N° d‟ordre : 4317

THÈSE

PRÉSENTÉE A

L’UNIVERSITÉ BORDEAUX 1

ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES

Par Mme Luma NASSAR-HARDY

POUR OBTENIR LE GRADE DE

DOCTEUR

SPÉCIALITÉ : CHIMIE ORGANIQUE

Tandem Reactions Using Multi-task Catalysts

Directeurs de thèse : FOUQUET Eric

FELPIN François-Xavier

Soutenue le : 26 Septembre 2011

Devant la commission d‟examen formée de :

M. EL KAIM Laurent Professeur, E.N.S.T.A Rapporteur

M. GRAS Emmanuel Chargé de Recherche, Université de Toulouse Rapporteur

M. LEBRETON Jacques Professeur, Université de Nantes Examinateur

M. BENNETAU Bernard Directeur de Recherche, CNRS Président de Jury

M. FOUQUET Eric Professeur, Université de Bordeau Directeur de Thèse

M. FELPIN François-Xavier Professeur, Université de Nantes 1 Directeur de Thèse

Table of Content

Chapter A………………………………………………………………………………….….3

I. General introduction on palladium chemistry…………………………..…….………….3

II. Homogeneous vs heterogeneous catalysis……………….…….……………….………...6

III. Heck-Mizoroki reaction………………………….……….…………………….………..7

III. 1. General considerations..................................................….................................7

III. 2. Traditional mechanism………………………………………………………10

IV. Diazonium salts……………………………………………………….…………………13

IV. 1. Properties……………………………………….……………….…………….13

IV. 2. Preparation…………………………………………….…..……….…………14

IV. 3. General reactivity……………………..……………….……………………..16

V. Heck-Matsuda reaction…………………………..………….…………………………..18

V. 1. Early developments on Heck-Matsuda reaction…….....…………………....18

V. 2. Recent developments on Heck-Matsuda reaction…..…………………….…21

V. 2. a. Heterogeneous catalysis…………………………………………..…...21

V. 2. b. Preparation of highly substituted olefins………….……………….…26

V. 2. c. Heck-Matsuda reaction in heterocyclic chemistry…………………...28

V. 3. Mechanistic investigations……………………………………………………...30

V. 4. Influence of the counterion on the Heck-Matsuda reaction……………….….33

V. 5. General considerations on experimental conditions…………………………..34

Chapter B………………………………………………………………………….…………39

I. Cascade, Tandem reactions…………………………….…...............................................39

I. 1. Old classification of tandem catalysis in domino reaction..………….……..40

I. 1. a. Tandem in domino reaction………………………………………..…...40

I. 1. b. Tandem in one-pot reaction……………………………………………41

I. 1. c. Tandem in Multicomponent reaction (MCR)-named afterwards

Concurrent Tandem Catalyst (CTC)……………………………….. ………..42

I. 2. Actual Subclasses of the tandem catalysis in domino reactions-A focus on

metal catalyzed tandem reactions…………………………………………….….....43

I. 2. a. Orthogonal tandem catalysis……………………………………….…..44

I. 2. b. Assisted tandem catalysis……………………….……………………....45

I. 2. c. Auto-tandem catalysis………………………………….……………….47

I. 3. Palladium in tandem reactions………...............................................................50

I. 4. Diazonium salts used for tandem reactions………………………….…….….53

Chapter C…………………………………………………………………………………….59

I. HRC (Heck-Reduction-Cyclization): Oxindoles, Indoles, Indanones………….....…...59

I. 1. Oxindoles………………….…………………….………………………………60

I. 1. a. Oxindoles in natural products………………………………………….60

I. 1. b. Synthetic point of view for preparing oxindoles by HRC stratey…....62

I. 1. c. Preparation of starting materials..……..………………………………63

I. 1. c. i. Diazonium salts……………..…………….………………………..63

I. 1. c. ii. Acrylates………………………………...…………………………63

I. 1. d. Optimization of the HRC strategy-Oxindoles………….……….…….64

I. 1. e. Scope of the HRC reaction strategy…………….……………………..66

I. 1. f. Catalysts recycling tests……………………............................................67

I. 2. Indoles…………………………………………..………………..……………...70

I. 2. a. Indoles in Natural products……..………………………………….…..70

I. 2. b. Synthetic point of view for preparing Indoles by the HRC strategy...71

I. 3. Spiro-oxindoles………………………………………........................................76

I. 3. a. Spiro-oxindoles in natural producls………………………..….…….…76

I. 3. b. Synthetic point of view for preparing Spiro-oxindoles by the HRC

strategy………………………………………………………………………….77

I. 4. Tricyclic heterocycles………………..…….……………………….……..……79

I. 5. Functionalized Indanones……………………………..…………………….…81

I. 5. a. Functionalized Indanones in natural products……………………......81

I. 5. b. Synthetic point of view for preparing functionalized Indanones by the

HRC strategy……….……………………….......................................................82

I. 5. c. Optimization studies on the Heck-Reduction one-pot reaction…........87

I. 5. d. Optimization studies on the one-pot HRC (Heck-Reduction-

Cyclization) strategy for the preparation of Indanones………………….......89

I. 6. Synthetic point of view for preparing functionalized Indanones by HRCA

strategy………………………………………………………………….…………....91

I. 6. a. Scope of the HRCA reaction strategy………………………….……...93

I. 7. Conclusion……………………………………....................................................96

Chapter D……………………………………………………………………………………97

I. Naphthoxindoles…………………………….………………….………………………....97

I. 1. Naphthoxindoles –Synthetic access………………….…………………..…….97

I. 2. Synthetic point of view for the preparation of naphthoxindoles .………..…99

I. 3. Preparation of intermediates………………………………………………...100

I. 3. a. Stilbenes…………………………………………………………………100

I. 3. b. Optimization studies on phenanthrenes…………….……..………….102

I. 3. c. Scope of the preparation of phenanthrenes...........................................105

I. 4. Scope of the preparation of naphthoxindoles………………………………..108

I. 5. Studies on the preparation of naphthoxindoles using the Heck-direct C-H

arylation-Reduction-Cyclization one-pot strategy……………………………….110

II. Conclusion………………………………………………………………………………112

General conclusion and perspectives……………………...………………………………113

Experimental Section………………………………………………………………………115

Acknowledgement

First of all I’d like to thank Prof. Eric FOUQUET for accepting me being a

member of his team.

A great thanks to a person with great qualifications, a person holding in

his heart an elegant, a respectful and a competitive character, Prof.

Felpin I was honored working with you.

I’d like to thank all my friend and colleagues, whom I worked with for 4 years or less,

Cybille Rossy: My office mate, dear you were a very nice company.

Thomas Bordenave: We shared the same office for a short time but you

always showed respect and politeness.

Marie Gueroux: A very pure heart with a joyful character

François Le Callonnec: You always told me “life is simple why complicating

it!!! ”…and that’s so true…we can handle things without complicating life....

Sandy Fabre: My dearest friend, you always showed care and help, you

were always there for me , we shared a lot of moments together that

meant a lot to me , we shared nice moments for the last 2 years that

passed quickly , but I won’t ever forget you…

Anthony Martin: An amazing character, you certainly left a mark in my

heart, I loved your sense of humor.

Jürgan Shulz: Such an educated person, you know A LOT……Woow, I wish I

had 1/3 of your knowledge..

Magali: A very calm personality that reminds me of myself….

Emiline Girard: My colleague since master 2. I am grateful for all the help

you’ve offered me.

Valéri and Fred: Caring couple, you’ll soon be living in my district

Jérome, Verginie: Unfortunately, we shared very few moments together,

but lunch together from time to time was very refreshing

Laurent Huet: A person that marked everyone’s heart you’re unique and

hilarious

Muriel Berland, Marie-Héléne : thanks for the chemical products and the

materials supply, thanks for being so kind, sensitive and caring

For the new PHD starters Jessica, Cherine good luck

I’d like to thank my family in particular my mom and dad for being always

by my backside…..I am proud of having parents as you, hope you are proud

me….

Adam HARDY…..my buddy… you were such a nice boy …You were always

polite and calm excluding few moments, which is totally normal for your

age , I am proud of you..

Finally, the hardest part is thanking someone that means the world to

me…….words are so few and phrases are so short to express my love to my

sweetheart, the love of my heart and the joy of my life Maxime

HARDY…..Honey you were always beside me, in each step, and during my

ups and downs....Thank you honey for filling my heart with love and

happiness, what can I say more than I LOVE YOU ??...

Abbreviations

AChE: Acetylcholinesterase

AD: Alzheimer‟s disease

Ar: Aromatic

13C NMR : Carbon Nuclear Magnetic Resonance

CG: Gas Chromatography

CNS : Central Nervous System

CTC : Concurrent Tandem Catalysis

dba: dibenzylidine acetone

DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

DFT: Density Functional Theory

DMAc: Dimethylacetamide

DMF: Dimethylformamide

DSC: Differential Scanning Calorimetry

DTBMP : 2,5-ditert-butyl-4-methylpyridine

ee : Enantiomeric excess

EWG: Electron withdrawing group

eq: Equivalent

HPLC: High Performance Liquid Chromatography

HRC: Heck-Reduction-Cyclization

HRCA: Heck-Reduction-Cyclization- Alkylation

1H NMR: Proton Nuclear Magnetic Resonance

HRMS : High Resolution Mass Spectroscopy

IR : Infrared

MMD2: monocyte to macrophage differentiation-associated2

MRC: Multicomponent reaction

PCy3: tricyclohexylphosphine

Pd/C: Palladium on charcoal

ppb: part per billion

ppm: part per million

RT: Room Temperature

TEM : Transmission Electron Microscopy

THF : Tetrahydrofurane

TON : Turn Over Number

Wt : weight

Chapter A

I. General introduction on palladium chemistry

At the 21st century, organic molecules have been industrially developed, having

potential applications, forming more complex molecules. Their use has been quite important

for medicinal chemistry, cosmetics, agrochemicals, and organic materials that involve the

development of new and efficient synthetic methods as the formation of C-C and C-X bonds.

In this context, the organometallic chemistry (that was discovered at the end of the 19th

century by introducing alkaline and alkaline earth metals in synthesis) gave new solutions and

new synthetic possibilities in synthetic chemistry.

The use of new catalysts was a revolution to the classical organic synthesis. Catalysts

gave a new access to impossible or forbidden reactions. For the past 10 years, these new tools

of synthetic chemistry are of great importance, besides, palladium complexes are the most

used and studied. In the domain of organic synthesis, a great interest in palladium‟s chemistry

originates from the Wacker process discovered in the late 50‟s. Many years after this

discovery, organic chemists have succeeded in discovering new reactions that are chemo- and

stereo-selective by the help of catalysts and palladium derived reagents.

Palladium is significantly less expensive than, rhodium, platinum, iridium and to a less

extent cheaper than gold. For that, palladium metal has been widely used for a century in

organic chemistry as a powerful tool in organic synthesis. This useful metal has been used for

so many years as a hydrogenation, hydrogenolysis, and hydrodechlorination catalyst

essentially under heterogeneous forms. More recently, palladium catalyzed reactions for C-C

bond formation, including Suzuki, Heck, Sonogashira, Tsuji-Trost as well as other reactions

have gained a predominant place in organic chemistry.

Indeed, in the last 20 years, the use of palladium complexes as homogeneous catalysts

in organic synthesis has undergone tremendous developments. Catalysts are substrates that

transform reactants into products, through an uninterrupted and repeated cycle of elementary

steps. The catalyst participates while being regenerated to its original form at the end of each

cycle during its life time.1 However, catalysts change the kinetics of the reaction but do not

change the reaction‟s thermodynamics.

The use of palladium complexes as catalysts became a very powerful tool in both

industrial and academic laboratories all over the world.2 Indeed, possible modulations using

these complexes are applicable on a wide number of substrates and reactions. Besides,

palladium complexes are compatible with the presence of various functionalized substrates as

ketones, alcohols, aldehydes and sulfur-substituted groups. Moreover, palladium complexes

are not very toxic and their traces could be removed from their medium easily,3 that allows its

use in industrial mediums as for example, the industrial synthesis of medicines as Losartan.4

The development of these catalysts gave a wide access to new chemical reactions that are

difficult to apply or dangerous to use. Scheme 1 below illustrates the synthetic potentials of

this new catalyst4 in which the diene (1) is a direct precursor of himbacine, a natural product

and antagonist to the Muscarinic receptors that was tested to treat Alzehimer disease. The

traditionally used method5, to synthesize this diene (1), took place under four steps that

requires delicate intermediate purifications to eliminate sulfur-by products. A more recent

1 M. Boudart, Perspectives in catalysis, J. M. Thomas, K. I. zamaraev (Eds.), Blackwell, Oxford, 1992, p. 183.

2 For selected reviews, see: a) V. Farina, Adv. Synth. Catal. 2004, 346, 1553-1582; b) H.-U. Blaser, A. Indolese,

F. Naud, U. Nettekoven, A. Schnyder, Adv. Synth. Catal. 2004, 346, 1583-1598; c) A. Zapf, M. Beller, Chem.

Commun. 2005, 431-440; d) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44, 4442-

4489; e) G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644-4680. 3 V. W. Rosso, D. A. Lust, P. J. Bernot, J. A. Grosso, S. P. Modi, A. Rusowicz, T. C. Sedergam, J. H. Simpson,

S. K. Srivastava, M. J. Humora, N. G. Anderson, Org. Proc. Res. Dev. 1997, 1, 311-314. 4 R. D. Larsen, A. O. King, C. Y. Chen, E. G. Corley, B. S. Foster, F. E. Roberts, C. Yang, D. R. Liebrman, P. J.

Reider, Y. S. Lo, L. T. Rossano, A. S. Brookes, D. Meloni, R. J. Moore, J. F. Arnett, J. Org. Chem. 1994, 59,

6391-6394. 5 S. Chackalamannil, R. J. Davies, T. Asberom, D. Doller, D. Leone, J. Am. Chem. Soc. 1996, 118, 9812-9813.

strategy, developed industrially6, involves a Heck-reaction catalysed by Pd

0. This reaction

sequence is much shorter (2 steps), do not need to perform intermediate purifications, and

therefore, presents a double advantage to be more economical and environmentally friendly

(producing less waste products).

Scheme 1. Comparison between a traditional and a new synthesis method.

6 G. Lai, T. McAllister, Synth. Comm. 1999, 29, 409-413.

II. Homogeneous vs heterogeneous catalysis

A number of palladium catalysts are commercially available and their reactivity,

stability and selectivity can be tuned by the presence of ligands such as phosphines, carbenes,

amines etc. and/or additives. In the past few years an intense use of palladium as

homogeneous catalysts showed a high degree of sophistication and efficiency leading to

transformations unattainable by other standard synthetic operations. Most of these studies

have been focused on homogeneous catalysis which provides excellent activity and

selectivity. Catalytic species at the molecular level are now well characterized allowing the

establishment of structure-activity relationships and ligand selection. Despite its remarkable

usefulness, homogeneous catalysis suffers from a number of drawbacks. Those drawbacks lie

on the sensitivity, the reuse, and on the removal of the catalyst from the products which can

be problematic. The in vivo use of biologically active compounds requires low palladium

contamination (at best below 4 ppm). Indeed, contamination of advanced chemical

intermediates by palladium residues is a critical issue for large-scale synthesis, especially in

the pharmaceutical industry where metal contaminations are closely monitored.

Economical and environmental views make the catalyst‟s recycling crucial. Based on

these perspectives, heterogeneous catalysis seems particularly desired since palladium metal

fixed on a support could be easily removed from the medium by simple filtration leaving the

medium and the products free of its traces.7 A number of organic (mainly organic polymers),

inorganic (silica, zeolite, metal oxides, and carbon material etc.) and hybrid organic-inorganic

supports (mainly grafted silica) for palladium nanoparticles have been used. Alternatively,

7 J. A. Gladysz, Pure Appl. Chem. 2001, 73, 1319-1324.

molecular complexes bound to a ligand anchored on a support have also been studied as

recyclable catalysts.8

Therefore, the heterogeneous catalysis is of vital importance to the world‟s economy,

allowing us to convert raw materials into valuable chemicals and fuels, in an economical,

efficient, and environmentally benign manner. Heterogeneous catalysts have numerous

industrial applications in the chemical, food, pharmaceutical, automobile and petrochemical

industries9, and it has been estimated that 90% of all chemical processes use heterogeneous

catalysts. Indeed, continued research into heterogeneous catalysis is required to allow us to

address increasingly complex environmental and energy issues facing our industrialized

society. The main advantage of using a heterogeneous catalyst is that, being a solid material,

it is easy to separate from the reaction media by filtration. The main disadvantage of the

heterogeneous catalysts lies with the kinetics which are usually lower from that of

homogeneous ones. Moreover, the rates of generating the active species into the medium are

sometimes slower with heterogeneous catalysts compared to that of homogeneous catalysts.

III. Heck-Mizoroki Reaction

III. 1. General considerations

The palladium-catalyzed vinylation of unsaturated moieties (aryl, alkenyl) bearing

halide or pseudohalide leaving groups (tosylate, triflate, diazonium salts, iodonium salts etc.)

is known as the Heck-Mizoroki reaction.10

This reaction type is a powerful and a widely used

reaction in industrial and academic applications, mainly for the coupling of aryl halides to

8 For reviews, see: a) F.-X. Felpin, T. Ayad, S. Mitra, Eur. J. Org. Chem. 2006, 2679-2690; b) M. Seki,

Synthesis. 2006, 2975-2992; c) L. Jin, J. Liebscher, Chem. Rev. 2007, 107, 133-173. 9 a) J. M. Thomas, W. J. Thomas, Principles and practice of Heterogeneous Catalysis, 1997, 669; b) J. N.

Armor, Appl. Catal., A, 2001, 222, 407; c) I .Chorkendorff, J. W. Neimantsverdriet, Concepts of Modern

Catalysis and Kinetics, 2003, 452; d) R. J. Farrauto, C. H. Bartholomew, Fundamentals of Industrial Catalytic

Processes, 1997, 754; d) R. A. van Santen, P. W. N. M. v. Leeuwen, J. A. Mooulijn, B. A. Avrerill, Catalysis:

Integrated Approach, 1999, 574. 10

T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 1971, 44, 581 – 582; b) R. F. Heck, J. P. Nolley Jr, J.

Org. Chem. 1972, 37, 2320 – 2322.

electron withdrawing terminal olefins.11,12

It worth mentioning that the Heck-Mizoroki

vinylation is also historically one of the first direct palladium C-H activation for C-C

couplings having such a remarkably wide scope which makes this coupling of particular

interest in terms of sustainable chemistry.

Nowadays, this reaction has found several commercial applications for the production

of fine chemicals on multi-ton scale / year13

as herbicide,14

anti-inflammatory,15

or anti-

asthma agents.16

In recent years, a number of heterogeneous catalysts have been developed for

use in the Heck-reaction. The palladium Pd0-catalyzed arylation of alkenes with an organic

halide (Scheme 2) was first reported by Mizoroki and Heck in the early 70‟s. The classical

reaction involves a bond formation between sp2 C-centers by an overall substitution of a C-H

bond of an alkene (substrates poor in electrons) by R1

from the R1X substrates (R

1=aryl or

vinyl; X = I, Br; R2= electron withdrawing group or an electron donating group) under basic

conditions. The transformation has since become known as one of the most important

methods to perform a C-C cross coupling reaction.

Scheme 2. General representation of the Heck-Mizoroki reaction.

11

N. T. S. Pham, M. Van Der Sluys, C. W. Jones, Adv. Synth. Catal. 2006, 348, 609-679. 12

a) G. T. Crisp, Chem. Soc. Rev. 1998, 27, 427 – 436; b) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000,

100, 3009 – 3066; c) N. J. Whitcombe, K. K. Hii, S. E.Gibson, Tetrahedron, 2001, 57, 7449 – 7476; d) J. G.

de Vries, Can. J. Chem. 2001, 79, 1086 – 1092; e) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 –

2963; f) J. P. Knowles, A. Whiting, A. Org. Biomol. Chem. 2007, 5, 31 – 44; g) V. Polshettiwar, A. Molnár,

Tetrahedron 2007, 63, 6949 – 6976. 13

C.E. Tucker, J.G. de Vries, Top. Catal. 2002, 19, 111; b) M. Beller, A. Zapf, in: E.-i. Negishi (Ed.), Handbook

of Organopalladium Chemistry for Organic Synthesis, vol. 1, Wiley, Hoboken, 2002, p. 1209. 14

P. Baumeister, W. Meyer, K. Oertle, G. Seifert, H. Steiner. Chimia. 1997, 51, 144-146. 15

J. McChesney, Spec. Chem. 1999, 6, 98. 16

I. Shinkai, A. O. King, R. D. Larsen, Pure Appl. Chem. 1994, 66, 1551.

Since its discovery, the methodology has been found to be highly versatile and

applicable to a wide range of aryl species Ar-X, where X = Cl, Br, I, OTs, OTf and N2+. A

diverse range of olefins has been also found to undergo the Heck reaction. The popularity of

the Heck reaction started to flourish in the mid 80‟s when synthetic chemists found that they

were able to control the selectivity by using certain protocols to give predictable results. The

unsaturated halides could be as well aryl, benzyl, or vinyl halides. Bromo- and especially

chloro-compounds are more reluctant to undergo catalytic reactions, than iodo-derivatives,

due to their stronger C-X bond, a problem made worse if the group carries electron-rich

substituents. Bromides and chlorides are however very useful substrates to synthetic chemists,

as they are cheaper than iodides. Some confusion concerning the reactivity of aryl halides was

found in the literature. In many studies, reactive aryl iodide substrates are routinely used to

test the efficiency of a novel catalytic system, when it has been clearly demonstrated that

unligated palladium-precursors can easily achieve extremely high turnover numbers (TONs).

Furthermore, the coupling of aryl iodides and bromides with methylacrylate has very different

rate-determining steps.17

This has important implications for the development of catalysts for

the activation of aryl bromides and chlorides.

Numerous papers have reported catalytic systems with impressive TONs. The majority

of these studies were performed using electron-poor aryl halides, such as 4-

bromoacetophenone, and electron-poor olefins such as acrylates and styrenes. The current

challenge lies in the development of catalytic systems that will activate non reactive aryl

halides towards Heck catalysis, especially aryl chlorides where the TONs are low.

17 M. Qadir, T. Mӧchel, K. K. Hii, Tetrahedron, 2000, 56, 7975-7979.

III. 2. Traditional Mechanism

The traditional mechanism for the Heck reaction illustrated in Scheme 318

shows the

catalytic cycle of palladium. A number of sources have been used in the Heck reaction,

however, PdII precatalyst such as Pd(OAc)2, PdCl2(PPh3)2 or PdCl2CH3CN are usually

preferred in association with certain ligands (L), such as phosphines or carbenes, that are

often used to improve the catalyst stability. This catalytic cycle undergoes 4 steps: a)

formation of the catalytic species, b) formation of an organopalladium species (oxidative

addition), c) insertion of the organopalladium to an olefin, d) elimination of the palladium (β-

elimination) and regeneration of the catalytic species Pd0L2.

Improvements of the catalytic system over the years have led to design and develop

new ligands, including chiral ones for asymmetric Heck processes.18,19

From a mechanistic

point of view, it is generally admitted that the Pd catalyst cycles between Pd0 and Pd

II

oxidation states during the course of the reaction although PdII-Pd

IV cycles have also been

proposed when using palladacycle precatalyst as a Pd source.18,20

The usual admitted

mechanism of the Heck reaction involves an oxidative addition of electron rich and

nucleophilic Pd0 species to the R-X electrophile, followed by carbometallation of the olefin

(A) (Scheme 3, right), elimination of Pd-hydride from the intermediate (B) provides the

olefin (C) and the L2PdIIHX complex. It is agreed that the base reduce L2Pd

IIHX to regenerate

the active Pd0L2 complex. It‟s also agreed that the oxidative addition of aryl iodides

21 and

activated aryl bromides22

to palladium is not the rate determining step, in contrast, the lower

18

F.-X. Feplin, L. Nassar-Hardy, F. Le Callonnec, E. Fouquet, Tetrahedron, 2011, 67, 2815-2831. 19

M. Shibasaki, E. M. Vogl, T. Ohshima, Adv. Synth. Catal. 2004, 346, 1533-1552. 20

M. Ohff, A. Ohff, M. E. van der Boom, D. Milstein, J. Am. Chem. Soc. 1997, 119, 11687-11688. 21 G. P. F. van Strijdonck, M. D. K. Boele, P. C. J. Kamer, J. G. de Vries, P. W. N. M. Leewen, Eur. J. Inorg.

Chem. 1999, 1073-1076. 22

T. Rosner, J. Le Bars, A. Pfaltz, D. G. Blackmond, J. Am. Chem. Soc. 2001, 123, 1848-1855.

activity of the aryl chlorides and electron rich aryl bromides tends to consider the oxidative

addition step as a determining rate step, but other steps may also determine the reaction rate.23

While this catalytic cycle involving neutral intermediates would be quite general with

aryl or vinyl halides, it has been suggested that cationic pathway could be involved with aryl

and vinyl sulfonates (Scheme 3, left).18

This feature could be explained by the easy

dissociation of the Pd-X bond (X = OTs, OTf) after the oxidative addition step.

Scheme 3. Cationic vs neutral catalytic cycles of the Heck-Mizoroki reaction

Other metals were also used for the Heck reaction such as nickel but with a decreased

efficiency. In 1986 a bimetallic system for executing the Heck reaction was developed by

using NiCl2(PPh3)2 in the presence of Zinc as a reductant (Scheme 4).24

Along with the Heck

23

W. A. Herrmann, C. Brossmer, K. Ofele, M. Beller, H. Fischer, J. Mol. Catal. A. Chem. 1995, 103, 133-146. 24

G. P. Boldrini, D. Savois, E. Taglivini, C. Trombini, A. U. Ronchi, J. Organomet. Chem, 1986, 301, C62-C64.

product (trans-isomer), the formation of saturated and homocoupled by-products were also

observed. Therefore, the yields were generally poor.

Scheme 4. Nickel complex in the presense of Zinc as a reductant in Heck Reaction

While the Heck reaction has been intensively studied, a related approach, also called

Heck-Matsuda reaction was represented by the use of aryl diazonium salts instead of an aryl

halide (Scheme 5). This approach succeeded in overcoming the drawbacks of the classical

Heck reaction. The Heck-Matsuda overcame the use of ligands and base and the need of high

temperatures. Moreover, the Heck-Matsuda reaction takes place under mild conditions in

alcoholic solvents or acetonitrile. These features make Heck-Matsuda an interesting reaction

to focus on.

Scheme 5. General representation of the Heck-Matsuda reaction

IV. Diazonium Salts

IV. 1. Properties

Aryl diazonium compounds have been discovered in 1858 by the German chemist

Johann Peter Griess.25

Diazonium salts are a class of compounds with the common structure

of R-N2+X

- where R is an aryl or alkyl fragment and X

- is a weakly nucleophilic organic or

inorganic anion. Although in theory a large variety of R/X combinations might be feasible,

the nature of both the cation and the anion strongly influences the stability of diazonium salts

and, thereby, limit their use for synthetic applications. For instance, alkyl diazonium salts are

usually not isolable and rarely exploited in synthesis. By contrast, aryl diazonium salts are

much more stable due to the electronic delocalization between the aromatic ring and the

nitrogens. When associated with a proper stabilizing anion, they can be isolated as crystalline

compounds. Although aryl diazonium salts are known for more than 150 years, they have

been underutilized in organic synthesis due to a reputation of unstable compounds. This

reputation originates from the fact that aryl diazonium salts were mainly used with chloride as

counterion. Unfortunately, aryl diazonium chlorides are usually highly unstable above 0°C

and even explosive. However, later developments showed that the stability of the diazonium

salts can be modulated by varying the counterion. In this prospect, tetrafluoroborates26

became the most used salts but, disulfonimides27

, carboxylates28

as well as other salts have

also been described for their good stability. From our own experience, we routinely use aryl

diazonium tetraflouroborates that have been stored at -20°C for more than 3 years without

noticeable decomposition as judged by 1H NMR. As mentioned by Filimonov,

29 and

confirmed by the DSC analysis, that aryl diazonium tosylates are not explosive in the range of

25

P. Griess, Liebigs Ann. Chem. 1858, 106, 123-125. 26

D. T. Flood, Org. Synth. 1943, 2, 295-298. 27 M. Barbero, M. Crisma, I. Degani, R. Fochi, P. Perracino, Synthesis 1998, 1171-1175. 28

C. Colas, M. Goeldner, Eur. J. Org. Chem. 1999, 1357-1366. 29

V. D. Filimonov, M. Trusova, P. Postnikov, E. A. Krasnokutskaya, Y. M. Lee, H. Y. Hwang, H. Kim, K.-W.

Chi, Org. Lett. 2008, 10, 3961-3964.

0°C to 600°C. The stability of the diazonium salt is attributed to the high affinity between

anion and the cation. The shorter the distance between the anion and the cation, the more

stable the diazonium salt is. The X-ray crystal structure of aryl diazonium tosylates revealed

that one independent cation is surrounded by three tosylate anions with a short inter-ionic

distance (2.7Å). By contrast, with the less stable aryl diazonium chlorides, X-ray structure

showed a shorter distance between N-Cl at a measure of 3.22 vs 2.7Å.30

IV. 2. Preparation

Aryl diazonium salts have been prepared by various methods, the oldest and

commonly used involves the diazotation of the anilines with sodium nitrates in the presence

of an aqueous Brønsted acid.31, 26

The counterion (X-), determined by the choice of the acid, has a crucial role for both

the stability and the reactivity of the diazonium salts. Numerous variants of the acids and the

solvents have been reported and usually give good yields of water insoluble diazonium salts.

However, isolation of the dry aryl diazonium salts from an aqueous mixture can be tricky for

stability and safety reasons. Anhydrous aryl diazonium salts with tetraflouroborate as

counterion can be prepared by reacting the anilines with alkyl nitrite in the presence of boron

trifluoride with THF or ether as solvent.32

Anhydrous diazonium salts can also be obtained by

acidic decomposition of triazenes.33

Notably, this method has been elegantly exploited by

Bräse and co-workers for the preparation of aryl diazonium salts from polymer-supported

triazenes.34

Alternate methods for unreactive anilines have also been reported and involve the

30

C. Romming, Acta Chem. Scand. 1963, 17, 1444-1454. 31

G. Schiemann, W. Winkelmüller, Org. Synth. 1943, 2, 299-302. 32

M. P. Doyle, W. J. Bryker, J. Org. Chem. 1979, 44, 1572-1574. 33 (a) S. Bhattacharya, S. Majee, R. Mukherjee, S. Sengupta, Synth. Commun. 1995, 25, 651-657; (b) S.

Sengupta, S. K. Sadhukhan, Org. Synth. 2004, 10, 263-266. 34

S. Bräse, M. Schroen, Angew. Chem. Int. Ed. 1999, 38, 1071-1073.

use of strong nitrosating agents such as NOCl, NOHSO4, NOBF4, and NOOCOCF3.35

However, due to their high reactivity and dangerousness, these compounds must be handled

with an extreme care.

The preparation of substituted diazonium salts requires the functionalization of the

corresponding anilines. Generally, the sensitivity of free anilines to various experimental

conditions usually requires the use of protecting groups. In this context, the functionalization

of hydroxyacetamides followed by a one-pot sequence of deacetylation, diazotation and

precipitation was reported by Schmidt36

(Scheme 6). To the credit of this protocol, the

convenient one-flask transformation with consecutive addition of the reagents and the final

isolation of the diazonium salt by simple filtration.

Scheme 6. Preparation of diazonium salts from hydroxyacetamides by Schmidt et al.36

35 (a) M. P. Doyle, W. Wierenga, M. A. Zaleta, J. Org. Chem. 1972, 37, 1597-1601; (b) J. M. Tedder,

Tetrahedron 1957, 1, 270-271. 36

B. Schmidt, R. Berger, F. Hӧlter, Org. Biomol. Chem. 2010, 8, 1406-1414.

IV. 3. General reactivity.

The general reactivity of diazonium salts, represented in (Scheme 7), can be divided

into three classes of reactions: (A) addition over the diazonium function, (B) substitution of

the nitrogens, (C) reduction of the diazonium salts.

Scheme 7. General reactivity of diazonium salts.

The addition of nucleophiles such as tertiary anilines37

, phenols38

, and aryl zinc

compounds39

leads to the formation of aryl azo compounds that are of commercial interest as

dyes and pigments40

while the addition of free amines leads to the formation of triazenes.41

The intramolecular reaction of alkenes with diazonium salts have been used for the

Widman42

-Stoermer43

preparation of cinnoline heterocycles.

A number of reactions have exploited the diazonium function as an excellent leaving

group. From others, the most representative ones are Sandmeyer,44

the Balz-Schiemann,45

the

37 H. T. Clarke, W. R. Kirner, Org. Synth. 1941, 1, 374-376. 38

J. L. Hartwell, L. F. Fieser, Org. Synth. 1943, 2, 145-147. 39

D. Y. Curtin, J. A. Ursprung, J. Org. Chem. 1956, 21, 1221-1225. 40 K. Hunger, P. Mischke, W. Rieper, R. Raue, K. Kunde, A. Engel, „Azo Dyes‟ in Ullmann‟s Encyclopedia of

Industrial Chemistry, Wiley-VCH: Weinheim, 2005. 41

W. W. Hartman, J. B Dickey, Org. Synth. 1943, 2, 163-165. 42

O. Widman, Ber. 1884, 17, 722-727. 43

R. Stoermer, H. Fincke, Ber. 1909, 42, 3115-3132. 44

T. Sandmeyer, Ber. 1884, 17, 1633-1635. 45

G. Balz, G. Schiemann, Ber. 1927, 60, 1186-1190.

Meerwein,46

the Pschorr,47

and the Gomberg-Bachmann48

reactions. More recently, aryl

diazonium salts have also been used as aryl halides substrates in a variety of palladium

catalyzed reactions49

including the Heck-Matsuda coupling. It should be noted that the

Meerwein reaction is synthetically related to the Heck-Matsuda coupling although it involves

free-radical intermediates and has a more limited scope.46

Last, the reduction of the diazonium

function by sodium sulfite leads to the corresponding hydrazine.50

46

H. Meerwein, E. Buchner, K. van Emsterk, J. Prakt. Chem. 1939, 152, 237-266. 47

R. Pschorr, Ber. 1896, 29, 496-501. 48

M. Gomberg, W. E. Bachmann, J. Am. Chem. Soc. 1924, 42, 2339-2343. 49 A. Roglans, A. Pla-Quintana, M. Moreno-Mañas, Chem. Rev. 2006, 106, 4622-4643. 50

R. Huisgen, R. Lux, Chem. Ber. 1960, 93, 540-544.

V. Heck-Matsuda reaction

V. 1. Early developments on Heck-Matsuda reaction

Although the Heck-Matsuda reaction has been mostly overlooked until the end of the

90‟s, it has been first described in the laboratory of Kikukawa and Matsuda as early as

1977.51,52,53

In this remarkable seminal work, the group reported that styrene,

cyclopentene, allylic alcohols, ethyl acrylate, n-butyl vinyl ether and ethylene were

arylated with aryl diazonium chlorides in the presence of catalytic amounts of

palladium(0) complexes in buffered (pH ~4.5) aqueous acetonitrile solution (Scheme 8).

Interestingly, the authors also pointed out the complementary nature of this method with

the well known copper-catalyzed Meerwein arylation reaction that involves free radical

intermediates.54

Although the exact nature of the mechanism was unknown at that time,

the authors noticed that the reaction was completed in 1 hour at only 40 to 50°C.

However, they also pointed out the instability of aryl diazonium chlorides at room

temperature leading to safety issues and modest yields of coupled products.

51 K. Kikukawa, T. Matsuda, Chem. Lett. 1977, 159-162. 52

K. Kikukawa, K. Nagira, T. Matsuda, Bull. Chem. Soc. Jpn. 1977, 50, 2207. 53 K. Kikukawa, K. Nagira, N. Terao, F. Wada, T. Matsuda, Bull. Chem. Soc. Jpn. 1979, 52, 2609-2610. 54

C. S. Rondestveldt, Jr. Org. React. 1960, 11, 189-260.

Scheme 8. Selected examples from Matsuda and co-workers.51, 52, 53

They also noticed that aryl diazonium tetrafluoroborates were more stable and could be

handled at room temperature as crystalline salts.55

As a consequence, improved yields were

usually observed and sometimes in a significant extent as shown in the following example

(Scheme 9).

55

K. Kikukawa, K. Nagira, F. Wada, T. Matsuda, Tetrahedron 1981, 37, 31-36.

Scheme 9. Influence of the diazonium salt counterion.55

To avoid the manipulation of potentially unstable diazonium salts, they subsequently

developed a protocol where the aryl diazonium salt was in situ prepared by reaction of the

corresponding aniline with tert-butyl nitrite.56,57

To succeed in such a purpose, they opted for

an acidic medium (CH3COOH-ClCH2COOH) that played the role of solvent, Brønsted acid,

and counterion (RCOO-). With this protocol in hands, Matsuda et al. reported much improved

yields of coupling products for the reaction of aryl diazonium salts with styrenes, acrylates,

and cyclic olefins (Scheme 10). It is interesting to note that under these conditions a base was

required. Although not fully satisfactory due to large variations of the yields according to the

substitution of aniline; in the context of the end of 70‟s and beginning of the 80‟s, this work

already represented an excellent preamble that appealed further developments.

56

K. Kikukawa, K. Maemura, K. Nagira, F. Wada, T. Matsuda, Chem. Lett. 1980, 551-552. 57 K. Kikukawa, K. Maemura, Y. Kiseki, F. Wada, T. Matsuda, J. Org. Chem. 1981, 46, 4885-4888.

Scheme 10. Heck-Matsuda using in situ generated diazonium salts.56, 57

V. 2. Recent developments on Heck-Matsuda reaction

V. 2. a. Heterogeneous catalysis

While most arylation studies have been reported under homogeneous catalysis, essentially

with Pd(OAc)2 and Pd2dba3 as molecular complexes, the use of Pd/C as heterogeneous

catalyst gave good results for the arylation of ethyl acrylate,58

and methyl vinyl ketone.59

In

our laboratory, we conducted a property-activity relationship study of various Pd/C catalysts

for the arylation of acrylates with aryldiazonium salts60

. The optimized protocol showed that a

PdII on charcoal with an eggshell distribution was required for optimal results (table 1). Other

combinations of oxidation degree and distribution of palladium gave a significantly decreased

activity. The greatest activity of the catalysts having an eggshell distribution could be

explained by a higher exposition of the palladium nanoparticles (at the outer surface of the

58

M. Beller, K. Kühlein, Synlett 1995, 441-442. 59

T. Stern, S. Rückbrod, C. Czekelius, C. Donner, H. Brunner, Adv. Synth. Catal. 2010, 352, 1983-1992. 60

F.-X. Felpin, E. Fouquet, C. Zakri, Adv. Synth. Catal. 2008, 350, 2559-2565.

charcoal) towards the diazonium salt during the oxidative step. This result contrast with those

obtained by Köhler et al.61

for the Heck-reaction of arylbromides with styrene at 140°C where

a PdII/C catalyst with a uniform palladium distribution on the charcoal displayed a higher

catalytic activity. It is clearly understood that the unique electronic properties of diazonium

salts and low temperature 25°C can lead to differences on the known mechanism of the

reaction. Although the catalyst could not be recycled, low palladium leaching measured by

ICP-MS renders the method safer to the environment compared to homogeneous conditions.

However, continuous trials done by our group for using aryl diazonium salts with acrylates in

the presence of Pd/C under mild conditions were tested. The immobilization of palladium on a

support allows its recovery by simple filtration and permitting the catalyst‟s reuse for further

reactions. Among the supports used for palladium, activated charcoal is certainly one of the

most convenient in terms of coast, inertness, safety and availability.

Table 1. Optimization trails for the choice of catalyst

61

K. Kӧhler, R. G. Heidenreich, J. G. E. Krauter, J. Pietsch, Chem. Eur. J. 2002, 8, 622 – 631.

After optimization of various parameters including equivalents of reagents,

concentration and catalyst loading we were able to carry out the cross-couplling at a low

loading of palladium (0.1 mol %), (table 2). These results showed two important remarks; 1)

solutions of concentrations >0.5 M are not recommended since a drop in the reaction yield

was observed; 2) low Pd loadings were sufficient to give the desired product with excellent

yields under ligand-free reactions at room temperature.

Table 2. Optimization trails for the reaction conditions

After those promising results, our group has further explored the scope of this process

with a variety of cross-coupling partners (table 3). A high level of chemoselectivity for the

diazonium groups was observed with 2-bromobenzene diazonium salt (entry 2). Indeed, no

evidence for competing electrophilic reactivity of the bromine atom was observed. Electron

poor diazonium salts reacted smoothly at 25°C with low loadings of catalyst as 0.1 mol%,

while electron rich substrates required higher loading of the catalyst and a moderate heating

activation (entries 3-4). The use of CaCO3 as an additive proved to be useful in terms of yields

and kinetics for less reactive diazonium salts (entries3- 4). The base enhances the rate of the

reductive elimination step, however, the choice of the base also proved to be essential since

the use of Na2CO3 led to a rapid and complete decomposition of the diazonium salt. Besides,

to avoid any transesterification of acrylates (entries 5-6) it is recommended to use 0.5-0.6

equivalents of CaCO3.

Table 3. Scope of the cross-coupling

Since Pd/C could be easily filtrated from the reaction mixture, our group has examined

its recyclability from the formed product after cross coupling of acrylate with an

aryldiazonium salt. Unfortunately, a drop in the catalysts catalytic activity after the catalysts

first reuses (Scheme 11).

Scheme 11. Recycling tests

Therefore, ICP-MS analysis was used to evaluate the amount of Pd leached into the

solvent that did not re-deposit on charcoal at the end of the reaction. After 12 hours of stirring

only 1.6 ppm of Pd was solubilized in the solution, indicating that only 0.9 % of the used

metal has leached into the solvent. We concluded that all palladium remained on the charcoal

and the decrease in the catalytic activity is not related to the low loadings of the Pd over

Charcoal. The low concentrations of the palladium proved to be inactive in promoting a

further reaction after separation of the catalyst by filtration. Characterization of the fresh and

the reused catalysts by transmission electron microscopy (TEM) showed that the deactivation

could be correlated to the increase in the average crystallite size from 20 nm to 60 nm.

(Figure 1).60

The change in the nanoparticles size indicates that the palladium is leached from

the support during the oxidative addition step and later re-precipitated on the charcoal after

the reductive elimination step. The mild conditions (25°C) used in this study ruled out a

temperature induced leaching, indicating that oxidative addition of the diazonium salt could

be responsible of the palladium desorption. The use of PdII precatalyst was crucial for the

success of the cross-coupling but, according to the widely accepted mechanism of the Heck-

reaction, the reused Pd/C catalyst should be reduced to its Pd0 form. This point is fully

consistent with the strong reactivity decrease observed with reused catalyst.

Figure 1. TEM images of fresh catalyst (left) and reused catalyst (right) at the same

magnification.

V. 2. b. Preparation of highly substituted olefins

Unsymmetrical β,β-diaryl acrylates are notoriously difficult to prepare with high

stereoselectivities, but the mechanism of the Heck reaction dictates that the stereochemical

outcome for the arylation of a disubstituted alkene giving a trisubstituted alkene proceeds in a

stereospecific manner. A remarkable dependence of the diastereoselectivity on the nature of

the arenediazonium salt was discovered by Correia and co-workers for the arylation of methyl

cinnamate.62

Notably, the diastereoselectivity was much higher for salts bearing electron-

withdrawing groups instead of electron-donating groups. Low stereoselectivities were

attributed to the well-known elimination–reverse addition-elimination of a putative cationic

62

a) J. C. Pastre, C. R. D. Correia, Adv. Synth. Catal. 2009, 351, 1217. b) J. G. Taylor, C. R. D. Correia, J. Org.

Chem. 2011, 76, 857-869.

PdH species. The synthesis of most Heck adducts in geometrically pure form could be

guaranteed by the use of either NaOAc or 2,5-ditert-butyl-4-methylpyridine (DTBMP) as

base to eliminate PdH and prevent isomerization (table 4).

Table 4. Pd-catalyzed coupling of diazonium salts to cinnamate esters

Contrary to the synthesis of β,β-diarylacrylates that was produced using relatively high

catalytic loadings (5-10 mol%), the synthesis of substituted cis-stilbenes, achieved by our

group, by arylation of 2-arylacrylates derivatives required low catalytic loadings (0.1-1.5

mol%).63

Table 5 shows optimization studies for the preparation of stilbenes that conducted

the reaction at 25°C and preserved the catalytic activity. Upon exploring the reaction‟s scope,

it was revealed that an o-substituted 2-arylacrylate was essential for getting high

stereoselectivities. It should also be mentioned that the E/Z ratios were generally very good.

Besides, it is interesting to know that this type of arylation is very important since large

63

F.-X. Felpin, K. Miqueu, J.-M. Sotiropoulos, E. Fouquet, O. Ibarguren, J. Laudien, Chem. Eur. J. 2010, 16,

5191-5204.

varieties of analogues are prepared in the absence of base and ligands, which renders the

reaction to be an environmentally clean reaction.

Table 5. Arylation of 2-arylacrylate

V. 2. c. Heck-Matsuda reaction in heterocyclic chemistry

The arylation of chiral L-3-dehydroproline is a striking example of stereo- and regio-

control accomplished with the Heck-Matsuda reaction (table 6).64

Several arenediazonium

tetrafluoroborates could be employed to produce a collection of (4S)-aryl-2,3-dehydroproline,

which is then followed by dehydration/methanol elimination of the initial 4-aryl-2-hydroxy or

the 4-aryl-2-methoxy proline adducts. Capturing the primary Heck adduct by water or MeOH

64 K. P. da Silva, M. N. Godoi, C. R. D. Correia, Org. Lett. 2007, 9, 2815.

is apparently beneficial as it prevents conversion of the Heck product to the corresponding

pyrroles.

Table 6. Arylation of chiral L-3-dehydroproline

A synthetic methodology has been applied to the arylation of chiral dihydropyrans for the

preparation of all four stereoisomers of centrolobine (Scheme 12).65

The preparation, of two

isomers, of the centrolobine started with the Heck-Matsuda reaction between 4-

methoxybenzene diazonium salt and the cyclic enol ether. The reaction took place in the

presence of NaOAc and Pd(OAc)2 (5 mol%) at room temperature for three hours in CH3CN as

a solvent. The formed arylated pyrane product was collected with excellent yields giving 91%

of (3R, 7S)-dehydrocentrolobine with very high diastereoselectivity (> 98:2). The other

isomers are prepared in the same way when replacing (S)-cyclic enol ethers with (R)-cyclic

enol ether.

65

B. Schmidt, F. Hölter, Chem. Eur. J. 2009, 15, 11948-11953.

Scheme 12. 4 isomers of centrolobine starting from Heck-Matsuda

V. 3. Mechanistic investigations

The catalytic cycle was first proposed by Matsuda et al.55

on the bases of the

postulated Heck-Mizoroki mechanism. However, significant differences were assumed by the

authors due to distinctive nature of the diazonium salts. Indeed, the observation of the

nitrogen evolution during the oxidative addition step led the authors to postulate the formation

of highly active cationic palladium intermediates as shown in (Scheme 13).

Scheme13. Proposed mechanism by Matsuda et al.

The mechanism has been accepted for almost 25 years without experimental evidence

to confirm the hypothesis of Matsuda et al. In 2004, the Eberlin et al studied the Heck-

Matsuda reaction by electrospray mass and tandem mass spectrometry.66

This interesting

study confirmed the catalytic cycle proposed by Matsuda et al. Indeed, they were able to

detect and characterize several cationic intermediates corresponding to the elementary steps of

the catalytic cycle. They also showed that cationic palladium species were stabilized by

solvent molecules such as CH3CN and dba ligands.

In order to understand the role of solvent in stabilizing cationic palladium

intermediates, we recently performed DFT calculations.63

Our group compared the 2-

coordination energy of PhPd+ with various solvents (CH3OH, THF, and CH3CN) and methyl

2-(2-nitrophenyl) acrylate. Theoretical results showed that the PhPd+-acrylate complex is

exoergic in CH3OH, isoergic in THF, and endoergic in CH3CN. These calculations were in

good agreed with experimental observations on the Heck-Matsuda reaction since we observed

the higher kinetics in CH3OH compared to THF and CH3CN.

66 A. A. Sabino, A. H. L. Machado, C. R. D. Correia, M. N. Eberlin, Angew. Chem. Int. Ed. 2004, 43, 2154-

2158.

Thereby, the PhPd+(CH3OH)n complex can easily dissociate in favor of the formation

of the PhPd+-acrylate complex. Solvents with higher coordination energy (i.e., CH3CN) retard

the olefin insertion step and slow down the reaction rate. The presence of a cationic palladium

intermediate was also confirmed by Roglans and Pla-Quintana with the aid of electrospray

ionization mass spectrometry analyses.67

However, in this work, the cationic palladium

species were stabilized with the triolefinic macrocyclic ligand having a strong affinity for the

palladium and not with the solvent molecules. Based on these recent mechanistic studies, a

general catalytic cycle can be drawn in Scheme 14 in which cationic palladium intermediates

are stabilized with solvent molecules or a proper ligand.

It should be noted that trivalent phosphorus compounds (phosphines and phosphites)

are usually not considered as ligands of choice for the Heck-Matsuda reactions. Indeed, it has

been reported that they give rise to de-diazonization pathway through the formation of aryl

radicals.68

As a consequence, Heck-Matsuda reactions are frequently carried out under ligand-

free conditions.

67

A. Pla-Quintana, A. Roglans, ARKIVOC 2005, ix, 51-62. 68 S. Yasui, M. Fujii, C. Kawano, Y. Nishimura, A. Ohno, Tetrahedron Lett. 1991, 32, 5601-5604.

Scheme 14. General catalytic cycle for the Heck-Matsuda Reaction

V. 4. Influence of the counterion on the Heck-Matsuda reaction

Aryl diazonium salts are very reactive electrophiles when involved in palladium

catalyzed reactions, including Heck-Matsuda coupling, due to an excellent nucleofugic

property of nitrogen. Although, a systematic study of an anion-activity relationship has not

been realized yet, the compilation of several independent works allows a first look. Aryl

diazonium tetrafuoroborates26

, sulfonates29

, and disulfonamides27

appear to be the most stable

compounds that can be usually isolated as crystalline salts under safe conditions. It is thus not

surprising to see excellent results when these salts are involved in the Heck-Matsuda

reaction.69

By contrast, aryl diazonium chlorides and acetates are much less stable and usually

not easy to isolate under pure forms. These salts are inappropriate electrophiles for the Heck-

Matsuda coupling. In an interesting work, Sengupta et al. studied the anion activity

69 E. Artuso, M. Barbero, I. Degani, S. Dughera, R. Fochi, Tetrahedron 2006, 62, 3146-3157.

relationship by treating triazenes with mineral and organic acids.70

Thus, the in situ generated

diazonium salts were reacted with ethyl acrylates in ethanol. This study revealed that

diazonium salts with BF4-, ClO4

-, CF3CO2

-, F

-, and CH3SO3

- as counterions were effective

partners for the Heck-Matsuda reactions while CH3CO2- and Dowex 50W-X8(P-SO3-) gave

low yields of the coupled product. In summary, systematic studies have been done with a

large variety of counterions evaluates their reactivity towards Heck-Matsuda reaction.

However, based on the work of Sengupta and others it appears that yields depend, at least in

part, on the diazonium salt stability. Other factors such as the interaction of the counterion

with cataionic palladium species during the catalytic cycle have not been studied but would

provide useful information towards the establishment of an optimal catalytic system.

V. 5. General considerations on experimental conditions

Heck-Matsuda reaction has been mainly described in alcoholic solvents such as

EtOH,71

and MeOH,72

under dry or aqueous conditions.73

Alternatively, CH3CN has also been

widely used for various applications. Other solvents such as THF,74,75

ionic liquids,76

PhCN77

has also been considered with success for specific applications but usually led to lower

catalytic activities. It has been frequently observed that alcoholic solvents and especially

MeOH, contrary to CH3CN, considerably increase the reactivity of the diazonium salts under

70

S. Sengupta, S.K. Sadhukhan, S. Bhattacharyya, Tetrahedron 1997, 53, 2213-2218. 71 (a) W. Yong, P. Yi, Z. Zhuangyu, H. Hongwen, Synthesis 1991, 967-969; (b) S. Sengupta, S. K. Sadhukhan,

S. Bhattacharyya, J. Guha, J. Chem. Soc., Perkin Trans. 1 1998, 407-410; (c) R. Perez, D. Veronese, F. Coelho,

Antunes, O. A. C. Tetrahedron Lett. 2006, 47, 1325-1328; (d) T. Konno, S. Yamada, A. Tani, T. Miyabe, T.

Ishihara, Synlett 2006, 3025-3028; (e) T. Konno, S. Yamada, A. Tani, T. Miyabe, T. Ishihara, M. J. Nishida,

Fluorine Chem. 2009, 130, 913-921. 72

(a) S. Sengupta, S. K. Sadhukhan, S. Bhattacharyya, J. Chem. Soc., Perkin Trans.1,1998, 275-277; (b) S.

Sengupta, S. K. Sadhukhan, R. S. Singh, Indian J. Chem. 2001, 40B, 997-999; (c) S. Darses, M. Pucheault, J.-P.

Genêt, Eur. J. Org. Chem. 2001, 1121-1128; (d) J. Cesar-Pastre, C. Roque Duarte Correia, Adv. Synth.

Catal. 2009, 351, 1217-1223. 73 (a) S. Sengupta, S. Bhattacharyya, J. Chem. Soc., Perkin Trans.11993,1943-1944; (b) S. Sengupta, S.

Bhattacharyya, Tetrahedron Lett. 1995, 36, 4475-4478; (c) M. Barbero, S. Cadamuro, S. Dughera, Synthesis

2006, 3443-3452. 74 G. Bartoli, S. Cacchi, G. Fabrizi, A. Goggiamani, Synlett 2008, 2508-2512. 75

M. B. Andrus, C. Song, J. Zhang, Org. Lett. 2002, 4, 2079-2082. 76 G. W. Kabalka, G. Dong, B. Venkataiah, Tetrahedron Lett. 2004, 45, 2775-2777. 77

A. V. Moro, F. S. Cardoso, C. Correia, Tetrahedron Lett. 2008, 49, 5668-5671.

palladium catalysis. However, electron poor diazonium salts bearing, for instance, ester or

nitro functions are so reactive in protic solvents that de-diazonization pathways compete with

the desired coupling reaction (Scheme 15).

Scheme 15. Side products observed in protic solvents

In contrast, in CH3CN, diazonium salts are usually much more stable and sensitive

substrates may be cleanly reacted. As a consequence, kinetics of coupling reactions is higher

in protic solvents, leading frequently to a complete conversion in a couple of minutes at

moderately elevated temperatures (40 - 60°C).

The use of base also depends on the choice of solvent. While in CH3CN, the use of a

base such as NaOAc or Na2CO3 seems to be mandatory for the success of the coupling, it

proved to be useless in MeOH and EtOH. However, to avoid any transesterification products

with reagents bearing ester functions, the use of CaCO3 has been reported to neutralize the

liberated HBF4.78

Many studies on the “traditional” Heck-Mizoroki coupling have focused on the

improvement of the catalytic system for diminishing palladium loadings. Surprisingly, until

recently, the palladium loading has rarely been the preoccupation of chemists using the Heck-

Matsuda reaction. As a consequence, it has been reported that high loading 5-10 mol % are

required for optimal results. However, we recently reported that aryl diazonium salts can be

coupled with various substituted olefins in MeOH at 25°C and with palladium loadings as low

as 0.005 mol % under ligand-free and base-free conditions. Interestingly, we also showed that

78

H. Brunner, N. Le Cousturier de Courcy, J.-P. Genêt, Synlett 2000, 201-204.

under such mild conditions, nitro-substituted benzene diazonium salts are stable and can be

reacted with excellent efficiency.60

(Scheme 16)

Scheme 16. Low catalytic loading used for the cross-coupling reaction

In palladium chemistry, the use of stabilizing ligands represents the classical strategy

for reducing the palladium loading. As already previously mentioned, trivalent phosphorous

ligands cannot be used in the Heck-Matsuda reaction since they give rise to the de-

diazonization pathways through the formation of aryl free radicals. On the other hand, it has

been reported that aryl diazonium salts are compatible with molecular palladium complexes

stabilized with N-heterocyclic carbenes (Figure 2)79

, thiourea (Figure 3a)80

, as well as

triolefin macrocyl (Figure 3b)81

. However, Palladium loadings ranging between 0.5 - 5 mol%

79 K. Selvakumar, A. Zapf, A. Spannenberg, M. Beller, Chem. Eur. J. 2002, 8, 3901-3906. 80

M. Dai, B. Liang, C. Wang, J. Chen, Z. Yang, Org. Lett. 2004, 6, 221-224. 81 (a) J. Masllorens, M. Moreno-Manas, A. Pla-Quintana, A. Roglans, Org. Lett. 2003, 5, 1559-1561; (b) J.

Masllorens, S. Bouquillon, A. Roglans, F. Hénin, J. Muzart, J. Organomet. Chem. 2005, 690, 3822-3826.

Pd demonstrated the weak influence of these ligands as stabilizing agents and, in some extent,

the real impact of these ligands on the catalytic system efficiency may be questionable.

Figure 2. N-heterocyclic carbene palladium complexes.

Figure 3 a,b. Thiourea ligand and palladium triolefinic macrocyclic catalyst

The safety issue linked with the manipulation of diazonium salts as crystalline

compounds has been addressed with a protocol allowing their in situ preparation. Indeed,

prior the coupling reaction with the olefin under palladium catalysis, aniline can be in situ

diazoted with t-BuONO and BF3-Et2O76

or NaNO2 and HBF4.74a

However; it seems that

yields observed were slightly inferior to protocols employing crystalline salts. Clearly, a

general and efficient protocol addressing the safety issue remained to be established.

As in alcoholic solvents a base is not required and temperatures can be maintained

below 80°C, a high chemoselectivity at the diazonium group can be reached in the presence

bromine and iodine atom on the aryl partner. Sengupta and Sadhukhan have exploited this

interesting property for the development of sequential couplings using the aryl partner having

a dual reactivity (Scheme 17).82

Scheme 17. Sequential Heck-Matsuda and Heck-Mizoroki reaction

82

S. Sengupta, S. K. Sadhukhan, Tetrahedron Lett. 1998, 39, 715-718.

Chapter B

A new area of research seeks to use catalysts to mediate 2 or more reactions that are

fundamentally different in nature (e.g. carbon-carbon bond formation followed by alkene

hydrogenation). This research area has a great potential, as there are many different reactions

susceptible to catalysis which might be linked in sequence. Numerous examples have been

reported over the past 10 years under labels such as tandem, dual, multifunctional catalysis.

The following section aims to describe the different variations in one-pot transformations.

I. Cascade, Tandem reactions

Cascade reactions are important tools to meet challenges currently facing synthetic

chemists and are therefore drawing considerable attention. Cascade reactions are sequences of

transformation, in the same reactor, where the product of the first step serves as the substrate

for the second step, whose product is again the substrate for the next step and so on. This

process repeats until a product stable under the reaction conditions is formed. The advantage

of such cascade reactions is the economy of steps. Multiple bond formations are combined in

one-pot, which lowers the amount of steps required to reach the same product. As a result, an

increase of molecular complexity in economically feasible compounds is realized. Cascade

reactions are also considered to contribute the green chemistry because of the reduced number

of waste production and increased atom efficiency. In addition, cascade reactions in some

cases open up new synthetic possibilities by producing and utilizing reactive intermediates in

situ that are otherwise difficult or impossible to isolate and use.

Cascade reactions require a combination of highly selective transformations

compatible with different functional groups, which can be challenging to engineer.

Consequently, a good understanding of the combined processes is required in order to develop

such combinations nevertheless, there is significant interest in the field and important cascade

reactions have been developed. The concept of the “tandem catalysis” in domino reactions is

categorized into three subclasses: Orthogonal-, auto-, and assisted-tandem catalyses. Having a

detailed look on each type and on its old classifications might help in a better understanding

to tandem catalysis.

I. 1. Old classification of “tandem catalysis” in domino reactions

The concept of “tandem catalysis” in domino reactions that are efficient synthetic

methods for the construction of structurally complex molecules from simple starting materials

has been monitored. Catalysis in domino reactions activates sequentially more than 2

mechanistically distinct reactions. Currently, great attention is being given to domino

reactions, one-pot reactions, and multicomponent reactions83

, because they have several

inherent advantages over multistep synthesis, including the time and cost-saving, atom

economy, environmental friendliness, and applicability to diversity-oriented high-throughput

synthesis and combinatorial chemistry. These methods are recognized as powerful and useful

tools in broad areas of organic chemistry, including natural product synthesis, drug discovery,

and process chemistry.

I. 1. a. Tandem in domino reactions

The conceptual term “domino reaction” has been used to describe a process of two or

more chemical transformations occurring under identical conditions, in which the subsequent

transformation takes place at the functionalities obtained in the former transformation.84

Several analogous terms are sometimes used in place of domino reaction, such as “tandem

reaction”, and “sequential reaction”. A large variety of domino reactions have been

83

a) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Chemistry, Wiley-VCH, Weinheim,

2007; b) Multicomponent Reactions (Eds.: J. Zhu, H. Bienaym), Wiley-VCH, Weinheim, 2005. 84

L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136.

extensively exploited. Their catalytic variants are also being investigated as more efficient

processes.

Scheme 18. Schematic diagram of general catalysis in domino reaction

Scheme 1885

is an illustration of a catalytic domino reaction. First, Substrate A and B

(whether intra- or intermolecular) react to give intermediate C, then C further reacts with

reactant R, or with another reactive moiety in C itself, to afford the final product D. in the

reaction sequence, once substrates A and/ or B are activated by catalyst X, further activation

of intermediate C by X is not necessary to promote a successive reaction to give product D.

Thus, the diversity and complexity of product D is determined at the 1st catalytic reaction

stage. Moreover, it is worth noting that the lifetime of intermediate C is, in general, too

transient to be isolated, therefore, it is necessary that all the reactants, reagents and catalysts

are added to the reactor at a time in many cases.

I. 1. b. Tandem in one-pot reactions

The term “one-pot” refers to a process whereby a reactant is subjected to successive

chemical reactions in just one reactor, without purification or separation. The term “one-pot

synthesis” is frequently used to mean the same thing. It avoids purification and separation

steps, saves time and increases, sometimes, the reaction yield. In contrast to domino reactions,

85

N. Shindoh, Y. Takemoto, K. Takasu, Chem. Eur. J. 2009, 15, 12168-12179.

the reaction intermediates in the one-pot reactions are, in general, isolable and stable.

Reagents and catalysts required in each chemical transformation are added after the previous

transformation is complete.

I. 1. c. Tandem in multicomponent reactions (MCR)-named afterwards

Concurrent tandem catalyst (CTC).

It is a chemical process in which reactants successively react in one reactor to give a

product that incorporates substantial portions of all the substrates. MCR posses several

advantages such as time, cost, atom economy and environmental friendliness. The term MCR

is used by chemists in both narrow and wide senses. The rarely used narrow sense refers to

cases in which all the starting materials must be added to the reactor simultaneously, as in

domino reactions. The wider sense is used to one-pot reactions that are the reactants and

reagents can be added one by one. To avoid the confusion, Baker and Bazan86

proposed the

term Concurrent Tandem Catalysis (CTC), which involves the cooperative action of two or

more catalytic cycle in a single reactor.

Scheme 19. Schematic diagram of general catalysis in domino reactions

As illustrated in Scheme 19,86

substrates A and B transforms into isolable intermediate

C and the subsequent conversion of C into product D are catalyzed by catalyst(s), two or

86 J.-C. Wasilke, S. J. Obrey, R. T. Baler, G. C. Bazan, Chem. Rev. 2005, 105, 1001–1020.

more catalytic cycles are mechanistically different and independent. The catalyst(s) interacts

with the substrates and the intermediate.

I. 2. Actual Subclasses of “tandem catalysis” in domino reactions- A focus on

metal catalyzed tandem reactions

Numerous examples have been reported over the past 10 years concerning sequential

catalysis. The sequential catalysis systems (auto-tandem catalysis) are usually easy to develop

and generally have a broad scope in which multiple transformations are mediated by a single

metallic complex in a single reactor. Each new reaction is initiated by a change in conditions

(e.g. change in temperature) or by the addition of a new reagent. In some cases, the nature of

the catalyst will change, such that it can no longer mediate the first reaction. Many metals

were used for sequential catalysis as ruthenium developed by Grubbs and co-workers 87

in

which they developed ruthenium metathesis catalysts. Robinson and co-workers88

developed,

using rhodium, a sequential hydrogenation-hydroformylation reaction. Shibasaki and co-

workers 89

developed, using Yittirum, a sequential cyanation and nitroaldol addition reactions.

Dud Ding90

developed the hetero-Diels-Alder and diethylzinc addition using zinc metal, while

Thandanid and Rawal91

developed haloallylations followed by cross-coupling or Wacker-

Tsuji oxidation using a palladium catalyst.

After all these efforts done to classify tandem catalysis, it was finally agreed to

classify the tandem catalysis into three subcategories based on the catalyst(s) efficiency: 1-

Orthogonal tandem catalysis, 2- Assisted tandem catalysis, 3- Auto tandem catalysis. This

87

T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34,18 88

E. Teoh, E. M. Campi, W. R. Jackson, A. J. Robinson, Chem. Commun. 2002, 978. 89

J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Angew. Chem. 2002, 114, 3788; Angew. Chem. Int. Ed.

2002, 41, 3636. 90

H. Du, K. Ding, Org. Lett. 2003, 5, 1091. 91 a) A. N. Thadani,V . H. Rawal, Org. Lett. 2002, 4, 4317; b) A. N. Thadani,V . H. Rawal, Org. Lett. 2002, 4,

4321.

classification of tandem catalysis was proposed by Fogg and dos Santos.92

They have

explained their classifications as follow.

I. 2. a. Orthogonal tandem catalysis:

The orthogonal tandem catalysis consists of two or more non interfering catalysts or

pre-catalysts, each of which catalyzes an independent chemical transformation, as shown in

Scheme 20.86

Scheme 20. Schematic diagram of orthogonal-tandem catalysis

Catalysts X and Y are compatible and separately activate two different reactions to

afford intermediate C from A with B. Product D is obtained from intermediate C with reagent

R. While the operational efficiency is high, orthogonal tandem catalysis suffers from some

drawbacks, difficulty of recovering each catalyst and the possibilities of negative interactions

between one catalyst and the other.

An example of orthogonal tandem catalysis is shown in scheme 21.93

In the first stage,

the ruthenium catalyst activates the substitution reaction of propargylic alcohol (44) with

acetone to give ketoalkyne (46). Subsequently, PtCl2 catalyzes the hydration of alkyne moiety

of (46), followed by the intramolecular cyclization of resulting diketone (47) to give furan

92 D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248, 2365–2379. 93

Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. D. Milton, M. Hidai, S. Uemura, Angew. Chem. 2003, 115,

2785-2788; Angew. Chem. Int. Ed. 2003, 42, 2681-2684.

derivative (48). These events occur successively and simultaneously in the presence of both

catalysts knowing that both intermediates (46) and (47) are isolable.

Scheme 21. Synthesis of substituted furans catalyzed by using Ru and Pt Catalysts

An Example of Orthogonal-tandem catalysis

I. 2. b. Assisted tandem catalysis:

The assisted tandem catalysis employs only one catalyst, after the 1st catalytic cycle is

completed, chemical triggers are added to change the species of the catalyst and start the

second cycle, (Scheme 22).86

Scheme 22. Schematic diagram of assisted-tandem catalysis

As shown in the above Scheme 2286

, Catalyst X activates substrates A and B to give

intermediate C. Then catalyst X is changed into catalyst X’ by the interaction with the

chemical trigger T. Then the newly generated X’ promotes another reaction to give product D

from C. Knowing that X and X’ are the same catalyst, but of different oxidation state. In

principle, the two catalytic cycles do not proceed concurrently in this catalysis because the

two different catalytic species do not coexist; avoiding, therefore, negative interactions or

competition between one catalyst and the other. Scheme 23 illustrates a representative

example of assisted tandem catalysis.94

In the reaction shown, the TiIV

complex first initiates

the hydroamination of acetylene (50) with aniline to give imine (51), then the TiIII

species,

which is generated by using PhSiH3 as a chemical trigger, promotes hydrosilylation. As a

result, secondary amine (53) is produced after N-Si bond cleavage of (52) during the basic

work-up.

94

A. Heutling, F. Pohliki, I. Bytschohkov, S. Doye, Angew. Chem. 2005, 117, 3011-3013; Angew. Chem. Int. Ed.

2005, 44, 2951-2954.

Scheme 23. TiIV-catalyzed hydroamination catlyzed by TiIV and subsequent

hydrosilylation catalyzed by in situ-generated TiIII

: An example of assisted -tandem

catalysis

I. 2. c. Auto-tandem catalysis:

The auto-tandem catalysis is when only one catalyst promotes more than two chemical

transformations, in which the reaction mechanisms are different from each other and no

trigger reagent is required.

Scheme 24. Schematic diagram of auto-tandem catalysis in domino reactions

Scheme 24 shows that catalyst X acts on A and B to give intermediate C. The same

catalyst X interacts with intermediate C to afford D. Several advantages posses this auto

tandem catalysis in which operational complexity is minimal and the used catalyst is of high

efficiency.

As an example to auto-tandem catalysis, an approach reported by Genet et al.95

showing an interesting method to synthesize biaryl ketones (57) from aromatic aldehydes (55)

Scheme 25.

Scheme 25. Rh-catalyzed domino arylation- oxidation reaction: An example on

auto catalysis

As shown in (Scheme 25), an interesting methodology, which consists of the Rh-

catalyzed arylation of the ketone and the dehydrogenation of the alcohol, can transform

aldehydes into ketones in a single operation. This process corresponds to the formal C-H

activation of aldehydes.

The mechanistic process seemed to be of two consecutive catalytic reactions under the

previously mentioned reaction conditions (scheme 26). The first catalytic cycle is the addition

of the boronic acid to aldehydes (A) to produce the carbinol (B), followed by the second

catalytic cycle in which the oxidation of the resulting alcohol to give desired ketone (C). The

results were confirmed by the fact that in the absence of base, only carbinol (B) was formed in

quantitative yields.

95

G. Mora, S. Darses, J.-P. Genet, Adv. Synth. Catal. 2007, 349, 1180-1184.

Scheme 26. Postulated mechanism

The overall mechanism is believed to involve a tandem process including rhodium-

catalyzed addition of boronic acid to aldehydes (Scheme 26, cycle 1) followed by slow

oxidation of the resulting carbinol via a β-hydride transfer (Scheme 26, cycle 2). Indeed

transmetallation of the organometallic reagent to the rhodium(I) complex followed by the

insertion of the aldehyde into the aryl-rhodium(I) furnishes an alkoxo-rhodium species. It is

known that boronic acids are prone to dehydration, resulting in the formation of boroxine and

water. The presence of base was believed to have a role in regenerating an alkoxo-rhodium

compound that initiates the second catalytic cycle. β-Hydride elimination from the generated

alkoxo-rhodium(I) complex would release the diaryl ketone and a rhodium(I) hydride species.

Finally, rhodium(I) hydride species reacts with the acetone to afford an alkoxo-rhodium(I)

complex which is suitable for transmetallation with the boron reagent.

I. 3. Palladium in tandem reactions

As known, palladium is a versatile transition metal which is an essential element to

perform a cross–coupling reaction to form a C-C bond. The significance of palladium

catalysis has recently been illustrated by the Nobel Prize for chemistry in 2010, which was

awarded to Heck, Negishi, and Suzuki for the development of palladium catalyzed cross-

coupling reactions. Palladium catalyzed cross-couplings are reactions in which two different

hydrocarbon fragments are coupled with the aid of palladium containing catalyst. Many

examples on cascade reactions were done to perform a double cross-coupling of Heck96

, or

cross-coupling of Heck/C-H activation97

, double Suzuki-Miyaura98

, Heck/Suzuki99

and

Heck/Reduction99

and many others.

Heck reaction catalyzed by palladium catalysts showed many interest in which tandem

reactions has been applied. Heck reaction with double alkene insertion was reported by Hu et

al.96

this double alkene insertion took place between N-alyl-N-(2-butenyl)-p-

toluenesulfoamide and various benzylic halides (Scheme 27). Hu et al.97

also used a diene for

Heck-type reaction with double alkene insertion, but the catalytic cycle ended with a C-H

activation. (Scheme 28)

96

Y. M. Hu, J. Zhou, X. T. Long, J. L. Han, C. J. Zhu, Y. Pan, Tetrahedron Lett. 2003, 44, 5009–5010. 97

Y. M. Hu, F. F. Song, F. H. Wu, D. Cheng, S. W. Wang, Chem. Eur. J. 2008, 14, 3110–3117. 98

F.-X. Felpin, R. H. Taylor, Org. Lett., 2007, 9, 2911-2914. 99

M. Gruber, S. Chouzier, K. Koehler, L. Djakovitch, Appl. Catal. A 2004, 265, 161-169.

Scheme 27. Heck reaction with double alkene insertion96

Scheme 28. Heck-reaction followed by C-H activation cascade.97

Gruber and co-workers99

have described a one-pot Heck/Suzuki-Miyaura reaction

which is a good example for the use of Pd/C as a single catalyst for a several successive

transformations. The heterogeneous nature of the catalyst makes the utility of this

transformation even higher. Then Pd/C catalyzed Heck-coupling was further combined with

subsequent Suzuki coupling in order to synthesize 4-styrylbiphenyl, a substructure of

pharmaceutically active compounds. Because the Heck reaction is more selective for different

leaving groups than the Suzuki coupling, the Heck coupling was applied as the first reaction

step and the Suzuki coupling as the second reaction step (Scheme 29).

Scheme 29. One-Pot Heck-Suzuki-Miyaura reaction sequence

A one-pot Heck cross-coupling followed by hydrogenation also gave excellent yields

for the preparation of 1,2-diphenylethanes from styrene and bromobenzene. (Scheme 30).99

Scheme 30. One-pot Heck - hydrogenation

I. 4. Diazonium salts Used for Tandem Reactions

Metal catalysis is usually used to prepare complex molecules. The use of metal

catalysis is not any more limited to simple oxidation and reduction as was 50 years ago.100

Although many metal catalysts often employ expensive metals or ligands, the fact that they

can be used in catalytic amounts, combined with their often high chemo- and stereoselectivity,

outweighs their high costs. One common goal in catalyst development is high catalyst

efficiency. A new area of research seeks to use a single catalyst to mediate two or more

reactions that are fundamentally different in nature (e.g. C-C formation followed by

hydrogenation).

In our laboratory we are more specifically interested by the development of

heterogeneous monometallic multi-task catalysts. Tandem reactions mediated by single

metallic complex (Figure 4) are usually limited to reactions that have similar mechanisms101

(i.e. successive Pd-catalyzed cross-coupling), although some examples of tandem processes

involving two or more fundamentally different reactions have been described.102

Figure 4. Tandem reactions mediated by a single transition metal.

Most of the procedures described require the use of homogeneous metallic complexes.

Although they are extremely efficient in synthetic chemistry, homogeneous catalysts are

100

R. B. Woodward, M. P. Cav,W. D. Ollis, A. Hunger, H. U. Daeniker, K. Schenker, J. Am. Chem . Soc. 1954,

76, 4749. 101

a) R. Grigg, V. Sridharan, J. Organomet. Chem. 1999, 576, 65–87; b) A. De Meijere, S. Bräse, J. Organomet.

Chem. 1999, 576, 88–110; c) G. Poli, G.Giambastiani, A. Heumann, Tetrahedron 2000, 56, 5959–5989; d)

G.Balme, E. Bossharth, N. Monteiro, Eur. J. Org. Chem. 2003, 4101–4111; e) A. De Meijere, P. Von

Zezschwitz, S. BrQse, Acc. Chem. Res. 2005, 38,413–422. 102 a) A. Ajamian, J. L. Gleason, Angew. Chem. 2004, 116, 3842–3848; Angew. Chem. Int. Ed. 2004, 43, 3754–

3760; b) J.-P. Leclerc, M. André, K. Fagnou, J. Org. Chem. 2006, 71, 1711–1714; c) T. O. Vieira, H. Alper,

Org. Lett. 2008, 10, 485–487.

frequently sensitive and should be handled with care. Also, their low potential of being

recycled could limit their use on large scale as a result of the constant increase in the cost of

metals. Moreover, contamination of the products by metallic residue even after the

purification step remains an acute problem for the large-scale synthesis of biologically active

compounds where contamination of products by the metal must be closely monitored,

especially in the pharmaceutical industry. As a consequence, the development of sustainable

tandem processes will undoubtedly require more practical, cost-saving, and environmentally

benign procedures.

To address these issues, heterogeneous metal catalysts constitutes a useful alternative

for the development of metal catalyzed tandem reactions in the easiest way possible.103

The

use of robust heterogeneous catalysts, which are active under mild conditions with few or no

additives, offers many advantages, including: 1) the removal of the catalyst by filtration at the

end of the reaction; 2) the absence of contaminated products and solvents with transition

metal which reduces environmental concerns; 3) the recycling of the catalyst in another

reaction for economic viability; and 4) the stabilization of metallic particles by the support

thus avoiding the use of a ligand and reducing its sensitivity towards moisture and oxygen.

Clearly, these simplified protocols usually show lower catalytic activity or kinetics but

still have advantages in many cases in terms of cost and waste products. However, the interest

among the scientific community for the development of heterogeneously catalyzed reactions

is quite recent and remains underexplored.

Historically, whatever the transition metal, heterogeneous catalysis has been mostly

developed for reduction or oxidation processes. The heterogeneous catalyst mediated the

103 For a reflection on practical chemical syntheses, see: R. Noyori, Chem. Commun. 2005, 1807–1811.

formation of C-C or C-X bonds is more recent and essentially limited to palladium,8 nickel,

104

and copper.105

These different reactivities were recently exploited by several groups.

Our laboratory has done a lot of progress in the domain of the one-pot method using

diazonium salts instead of aryl halides. Aryl diazonium salts are very reactive electrophiles

when involved in Pd-catalyzed reactions, due to an excellent nucleofugic property of nitrogen.

Several reactions advantageously exploit the diazonium function as excellent leaving group

that makes it even more interesting to be applied in cross coupling reactions. Diazonium salts

are easily prepared from anilines, and can be used without any external additive (base or

ligand) under palladium catalysis, making it ideal for the tandem transformation. Since

diazonium salts involved in palladium-catalyzed reactions usually do not require the use of

additive, ligand and even base, they are ideal candidate for sequential one-pot transformations

where simplicity is a requisite.

In 2000 Genêt and co-workers78

were the first to exploit orthogonal reactivities of

supported palladium catalysts in tandem Heck-hydrogenation reactions using diazonium salts.

They described Heck-type cross-couplings of aryldiazonium salts with vinylphosphates

followed by a hydrogenation step leading to useful Wadsworth-Emmons reagents (Scheme

31).

104

a) B. H. Lipshutz, Adv. Synth. Catal. 2001, 343, 313–326; b) B. A. Frieman,B. R. Taft, C.-T. Lee, T. Butler,

B. H. Lipshutz, Synthesis 2005, 2989–2993;c) B. H. Lipshutz, B. A. Frieman, C.-T. Lee, A. Lower, D. M. Nihan,

B. R. Taft, Chem. Asian J. 2006, 1, 417–429; d) T. A. Butler, E. C. Swift, B. H. Lipshutz, Org. Biomol. Chem.

2008, 6, 19–25. 105

a) B. H. Lipshutz, B. R. Taft, Angew. Chem. 2006, 118, 8415–8418; Angew.Chem. Int. Ed. 2006, 45, 8235–

8238; b) B. H. Lipshutz, J. B. Unger, B. R.Taft, Org. Lett. 2007, 9, 1089–1092.

Scheme 31. Preparation of Wadsworth-Emmons reagents by tandem

Heck-hydrogenation sequence.

The overall process was catalyzed with unusual Pd0/CaCO3 catalyst (2 mol% Pd) in

methanolic solution. Although, nothing was stated about recyclability of the catalyst, the

simplicity and efficiency of the experimental protocol make the method relevant for such

transformations. Note that the use of aryldiazonium salts as more reactive electrophile to

conventional aryl halides allows the use of mild conditions (50°C) without any additive

(ligand and base).

The useful reactivity of aryldiazonium salts was also exploited by our team106

in one-

pot Suzuki-reduction sequence for a novel synthesis of the acaricide bifenazate (80) (Scheme

32).

106

F.-X. Felpin, E. Fouquet, Adv. Synth. Catal. 2008, 350, 863–868.

Scheme 32. synthesis of bifenazate (80) by a tandem Suzuki couplin-reduction sequence.

In this approach, the dual activity of Pd0/BaCO3 (i.e. C-C bond formation and

reduction) was exploited to shorten the overall process under extremely mild conditions

(25°C, 2 mol% Pd) and without any additive. Interestingly, this was the first report of the use

of Pd0/BaCO3 in C-C bond formation process.

One-pot chemoselective double Suzuki cross-coupling reactions were carried out

using bromo- or iodo- substituted aryl diazonium salts (82) and (86) for the preparation of

unsymmetrical terphenyls98, 106

(Scheme 33).

Scheme 33. Heterogeneous palladium-catalyzed synthesis of unsymmetrical

terphenyls using halide substituted aryldiazonium salts.

Indeed, by taking advantage of the greater reactivity of the diazonium function relative

to bromide and even iodide, an extremely efficient synthesis of unsymmetrical terphenyls was

developed using either Pd0/C (5 mol% Pd) or Pd

0/BaCO3 (2 mol % Pd) as catalysts under

mild conditions. The method features inexpensive reagents of low toxicity, making it

environmentally benign and very practical. However, while Pd/C could be recovered by

simple filtration to leave the product and solvent uncontaminated by Pd species, Pd0/BaCO3

could not be filtered due to the particle decomposition of the support in the acidic reaction

medium.

Chapter C

I. HRC (Heck-Reduction-Cyclization): Oxindoles, Indoles, Indanones.

The laboratory having a good background in the chemistry of diazonium salts and

palladium we envisaged a program including this knowledge. Starting from the observation

that palladium complexes and especially Pd/C catalysts can perform reductive processes as

well as C-C bond formation, we designed a simple one-pot multi-step sequence called Heck-

Reduction-Cyclization (HRC). This sequence is based on the exploitation of the dual activity

of the palladium catalyst (C-C bond formation followed by a hydrogenation step) in a one-pot

vessel. Scheme 34 shows our general view for the Heck-Reduction-Cyclization (HRC)

strategy. We realized that the Heck coupling between an olefin and an electrophile

(diazonium salt) could give a functionalized olefin which could be further transformed under

reductive conditions to give an intermediate properly functionalized for a last cyclization. We

anticipated that such a sequence would be ideally designed for the rapid preparation of

heterocycles.

Scheme 34. General Heck-Reduction-Cyclization (HRC) strategy

I. 1. Oxindoles.

Based on our interest in designing biologically active heterocycles, oxindoles were our

first target for the validation of the HRC concept.

I. 1. a. Oxindoles in natural products.

Oxindoles-containing heterocycles, particularly those substituted at C3 position are

commonly found in natural products107

and pharmaceutical compounds.108

Figure 5. Representative Oxindole-containing natural products (90, 91)

and drugs (92, 93, 94)

107

C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209–2219. 108

(a) C. Robinson, Drugs Future 1990, 15, 898–901; (b) D. B. Mendel, A. D. Laird, X. H. Xin, S. G. Louie, J.

G. Christensen, G. M. Li, R. E. Schreck, T. J. Abrams, T. J. Ngai, L. B. Lee, L. J. Murray, J. Carver, E. Chan,

K. G. Moss, J. O. Haznedar, J. Sukbuntherng, R. A. Sun, L. Blake, C. Tang, T. Miller, S. McMahon G.

Shirazian, J. M. Cherrington, Clin. Cancer Res. 2003, 9, 327–337; (c) L. Sun, C. Liang, S. Shirazian, Y. Zhou, T.

Miller, J. Cui, J. Y. Fukuda, J. Y. Chu, A. Nematalla, X. Y. Wang, H. Chen, A. Sistla, T. C. Luu, F. Tang, J.

Wei, C.Tang, J. Med. Chem. 2003, 46, 1116–1119.

They display a wide range of biological properties including antiarthritis109

,

antitumoral110

, and antiviral111

activities. More specifically, we were interested by the

disclosure of a patent from Hoffmann-La Roche describing the anti-cancer activity of C3

disubstituted oxindoles such as (94). From a synthetic point of view, base-mediated C3

functionnalisation generally gives a mixture of C- and N-alkylated products as a consequence

of the close acidity of the protons in C3 and N1 positions. Thereby, a less direct method is

generally preferred involving the condensation of benzaldehyde derivatives with the oxindole

core, followed by the reduction of the corresponding 3-arylideneoxindoles.112

(Scheme 35)

Scheme 35. Preparation of C3 substituted oxindoles

109

(16) R. P. Robinson, L. A. Reiter, W. E. Barth, A. M. Campeta, K. Cooper, B. J. Cronin, R. Destito, K. M.

Donahue, F. C. Falkner, E. F. Fiese, D. L. Johnson, A. V. Kuperman, T. E. Liston, D. Malloy, J. J. Martin, D. Y.

Mitchell, F. W. Rusek, S. L. Shamblin, C. F. Wright, J. Med. Chem. 1996, 39, 10–18. 110

(a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Qiu, S. Shangary, W. Gao, D. Qin, J. Stuckey, K..

Krajewski, P. P. Roller, S. Wang, J. Med. Chem. 2006, 49, 3432. (b) K. C. Luk, S. S. So, J. Zhang, Z. Zhang,

WO Patent 2006136606, 2006. 111

(a) T. Jiang, K. L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell, B. Bursulaya, T. Y.-H. Wu, Y. He,Bioorg.

Med. Chem. Lett. 2006, 16, 2105–2108. (b) T. Jiang, K. L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell, B.

Bursulaya, T. Tuntland, K. Zhang, D. Karanewsky, Y. He, Bioorg. Med. Chem. Lett. 2006, 16, 2109–2112. 112

(a) G. N. Walker, J. Am. Chem. Soc. 1955, 77, 3844–3850. (b) G. N. Walker, R. T. Smith, B. N. Weaver, J.

Med. Chem. 1965, 8, 626–637. (c) B. Volk, G. Simig, Eur. J. Org. Chem. 2003, 3991–3996.

I. 1. b. Synthetic point of view for preparing Oxindoles by the HRC strategy

Having selected a general target, we designed our HRC strategy in order to get a novel

approach where the oxindole core and the C3 functionalization are executed in the same

reaction vessel (Scheme 36). The HRC strategy, is based on a Heck cross-coupling of a 2-(2-

nitrpphenyl)acrylate A with an aryl diazonium tetrafluoroborate salt B. The cross coupling

could be followed by Pd-mediated reductions of the double bond and nitro group, giving the

corresponding aniline D, which should be spontaneously cyclized to give variously

substituted oxindoles E.113

Scheme 36. General preparation of oxindoles

113

F.-X. Felpin, O. Ibarguren, L. Nassar-Hardy, E. Fouquet, J. Org. Chem. 2009, 74, 1349-1352.

I. 1. c. Preparation of starting material

I. 1. c. i. Diazonium salts

Since we were interested in using diazonium salts, in particular aryl diazonium

tetrafluoroborate salts to be applicable in our HRC strategy we had to prepare those salts from

their corresponding inexpensive anilines that are commercially available. Aryl diazonium

tetrafluoroborates are easily accessed when reacting anilines with tetrafluoroboric acid at 0°C

for couple of minutes, followed by the dropwise addition of aqueous NaNO2. The reaction is

stirred for 30 minutes to 2 hours depending on the type of diazonium salt. The produced

diazonium salts are usually white solids, formed quantitatively, when being filtrated and

washed with EtOH and Et2O. Several crystallizations might be required with acetone and

Et2O to get a clean pure crystalline diazonium salt. The collected salts are dried under vacum

and kept in the freezer for further use. The collected salts showed excellent stability for years

when stored at -20°C. Scheme 37 below shows a general preparation of diazonium salts.

Scheme 37. General preparation of diazonium salts

I. 1. c. ii. Acrylates

In order to apply our HRC strategy we had to prepare funtionnalized acrylates for their

further use in the Heck cross-coupling. The substituted acrylates were accessed by

methylenation of the corresponding ester in good yields. Methylenation was performed with

paraformaldehyde, potassium carbonate and tetrabutyl ammonium iodide in toluene. Reaction

time and temperature was closely monitored since some acrylates showed a tendency to

polymerization. However, we observed no decomposition over time when stored at -20°C.

(Scheme 38)

Scheme 38. Preparation of acrylates

I. 1. d. Optimization of HRC strategy- oxindoles

We started our optimization studies with a model reaction involving the reaction of

methyl 2-(2nitrophenyl) acrylate (95) and the 4-(methoxycarbonyl) benzenediazonium

tetrafluoroborate salt (98).

Table 7. Oxindoles from optimization studies on HRC Sequence

Table 7 shows our trials done for preparing the C3 substituted oxindoles in which,

unfortunately, commercially available supported catalysts such as PdII/C and Pd

0/BaCO3 were

poorly effective, leading to a mixture of inseparable products (entry1, 3). Close inspection of

the crude reaction mixture after the coupling step showed a large amount of methylbenzoate

(formed by dediazoniation). This issue could not be addressed with a non protic solvent (entry

2, 4). Considering that the nature of the palladium source could be crucial for the success of

the tandem process, we examined the possibility of forming, in situ, the heterogeneous

catalyst by mixing a well-defined homogeneous complex with charcoal. The addition of 5

mol% of Pd(OAc)2 smoothly allowed the HRC process (entry 5), while PdCl2 and Pd2dba3

were less efficient for the cross-coupling step (entries 7, 8). This unusual approach opened the

door for the development of many simplified protocols. After the 2-(2-nitrophenyl)acrylate

has been consumed, as indicated by N2 evolution (~30min), the reaction mixture was stirred

under H2 atmosphere for 24h, leading to the oxindole core with a good yield (81%). At the

end of the reaction, a simple filtration of the charcoal left the solvent and the product almost

free of palladium traces as indicated by ICP-MS analysis (<50 ppb). This result indicated that

all palladium species remained on the charcoal (>99.9 %), rendering the purification step

easier. Entry 6 showed that when the reaction occurs in the absence of charcoal, the

hydrogenation step never reached a full conversion even when extending the reaction time

(>48 h).

I. 1. e. Scope of the HRC reaction strategy

After having successfully optimized the HRC protocol on the model sequence, we

afterwards, explored various coupling partners. A variety of diazonium salts were engaged in

the HRC tandem protocol. This protocol furnished the required oxindoles with very good

yields (70-80 %) whatever the structure of the coupling partner (Table 8). It was observed

that the electronic effect of the substituents on the diazonium salts only have a minor impact

on the tandem process. Diazonium salts having electron-withdrawing substituents (entries 1,

4) react faster with the corresponding acrylate in the Heck cross-coupling than those having

electron-donating ones (entries 3, 5, 6). However, these electronic effects had no considerable

influence of on the yields of the reduction-cyclization sequence. On the other hand, the nature

of the acrylates has also a low influence on both kinetics and yields.

Table 8. Some various substituted oxindoles by HRC strategy

I. 1. f. Catalysts recycling tests.

After the success in preparing various C3-benzylated oxindoles by the HRC method

that proved the success of this HRC sequence, recycling tests were performed to test the

activity of the catalyst after filtration.108

Since the catalyst could be easily separated from the

mixture free of palladium traces by filtration, the recyclability was examined (Scheme 39). A

drop in the catalysts catalytic reactivity after the first reuse, giving lower yields of oxindole

(99) (~42%) was observed. Additional trials showed that the reused catalyst was less active

for the Heck reaction (Scheme 40) but remained still and even more active for the reduction-

cyclization steps (Scheme 41). It is likely that the reduced form Pd0/C of the reused catalyst is

detrimental for the success of the Heck reaction for which PdII precatalyst is preferred.

Besides, the reduction-cyclization sequence requires preferably a palladium with a low

oxidation degree.

Scheme 39. Recycling test of the catalyst

Scheme 40. Recycling test of the catalyst

Scheme 41. Recycling test of the catalyst

As an extension to our interest in developing the HRC method to a wider range of

heterocycles, this strategy was adopted and finely modified by our group to prepare 2-

quinolones (scheme 42 (Eq. 1, 2)) and isoquinolones114

(scheme 42 (Eq. 3)).

Scheme 42. Preparation of 2-quinolone by HRC

114

a) J. Laudien, E. Fouquet, C. Zakari, F.-X. Felpin, Synlett 2010,10, 1539-1543; b) F.-X. Felpin, J. Coste, C.

Zakari, E. Fouquet, Chem. Eur. J. 2009, 15, 7238.

After a successful work reported by our team, we thought of working on various

heterocyclic molecules using a similar HRC strategy.

I. 2. Indoles

I. 2. a. Indoles in natural products

The indole nucleus is an important substructure found in numerous natural products115

,

synthetic drugs and synthetic alkaloids.116

The diversity of the structures encountered, as well

as their biological and pharmaceutical relevance, have motivated research aimed at the

development of new economical, efficient, and selective synthetic strategies, particularly for

the synthesis of functionalized indole rings117

(Figure 6).

Figure 6. Selected examples of natural products containing the indole nucleus.

115

W. G. Sumpter, F. M. Miller, Chapter VIII. Natural products containing the indole nucleus, WIELY 2008. 116

a) R. J. Sundberg, Indoles, Academic press, London, 1996; b) J. A. Joule, Science of Synthesis, Vol. 10, (Ed.:

E. J. Thomas), Thieme, Stuttgart, 2001, p. 361. 117

R. J. Sundberg, in: Comprehensive Heterocyclic Chemistry,Vol. 4, (Eds.: A. R. Katritzky, C. W. Rees),

Pergamon, Oxford, 1984, p. 313; b) J. Tois, R. Franze´n, A. Koskinen, Tetrahedron 2003, 59, 5395.

I. 2. b. Synthetic point of view for preparing indoles by the HRC strategy

The synthesis and functionalization of indoles has been the subject of many researches

for over 100 years. Indoles with substituent in C3 position is of high degree of importance in

the Central-Nervous-System (CNS) drugs, in particularly anti-psychotics.118

From the

synthetic point of view, a recent palladium catalyzed hetero-annulation of 2-iodoaniline with

internal alkynes known as the Larock indole synthesis2e

(Scheme 43) has emerged as one of

the most powerful synthetic procedures to provide 2,3-substituted indoles.

Scheme 43. Larock indoles synthesis

Our group intended to prepare indoles by the HRC process in a single vessel reactor.

The HRC strategy is based on the Heck cross-coupling of a 2-(2-nitrophenyl)acrylonitrile (A)

with an aryl diazonium tetrafluoroborate salt (B). The cross coupling could be followed by Pd

–mediated reduction of the double bond and the nitro group, giving the corresponding aniline

(D), which should spontaneously cyclize to give various substituted indoles (E) (Scheme 44).

118

For an overview, see: K. P. BØgesØ, B. Bang-Andersen in Textbook of Drug and Discovery, 3rd

ed. (Eds. : P.

Krogsgaard-Larsen, T. Liljefors, U. Madesen), Taylor and Francis, London, UK, 2002, Chap. 11.

Scheme 44. General proposed preparation of Indoles showing the intermediate.

Our optimization studies were based on optimizing each step before applying the one-

pot trial system. Table 9 shows the trials in optimizing the Heck reaction between acrylate

(116) and aryldiazonium salt (117) to get our coupled product (118). Entry 1 shows the

formation of 39% of the coupled product (118) when 5 mol % of Pd(OAc)2 was added on the

partners (116) and (117) at 40°C for 24 h. Entry 2 shows that increasing the catalysts loading

to 10 mol % gave only a slight increase of the coupled product yield (42%). We tried another

palladium source with Pd2dba3 but it was poorly effective in producing (118) with only 32%

of the product formed (Entry 3). The use of EtOH instead of MeOH produced only low yield

of the desired compounds even at higher temperature (Entires 4-5). It was therefore noticed

that the increase in temperature could be the cause of the decomposition of the majority of the

diazonium salt in the medium. The observed low yields could be explained by presence of the

nitrile function which could deactivate the palladium catalyst by acting as a ligand.

Table 9. Optimization studies on the Heck coupling reaction

Even though we weren‟t able to get better yields for the Heck cross coupling step, we

collected the produced coupled product (118) and tried the further reduction-cyclization steps.

As shown in Table 10, the collected coupled product (118) was placed in MeOH at

40°C under H2 for 24 h with 5 mol% Pd(OAc)2. Unfortunately, indole was produced with only

49% yield (entry 1). To improve the yields, 10 mol% of Pd(OAc)2 in MeOH under H2 was

used, unfortunately, only 52% of the desired product was collected (entry 2). A third trial was

done by replacing the Pd(OAc)2 with Pd/C keeping the catalytic loading at 10 mol%. The

reaction, stirred under H2 at 40°C for 24 h in MeOH, showed that the use of Pd/C was poorly

effective in forming the desired indole, since only 29% was collected (entry 3).

Table 10. Optimization studies on the reduction, cyclization step

To test the one pot method, we reacted the two partners 2-(2-nitrophenyl)acrylonitrile

(116) and diazonium salt (117), in the presence of Pd(OAc)2 (5 mol%) in MeOH for 24 h at

40°C. At the end of the first reaction, as judged by the liberated N2, charcoal was added and

the resulting reaction mixture was stirred for 24 h at 40°C under H2. As observed by the NMR

of the crude product, only a few amounts of unreacted 2-(2-nitrophenyl)acrylonitrile, along

with unidentified degradation products were observed (table 11). We replaced Pd(OAc)2 with

the Beller catalyst (37), but in this case, the only collected product was the starting material

(116) and few amounts of the cross coupled Heck product. Late after, we realized that this

type of indoles might be very unstable in presence of HBF4, liberated from the Heck cross-

coupling step.

Table 11. Optimization studies on the reduction, cyclization step

Figure 7. Beller catalyst

After these failures in preparing indoles by HRC, we decided to drop off the idea on

working on indoles and we searched for another type of heterocycle. Based on an interest of

the laboratory for spiro-compounds (in nucleoside chemistry) in the context of a medicinal

chemistry project, we selected spiro-oxindoles to be our next targets.

I. 3. Spiro-oxindoles

I. 3. a. Spiro-oxindoles in natural products

Spiro-oxindoles are commonly occurring heterocyclic ring system found in many

natural products and pharmaceuticals.119

A range of biologically active compounds possessing

the spiro-pyrrolidine framework is well documented. For instance, coerulescine, the simplest

spiro-oxindole found in nature, displays a local anesthetic effect.120

Polycyclic alkaloids as

pteropodine have a long history for its medicinal application. The recent discovery of the

small-molecule MDM2 inhibitor MI-219 and its analogue has led to their advanced

preclinical development as cancer therapeutics.

Figure 8. Selection of natural and biologically active spiro-oxindoles

119

Recent reviews: a) C. V. Galliford, K. A. Scheidt, Angew. Chem.,Int. Ed. 2007, 46, 8748. b) R. M. Williams,

R. Cox, J. Acc. Chem. Res. 2003, 36, 127. c) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209. Recent

pharmaceuticals: d) S. Shangary, Wang, S. Annu. ReV.Pharmacol. Toxicol. 2009, 49, 223. e) K. Ding, Y. Lu, Z.

Nikolovska-Coleska, G. Wang, S. Qiu, S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Krajewski, P. P. Roller, S.

Wang, J. Med. Chem. 2006, 49, 3432. 120 a) S. M. Colegate, N. Anderton, J. Edgar, C. A. Bourke, R. N. Oram, Aust. Vet. J. 1999, 77, 537; b) M. J.

Kornet, A. P. Thio, J. Med. Chem. 1976, 19, 892. c) M. A.-F. Abdel-Fattah, K. Matsumoto, K. Tabata,

H. Takayama, M. Kitajima, N. Aimi, H. Watanabe, J. Pharm. Pharmacol. 2000, 52, 1553. d) T.-H. Kang, Y.

Murakami, K. Matsumoto, H. Takayama, M. Kitajima, N. Aimi, H. Watanabe, Eur. J. Pharmacol. 2002, 455, 27.

I. 3. b. Synthetic point of view for preparing spiro-oxindoles by the HRS strategy

We envisaged preparing the spiro-oxindoles skeleton by the HRC process in a single vessel

reaction. The HRC strategy is based on the Heck cross-coupling starting from methyl (2-

nitrophenyl)acrylate (95) and 2-(methoxycarbonyl) benzenediazonium tetrafluoroborate salt

(123). The cross coupling product (124) produced from the two partners (95) and (123) could

be followed by a Pd–mediated reduction of the double bond and the nitro group, giving the

corresponding aniline (125), which should cyclize into the corresponding oxindole (126). A

last base-mediated cyclization of (126) would furnish the expected spiro-oxindoles (127)

(Scheme 45).

Scheme 45. General strategy for the preparation of Spiro-oxindoles

Table 12 illustrates the results when the two partners methyl (2-nitrophenyl)acrylate

and 2-(methoxycarbonyl) benzenediazonium tetrafluoroborate salt were placed together in the

presence of 5 mol% Pd(OAc)2 for 24 h. We obtained a disappointing result of the coupled

product since we only collected 20% of our desired product along with some unidentified

decomposed residues and few amounts of the starting material (entry 1). Unfortunately, we

noticed that replacing MeOH with dioxane was not efficient in performing the cross-coupling

reaction (entry 2). When Pd(OAc)2 was replaced with the Beller catalyst no cross-coupling

reaction occurred (entry 3).

Table12. Optimization on Heck-Cross coupling

After unsuccessful trials in preparing spiro-oxindoles, we thought of skipping over this

preparation and moving on to prepare original heterocycles, still with the HRC process.

I. 4. Tricyclic heterocycles

Although we failed in preparing indoles and spiro-oxindoles with our HRC strategy

we were interested in extending this chemistry to cyclic acrylates such as compound (128).

With such starting materials we could reach original tricyclic compounds with our standard

HRC strategy following Scheme 46. The Heck cross-coupling of dimethyl 5,6-

dihydropyridine-1,3(4H)-dicarboxylate (128) with 2-nitrophenyl diazonium tetrafluoroborate

salt (70) would give the cross coupled product (129). A subsequent diastereo-controlled Pd–

mediated reduction of the double bond and the nitro group, would give the corresponding

aniline (130), which should spontaneously cyclize to give the quite complex structure (131)

(Scheme 46).

Scheme 46. General strategy for the preparation of tricyclic alkaloids

To validate our hypothesis we first studied the Heck coupling of dimethyl 5,6-

dihydropyridine-1,3(4H)-dicarboxylate (128) with aryl diazonium tetrafluoroborate salts (B)

under the conditions previously developed (HRC oxindoles). Table 13 illustrates our main

unsuccessful results. Indeed, whatever the diazonium salt used, the cross-coupling didn‟t take

place under our conditions (MeOH, 40°C) and the only collected product was the starting

material. The use of the Beller catalyst did not improve our results (entry 3). This failure

could be understandable with the 2-nitrobenzene diazonium salt (70) as partner because of its

tendency to dediazonization pathways due to its high red-ox potential.68

However, the inability of 4-(methoxycarbonyl) benzenediazonium tetrafluoroborate

salt (98) in reacting with the olefin is more surprising. Actually, few months later,

independent studies conducted in our laboratory showed that the ester function on the cyclic

enamine was incompatible with the coupling. Indeed we observed that the corresponding

cyclic enamine, free of the ester function, reacted well with (98) under similar conditions.

Table 13. Optimization studies on the Heck cross-coupling

While we experienced many failures in extending the scope of our HRC strategy, we

did not give up and we focused our effort on another strategy to get highly substituted

indanones.

I. 5. Functionalized Indanones

I. 5. a. Functionalized indanones in drugs

Indanones has been shown to have many efficient aspects for Alzheimer‟s disease

(AD)121

Considerable research efforts have been devoted to study the molecular, biochemical,

and cellular mechanism of Alzheimer‟s disease in the past decades. Up till now, AChE

inhibitors are still the major and the most developed class of drugs approved for AD therapy,

such as donepezil, rivastigine, and galanthamine. For instance, a series of 2-phenoxy-indan-1-

one derivatives were proven as potent and selective AChE inhibitors in vitro (figure 9 (134)),

which were characterized by combining 5,6-dimethoxy-indan-1-one from donepezil (figure 9

(132)) and dialkylbenzyl amine from rivastigmine (figure 9 (133)), with oxygen as the

linkage.

Figure 9. Series of 2-phenoxy-indan-1-one derivatives used as AChE inhibitors

121

K. L. Debomoy, R. F. Martin, H. G. Nigel, S. Kumar, Drug Dev. Res. 2003, 56, 267-281.

I. 5. b. Synthetic point of view for preparing functionalized indanones by the

HRC strategy

From a synthetic point of view, our HRC one-pot strategy was proposed to prepare the

functionalized indanones. Scheme 47 below, shows the HRC one-pot process, in which the

Heck cross-coupling would occur between 2-(methoxycarbonyl) benzenediazonium

tetrafluoroborate salt (123) and methyl acrylate (17) to produce the coupled product (135).

Intermediate (135) could be followed by Pd-mediated reduction of the double bond giving

another intermediate (136). Deprotonation of the acidic proton α to the carbonyl group on

(136) by the aid of a base would give the desired indanone (137).

Scheme 47. General strategy for the preparation of indanones

After having a look on the general proposed preparation of indanones using our HRC

strategy, the experimental protocol was based on the results obtained from our previous

studies. Therefore, the first cross-coupling step was based on the use of Pd(OAc)2 in MeOH

under heterogeneous conditions, followed by a reduction step in the presence of H2. Table 14

below shows the trials done in performing both cross-coupling and reduction step in a single

reactor. We obtained an excellent yield (90%) of our desired product (136) when 5 mol % of

Pd(OAc)2 was mixed with charcoal in MeOH at 40°C followed by the addition of H2 for 24 h

(entry 1). Entry 2 shows a drop in the yield (70%) when performing the reaction in THF.

However, when the charcoal was added in the second step, an obvious jump in the yield

(86%) was observed (entry 3).

Table 14. Optimization studies on the Heck-reduction steps

Having these results in hand, we decided to move on to the third step. As previously

mentioned, the need of the base is crucial in order to perform the cyclization step from

compound (136). Table 15 below shows all the possibilities done to identify the optimal

reaction conditions. Entries 1-5 show an evident difficulty in getting the cyclized product in

the presence of MeOH even when varying the base, reaction‟s time and temperature. The only

collected product was the starting material indicating that conversions did not occur. Many

difficulties also faced us in getting the cyclized product when using THF instead of MeOH.

Varying the nature of the base weren‟t sufficient to perform the desired conversion (entries 6-

12). We observed the formation of the cyclized product when a strong base as dry NaH (95%)

was used (entry 13-14). Entry 14 showed the formation of 46% of the cyclized product when

keeping the reaction mixture at 75°C for 15 min with two equivalents of dry NaH (95%). Up

on this result, a one-pot reaction was tested.

Table 15. Optimization studies on the cyclization step

Several optimization studies were done (table 16) to test a one-pot protocol in getting

the cyclized product (137). Having observed that the cyclization step did not occur in MeOH,

we privileged the use of THF. Unfortunately, with conditions developed in the sequential two-

pot procedure we were unable to get compound (137) whatever the reaction temperature

(entries 1-2). However, when five equivalents of NaH (95%) were used at 30°C, we were

able to isolate the targeted cycle with an interesting 53% yield (entry 3).

Table 16. Optimization studies on the one-pot strategy.

Although a successful preparation of the cyclized product was achieved, we were still

in a research for a different base. Indeed, NaH is a sensitive and easily flammable base that

renders the manipulation of this reaction a bit tricky. As a result, we decided to change the

acrylate, and chose the commercially available methylvinyl ketone instead of methyl acrylate,

since we expect the cyclization of a keto-form intermediate would be much easier than the

cyclization an ester intermediate due to the higher reactivity of the ketone with respect to an

ester (acidity of protons α to the carbonyl).

I. 5. c. Optimization studies on the Heck- Reduction one-pot reaction

We clearly found that the Heck-reduction sequence between 2-(methoxycarbonyl)

benzenediazonium tetrafluoroborate salt (123) and methyl vinyl ketone (138) gave a lower

yield, (table 17), than when methylacrylate was used (table 14). Optimization studies on the

Heck-reduction one-pot strategy between the two partners is shown below (table 17). The two

partners 2-(methoxycarbonyl) benzenediazonium tetrafluoroborate salt (123) and methyl vinyl

ketone (138) were placed in the presence of Pd(OAc)2 (5 mol%) in dry THF (8 mL) at 40°C

for 6 hours. Then H2 was added to the mixture and kept at 25°C for 24 hours, giving 51% of

the product (139), (entry 1). This modest yield has been explained by the simultaneous

formation of the methyl-2-butylbenzoate by-product (140). In order to limit the formation of

(140), we carefully controlled the reaction time of the reduction step. After several

optimizations we found that the reduction can be best achieved in 6 hours with limited

formation of (140) (~ 10 %).

Table 17. Optimization studies on the Heck-Reduction step

To succeed in the cyclization step, we tested various bases (table 18). NaOMe and

DBU were not able to succeed in this transformation (entries 1-2). On the other hand, NaOEt,

NaH (95%), and t-BuOK did protonate the acidic proton α to the ketone and were able to

convert (139) to methyl 2-(3-oxobutyl)benzoate (141) (entries 3-5). Indeed, we observed a

successful conversion when using NaH (95%), t-BuOK, and NaOEt. NaH (95%) was able to

convert the starting material in 1 hour to produce 47% of (141), while t-BuOK converted the

starting material after 18 hours giving 63% of (141) (entries 3 vs 4). We found that the best

conversion was performed in NaOEt giving 70% of the cyclized product (entry 5).

Considering its low cost and being innocuous, we decided to use NaOEt as the base to

perform the cyclization step.

Table 18. Optimization studies for the cyclization step

After having these results, we decided to move on with studies on a one-pot procedure.

I. 5. d. Optimization studies on the one-pot HRC (Heck- Reduction- Cyclization)

strategy for the preparation of Indanones

After having successfully optimized each step, we next explored the opportunity of

conducting a one-pot sequence. Table 19 below, shows a representative selection of

conditions explored to get our desired cyclized product from diazonium salt (123) and methyl

vinyl ketone (138). The previously optimized Heck-Reduction steps were conserved, while

the cyclization step was still under optimization (table 19). We found that three equivalents of

NaH (95%) were not sufficient to get the final product since only 25% of (143) was collected

(entry 1). We observed a great drop in the formed yield when replacing NaH (95%) with t-

BuOK giving only 6% of the desired product. However, we subsequently discovered that the

cyclization step was highly dependent of the quantity of base. Indeed, when ten equivalents of

t-BuOK were used, a considerable increased of the product yield (45%) was observed.

Fortunately, the use of the less expensive base NaOEt did increase significantly the yield

(56%). It is important to note that we observed a decomposition of the cyclized product when

kept the mixture for longer than 24 h under basic medium.

Table 19. Optimization studies on one-pot Heck-Reduction-Cyclization strategy

At this point we noticed that the key point was the amount of base needed to perform

the transformation. In a one-pot method all by-products remain in the reactor. For instance, in

our case, one equivalent of HBF4 was formed during Heck cross-coupling. The neutralization

of HBF4 required five equivalents of a nucleophilic base such as NaOEt (scheme 48). As a

consequence, a large excess of NaOEt was required for the whole process including

neutralization and base-mediated cyclization.

Scheme 48. Neutralization of 1 eq HBF4

After our success in preparing the functionalized indanones by the HRC strategy with

good yields we thought of adding an extra step. To the HRC strategy we added an alkylation

step to perform a HRCA (Heck-Reduction-Cyclization-Alkylation) sequence in a single

vessel, to get four sequential transformations and more complex molecular structures.

I. 6. Synthetic point of view for preparing functionalized indanones by the HRCA

strategy

From a synthetic point of view, our HRCA one-pot strategy was proposed to prepare

functionalized indanones having a quaternary carbon center. Scheme 49 below, shows the

general HRCA one-pot process in which the Heck cross coupling would occur between an

otho-substituted diazonium salt (123) and methyl vinyl ketone (138) producing the coupled

product (142). Formation of intermediate (142) would be followed by a Pd-mediated

reduction of the double bond giving another intermediate (139). Deprotonating the acidic

proton of (139) by the aid of a base would give the indanone (141). The same base previously

added to the medium would easily deprotonate the highly acidic proton α to the carbonyl

groups of the cyclized indanone. The generated anion would be trapped with an alkylating

agent to get the desired functionalized indanone (143) and the formation of a quaternary

carbon center.

Scheme 49. General proposed preparation of funtionalized indanones by HRCA

showing the intermediates

After a successful formation of the desired cyclized product (141) by the HRC

strategy, we envisaged an alkylation step that would reinforce the synthetic utility of our

approach. We realized that the deprotonation the very acidic proton of (139) would be feasible

since the medium contained an excess of NaOEt, (previously added at the end of step 2). We

observed that the addition of benzyl bromide furnished the corresponding indanone with a

very satisfactory yield of 56% (scheme 50).

Scheme 50. Synthetic view of one-pot Heck-Reduction-Cyclization-Alkylation strategy

I. 6. a. Scope of the HRCA reaction strategy

Having successfully demonstrated the viability of our HRCA method, we screened a

variety of alkylating agent (table 20). We observed that benzyl bromide derivatives usually

gave synthetically useful yields. Other quite reactive alkylating agents such as methyl iodide,

allyl bromide, and propargyl bromide gave also satisfactory results. Unfortunately with

unactivated iodobutane we were unable to isolate the targeted product. Close examination of

the crude reaction mixture showed only decomposition products. (Table 20).

Table 20. Preparation of various analogues by HRCA strategy

After the successful screening of various alkylating agents, we thought of varying the

diazonium salt partner to get more complex and substituted structures. Toward this end, we

prepared the 2-(methoxycarbonyl)-4,5-dimethoxybenzenediazonium tetrafluoroborate salt

(151) and the 2,4-(dimethoxycarbonyl)benzene diazonium tetrafluoroborate salt (152).

Table 21 below shows the results of the one-pot HRCA preparation of different

substrates starting with diazonium salts (151) and (152). We clearly observed that the final

yield ranged from good to poor depending on the type of the diazonium salts and the

alkylating agent. In general, diazonium salt (151) gave better yields and the formed cyclized

product was found to be relatively stable. By contrast, the cyclized products originating from

diazonium salt (152) rapidly decomposed leading to complex mixtures (table 21). Moreover,

we faced some difficulty in purifying a couple of products (160), (161), and (164) by column

chromatography. We then thought of using preparative HPLC to purify these substrates.

HPLC purification proved to be successful for compounds (153), (155), and (158), but by lack

of time we were not able to submit all compounds to this technique.

Table 21. Preparation of various analogues using HRCA strategy starting with (151) and

(152) diazonium salt

I. 7. Conclusion

In this chapter, we described a successful extension of our HRC strategy for the

preparation of functionalized indanones. The complexity of the one-pot sequence was even

raised with the introduction of an additional alkylation step. The HRCA process consists of a

Heck cross-coupling between a diazonium salt and methyl vinyl ketone followed by a

reduction step of the formed coupled double bond. Then a cyclization step occurred by the aid

of a base that was also essential to perform the alkylation step. Therefore, this HRCA process

demonstrates the use of a single bifunctional homogeneous catalyst (Heck-reduction) in which

four transformations were carried out in a single vessel, to get a quaternary carbon center. We

are aware that this strategy must be improved, but we anticipate that such a simple and

friendly process would be useful for synthetic chemists.

Chapter D

After the successful preparation of indanones by the HRCA strategy, we were

interested in preparing alkaloids-type structures. A conceptually related strategy was

envisaged and consisted in the succession of Heck, direct C-H arylation, reduction, and

cyclization reactions performed in a one-pot strategy. In this chapter we wish to describe our

work toward this end that ultimately led to the preparation of novel naphthoxindoles.122

I. Naphthoxindoles

I. 1. Naphthoxindoles – Synthetic access

Naphthoxindoles are unusual tetracyclic structures that are related to various

biologically active natural compounds such as prioline, and piperumbellactam (figure 10).

Figure 10. Naphthoxindoles in different biologically active natural compounds

The naphthoxindoles core comprises a phenanthrene unit. The phenanthrene nucleus

constitutes an important class of polycyclic hydrocarbons extensively found in natural

122

L. Nassar-Hardy, C. Deraedt, E. Fouquet, F.-X. Felpin, Eur. J. Org. Chem. 2011,

products and biologically active compounds.123

It has also been widely used in material

science with photophysic applications.124

A variety of available methods for the preparation of phenanthrene-based compounds

are found.125

Among the different strategies, the cyclization of stilbene derivatives into the

corresponding phenanthrenes is currently the preferred approach. For instance, oxidative

cyclization of stilbenes has been widely described, even though this method, mostly, requires

electron-rich substrates.126

Photocyclizations in the presence of an oxidant such as iodine have

been also successfully reported but suffer from modest group compatibility, although an

improved protocol has been recently published to overcome this lack of generality.127

Wang

and co-workers also reported recently an elegant total synthesis of papilistatin with a radical

cyclization of a bromostilbene intermediate with a modest yield (30%).128

On the other hand,

cyclization of stilbenes by direct C-H arylation has mostly been overlooked till now.129

123

For recent examples, see: a) T.-S. Wu, L.-F. Ou, C.-M. Teng, Phytochemistry 1994, 36, 1063-1068; b) T.-H.

Chuang, S.-J. Lee, C.-W. Yang, P.-L. Wu, Org. Biomol. Chem. 2006, 4, 860-867; c) A. Kovács, A. Vasas, J.

Hohmannd, Phytochemistry 2008, 69, 1084-1110; d) M. Cui, Q. Wang, Eur. J. Org. Chem. 2009, 5445-5451; e)

L. M. Rossiter, M. L. Slater, R. E. Giessert, S. A. Sakwa, R. J. Herr, J. Org. Chem. 2009, 74, 9554-9557; f) Z.

Wang, Z. Li, K. Wang, Q. Wang, Eur. J. Org. Chem. 2010, 292-299. g) G. R. Pettit, Q. H. Ye, D. L. Herald, F.

Hogan, R. K. Pettit, J. Nat. Prod. 2010, 73, 164-166. 124

a) J. B. Birks, Photophysics of Aromatic Molecules; Wiley-Interscience: London, 1970. b) A. M. Machado,

M. Munaro, T. D. Martins, L. Y. A. Dávila, R. Giro, M. J. Caldas, T. D. Z. Atvars, L. C. Akcelrud,

Macromolecules 2006, 39, 3398-3407. 125

A. J. Floyd, S. F. Dyke, S. E. Ward, Chem. Rev. 1976, 76, 509-562. 126

K. Wang, M. Lü, A. Yu, X. Zhu, Q. Wang, J. Org. Chem. 2009, 74, 935-938 127

A. G. Neo, C. López, V. Romero, B. Antelo, J. Delamano, A. Pérez, D. Fernández, J. F. Almeida, L. Castedo,

G. Tojo, J. Org. Chem. 2010, 75, 6764-6770. 128

M. Wu, L. Li, A.-Z. Feng, B. Su, D.-M. Liang, Y.-X. Liu, Q.-M. Wang, Org. Biomol. Chem. 2011, 9, 2539-

2542. 129

a) A. de Meijere, Z. Z. Song, A. Lansky, S. Hyuda, K. Rauch, M. Noltemeyer, B. König, B. Knieriem, Eur. J.

Org. Chem. 1998, 2289-2299 ; b) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006,

128, 581-590; c) K. Kamikawa, I. Takemoto, S. Takemoto, H. Matsuzaka, J. Org. Chem. 2007, 72, 7406-7408;

d) H. Tsuji, Y. Ueda, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2010, 132, 11854-11855; e) A. K. Yadav, H. Ila,

H. Junjappa, Eur. J. Org. Chem. 2010, 338-344.

I. 2. Synthetic point of view for the preparation of naphthoxindoles

Our approach entails a fully palladium-catalyzed synthesis naphthoxindoles, through a

key intramolecular direct C-H arylation step leading to the phenanthrene core. The three-step

process involves a highly efficient Heck coupling of aryl diazonium salts with phenylacrylates

giving the corresponding cis-stilbene (C) (Scheme 51). Cyclization of stilbenes (C) into

phenanthrenes (D) via a direct intramolecular direct C-H arylation, followed by a palladium-

mediated cyclization of an amino-ester led to the formation of novel naphthoxindoles (E).

Scheme 51. General proposed preparation of naphthoxindoles

I. 3. Preparation of intermediates

I. 3. a. Stilbenes

Previous studies from this laboratory on the Heck coupling of aryl diazonium salts

with methyl-2-(2-nitrophenyl)acrylates proceeded with a high stereoselectivity for the control

of the double bond geometry.63

With this information in hands, we started our study on

naphthoxindoles with the preparation of a variety of bromo-stilbenes by the coupling of aryl

diazonium salts with methyl-2-(2-nitrophenyl)acrylates18

based on our recently published

procedure (Table 22).63

The reaction, carried out in MeOH at room temperature, proceeds

with good to excellent yields under ligand-free and base-free conditions. The simplicity and

the robustness of the catalytic system make this protocol highly reproducible, even for non

specialized chemists. We also prepared stilbenes (178, 179) that do not bear a nitro group in

order to evaluate the scope of the direct C-H arylation, although they could not be further

transformed into the targeted naphthoxindoles. We observed that the preparation of the cyano-

stilbene (177) required a higher palladium loading. We assumed that a strong complexation of

cationic palladium intermediates with the cyano group could explain this lower activity. As

expected, a perfect control of the olefin geometry, in favour of the cis-stilbenes, was

consistently obtained, and the trans-stilbenes were never observed by 1H NMR of the crude

reaction mixture. The E geometry of cis-stilbenes prepared in this study was assigned by

means of the 1H NMR shift of the olefinic proton at ~8 ppm (vs. ca. 7 ppm for the Z isomer)

and by analogy with stilbenes of related structure previously prepared in our laboratory. This

behaviour was rationalized by DFT calculations.63

The lower activation barrier is predicted

for structures having, in the transition state, the two phenyl groups in a cis relation, thus,

leading to the corresponding cis-stilbene.

Table 22. Preparation of stilbenes by the Heck cross-coupling

I. 3. b. Optimization studies on phenanthrenes

After having those series of bromo-stilbenes (171-180), we studied the direct C-H

arylation step to get our desired phenanthrenes. The optimization studies were conducted with

stilbene (171) as the model substrate (Scheme 52 and table 23).

Scheme 52. Model substrate for preparing phenanthrene from stilbenes

Since direct C-H arylations of non heterocyclic substrates frequently require high

palladium loading (>5 mol %),130

we initially screened heterogeneous palladium sources in

order to recover palladium metal after completion (table 23). Unfortunately, every palladium-

supported on charcoal catalysts tested were ineffective for the expected transformation

(entries 1-5).131,8(a,b)

Even the Pearlman‟s catalyst [Pd(OH)2/C], that has been successfully

used for the C-H arylation of heterocycles,132

was inactive with this substrate. By contrast, the

use of Pd(OAc)2 (10 mol%) furnished phenanthrene (181) with good yield in DMAc with

K2CO3 as base at 130 °C (entry 6). Decreasing the palladium loading to 2 mol% slightly

improved the yield, but a lower loading (1 mol %) was detrimental for the conversion (entry

130

For selected reviews, see: a) L.-C. Campeau, K. Fagnou, Chem. Commun. 2006, 1253-1264. b) D. Alberico,

M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174-238. c) L.-C. Campeau, D. R. Stuart, K. Fagnou,

Aldrichimica Acta 2007, 40, 35-41. d) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173–1193. e) B.-

J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949-957. 131

For reviews on Pd/C chemistry, see: a) F.-X. Felpin, E. Fouquet, Chem Sus Chem. 2008, 1, 718-724; b) M.

Pal, Synlett 2009, 2896-2912. 132

a) M. Parisien, D. Valette, K. Fagnou, J. Org. Chem. 2005, 70, 7578-7584; b) S. Sahnoun, S. Messaoudi, J.-F.

Peyrat, J.-D. Brion, M. Alami, Tetrahedron Lett. 2008, 49, 7279-7283; c) S. Sahnoun, S. Messaoudi, J.-D. Brion,

M. Alami, Org. Biomol. Chem. 2010, 7, 4271-4278; d) F. Jafarpour, S. Rahiminejadan, H. Hazrati, J. Org.

Chem. 2010, 75, 3109-3112.

9). A strong impact of the base on the reaction outcome was observed since K2CO3 was by far

superior to AcOK, Na2CO3, and t-BuOK (entries 8 vs 10-12). The same behaviour was

observed with the solvent. Indeed DMAc proved to be more effective than NMP and DMF

while with xylene and dioxane, we did not observed any conversion (entries 13-16). The

temperature parameter had a considerable impact on the reaction outcome and the reagent

stability. Indeed, at 150 °C we observed extensive decomposition products (entry 17), while at

90 °C the conversion was rather low (entry 19). After careful optimization, we found that, for

this substrate, the reaction was best performed at 110 °C (entry 17). Because we were still

interested in performing this transformation with a heterogeneous catalyst, we observed that

the addition of charcoal slightly improved the yield (entry 20). Interestingly, the use of PCy3

as ligand, still in the presence of charcoal, led to a much cleaner crude mixture and with 86%

yield of isolated (181) (entry 21). We believe that charcoal acts as a stabilizer for active

palladium species and as sponge for inactive ones that would form black palladium in its

absence. ICP-MS analysis of the crude mixture after a simple filtration showed that at least

80% of the palladium initially introduced was adsorbed on the charcoal, allowing its recovery

for a further reprocessing.

Table 23. Optimization studies of the intramolecular direct C-H arylation

I. 3. c. Scope of the preparation of phenanthrene

We then applied the optimized conditions to our set of bromo-stilbenes (171-180)

previsously prepared (Table 24). A higher palladium loading was required for the

intramolecular C-H arylation of stilbene (173) leading to phenanthrene (184) due to the

competitive palladium-mediated debromination reaction observed at a lower loading. In the

absence of phosphine, the protocol is selective to the bromine atom since no reaction occurred

at the chlorine atom on substrate (175). However, it should be noted, that the use of PCy3 on

stilbene (175) led to a much lower yield of (185) (56% vs 80%) due to side-reactions at the

chlorine atom. As already noted on the Heck reaction, the cyano-substituted stilbene (177)

was much less reactive and required a higher palladium loading for optimal conversion and

good yield of (187).

Table 24. Scope studies of the intermolecular direct C-H arylation

The case of the methoxylated stilbene (176) was quite interesting since the major

reaction product was highly dependent of the DMAc quality (Scheme 53). When using

undistilled DMAc we only observed the formation of the unexpected and highly unstable

quinone (190) (52% yield) along with degradation products. On the other hand, with twice-

distilled DMAc we were able to isolate the targeted phenanthrene (186) with modest yield

(33%) along with trace of quinone (190).

Scheme 53. Unexpected formation of quinone (199) in undistilled DMAc

The formation of quinone (190) is still unclear at this time since in the absence of

palladium we did not observed its formation. However, we assume that a push-pull effect

would give a highly hydrolysable intermediate (192), which ultimately furnished quinone

(190) in the presence of water (Scheme 54).

Scheme 54. Mechanistic interpretation for the formation of (199) by the Push-Pull effect.

I. 4. Scope of the preparation of naphthoxindoles

Lastly, phenanthrenes (181-189) were converted with good yields into the targeted

naphthoxindoles (193-199) in MeOH through a palladium-mediated reductive cyclization

(Table 25). This step was conducted following an extension of our recently published

procedure for the hydrogenation of olefins and the hydrogenolysis of benzyl ethers.133

The

catalytic system proceeds via the formation of a highly active Pd(0)/C catalyst, in situ

prepared from Pd(OAc)2 and charcoal. This strategy allows low palladium loadings and

avoids the handling of pyrophoric Pd/C catalysts. ICP-MS analyses of the crude mixtures

after a single filtration showed only ppb amounts (2-3 ppb) of residual palladium species in

the supernatant, which means that more than 99.9% of the palladium initially introduced has

been adsorbed on the charcoal.

133

F.-X. Felpin, E. Fouquet, Chem. Eur. J. 2010, 16, 12440-12445.

Table 25. Preparation of naphthoxindoles

I. 5. Studies on the preparation of naphthoxindoles using the Heck-direct C-H

arylation-Reduction-Cyclization one-pot strategy

Our work on the first step of the reaction, i.e. the preparation of stilbenes, showed that

the reaction works perfectly in MeOH but does not in DMAc. On the other hand, the second

step, i.e. the direct C-H arylation, functions only in DMAc and not in MeOH. We then

decided to prepare separately the stilbenes intermediates. (Scheme 55).

Scheme 55. Problems facing the one-pot strategy for the preparation of naphthoxindoles

We then studied the opportunity of performing the direct C-H arylation followed by

the reductive cyclization in DMAc following a one-pot strategy. Although we observed, on

the crude reaction mixture, the clean formation of naphthoxindole (193) we were unable to

isolate it in more than 25% yield. (Scheme 56).

Scheme 56. Low yields of (193) in DMAc using one-pot strategy.

We explained this low yield by the strong adsorption of the naphthoxindole on the

charcoal. We estimate that the one-pot strategy might change the structural nature of the

charcoal. By lack of time, we did not studied more in depth this issue.

II. Conclusion

Although, we were unable to perform the one-pot method to prepare naphthoxindoles

from the coupling partners methyl 2-(2-nitrophenyl)acrylates and aryl diazonium salts, we

reported a novel route for unusual alkaloids. Our approach entails a fully palladium-catalyzed

three-step sequence composed of a Heck coupling of diazonium salts, a direct C-H arylation,

and a reductive cyclization. The direct C-H arylation was carried out in the presence of

charcoal which stabilizes active palladium species and adsorbs unstable palladium particles

that would form palladium black in its absence. Such a protocol allows the preparation of

naphthoxindoles with only ppb of palladium contamination. We believe that this piece of

work would be of interest for synthetic chemists enrolled in palladium catalysis as well as

medicinal chemists concerned by the contamination of biologically active compounds with

palladium residues and interested by the access to structurally intriguing naphthoxindoles.

General Conclusion and perspectives

We described a successful sequential three step one pot strategy based on the Heck

cross coupling followed by a reduction and a cyclization step for the preparation of C3

substituted oxindoles. After succeeding in preparing the five member heterocyclic oxindoles

using our HRC strategy an extension to this idea was the HRCA strategy to prepare

functionalized indanones. The HRCA process consists of a Heck cross-coupling between a

diazonium salt and methyl vinyl ketone followed by a reduction step of the formed coupled

double bond. Then a cyclization step occurred by the aid of a base that was also essential to

perform the alkylation step. Therefore, this HRCA process demonstrates the use of a single

bifunctional homogeneous catalyst (Heck-reduction) in which four transformations were

carried out in a single vessel, to get a quaternary carbon center. We are aware that this

strategy must be improved, but we anticipate that such a simple and friendly process would be

useful for synthetic chemists.

After the successful preparation of indanones by the HRCA strategy, we were also

able to prepare alkaloids-type structures. A conceptually related strategy was envisaged and

consisted in the succession of Heck, direct C-H arylation, reduction, and cyclization reactions

performed in a one-pot strategy. We were unable to perform the one-pot method to prepare

naphthoxindoles from the coupling partners methyl 2-(2-nitrophenyl)acrylates and aryl

diazonium salts, but we reported a novel route for unusual alkaloids. Our approach is a fully

palladium-catalyzed three-step sequence composed of a Heck coupling of diazonium salts, a

direct C-H arylation, and a reductive cyclization.

The direct C-H arylation was carried out in the presence of charcoal which stabilizes

active palladium species and adsorbs unstable palladium particles that would form palladium

black in its absence. This protocol allowed the preparation of naphthoxindoles with negligible

palladium contamination.

We believe that this work would be interesting for synthetic chemists enrolled in

palladium catalysis as well as medicinal chemists concerned by the contamination of

biologically active compounds with palladium residues and interested by the access to

structurally intriguing naphthoxindoles.

Experimental part

General experimental conditions

All commercial materials were used without further purification, unless indicated.

Analytical thin layer chromatography (TLC) was performed on Fluka Silica Gel 60 F254.

Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials.

1H NMR and

13C NMR were recorded on Brüker DPX-200 FT (

1H: 200 MHz,

13C: 50.2

MHz), Brüker AC-250 FT (1H: 250 MHz,

13C: 62.5 MHz), Brüker Avance-300 FT (

1H: 300

MHz, 13

C: 75.4 MHz), Brüker DPX-400 FT (1H: 400 MHz,

13C: 100.2 MHz), Brüker DPX-

600 FT (1H: 600MHz,

13C: 150.6 MHz) apparatus using CDCl3 as internal reference unless

indicated. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz

respectively. The chemical shift of CDCl3 peak was fixed at 7.26 ppm (1H) or 77.0 ppm (

13C).

The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t

= triplet, app. t = apparently triplet, q = quartet, m = multiplet, br. = broad, dd = doublet of a

doublet. High resolution mass spectra were recorded on a FT-ICR mass spectrometer Brüker

4.7T BioApex II. Infrared (IR) spectra were recorded as neat samples on NaCl plates or with

KBr pellets. Melting points were not corrected and determined by using a Stuart Scientific

apparatus (SMP3). Macherey Nagel silica gel 60M (230-400 mech ASTM) was used for flash

chromatography. Diazonium salts used in our study were all known and prepared as described

in the literature. We used DARCO® G-60 activated charcoal having a 100 mech particle size

produced from lignin. THF was distilled from sodium and benzophenone.

To Methyl acrylate (0.089 mL, 1 mmol, 2 eq) a previously prepared o-methylbenzoate

diazonium salt (125 mg, 0.5 mmol, 1 eq) was added. Then Pd(OAc)2 (56 mg , 0.025 mmol

0.05 eq), Charcoal (90 mg), and MeOH (5 mL) were added sequentially and stirred for 30 min

at 40°C. Then in the same pot we added H2 gas and stirred the mixture for 24 hours at room

temperature. The resulting mixture was concentrated in vacuo. Purification by flash

chromatography (silica gel, 20% EtOAc-petroleum ether) gave the desired product (85 mg,

75% yield) as light yellow oil.

IR (KBr) ν 1602, 1721, 2953, 3067 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.66 (t, 2H, J = 9.0 Hz), 3.27 (t, 2H, J = 9.0 Hz), 3.65

(s, 3H), 3.88 (s, 3H), 7.23-7.29 (m, 2H), 7.39-7.46 (m, 1H), 7.90 (d, 1H, J = 9.5 Hz).

13

C NMR (75MHz, CDCl3) δ (ppm) 29.9, 35.6, 51.5, 51.9, 126.4, 129.2, 130.9, 131.1,

132.2, 142.4, 167.6, 173.4.

HRMS (electrospray) Calcd. For C12H14O4 Na [M+Na]+ 245.0784, found: 245.0786.

To a clean, dry round bottom flask, a solution of dry NaH 95% (126 mg, 5 mmol, 5

eq) in dry THF (2 mL) was prepared and kept under N2, then a solution of the previously

prepared methyl 2-(3-methoxy-3-oxopropyl) benzoate (483 mg, 2.1 mmol, 1 eq) in THF (2

mL) was added dropwise and stirred for 24 hours at 33°C. The mixture was quenched

dropwise with 1N HCl till PH= 7-8. Then the solution was extracted with 3 portions of

dichloromethane (8 mL), the collected organic phase was dried over MgSO4 and concentrated

in vacuo. Purification by flash chromatography (silica gel, 20% EtOAc-petroleum ether) gave

the desired product (173 mg, 44% yield) as a yellow oil.

IR (KBr) ν 1720, 1743, 2954, 3032 cm-1

1H NMR (250MHz, CDCl3) δ (ppm) 3.34 (dd, 1H, J = 8.1, 17.2 Hz), 3.53 (dd, 1H, J = 4.0,

17.2 Hz), 3.71 (dd, 1H, J = 4.2, 8.3 Hz), 3.75 (s, 3H), 7.32-7.42 (m, 1H), 7.47 (d, 1H, J = 7.7

Hz), 7.59 (app t, 1H, J = 7.3 Hz), 7.73 (d, 1H, J = 7.7 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 30.2, 52.7, 53.1, 124.6, 126.5, 127.7, 135.1, 135.4,

153.5, 169.5, 199.4.

HRMS (electrospray) Calcd. For C11H10O3Na [M+Na]+213.0522, Found: 213.0527

To Methylvinylketone (0.327 mL, 4 mmol, 2 eq) was added 2-methylbenzoate

diazonium salt (500 mg, 2 mmol, 1 eq), Pd(OAc)2 (22.4 mg, 0.1 mmol, 0.05 eq) and THF (16

mL). The mixture was stirred for 16 hours at 40°C. To the same mixture, H2 was added and

stirred at 30°c for 6 hours. The mixture was concentrated in vacuo. Purification by flash

chromatography (silica gel, 20% EtOAc-petroleum ether) gave the desired product (220 mg,

56% yield) as a pale yellow oil.

IR (KBr) ν 1710, 1730, 2952, 3024, 3068 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.07 (s, 3H), 2.72 (t, 2H, J = 7.5 Hz), 3.13 (t, 2H, J =

7.5 Hz), 3.81 (s, 3H), 7.16-7.21( m, 2H), 7.35 (app t, 1H, J = 7.5 Hz) 7.83 (d, 1H, J = 7.9 Hz)

13C NMR (75MHz, CDCl3) δ (ppm) 28.5, 29.4, 44.9, 51.6, 125.9, 128.9, 130.5, 130.9, 131.9,

142.8, 167.3, 207.5.

HRMS (electrospray) Calcd. For C12 H14O3Na [M+Na]+229.0835, found: 229.0833.

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. To the same pot, H2 was added

and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq) and THF (8 mL) were

added and stirred for 15 hours at 36°C. The cooled mixture was quenched with 1N HCl and

then extracted with 3 portions of CH2Cl2 (15 mL). The mixture was dried over MgSO4,

concentrated in vacuo. Purification with flash chromatography (silica gel, 10% EtOAc-

toluene) gave the desired product (80 mg, 46% yield) as a pale red solid.

mp 72°C

IR (KBr) ν 1598, 1666, 2903 cm-1

1H NMR (250MHz, CDCl3) δ (ppm) 2.13 (s, 3H X 0.85), 2.46 (s, 3H X 0.15), 3.08 (dd, 1H

X 0.15, J = 7.7, 17.6 Hz), 3.51 (s, 3H X 0.85), 3.69 (dd, 1H X 0.15, J = 3.3, 17.4 Hz), 3.93

(dd, 1H X 0.15, J = 3.4, 7.7 Hz), 7.33-7.39 (m, 1H), 7.43-7.57 (m, 2H), 7.69 (d, 1H X 0.15, J

= 8.1 Hz), 7.77 (d, 1H X 0.85, J = 7.6 Hz)

13C NMR (75MHz, CDCl3) δ (ppm) 21.1, 30.3, 110.4, 123.2, 125.7, 127.3, 132.7, 135.4,

138.2, 147.5, 177.6, 191.4.

HRMS (electrospray) Calcd. For C11 H11O2 [M+H]+ 175.0753, found: 175.0745.

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq) were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. To the same pot, H2 was added

and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF (8 mL)

were added and stirred for 15 hours at 36°C. Then allylbromide (0.216 mL, 2.5mmol, 2.5 eq)

was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture was quenched

with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture was dried over

MgSO4, concentrated in vacuo. Purification by flash chromatography (silica gel, 10% EtOAc-

petroleum ether) gave the desired product (97 mg, 40% yield) as a pale yellow oil.

IR (KBr) ν 1589, 1606, 1640, 1701, 1719, 2923, 2979, 3078 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.26 (s, 3H), 2.66 (dd, 1H, J = 6.4, 14.3 Hz), 2.87 (dd,

1H, J = 7.5, 14.3 Hz), 2.95 (d, 1H, J = 17.6 Hz), 3.79 (d, 1H, J = 17.6 Hz), 5.04 (d, 1H, J =

10.2 Hz), 5.12 (d, 1H, J = 17.0 Hz), 5.50-5.61 (m, 1H), 7.35 (app t, 1H, J = 7.7 Hz), 7.47 (d,

1H, J = 7.6 Hz), 7.59 (app t, 1H, J = 7.4 Hz), 7.71 ( d, 1H, J = 7.7 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 25.9, 33.7, 39.4, 68.2, 119.1, 124.4, 126.4, 127.6, 132.3,

135.4, 153.3, 202.7, 203.3.

HRMS (electrospray) Calcd. For C14 H14O2Na [M+Na]+ 237.0886, found: 237.0888

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. To the same pot, H2 was added

and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF (8 mL)

were added and stirred for 15 hours at 36°C. Then Benzylbromide (0.356 mL, 3 mmol, 3 eq)

was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture was quenched

with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture was dried over

MgSO4, concentrated in vacuo. Purification by flash chromatography (silica gel, 5% EtOAc-

petroleum ether) gave the desired product (164 mg, 61% yield) as a yellow oil.

IR (KBr) ν 1590, 1605, 1701, 1719, 2926 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.27 (s, 3H), 2.98 (d, 1H, J = 17.4 Hz), 3.34 (d, 1H, J =

14.3 Hz), 3.45 (d, 1H, J = 14.3 Hz), 3.74 (d, 1H, J = 17.4 Hz), 7.06-7.17 (m, 5H), 7.28-7.34

(m, 2H), 7.49-7.54 (m, 1H), 7.68 (d, 1H, J = 7.6 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 26.1, 33.6, 39.9, 69.7, 124.4, 126.3, 126.8, 127.6,

128.4, 129.5, 135.2, 135.4, 136.3, 153.6, 203.1, 203.5.

HRMS (electrospray) Calcd. For C18 H16O2Na [M+Na]+ 287.1042, found: 287.1050

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the same pot, H2 was

added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF

(8mL) were added and stirred for 15 hours at 36°C. Then p-iodobenzylbromide (891 mg, 3

mmol, 3 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture

was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture

was dried over MgSO4, concentrated in vacuo. Purification by flash chromatography (silica

gel, 5% EtOAc-petroleum ether) gave the desired product (195 mg, 50% yield) as a white-

yellow solid.

mp 131-135°C

IR (KBr) ν 1605, 1720, 1698, 2925, 3037 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.23 (s, 3H), 2.94 (d, 1H, J = 17.6 Hz), 3.23 (d, 1H, J =

14.4 Hz), 3.40 (d, 1H, J = 14.2 Hz), 3.70 (d, 1H, J = 17.6 Hz), 6.82 (d, 2H, J = 10. 6 Hz),

7.28-7.37 (m, 2H), 7.44-7.55 (m, 3H), 7.68 (d, 1H, J = 7.7 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 26.0, 33.5, 39.1, 69.2, 92.3, 124.4, 126.3, 127.7, 131.5,

135.2, 135.5, 135.9, 137.4, 153.3, 202.8, 203.0.

HRMS (electrospray) Calcd. For C18 H15O2INa [M+Na]+ 413.0009, found: 413.0005

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the same pot, H2 was

added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF (8

mL) were added and stirred for 15 hours at 36°C. Then o-bromobenzylbromide (750 mg, 3

mmol, 3 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture

was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture

was dried over MgSO4, concentrated in vacuo. Purification by flash chromatography (silica

gel, 5% EtOAc-petroleum ether), gave the desired product (195 mg, 50% yield) as an orange-

yellow oil.

IR (KBr) ν 1590, 1606, 1697, 1721, 2929, 3068 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.27 (s, 3H), 2.95 (d, 1H, J = 17.6 Hz), 3.55 (d, 1H, J =

15.1 Hz), 3.72 (d, 1H, J = 14.9 Hz), 3.82 (d, 1H, J = 17.4 Hz), 6.99-7.03 (m, 1H), 7.09 (dd,

2H, J = 1.1, 5.3 Hz), 7.31-7.40 (m, 2H), 7.50-7.57 (m, 2H), 7.73 (d, 1H, J = 7.6 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 26.0, 33.5, 38.6, 69.5, 124.5, 125.9, 126.3, 127.6,

128.4, 130.4, 133.0, 134.9, 135.5, 136.3, 153.9, 202.8, 203.2.

HRMS (electrospray) Calcd. For C18 H15O2Br Na [M+Na]+ 365.0147, found: 365.0147

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the same pot, H2 was

added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF (8

mL) were added and stirred for 15 hours at 36°C. Then iodomethane (0.186 mL, 3 mmol, 3

eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture was

quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture was

dried over MgSO4, concentrated in vacuo. Purification with flash chromatography (silica gel,

10% EtOAc-petroleum ether) gave the desired product (98 mg, 52% yield) as a yellow oil.

IR (KBr) ν 1589, 1607, 1699, 1723, 2931, 2974, 3035 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.53 (s, 3H), 2.21 (s, 3H), 2.82 (d, 1H, J = 17.4 Hz),

3.82 (d, 1H, J = 17.6 Hz), 7.35-7.40 (m, 1H), 7.47 (dt, 1H, J = 7.6 Hz), 7.58-7.64 (m, 1H),

7.73 (d, 1H, J = 7.7 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 21.5, 25.9, 37.6, 64.0, 124.7, 126.5, 127.8, 134.8,

135.5, 152.9, 204.1, 204.6.

HRMS (electrospray) Calcd. For C12 H12O2Na [M+Na]+ 211.0729, found: 211.0727

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added 2-methylbenzoate

diazonium salt (250 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 eq), and dry

THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the same pot, H2 was

added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10 eq), and THF (8

mL) were added and stirred for 15 hours at 36°C. Then propargylbromide (0.334 mL, 3

mmol, 3 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled mixture

was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The mixture

was dried over MgSO4, concentrated in vacuo. Purification by flash chromatography (silica

gel, 20% EtOAc-petroleum ether) gave the desired product (100 mg, 47% yield) as a yellow

oil.

IR (KBr) ν 1606, 1699, 1723, 2924 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.89 (s, 1H), 2.24 (s, 3H), 2.75 (d, 1H, J = 18.0 Hz),

3.05 (d, 1H, J = 18.0 Hz), 3.20 (d, 1H, J = 18.0 Hz), 3.80 (d, 1H, J = 18.0 Hz), 7.40 (app t,

1H, J = 6.0 Hz), 7.54 (d, 1H, J = 9.0 Hz), 7.65 (app t, 1H, J = 6.0 Hz), 7.76 (d, 1H, J = 9.0

Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 24.2, 25.9, 34.9, 67.0, 70.9, 79.2, 124.8, 126.5, 127.9,

135.0, 135.8, 153.6, 201.6, 202.0.

HRMS (electrospray) Calcd. For C14 H12O2Na [M+Na]+ 235.0729, found: 235.0735

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added methyl 3,4-

dimethoxybenzoate diazonium salt (310 mg, 1 mmol, 1eq,), Pd(OAc)2 (11.2 mg, 0.05 mmol,

0.05 eq), and dry THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the

same pot, H2 was added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10

eq), and THF (8 mL) were added and stirred for 15 hours at 36°C. Then allylbromide (0.173

mL, 2 mmol, 2 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled

mixture was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The

mixture was dried over MgSO4, concentrated in vacuo. Purification by flash chromatography

(silica gel, 35% EtOAc-petroleum ether) gave the desired product (89 mg, 33% yield) as a

pale yellow solid.

mp 72-73°C

IR (KBr) ν 1591, 1689, 1713, 2837, 2939, 3004 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.21 (s, 3H), 2.63 (dd, 1H, J = 6.4 Hz, J = 14.1 Hz),

2.80 (dd, J = 7.7 Hz, 1H, J = 14.1 Hz), 2.84 (d, 1H, J = 17.3 Hz), 3.63 (d, 1H, J = 17.3 Hz),

3.85 (s, 3H), 3.93 (s, 3H), 5.00 (d, 1H, J = 10.0 Hz), 5.09 (d, 1H, J = 17.00 Hz), 5.47-5.61

(m, 1H), 6.86 (s, 1H), 7.08 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 25.9, 33.4, 39.2, 56.0, 56.2, 68.3, 104.5, 107.2, 118.9,

127.7, 132.6, 148.9, 149.6, 156.1, 201.0, 204.0.

HRMS (electrospray) Calcd. For C16 H18O4Na [M+Na]+ 297.1097, found: 297.1112

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added methyl 3,4-

dimethoxybenzoate diazonium salt (310 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol,

0.05 eq), and dry THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the

same pot, H2 was added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10

eq), and THF (8 mL) were added and stirred for 15 hours at 36°C. Then benzylbromide

(0.237 mL, 2 mmol, 2 eq) was added. The mixture was stirred at 36°C for 24 hours. The

cooled mixture was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15

mL). The mixture was dried over MgSO4, concentrated in vacuo. Purification by flash

chromatography (silica gel, 40% EtOAC-petroleum ether), gave the desired product (89 mg,

33% yield) as a yellow solid.

mp 135- 137°C

IR (KBr) ν 1591, 1700, 1715, 2932, 3004 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.27 (s, 3H), 2.89 (d, 1H, J = 17.3 Hz), 3.31 (d, 1H, J

= 14.3 Hz), 3.47 (d, 1H, J = 14.1 Hz), 3.62 (d, 1H, J = 17.3 Hz), 3.87 (s, 3H), 3.90 (s, 3H),

6.76 (s, 1H), 7.07-7.18 (m, 6H).

13C NMR (75MHz, CDCl3) δ (ppm) 26.1, 33.2, 39.6, 56.0, 56.2, 69.8, 104.6, 107.1, 126.7,

128.0, 128.3, 129.5, 136.5, 149.2, 149.6, 156.0, 201.4, 204.1.

HRMS (electrospray) Calcd. For C20 H20O4Na [M+Na]+ 347.1253, found: 347.1257.

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added methyl 3,4-

dimethoxybenzoate diazonium salt (310 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol,

0.05 eq), and dry THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the

same pot, H2 was added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10

eq), and THF (8 mL) were added and stirred for 15 hours at 36°C. Then 4-iodo-

benzylbromide (0.237 mL, 2 mmol, 2 eq) was added. The mixture was stirred at 36°C for 24

hours. The cooled mixture was quenched with H2O and then extracted with 3 portions of

CH2Cl2 (15 mL). The mixture was dried over MgSO4, concentrated in vacuo. Purification was

performed by preparative high-performance liquid chromatography (HPLC) on a semi-

preparative column (Luna C-18, 10 x 250 mm; phenomenex). The mobile phase consisted of

66 % CH3CN and 44 % H2O and the flow rate was set at 5 mL / min. Retention time = 10 min

30 s. The desired product was formed as a white solid (86 mg, 19% yield).

mp 72- 73°C

IR (KBr) ν 1688, 1716, 1715, 2930, 3003 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.23 (s, 3H), 2.84 (d, 1H, J = 17.7 Hz), 3.19 (d, 1H, J

= 14.3 Hz), 3.44 (d, 1H, J = 14.1 Hz), 3.56 (d, 1H, J = 17.3 Hz), 3.89 (s, 3H), 3.93 (s, 3H),

6.77 (s, 1H), 6.84 (d, 2H, J = 8.3 Hz), 7.10 (s, 1H), 7.49 (d, 2H, J = 8.3 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 26.0, 33.1, 39.0, 56.1, 56.2, 69.4, 92.3, 104.6, 107.2,

128.1, 131.7, 136.2, 137.4, 149.1, 149.8, 156.2, 201.2, 203.7.

HRMS (electrospray) Calcd. For C20 H19 IO4Na [M+Na]+ 473.0231, found: 473.0220.

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added methyl 3,4-

dimethoxybenzoate diazonium salt (310 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol,

0.05 eq), and dry THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the

same pot, H2 was added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10

eq), and THF (8 mL) were added and stirred for 15 hours at 36°C. Then propargyle bromide

(0.13 mL, 2 mmol, 2 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled

mixture was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The

mixture was dried over MgSO4, concentrated in vacuo. Purification was performed by

preparative high-performance liquid chromatography (HPLC) on a semi-preparative column

(Luna C-18, 10 x 250 mm; phenomenex). The mobile phase consisted of 40 % CH3CN and 60

% H2O and the flow rate was set at 4 mL / min. Retention time = 15 min . The desired product

was formed as a white solid (85 mg, 31% yield).

mp 113- 114°C

IR (KBr) ν 1607, 1678, 1716, 2930, 2924, 3241 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.88 (t, 1H, J = 5.3 Hz), 2.22 (s, 3H), 2.75 (dd, 1H, J =

2.6, 2.6 Hz), 3.02 (dd, 1H, J = 2.8, 2.6 Hz), 3.11 (d, 1H, J = 17.4 Hz), 3.66 (d, 1H, J = 17.4

Hz), 3.90 (s, 3H), 3.99 (s, 3H), 6.93 (s, 1H), 7.15 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 24.0, 25.8, 34.7, 56.1, 56.3, 67.2, 70.7, 79.5, 104.8,

107.2, 127.7, 149.2, 149.9, 156.4, 199.9, 202.6.

HRMS (electrospray) Calcd. For C16 H16 O4Na [M+Na]+

295.0940, found: 295.0938.

To Methylvinylketone (0.163 mL, 2 mmol, 2 eq), were added methyl 3,4-

dimethoxybenzoate diazonium salt (310 mg, 1 mmol, 1eq), Pd(OAc)2 (11.2 mg, 0.05 mmol,

0.05 eq), and dry THF (8 mL). The mixture was stirred for 18 hours at 40°C. Then to the

same pot, H2 was added and stirred at 25°C for 5 hours. Then EtONa (680 mg, 10 mmol, 10

eq), and THF (8 mL) were added and stirred for 15 hours at 36°C. Then 4-iodomethane (284

mg, 2 mmol, 2 eq) was added. The mixture was stirred at 36°C for 24 hours. The cooled

mixture was quenched with H2O and then extracted with 3 portions of CH2Cl2 (15 mL). The

mixture was dried over MgSO4, concentrated in vacuo. Purification was performed by

preparative high-performance liquid chromatography (HPLC) on a semi-preparative column

(Luna C-18, 10 x 250 mm; phenomenex). The mobile phase consisted of 50 % CH3CN and

50% H2O and the flow rate was set at 5 mL / min. Retention time = 6min. The desired product

was formed as a white solid (99 mg, 40 % yield).

mp 125- 126°C

IR (KBr) ν 1691, 1708, 2936, 2960, 3072 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.51 (s, 3H), 2.20 (s, 3H), 2.73 (d, 1H, J = 17.3 Hz),

3.70 (d, 1H, J = 17.3 Hz), 3.89 (s, 3H), 3.97 (s, 3H), 6.89 (s, 1H), 7.14 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 21.3, 25.8, 37.4, 56.1, 56.3, 64.2, 104.8, 107.3, 127.4,

148.4, 149.8, 156.1, 202.5, 205.1.

HRMS (electrospray) Calcd. For C14 H16 O4Na [M+Na]+ 271.0938, found: 271.0940.

A solution of 2-nitrophenylmethylacetate (2.3 g, 11.1 mmol, 1eq), paraformaldehyde

(1 g, 31.1 mmol, 2.8 eq), K2CO3 (4.6 mg, 33 mmol, 3 eq), nBu4NI (173 mg, 0.47 mmol, 0.04

eq,) in Toluene (16 mL) was stirred for 12 hours at 80°C. The resulting cooled mixture was

quenched with water (10 mL) and then extracted with three portions of toluene (15 mL). The

collected organic phase was dried over MgSO4, and concentrated in vacuo. Purification by

flash chromatography (silica gel, 20% EtOAc-petroleum ether) gave the desired product

(174.5 mg, 77% yield) as a yellow oil.

IR (KBr) ν 1608, 1727, 2963, 3075 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 3.63 (s, 3H), 5.83 (d, 1H, J = 0.8 Hz), 6.46 (d, 1H, J =

0.8 Hz), 7.34 (dd, 1H, J = 1.6, 7.6 Hz), 7.42-7.50 (m, 1H), 7.56-7.63 (m, 1H), 8.02 (dd, 1H, J

= 1.1, 8.1 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 51.9, 124.2, 127.3, 129.2, 131.9, 132.6, 133.6, 139.5,

147.5, 165.0

HRMS (electrospray) Calcd. For C10H9 N O4Na [M+Na]+ 230.0423, found: 230.0425.

A solution of Methyl 2-(4,5-dimethoxy-2-nitrophenyl)acetate (2 g, 12 mmol, 1eq),

paraformaldehyde (0.7 g, 32 mmol, 2.7 eq), K2CO3 (340 mg, 25 mmol, 2 eq), nBu4NI (53 mg,

0.14 mmol 0.012 eq,) in toluene (15 mL) was stirred for 12 hours at 50°C. The resulting

cooled mixture was quenched with water (10 mL) and then extracted with three portions of

toluene (15 mL). The collected organic phase was dried over MgSO4, and concentrated in

vacuo. Purification by flash chromatography (silica gel, 20% EtOAc-petroleum ether) gave

the desired product (1.63 g, 79% yield) as a yellow solid.

mp 92-93°C

IR (KBr) ν 1521, 1576, 1726, 2950 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.69 (s, 3H), 3.95 (s, 3H), 3.95 (s, 3H), 5.78 (d, 1H, J =

1 Hz), 6.45 (d, 1H, J = 0.9 Hz), 6.73 (s, 1H), 7.70 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 52.2, 56.4, 107.6, 113.4, 126.3, 127.5, 140.0, 140.3,

148.7, 153.2, 165.5.

HRMS (electrospray) Calcd. For C12H13NO6Na [M+Na]+ 290.0635, found: 290.0645.

To a solution of ester (15 mmol, 1 eq) in toluene (20 mL) was added HCHO (42

mmol, 2.8 eq), Bu4NI (0.3 mmol, 0.04 eq) and K2CO3 (45 mmol, 3 eq) at room temperature.

The resulting mixture was stirred for 12 h at 80°C. After cooling to room temperature, water

(15 mL) was added and the aqueous phase was extracted twice with toluene (2 x 20 mL). The

collected organic extracts were dried (MgSO4), filtered and concentrated under reduced

pressure to give the corresponding methylene ester which was purified by flash

chromatography. Purification by flash chromatography (20% EtOAc-petroleum ether) gave a

white solid (66% yield).

mp 55°C.

IR (KBr) ν 1617, 1731, 2956, 3004, 3092 cm-1

.

1H NMR (CDCl3, 300 MHz) δ (ppm) 3.71 (s, 3H), 3.97 (s, 3H), 5.93 (s, 1H), 6.59 (s, 1H),

7.48 (d, 1H, J = 7.9 Hz), 8.27 (dd, 1H, J = 1.5, 7.9 Hz), 8.71 (d, 1H, J = 1.5 Hz).

13C NMR (CDCl3, 75 MHz) δ (ppm) 52.3, 52.8, 125.6, 128.4, 131.5, 132.4, 134.1, 136.8,

139.0, 147.9, 164.6, 164.7.

HRMS (electrospray) Calcd for C12H11NO6Na [M+Na] + 288.0478, found 288.0476.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (40% EtOAc-petroleum ether) gave a white solid (81% yield).

mp 156°C.

IR (KBr) ν 1701, 1719, 2956, 3035, 3080, 3179 cm-1

.

1H NMR (CDCl3, 250 MHz) δ (ppm) 3.05 (dd, 1H, J = 8.7, 13.8 Hz), 3.51 (dd, 1H, J = 4.8,

13.7 Hz), 3.78 (dd, 1H, J = 4.8, 8.7 Hz), 3.89 (s, 3H), 6.76-6.94 (m, 3H), 7.14-7.26 (m, 3H),

7.91 (d, 2H, J = 8.1 Hz), 8.94 (br s, 1H).

13C NMR (CDCl3, 75 MHz) δ (ppm) 36.4, 47.1, 52.0, 109.8, 122.1, 124.6, 128.1, 128.4,

128.6, 129.5, 129.6, 141.4, 143.1, 167.0, 179.2.

HRMS (electrospray) Calcd for C17H15NO3Na [M+Na] +

304.0944, found 304.0942.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (40% EtOAc-petroleum ether) gave a pale yellow solid (81% yield).

mp 109°C

IR (KBr) ν 1699, 1731, 2958, 3034, 3078, 3175 cm-1

.

1H NMR (CDCl3, 250 MHz) δ (ppm) 2.91 (dd, 1H, J = 9.1, 13.9 Hz), 3.43 (dd, 1H, J = 4.6,

13.7 Hz), 3.72 (dd, 1H, J = 4.6, 9.1 Hz), 3.76 (s, 3H), 6.76-6.94 (m, 5H), 7.07-7.20 (m, 3H),

9.20 (br s, 1H).

13C NMR (CDCl3, 75 MHz) δ (ppm) 35.7, 47.7, 55.1, 109.8, 113.6, 121.9, 124.7, 127.8,

129.0, 129.7, 130.3, 141.5, 158.2, 180.0.

HRMS (electrospray) Calcd for C16H15NO2Na [M+Na] + 276.0995, found 276.0998.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (30% EtOAc-petroleum ether) gave a white solid (61% yield).

mp 206°C.

IR (KBr) ν 1622, 1707, 2961, 3002, 3031, 3079, 3176 cm-1

.

1H NMR (CDCl3, 300 MHz) δ (ppm) 2.18 (s, 6H), 2.32 (s, 3H), 2.90 (dd, 1H, J = 11.7, 13.9

Hz), 3.45 (dd, 1H, J = 5.6, 13.9 Hz), 3.71 (dd, 1H, J = 5.6, 11.7 Hz), 6.33 (d, 1H, J = 7.5 Hz),

6.80 (t, 1H, J = 7.5 Hz), 6.89 (s, 2H), 6.95 (t, 1H, J = 7.5 Hz), 7.18 (t, 1H, J = 7.7 Hz), 9.26

(br s, 1H).

13C NMR (CDCl3, 75 MHz) δ (ppm) 20.2, 20.9, 30.6, 44.8, 109.7, 121.9, 125.0, 127.8,

128.9, 129.2, 131.8, 136.0, 137.0, 141.4, 180.4.

HRMS (electrospray) Calcd for C18H19NONa [M+Na] + 288.1358, found 288.1356.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (40% EtOAc-petroleum ether) gave a yellow oil (86% yield).

IR (neat) ν 1620, 1699, 2930, 3215 cm-1

.

1H NMR (CDCl3, 250 MHz) δ (ppm) 3.08 (dd, 1H, J = 8.5, 13.7 Hz), 3.50 (dd, 1H, J = 4.6,

13.7 Hz), 3.77 (dd, 1H, J = 4.6, 8.3 Hz), 6.80-6.88 (m, 2H), 6.95 (dt, 1H, J = 1.0, 7.5 Hz),

7.19 (t, 1H, J = 7.5 Hz), 7.34-7.48 (m, 4H), 9.21 (br s, 1H).

HRMS (electrospray) Calcd for C16H12NOF3Na [M+Na+] 314.0769, found 314.0766.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (70% EtOAc-petroleum ether) gave an orange solid (80% yield).

mp 106°C.

IR (KBr) 1627, 1712, 2934, 2998, 3191 cm-1

1H NMR (CDCl3, 250 MHz) δ (ppm) 2.78 (dd, 1H, J = 9.9, 13.3 Hz), 3.49 (dd, 1H, J = 4.8,

13.3 Hz), 3.63 (s, 3H), 3.66-3.71 (m, 1H), 3.74 (s, 3H), 3.82 (s, 3H), 6.20 (s, 1H), 6.52 (s,

1H), 6.76-6.80 (m, 3H), 7.18 (t, 1H, J = 8.5 Hz), 9.42 (s, 1H).

13C NMR (CDCl3, 75 MHz) δ (ppm) 37.0, 47.8, 55.1, 56.1, 56.3, 95.5, 109.8, 112.3, 114.9,

119.6, 121.8, 129.3, 135.1, 139.5, 144.3, 149.1, 159.5, 180.7.

HRMS (electrospray) Calcd for C18H19NO4Na [M+Na] + 336.1212 found 336.1210.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (50% EtOAc-petroleum ether) gave a yellow solid (71% yield).

mp 158°C.

IR (KBr) ν 1626, 1709, 2958, 3196 cm-1.

1H NMR (CDCl3, 300 MHz) δ 1.23 (s, 6H), 2.73 (dd, 1H, J = 10.6, 13.6 Hz), 2.89 (qt, 1H, J

= 7.5 Hz), 3.52 (dd, 1H, J = 4.5, 13.6 Hz), 3.58 (s, 3H), 3.66 (dd, 1H, J = 4.5, 10.5 Hz), 3.84

(s, 3H), 6.05 (s, 1H), 6.52 (s, 1H), 7.12-7.18 (m, 4H), 8.80-8.92 (m, 1H).

13C NMR (CDCl3, 75 MHz) δ 24.0, 24.1, 33.7, 36.6, 47.9, 56.1, 56.1, 95.4, 109.7, 119.7,

126.4, 129.5, 134.9, 135.4, 144.2, 147.4, 149.0, 180.7.

HRMS (electrospray) Calcd for C20H23NO3Na [M+Na]+ 348.1570, found 348.1570.

To a solution of diazonium salt (1.2 mmol) in MeOH (5 mL) were added acrylate (1

mmol), Charcoal (45 mg) and Pd(OAc)2 (5 mol %). The reaction was stirred for 1 hour at

40°C and then, stirred under H2 for 24 h at 40°C. After filtration, the crude material was

purified by flash chromatography to give the corresponding oxindole. Purification by flash

chromatography (20% EtOAc-petroleum ether) gave a yellow oil (75% yield).

IR (KBr) ν 1627, 1713, 2955, 3143 cm-1.

1H NMR (CDCl3, 300 MHz) δ 3.00 (dd, 1H, J = 8.6, 13.9 Hz), 3.49 (dd, 1H, J = 4.9, 14.3

Hz), 3.78 (dd, 1H, J = 4.5, 8.3 Hz), 3.91 (s, 3H), 6.84 (d, 1H, J = 7.6 Hz), 7.28-7.37 (m, 3H),

7.48 (d, 1H, J = 7.5 Hz), 7.73 (d, 1H, J = 7.5 Hz), 7.75 (s, 1H).

HRMS (electrospray) Calcd for C18H14F3NO3Na (M+Na+) 372.0823, found 372.0825.

To 2-Nitrophenylmethylacrylate (208 mg, 1 mmol, 1eq) were added 4-Bromo benzene

diazonium salt (406 mg, 1.5 mmol, 1.5 eq), Pd(OAc)2 (2mg, 0.01 mmol, 0.01eq), and MeOH

(6 mL). The reaction mixture was stirred for 15 hours at 25°C. The mixture was concentrated

in vacuo. Purification by flash chromatography (silica gel, 30% EtOAc-petroleum ether) gave

the desired product (334 mg, 98% yield) as a pale yellow solid.

IR (neat) ν 1633, 1717, 1733, 2846, 2904, 2953, 3001, 3033, 3068 cm-1

.

1H NMR (CDCl3, 200 MHz) δ (ppm) 3.75 (s, 3H), 3.85 (s, 3H), 7.06 (d, 2H, J = 8.3 Hz),

7.11-7.15 (m, 1H), 7.46-7.59 (m, 2H), 7.82 (d, 2H, J = 8.4 Hz), 7.94 (s, 1H), 8.19-8.27 (m,

1H).

13C NMR (CDCl3, 50 MHz) δ (ppm) 52.2, 52.6, 125.0, 129.5, 129.5, 129.9, 130.3, 131.4,

132.1, 132.5, 133.9, 138.4, 138.7, 148.6, 165.9, 166.3.

HRMS (electrospray) Calcd for C18H15NO6Na [M+Na] + 364.0791, found 364.0792.

To 2-Nitrophenylmethylacrylate (208 mg, 1 mmol, 1eq) were added 2-Bromo benzene

diazonium salt (406 mg, 1.5 mmol, 1.5 eq), Pd(OAc)2 (2mg, 0.01 mmol, 0.01eq), and MeOH

(6 mL). The reaction mixture was stirred for 15 hours at 25°C. The mixture was concentrated

in vacuo. Purification by flash chromatography (silica gel, 20% EtOAc-petroleum ether) gave

the desired product (300 mg, 83% yield) as a yellow solid.

mp 125°C

IR (KBr) ν 1527, 1709, 2956, 3064 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.77 (s, 3H), 6.39 (dd, 1H, J = 1.1, 7. 6 Hz), 6.95 (t,

1H, J = 7.9 Hz), 7.01-7.09 (m, 2H), 7.38-7.48 (m, 2H), 7.56 (d, 1H, J = 7.9 Hz), 8.05 (s, 1H),

8.16 (dd, 1H, J = 2.3, 6.8 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 52.5, 124.6, 127.0, 129.1, 130.1, 130.8, 131.2, 132.6,

132.9, 133.6, 135.2, 139.5, 149.0, 165.6.

HRMS (electrospray) Calcd. For C16H12NO4 NaBr [M+Na]+ 383.9848, found: 383.9848

To 2-Nitrophenylmethylacrylate (404 mg, 1 mmol, 1eq) were added 2-Bromo-4-

isopropyle benzene diazonium salt (406 mg, 1.5 mmol, 1.5 eq), Pd(OAc)2 (2 mg, 0.01 mmol,

0.01eq), and MeOH (6 mL). The reaction mixture was stirred for 15 hours at 25°C. The

mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, 20%

EtOAc-petroleum ether) gave the desired product (315 mg, 78% yield) as a yellow solid.

mp 125°C

IR (KBr) ν 1526, 1717, 2870, 2962, 3030, 3066 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 1.16 (d, 6H, J = 6.9 Hz), 2.78 (sept, 1H, J = 6.9Hz),

3.76 (s, 3H), 6.64 (d, 1H, J = 8.1 Hz), 6.80 (dd, 1H, J = 1.7, 8.1 Hz), 8.05-7.09 (m, 1H), 7.40-

7.50 (m, 3H), 8.06 (s, 1H), 8.13-8.21 (m, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 23.5, 33.6, 52.5, 124.6, 125.0, 125.4, 129.1, 130.6,

130.7, 131.5, 131.7, 132.2, 132.9, 133.6, 139.4, 149.0, 151.7, 165.8.

HRMS (electrospray) Calcd. For C19H18NO4NaBr [M+Na]+ 426.0311, found: 426.0317

To 2-Nitrophenylmethylacrylate (208 mg, 1 mmol, 1eq,) were added 2-Bromo-5-

triflourobenzene diazonium salt (754 mg, 2 mmol, 2 eq), Pd(OAc)2 (2.24 mg, 0.01 mmol,

0.01 eq), and MeOH (4 mL). The reaction mixture was stirred for 18 hours at 25°C. The

mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, 20%

EtOAc-petroleum ether) gave the desired product (417 mg, 97% yield) as a yellow solid.

mp 104- 105°C

IR (KBr) ν 1550, 1605, 1723, 2955, 3072 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.79 (s, 3H), 6.95 (s, 1H), 6.99-7.02 (m, 1H), 7.30 (dd,

1H, J = 2.2, 8.4 Hz), 7.44-7.49 (m, 2H), 7.70 (d, 1H, J = 8.3Hz), 8.03 (s, 1H), 8.17 (dd, 1H, J

= 1.8, 7.4 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 52.6, 121.2, 124.8, 126.4, 127.6, 128.3, 128.4, 129.7,

130.3, 132.4, 133.3, 133.6, 134.2, 136.0, 137.6, 148.9, 164.3.

HRMS (electrospray) Calcd. For C17H11NO4F3NaBr [M+Na]+ 451.9715, found: 451.9713

To 2-Nitrophenylmethylacrylate (208 mg, 1 mmol, 1eq) were added 2-Bromo-4-

methylbenzene diazonium salt (371 mg, 1.3 mmol, 1.3 eq), Pd(OAc)2 (3.3 mg , 0.01 mmol,

0.01 eq), and MeOH (6 mL). The reaction mixture was stirred for 18 hours at 25°C. The

mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, 20%

EtOAc-petroleum ether) gave the desired product (371 mg, 99% yield) as a yellow solid.

mp 103- 104°C

IR (KBr) ν 1526, 1718, 2923, 2952, 3031, 3066 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.24 (s, 3H), 3.76 (s, 3H), 6.61 (d, 1H, J = 7.9 Hz),

6.75 (d, 1H, J = 7.9 Hz), 7.03-7.06 (m, 1H), 7.40-7.49 (m, 3H), 8.04 (s, 1H), 8.16 (m, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 20.9, 52.5, 124.7, 124.8, 128.0, 129.2, 130.6, 131.5,

131.9, 132.1, 133.0, 133.2, 133.7, 139.5, 140.9, 149.1, 165.9.

HRMS (electrospray) Calcd. For C17 H14NO4NaBr [M+Na]+ 397.9998, found: 397.9999

To 2-Nitrophenylmethylacrylate (208 mg, 1 mmol, 1eq) were added 2-Bromo-4-

chlorobenzene diazonium salt (395 mg, 1.3 mmol, 1.3 eq), Pd(OAc)2 (2.24 mg, 0.01 mmol,

0.01 eq), and MeOH (3 mL). The reaction mixture was stirred for 18 hours at 25°C. The

mixture was concentrated in vacuo. Purification by flash chromatography (silica gel,

20%EtOAc-petroleum ether) gave the desired product (356 mg, 90% yield) as a yellow solid.

mp 91- 93°C

IR (KBr) ν 1527, 1580, 1719, 2952, 3068 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 3.75 (s, 3H), 6.68 (d, 1H, J = 8.4 Hz), 6.92-7.04 (m,

2H), 7.41-7.51 (m, 2H), 7.57 (s, 1H), 7.97 (s, 1H), 8.13-8.18 (m, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 52.6, 124.7, 125.0, 127.4, 129.4, 130.8, 131.4, 132.3,

132.7, 133.1, 133.7, 135.2, 138.1, 149.0, 165.4

HRMS (electrospray) Calcd. For C16 H11NO4NaCl Br[M+Na]+ 417.9452, found: 419.9428

To methyl 2-(2-cyanophenyl)acrylate (187 mg, 1 mmol, 1eq) were added 2-Bromo

benzene diazonium salt (352 mg, 1.3 mmol, 1.3 eq), Pd(OAc)2 (7.8 mg, 0.032 mmol, 0.032

eq), and MeOH (5 mL). The reaction mixture was stirred for 72 hours at 25°C. The mixture

was concentrated in vacuo. Purification by flash chromatography (silica gel, 30% EtOAc-

petroleum ether) gave the desired product (275 mg, 98% yield) as a yellow solid.

mp 75- 76°C

IR (KBr) ν 1631, 1714, 2225, 2955, 3009, 3065, 3408 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.85 (s, 3H), 6.63 (dd, 1H, J = 1.7, 7.9 Hz), 6.95 (dt,

1H, J = 1.1, 7.9 Hz), 7.07 (dt, 1H, J = 1.9, 7.5 Hz), 7.21 (dd, 1H, J = 1.1, 7.2 Hz), 7.39 (dt,

1H, J = 1.5, 7.7 Hz), 7.48 (dt, 1H, J = 1.5, 7.6 Hz), 7.56 (dd, 1H, J = 1.1, 7.9 Hz), 7.65 (dd,

1H, J = 1.1, 7.5 Hz), 8.21 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 52.4, 113.3, 117.1, 124.8, 126.6, 128.2, 130.2, 130.9,

131.0, 132.4, 132.6, 132.6, 134.1, 138.7, 142.5, 165.8.

HRMS (EI) Calcd. For C17 H12NO2Br Na [M+Na]+ 363.9943, found: 365.9917

To Methyl 2-o-tolylacrylate (200 mg, 1.1 mmol, 1eq) were added 2-Bromo-4-

methylbenzene diazonium salt (374 mg, 1.4 mmol, 1.3 eq), Pd(OAc)2 (2.5 mg, 0.011 mmol,

0.01eq), and MeOH (3 mL). The reaction mixture was stirred for 18 hours at 25°C. The

mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, 10%

EtOAc-petroleum ether) gave the desired product (331 mg, 96% yield) as a pale yellow oil.

IR (NaCl) ν 1598, 1622, 1714, 2953, 3021, 3060 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.22 (s, 3H), 2.25 (s, 3H), 3.83 (s, 3H), 6.65 (d, 1H, J =

8.1 Hz), 6.76 (d, 1H, J = 8.1 Hz), 7.11-7.28 (m, 4H), 7.44 (s, 1H), 8.22 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 19.3, 20.5, 52.0, 125.1, 125.7, 127.5, 129.7, 129.9,

131.7, 132.9, 132.9, 134.4, 136.3, 139.2, 140.3, 167.5

HRMS (electrospray) Calcd. For C18 H17O2NaBr [M+Na]+ 367.0304, found: 367.0310

To Methyl 2-(4,5-dimethoxy-2-nitrophenyl)acrylate (134 mg, 0.5 mmol, 1eq) were

added 2-Bromobenzene diazonium salt (176 mg, 0.65 mmol, 1.3 eq), Pd(OAc)2 (11.2 mg,

0.05 mmol, 0.01eq), and MeOH (3 mL). The reaction mixture was stirred for 18 hours at

25°C. The mixture was concentrated in vacuo. Purification by flash chromatography (silica

gel, 30% EtOAc -petroleum ether) gave the desired product (192 mg, 91% yield) as a dark

yellow solid.

mp 110-111°C

IR (KBr) ν 1520, 1573, 1714, 2835, 2956, 3004 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.60 (s, 3H), 3.74 (s, 3H), 3.91 (s, 3H), 6.36 (s, 1H),

6.74 (dd, 1H, J = 1.5, 7.5 Hz), 6.94-7.07 (m, 2H), 7.52 (dd, 1H, J =1.3, 7.9 Hz), 7.71 (s, 1H),

7.93 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 52.4, 56.1, 56.2, 107.5, 113.7, 124.0, 125.5, 127.2,

129.9, 130.5, 132.2, 133.6, 135.6, 138.5, 141.2, 148.4, 153.0, 165.7

HRMS (electrospray) Calcd. For C18 H16NO6NaBr [M+Na]+ 446.0053, found: 446.0030

To Methyl 2-(4,5-dimethoxy-2-nitrophenyl)acrylate (272 mg, 1 mmol, 1eq) were

added 2-bromo-4-methybenzene diazonium salt (433 mg, 1.5 mmol, 1.3 eq), Pd(OAc)2 (2.23

mg, 0.01 mmol, 0.01eq), and MeOH (2 mL). The reaction mixture was stirred for 18 hours at

25°C. The mixture was concentrated in vacuo. Purification by flash chromatography (silica

gel, 30% EtOAc-petroleum ether) gave the desired product (191 mg, 88% yield) as a brown

solid.

mp 128-129°C

IR (KBr) ν 1520, 1573, 1604, 1629, 1714, 2837, 2954, 3005, 3065, 3093 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.11 (s, 3H), 3.54 (s, 3H), 3.64 (s, 3H), 3.83 (s, 3H),

6.32 (s, 1H), 6.53 (d, 1H, J = 8.1 Hz), 6.68 (d, 1H, J = 8.5 Hz), 7.26 (s, 1H), 7.65 (s, 1H),

7.83 (s, 1H).

13C NMR (75MHz, CDCl3) δ (ppm) 20.4, 52.0, 55.9, 107.2, 113.5, 123.8, 125.4, 127.8,

130.0, 132.1, 132.5, 132.6, 138.1, 140.3, 141.0, 148.2, 152.8, 165.5

HRMS (electrospray) Calcd. For C19 H18NO6NaBr [M+Na]+ 458.0209, found: 460.0202

To Methyl 2-o-tolylacrylate (200 mg, 1 mmol, 1eq) were added 2-Bromobenzene

diazonium salt (374 mg, 1.4 mmol, 1.3 eq), Pd(OAc)2 (2.5 mg, 0.011 mmol, 0.01eq), and

MeOH (3mL). The reaction mixture was stirred for 18 hours at 25°C. The mixture was

concentrated in vacuo. Purification by flash chromatography (silica gel, 10% EtOAc-

petroleum ether) gave the desired product (328 mg, 99% yield) as a pale yellow oil

IR (KBr) ν 1625, 1716, 2924, 2950, 3020, 3063 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 2.13 (s, 3H), 3.82 (s, 3H), 6.67 (dd, 1H, J = 1.6, 7.6

Hz), 6.91 (dt, 1H, J = 1.3, 7.6 Hz), 6.99-7.26 (m, 6H), 7.56 (dd, 1H, J = 1.4, 8.1 Hz), 8.10 (s,

1H).

13C NMR (75MHz, CDCl3) δ (ppm) 19.6, 52.5, 125.3, 125.9, 126.7, 128.1, 129.9, 130.0,

130.1, 130.5, 132.7, 133.9, 134.6, 135.0, 136.6, 139.6, 167.8

HRMS (electrospray) Calcd. For C17 H15O2NaBr [M+Na]+ 353.0147, found: 353.0161

To the previously prepared (E)-Methyl 3-(2-bromophenyl)-2-(2-nitrophenyl) acrylate

(362 mg, 1 mmol, 1 eq) were added K2CO3 (280 mg, 2 mmol, 2 eq), Pd(OAc)2 (11.2 mg, 0.05

mmol, 0.05 eq) and DMA (6 mL). The reaction mixture was stirred for 15 hours at 110°C.

The mixture filtrated over Celite, concentrated in vacuo. Purification by flash chromatography

(silica gel, 25% EtOAc-petroleum ether) gave the desired product (484 mg, 86% yield) as

yellow solid.

mp 140°C

IR (KBr) ν 1523, 1712, 2942, 2993, 3040 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.92 (s, 3H), 7.63-7.76 (m, 3H), 7.92 (d, 1H, J = 7.9

Hz), 8.10 (d, 1H, J = 7.7 Hz), 8.37 (s, 1H), 8.54 (d, 1H, J = 8.3 Hz), 8.83 (d, 1H, J = 8.5 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 52.0, 120.6, 122.8, 124.0, 125.2, 125.9, 127.7, 128.4,

129.6, 129.8, 130.0, 130.2, 132.4, 134.0, 148.5, 167.5

HRMS (electrospray) Calcd. For C16 H11N O4 Na [M+Na]+304.0580, Found : 304.0581.

To the previously prepared ((E)-methyl 3-(2-bromo-5-(trifluoromethyl)phenyl)-2-(2-

nitrophenyl)acrylate (214 mg, 0.5 mmol, 1 eq) were added K2CO3 (138 mg, 1 mmol, 2 eq),

Pd(OAc)2 (2.24 mg, 0.01 mmol, 0.02 eq), charcoal (20mg), HPCy3BF4 (7.36 mg, 0.02 mmol,

0.04 eq), and DMA (3 mL). The reaction mixture was stirred in a sealed tube for 18 hours at

110°C. The mixture was filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 10% EtOAc-petroleum ether) then (20% EtOAc-petroleum ether)

gave the desired product (135 mg, 77% yield) as a white powder.

mp 204-205°C

IR (KBr) ν 1523, 1725, 2925, 2957, 3078 cm-1

1H NMR (300MHz, (CDCl3) δ (ppm) 3.93 (s, 3H), 7.85 (dd, 1H, J = 7.7, 8.3 Hz), 8.02 (dm,

1H, J = 8.7 Hz), 8.25-8.30 (m, 2H), 8.49 (s, 1H), 8.80 (d, 1H, J = 8.7 Hz), 8.99 (dd, 1H, J =

1.1, 8.6 Hz).

13C NMR (75MHz, ((CD3)2CO) δ (ppm) 52.3, 121.2, 124.1, 125.2, 125.5, 125.5, 126.7,

127.0, 127.1, 127.2, 128.1, 129.7, 130.2, 131.8, 133.5, 167.0

HRMS (electrospray) Calcd. For C17H10NO4F3 Na [M+Na]+ 372.0454, Found : 372.0453

To the previously prepared (E)-methyl 3-(2-bromo-5-methylphenyl)-2-(2-

nitrophenyl)acrylate (188 mg , 0.5 mmol, 1 eq) were added K2CO3 (138 mg, 1 mmol, 2 eq,),

Pd(OAc)2 (2.24 mg, 0.01 mmol, 0.02 eq), charcoal (20 mg), HPCy3BF4 (7.4 mg, 0.02 mmol,

0.04 eq), and DMA (3 mL). The reaction mixture was stirred in a sealed tube for 16 hours at

110°C. The mixture filtrated over Celite, concentrated in vacuo. And then purified with flash

chromatography (silica gel, 20% EtOAc-petroleum ether) then (3O% EtOAc-petroleum ether)

gave the desired product (140 mg, 94% yield) as yellow solid.

mp 180-181°C

IR (KBr) ν 1512, 1526, 1708, 1733, 2923, 2950 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.61 (s, 3H), 3.91 (s, 3H), 7.49 (dd, 1H, J = 1.1, 8.1

Hz), 7.62 (dd, 1H, J = 7.9, 8.3 Hz), 7.81 (d, 1H, J = 8.1 Hz), 8.07 (dd, 1H, J = 1.3, 7.7 Hz),

8.32 (s, 1H), 8.33 (s, 1H), 8.80 (dd, 1H, J = 1.0, 8.5 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 22.3, 51.9, 120.8, 122.7, 123.9, 124.2, 125.5, 127.6,

128.0, 129.7, 130.1, 130.4, 132.1, 134.0, 140.1, 148.5, 167.7

HRMS (electrospray) Calcd. For C17 H13N O4 Na [M+Na]+318.0736, Found : 318.0732

To the previously prepared (E)-Methyl 3-(2-bromo-4-isopropylphenyl)-2-(2-

nitrophenyl)acrylate (323 mg, 1 mmol, 1 eq) were added K2CO3 (276 mg, 2 mmol, 2 eq,),

Pd(OAc)2 (4.48 mg, 0.02 mmol, 0.02 eq), charcoal (45 mg), HPCy3BF4 (14.8 mg, 0.04 mmol,

0.04 eq), and DMA (6 mL). The reaction mixture was stirred in a sealed tube for 16 hours at

110°C. The mixture filtrated over Celite, concentrated in vacuo. And then purified with flash

chromatography (silica gel, 20% EtOAc-petroleum ether) then (3O% EtOAc-petroleum ether)

gave the desired product (249 mg, 77% yield) as yellow solid.

mp 155°C

IR (KBr) ν 1529, 1718, 2927, 2962, 3055 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.42 (d, 6H, J = 7.0 Hz), 3.22 (sept, 1H, J = 7.0 Hz),

3.91 (s, 3H), 7.63 (dd, 1H, J = 1.5, 8.3 Hz), 7.74 (dd, 1H, J = 7.7, 8.3 Hz), 7.94 (d, 1H, J =

8.1 Hz), 8.15 (dd, 1H, J = 1.3, 7.7 Hz), 8.42 (s, 1H), 8.47 (s, 1H), 8.97 (d, 1H, J = 8.5 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 24.0, 35.0, 52.0, 120.2, 121.0, 124.0, 124.4, 125.7,

127.7, 128.6, 130.1, 130.6, 132.5, 134.1, 148.7, 150.9, 167.7

HRMS (electrospray) Calcd. For C19H17N O4 Na [M+Na]+

346.1049, Found : 346.1047

To the previously prepared ((E)-Methyl 3-(2-bromo-4-chlorophenyl)-2-(2-

nitrophenyl)acrylate (318 mg, 0.8 mmol, 1 eq,) were added K2CO3 (207 mg, 1.6 mmol, 2 eq),

Pd(OAc)2 (8.9 mg, 0.04 mmol, 0.05 eq), charcoal (89 mg), and DMA (3 mL). The reaction

mixture was stirred in a sealed tube for 21 hours at 110°C. The mixture filtrated over Celite,

concentrated in vacuo. Purification by flash chromatography (silica gel, 20% EtOAc-

petroleum ether) gave the desired product (202 mg, 80% yield) as white powder.

mp 204-205°C

IR (KBr) ν 1531, 1615, 1709, 1730, 2924, 3098 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 3.92 (s, 3H), 7.67 (dd, 1H, J = 1.9, 8.5 Hz), 7.77 (dd,

1H, J = 7.9, 8.3 Hz), 7.93 (d, 1H, J = 8.5 Hz), 8.20 (dd, 1H, J = 1.1, 7.7 Hz), 8.38 (s, 1H),

8.59 (t, 1H, J = 1.1 Hz), 8.83 (dd, 1H, J = 1.1, 8.8 Hz).

13C NMR (75MHz, DMSO) δ (ppm) 52.0, 119.9, 123.4, 125.0, 125.4, 127.2, 128.2, 129.2,

129.5, 131.1, 131.3, 132.0, 133.2, 135.3, 147.7, 166.8

HRMS (electrospray) Calcd. For C16H10NO4Na Cl [M+Na]+ 338.0190, Found : 338.0186

To the previously prepared (E)-methyl 3-(2-bromophenyl)-2-(2-cyanophenyl)acrylate

(287 mg, 1mmol, 1eq) were added K2CO3 (276 mg, 2mmol, 2eq), Pd(OAc)2 (22.4 mg, 0.1

mmol, 0.1 eq), charcoal (200 mg), HPCY3BF4 ( 74 mg, 0.2 mmol, 0.2 eq), and DMA (3 mL).

The reaction mixture was stirred in a sealed tube for 18 hours at 110°C. The mixture was

filtered over Celite, concentrated in vacuo. Purification by flash chromatography (Silica gel,

20% EtOAc-petroleum ether) gave the desired product (177 mg, 70% yield) as a white solid.

mp 129-130°C

IR (KBr) ν 1726, 2221, 2923, 2953, 3003, 3039 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 4.1 (s, 3H), 7.67-7.80 (m, 3H), 7.93 (d, 1H, J = 7.8

Hz), 8.02 (d, 1H, J = 7.4 Hz), 8.15 (s, 1H), 8.61 (d, 1H, J = 8.3 Hz), 8.92 (d, 1H, J = 8.5 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 52.7, 109.8, 118.3, 122.7, 126.4, 127.7, 127.8, 128.2,

128.3, 129.2, 129.6, 130.2, 130.5, 131.3, 132.1, 134.9, 168.9

HRMS (electrospray) Calcd. For C17H11NO2Na [M+Na]+ 284.0681, Found : 284.0677

To the previously prepared (E)-methyl 3-(2-bromo-4-methylphenyl)-2-o-tolylacrylate

(424 mg, 1.2 mmol, 1 eq) were added K2CO3 (370 mg, 2.4 mmol, 2 eq,), Pd(OAc)2 (9.0 mg,

0.036 mmol, 0.03 eq), charcoal (90mg), HPCy3BF4 (74 mg, 0.048 mmol, 0.04 eq), and DMA

(3 mL). The reaction mixture was stirred in a sealed tube for 16 hours at 110°C. The mixture

filtrated over Celite, concentrated in vacuo. And then purified with flash chromatography

(silica gel, 5% EtOAc-petroleum ether) gave the desired product (264 mg, 70% yield) as a

white solid.

mp 116-117°C

IR (KBr) ν 1710, 2948, 2970, 3018, 3058 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.63 (s, 6H), 4.00 (s, 3H), 7.42-7.48 (m, 2H), 7.57 (dd,

1H, J = 7.1, 8.1 Hz), 7.78 (d, 1H, J = 8.1 Hz), 7.90 (s, 1H), 8.46 (s, 1H), 8.62 (d, 1H, J = 8.3

Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 22.1, 22.3, 52.6, 121.1, 122.7, 126.6, 127.5, 127.6,

128.6, 128.7, 128.8, 129.0, 130.2, 131.1, 131.6, 134.5, 138.1, 171.9

HRMS (electrospray) Calcd. For C18H16 O2 Na [M+Na]+

287.1042, Found : 287.1051.

To the previously prepared (E)-methyl 3-(2-bromophenyl)-2-o-tolylacrylate (396 mg, 1.2

mmol, 1 eq) were added K2CO3 (370 mg, 2.4 mmol, 2 eq,), Pd(OAc)2 (5.4 mg, 0.024 mmol,

0.02 eq), charcoal (90mg), HPCy3BF4 (54 mg, 0.048 mmol, 0.04 eq), and DMA (3 mL). The

reaction mixture was stirred in a sealed tube for 16 hours at 110°C. The mixture filtrated over

Celite, concentrated in vacuo. And then purified with flash chromatography (silica gel, 5%

EtOAc-petroleum ether then 10% EtOAc-petroleum ether) gave the desired product (180 mg,

60% yield) as a white solid.

mp 70°C

IR (KBr) ν 1712, 2942, 2968, 3058 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 2.66 (s, 3H), 4.02 (s, 3H), 7.48 (dm, 1H, J = 6.5 Hz),

7.56-7.74 (m, 3H), 7.89 (dd, 1H, J = 1.6, 7.6 Hz), 7.94 (s, 1H), 8.65 (app t, 2H, J = 8.1 Hz).

13C NMR (75MHz, CDCl3) δ (ppm) 22.0, 52.6, 121.1, 122.9, 126.8, 127.0, 127.3, 128.1,

128.9, 129.0, 129.6, 129.7, 130.3, 131.4, 131.6, 171.8

HRMS (electrospray) Calcd. For C17H14 O2 Na [M+Na]+

273.0886, Found : 273.0895.

To the previously prepared (E)-methyl 3-(2-bromo-4-methylphenyl)-2-(4,5-

dimethoxy-2-nitrophenyl)acrylate (190 mg, 0.43 mmol, 1 eq) were added K2CO3 (180 mg, 1.3

mmol, 3 eq,), Pd(OAc)2 (15.0 mg, 0.065 mmol, 0.15 eq), charcoal (150 mg), HPCy3BF4 (50

mg, 0.13 mmol, 0.3 eq), and DMA (3 mL). The reaction mixture was stirred in a sealed tube

for 16 hours at 110°C. The mixture filtrated over Celite, concentrated in vacuo. And then

purified with flash chromatography (silica gel, 20% EtOAc-petroleum ether) gave the desired

product (22 mg, 33% yield) as a yellow powder .

mp 173-175°C

IR (KBr) ν 1514, 1526, 1705, 2955, 3091 cm-1

1H NMR (200MHz, CDCl3) δ (ppm) 2.63 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H), 4.09 (s, 3H),

7.53 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 7.9 Hz), 7.94 (s, 1H), 8.24 (s, 1H) 9.42 (s, 1H)

13C NMR (75MHz, CDCl3) δ (ppm) 22.7, 52.0, 56.8, 60.3, 110.6, 117.5, 124.1, 126.6, 127.8,

128.9, 129.7, 129.8, 130.0, 133.3, 139.9, 144.1, 150.2, 151.1, 167.7

HRMS (electrospray) Calcd. For C19H17 NO6 Na [M+Na]+

378.0948, Found : 378.0955.

To the previously prepared Methyl 8- nitrophenanthrene-9-carboxylate (7.6 mmol, 214

mg, 1 eq) were added Pd(OAc)2 (0.1 eq, 0.07 mmol, 15.6 mg), Charcoal (90 mg), and MeOH

(4 mL). The reaction mixture was stirred under H2 for 15 hours at 40°C. The mixture filtrated

over Celite, concentrated in vacuo. Purification by flash chromatography (silica gel, 15 %

EtOAc- CH2Cl2) gave the desired product (1482 mg, 89 % yield) as yellow powder.

mp 230- 231°C

IR (KBr) ν = 1628, 1707, 2929, 3031, 3069, 3192 cm-1

1H NMR (300MHz, DMSO) δ (ppm) 7.09 (d, 1H, J = 7.1 Hz), 7.63 (dd, 1H, J = 7.4, 8.3

Hz), 7.76 (app t, 1H, J = 8.1 Hz), 7.87 (app t, 1H, J = 7.1 Hz), 8.25 (d, 1H, J = 8.3 Hz.), 8.34

(d, 1H, J = 8.0 Hz), 8.52 (s, 1H), 8.80 (d, 1H, J = 8.1 Hz)

13C NMR (75MHz DMSO) δ (ppm) 106.6, 115.5, 122.0, 123.7, 125.4, 126.4, 126.5, 127.2,

129.3, 129.4, 131.4, 131.9, 133.1, 138.4, 168.3

HRMS (EI) Calcd. For C15H9NO Na [M+Na]+ 242.0576, Found : 242.0575

To the previously prepared Methyl 8-nitro-2-(trifluoromethyl)phenanthrene-9-

carboxylate (101 mg, 0.3 mmol, 1 eq) were added Pd(OAc)2 (0.7 mg, 0.003 mmol, 0.01 eq),

Charcoal (7 mg), and MeOH (3 mL). The reaction mixture was stirred under H2 for 18 hours

at 40°C. The mixture filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 5% EtOAc-CH2Cl2) gave the desired product (22 mg, 84% yield)

as yellow powder.

mp 234- 235°C

IR (KBr) ν 1624, 1701, 2924, 3025, 3072, 3172 cm-1

1H NMR (200MHz, THF-d8) δ (ppm) 7.07 (d, 1H, J = 7.3 Hz), 7.63 (app t, 1H, J = 7.3

Hz), 8.03 (dd, 1H, J = 1.8, 8.5 Hz), 8.21 (d, 1H, J = 8.4 Hz), 8.54 (s, 1H), 8.63 (s, 1H), 8.92

(d, 1H, J = 8.7 Hz), 9.89 (br.s, 1H).

13C NMR (75MHz THF-d8) δ (ppm) 107.6, 116.0, 124.6, 124.9, 125.5, 126.4, 126.8, 127.3,

128.4, 129.6, 129.6, 130.4, 133.9, 134.0, 140.1, 168.4

HRMS (electrospray) Calcd. For C16H8NOF3 Na [M+Na]+ 288.0630, Found : 288.0593

To the previously prepared Methyl Methyl 3-methyl-8-nitrophenanthrene-9-

carboxylate (148 mg, 0.5 mmol, 1 eq) were added Pd(OAc)2 (1.2 mg, 0.005 mmol, 0.01 eq),

Charcoal (12 mg), and MeOH (3 mL). The reaction mixture was stirred under H2 for 18 hours

at 40°C. The mixture filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 30% EtOAc-petroleum ether) gave the desired product (86 mg,

74% yield) as yellow powder.

mp 255- 256°C

IR (KBr) ν 1606, 1629, 1688, 2921, 3020, 3093, 3184 cm-1

1H NMR (300MHz, DMSO) δ (ppm) 2.60 (s, 3H), 7.05 (d, 1H, J = 7.1 Hz), 7.54-7.62 (m,

2H), 8.18 (d, 2H, J = 8.5 Hz), 8.44 (s, 1H), 8.56 (s, 1H), 10.82 (s, 1H).

13C NMR (75MHz DMSO) δ (ppm) 21.6, 106.5, 115.4, 122.3, 123.2, 124.5, 126.1, 126.3,

128.9, 129.1, 131.0, 131.6, 138.5, 139.4, 168.5

HRMS (electrospray) Calcd. For C16H11NONa [M+Na]+ 256.0732, Found : 256.0738

To the previously prepared Methyl Methyl 3-chloro-8-nitrophenanthrene-9-

carboxylate (126 mg, 0.4 mmol, 1 eq) were added Pd(OAc)2 (4.5 mg, 0.002 mmol, 0.005 eq),

Charcoal (45 mg), and MeOH (6 mL). The reaction mixture was stirred under H2 for 18 hours

at 40°C. The mixture filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 10% EtOAc-CH2Cl2) gave the desired product (90 mg, 89%

yield) as yellow powder.

mp 301°C (decomposition)

IR (KBr) ν 1603, 1630, 1717, 3093, 3186 cm-1

1H NMR (200MHz, DMSO) δ (ppm) 7.11 (d, 1H, J = 7.2 Hz), 7.64 (dd, 1H, J = 7.3, 8.4

Hz), 7.81 (dd, 1H, J = 2.0, 8.5 Hz), 8.32 (d, 1H, J = 8.4 Hz), 8.38 (d, 1H, J = 8.7 Hz), 8.56 (s,

1H), 8.91 (d, 1H, J = 2.0 Hz), 10.90 (br.s, 1H)

13C NMR (75MHz DMSO) δ (ppm) 107.3, 115.8, 122.4, 123.3, 125.7, 125.9, 125.9, 127.6,

129.7, 131.7, 132.7, 133.7, 134.4, 138.6, 168.2

HRMS (electrospray) Calcd. For C15H8NONaCl [M+Na]+ 276.0186, Found : 276.0180.

To the previously prepared Methyl 5,6-dimethoxy-8-nitrophenanthrene-9-carboxylate

(24 mg, 0.07 mmol, 1 eq) were added Pd(OAc)2 (0.5 mg, 0.002 mmol, 0.03 eq), Charcoal (5

mg), and MeOH (3 mL). The reaction mixture was stirred under H2 for 18 hours at 40°C. The

mixture filtrated over Celite, concentrated in vacuo. Purification by flash chromatography

(silica gel, 40% EtOAc-petroleum ether then 10% EtOAc-CH2Cl2) gave the desired product

(15 mg, 79% yield) as yellow powder.

mp 225- 226°C

IR (KBr) ν 1633, 1699, 1717, 3180 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 4.02 (s, 3H), 4.05 (s, 3H), 6.96 (s, 1H), 7.67-7.73 (m,

1H), 7.79-7.85 (m, 1H), 8.13 (d, 1H, J = 7.1 Hz), 8.33 (s, 1H), 8.39 (br.s, 1H), 9.40 (d, 1H, J

= 8.7 Hz).

13C NMR (75MHz DMSO) δ (ppm) 57.1, 60.0, 97.1, 120.5, 124.8, 125.6, 127.0, 127.3,

129.4, 130.8, 132.1, 133.9, 135.1, 140.5, 153.7, 168.9

HRMS (electrospray) Calcd. For C17H13NO3Na [M+Na]+ 302.0787, Found : 302.0800

To the previously prepared Methyl Methyl 3-methyl-8-nitrophenanthrene-9-

carboxylate (60 mg, 0.18 mmol, 1 eq) were added Pd(OAc)2 (0.6 mg, 0.0027 mmol, 0.015

eq), Charcoal (6 mg), and MeOH (3 mL). The reaction mixture was stirred under H2 for 18

hours at 40°C. The mixture filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 40% EtOAc-petroleum ether then 10% EtOAc) gave the desired

product (38 mg, 71% yield) as yellow powder.

mp 219- 221°C

IR (KBr) ν 1635, 1701, 2939, 3061, 3088, 3191 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 2.67 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H), 6.94 (s, 1H),

7.53 (dm, 1H, J = 8.1 Hz), 8.02 (d, 1H, J = 8.3 Hz), 8.18 (br s, 1H), 8.29 (s, 1H), 9.20 (s, 1H).

13C NMR (75MHz DMSO) δ (ppm) 22.1, 57.0, 59.8, 96.9, 116.4, 120.1, 124.7, 126.6, 128.7,

130.9, 131.7, 131.8, 134.9, 139.1, 140.5, 153.4, 168.8

HRMS (electrospray) Calcd. For C18H15NO3Na [M+Na]+ 316.0944, Found : 316.0949

To the previously prepared Methyl Methyl 3-methyl-8-nitrophenanthrene-9-

carboxylate (162 mg, 0.5 mmol, 1 eq) were added Pd(OAc)2 (1.2 mg, 0.005 mmol, 0.005 eq),

Charcoal (12 mg), and MeOH (3 mL). The reaction mixture was stirred under H2 for 18 hours

at 40°C. The mixture filtrated over Celite, concentrated in vacuo. Purification by flash

chromatography (silica gel, 20% EtOAc-petroleum ether, then 30% EtOAc-petroleum ether)

gave the desired product (92 mg, 70% yield) as yellow powder.

mp 180- 181°C

IR (KBr) ν 1608, 1631, 1707, 2954, 3023, 3071, 3173 cm-1

1H NMR (300MHz, CDCl3) δ (ppm) 1.43 (d, 6H, J = 7.0 Hz), 3.22 (sept, 1H, J = 7.0 Hz),

7.11 (d, 1H, J = 7.3 Hz), 7.56-7.61 (m, 2H), 8.07 (d, 1H, J = 8.5 Hz), 8.12 (d, 1H, J = 8.3 Hz),

8.42 (s, 1H ), 8.45 (s, 1H), 9.28 (s, 1H).

13C NMR (75MHz CDCl3) δ (ppm) 24.0, 34.7, 106.9, 115.9, 120.5, 122.9, 124.3, 126.4,

126.9, 127.3, 128.6, 131.7, 131.9, 132.5, 137.5, 150.4, 170.2

HRMS (electrospray) Calcd. For C18H15NONa [M+Na]+ 284.1045, Found : 284.1046.