palladacycles 1.26 and 1.27 can undergo base decoordination and subsequent reductive elimination to furnish the desired cyclized products, respectively 1.28 or 1.29. Alternatively, a proton transfer can occur to form the alkyl palladium species

1.30, which can undergo subsequent β-hydride elimination if a

proton is present in β position, yielding in this case the olefin 1.31.

Figure 2: C(sp3)-H activation mechanism for the synthesis of olefins and carbocycles

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The C(sp

³

)-H bond activation step being the most intriguing in this mechanism, further DFT calculation studies were run by Baudoin and Clot in 2008 in the specific case of the BCB synthesis.

^37,44

Simplified computing results using PMe

3

as a ligand instead of P(t-Bu)

3

or AcO

^-

and HCO

3-

instead of CO

32-

were readily discarded, showing energy profiles in disagreement with the results obtained by preliminary experimental observations, in particular kinetic isotope effect (KIE) studies previously performed.

Finally, using the experimental system in the calculations (i.e. bulky ligand P(t-Bu)

3

and carbonate base CO

32-

), three plausible transition states were considered. The transition state (TS) displaying an intermolecular proton abstraction was readily discarded, considering the very high activation barrier in this case, probably due to the elevated entropic cost.

Two reasonable TS were finally proposed, both of them going through intramolecular proton abstraction.

-

Cis-activation model, which was previously proposed by Fagnou and Gorelsky was

envisioned.

⁴³

In this case, the C-H activation step would occur via a relatively stable precomplex

1.33 involving ²

-carbonate coordination (Scheme 12). However, calculations showed that the inherent stability of this species

1.33 would have a

significant impact on the required energy (37.9 kcal/mol) to access the transition-state

1.34.

-

Trans-activation model, proposed by Baudoin and Clot, which in this case imply the

formation of a comparatively less stable 

¹

-precomplex. An agostic interaction caused by a free coordination site was observed in 1.36, which enhances the protic character of the geminal proton. Because of the

¹

coordination-type of the carbonate and this agostic interaction in 1.36, the activation barrier was lower in this case (26.2 kcal/mol) to access the transition state 1.37. To note, the C-H bond cleaved in this model is the geminal and not the agostic one.

It was then concluded through DFT calculation that trans-activation mode would be the most likely to occur in the BCB

1.39 synthesis methodology, however in the event of other

palladium-catalyzed C(sp

³

)-H activation methodology, in particular to access other substrates, both models should be considered.

After years of emerging methodologies in the field of Pd(0)-catalyzed intramolecular C(sp

³

)-

H activation,

⁴⁵

along with several computational studies, an empirical selectivity guideline for

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this type of reaction has been suggested. This selectivity trend is mainly depending on several factors, each of them having a variable importance depending on the substrate used:

- The size of the palladacycle formed upon C(sp

³

)-H activation step, the 5-membered palladacycle being generally preferred (5-membered>6-membered>>7-membered).

- Both acidity and steric environment of the cleaved C-H bond are of great importance, generally following this trend: aromatic>cyclopropyl>benzylic >methyl>methylene>methine

Scheme 12: Plausible TSs for C-H activation step determined by DFT calculations

-

The steric environment, such as tetrasubstituted carbon center and its relative vicinity and steric hindrance to the cleaved C(sp

³

)-H bond.

- Ring-strain and stability of the product formed can impact the outcome and selectivity of such reactions.

These different factors should be carefully considered during substrate choice for a define

target constructed by intramolecular C(sp

³

)-H activation. Common side-products such as

proto-dehalogenation, β-hydride elimination or nucleophilic addition of organopalladium

species can be avoided using a clever substrate design along with carefully optimized reaction

conditions.

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4.5 Intramolecular activation of unactivated C(sp

³

)-H bonds

Thanks to these pioneering examples, as well as the ever increasing attractivity of C(sp

³

)-H bond activation, the field of small-rings construction using this strategy had undergone intense development in recent years.

⁴⁵

Indeed, several research groups used intramolecular activation of unactivated C(sp

³

)-H bonds to develop methodologies allowing the atom-economic and straightforward access to various fused-ring systems. Some of the fused-ring systems formed thanks to this strategy are depicted below (Scheme 13). Hetero- or non-heterocyclic products could be obtained in different size, the most common being 5-membered rings, formed from the easily accessible 6 or 7-membered palladacycles, such as dihydrobenzofurans

1.41,⁴⁶

indolines 1.42,

⁴⁷

benzolactams 1.44,

⁴⁸

benzosultams 1.45,

⁴⁸

dihydroquinolinone 1.46,

⁴⁹

as well as fused carbacycles indanes 1.42,

³⁵

indanones 1.43,

⁴⁶

and indanols 1.47

⁵⁰

Methylene C(sp

³

)-H bond activation example are scarce, due to the difficulty to directly functionalize these particular bonds. However in 2008, Ohno group succeeded to activate C(sp

³

)-H methylene bonds, forming fused indoline 1.42.

⁴⁶

Scheme 13: Pd(0)-catalyzed intramolecular C(sp³)-H activation for small ring formation (selected examples)

Until recently, C(sp

³

)-H activation were mostly limited to aryl halide and triflate precursors,

forming after key C(sp

³

)-H activation fused arylated products. In 2012, Baudoin and co-

workers described a C(sp

³

)-H alkenylation, by using bromoalkene starting materials, greatly

extending the scope of this reaction. For instance, they developed a unique route to

hexahydroindole compounds

1.49.⁵¹

In 2016, access to γ-lactams

1.50 was described, also

using similar C(sp

³

)-H alkenylation.

⁵²

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31

Alkene moieties being more modulable than their aryl counterparts, these products were suitable for easy subsequent derivatization, which led for the hexahydroindole synthesis methodology to several applications: the collective synthesis of aeruginosins, which will be discussed later in this manuscript, and the divergent total synthesis of dithiodiketopiperazines, which will be the subject of a whole part of this manuscript.

As seen previously, C(sp

³

)-H bond in alpha position of some heteroatoms such as nitrogen can be activated. Baudoin and co-workers took advantage of this observation to access benzoxazines 1.51.

⁵³

Direct C(sp

³

)-H activation first formed benzazetidines, which underwent spontaneous electrocyclic rearrangement under the reaction conditions to deliver benzoxazines.

5 C(sp

³

)-H activation in total synthesis

For a long time, the functionalization of C-H bonds has been largely ignored in synthetic chemistry, due to the relative inertness of these bonds. This is why total synthesis, in its early ages, did not consider this strategy as suitable, especially in complex settings where sensitive parts of the molecule should be preserved, and where obtaining high selectivity was essential.

However, in the last two decades, C-H activation approaches have started to be used more commonly (Figure 3).

⁵⁴

In this part of this bibliographic introduction, we will discuss some reported total syntheses using C(sp

³

)-H activation steps starting from early examples to recent total synthesis applications.

Figure 3: Number of articles published in journals on the topic “C-H activation/functionalization” and “total synthesis” in the last 40 years (from Scifinder®)

Early results in this area were reported by Löffler, by using radical formation from N- bromoamine 1.52, the latter possessing a labile N-Br bond able to readily undergo homolysis.

High energy N-centered radical intermediate

1.53 was formed, which then regioselectively

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32

abstracted a hydrogen atom via 1,5-hydrogen atom transfer (HAT, through 6-membered transition state) , giving a lower energy carbon centered radical which underwent radical recombination to yield

1.54. The halogen was readily displaced by the newly generate

secondary amine, allowing a straightforward access to nicotine 1.55 (Scheme 14).

⁵⁵

Scheme 14: Nicotine first synthesis via C(sp³)-H activation

Fifty years later, in a similar fashion, Corey and Arigoni independently accessed aminosteroid analogues, using the same C(sp

³

)-H activation conditions.

⁵⁶

Indeed, starting from broadly available steroid precursors, they activated C18 methyl group by radical C(sp

³

)-H activation via the secondary amine of compound 1.56, the latter being correctly oriented to allow desired 1,5-HAT. This methodology was used to access dihydroconessine 1.57 in 56% yield, by in-situ formation of chloramine from 1.56 and exposure to light (Scheme 15).

Scheme 15: Corey’s total synthesis of dihydrocanessine

In 2016, the Baran group described a highly efficient synthesis of phorbol (1.60 scheme 16).

⁵⁷

As previously used in this research group, their retrosynthetic design is based on on a

bioinspired cyclase/oxidase phases strategy. Biosynthetic analysis suggested that ingenol, a

diterpenoid previously successfully synthesized by their group and targeted phorbol have a

biosynthetic relationship and could arise from the same intermediate in Nature.

⁵⁸

Thus, the

team decided to utilize previously synthesized intermediate 1.61, and to install the oxidation

pattern at C12 and C13, which is absent in ingenol structure. To this end, they devised a strategy

where C(sp

³

)-H oxidation would be a primordial keystone toward installation of the sought-

after trans vicinal-diol. After thorough screening, trifluoromethylmethyl dioxirane was found

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to display impressive regio and diastereoselectivity for C12 methylene oxidation over tertiary C-H bonds and other present methylene groups (1.62, scheme 16). After obtention of the desired alcohol, cyclopropane moiety could be ruptured and then extend the functionality to C13 as olefin 1.63. This double-bond was then easily oxidized into the desired diol followed by cyclopropane reformation. Finally, the remaining oxidation pattern was installed in a more traditional manner.

Scheme 16: Baran’s synthesis of (+)-phorbol via C(sp³)-H bond oxidation

In 2014, the Maimone group described a synthesis of podophyllotoxin (1.68, Scheme 17) which

is a bioactive natural product in addition of being a precursor to several drug molecules.

⁵⁹

The

main strategy was to install the trimethoxyarene moiety via directed Pd(II)-catalyzed C(sp

³

)-H

arylation, which would considerably ease the synthesis of the tetrahydronaphtalene core (as in

1.65 and 1.67). The latter was readily synthesized via benzocyclobutane-derived ortho-

quinonedimethane [4+2] cycloaddition. Initial attempts to perform the directed C-H arylation

on 1.64 resulted in unexpected C(sp

³

)-H amination of the amino-quinoline directing group to

form beta-lactam

1.65 in low yield.⁶⁰

Finally, it was determined by ORTEP of the C–H

activated palladium complex that the cyclohexane conformation of

1.64 was inhibiting the

desired C-H arylation with the aryl iodide. Indeed, the structurally rigidified 1.66, after some

optimization, participated in the desired directed C(sp

³

)-H activation and provided 1.67 in good

yield. In a single step, 1.67 was then converted to the target molecule

1.68. This impressive

synthesis of podophyllotoxin shows well the power of Pd(II)/Pd(IV) catalysis in C(sp

³

)-H

activation, and in a certain extent in total synthesis, especially when the necessary directing

group is easily removable.

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Scheme 17: Maimone’s total synthesis of podophyllotoxin via directed Pd(II)-catalyzed C(sp³)-H activation

Taking advantage of a previously described BCB synthesis via C(sp

³

)-H activation (Scheme 18), Baudoin and co-workers developed a new method to access 3,4-dihydroisoquinolines (DHIQ).

⁶¹

This strategy is based on two key steps, namely Pd(0)-catalyzed C(sp

³

)-H activation and subsequent pericyclic reaction. BCB 1.71 was obtained in good yield from substrate 1.70, and easily converted in two steps to the corresponding amine

1.72, by sequential ester

hydrolysis/Curtius rearrangement. Then, imine formation with the adequate aldehyde furnished upon thermal activation the DHIQ 1.74 via tandem electrocyclic ring-opening/6π- electrocyclization. Total synthesis of the tetrahydroprotoberberine alkaloid (±)-coralydine

1.75 was finally achieved via a three-steps sequence in good overall yield (Scheme 18).

Moreover, it was shown by this research group, in collaboration with Servier Industry, that the

C-H activation for BCB formation could be efficiently applied to the synthesis of the marketed

drug Ivabradine.

⁶²

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Scheme 18: Baudoin’s synthesis of (±)-coralydine

The Baudoin group later explored the total synthesis of γ-lycorane (1.78), a degradation product of the pentacyclic Amaryllidaceae alkaloid lycorine,

⁶³

via simultaneous double C(sp

²

)/C(sp

³

)- H arylation.

⁶⁴

This polycyclic system was rapidly constructed thanks to a judicious choice of precursor. Indeed, site-selectivity issues arose when nature and position of the halogen atoms were not carefully chosen. Finally, first C-H arylation taking place at the most reactive C(sp

²

)- H position on the D ring was directed by bromine atom on the B ring, and second C-H arylation occurred between C-Cl bond and activated C(sp

³

)-H bond in alpha position of the carbonyl from the amide group. Furthermore, intermediate

1.76 was readily obtained in a single step

from commercially available starting materials, which make the synthesis very concise. Indeed, racemic γ-lycorane 1.78 was obtained in 47% over 4 steps. To date, this sequence remains the shortest and most efficient synthetic pathway for this molecule (Scheme 19).

Scheme 19: Baudoin (±)--lycorane synthesis via double C-H activation

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6 Research aim and projects covered in this thesis :

In the last decades, transition metal-catalyzed C(sp

³

)-H activation methodologies were used as a key tool for achieving the total synthesis of complex natural products in an efficient and concise manner. On the other hand, new methodologies from this quickly growing field allowed the formation of small and medium-sized ring, which can be hard to reach using other methods. Overall, the complexity of targets, natural or not, obtainable via C(sp

³

)-H activation is ever increasing.

This thesis is divided in two parts: the first one will cover the total synthesis of dithiodiketopiperazine natural products achieved using double palladium-catalyzed C(sp

³

)-H activation. This project showed overall that direct C(sp

³

)-H activation is a valuable tool for natural product total synthesis.

The second part will focus on accessing another hard-to-reach target: cyclopropane rings, via

the use of a double distal C(sp

³

)-H activation. This new approach allows the formation of these

strained rings by activating in one step two unactivated C(sp

³

)-H bonds.

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Part II: Dithiodiketopiperazine Synthesis via double

Pd(0)-catalyzed C(sp ³ )-H activation

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1 Research summary

(–)-Epicoccin G (2.1) and (–)-rostratin A (2.2) are members of the pentacyclic dithiodiketopiperazine family of natural product (featuring a 2,5 diketopiperazine core, along with sulfur atoms in open or bridged form at 1,4 positions). These members exhibit a large array of biological properties, such as in vitro anti-HIV-1 activity or cytotoxicity against cancer cells.

⁶⁵

Only three research groups reported total syntheses of such compounds, illustrating well the challenge of accessing these natural products (Figure 4).

⁶⁶

Figure 4: Selected natural DTPs with a pentacyclic framework

We envisioned an innovative strategy to access pentacyclic DTP natural products via Pd(0)- catalyzed double C(sp

³

)-H activation. The starting materials for this study would readily arise from enantioselective catalysis (epoxide 2.6) and the chiral pool (L-alanine derivate 2.7). The key intermediate 2.4 formed upon C(sp

³

)-H activation would enable the divergent synthesis of several DTP natural products such as 2.1 (Figure 5).

Figure 5: Retrosynthetic analysis

Our key intermediate synthesis started with a List organocatalytic enantioselective epoxidation,

which furnished the desired chiral epoxy ketone 2.9 in high yield and stereoselectivity. Epoxide

2.9 was then derivatized in five steps into the key diketopiperazine substrate 2.5. Subsequent

double C(sp

³

)-H activation was successfully conducted and provided the pentacyclic key

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39

intermediate

2.4 on multi-gram scale. The route toward 2.4 was short and scalable, enabling

further investigations toward the synthesis of DTP natural products (Scheme 20).

Scheme 20: Key intermediate synthesis

(–)-Epicoccin G was readily accessed via initial Upjohn dihydroxylation on common precursor

2.4, providing tetraol 2.10 in quantitative yield and complete cis diastereoselectivity. Epicoccin

was accessed in 7 steps from this tetraol 2.10. Overall, (–)-epicoccin G was obtained in 19.6%

yield and 14 steps via this strategy (Scheme 21).

Scheme 21: (–)-epicoccin G synthesis

The synthesis of (–)-rostratin A, possessing a more challenging structure thanks to its

trans

ring junctions, was then investigated.

Trans ring junction-containing substrate for the final

sulfenylation was obtained in 8 steps from the previously synthesized tetraol

2.10. Finally,

compound

2.11 was derivatized in two steps to (–)-rostratin A. Overall, this hard-to-reach

natural product was accessed in 12.7% yield over 17 steps (Scheme 22).

Scheme 22: (–)-rostratin A synthesis

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40

Finally, MTT assays in the leukemia cell line K562 were run using intermediates and analogues synthesized during this study. In conclusion, the disulfide bridge was found to be essential to observe cytotoxicity and dianhydrorostratin A (2.16) was found to be twenty times more potent than rostratin A.

In the following part of this manuscript, we disclose a detailed report of our investigations

which led to the divergent, concise and scalable total synthesis of these two complex DTP

natural products, (–)-epicoccin G and (–)-rostratin A, under the form of two publications: a

short communication

⁶⁷

and a full paper.

⁶⁸

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2 1

^st

publication about this work (Communication)

P. Thesmar, O. Baudoin, Journal of the American Chemical Society 2019, 141, 15779–

15783.

Reproduced with permission from P. Thesmar, O. Baudoin, Journal of the American

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3 2

^nd

publication about this work (Full Paper)

P. Thesmar, S. Coomar, A. Prescimone, D. Häussinger,D. Gillingham, O. Baudoin,

Chemistry – A European Journal 2020, 141, 15779–15783.

Reproduced with permission from P. Thesmar, S. Coomar, A. Prescimone, D. Häussinger,D.

Gillingham, O. Baudoin, Chemistry – A European Journal 2020, 141, 15779–15783.

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Part III: Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C(sp ³ )−H

Activation

Work realized in collaboration with Dr Antonin Clemenceau and Oril industries (Laboratoires Servier )

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66

1 1,4-Pd shift reactivity

1.1 Introduction to the 1,4-Pd shift

Palladium, one of the most widely used transition metal in organic chemistry, has been found to catalyze a large array of C-H activation reactions. In particular, this metal is able to functionalize unactivated C-H bonds with high efficiency. However, in most cases, palladium can only catalyze the functionalization of C-H bonds in close vicinity to a coordinating directing group, or arising from oxidative addition, which greatly increases the selectivity but limits the synthetic utility of these functionalizations (Scheme 23).

Scheme 23: Direct C-H functionalization

To address these limitations, methods have been developed for the remote functionalization of C-H bonds. In particular several 1,n-palladium migration methods have been reported,

⁶⁹

mainly to form various carbo- or heterocyclic products.

70,71,72,73

Additionally, other metals such as rhodium,

⁷⁴

platinum

⁷⁵

and iridium

⁷⁶

are also known to be able to perform such migrations. This intriguing reactivity has been studied by computational chemists, who conducted studies toward mechanistic elucidation via transition states determination.

^77-78

In the case of palladium catalysis, the distal functionalization of C-H bonds is achieved via a three-steps process, called through-space palladium migration. The first step is a classic oxidative addition or carbopalladation, placing the palladium center in a position suitable for the subsequent second step. Then, proximity of the palladium with a C-H bond allows the cleavage of the latter and formation of a palladacycle. Finally, presumed proton-mediated palladacycle opening overall allows the relocation of the palladium center to a remote carbon.

This palladium migration allows functionalization of distal positions, via this palladium species, which could be difficult via direct introduction of the latter (Scheme 24).

^37,79

Scheme 24: 1,n-Pd shift principle

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67

To note, 1,4-Pd shift is the most commonly observed among all palladium migration, since a relatively strain-free 5-membered palladacycle intermediate is formed, facilitating the whole process. Moreover, reductive elimination towards the formation of strained 4-membered ring is difficult, favoring the desired metal shift (Scheme 25). Current reports from the literature indicate that palladium has the ability to migrate from a wide range of C(sp

²

) or C(sp

³

)- hybridized positions to either C(sp

²

)/C(sp

³

) positions.

^66,80

Scheme 25: 1,4-Pd shift concept

1.2 Early example of 1,4-Pd shift :

In 1972, Heck reported the first observed 1,4-Pd shift (Scheme 26). Alkyl mercury was transmetallated with palladium, and subsequent reaction with methyl acrylate yielded a mixture of products

3.2 and 3.3, respectively from direct Heck coupling and 1,4-Pd shift/Heck

coupling.

⁸¹

Scheme 26: Heck early results on 1,4-Pd shift

In 2002, Larock observed a new aryl to aryl 1,4-Pd shift/Heck sequence, with ethyl acrylate as

a partner for final remote functionalization. An equimolar mixture of direct

3.6 and remote

Heck product 3.5 was obtained with initial conditions (Scheme 27). To note, the use of TBAC

as an additive and a higher concentration allowed the exclusive obtention of direct coupling

product 3.6.

⁸²

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Scheme 27: Example of 1,4-Pd shift by Larock

Other reports from Larock showed that 1,4-Pd shift can also be used to obtain olefin

3.9 by

distal -hydride elimination,

^83,84

or C-O coupling products (3.10) with carboxylate (Scheme 28).

⁸³

Scheme 28: olefins and C-O coupling products via 1,4-Pd shift

Later, a C(sp

²

)-C(sp

³

) shift-mediated coupling was observed by Buchwald and co-workers (Scheme 29). After initial oxidative addition of palladium into the C-Br bond, the two bulky ortho substituents prevented direct cross-coupling. Instead, a 1,4-Pd shift occurred, which was followed by remote Suzuki-Miyaura reaction with an aryl boronic acid partner.

Scheme 29: Example of 1,4-Pd shift by Buchwald

Recently, Baudoin and co-workers took advantage of this 1,4-Pd shift to obtain amides and

esters (3.15) in good yield via C(sp

³

)-H carbonylation of a distal position and subsequent

trapping with an amine or alcohol partner (Scheme 30).

⁸⁵

As for previous described examples,

use of a weak carboxylated base was essential to initiate the proton-transfer process leading to

the desired Pd-1,4 shift.

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Scheme 30: Baudoin’s amides and esters synthesis via 1,4-Pd shift

1.3 1,4-Pd migration/ C-H functionalization

We have seen that upon 1,4-Pd shift, the organopalladium species formed at a distal position can further react in different ways, mainly via Pd-catalyzed cross-coupling reactions. However, the pioneering work of Larock showed that this organopalladium species could also perform C-H activation reactions.

Indeed Larock described in 2003 an example of 1,4-Pd shift/C-H activation, in this case for C(sp

²

)-H arylation methodology (Scheme 31).

⁸⁶

Starting from

o-iodobiaryl 3.16, and upon

oxidative addition, 1,4-aryl-to-aryl palladium shift was observed to give palladium intermediate 3.19, which further reacts in a classical C-H arylation reaction, affording valuable dibenzofurans or fluorenes 3.17 in good yields.

Scheme 31: 1,4-Pd shift/C-H arylation from Larock

Recently, Baudoin reported an unprecedented 1,4-Pd shift followed by C(sp

³

)-H activation for

the formation of a broad range of -arylidene: -lactams and indanones through C(sp

²

)-C(sp

³

)

bond formation (Scheme 32).

⁸⁷

In this case, 1,4-Pd shift occurred after initial oxidative addition

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of palladium into C-Br bond. Then subsequent C(sp

³

)-H activation, via a 6-membered palladacycle led to the desired 5-membered ring 3.21.

Scheme 32: 5-membered rings formation via 1,4-Pd shift

2 C-H activation for C(sp

³

)-C(sp

³

) bond generation

One of the major way to form carbon-carbon bonds in organic chemistry is via the use of transition-metal catalysis.

⁵

These methods had been widely studied in the past decades, in particular cross-coupling reactions and C-H activation reactions have become valuable tools for any synthetic organic chemist. Indeed, many methods to form C(sp

²

)-C(sp

²

) or C(sp

²

)- C(sp

³

) arose recently, using a myriad of different metal-catalysts and in a large range of conditions, allowing the easy formation of valuable products, and this in a straightforward manner compared to more classical methods.

⁸⁸

Similarly, the field of C-H activation witnessed an exponentially growth in direct and remote functionalization via palladium-catalysis to form either C(sp

²

)-C(sp

²

) or C(sp

²

)-C(sp

³

) bonds (Figure 6a). Most of these methods are efficient and nowadays widely used among the research community. However, the formation of C(sp

³

)-C(sp

³

) bonds is still understudied compared to the two previously mentioned bond formations (Figure 6b).

⁸⁹

Figure 6: C(sp²)-C(sp³) and C(sp³)-C(sp³) bonds formation via C(sp³)-H activation

2.1 C(sp

³

)-C(sp

³

) bond formation via direct Pd-catalyzed C(sp

³

)-H activation

Several methodologies were developed for C(sp

³

)-C(sp

³