New Reagents for Fluoroalkylchalcogenations : Applications to Hot Chemistry Ermal Ismalaj

Home , Benzeneselenol, Difluorocarbene, Methyl fluoroacetate, Trifluoromethyl group

New Reagents For Fluoroalkylchalcogenations : applications To Hot Chemistry Ermal Ismalaj

To cite this version:

Ermal Ismalaj. New Reagents For Fluoroalkylchalcogenations : applications To Hot Chemistry. Or- ganic chemistry. Université de Lyon, 2017. English. NNT : 2017LYSE1021. tel-01522960

HAL Id: tel-01522960 https://tel.archives-ouvertes.fr/tel-01522960 Submitted on 15 May 2017

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés.

N°d’ordre NNT : 2017LYSE1021

THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de l’Université Claude Bernard Lyon 1

Ecole Doctorale ED 206 (Ecole Doctorale de Chimie)

Spécialité de doctorat : Chimie Discipline : Chimie Organique

Soutenue publiquement 10/02/2017, par : (Ermal Ismalaj)

New Reagents For Fluoroalkylchalcogenations. Applications To Hot Chemistry

Devant le jury composé de :

Popowycz Florence Professeur INSA Lyon Présidente Gouverneur Véronique Professeur University of Oxford Rapporteur Magnier Emmanuel, DR CNRS Université de Versailles-Saint-Quentin Rapporteur Zimmer Luc, Professeur, Université Claude Bernard Lyon-1, Examinateur Billard Thierry DR CNRS Université Lyon 1 Directeur de thèse Le Bars Didier, MCU-PH, Universite Lyon 1. Membre invite

UNIVERSITE CLAUDE BERNARD - LYON 1

Président de l’Université M. le Professeur Frédéric FLEURY

Président du Conseil Académique M. le Professeur Hamda BEN HADID

Vice-président du Conseil d’Administration M. le Professeur Didier REVEL Vice-président du Conseil Formation et Vie Universitaire M. le Professeur Philippe CHEVALIER Vice-président de la Commission Recherche M. Fabrice VALLÉE Directeur Général des Services M. Alain HELLEU

COMPOSANTES SANTE

Faculté de Médecine Lyon Est – Claude Bernard Directeur : M. le Professeur J. ETIENNE Faculté de Médecine et de Maïeutique Lyon Sud – Charles Directeur : Mme la Professeure C. BURILLON Mérieux Directeur : M. le Professeur D. BOURGEOIS Faculté d’Odontologie Directeur : Mme la Professeure C. VINCIGUERRA Institut des Sciences Pharmaceutiques et Biologiques Directeur : M. le Professeur Y. MATILLON Institut des Sciences et Techniques de la Réadaptation Directeur : Mme la Professeure A-M. SCHOTT Département de formation et Centre de Recherche en Biologie Humaine COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE

Faculté des Sciences et Technologies Directeur : M. F. DE MARCHI Département Biologie Directeur : M. le Professeur F. THEVENARD Département Chimie Biochimie Directeur : Mme C. FELIX Département GEP Directeur : M. Hassan HAMMOURI Département Informatique Directeur : M. le Professeur S. AKKOUCHE Département Mathématiques Directeur : M. le Professeur G. TOMANOV Département Mécanique Directeur : M. le Professeur H. BEN HADID Département Physique Directeur : M. le Professeur J-C PLENET UFR Sciences et Techniques des Activités Physiques et Sportives Directeur : M. Y.VANPOULLE Observatoire des Sciences de l’Univers de Lyon Directeur : M. B. GUIDERDONI Polytech Lyon Directeur : M. le Professeur E.PERRIN Ecole Supérieure de Chimie Physique Electronique Directeur : M. G. PIGNAULT Institut Universitaire de Technologie de Lyon 1 Directeur : M. le Professeur C. VITON Ecole Supérieure du Professorat et de l’Education Directeur : M. le Professeur A. MOUGNIOTTE Institut de Science Financière et d'Assurances Directeur : M. N. LEBOISNE

Abbreviations GENERAL INTRODUCTION ...... 1 CHAPTER I: Synthesis of SCF2R derivatives and their application in electrophilic reactions.

I. BIBLIOGRAPHY SCF3 AND SCF2R ...... 10

I.1 INDIRECT INSERTION OF SCF3 GROUP: ...... 10 I.1.1 Radical trifluoromethylation of thiols, thiolates and disulfides...... 10 I.1.2 Electrophilic trifluoromethylation of thiols and thiolates...... 12 I.1.3 Nucleophilic trifluoromethylation of thiols, thiolates and disulfides...... 13

I.2 DIRECT INSERTION OF SCF3 GROUP ...... 15 I.2.1 Radical trifluoromethylthiolation reactions ...... 15 I.2.1.1 Trifluoromethanethiol and trifluoromethanesulfenyl chloride ...... 15 I.2.1.2 Trifluoromethylthiosilver (I) ...... 16 I.2.1.3 N- and O- trifluoromethylthiolating reagents ...... 18 I.2.2 Nucleophilic trifluoromethylthiolation reactions ...... 19 I.2.2.1 Difluorothiophosgene ...... 19 I.2.2.2 Mercury (II) trifluoromethylthiolate ...... 19 I.2.2.3 Trifluoromethylthiosilver (I) ...... 20 I.2.2.4 Trifluoromethylthiocopper (I) ...... 23 I.2.2.5 Trifluoromethylthio ammonium/cesium ...... 25

I.2.2.6 S8 and ¯CF3 anion ...... 27 I.2.2.7 O-Octadecyl-S-trifluorothiolcarbonate ...... 28 I.2.2.8 Trifluoromethanesulfenamides used in nucleophilic reaction ...... 29 I.2.3 Electrophilic trifluoromethylthiolation reactions ...... 30 I.2.3.1 Trifluoromethanesulfenyl chloride and bis-trifluoromethyl disulfide ...... 30 I.2.3.2 Trifluoromethanesulfenamides ...... 31 I.2.3.3 N-Trifluoromethylthiophtalimide and N-trifluoromethylthiosuccinimide ...... 34 I.2.3.4 Trifluoromethylsulfenate reagents ...... 36 I.2.3.5 N-Trifluoromethylthiosaccarin ...... 37 I.2.3.6 Trifluoromethanesulfenyl hypervalent iodonium ylide ...... 39 I.2.3.7 Trifluoromethylthiosilver (I) as an electrophilic reagent ...... 39

I.3 S-CF2H AND S-CF2FG BOND FORMATION; INDIRECT APPROACH ...... 41 I.3.1 Difluoromethylation with difluorocarbene sources ...... 41

I.3.1.1 ClCF2H as a difluorocarbene source ...... 41

I.3.1.2 CF2Br2 and ClCF2Br as difluorocarbene sources ...... 42 I.3.1.3 SCDA, PDFA and TFDA as difluorocarbene sources ...... 43

I.3.1.4 Diethyl bromodifluoromethylphosphonate and Difluoromethyltri(n-butyl)ammonium chloride ...... 44

I.3.1.5 HCF3, TMSCF2Br and HCF2OTf as difluorocarbene sources ...... 44 I.3.1.6 N-Tosyl-S-difluoromethyl-S-phenylsulfoximine as a difluorocarbene source ...... 45 I.3.2 Radical Difluoromethylation ...... 45

I.3.2.1 DFMS, ICF2COOEt; new reagents for radical difluoromethylation ...... 46 I.3.3 Nucleophilic difluoromethylation of disulfides ...... 46 I.3.3.1 Difluoromethyl trimethylsilane, difluoromethyl phenyl sulfone and α- fluorodiaroylmethanes ...... 46

I.3.3.2 (NHC)Ag(CF2H) in nucleophilic difluoromethylations ...... 47 I.3.4 Electrophilic difluoromethylation of thiols and thiolates ...... 48 I.3.4.1 Rupert-Prakash reagent and a sulfoximine derivative used in electrophilic difluoromethylation ...... 48

I.3.4.2 Hypervalent iodine(III)-CF2SO2Ph reagent ...... 49

I.3.5 C-S-CF2H(FG) in situ bonds formation ...... 49 I.3.5.1 Copper thiocyanide and N-thiocyanatosuccinimide ...... 49

I.4 C-SCF2H AND C-SCF2FG BOND FORMATION; DIRECT APPROACH ...... 51 I.4.1 Radical difluoromethylthiolation reactions ...... 51 I.4.1.1 N-difluoromethylthiophtalimide ...... 51 I.4.2 Nucleophilic difluoromethylthiolation reactions ...... 52

I.4.2.1 (NHC)Ag(SCF2H) complex in difluoromethylthiolation ...... 52 I.4.3 Electrophilic difluoromethylthiolation reactions ...... 52 I.4.3.1 N- difluoromethylthiophtalimide ...... 53 I.4.3.2 Difluoromethanesulfenyl hypervalent iodonium ylides reagents ...... 53

I.4.3.3 MesNHSCF2PO(OEt)2 reagent ...... 55

II. RESULTS AND DISCUSSION- C-SCF2FG BOND FORMATION ...... 56

II.1 SYNTHESES OF NOVEL SULFENAMIDES BEARING A SCF2FG GROUP ...... 56 II.1.1 State of the art: Syntheses of sulfenamides ...... 56

II.1.2 Syntheses of (PhSO2)CF2TMS ...... 57 II.1.3 Syntheses of sulfenamides ...... 59 II.1.3.1 N-methylation of sulfenamides ...... 63 II.2 ELECTROPHILIC (PHENYLSULFONYL)DIFLUOROMETHYLTHIOLATION USING A SHELF-

STABLE REAGENT ...... 64 II.2.1.1 State of the art: interest of phenylsulfonyl part...... 64

II.2.1.2 SEAr reactions using (phenylsulfonyl)difluoromethanesulfenamide ...... 65 II.2.1.3 Electrophilic addition reactions on alkenes and alkynes ...... 68

II.2.1.4 Reductive desulfonylation: Access to SCF2H compounds ...... 71

II.2.1.5 Reductive desulfonylation: Access to SCF2D compounds ...... 73 II.2.1.6 Post-functionalization of phenylsulfonyl moiety ...... 74 II.3 (METHOXYCARBONYL)DIFLUOROMETHANESULFENAMIDE: A NEW SHELF-STABLE

REAGENT ...... 78

II.3.1.1 SEAr using compound 1d ...... 78 II.3.1.2 Acid activation of α-ketones ...... 80 II.3.1.3 Post-functionalization reactions ...... 82

III.CONCLUSIONS ...... 90

IV.REFERENCES: ...... 91

CHAPTER II: Synthesis of benzyl fluoroalkyl selenide reagents: Application to SEAr reactions

I. BIBLIOGRAPHY SECF3 AND SECF2R ...... 99

I.1 INTRODUCTION OF CF3 GROUP INTO SELENIUM-CONTAINING DERIVATIVES ...... 100 I.1.1 Radical trifluoromethylation of Se-centers ...... 100 I.1.1.1 Trifluoromethaneselenosulfonates and sodium trifluoromethanesulfinate ...... 100 I.1.1.2 Trifluoroiodomethane ...... 101 I.1.2 Nucleophilic trifluoromethylation of Se-centers ...... 102 I.1.2.1 Trifluoromethyl trimethylsilane ...... 102 I.1.2.2 Trifluoromethane and hemiaminals of fluoral ...... 103 I.1.2.3 Diethyl trifluoromethylphosphonate ...... 104

I.2 DIRECT INSERTION OF SECF3 GROUP ...... 104 I.2.1 Nucleophilic trifluoromethylselenolation reactions ...... 105 I.2.1.1 Trifluoromethyselenocopper ...... 105 I.2.1.2 Tetramethyl ammonium trifluoromethylselenate (0) ...... 108 I.2.2 Radical trifluoromethylselenolation reactions ...... 109 I.2.3 Electrophilic trifluoromethylselenolation reactions ...... 110 I.2.3.1 Trifluoromethaneselenyl chloride ...... 110

I.3 SE-CF2R BOND FORMATION; INDIRECT APPROACH ...... 112

I.3.1 Se-CF2R bond formation through a radical pathway ...... 112

I.3.1.1 HCF2Cl as difluorocarbene source ...... 112 I.3.1.2 Dibromodifluoromethane ...... 112 I.3.1.3 Sodium chlorodifluoroacetate ...... 113 I.3.1.4 Aryl difluoromethyl chlorides used as radical sources ...... 113

I.3.1.5 RFI used as perfluorinating reagent in radical perfluoroalkylations ...... 114

I.3.2 Se-CF2R bond formation through a nucleophilic pathway ...... 114 I.3.2.1 Hemiaminals and α-Difluorodiaroylmethanes ...... 114 I.3.2.2 Metal-catalyzed perfluoroalkylations ...... 115

II. RESULTS AND DISCUSSION: SECF2R INSERTION ...... 116 II.1 SYNTHESIS OF BENZYL FLUOROALKYL SELENIDES ...... 116

II.1.1 State of the art: Synthesis of the CF3SeCl ...... 116 II.1.2 Synthesis of benzyl fluoroalkyl selenides ...... 117

II.1.2.1 CF3SeCl: in situ preparation of the reactive species ...... 121

II.1.2.2 Benzyltrifluoromethyl selenide used as a CF3SeCl source in SEAr reactions ...... 122 II.1.2.3 Fluoroalkylselenolation of arenes ...... 124 II.1.3 Post-functionalization reactions ...... 127 III. CONCLUSIONS ...... 128

IV.REFERENCES ...... 129

CHAPTER III: Trifluoromethylchalcogens; Late-stage [18F]F¯ radiolabeling.

I. BIBLIOGRAPHY ...... 132

I.1 INTRODUCTION TO POSITRON EMISSION TOMOGRAPHY PRINCIPLES, NON-METALLIC

RADIONUCLIDES AND APPLICATIONS ...... 132 18 18 18 I.2 SYNTHESES OF SCF2 F, OCF2 F AND OCHF F COMPOUNDS BY NUCLEOPHILIC SUBSTITUTION REACTIONS: STATE OF ART ...... 134 18 I.2.1 [ F]-labeling of aryl-OCF2Br and aryl-OCHFBr compounds ...... 135 18 I.2.2 [ F]-labeling of aryl-SCF2Br compounds ...... 135

II. RESULTS AND DISCUSSION ...... 137 18 II.1 F-LABELING OF ARYL-SCF2FG SUBSTRATES ...... 137 18 II.2 F-LABELING OF ARYL-SECF2BR SUBSTRATES ...... 138

III. CONCLUSIONS ...... 140

IV.REFERENCES: ...... 141

Experimental Part

I. GENERALITIES ...... 143

I.1 ANALYTIC TECHNIQUES ...... 143

I.2 WORKING PROCEDURES AND CONDITIONS ...... 144

II. SYNTHESES AND CHARACTERIZATION OF THE PRODUCTS ...... 145

II.1 SYNTHESIS AND CHARACTERIZATION OF REAGENT 1A AND THE PRECURSORS INVOLVED

IN THE PREPARATION ...... 145 II.1.1 (Benzenesulfonyl)difluoromethylthiolation of aromatic and heteroaromatic compounds ...... 147 II.1.1.1 General synthetic procedures ...... 147 II.1.2 Addition of (Benzenesulfonyl)difluoromethylthio moiety to alkenes and alkynes ... 153 II.1.2.1 General synthetic procedures ...... 153

II.1.3 Phenylsulfonyl reduction and access to SCF2H ...... 159 II.1.4 Post-functionalization of the phenylsulfonyl moiety ...... 162

II.2 SYNTHESIS AND CHARACTERIZATION OF REAGENT 1D ...... 164

II.2.1 SEAr reactions using reagent 1d ...... 164 II.2.2 Acid activation of α-ketones ...... 168

II.2.3 Post-functionalization of the SCF2CO2Me motif ...... 170 II.2.3.1 Reduction od SCF2CO2Me to alcohol ...... 170 II.2.3.2 Aminolysis reactions ...... 170 II.2.3.3 Saponification reactions ...... 171 II.2.3.4 Decarboxylative bromination reaction ...... 173 II.2.3.5 Oxidative decarboxylation reactions ...... 173 II.3 SYNTHESIS AND CHARACTERIZATION OF PRE-REAGENTS 2A-G ...... 175 II.3.1 Fluoroalkylselenolationation reactions ...... 179

REFERENCES: ...... 191

11 Abbreviations

Å : Angström

πR : Hansch parameter χ : Pauling’s scale Ar : aryl Ac : acetyl binap : (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BuLi : butyl lithium Boc : tert-butoxucarboxyle bpy : 2-2′ bipyridine Bu : butyl Ci : Curie CN : cyanide CT : computerized imaging d : doublet DABCO : 1,4-Diazabicyclo[2.2.2]octane DAST : Diethylaminosulfur trifluoride DIEA : N,N-Diisopropylethylamine DFMS : zinc difluoromethanesulfinate DMA : dimethylacetamide DMF :dimethylformamide DMSO : dimethylsulfoxide dppf : 1,1′-Ferrocenediyl-bis(diphenylphosphine), dppf dtbpy : 4,4′-di-tert-butyl-2,2′bipyridyl Et : ethyl FDA : Food and Drug Administration [18F]FDG : [18F]fluodeoxyglucose g : gram h : hour het : heterocycles HMPA : hexamethylphosphoramide HPLC : high-performance liquid chromatography Hz : hertz i-Pr : iso-propyl KHMDS : Potassium bis(trimethylsilyl)amide Abbreviations

LDA : Lithium diisopropylamide IUPAC : International union of pure and applied chemistry Liq. : liquid M : Molarity m :multiplet Me : methyl min : minutes mL : millilitres mol : mole Morph : morpholine MRI : magnetic resonance imaging NBS : N-Bromosuccinimide NSI : N-Iodosuccinimide NMR : nuclear magnetic resonance OLED : organic light-emitting diode OTf : triflate PDFA : difluoromethylene phosphobetaine PET : positron emission tomography Ph : phenyl Phen : 1,10-phenantroline pKa : logarithm of the acid dissociation constant ppm : parts per million pyr : pyridine q: quadruplet RCY: radiochemical yield r. t : room temperature SDS : sodium dodecyl sulphate SPECT : single photon emission computed tomography s : singlet SCDA : Sodium chlorodifluoroacetate

SEAr : electrophilic aromatic substitution

SNAr : nucleophilic aromatic substitution S-Phos : 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl t : triplet Abbreviations

T : temperature TASF : Tris(dimethylamino)sulfonium difluorotrimethylsilicate TBAT : Tetrabutylammonium difluorotriphenylsilicate TBHP : tert-butylhydroperoxide TCCA : Trichloroisocyanuric acid TDA : 4,4'-Thiodianiline TDAE : Tetrakis(dimethylamino)ethylene TDFA : trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate THF : Tetrahydrofuran TfOH : triflic acid TMG : Tetramethylguanidine TMS : Trimethylsilyl US : ultrasound UV : ultraviolet

General Introduction

Fluorine is the 13th most abundant element of earth’s crust and ranks 24th in universal abundance. Despite its high presence, only a dozen of fluorine-containing natural compounds are known deriving from a few plants and bacteria.[1] Elemental fluorine was first isolated by Henry Moissan (Noble Prize in 1906), and Ferdinand Swarts reported the first synthesis of an organofluorine compound, methyl fluoroacetate. Since then, the interest towards fluorine increased due to the fascinating intrinsic properties that owes. The presence of fluorine in organic compounds highly modifies the electronic properties of the molecule, being the most electronegative element (χ = 4 in Pauling’s scale)[2], and on the other hand does not affect too much the steric properties considering its small size (Van Der Waals radii = 1.47 Å).[2] Its presence, also increases the metabolic stability of the molecules considering that the C-F bond is very strong (bond dissociation energy is 105 kj mol-1).[2] Nowadays fluorinated compounds find several applications in different fields of chemistry as electro-materials, coatings (Teflon®), textiles (Gore-tex®), agrochemicals and pharmaceuticals.[3] Although the presence fluorinated molecules at the early beginnings was mostly limited to agrochemicals, during recent years the presence of fluorine in pharmaceuticals increased and approximately 20-25 % of pharmaceuticals contain fluorine.[3c]

In 1954 Fried and Sabo[4] reported the first introduction of fluorine atom into a pharmaceutical compound (figure 1), fludrocortisone, demonstrating that the presence of fluorine improved the anti-inflammatory activity.

OH O

HO OH

F O Fludrocortisone Figure 1 First fluorinated pharamaceutical to be developed

The presence of fluorine and fluorinated moieties has a key role in determining ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of the small molecules.[5] By increasing the lipophilicity of the molecules they could bring drastic changes exploited in agrochemicals and pharmaceuticals. Furthermore, the high electronegative character of fluorine

1 General Introduction has a strong effect on the acidity or basicity of functional groups adjacent to it, thus modifying the pKa of the molecules, thus the bioavailability of the drugs. [6] According to the US sales in 2015, four of the first ten most sold drugs contain fluorine or a trifluoromethyl group (figure 2). Fluticasone proprionate sold under the name of Advair Diskus is the second most prescribed drug in the US in 2015.

F O S F F HO OCOC2H5 F N N O F S O H N 2 O F Advair Diskus® (Fluticasone ® Crestor (Rosuvastatin) propionate + salmeterol) NSAID drug anti-asmathic O F F NH F F N N O N O N O N P O O NH O NH F 2 F O OH F O Januvia® (Sitagliptine) Sovaldi® (Sofosbuvir) antidiabetic drug anti-HCV Figure 2 Structures of fluorine containing market leading pharmaceuticals

In literature is reported that the association of fluorine with a heteroatom increases the Hansch – Leo[7] parameter of the compounds (table 1), thus leading to the expected modulations of these scaffolds.1

1 http://www.medscape.com/viewarticle/849457

2 General Introduction

Table 1 Lipophilicity Increments π as assessed for momosubstituted benzenes C6H5-X

π Substituent X π Substituent X R R 0.14 OCH -0.02 F 3 0.71 OCF 1.04 Cl 3

-0.27 SCH3 0.61 NO2

0.56 SCF3 1.44 CH3

0.88 SO2CH3 -1.63 CF3 -0.67 SO CF 0.55 OH 2 3

In recent years, there has been a growing interest in exploring various fluorinated groups, as

OCF3 and SCF3 as well as SeCF3. As shown in Table 1 and Table 2, these functional groups have similar electronic properties to CF3, and a higher lipophilic parameter. Often the SCF3 group has been described as an enhanced version of the CF3 especially due to the higher lipophilicity value, and the number of methods to access SCF3 containing compounds has been continuously increasing.

Table 2 Resonance constants as assessed for monosubstituted aromatics

CF3 OCF3 SCF3 SeCF3

σ m 0.43 0.38 0.40 0.44

σ p 0.54 0.35 0.50 0.45

Based on the reported data in literature, we suppose that fluorinated functional groups bound to chalcogens (especially, S and Se) can modulate the physico-chemical properties of the molecules. Despite the fact that compounds containing such moieties still do not find use in therapeutics, the interests towards their use as potential candidates has been growing.

Various trifluoromethylthiolating molecules as the adenosine analogue and the losartan analogue, an antihypertensive drug, are already accessible to medicinal chemists. Toltrazuril, a coccidiostatic

[8] drug for veterinary use, contains a SCF3 moiety (Figure 3). Also compounds containing a difluoromethylthio group are already known and some of them are defined as biologically active compounds. The benzoxazole derivative reported in Figure 3 has shown to be active against

HIV-1 meanwhile its OCF2 analogue showed no activity. Flomofex sodium, a molecule

3 General Introduction

containing a SCF2H moiety distinguished for its antibacterial activity showed to be resistant to β- lactamase enzymes (Figure 3).

NH2 H N O N O N F3CS N N N nBu N K N N NN SCF3 N N F3CS O O O OH OH Toltrazuril Losartan analogue Adenosine analogue HO

N N F F CO2Na N N O N N O S N N HN O O H Benzoxazole derivative O anti HIV-1 HF2CS Flomofex Sodium β-lactamase resistant Figure 3 Biologically active compounds cotaining chalcogens

Although the similitudes between sulfur and selenium, the chemistry of selenium has been less developed. The malodorous smell as well as the unknown toxicity data of selenium compounds limited the advancement of this field towards the development synthetic methodologies. Nevertheless compounds containing selenium gave promising results in several fields. Selenolated derivatives have been tested as sensitizers in photodynamic therapy as well as potential anti- tumor agents. Ebselen, a synthetic organoselenium compound, has shown anti-inflammatory, anti-oxidant was well as cytoprotective activity. It has shown a remarkable activity in the treatment of different pathologies as bipolar disorders as well as hear loss and tinnitus. Moreover Ebselen has shown a good bactericidal activity towards multi-drug resistant clinical isolates of staphylococcus aureus.[9]

H2N O

Se N O Se C C C Se H H H HO N O Se Cl

OH OH Ebselen Sensitizer in photodynamic therapy Selenoazofurin anti tumor Figure 4 Se-containing active molecules

4 General Introduction

Despite the promising preliminary results obtained by the SCF2R containing compounds or Se containing compounds, accessing to such compounds is far away than trivial. With the recent advances made in the field and the interest of medicinal chemists towards these molecules there is still need for the development of new synthetic methodologies that easily conducts to such scaffolds. The work reported on this dissertation is based on the synthesis of fluoroalkylchalcogens that

+ + acts as SCF2R and SeCF2R donors. All the synthesized reagents were used to perform electrophilic reactions leading to different scaffolds bearing SCF2R as well as SeCF2R.

Nu XCF2R Nu XCF2R

X= S, Se

R= SO2Ph,CO2Me, CF2CF2CF3, F, Br, H,

Scheme 1

5 General Introduction

References:

[1] D. B. Harper, D. O’Hagan, C. D. Murphy in Natural Production of Organohalogen Compounds (Ed.: G. Gribble), Springer Berlin Heidelberg, Berlin, Heidelberg, 2003, pp. 141-169. [2] a) D. O'Hagan, Chem. Soc. Rev. 2008, 37, 308-319; b) C. Ni, M. Hu, J. Hu, Chem. Rev. (Washington, DC, U. S.) 2015, 115, 765-825. [3] a) P. Jeschke, ChemBioChem 2004, 5, 570-589; b) F. Babudri, G. M. Farinola, F. Naso, R. Ragni, Chem. Commun. 2007, 1003-1022; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330; d) P. Jeschke, Pest Manage. Sci. 2010, 66, 10-27; e) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432-2506; f) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422-518. [4] J. Fried, E. F. Sabo, J. Am. Chem. Soc. 1954, 76, 1455-1456. [5] a) P. D. Leeson, B. Springthorpe, Nat. Rev. Drug Discov. 2007, 6, 881-890; b) P. D. Leeson, S. A. St-Gallay, Nat. Rev. Drug Discov. 2011, 10, 749-765; c) J. A. Arnott, S. L. Planey, Expert Opinion on Drug Discovery 2012, 7, 863-875. [6] M. Morgenthaler, E. Schweizer, A. Hoffmann-Röder, F. Benini, R. E. Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, J. Schneider, F. Diederich, M. Kansy, K. Müller, ChemMedChem 2007, 2, 1100-1115. [7] a) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525-616; b) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, E. J. Lien, J. Med. Chem. 1973, 16, 1207-1216. [8] a) L. M. Yagupolskii, I. I. Maletina, K. I. Petko, D. V. Fedyuk, R. Handrock, S. S. Shavaran, B. M. Klebanov, S. Herzig, J. Fluorine Chem. 2001, 109, 87-94; b) X.-H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 2015, 115, 731-764; c) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827-856. [9] a) J. Schacht, A. E. Talaska, L. P. Rybak, Anatomical record (Hoboken, N.J. : 2007) 2012, 295, 1837-1850; b) S. Thangamani, W. Younis, M. N. Seleem, Sci. Rep. 2015, 5, 11596; c) N. Singh, T. Sharp, S. R. Vasudevan, G. C. Churchill, N. Singh, A. L. Sharpley, C. Masaki, C. J. Harmer, P. J. Cowen, U. E. Emir, M. M. Herzallah, M. A. Gluck, M. M. Herzallah, Neuropsychopharmacology 2016, 41, 1768-1778.

6 CHAPTER I

SYNTHESIS OF SCF2R DERIVATIVES AND THEIR APPLICATION IN ELECTROPHILIC REACTIONS Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I. BIBLIOGRAPHY SCF3 AND SCF2R ...... 10

I.3 S-CF2H AND S-CF2FG BOND FORMATION; INDIRECT APPROACH ...... 41 I.3.1 Difluoromethylation with difluorocarbene sources ...... 41

I.3.1.1 ClCF2H as a difluorocarbene source ...... 41

I.3.1.2 CF2Br2 and ClCF2Br as difluorocarbene sources ...... 42 I.3.1.3 SCDA, PDFA and TFDA as difluorocarbene sources ...... 43 I.3.1.4 Diethyl bromodifluoromethylphosphonate and Difluoromethyltri(n-butyl)ammonium chloride 44

7 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.3.4.2 Hypervalent iodine(III)-CF2SO2Ph reagent ...... 49

I.3.5 C-S-CF2H(FG) in situ bonds formation ...... 49 I.3.5.1 Copper thiocyanide and N-thiocyanatosuccinimide ...... 49

I.4.3.3 MesNHSCF2PO(OEt)2 reagent ...... 55

II. RESULTS AND DISCUSSION- C-SCF2FG BOND FORMATION ...... 56

II.1 SYNTHESES OF NOVEL SULFENAMIDES BEARING A SCF2FG GROUP ...... 56 II.1.1 State of the art: Syntheses of sulfenamides ...... 56

STABLE REAGENT ...... 64 II.2.1.1 State of the art: interest of phenylsulfonyl part...... 64

II.2.1.2 SEAr reactions using (phenylsulfonyl)difluoromethanesulfenamide ...... 65 II.2.1.3 Electrophilic addition reactions on alkenes and alkynes ...... 68

II.2.1.4 Reductive desulfonylation: Access to SCF2H compounds ...... 71

REAGENT ...... 78

8 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.3.1.1 SEAr using compound 1d ...... 78 II.3.1.2 Acid activation of α-ketones ...... 80 II.3.1.3 Post-functionalization reactions ...... 82

III.CONCLUSIONS ...... 90

IV.REFERENCES: ...... 91

9 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

In this chapter, we report the syntheses of two new shelf-stable, functionalized

+ difluoromethanesulfenamides reagents, which were successfully used in reactions as SCF2R donors. Both reagents showed a good reactivity in electrophilic reactions. Moreover, taking advantage of the good ability of the functional groups to be displaced, post-functionalization reactions were performed leading to newly synthesized compounds.

I. Bibliography SCF3 and SCF2R

In the first part of the chapter a detailed bibliographic summary of different synthetic methodologies capable to lead to SCF3 and SCF2R containing compounds will be reported. Such methodologies were divided in two classes, direct and indirect SeCF3 and SeCF2R bond formation. In both cases the methodologies were reported by classifying them in radical, nucleophilic or electrophilic pathway. The below reported bibliography includes works published prior October 2016.

I.1 Indirect insertion of SCF3 group:

Herein is reported a short summary of radical, electrophilic and nucleophilic trifluoromethylation of aliphatic and aromatic thiols, thiolates, disulfides based on the use of different sources of CF3.

I.1.1 Radical trifluoromethylation of thiols, thiolates and disulfides.

Radical trifluoromethylation has been widely applied to different compounds, such as aliphatic and aromatic thiols, thiolates and disulfides. One of the most used reagents for the syntheses of these compounds is the non-ozone depleting, environmentally-acceptable trifluoroiodomethane,

CF3I. In the early 70’s Haszeldine et al. reported the synthesis of alkyl-trifluoromethylthiolates by irradiation of the reaction media. The reaction proceeds slowly (Scheme 1, eq. a) and in the case of the higher homolog, as diethyl disulfide, the formation of CF3H is observed. Such phenomenon may depend partly due to a larger number of available H and partly by the fact that diethyl disulfide contains four secondary C-H bonds.[1] Aromatic disulfides were [2] trifluoromethylated in liq. NH3 (Scheme 1, eq. b).

Soloshonok and coll. reported the direct trifluoromethylation of homocystine in liq. NH3 under ultraviolet irradiation.[3] Yagupolskii and coll. accessed to various p-substituted thiols by replacing [4] liq. NH3 with a biphasic system in presence of a phase transfer catalyst (Scheme 1 eq. d). [5] Another route to access Ar-SCF3 adducts is using methylviologen as radical generator. Recently

10 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Shibata and coll., reported the trifluoromethylation of homocystine by adapting the Birch reduction conditions, Na/NH3 liq. in presence of CF3I as trifluoromethylating agent (Scheme 1, eq. c) in order to avoid the inconveniencies of ultraviolet irradiation.[6]

In situ preformed thiolates in presence of NaH gave Het-SCF3 compounds in good yields (Scheme 1, eq. e). The authors avoided the use of ultra-violet irradiation, leading to simpler synthetic procedures.[7] Recently a ruthenium-based photocatalyst activated by visible light has been used in the trifluoromethylation of thiols, in batch as well as in flow chemistry (Scheme 1, eq. f).[8] Ritter and coll., by using the halogen bonding ability, accessed to an easy-to-handle, liquid and stable CF3I-TMG reagent used in trifluoromethylation of arenes and thiophenols (Scheme 1, eq. g).[9]

CF3I as a source

hv (a) Me SCF3 21-48 Days 92 %

hv R (b) NH liq. 72 % Ph SCF CF3Br, SO2 3 3 (h) SCF 63 % 3 SCF Na n 3 (c) HOOC NHAc CF3SO2Na (i) NH3 liq. NH F3CS 60-93 % 2 70 % COOH t-BuOOH R S S R (j) (d) O or hv F COCHN hv + - 3 RSH Et3(tolyl)N , Cl F3CS SCF CF3COSR NaOH acq., Et2O MeO2C 3 RS 52 - 61 % 60 % F CS C7H15 hv (k) (e) NaH 3 Het S CF N(NO)SO CF F C 3 2 3 DMF 3 0 - 88 % 43 % (f) Ru(bpy)2Cl2 cat. O SCF Bi(CF ) 3 3 3 (l) Et3N, CH3CN, N 24 W, In Flow 79 % Cu(OAc)2 SCF3 SCF3 (g) TMG Cl 83 % Scheme 1 Radiacal trifluoromethylation of thiolates, thiols and disulfides

Despite its toxicity and its environmentally-known hazards, CF3Br has been used in, trifuoromethylation reactions. Wakselman and coll. accessed to aryl-SCF3 compounds starting [10] from the potassium thiolates in presence of CF3Br. They also reported the trifluoromethylation of aliphatic and aromatic thiols and disulfides, using sodium hydroxymethane sulfinate as a

11 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

•- [11] source of radical SO2 under pressurized atmosphere (Scheme 1, eq. h). Some years ago in our group has been studied the generation of the trifluoromethyl radical under oxidative conditions, from sodium trifluoromethanesulfinate, which in presence of disulfides gave the excepted compounds (Scheme 1, eq. i).[12] Also trifluorothioacetates and trifluoromethanethiosulfinates have been used in the trifluoromethylation of sulphur-containing compounds (Scheme 1, eq. j).[13] Two different N-trifluoromethyl-N-nitroso sulfenamides have been prepared and used in the

[14] trifluoromethylation of thiols and disulfides. Another possibility to access to Ar-SCF3 compounds is the trifluoromethylation of tetrabutylammonium phenylthiolate using Bi(CF3)3 as a source of CF3 radicals in presence of a Cu salt (Scheme 1, eq. l).

I.1.2 Electrophilic trifluoromethylation of thiols and thiolates.

Although electrophilic trifluoromethylation reactions have been widely used for the synthesis of trifluoromethylated adducts, in the case of S-containing compounds still remains limited to a few number of papers. The first reagent involved in electrophilic trifluoromethylation of thiolates has been developed by Yagupolskii and coll, a diaryl(trifluoromethyl)sulfonium salt used in the trifluoromethylation of S- containing starting materials (Scheme 2, eq. a).[15]

Cl R2 R1

CF3 SbF6 (a) F3CS NO2 Cl R1 65 % S Ph RSH (b) CF3 X RS O SCF3 78 % I CF3 COOH (c)

N SCF3 95 % Scheme 2 Electrophilic trifluoromethylation of thiols, thiolates and disulfides

Later, Umemoto and coll. described the trifluoromethylation of thiolates, among other substrates, using trifluoromethyl dibenzochalcogenophenium salts. Their efficiency as trifluoromethylating agents depends on the chalcogen itself and the reaction system in which is applied (Scheme 2, eq.

12 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions b).[16] Nevertheless, the formation of the product is accompanied by the formation of a considerable amount of disulfide as a by-product.[17] A huge step forward in these reactions has been made by Togni and coll., by designing the synthesis of a relatively cheap and readily accessible hypervalent iodine(III)-CF3 reagent. Their methodology does not require the use of a base or thiolates as starting materials, Moreover, th the formation of disulfides is avoided. With their work, they showed also the synthetic convenience of this reagent, as well as its high functional group tolerance and solvent independence. Aromatic, heteroaromatic, aliphatic compounds, as well as unprotected or protected esters of cysteine and protected carbohydrates were trifluoromethylated leading to

[18] SCF3 containing compounds (Scheme 2, eq. c).

I.1.3 Nucleophilic trifluoromethylation of thiols, thiolates and disulfides.

Unlike electrophilic reactions, different ways and reagents already exist for nucleophilic trifluoromethylation reactions. The generated CF3 anion is very unstable and can easily collapse into difluorocarbene and fluoride.[19]

One of the ways to generate CF3 anion is the use of CF3Br in presence of zinc and pyridine [20] (Scheme 3, eq. a). Yagupolskii and coll. described the formation of Ar-SCF3 by using TMSCF3 as a source of trifluoromethyl anion in presence of TASF, starting from the ArS-Cl derivatives (Scheme 3, eq. b).[21] In our group was performed the trifluoromethylation of thiocyanates and disulfides by using TMSCF3 as a trifluoromethylating reagent in presence of TBAF. Thus, by using easy-to-handle starting materials in a simple process an improvement in terms of yield was also obtained (Scheme 3, eq. c and n).[22] By adapting the same strategy the synthesis of trifluoromethylthiolated amphiphilic cyclodextrins, important carriers in encapsulation and drug delivery, has been reported.[23]

Since the use of CF3Br has been restricted by the Montreal protocol due to its ozone-depleting character, its use is becoming limited and expensive. Also TMSCF3, a well-known trifluoromethylating agent, was obtained by using CF3Br as a starting material in the early beginnings. More recently, huge efforts has been made to substitute ozone depleting substances, and the use of fluoroform (CF3H), a large-volume by-product in manufacture and a stable greenhouse gas, seems a breakthrough considering the economical advantage and the easy accessibility.[24] Fluoroform has been used in nucleophilic trifluoromethylation of C-, Si- (leading to the synthesis of TMSCF3 itself) and S-centers. By deprotonating CF3H with t-BuOK, the generated CF3 anion is able to substitute aryl disulfides, aryl sulfonyl chlorides as well as aryl [25] thiosulfonates leading to the formation of Ar-SCF3 (Scheme 3, eq. d).

13 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

(a)

CF3Br SCF3 Zn / Pyridine 22 % (b) 59 - 69 % TMSCF3, TASF R SCF3 RSX TMSCF3, TBAF (c) 32 - 87 %

X= CN, Cl, SO2Ph (d) SCF CF3H, t -BuOK 3 R

60 - 90 % (e) CF3H, t -BuOK R SCF3 0 - 95 % or P4-t-Bu

(f) CF3CO2K SCF3 R

32 - 85 %

(h) SCF3 PhSO2CF3, t-BuOK

NR2 26 % (j) R O CF TBAT R S 1 3 R SCF S R 3 O 5 - 97 % R= Aryl, alkyl S (k) F3C NR2 t-BuOK R SCF3 HO 30 - 50 % O N (l) F3C CF3 N SCF3 t-BuOK H

O (m) 73 % P F C OEt SCF 3 OEt t-BuOK 3

26 % TMSCF3 (n) C8H17SCF3 TBAF 80 % Scheme 3 Nucleophilic trifluoromethylation of thiols, thiolates and disulfurs

As shown in Scheme 3, most of the procedures involve the trifluoromethylation of disulfides, despite the fact that lacks of high yields (substrate dependence). Moreover only one part of the molecule is trifluoromethylated in general, causing the loss of the second part as thiolate. Nevertheless, by adapting this synthetic procedure is easy to access to a wide number of different classes of compounds.

14 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Also in our group the trifluoromethylating capacity CF3Hhas been exploited. Deprotonation with a strong base and subsequent trapping of the CF3 anion by DMF produces a reservoir-like adduct directly implied in the trifluoromethylation of disulfides[26] (Scheme 3, eq. e). In the case of disulfides the reaction is not DMF-dependent, working also in THF.

Shibata and coll. employed an organo-superbase to form the CF3 anion which was trapped by the disulfide (Scheme 3, eq. e).[27] Also the thermal decomposition of potassium trifluoroacetate, in

[28] presence of disulfides led to the formation Ar-SCF3 (Scheme 3, eq. f). Trifluoromethyl sulfoxide also has been employed to generate CF3 anion, after activation with t-BuOK and gave [29] PhSCF3 with only 26 % yield (Scheme 3, eq. h). In our group has been reported the trifluoromethylation of disulfides, among other substrates, by using two novel reagents, the fluoral hemiaminal derivatives in presence of TBAT[30] (Scheme 3, eq. j), and the trifluoromethanesulfinic acid derivatives in presence of t-BuOK[31] (Scheme 3, eq. k). However, in the case of disulfides, the hemiaminal derivatives are more efficient than the trifluoromethanesulfinic acid derivatives in trifluoromethylation reactions. Recently, Colby and coll. reported the synthesis of an aminidate salt of hexafluoroacetone hydrate as an alternative for – [32] the generation of CF3 species in situ (Scheme 3, eq. l). Beier and coll. explored the trifluoromethylation of disulfides by using diethyl trifluoromethylphosphonate as reagent in presence of t-BuOK (Scheme 3, eq m).[33] Dolbier and coll. demonstrated that the system [34] CF3I/TDAE is effective in both nucleophilic and radical trifluoromethylation of disulfides.

I.2 Direct insertion of SCF3 group

Late-stage trifluoromethylthiolation of organic adducts is an important issue in SCF3 chemistry. The direct insertion of the motif could circumvent the use of thiols or pre-functionalized thiolates as starting materials, thus permitting to access to a wider range of CF3S-containing compounds. Recently, the interest for developing such strategies and reagents involved in C-SCF3 bond formation has been growing.

I.2.1 Radical trifluoromethylthiolation reactions

I.2.1.1 Trifluoromethanethiol and trifluoromethanesulfenyl chloride

The free radical addition of trifluoromethanethiol (CF3SH) and trifluoromethanesulfenyl chloride

(CF3SCl) to olefins, described by Harris and coll. resulted in the formation of various alkyl trifluoromethyl sulfides. Using CF3SH the reaction gave the regioselective compound with 62 % yield. Also minor products have been formed due to radical propagation in lower yields (Scheme

4, eq a). On the other hand, the use of CF3SCl (Scheme 4, eq. b) led to a mixture of isomers

15 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions where the one formed in eq. (a) is the minor one in this case. The direction of the attack could be attributed to the stability of the intermediate.[35]

(a) F3CS H F Cl F Cl CF3SH F Cl + F3CS C C C C H F F F F F F Cl hv 62 % 20 % F F F CS Cl Cl SCF3 (b) F CF SCl 3 3 F Cl + F Cl hv F F F F 12 % 42 % Scheme 4 Radical trifluorothiomethylation of olefins

A few years later the same authors described the preparation of trifluoromethylthiolated alkanes,

[36] olefins and acetylenes with a various number of SCF3 substituents.

The trifluoromethylthiolation of alkanes has been explored by Harris using CF3SCl under irradiation. As reported in Scheme 5 a mixture of compounds has been obtained. Nevertheless, the trifluoromethylthiolated compound has been obtained as the major product in terms of yield.[37]

SCF3 Cl

CF3SCl + + CF3SSCF3 hv 45 % 28 % 35 % Scheme 5 Radical trifluorothiomethylation of alkanes

In the early 2000’s Munavalli and coll, reported several works describing the radical

[38] trifluoromethylthiolation using CF3SCl.

OTMS O O O SCF3 CF SCl SCF3 F3CS SCF3 3 + SCF3 +

Scheme 6

Unfortunately, the above reported reagents are known to be gaseous and highly toxic, thus the need for designing less toxic synthetic approaches and reagents has been a primary importance in direct trifluoromethylthiolation.

I.2.1.2 Trifluoromethylthiosilver (I)

As reported in Scheme 7 the most used reagent in these reactions is trifluoromethylthiosilver (I) Wang and coll. accessed to trifluoromethylthiolated oxindoles starting from activated alkenes in [39] presence of K2S2O8 and HMPA as a base (Scheme 7, eq. a). Qing and coll. described the Cu-

16 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions mediated oxidative trifluoromethylthiolation of unactivated terminal alkenes in presence of

[40] K2S2O8 and K3PO4 (Scheme 7, eq. b). The same group reported the first Cu-catalyzed direct 3 trifluoromethylthiolation of benzylic Csp bonds using t-BuOOBz(3-CF3) as the oxidant and [41] AgSCF3 as the SCF3 active source. Nevado and coll. reported the synthesis of trifluoromethylthiolated highly functionalized heterocycles, via a chemoselective addition of an in-situ generated radical able to activate double bonds, which triggered a multi-step reaction cascade and led to the desired compounds.[42]

R O N 2 R1 R O N O 2 SCF3 (e) R3 (a) R1 O N K2S2O8, TBHP N HMPA, CH3CN K2S2O8, HMPA R O CH3CN, 75 °C, 12 h 3 30 - 91 %

R (b) R SCF3 AgSCF3 Cu(OAc)2, K 2S2O8 46 - 76 % K3PO4, DMSO, 60 °C 6 h O R X 2 (c) K2S2O8, HMPA, N SCF Y R1 3 CH3CN X (d) R1 O R Y terpyridine 3 R2 R K2S2O8, HMPA N 4 SCF3 CH3CN/ DMF 50 - 73 % O S O R3

X= NTs, C(COOMe)2, Y= CH2 R4 X= O, Y= carbonyl group

Scheme 7 Radical trifluoromrthylthiolation using AgSCF3

Wang and coll. disclosed the synthesis of 3-trifluoromethylthiolated coumarins, in presence of [43] AgSCF3/K2S2O8 in DMSO, by a radical cyclization reaction of aryl alkynoate esters. Liang and coll. first reported a radical cascade trifluoromethylthiolation/cyclization of 1,6-enynes to synthesize various SCF3 containing adducts, in presence of K2S2O8/HMPA and a 2,2′:6′,2′′- terpyridine ligand, which in association with HMPA seems to coordinate AgSCF3 in order to reduce the potential redox of the high valent silver species, thus blocking the further oxidative decomposition of substrates and products (Scheme 7, eq d).[44] Later the same group reported the synthesis of 3-trifluoromethylthiospiro trienones, starting from alkynes, through a radical

17 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions oxidative trifluoromethylthiolation/dearomatization process, in presence of a dual system such as

[45] K2S2O8/TBHP (Scheme 7, eq. e).

I.2.1.3 N- and O- trifluoromethylthiolating reagents

Very recently, 2 electrophilic reagents have been implied in radical trifluoromethylthiolation reactions (Scheme 8). Shen and coll. reported a silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary aliphatic carboxylic acids in an aqueous emulsion, formed by the addition of SDS to water. Although the reaction tolerates various functional groups, decarboxylation of primary as well as aromatic carboxylic acids does not work (Scheme 8, eq. a).[46] Later Glorius and coll. implied a phtalimide reagent for the decarboxylative trifluoromethylthiolation of primary, secondary and tertiary carboxylic acids as well as heteroarenes, activated by visible light in presence of an iridium catalyst. The method demonstrated to be efficient also when the iridium catalyst has been substituted by an oxidizing organic dye (Scheme 8, eq. d).[47]

(c)

TMSOTf, 2,6-Lutidine SCF3 DMF R1= α- (1-Hydroxycyclobutyl)

R1 fac-Ir(ppy) O 3 nBu4NCl, Additive R1 H R1 SCF3 blue LEDs (λ= 455 nm) Ar CH CN R1= H, Ar Ar 3 39-94 % R COOH (d) (a) O PCI or PCII Me R COOH CSOBz, Additive Ar O SCF3 R SCF3 F3CS N AgNO3 C6H5F, Me nC H SO Na 12 25 3 blue LEDs (λ= 455 nm) O K2S2O8, H 2O 0 - 91 % 49 - 94 % R 1 (b) R1 (b) R2 R2 Fe(NO3)3.9H2O SCF Fe(NO3)3.9H2O R3 3 R3 BH3. THF R1 BH3. THF R3 R2 CH3CN/H2O CH3CN/H2O H 0 - 73 % Scheme 8 Radical trifluoromethylthiolation using two electrophilic reagents

The same group developed a new, efficient trifluoromethylthiolation method of styrenes; based on the combination of a dual photoredox/halide catalytic system. Moreover, the synthesis of

SCF3-oxindoles and cyclic ketones employing a radical-polar crossover process involving ring expansion or cyclization has been reported (Scheme 8, eq. c).[48] The two reagents reported above have been also used in an iron-mediated Markovnikov hydro-trifluoromethylthiolation reaction of unactivated olefins (Scheme 8, eq. b).[49]

18 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.2 Nucleophilic trifluoromethylthiolation reactions

Nucleophilic trifluoromethylthiolation reactions have been widely used in organic chemistry - although synthetic problems such as the instability of the SCF3 anion have been reported 50 years ago.[50] Thus potassium trifluoromethylthiolate forms a right-side-favoured equilibrium leading to the formation of difluorothiophosgene and potassium fluoride (Scheme 9).[51]

F F S S + K + KF F F F Scheme 9 Dissociation of potassium trifluoromethylthiolate into difluorothiophosgene and KF

Herein, the nucleophilic trifluoromethylthiolation of substrates will be reported and the methodologies are ordered based on the use of the various reagents.

I.2.2.1 Difluorothiophosgene

The above reported equilibrium (See Scheme 9) has been successfully implied for the generation of trifluoromethylthiolate anion in situ and applied to the nucleophilic aromatic substitution and also extended to the addition of different fluoride sources to other difluorothiophosgene analogs.

X S MF X EWG EWG X= F, Cl, SCF3 Y F Y SCF3 MeCN Y= CH, N Y= CH, N Scheme 10 Trifluoromethylthiolation reactions based on thiophosgene derivatives

Such strategy finds application only in reactions involving electron-deficient molecules (Scheme 10). [51]

I.2.2.2 Mercury (II) trifluoromethylthiolate

One of the first ever employed sources of SCF3 anion is the bis(trifluoromethylthio)mercury [52] generated by reacting carbon disulfide (CS2) and mercuric fluoride (HgF2) or reducing [53] CF3SSCF3 by employing metallic Hg. Muetterties and coll. reported the synthesis of alkyl and acyl trifluoromethylthiolates starting from the chlorinated derivatives (Scheme 11, eq. b).[52] Alkyl as well as bis halogenates gave corresponding trifluoromethylthio containing compounds as well (Scheme 11, eq. a).[36]

19 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

(a) O n (b) R X or X X R Cl or R Cl O

R SCF3 R= alkyl R= alkyl R SCF X= I, Br 3 or Hg(SCF3)2 or n 18 - 83 % 23 - 80 % F3CS SCF3 R SCF3 Scheme 11 Trifluoromethylthiolation reactions using bis(trifluoromethylthio)mercury

I.2.2.3 Trifluoromethylthiosilver (I)

The first synthesis of AgSCF3 has been reported by Muetterties and coll. reacting aqueous silver [52] nitrate with bis(trifluoromethylthio)mercury. Later on, MacDuffie and coll. synthesized AgSCF3 from silver fluoride (AgF) and carbon disulfide in autoclave at 140 °C and yielded 70 – 80 %.[54]

Since then, it has been used in several nucleophilic reactions with the aim to access CF3S- containing motifs. It allows to convert propargylic halides,[55] tropylium bromide,[56] α-

[57] [58] [59] haloketones, electron-poor benzyl halides, and aromatic halides to the corresponding CF3S- containing analogs. However, the addition of an inorganic iodide salt seems to be crucial for the - reaction in some cases, as it leads to the in-situ formation of active species, such as [Ag(SCF3)I [58-59] ]. Sambur and coll. described the synthesis of aryl-SCF3 compounds starting from aryl diazonium salts.[60]

Br Mes I R OTf SCF3 SCF R 3 (c) CuI Pd S-Phos Brettphos (a) DMF PhEt NI R R 3 toluene 29 - 94 % 83 - 99 %

AgSCF3 DG H DG X DG Pd(OAc)2 SCF DG X= I, Br Selectfluor 3

F3CS CuBr Phen (d) HOAc, DMF (b) 5 - 91 % CH3CN 49 - 95 %

Scheme 12 AgSCF3-based trifluoromethylthiolation of arenes

In the recent years, with the breakthrough of organometallics into fluorine chemistry, several methodologies able to form aryl-SCF3 compounds have been reported (Scheme 12). Buchwald and coll. described the Pd-catalyzed synthesis of Ar-SCF3 compounds, in presence of a bulky phosphine ligand and an iodide salt that generates an anionic “ate” complex, starting from the

20 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Br-derivatives. The mild reaction conditions tolerated a wide range of functional groups and the methodology has been successfully extended to heterocyclic moieties (Scheme 12, eq. a).[61] Cu- catalyzed trifluoromethylthiolation of aryl halides in presence of a directing group does not require the use of iodine-containing additives to access Ar-SCF3 compounds. A wide range of coordinating groups have been employed and demonstrated to be efficient. In the case of strong directing groups such as pyridine the reaction gave satisfying results even at room temperature (Scheme 12, eq. b).[62] Cu-catalyzed trifluoromethylthiolation has been reported in absence of a ligand[63] as well as in presence of S-Phos[64] as a ligand starting from aryliodonium salts (Scheme 12, eq. c). After a detailed mechanistic study Anbarasan and coll. concluded that the in-situ trifluoromethylthiocopper formed complex is responsible for the trifluoromethylthiolation of di(hetero)aryl-λ3-iodines. Nevertheless, in the presence of a coordinating counterion such as TfO¯, the presence of the silver is crucial for promoting the oxidative addition of the iodonium salts onto the S-PhosCuSCF3 complex. On the other hand, the presence of a non-coordinating ¯ counterion such as SbF6 , increases the electron deficiency of the iodonium center, thus promoting the oxidative addition step without the need of the silver salt. Huang and coll. reported a palladium-catalyzed ortho-selective trifluoromethylthiolation of arenes (Scheme 12, eq. d). Several functional groups were tolerated and different directing groups showed a good efficiency in directing the C-H activation. Selectfluor was found to be the best F+ source for the formation of Ar-Pd(IV)-F intermediate, which might be involved in the CF3S-F ligand exchange leading to

Ar-SCF3 compounds. The use of acetic acid seems to be crucial to suppress the oxidative dimerization of the starting material.[65] Recently Qing and coll. reported the trifluoromethylthiolation of primary and secondary aliphatic alcohols passing through a carbonofluoridothioate intermediate, generated in situ by the reaction of the alcohol and the difluorothiophosgene (Scheme 13). During this reaction formation of alkyl fluorides is also observed. Nevertheless, such drawback has been fine-tuned by changing the amount of equivalents of AgSCF3 and nBu4NI, leading to the formation of the desired compound.[66]

21 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

AgSCF3 SCF3

S F + R SCF3 F F S ROH R O F Scheme 13 Trifluoromethylthiolation of alcohols

Contrary to known methods that require aromatic precursors, Lee and coll. reported the synthesis of aryl-SCF3 compounds starting from non-aromatic building blocks such as triynes, which underwent a thermal hexadehydro-Diels-Alder reaction leading to the silver-coordinated aryne.

¯ The formed intermediate was trapped by a nucleophile such as SCF3 to form the final compound (Scheme 14, eq. a).[67] Both ring formation and subsequent trifluoromethylthiolation of the intermediate occur in a single step and in most of the cases the reaction presents an excellent regioselectivity. 2-Alkynylbenzaldoximes have been activated in presence of p- methoxybenzenesulfonyl chloride and AgOTf as a catalyst, trifluoromethylthiolated by using

AgSCF3 as a source, to access CF3S-containing isoquinolines. Also a thiophene-containing substrate led to the formation of the desired compound in good yield (Scheme 14, eq. b).[68]

X R1 Y R1 Z R2 X R2 (a) Toluene Y Z X= CO, CH2; Y= NTs, CH2; SCF3 Z= NTs, CH2 53 - 95 % R1= Alk; R2= Alk, SiMe3, H

OH AgSCF N 3 R1

R2 SCF3 R1= H, F, Cl, Me, OMe (b) R = Alk, Ar 2 N R1 AgOTf, p-MeOC6H4SO2Cl, R2 K3PO4, DMF 23 - 90 %

Scheme 14 C-SCF3 bond formation

22 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.2.4 Trifluoromethylthiocopper (I)

The first Cu-based nucleophilic reagent involved in trifluoromethylthiolations was CuSCF3. Several procedures concerning its preparation have been already reported involving the reaction [52] [69] between Hg(SCF3)2 with Cu powder in autoclave, or in dimethylformamide solution. It has [70] [71] been also prepared by reacting AgSCF3 with CuBr, , CuCl or bis(trifluoromethyl) disulfide with Cu powder.[72] [70, Aryl-SCF3 compounds were obtained starting from iodo-derivatives whether isolating CuSCF3, 73] or preparing it in situ following by addition of the starting materials to the reaction media.[72] It has been demonstrated the compatibility of such reaction in presence of carboxylic and ester[69] functionalities.[74] The reaction worked well also in the presence of adjacent fluoride atoms.[75] Metzler-Nolte and coll. described the synthesis of trifluoromethylthioferrocene, through an in situ formation of the copper salt, using the Br-analog as a starting material.[76] Clark and coll. reported the synthesis and the use of an Alumina-supported CuSCF3 reagent. Contrary to the unsupported copper salt, this reagent was found to decompose with time, and therefore should be used immediately after preparation. On the other hand, the reagent was found to undergo reactions with iodoaromatics and activated bromoaromatics leading to higher isolated yields than the previous methodologies (Scheme 15, eq. a, for all above-reported reactions).[77]

I R SCF (a) 3 R R DMF or NMP R I R1 30 - 87 % SCF3 (c (a)) R1 R2 R CuSCF3 2 Pyridine

84 - 98 % N2 BF4 R SCF3 (b (a)) R CH3CN 3 - 98 %

Scheme 15 CuSCF3 based trifluoromethylthiolation

The synthesis of CF3S-containing aromatic compounds has been achieved also using diazonium salts as starting materials (Scheme 15, eq. b). Despite drawbacks such as explosive-related as well as the restriction to electron-poor moieties, the reaction involving diazonium salts gave high- yielded reactions and the final compounds were obtained after a simple work-up procedure.[78] Rueping and coll. reported the synthesis of different alkyl and aryl di-, tri- and tetra-substituted vinyl trifluoromethyl thioethers, starting from the corresponding vinyl iodides, with high yields.

23 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

The reaction showed also full stereochemical retention (Scheme 15, eq.).[79] The same group described the synthesis of aryl and allylic trifluoromethylthioethers starting from the [80] corresponding alcohols, using CuSCF3 and BF3.Et2O as a Lewis acid.

The group of Weng has extensively studied copper trifluoromethylthiolate complexes in trifluoromethylthiolation reactions. They reported the synthesis of different copper trifluoromethylthiolate complexes. By reacting CuF2 with TMSCF3 and S8 in presence of diimine ligands[81] or a phosphine ligand,[82] they accessed to monomeric or dimeric N-coordinated

CuSCF3 complexes and monomeric bis(PPh3)-CuSCF3 chelating complexes. [81] [82-83] [83-84] Aryl and heteroaryl, alkyl, allyl and benzyl, CF3S-containing substrates have been prepared starting from their corresponding halide analogs (Scheme 16, eq. a). Allylic trifluoromethylthioethers have been prepared also by using the phosphine complex as an anionic donor. Different complexes capable to chelate copper were prepared, thus enhancing the stability even in presence of air,[81] differently from the unchelated copper trifluoromethylthiolate[85] previously used. The use of such N-containing ligands improved the trifluoromethylthiolation of aryl and heteroaryl moieties especially, increasing the yields in comparison to previous methods. The best ligand seems to be bipyridine, probably due to its preference to maintain the monomeric form, more active towards cross-coupling reactions as observed by the authors.[81]

O O Br SCF3 R RX R (c) (a) R SCF R= (hetero) aryl, 3 alkyl, allyl 23 - 91 % CH2Cl2 CH CN or CH Cl 3 2 2 12 - 98 % X= Br, I Br R1 X SCF3 N N O Cu R2 R3 R SCF O (b) 1 3 (d) SCF3 CH3CN/toluene KF, diglyme R R 32 - 93 % 2 3 23 - 91 %

Scheme 16 bpy-CuSCF3 mediated trifluoromethylthiolation

The same group reported also the synthesis of vinyl-SCF3, α-and β-trifluoromethylthio-α,β- unsaturated carbonyl compounds (Scheme 16, eq. b and d),[86] and α-trifluoromethylthio substituted ketones starting from their halide analogs. The reaction seems to go through an oxidative addition/reductive elimination mechanism in most of the cases.

AgSCF3 reacted with CuCl to prepare in situ CuSCF3, which is the active donor species of SCF3 anion. Different (hetero)aryl diazo compounds have been trifluoromethylthiolated (Scheme 17,

24 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[71] eq. b and c). (bpy)CuSCF3 showed less efficacy in trifluoromethylthiolating diazo compounds yielding only 13 % of the desired compound (Scheme 17, eq. a).[71a] Wang and coll. described the trifluoromethylthiolation of diazo compounds after an in situ formation of CuSCF3 reacting

[87] AgSCF3 and CuI (Scheme 17, eq.c). Rueping and coll. reported the synthesis of α-SCF3 substituted esters starting from the diazo compounds using CuSCF3. N- trifluoromethylthiophtalimide was used, in absence of H2O, for the insertion of a second SCF3 motif in α position (Scheme 17, eq. d).[88]

(a) (bpy)-CuSCF3

NMP 13 %

(b) CuCl, H2O

NMP/CH3CN N 2 AgSCF3 13 - 85 % SCF3 R R1 46 - 77 % R R1 (c) Cul, H2O NMP/CH CN 3 R= (hetero)aryl 51 - 86 % R1= ester, CF3 (d) CuCF3, Additive CH CN 3 PhtSCF

3 F3CS SCF3 R R1 58 - 75 % Scheme 17 Trifluorothiomethylation of -diazo compounds

I.2.2.5 Trifluoromethylthio ammonium/cesium

As shown above, the association of SCF3 with a metal stabilizes the anion making possible its involvement in nucleophilic trifluoromethylthiolation reactions. Ag (I), Cu (I) and Hg (II) –SCF3 found a wide use in nucleophilic trifluoromethylthiolations, as shown above. Several other [51a, 51c, 89] MSCF3 derivatives (where M = K, Cs, NMe4, TDAE) have been reported to literature. Difficult synthetic steps and employment of highly toxic materials are required and most of these complexes are reported as unstable at ambient temperature. The in situ formation of such [51c] complexes has been exploited to access aryl-SCF3 moieties from aryl halogens. A stable

(SCF3)2TDAE complex has been synthesized and characterized, with a yield of 98 %, starting from (SCF3)2 and TDAE, and has been used as a SCF3 source in nucleophilic trifluoromethylthiolation of aryl halogenated compounds. (NMe4)SCF3 and CsSCF3 have been used in nucleophilic substitution reactions over a few allylic, benzylic and (hetero)aromatic [90] substrates. (NMe4)SCF3 has been used also in the synthesis of S-trifluoromethyl esters of the

25 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions corresponding carboxylic acids in a halogen substitution reaction.[91] The same complexes have been used in inorganic and organometallic chemistry for the synthesis of Hg(SCF3)2, CuSCF3 and [90] AgSCF3, which have also been quantitatively prepared (Scheme 18).

THF or glyme + TMSCF3 S8 + MF MSCF3 M=NMe4, Cs

CH3CN HgCl2, CuCl, AgNO3

M1(SCF3)n

n= 1, M1= Cu, Ag n=2, M1=Hg

Scheme 18 Alternative syntheses of Ag-, Hg- and Cu- SCF3 reagents

[51c] (NMe4)SCF3 has been described as thermally unstable at high temperatures , and later its thermal stability has been related to the preparation procedures.[90] Vicic and coll. found that

(NMe4)SCF3 is thermally stable in THF up to 60 °C. They described the synthesis of aryl-SCF3 compounds starting from the iodo- and bromo- derivatives in mild conditions, using a Ni/bpy catalytic system. Chloro derivatives showed to be unreactive toward Ni-catalyzed system in such conditions (Scheme 19, eq. a).[92]

R2 R I ArX R R1 Ni(COD) or Pd 2 (a) 2 R CuI (d) dmbpy or dppf SCF3 pyridine THF or CH3CN/Tol R1 0 - 99 %

86 - 93 % M= NMe4 Ar(BOH)2 Cu(OTf)2, dtbpy M= NMe4 (b) CsCO3 ArSCF MSCF3 3 THF 16 - 91 % OCOMe M= NMe4, Cs R ArN2BF4 Ru cat CuSCN R SCF3 CH CN CH3CN (e) (c) 3 8 - 89 % 55 - 99 %

Scheme 19 Nucleophilic trifluoromethylthiolations based on MSCF3 use

Schoenebeck and coll. explored the importance of the ligands chelating Ni and showed that the use of a Ni/wide-bite-angle phosphine ligand (xantphos, dppf or binap) system allowed the synthesis of aryl-SCF3 starting from the chloro derivatives (Scheme 19, eq. a). Although small bite-angle ligands render the metal center more nucleophilic, wide bite-angle ligands contribute

26 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions on lowering the energy barriers during the transition states, making the oxidative addition step easier. Moreover, addition of CH3CN led to the in situ formation of a more reactive version of catalyst that undergoes easily oxidative addition easily.[93] Meanwhile, the same group reported the trifluoromethylthiolation of different aryl bromo and iodo derivatives in a cross-coupling reaction, by using a S-bridged dinuclear PdI catalyst (Scheme 19, eq. a).[94] Vicic and coll. reported the Cu-mediated cross-coupling reaction under air, between (NMe4)SCF3 and aryl/vinyl boronics, [95] in presence of dtbpy as a ligand and CsCO3 as a base. (Scheme 19, b) Goossen and coll. reported the trifluoromethylthiolation of diazonium salts in a Cu-mediated Sandmeyer-type reaction (Scheme 19, eq. c).[96] Also vinyl iodides have been successfully trifluoromethylthiolated in presence of catalytic amounts of CuI (Scheme 19, eq. d).[79] You and coll. extended the use of

(NMe4)SCF3 and CsSCF3 by developing an efficient Ru-catalyzed, regioselective trifluoromethylthiolation reaction involving allelic carbonates as starting materials (Scheme 19, eq. e). Their mechanistic studies revealed that the reaction proceeded through a double allelic trifluoromethylthiolation reaction leading only to linear allylic compounds.[97]

¯ I.2.2.6 S8 and CF3 anion

Another way to access trifluoromethylthiolated compounds is the in situ formation of C-S-CF3 bonds using elemental sulfur, and a source of trifluoromethyl anion. Duan and coll. reported the first example using sulfur (S8), fluorosulfonyldifluoroacetate (FSO2CF2CO2Me) as a generator of - difluorocarbene and F , which in presence of a source of copper forms CuSCF3 in situ, a well- known trifluoromethylthiolating agent. They transformed aryl- and alkyl- halides into CF3S- bearing compounds.[98] From a cost effectiveness point of view, the best way to access trifluoromethylthiolated molecules could be the use of the Ruppert-Prakash reagent (TMSCF3) and S8 in presence of copper salts. Qing and coll. fine-tuned a synthetic strategy to access aryl-SCF3 compounds starting from boronic acids, by mixing TMSCF3, S8 and CuSCN, under mild reaction conditions ( Scheme 20, eq. a). The proposed reaction mechanisms report the in-situ formation of a thiolate firstly, followed by a subsequent trifluoromethylation to give aryl-SCF3 compounds. Such evidence has been proven by GC/MS data observing the presence of the thiolate.[99] The same group studied the metal-free oxidative trifluoromethylthiolation of terminal alkynes, in DMF. They found

¯ evidence that the SCF3 anionic species might be involved in the reaction pathway and DMF acts as a reservoir for the S2- species generated in situ ( Scheme 20, eq. b).[100] Copper-mediated trifluoromethylthiolation of allylic halides, by using TMSCF3, S8 and KF, has been achieved ( Scheme 20, eq. c). Mechanistic studies report the formation of a bis(trifluoromethylthio)-CuISCN

27 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions complex which involves a CuI-III cycle, with oxidative addition and successive reductive elimination leading to the generation of CuSCN and the desired compound.[101]

Cl (d) Ar (a) ArB(OH)2 SCF3 CuI, phen CuSCN, phen Ar ArSCF3 KF, DMF K3PO4, Ag2CO3 58 - 91 % 75 - 85 % DMF (e) O Br (b) R R O SCF3 Cu(OTf)2, phen or CuI R1 KF, air S8 + TMSCF3 R SCF3 R R1 DMF KF, CH2Cl2 or DMF 28 - 91 % 13 - 93 % (f) LG EWG (c) R R X EWG CuI, phen or CuSCN, R R SCF3 SCF DMF or Dioxane 3 DABCO, KF KF 23 - 94 % 28 - 95 % DMF Scheme 20 Use of elemental sulfur and Ruppert-Prakash

Weng and coll. reported a catalytic copper-mediated trifluoromethylthiolation of allylic halogens in presence of catalytic amounts of phenantroline, in dioxane ( Scheme 20, eq. c). Trifluoromethylthiolation of propargylic chlorides has been reported successfully reported. Their mechanistic studies are consistent with the CI-III catalytic cycle, thus oxidative addition of the allyl halide to form a CuIII complex and reductive elimination that leads to the formation of the allylic-

[102] SCF3 and generation of a the BrCu-complex ( Scheme 20, eq. c and d). The same group reported the trifluoromethylthiolation of α-bromo ketones reacting S8, TMSCF3 and KF in presence of catalytic amounts of Cu and ligand ( Scheme 20, eq. e). They concluded that a radical

CF3 species might be involved in the reaction, due to the formation of TEMPO-CF3 when the radical scavenger was added to the reaction media.[103] α-trifluoromethylthio ketones have been obtained in absence of a ligand to chelate the copper salt ( Scheme 20, eq. e).[104] Also the trifluoromethylthiolation of Morata-Baylis-Hillman carbonates has been achieved leading to

[105] primary allylic-SCF3 compounds ( Scheme 20, eq. f).

I.2.2.7 O-Octadecyl-S-trifluorothiolcarbonate

¯ O-Octadecyl-S-trifluorothiolcarbonate has been prepared and used as a donor of SCF3 anion by Zard and coll. They reported the trifluoromethylthiolation of gramines and -bromoketones in presence of KF and pyrrolidine to access high-yielded trifluoromethylthiolated compounds (Scheme 21, eq. a). [106] The trifluoromethylthiolation of Morita-Baylis-Hillman carbonates to lead

28 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

to primary SCF3 allylic products has been obtained in good yields, in presence of catalytic quantities of DABCO (Scheme 21, eq. c).[105]

F3CS R (a) N H R THF N O H Br 25 - 97 % R O O (b) KF, pyrrolidine SCF R 3 F CS OC H 3 17 37 THF / H2O 40 - 93 % OBocO

R O (c) O DABCO cat R O

THF or CH3Cl SCF3 37 - 96 % Scheme 21 Trifluoromethylthiolation using Zard's reagent

I.2.2.8 Trifluoromethanesulfenamides used in nucleophilic reaction

In the late 2000’s trifluoromethanesulfenamides has been synthesized in our labs. Since then they found a wide use in electrophilic trifluoromethylthiolation reactions developed by both our group and others (For more details see Trifluoromethanesulfenamides). Recently, trifluoromethanesulfenamides has been involved also in nucleophilic trifluoromethylthiolations in presence of n-BuNI, through a change in polarization of SCF3 group induced by iodine after the formation of CF3SI. Aliphatic alcohols as well as halogen, mesyl and tosyl derivatives have been trifluoromethylthiolated using these conditions.[107]

O N Bu4NI S SCF 3 + R-X R-SCF3 O Acetone 27 - 92 %

X= OH, Br,I, Cl OTs, OMs Scheme 22Trifluoromethanesulfenamides used as trifluoromethylthiolating reagents

29 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.3 Electrophilic trifluoromethylthiolation reactions

Synthetic methodologies for the development of electrophilic trifluoromethylthiolation reactions has been growing in number these last years due to the synthesis of several reagents that act as

+ SCF3 donors to circumvent the use of CF3SCl, a highly volatile and toxic gas.

I.2.3.1 Trifluoromethanesulfenyl chloride and bis-trifluoromethyl disulfide

The first reagent used in electrophilic trifluoromethylthiolation is CF3SCl, despite its volatility and toxicity. Nevertheless, CF3SCl showed good reactivity in trifluoromethylthiolating various molecules. Electrophilic addition to olefins[108] and aromatic electrophilic substitution to arenes[109] and heteroarenes[109b, 110] were successfully obtained. It showed good reactivity also towards Grignard reagents,[110a, 111] enolates[112] and enamines[113] (Scheme 23, eq. a – d). Recently, Glorius and coll. formed in situ CF3SCl, starting from Munavalli reagent and catalytic amounts of Lewis base. They reported the trifluoromethylthiolation of N-heteroarenes without the need of a transition metal (Scheme 23, eq. e).[114]

N SCF3

O (e)

O R1 O NaCl R R 1 R2 (c) (a) 2 R2 R1 R2 R1 F3CS CF CO H 6 mol % SCF3 3 2 Cl 41 - 68 % 88 - 95 % CF3SCl SCF3 (Het)ArH RMgX (d) (b) Het R SCF3 8 - 54 % 58 - 99 % N- Heteroarene

N- Heteroarene SCF3 52 - 96 %

Scheme 23 Trifluoromethylthiolation using CF3SCl

Another trifluoromethylthiolating reagent is the CF3SSCF3. Despite its toxicity and volatility,

CF3SSCF3 has been used in trifluoromethylthiolations. Daugulis and coll. reported the Cu- mediated trifluoromethylthiolation of β-sp2 C-H bond of benzoic acid derivatives in presence of a directing group (Scheme 24, eq. a).[115] Zhang and coll. described the in situ preparation of

CF3SSCF3 from the stable sodium sulfinate (CF3SO2Na) and the trifluoromethylthiolation of β- Csp2 bonds in indoles (Scheme 24, eq. b).[116]

30 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

O (b) Et O H (a) P NaSO2CF3 O CuCl Et DMSO O

N H R1 R1 N SCF3 N R2 R = H or R = Me, Cl H 2 2 O R1 CF3S SCF3 N toluene Cu(OAc)2 0.5 eq N H DMSO H R1 42 - 94 % N R2

R2= SCF3 or R2= Me, Cl 43 - 76 %

Scheme 24 Trifluoromethylthiolation using CF3SSCF3

I.2.3.2 Trifluoromethanesulfenamides

Trifluoromethanesulfenamide reagents have been developed in our laboratory as powerful tools in direct electrophilic trifluoromethylthiolations. In 2008 was reported the synthesis of trifluoromethanesulfenamide reagents as potential interesting compounds for use in medicinal or agrochemistry. The reaction between DAST and Ruppert-Prakash reagent in presence of a tertiary amine needed to activate DAST, and followed by the addition of a primary amine led to trifluoromethanesulfenamides (Scheme 25).[117] However, in the early beginnings those compounds were prepared as potential biologically active compounds.

1. DIEA MeI, NaH Et CH2Cl2 -25 °C (R= Ph) H N CF3SiMe3 + F CS N N 3 R SCF3 2. RNH2 R SCF3 TfOMe, DIEA Et R= Ts 3. H2SO4 (R= Ts) R= Ph (1st generation) Ts (2nd generation) Scheme 25 Syntheses of trifluoromethanesulfenamides

Surprisingly, was found that trifluoromethanesulfenamides could behave as SCF3 donors. The reaction between alkenes/alkynes and trifluoromethanesulfenamides in presence of Lewis or [118] Bronsted acid gave the expected SCF3-containing compounds (Scheme 26, eq. g). Both first and second generation of sulfenamides reacted with double bonds.[119] Acidic acitavation- mediated trifluoromethylthiolation of (hetero)aromatic compounds has been reported by our group and others as well.[119-120] Organometallic species underwent trifluoromethylthiolation in presence of a base or in base-free conditions. Aromatic, heteroaromatic compounds as well as terminal alkynes,[119, 120c, 121] reacted well in presence of catalytic amounts of base and acid[122] as

31 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions well (Scheme 26, eq. a-d and o). Also primary and secondary amines were trifluoromethylthiolated in basic conditions (Scheme 26, eq. e).[123] Z R1 R2 (j) BiCl F3CS 3 (i) ZR TsOH 3 SCF R NR (38-97%) 3 3 1 R2 NHR N Z = Y = O, S, NMe, R1 R2 SO NR2, C(O)O R = H, Me (52-96%) 2 R1 Z = , Y = N R2 SCF3

O O AcCl 2 2 (h) R R (k) R2 SCF3 R1 R1 R1 (44-89%) 1 (56-96%) R2 R Me Si 3 OTs BF /Et O R (l) 3 2 1 R 2 R B(OH)2 (g) TsONa R SCF 2 3 CuI, L, H2O (7eq.) R SCF3 (37-82%) R1 O (33-85%) O R1 1 R2 N (m) F CS (f) RSH R H 3 F3CS SR 2 N N H+ R N H (30-99%) H R N [Pd], PivOH R2 SCF3 (e) N Li (23-45%) H (n) R2 N R1 F3CS F3CS N N R1 R1 R2 (d) (12-95%) (o) [Pd], PhCOCl ROLi AgOAc (a) (c) F3CS OR 1 R R2 (p) (60-82%) R X SCF3 F3CS R TMPMgCl•LiCl X=H : BuLi (cat.) R Het (b) (44-89%) H ArH X=TMS : BiCl3 R Het (46-88%) or HetArH H+ or LA RMgX or RLi F3CS R R SCF 3 R H (42-94%) or CuI F3CS Ar F3CS SCF3 Ligand (19-99%) R H 42 - 93 % Scheme 26 Trifluoromethylthiolation reactions using sulfenamides

Electrophilic trifluoromethylthiolation of thiols through acidic activation has been reported by Jereb et al (Scheme 26, eq. f).[124] Qing and coll. reported the transformation of allyl silanes into secondary allyl trifluoromethylthiolated adducts (Scheme 26, eq. h).[125] A sequential and selective trifluoromethylthiolation-cyclization of tryptamines led to pyrrolidinoindolinic alkaloid motifs, and their cytotoxic activity was tested against three cell lines (Scheme 26, eq. i).[126] Diverse alkynyl or propargylic derivatives underwent trifluoromethylthiolation and subsequent cyclization leading to trifluoromethylthio- dihydrofurans,[127] benzofurans and benzothiophenes,[128] indoles,[129]

32 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions isocoumarin derivatives[130] benzofulvenes,[131] and benzothiazine dioxides [132] (Scheme 26, eq. j).

In most of the cases the presence of BiCl3 seems to be crucial for the reaction. Electrophilic trifluoromethylthiolation of α-ketones and aldehydes has been described with both stoichiometric[133] and catalytic[134] amounts of acid (Scheme 26, eq. k). Cu-catalyzed cross-

[135] coupling of boronic acids led to the formation of CF3S-containing moieties (Scheme 26, eq. l). 3 A selective palladium-catalyzed C(sp )-SCF3 bond formation, in presence of a directing group, in β position respect to the carbonyl has been described (Scheme 26, eq. m).[136] Liu and coll. reported Pd(II)-catalyzed C-H activation trifluoromethylthiolation of arenes by using pyridines as directing groups.[137] Recently it was reported the catalytic Cu-mediated trifluoromethylthiolation of alkynes, in presence of 1,10-phenantroline as a ligand to access alkynyl trifluoromethylthiolated compounds. By changing the amounts of Cu and using 2,2’-bipyridine they obtained the bis(trifluoromethylthiolated) alkene compounds (Scheme 26, eq. p).[138] Considering the importance of the reagent and the wide use of the reagent, their synthesis has been optimized and scaled-up without any decrease in yield efficiency.[139]

33 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.3.3 N-Trifluoromethylthiophtalimide and N-trifluoromethylthiosuccinimide

The first synthesis of N-trifluoromethylthiophalimide has been described by Munavalli and coll. in

2000, reacting the phtalimide salt with CF3SCl (Scheme 27, eq. a). Despite the synthesis of the reagent they reported only an example of trifluoromethylthiolation of a carbonyl compound in α position, starting from enamines.[140]

O R=K , X= Cl ( No Yield given) NR + R= Br, X= Ag 93 % CF3SX R= Cl, X= Cu 90 % O O Ar CO2R1 R O R O (a) H Ar SCF n 3 N SCF R 3 Boc quinidine cat R O (g) (b) n CO2R1 CH2Cl2 N (DHQD)2Pyr cat 46 - 97 % Boc toluene 85 - 99 % ee 75 - 90 % O 84 - 95 % ee (f) (c) R B(OH)2 RSH RS SCF CuCl cat, bpy 3 N SCF3 R SCF3 PhCF3 K SO DME 48 - 86 % 2 3, 50 - 95 % O R1 (e) (d) R1 N Li N SCF R or R H R 3 65 - 85 % RNH2 Cul cat, bpy R SCF3 PhCF Cs CO DCE R N SCF3 3 2 3, 51 - 95 % H 39 - 82 % Scheme 27 N-trifluoromethylthiophtalimide; Synthesis and reactivity

Considering the high toxicity and the corrosive character of the CF3SCl, two other methods for the preparation of N-trifluoromethylthiophtalimide has been reported. The use of Cu[141] and

[142] Ag trifluoromethylthiolate as less-toxic source of SCF3 led to the formation of the expected compound (Scheme 27, eq. a). Since then, the reagent found a wide use as SCF3 source. Rueping and coll. accessed to highly enantiopure β-trifluoromethylthiolated ketoesters employing quinidine as a catalyst (Scheme 27, eq. b).[143] Catalytic Cu-mediated trifluoromethylthiolation of aryl and vinyl boronic acids as well as terminal alkynes gave the expected compounds (Scheme 27, eq. c- d).[141-142] Entantioselective cinchona alkaloid-catalyzed trifluoromethylthiolation of relevant moieties such as oxindoles has been reported. The authors established by X-ray crystal structure [144] analysis that the (S) configuration has been obtained, as expected (Scheme 27, eq. g). N-SCF3 bond formation starting from primary and secondary amines, as well as S-SCF3 bond formation that led to aliphatic and aromatic disulfides has been reported (Scheme 27, eq. e and f).[145]

Another trifluoromethylthiolating reagent is N-trifluoromethylthiosuccinimide, prepared for the [146] first time in 1996, reacting silver succinimide with CF3SCl. Nevertheless, its first use in

34 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions electrophilic trifluoromethylthiolation reactions dates 2014. The synthesis has been later

[142] improved in order to avoid the use of CF3SCl (Scheme 28, eq. a). Shen and coll. described a C- H bond trifluoromethylthiolation catalyzed by palladium and proposed a mechanism, which follows a PdIII or PdIV complex formation pathway (Scheme 28, eq. b).[147]

DG H DG

SCF3 O Pd(CH3CN)4(OTf)2 cat. (b) AcOH NR + CF3SX 41 - 94 % (a) 85 - 99 % ee O O R1 S R3 R=Ag, X= Cl 85 % (c) R R2 R2 1 R= Br, X= Ag 95 % N SCF3 F3CS O dihydroquinine cat. SR3 (d) O MS 13X, CH2Cl2 48 - 71 % 83 - 95 % ee AgSCF3 + N Cl (d) R H O R H K PO DMA 3 4, 61 - 93 % Scheme 28 N-trifluoromethylthiosuccinimide; Synthesis and and reactivity

Zhou and coll. reported the synthesis of trifluoromethylthiolated dithiokethals in presence of catalytic amounts of dihydroquinine (Scheme 28, eq. c).[148] N-trifluoromethylsuccinimide has been also prepared in situ and used as a trifluoromethylthiolating agent in presence of silver (Scheme 28, eq. d).[149]

35 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.3.4 Trifluoromethylsulfenate reagents

Among the various reagents reported by Shen’s group, trifluoromethylsulfenates occupy an important position as electrophilic SCF3 donors. The reagent has been obtained by reacting the chlorobenziodoxole with trifluoromethylthiosilver (Scheme 29, eq. a).[150] The first reported structural formula describing the formation of an iodine-sulfur bond has been corrected latter. Buchwald and coll. reported evidences of the formation of a stable open thioperoxide based on spectroscopic and crystallographic studies (Scheme 29, eq. b).[151]

O O THF I SCF3 I Cl + AgSCF3 (a)

51 %

SCF3 F3CS I O I O

(b)

Scheme 29 a) First synthesis of the presumed SCF3-iodine hypervalent reagent. b) Wrong and corrected structural formula of the trifluoromethylsulfenate.

Trifluoromethylsulfenates has been already used in different reactions as electrophilic trifluoromethylthiolating sources. β-ketoesters underwent trifluoromethylthiolation giving the corresponding α-trifluoromethylthiolated compounds (Scheme 30, eq. a).[150] [152] Cu-catalyzed trifluoromethylthiolation of alkyl as well as (hetero)arylboronic acids and alkynes led to the corresponding trifluoromethylthiolated products (Scheme 30, eq. b and c).[150, 152-153] The same group reported the acid-catalyzed synthesis of trifluoromethylthiolated indoles (Scheme 30, eq. d).[152, 154] Trifluoromethylthiolated arenes have been obtained also by starting from Grignard reagents (Scheme 30, eq. e).[152] Racemic [152] and enantioselective[155] β-trifluoromethylthiolation of oxindoles has been obtained in the presence of DMAP or a chincona alcaloid (Scheme 30, eq. f and g). The same group reported the base-catalyzed enantioselective trifluoromethylthiolation of β-ketoesters (Scheme 30, eq h).[156] Even when the base has been substituted by an enantioselective copper-boxmi complex the method led to the formation of highly entantioselective final compounds (Scheme 30, eq. h).[157] Dai and coll. described the synthesis of

β-SCF3 carbonyl compounds after Cu-mediated ring opening of propanols (Scheme 30, eq. i). A CuI-II or a CuI-III mechanism for the ring opening and coupling has been proposed by the authors.[158]

36 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

R O O R1 O R R1 SCF3 N O O Boc n OR R1 O (a) R1 OR N DMAP, CH2Cl2 DMAP n (f) SCF3 75 - 95 % Boc CH2Cl2 R 25 - 98 % R B(OH)2 (b) Cu(MeCN) PF bpy R O 4 6, R= aryl 1 R SCF3 R N SCF3 or CuCl2.H2O alkyl SCF3 R O 30 - 95 % (hetero)aryl Boc (g) K2CO3, diglyme or DCE R1 O N (c) R 92 - 99 % Boc R SCF3 O CuBr(SMe ), bpy 73 - 98 ee (h) R= I, H 2 61 - 92 % K2CO3, DCE R1 CO2R (d) O n R quinine, toluene 1 CO2R or R1 (i) N SCF3 SCF3 Cu(OTf)2, Boxmi n CH Cl R 2 2 R 49 - 97 % 1 (e) CSA, DCE N 20 - 94 ee OH MgBr R R R O SCF3 SCF3 R1 R R TFH CuSCF3, bpy R1 DMSO 44 - 92 % Scheme 30 Trifluoromethylsulfenates as trifluoromethylthiolated reagents

I.2.3.5 N-Trifluoromethylthiosaccarin

Another reagent developed by Shen’s group is the N-trifluoromethylthiosaccarin, obtained [159] reacting N-chlorosaccarin and AgSCF3. Different functional groups such as alcohols, thiols and amines underwent trifluoromethylthiolation in presence of N-trifluoromethylthiosaccarin (Scheme 31, eq. g). Also trifluoromethylthiolation of alkynes has been obtained in the presence of a copper salt (Scheme 31, eq. f). CF3S-containing β-ketoesters, α-ketones and aldehydes has also been obtained starting from the corresponding starting materials (Scheme 31, eq. e).[159] Trifluoromethylthiolation of electron-rich (hetero) arenes in presence of catalytic or equimolar amounts of Lewis or protic acid, has also been reported (Scheme 31, eq. b).[159-160] Trifluoromethylthiolation of pyrroles and indoles in presence of a directing group led to the formation of the desired products through a Rh-catalyzed C-H activation (Scheme 31, eq. a).[161]

Zhao and coll. reported the vicinal SCF3-amination and SCF3-esterification of double bonds in a multicomponent reaction mediated by selenium disulfide as a catalyst (Scheme 31, eq. d).[162] Also the trifluoromethylthio lactonization/lactamization of olefins catalyzed by a Lewis acid has been described (Scheme 31, eq. c).[163]

37 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

H N N Y= NHCOR, R OCOR R 1 Rh cat, AgSbF SCF YR R3 CN or 6 3 3 Zn(OTf) N R3 COOH 2 SCF3 (d) R Diarylselenide cat (a) DCE N R1 TfOH, H2O 42-94 % O CH3CN (Het)Ar H O 61-91 % R O O (b) FeCl or AuCl or H R (e) 3 3 R S FeCl3/AgSbF6 SCF3 1 N SCF (Het)Ar SCF 3 or TMSCl or 3 Et N, CH Cl O 3 2 2 CF SO H 50-97 % O 3 3 R R1 (f) DCE (c) SCF3 50-99 % R Y (g) 1

R1 R CuI, pyridine R1 Y= O, NHR R1 SCF3 57-86 % THF Y SCF3 TMSCl, CH CN 3 R RYH Y= O, S, NH R SCF3 35-98 % 66-95 % Et3N, CH2Cl2 Scheme 31 Reactivity of N-Trifluoromethylthiosuccinimide

38 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.2.3.6 Trifluoromethanesulfenyl hypervalent iodonium ylide

Shibata and coll. reported the synthesis of a novel trifluoromethanesulfonate hypervalent

Iodonium ylide, which showed good reactivity in presence of various nucleophiles. The CF3SO2 moiety is reduced into a reactive CF3S species by an intramolecular rearrangement. When an amine is added to the reaction media the authors reported the formation of an ammonium salt, which might be responsible of the trifluoromethylthiolation (Scheme 32, eq. a and b).[164] Also trifluoromethylthiolation of pyrroles in presence of copper has been achieved (Scheme 32, eq. c).[165] Aryl and vinyl boronic acids have been trifluoromethylthiolated in a Cu-mediated coupling [166] reaction leading to the SCF3-containing compounds (Scheme 32, eq. f). Shibata and coll. reported also the trifluoromethylthiolation of primary and secondary aromatic amines, this could be an alternative way to access to the trifluoromethanesulfenamide reagents (Billard reagents) (Scheme 32, eq. e).[167] Copper-catalyzed trifluoromethylthiolation of allyl silanes and silyl enol ethers under the same reaction conditions gave the corresponding compounds (Scheme 32, eq. d).[168]

R 1 NH

R OH R2 2 R R3 1 NH R R3 CuCl cat (a) R R R 3 R R 1 (d) dioxane 2 2 3 CuF 2 SCF3 CF3 R S DMAC 74-96 % R1 O (b) R R 15-85 % (e) O 2 1 SCF3 N SO2CF3 H R B(OH)2 R2 R1 R= aryl R SCF3 CuCl, PhNMe Cu(OAc) IPh N vinyl 12-55 % 2 dioxane H DMAC 32-84 % (f) (c) R1

R H (g) N N N Ar R R R1 SCF3 Ar SCF3 SiMe CuF2 cat 3 CuF NMP 71-95 % X 2, N NMP R R X 49-99 % R 1 SCF R 3 CuF2, DMAC R1 X= C, O 22-82 % Scheme 32 Trifluoromethanesulfenyl hypervalent Iodonium reagent ad its reactivity

I.2.3.7 Trifluoromethylthiosilver (I) as an electrophilic reagent

+ AgSCF3 has been used also an electrophilic CF3S reagent in presence of TCCA

(tricholoroisocyanuric acid). Tan and coll. reported the entantioselective synthesis of CF3S-

39 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions oxindoles in presence of a chincona-base organocatalyst (Scheme 32, eq. a).[169] Although

CF3SSCF3 has been identified as the trifluoromethylthiolating species; the authors reported also the involvement of other unidentified SCF3 species in the electrophilic trifluoromethylthiolation. (a) (b) Ar

R O O N Ar O N O SCF3 Boc R Cl Cl SCF3 (DHQD)2 pyr cat N N R O AgSCF + 3 THF N THF, then TFA O H O N O 70-94 % 50-95 % Cl 83-94 % ee

Scheme 33 AgSCF3 used as an electrophilic SCF3 donor

Also the synthesis of chromenones bearing an SCF3 unit has been obtained in presence of the [170] dual system AgSCF3/TCCA methodology (Scheme 32, eq. b).

40 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.3 S-CF2H and S-CF2FG bond formation; indirect approach

As shown in the SCF3 chemistry, the most common approach for the synthesis of SCF2H or

SCF2FG (FG= SO2Ph, COR, halogen except F, SAr) molecules is the difluoromethylation of thiols, thiolates or disulfides. When we started the project the direct introduction of SCF2H and

SCF2FG into molecules lacked of reagents and synthetic strategies. During the last two years there have been reported various methods and two shelf-stable reagents to access difluoromethylthiolated molecules.[171]

I.3.1 Difluoromethylation with difluorocarbene sources

There already exist several difluorocarbene sources in literature involved in difluoromethylation of C- O-, S-, Se-, N- and P- nucleophiles. Difluorocarbene precursors such as ClCF2H,

TMSCF2X (X= Cl, Br, F), CF3H, HCF2OTf, BrCF2PO(OEt)2, ClCF2CO2Na and many others has been extensively used throughout the years (For a more detailed review concerning difluorocarbene sources see reference [172]). Herein, we will report the difluoromethylation of S- centers.

I.3.1.1 ClCF2H as a difluorocarbene source One of the first compounds that have been employed as a difluorocarbene precursor is the chlorodifluoromethane, a gas, which is concerned by the Montreal Protocol restrictions due to its ozone depletion and global warming potentials. 1 In the late 50’s, Porter and coll. reported evidences of the formation of a difluorocarbene species in a α-dehydrohalogenation reaction catalyzed by sodium methoxide, with concerted loss of proton and chloride ion. They also noticed that such a reactive species, in presence of thiophenoxide gave the corresponding difluoromethylthiol (Scheme 34, eq. a). Furthermore, based on their kinetic calculations,d

[173] evidences were foun that such reaction could not pass through an SN2 mechanism. More than 20 years later such considerations has been proven unambiguously by deuterium exchange studies.[174] Schots and coll. reported the difluoromethylation of thiols, through the formation of a [175] difluorocarbene in presence of a strong base in dioxane/H2O media (Scheme 34, eq. b). Nevertheless, such methodologies suffer a main drawback, the consumption of difluorocarbene in presence of high concentrations of base.[176] Langlois described an improved synthetic strategy to tackle down such a inconvenience, using a biphasic solid-liquid system: NaOH being the solid

1 Halocarbon Scenarios, Ozone Depleting Potentials and Global Warming Potentials. Chapter 8 J. S. Daniel, G. J. M. Velders From: Scientific Assessment of Ozone Depletion 2006.

41 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions phase and TDA-1 used to transport anionic salts thus making easier their solubility (Scheme 34, eq. c).[177]

N SH N Ar SH N H (a) (e) SCF2H MeONa/MeOH 63 % N i-PrOH/H2O H 56 % O (b) Ar SH ClCF2H Ar SCF2H O NaOH, dioxane/H2O 60-81 % HS (d) (c) Ar SH NaOH, dioxane/H O 56-85 % HF2CS 2 48 % NaOH, TDA-1 toluene or trichlorobenzene Scheme 34 Chlorodifluoromethane as a difluorocarbene precursor

Difluoromethylation of heteroaromatic moieties like mercaptazoles has been also investigated. In the case of the mercaptazole shown in Scheme 34 eq. e, difluoromethylation of thiol is reported as a major product. N- and S- bis(difluoromethylation) has also been observed in a 5 % yield. On the other hand, the presence of electron-donating groups on the benzene ring highly influences the reaction pathway. Enhancement of the nucleophilicity over the N-center led to the formation of N- and S- bis(difluoromethylated) compounds.[178] Later on, Yagupolskii and coll. found out, in the difluoromethylation of 5-sulfonyltetrazoles, that at low temperatures the kinetic product is

[179] the S-CF2 whereas N-SCF2 product formation is favoured at high temperatures. Also the difluoromethylation of acetophenone has been reported in a scale-up reaction (700 mmol) confirming the robustness of such method (Scheme 34, eq. d).[180]

I.3.1.2 CF2Br2 and ClCF2Br as difluorocarbene sources Bromochlorodifluoromethane, a restricted-use gas nowadays from the Montreal Protocol, has been used as a difluorocarbene generator.

SH KOH, TEBA SCF2Br + CF2BrX R benzene R X= Br, Cl 10-75 % R= OMe, H, Br, NO2

Scheme 35 Bromodifluoromethylation using CF2Br2 and ClCF2Br

[181] Wakselman and coll. used both ClCF2Br and the more benign CF2Br2 as carbene precursors, in this case leading to the formation of SCF2Br an interesting moiety especially for post- functionalization. Although the formation of SCF2Br derivatives had been obtained using both

42 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

reagents, CF2Br2 gave a slightly higher yield. The presence of functional groups in para position influences the overall yield of the reaction. Meanwhile the electron-withdrawing power decreases the total yield, with an increase in the formation of SCF2H derivative at the expense of SCF2Br. An ionic mechanism through a carbenic pathway has been proposed totally in accordance with the obtained results.

I.3.1.3 SCDA, PDFA and TFDA as difluorocarbene sources

Sodium chlorodifluoroacetate (SCDA) has been one of the first difluorocarbene precursors used in carbene chemistry by Haszeldine. Moreover, it does not face any environmental or restrictive issues. Nevertheless, his role in difluorocarbene chemistry is quite modest.

N SH R O SH SCF2H N Cl OMe R K2CO3, DMF K2CO3, DMF SCF2H F F 61-91 % 51-93 % Scheme 36 SCDA as a difluorocarbene precursor

Greaney and coll. used SCDA as a source to difluoromethylate aromatic and heteroaromatic thiols compounds in relatively mild conditions. Also in this case, at high temperatures the N-SCF2H formation increases (Scheme 36).[182] Difluoromethylene phosphobetaine (PDFA) has also been used as a difluorocarbene precursor in the difluoromethylation of activated S-H bonds as well as primary and secondary benzylic thiols under mild conditions and in absence of a base (Scheme 37).[183]

X SH R R Ph O N SH SCF H Ph X X= C, N R 2 P R Ph O dioxane p-xylene N SCF H F F 2 43-61 % 65-92 % Scheme 37 PDFA as a difluorocarbene precursor

Trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TDFA) has been used as a difluoromethylating agent. S-difluoromethyl thioimidates have been obtained starting from thioamides in a reaction catalyzed by tetramethyldiaminonaphtalene (Proton Sponge) (Scheme 38).[184]

43 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

O O S O Proton Sponge cat SCF2H + S OSiMe R NHAr F 3 toluene R NAr F F 12-71 % Scheme 38 TFDA as a difluorocarbene precursor

I.3.1.4 Diethyl bromodifluoromethylphosphonate and Difluoromethyltri(n- butyl)ammonium chloride

Segall and coll. reported the difluoromethylation of thiophenols using BrCF2PO(Et)2 as a difluorocarbene generator, via a hydrolysis-based P-C bond cleavage, and subsequent trapping of the carbene species formed (Scheme 39, eq. a).[185]

BrF2C P OEt OEt (a)

KOH, CH3CN/H2O

SCF2H SH R 54-96 % n-Bu3N(CF2H)Cl (b) NaH, CH3CN

Scheme 39 Phosphonate-CF2Br and TBA-CF2Cl complexes as difluorocarbene sources

Hu and coll. disclosed the use of n-Bu3(CF2H)Cl as a difluorocarbene source to easily access S- [186] CF2H moieties, obtaining good yields (Scheme 39, eq. b).

I.3.1.5 HCF3, TMSCF2Br and HCF2OTf as difluorocarbene sources

As reported above in this dissertation, fluoroform (HCF3) is formed as a waste by-product in a large volume during the manufacture of refrigerants, Teflon, foams, and many other materials. Its non-toxic, environmentally-benign, ozone-non-depleting features combined with the low price make it an interesting trifluoromethylating reagent. It has been also used as a starting material in the synthesis of Ruppert-Prakash reagent TMSCF3. With the aim to avoid the use of ozone- depleting difluorocarbene generators and on the same time consume a waste formed from the manufacturing industry, Dolbier and coll. used fluoroform as a difluorocarbene precursor for the difluoromethylation of thiophenols (Scheme 40, eq. a).[187] Hartwig and coll. reported the synthesis of the non-ozone-depleting and liquid difluoromethyltriflate (HCF2OTf), starting from triflic acid and TMSCF3. HCF2OTf has been used in the synthesis of difluoromethylating aromatic thiols Scheme 40, eq. b).[188] The Rupert-

44 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Prakash reagent has been involved also in the synthesis of TMSCF2Br, another reagent belonging the silane family used in difluoromethylation.

(a) HCF3

KOH, H2O/dioxane or H2O/CH3CN R= (hetero)aryl (b) HCF OTf benzyl 2 R SCF H RSH 2 alkyl KOH, CH3CN/H2O 62-99 %

(c)

TMSCF2Br 20 % aq. KOH CH2Cl2

Scheme 40 Fluoroform, HCF2OTf and TMSCF2Br as difluorocarbene sources

Hu and coll. described the difluoromethylation of aryl, alkyl and heteroaryl thiols using bromodifluoromethane. In the case of heteroaryl compounds regioselective difluoromethylation at the S atom has been obtained.[189]

I.3.1.6 N-Tosyl-S-difluoromethyl-S-phenylsulfoximine as a difluorocarbene source

A novel shelf-stable difluoromethylating α-difluoromethylsulfoximine compound has been prepared starting from difluoromethylsulfoxide and PhINTs in presence of copper triflate. Efficient difluoromethylation of benzylic and heteroaromatic thiols has been performed in presence of NaH.

RSH

1. NaH, DMF S NTs R CF2H O O 2. NTs 44-94 % S I S CF2H + Cu(OTf)2 cat CF2H CH3CN 60 %

Scheme 41 Synthesis of a sulfoximine derivative and its use as a difluorocarbene source

Despite the fact the reagent lacks in efficiency concerning regioselective difluoromethylations

[190] over S atom it still remains a valuable tool in difluoromethylation reactions.

I.3.2 Radical Difluoromethylation

Less attention has been given to the insertion of CF2H or CF2FG groups into molecules through radical difluoromethylation reactions with the aim to obtain S-CF2H(FG) bonds. Herein are

45 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions disclosed the most used reagents and synthetic pathways involved to obtain S-containing compounds.

I.3.2.1 DFMS, ICF2COOEt; new reagents for radical difluoromethylation Important breakthrough in radical difluoromethylation of heteroarenes especially, is the work of

Baran and coll. where the preparation of Zn(SO2CF2H)2 has been reported. Although most of the work concerns difluoromethylation of N-heteroarenes, three valid examples of regioselective difluoromethylation over the S-atom of thiols has been reported (Scheme 42.[191]

R R X Zn(SO2CF2H)2 X SH SCF H t-BuOOH, TFA 2 N N CH2Cl2/H2O X= N, S, O 61-69 % R= H, CH3 Scheme 42 DFMS used as a difluoromethylating reagent

A visible light-induced Ru-mediated photocatalytic example of ethoxycarbonyldifluorometylation of a cysteine moiety has been performed using both batch and flow processes. Continous-flow microreactors show a slight increase in the yield of the final products (Scheme 43).[192]

F F OEt O SH O S Ru(bpy)3Cl2 O ICF2CO2Et

HN OtBu TMEDA, CH3CN HN OtBu

O O 75 %

Scheme 43 Insertion of CF2CO2Et as a functional group

I.3.3 Nucleophilic difluoromethylation of disulfides

I.3.3.1 Difluoromethyl trimethylsilane, difluoromethyl phenyl sulfone and α- fluorodiaroylmethanes

Difluoromethyl phenyl sulfone occupies an important position as a difluoromethylating agent in nucleophilic substitution reactions. Its peculiar ability to behave as difluoromethylene dianion 2- (CF2 ) has been exploited by Prakash et al. As reported in Scheme 44, by increasing the amount of equivalents of t-BuOK and disulphide, they could obtain the PhS-subsituted sulfone or PhS- disubstituted compound as a major product.[193]

46 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

O F O F F F t-BuOK F F F S F + PhSSPh S + S + S O H O S Ph S Ph H

t-BuOK 1.5 eq 91 % 3 % 6 % t-BuOK 3 eq PhSSPh 2 eq 41 % 44 % 14% t-BuOK 4 eq PhSSPh 2 eq 0 % 99 % 0 %

Scheme 44 Difluoromethyl phenyl sulfone and its reactivity in presence of nucleophiles

Difluoromethyl trimethylsilane (TMSCF2H) has been used in the difluoromethylation of disulfides giving rise to aromatic, heteroaromatic and alkyl difluoromethylthioethers employing CsF desilylating agent (Scheme 45, eq. a).[194] On the other hand, using t-BuOK as a base only formation of difluorobis(arylthio)methanes has been reported as the only product obtained (Scheme 45, eq. a and b).[194b] Also α,α-difluorodiaroylmethanes in presence of a nucleophile and a base can lead to the formation of aryl and heteroaryl α-thioaryl-α-α-difluoroacetophenones. However, increasing the temperature of the reaction the authors could obtain the aryl and heteroaryl difluoromethylated thiols in good yields (Scheme 45, eq c and d).[195]

Cs CO O O CsF 2 3 (d) (a) R SCF2H R SCF2H DMSO, rt Ar Ar DMF or NMP 70-98 % 34-99 % F F R S TMSCF2H O S R S Cs2CO3 t-BuOK (c) (b) R SCF2S R Ar R DMSO, 80 °C F F DMF 40-90 % 47-94 % Scheme 45 TMSCF2H and α-fluorodiaroyl methanes used as difluoromethylating agents

Hu and coll. reported the use of sodium bromodifluoroacetate as a perfluoroalkylating reagent with differently substituted aromatic thiols (Scheme 46).[196]

SH 1. NaH, dioxane SCF2COOH R R 2.BrCF2CO2Na 3. 3MHCl (aq) Scheme 46 Sodium bromodifluoroacetate as a perfluoroalkylating reagent

I.3.3.2 (NHC)Ag(CF2H) in nucleophilic difluoromethylations N-heterocyclic carbene difluoromethylated silver complex has been prepared by Shen and coll. It has been employed in the preparation of N-difluoromethylthiophtalimide, the first electrophilic reagent used in difluoromethylthiolations. The authors scaled the synthesis up to 175 mmol obtaining a yield of 66 %. Moreover, the chlorinated silver complex has been recycled to give the

47 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

NHC-ligated difluoromethylated silver complex yielding 83 %, in presence of TMSCF2H as a difluoromethylating agent (Scheme 47).[197].

TMSCF2H, tBuONa, THF, 83%

O iPr iPr O iPr iPr N N toluene N SCl + Ag CF2H N SCF2H + Ag Cl N N O iPr iPr O iPr iPr 66 %

Scheme 47 (NHC)Ag(CF2H) in the synthesis of N-difluoromethylthiophtalimide

Electrophilic difluoromethylthiolations using N-difluoromethylthiophtalimide will be reported on the appropriate section

I.3.4 Electrophilic difluoromethylation of thiols and thiolates

A few reagents and methodologies concerning electrophilic difluoromethylation of thiols and thiolates have been reported. Herein, three different reagents involved in electrophilic difluoromethylathion of molecules over the S-atom have been reported.

I.3.4.1 Rupert-Prakash reagent and a sulfoximine derivative used in electrophilic difluoromethylation

Recently, the use of Ruppert-Prakash reagent as a difluoromethylating source has been reported. Electrophilic difluoromethylation of aromatic and aliphatic thiols, after desilylation of the in situ formed (trimethylsilyl)difluoromethylthiol compounds, using a F- source has been successfully obtained (Scheme 48).[198]

LiH, LiBF4, DMF KF or TBAF RSH R SCF2TMS R SCF2H TMSCF3 24-86 % Scheme 48 Prakash-Ruppert as a difluoromethylating electrophilic reagent

N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate, Johnson’s trifluoromethylating agent analogue, is one of the few difluoromethylating reagents involved in S- C bond formation through electrophilic difluoromethylation reactions. Prakash et al. reported the synthesis of the before-mentioned reagent in 3 steps starting from difluoromethyl phenyl sulfoxide. However, the difluoromethylation of thiolates has been obtained after a second methylation of the reagent in situ and subsequent addition of the proper thiolate in a second time

48 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

(Scheme 49). Authors referred that deuterium studies led to the conclusion that an electrophilic pathway takes place.[199]

O R SCF2H S 19-78 % CF2H O BF4 NMe S 2 CF2H

1.MeO3BF4, CH2Cl2 NaN CH Cl 3, 2 2 2.RSNa, CH2Cl2 oleum (20 % SO3) in-situ formed O active species O NMe NH 1.MeO3BF4, CH2Cl2 S MeO3BF4 S CF2H CF2H 2.NaHCO3 CH2Cl2

Scheme 49 N,N-dimethyl-S-difluoromethyl-S- Sulfoximinium tetrafluoroborate as a difluoromethylating species formed in situ

I.3.4.2 Hypervalent iodine(III)-CF2SO2Ph reagent A Togni-analog reagent has been developed for electrophilic (phenylsulfonyl)difluoromethylation of aromatic, heteroaromatic and benzyl S-nucleophiles under mild conditions (Scheme 50). The reagent itself has been obtained after an acetoxylation of the hypervalent iodine(III)-Cl derivative and (phenylsulfonyl)difluoromethylation of the intermediate in situ with a 71 % yield.[200]

CF2SO2Ph I DMF RSH + O R SCF2SO2Ph 72-87 %

Scheme 50 Togni-like reagent for (phenylsulfonyl)difluoromethylation

I.3.5 C-S-CF2H(FG) in situ bonds formation

Another practical way to access SCF2R compounds is the consecutive C-S-CF2H(FG) bond formation. Two works embracing such strategy have been recently reported to literature.

I.3.5.1 Copper thiocyanide and N-thiocyanatosuccinimide

Copper thiocyanide has been employed as a SCN donor contributing in the C-SCN bond formation in situ and a further difluoromethylation of the intermediates in a Langlois-type nucleophilic substitution gave the desired SCF2H compounds. Goossen and coll. reported the synthesis of HCF2S-molecules in a one-pot methodology accessing to aryl, heteroaryl and alkyl [201] HCF2S containing compounds. Thiocyanates, bromo-derivatives, tosylates and diazonium salts used as starting materials underwent in a first moment thiocyanation and Cu-mediated difluoromethylation to give rise to HCF2S containing molecules (Scheme 51, eq. a, b and d).

49 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

R SCN Ar N2BF4 CuSCN 1 .CuSCN, Cs2CO3, NaSCN (d) (a) TMSCF2H, CsF Ar SCF2H R SCF H 2. CuSCN, CsF, TMSCF H DMF 2 61-95 % 2 85-99 % CH3CN/DMF O R CuSCN 1 R O 2 N2 (c) ROTs R1 (b) RBr R2 R SCF2H CuSCN, TMSCF2PO(OEt)2, 1. NaSCN SCF2PO(OEt)2 61-98 % CsF, H2O, CH3CN/NMP 2. CuSCN, CsF TMSCF2H, DMF 18-72 %

Scheme 51 CuSCN used for in situ SCF2H(FG) formation

Poisson and coll. accessed to α-difluoromethylthiolated phosphonates in a reaction involving α- diazocarbonyl compounds, CuSCN and a difluoromethylsilyl derivative containing a phosphonate group (Scheme 51, eq. c).[202]

1. NTS, AlCl3 N SCN 2. TMSCF H, CuSCN, CsF Ar H 2 Ar SCF H CH CN/DMF 2 O 3 59-88 % NTS Scheme 52 In situ thiocyanation and difluoromethylation

Goossen and coll. reported the difluoromethylthiolation of arenes in a one-pot two-step process, starting from AlCl3-mediated thiocyanation of arenes followed by Cu-mediated difluoromethylation of the thiocyanide formed in situ (Scheme 52).[203]

50 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.4 C-SCF2H and C-SCF2FG bond formation; direct approach

Direct insertion of SCF2H or SCF2FG into molecules is more appealing than indirect difluoromethylation of thiols because it could pave the way to access to a plethora of different compounds bearing SCF2H or SCF2FG group, thus not only limiting the choice to S-containing adducts. Since we have been working on this project, also other groups contributed on the progress of such chemistry by the development of new reagents or new methodologies for direct

SCF2H or SCF2FG insertion. Based on our bibliography research only 6 very recently published papers concerning difluoromethylthiolation have been reported, all of them during the period 2015-2016.

I.4.1 Radical difluoromethylthiolation reactions

I.4.1.1 N-difluoromethylthiophtalimide

N-difluoromethylthiophalimide, as its SCF3-analogue has been used in the radical difluoromethylthiolation of alkyl carboxylic acids. A visible light-promoted reaction, in presence of an Ir catalyst led to the difluoromethylation of primary, secondary and tertiary alkyl carboxylic acids. Mechanistic elucidations given by the authors suggest a hole-catalyst chain process as a possible mechanistic pathway.

O OCH3

O PCI cat X Z CsOBz cat, F3C X or Z F R COOH + N SCF H R SCF H tBu 2 blue LED's l= 455 nm 2 N 68-90 % N N F Ir R= alkyl O CF N N 3 N tBu

F F PCI Scheme 53 N-difluoromethylthiophtalimide in direct radical difluoromethylthiolation

The group of Shen reported the synthesis of a N-heterocyclic carbene difluoromethylthiolated

[204] silver complex starting from the previously synthesized compound ((NHC)Ag(CF2H)) and metallic sulfur (S8) in THF at room temperature (Scheme 54, eq. a). Shen and coll. reported the difluoromethylthiolation of aryl and heteroaryl diazonium salts in a Cu-mediated Sandmeyer-type reaction (Scheme 54, eq. b and c). Moreover, in order to circumvent the pre-syntheses of diazonium salts a one-pot procedure for their synthesis followed by difluoromethylthiolation has been reported (Scheme 54, eq. d).[205] CuI-II species are involved in the reaction leading through a single electron transfer (SET) mechanism.

51 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

N2BF4

SCF2H (b) Cu(MeCN)4PF6/bpy

CH3CN 45-92 % (a) (c) N2BF4 iPr iPr Het S8 (NHC)Ag(CF H) N SCF2H 2 Cu(MeCN)4PF6/bpy THF Ag SCF2H Het N CH3CN iPr iPr 32-88 % NH2 R

SCF2H (d) 1. tBuONO, HBF4, CH3CN R 2. Cu(MeCN)4PF6/bpy, CH3CN 53-95 % Scheme 54 (NHC)Ag(SCF2H) in SET reactions

I.4.2 Nucleophilic difluoromethylthiolation reactions

Up to now only one reagent has been used in nucleophilic difluoromethylthiolation reactions.

I.4.2.1 (NHC)Ag(SCF2H) complex in difluoromethylthiolation As reported above, direct difluoromethylthiolation of aromatic and heteroaromatic compounds is limited to the use of aryl and heteroaryl diazonium salts. Even though such methodology showed wide applicability in terms of group tolerance the explosive nature of diazonium salts could limit its practical applications.

(a) (b) X I R Het iPr iPr R SCF H X= I, Br, OTf 2 N SCF2H Pd(dba)2, DPEPhos R Het Ag SCF2H R Pd(dba)2 ou toluene (XantPhos)Pd(3-py)(Br) cat N 33-99 % XantPhos cat iPr iPr 46-99 %

Scheme 55 (NHC)Ag(SCF2H) in nucleophilic difluoromethylthiolations

In order to circumvent the use of diazonium salts Shen and coll. reported the difluoromethylthiolation of heteroaryl bromides, iodides, triflates and aryl iodides through a Pd- mediated cross-coupling reaction.[206]

I.4.3 Electrophilic difluoromethylthiolation reactions

Recently, two reagents involved in direct difluoromethylthiolation and one reagent able to

+ generate SCF2PO(OEt)2 has been reported to literature up to now.

52 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

I.4.3.1 N- difluoromethylthiophtalimide

The synthesis of N-difluoromethylthiophtalimide reported by Shen and coll. has already been described in the previous sections. It has been used in electrophilic difluoromethylthiolations of a variety of molecules (Scheme 56). Copper-catalyzed difluoromethylthiolation of alkynes, using copper(I)-thiophen-2-carboxylate had been successfully applied (Scheme 56, eq. a). The reagent showed a good reactivity also in difluoromethylthiolation of primary and secondary amines as well as aniline derivatives (Scheme 56, eq. b).

H R H R SCF2H CuTc, bpy (g) (a) R SCF H R K CO diglyme 2 2 3, 59-97 % TMSCF3, DCE 58-96 % O H (b) N SCF2H R1 R (HO)2B N SCF2H N toluene R1 R O (c) 74-99 % (f (d)) HF2CS CuI, bpy RSH R SSCF2H Li2CO3, diglyme DCE (d) 63-93 % 40-92 % O (e) R

O O CO2R R n N SCF2H SCF2H Boc O n CO2R K2CO3, CH2Cl2 K2CO3, CH2Cl2 N 75-96 % Boc 87-88 % Scheme 56 N-Difluoromethylthiophtalimide as a difluoromethylthiolationg source

Difluoromethyl substituted disulfides have been obtained by reacting the reagent with thiolated adducts (Scheme 56, eq. c). β-ketoesters and 2-oxindoles have been difluoromethylthiolated in presence of potassium carbonate as a base (Scheme 56, eq. d and e). Difluoromethylthiolation of electron-poor arenes has been achieved in a Cu-mediated coupling reaction of aryl boronic acids. Also vinyl boronic acids gave the difluoromethylthiolated products in good yields (Scheme 56, eq. f). Electron-rich heteroarenes has been difluoromethylthiolated in a Friedel-Craft reaction in presence of a Lewis acid (Scheme 56, eq. g).[197]

I.4.3.2 Difluoromethanesulfenyl hypervalent iodonium ylides reagents

Shibata and coll. reported the synthesis of a new hypervalent iodonium ylide difluoromethylthiolating reagent, the analog of the trifluoromethylthiolating iodonium ylide. A series of different ylides has been prepared and two of them successfully engaged in difluoromethylthiolations of different classes of compounds. α-bromoketones reacted with sodium difluoromethanesulfinate to give the corresponding sufonylacetophenones, which in

53 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions presence of KOH and hypervalent iodonium compounds led to the formation of iodonium ylides (Scheme 57).

O SO CF H PIDA, KOH 2 2

CH CN IPh O 3 R O O S R= H 71 % Br NaO CF2H SO2CF2H R= NO2 85 %

DMAc R R O R= H 79 % mesityl-I(OAc) 2 SO CF H R= NO2 76 % KOH 2 2 CH CN IMes 3 R R= H 39 % R= NO2 93 % Scheme 57 Syntheses of hypervalent iodonium ylides

β-enamino esters had been difluoromethylthiolated in presence of Cu-catalyzed reaction leading to the formation of α-SCF2H-β-enaminoesters (Scheme 58, eq. a). Adopting the above conditions, difluoromethylthiolation of heteroaromatic compounds as pyrroles and indoles has been performed (Scheme 58, eq. b and c).

NH2 O R R 1 N 2 R 1 R2 R R O R3 1 2 O N R2 1. CuBr (f) O SCF2H R SCF2H 2. 1N HCl (a) R3 1 CuBr cat dioxane 56-73 % O O 76-90 % (e) O O SO CF H R CO2R 2 2 SCF H (b) N 2 IR H R CO R R 2 CuBr or CuF2 cat 1 CuBr cat N SCF2H 36-75 % K2CO3 R= Ph, Mes dioxane H R =H, NO 1 2 (c) 46-91 % Ph SCF2H R R H NNH .H O (d) 2 1 2 2 2 N SCF2H N N dioxane O R H R2 R1 CuBr cat 68 % Ph NMe2 N dioxane R 42-85 % tBu N Ph tBuC( NH)NH2HCl N MeONa, dioxane SCF2H 65 % Scheme 58 Difluoromethylsulfonyl hypervalent iodonium ylide reagents for difluoromethylthiolations

β-ketoesters gave the corresponding difluoromethylthiolated products in presence of a base and

Cu salt ( Scheme 58, eq. e). α-SCF2H-β-esters and ketoesters has been obtained in a one-pot procedure starting from β-enamino esters followed by a hydrolysis (Scheme 58, eq. f). A similar

54 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions one-pot procedure based on the difluoromethylthiolation of N-protected β-enamino ester and subsequent cyclohydration gave compounds having a pyrazole and a pyrimidine structure (Scheme 58, eq. d). Mechanistically the reaction proceeds through a Cu-catalyzed carbene formation, leading to the formation of oxathiirine-2-oxide, itself involved in a further rearrangement to sulfoxide which collapses to a thioperoxoate that might be responsible for difluoromethylthiolation as authors claimed.[207]

I.4.3.3 MesNHSCF2PO(OEt)2 reagent Very recently, inspired by our works, Besset and coll., prepared a (phosphonate)difluoromethanesulfenamide reagent, through a (phosphonate)difluoromethylation of corresponding thiocyanate.

NHSCN CuSCN (a) TMSCF2PO(OEt)2, CsF

R SCF2PO(OEt)2 N R H H N (b) R TsOH, CH Cl R SCF PO(OEt) 2 2 N N 2 2 H (f) 83-91 % NHSCF2PO(OEt)2 R TFA, (c) SCF2PO(OEt)2 CH Cl 58-91 % 2 2 R (e) TsOH, CH2Cl2 R SH 56-70 % R SSCF2PO(OEt)2 MsOH (d) O 55-86 % CH2Cl2 R O R1 SCF2PO(OEt)2 CH3COCl 3 eq R1 25-72 % Scheme 59 (Phosphonate)difluoromethanesulfenamide reagent used as a source of (phosphonate)difluoromethylthiolations

SCF2PO(OEt)2 group has been transferred to aromatic and heteroaromatic compounds as well as in α position of ketones in acidic conditions (Scheme 59, eq. b, c, d). Also primary and secondary aromatic amines as well as thiols gave the compounds bearing the difluoromethylphosphonate (Scheme 59, eq. f and e).[208]

55 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II. Results and Discussion- C-SCF2FG bond Formation

Several methodologies and reagents used in electrophilic trifluoromethylthiolation were already known at the beginning of 2014. On the other hand, direct insertion of SCF2FG/H into molecules was totally unexplored. Thus, an urgent need for the development of reagents and/or methodologies in order to access moieties bearing SCF2FG could be a main interest especially in agrochemicals and pharmaceuticals.

In this chapter, we describe the syntheses of new reagents that act as SCF2FG donors and their use in electrophilic aromatic substitution and addition reactions.

II.1 Syntheses of novel sulfenamides bearing a SCF2FG group

II.1.1 State of the art: Syntheses of sulfenamides

As reported above, trifluoromethanesulfenamides were the first electrophilic trifluoromethylthiolating reagents that found a wide use in methodology thus becoming a real alternative to the highly volatile and toxic ClSCF3.

Since 2009, trifluoromethanesulfenamides has been used as donors of SCF3 activated by both electrophilic and nucleophilic ways (See Electrophilic Trifluoromethylthiolations). Trifluoromethanesulfenamides are prepared by reacting DAST with Ruppert-Prakash in presence of a base and later the reaction is quenched with a proper primary amine. Also a mechanism has been proposed by our group (Scheme 60).[117]

R1 R2 N Et F Et F Si CF3 F F F R3 F N Et S Et S NS F Si S Et N F N CF3 F Et F CF3 F Et Et

+ - Ar NH2 -H ,F

R -H+,F- H Ar H H F N N H F3C N S S Ar S _ N CF3 F3C N Scheme 60 Reaction mechanism for the syntheses of sulfenamides

56 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.1.2 Syntheses of (PhSO2)CF2TMS

Based on literature data shown above and our expertise in the synthesis of sulfenamides, we planned the syntheses of four different sulfenamide reagents.

H H H H N N N N SCF2SO2Ph SCF2H SCF2Br SCF2CO2Me

1a 1b 1c 1d Figure 1 Sulfenamide reagents: goal of the project

As reported in Scheme 60 to access sulfenamides, the reaction involves the use of DAST and a corresponding silane. Silanes Si2, Si3 and Si4 are commercially available and do not need to be prepared.

O F F F F CF2SiMe3 S F F O O Br Si H Si Si O

Si1 Si2 Si3 Si4 Figure 2 Silanes used as starting materials

On the other hand, silane Si1 needs to be synthesized. Several synthetic pathways were tested to obtain Si1. Firstly the reaction between difluoromethylphenylsulfone and BuLi as a strong base followed by the addition of a silane source to obtain the desired compound was explored.

Table 1 Preparation of (Trimethylsilyl)Difluoromethylphenyl

O F CF H R-SiMe BuLi O F S 2 3, S SiMe3 O THF, -78 °C O Si1 Entry R-TMS Additive Yield %

1 ClSiMe3 BuLi 1.2 eq 10 %

2 Imidazol-SiMe3 BuLi 1.2 eq

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard

When TMSCl was used as a silane source two peaks were detected at 19F NMR after 2 hours. A peak at -112.81 ppm corresponds to our desired compound and has been obtained with a 10 % dosed yield, and a doublet between -122.21 and -122.40 ppm corresponding to the starting material which is not entirely consumed (only 20 % found). In the case of trimethylsilylimidazol only difluoromethylphenyl sulfone was observed. Considering the low yield obtained we changes

57 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions synthetic strategy. In a first moment we planned the synthesis of bromodifluoromethyl phenylsulfone, which would lead to the silylated derivative after a transmetallation reaction. Based on literature procedures,[209] we tried to access S2 by using NaOBr formed in situ from aqueous NaOH and Br2. Bromine was added to the aqueous solution of NaOH at low temperatures (around 5 °C) dropwise, following the reported procedure. Unfortunately, as shown in the table below the reaction is not reproducible, neither on a small scale. At this point a new pathway for the synthesis of Si1 was explored.

Table 2 Synthesis of bromodifluoromethyl phenylsulfone

O O 1. NaOH aq. 15 % w/w, CF2Br CF2H S S Br2 , 0-5 °C O O 2. 75 °C, 3h

Entry Br source eq Yield %

1 3 eq -

2 5 75 %

3a 5 -

4 5 -

5 5 70 % 6 5 70 %

7 5 -

8b 3 45 %

9a 3 40%

10 3 -

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. Reactions were run over 1 mmol scale. a Reactions was run over 10 mmol scale. b Reaction was run over 5 mmol.

S1 was prepared from thiophenol and dibromodifluoromethane in DMF with a 60 % yield based on literature procedures.[210] Thiophenol is converted to the corresponding thiolate after addition of sodium hydride. Addition of CF2Br2 gave the desired compound, passing through the formation of a difluorocarbene. Three equivalents of m-CPBA gave the oxidized analog in a good yield in 24 h. Compound S2 underwent transmetallation in presence of BuLi and TMSCl following a slightly modified procedure[211] yielding 80 %. Using 1.1 equiv. of BuLi and 1.3 equiv. of TMSCl the reaction gave only 40 % of yield.

58 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

1. NaH 1,5 equiv. O SH CF2Br 0-25 °C, 1 h SCF2Br m-CPBA 3 equiv. S O 2. CF2Br2 3 equiv. CH2Cl2, 0-25 °C - 35 °C, DMF S1 24 h S2 60 % 93 %

BuLi 2.2 equiv. THF, -78 °C TMSCl 2.6 equiv. 3.5 h

BuLi 1.1 eq = 40 % TMSCl 1.3 eq O CF SiMe S 2 3 O

Si1 80 % Scheme 61 Synthesis of compound Si1

II.1.3 Syntheses of sulfenamides

We started exploring reaction conditions for the synthesis of sulfenamide reagents with the commercially available silanes Si2 and Si3 at the beginning. After the activation of DAST in

CH2Cl2 with DIEA we added (difluoromethyl)trimethylsilane, followed by the addition of aniline after one hour. However, at the end of the reaction TMSCF2H was found to be quantitative in the reaction mixture (Table 3,entry 1). TMSCF2H is known to be more stable than TMSCF3 with a bond order value (0.432) of almost the double respect to Ruppert-Prakash reagent (0.220). [212] Therefore, harsher reaction conditions are needed in order to cleave the Si-CF2 bond. When THF was used as a solvent, a slight consumption of the silane was observed, but the only 19 compound formed seems to be CH2F2, observed by F NMR. Even by increasing the temperature up to 70 °C (Table 3, entry 2-4), we did not observe the formation of the desired product. However, it seems that the fluoride generated from the DAST is not strong enough to cleave the Si-C bond, thus we thought that the addition of a supplementary fluoride source could be beneficent for the reaction. Nevertheless, no changes were observed in the reaction media when CsF was used, probably due to its insolubility in THF (Table 3, entry 5). On the other hand, using a soluble fluoride source as TBAT only 25 % of TMSCF2H was found in the reaction media after 19F NMR spectroscopy analysis. But still we were far from solving our problems, 19 because only the formation of CF2H2 was detected by F NMR spectroscopy (Table 3, entry 6).

Among various fluorinated moieties bromodifluoromethylthio (SCF2Br) could be a valuable group especially in post-functionalization reactions. Its direct introduction into molecules would supply very interesting building blocks that could find use in 18F radiolabeling. In order to

59 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

prepare SCF2Br donating sulfenamide reagent we first reacted TMSCF2Br with DAST, followed the addition of aniline after 1 hour. Unfortunately, no product was formed although only 10 % of the starting silane was found intact in the reaction mixture (Table 3, entry 7). Even running the reaction at lower temperatures, no formation of compound 1c was observed (Table 3, entries 8-

10). Using THF instead of CH2Cl2 no traces of silane were found in the reaction media (Table 3, entries 11-13). Also when 3 eq of TMSCF2Br were used in THF or CH3CN/DIEA the silane went to complete degradation (Table 3, entries 14-16).

Table 3 Tentatives for the synthesis of sulfenamides

F F F F 1. Base 1.1 equiv.,Temp °C, H 1 h, solvent N F Si + F S N Ph S R R F 2. Ph-NH2 1 equiv., 25 °C, 16 h R= H, Si2 1.1 eq R= H, 1b R= Br, Si3 R= Br, 1c 1 Remaining Entry R Base Solvent T (°C) (%) Silane (%)

1 H DIEA CH2Cl2 -25 °C - 100 % 2 H - THF -25 °C - 85 % 3 H - THF 25 °C - 85 % 4 H - THF 50 °C - 70 % 5a H - THF 70 °C - 70 % 6b H - THF -45 °C - 25 %

7 Br DIEA CH2Cl2 25 °C - 10 %

8 Br DIEA CH2Cl2 -25 °C - 45 %

9 Br DIEA CH2Cl2 -45 °C - 60 %

10 Br DIEA CH2Cl2 -80 °C - 100 % 11 Br - TFH 25 °C - - 12 Br - TFH -45 °C - - 13 Br - TFH -80 °C - - 14c Br - TFH 25 °C - -

c 15 Br DIEA CH3CN 25 °C - -

c 16 Br DIEA CH3CN -25 °C - -

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. Reactions were run for 1 hour before addition of aniline. a 1 eq of CsF were used. b 1 eq of TBAT were used. c 3 eq of TMSCF2Br were used.

Such results confirmed once more the instability of TMSCF2Br and its capacity to decompose into difluorocarbene. The addition of a silaphilic Lewis base (like F- source) to fluorinated silanes leads to the formation of a pentacoordinated intermediate, which reacts with a suitable electrophile. In the case of TMSCFBr, the generated pentacoordinate intermediate is unstable

60 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions and decomposes into a difluorocarbene. Such findings are consistent with data found in literature.[189] For the synthesis of sulfenamide 1a we first used the optimized conditions employed in the synthesis of the trifluoromethanesulfenamides. As shown in Table 4 entry 1, no formation of compound 1a was observed by 19F NMR. When the reaction was run at 25 °C the formation of an intermediate was detected by 19F NMR represented by an AB system between -104.5 and - 107.5 ppm. Quenching the reaction with aniline, we observed a new peak at -89.84 ppm in 19F NMR that corresponds to compound 1a, obtained with a 25 % dosed yield in 16 h (Table 4, entry 2). A further increase in temperature or the use of 2 equiv. of DIEA did not improve the yield significantly (Table 4, entries 3-7). Table 4 Synthesis of (phenylsulfonyl)difluoromethylsulfenamide

F F 1. Base 1.1 equiv., Temp °C, H O O F N 1 h, solvent Ph S S S Si + F S R F 2. Ph-NH2 1 equiv., O O 25 °C, 16 h F F 1.1 eq Si1 1a Yield Entry Base R Solvent T (°C) Time h (%) a 1 DIEA N(Et)2 CH2Cl2 -25 °C (1 h) -

2 DIEA N(Et)2 CH2Cl2 25 °C (1 h) 25 %

b 3 DIEA N(Et)2 CH2Cl2 40 °C (24 h) 35 %

4 DIEA N(Et)2 CH2Cl2 60 °C (1 h) 10 %

d 5 DIEA N(Et)2 CH2Cl2 60 °C (18 h) 25 %

b 6 DIEA N(Et)2 CH2Cl2 40 °C (2 h) 40 %

b 7 DIEA N(Et)2 CH2Cl2 40 °C (2 h) 45 %

8 DIEA Morpholine CH2Cl2 25 °C (2 h) -

c 9 DIEA Morpholine CH2Cl2 60 °C (2 h) -

10 - N(Et)2 THF 25 °C (2 h) 60 %

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. a Reactions were run for 48 h after the addition of aniline. b Reactions were run at 40 °C after the addition of aniline. c Reactions were run at 60 °C after the addition of aniline. d 2 eq of DIEA were used

Using Morph-DAST instead of DAST we did not observe any formation of intermediate or final product (Table 4, entries 8-9). After various efforts we discovered that the solvent play an important role in the reaction mechanism. Thus, by substituting CH2Cl2 with THF compound 1a was obtained with 60 % yield without adding any base. In the synthesis of trifluoromethanesulfenamides in CH2Cl2 the use of a base to activate DAST remains crucial, but

61 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions when THF was used as a solvent the electron pair belonging to the oxygen atom in the THF might play the role of the base activating the DAST. With the aim to access more sulfenamides reagents, difluoromethyl(trimethylsilyl)acetate, Si4, was involved in a reaction with DAST in presence of DIEA. Quenching the reaction with a proper amine would give the desired product. Based on the previous results obtained during the synthesis of 1a, we first tried the reaction in THF, and CH2Cl2/DIEA at 25 °C (Table 5, entries 1-2). In both cases the formation of the intermediate was observed in 19F NMR with a 20 % dosed yield, represented by an AB system signal between -110.35 and -112.62 ppm. After 1.5 h, aniline was added to the reaction media leading to the formation of a peak at -93.05 observed in 19F NMR. The peak corresponds to the compound 1d, which was obtained with a 20 % yield (total conversion of the in situ formed intermediate). Decreasing the temperature at -25 °C the yield was doubled up to 40 % when the reaction was run in CH2Cl2, 32 % by using CH3CN as a solvent and 35 % by using THF as a solvent (Table 5, entry 3-4 and 6). A further decrease of the reaction temperature up to -50 °C did not improve the overall yield of the reaction (Table 5, entry 5). The addition of the amine after only 30 minutes, did not lead to the formation of compound 1d (Table 5, entry 7).

Table 5 Synthesis of 1d

F F F F 1. Base 1.1 equiv., Temp °C, H 1 h N O F Si + F S N Ph S 2. Ph-NH 1 equiv., MeO C F 2 O 2 25 °C, 16 h Si4 1.1 eq 1d Yield Entry Base Solvent T (°C) Time h (%)

1 DIEA CH2Cl2 25 °C (1.5 h) 20 % 2 - THF 25 °C (1.5 h) 20 %

3 DIEA CH3CN -25 °C (1.5 h) 32 %

4 DIEA CH2Cl2 -25 °C (1.5 h) 40 %

5 DIEA CH2Cl2 -50 °C (1.5 h) 32 % 6 - THF -25 °C (1.5 h) 35 %

7 DIEA CH2Cl2 -25 °C (0.5 h) -

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

As shown above, the synthesis of two novel reagents has been successfully achieved and both reactions were scaled-up to 100 mmol without affecting the yield. Both compound 1a and 1d were successfully used as difluoromethylthioalkylating reagents in electrophilic reactions.

62 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.1.3.1 N-methylation of sulfenamides

Based on the previous studies concerning the use of sulfenamides as trifluoromethylthiolating reagents, we observed that a N-methylation leads to a fully-exploitation potential of those reagents. This is due to the acidic character of the hydrogen bounded to nitrogen. Thus, the N- methylated analogues have been used for the trifluoromethylthiolation of Grignard compounds, base-catalyzed trifluoromethylthiolation of α-ketones and alkynes, Cu-mediated trifluoromethylthiolation of boronic acids and alkynes, and trifluoromethylthiolation of alcohols in basic conditions. Keeping in mind the urge of pharmaceutical and agrochemical companies to access to different classes of adducts bearing SCF2R groups, capable to modulate their physico- chemical properties we planned the methylation of our two reactants.

Table 6 N-methylation reactions of reagents 1a and 1d

F F Base 1.2 equiv., F F H R -Me 1.2 equiv. N 1 N Ph S R Solvent, Temp °C Ph S R 3h R= SO2Ph 1a R= SO2Ph 1aa R= CO Me 1d 2 R= CO2Me 1dd T (°C) Yield Entry R Base Me-R Solvent 1 Time h (%)

1 SO2Ph NaH MeI DMF 0 - 25 °C -

a 2 SO2Ph DIEA MeOTf CH2Cl2 25 °C -

3 SO2Ph NaH MeOTf DMF 0 - 25 °C -

CO2Me -10 - 25 4 NaH MeI DMF - °C

5 CO2Me DIEA MeOTf DMF 25 °C -

6b CO2Me LDA MeOTf THF 0 - 25 °C -

7b CO2Me KHMDS MeOTf THF 0 - 25 °C -

c 8 CO2Me - TMSCH2N2 MeOH 25 °C -

d 9 CO2Me DIEA Me2SO4 CH2Cl2 -20 °C -

d 10 CO2Me n-BuLi Me2SO4 THF -20 °C -

11 CO2Me n-BuLi MeOTf THF -20 °C -

e 12 CO2Me DIEA BF4OEt3 CH2Cl2 -20 °C -

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. a 2 eq OF MeOTf were used. b 1.5 eq of both MeOTf and base were used. c 4 eq of TMSCH2N2 were used. d 1.3 eq of Me2SO4 were used. e 2.5 eq of BF4OEt3 were used.

Unfortunately, the N-methylation of 1a and 1b did not lead to the desired compounds 1aa and

1dd. Different methylating sources (MeI, MeOTf, Me2SO4, TMSCH2N2, BF4OEt3), in presence of various bases (NaH, DIEA, LDA, KHMDS, n-BuLi) and changing reaction conditions as

63 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions solvents and temperature has been unsuccessfully tested (Table 6, entries 1-12). In most of the cases only remaining starting material could be detected by 19F NMR.

II.2 Electrophilic (phenylsulfonyl)difluoromethylthiolation using a shelf-stable reagent

II.2.1.1 State of the art: interest of phenylsulfonyl part.

Sulfones were denominated “chemical chameleons” by Prof. Trost due to their ability to behave as nucleophiles in basic media and electrophiles in Lewis acid media.[213] Thus, molecules bearing a phenylsulfonyl group could represent a valuable choice to access new adducts through post- functionalization reactions by displacing the PhSO2 group. Moreover, its high electronic parameters (σm = 0.62 and σp = 0.68) and low Hansch parameter (πR = 0.27) could be exploited to modulate the physico-chemical properties of the molecules.

OH O NH O O O N S S OH S O O O N O N O O N CN NO O PSPC HDACI Rilmakalim

O O S S O O

S S N N O O

thiophene imino dye derivative

BPSPF Figure 3 Presence of phenylsulfonyl-containing molecules in material and life science

Over the years, phenylsulfonyl group has demonstrated to be a valuable tool in both material and life science. PSPC (3-(phenylsulfonyl)-pyrazinecarbonitrile) showed a remarkable antibacterial activity against both gram-negative and gram-positive bacteria, meanwhile its sulfide analog showed no activity at all.[214] Phenylsulfonyl-furoxan based hydroxamates showed histone deacetylase inhibitory and NO donating activities in a multifunctional drug approach strategy.[215] Phenylsulfonyl group is found also in Rilmakalim, a molecule that exhibits vasodilatation by

64 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions opening ATP-sensitive K+ channels.[216] Phenyl sulfonyl group has been also incorporated into molecules used in materials as dyes[217] or OLEDs.[218]

Consequently, the synthesis of molecules bearing a SCF2SO2Ph substituents could lead to valuable compounds for further applications.

II.2.1.2 SEAr reactions using (phenylsulfonyl)difluoromethanesulfenamide In order to test the efficiency of 1a as an electrophilic (phenylsulfonyl)difluoromethylthiolating [118, 120d] reagent and based on previous results obtained with electrophilic SCF3 reagents we planned the acid-mediated insertion of PhSO2CF2S moiety into aromatic and heteroaromatic compounds. Indole was chosen as the compound of choice with the aim to fine-tune the reaction conditions. Reagent 1a showed good reactivity in presence of excess, stoichiometric as well as catalytic amounts of p-toluenesulfonic acid leading to compound 3a with 89 %, 69 % and 48 % respectively (Table 7, entries 1-3).

Table 7 Acid-mediated activation of reagent 1a

F F SCF2SO2Ph H O N H+ or Lewis acid + S S Ph N O Solvent, Temp °C H N 16 h H 2a 1a 3a Entry Acid (eq) Solvent T (°C) Yield (%)

1 p-TsOH 2.5 equiv. CH2Cl2 50 °C 89 %

2 p-TsOH 1 equiv. CH2Cl2 50 °C 69 % 3 p-TsOH 20 mol % DCE 80 °C 48 %

4 TMSCl 1 equiv. CH3CN 80 °C 83 %

5 TMSCl 1 equiv. CH3CN 25 °C 75 %

6 TMSCl 20 mol % CH3CN 80 °C 48 %

7 TfOH 2.5 equiv. CH2Cl2 50 °C -

8 TfOH 1 equiv. CH2Cl2 50 °C 80 % 9 TfOH 20 mol % DCE 80 °C 61 %

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

Also the use of a stronger protic acid as triflic acid (TfOH) was found efficient in catalysing the reaction in stoichiometric or catalytic amounts with 80 % and 61 % yield respectively. (Table 7, entries 8-9). On the other hand, when 2.5 equiv. of TfOH were used neither product formation

65 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions was observed, nor traces of 1a were found in the reaction media after checking with 19F NMR (Table 7, entry 7). Activation of 1a was obtained also using stoichiometric amounts of a soft Lewis acid as trimethylsilyl chloride (TMSCl) at 80 °C and 25 °C in acetonitrile, with a yield of 83 % and 75 % (Table 7, entries 4-5). Addition of catalytic amounts of TMSCl led to compound 3a in a 48 % yield (Table 7, entry 6). With the optimized conditions in hand (Table 7, entry 1) we extended the reaction scope to other electron-rich aromatic and heteroaromatic substrates.

CO2H SCF2SO2Ph CO2H MeO NH2 SCF2SO2Ph SCF2SO2Ph N N N SCF2SO2Ph H H H N H 3a 3b 3c 3d 85 % (89 %) 57 % (61 %) 99 % (quant.) 80 % (quant.)

SCF2SO2Ph SCF2SO2Ph PhO2SF2CS OMe SCF2SO2Ph

Br N N N H H H MeO 3e 3f 3g 3i 86 % (95 %) 58 % (67 %)c 84 % (90 %)b 80 % (85 %) OH OH OH OMe

SCF2SO2Ph SCF2SO2Ph

HO I SCF2SO2Ph SCF2SO2Ph 3j 3k 3l 3m 89 % (95 %) 89 % (quant.)a 84 % (100 %) 30 % (45 %)a

SCF2SO2Ph OH Br O O2N SCF2SO2Ph SCF2SO2Ph O HO S N benzo[d][1,3]dioxole

3n 3p 3q 3o (0 %) 45 %a (22 %) (0 %)a

SCF2SO2Ph SCF2SO2Ph Br N N PhO2SF2CS N CHO H N N 3r 3s 3t (0 %)d, (0 %)d, (0 %)b, c, d Figure 4 SEAr reactions of electron rich arenes with reagent 1a. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR. a TfOH 1 equiv.; b TMSCl 1 equiv. 80 °C; c TMSCl 1 equiv. 25 °C; d TMSCl 1 equiv. 50 °C;

Heteroaromatic scaffolds as indoles and pyrroles, known for their use in pharmaceuticals and/or agrochemicals were successfully (phenylsulfonyl)difluoromethylthiolated. Compounds 3a-e were obtained with good to excellent yields except the β-methylated indole 3b which was obtained

66 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

with 57 % yield. Various functional groups as –Br, -OMe, -COOH, -NH2 were tolerated and in the case of the tryptophan 2d there was no need to protect the amino group and the carboxyl function. Compound 3f was obtained using 1 equiv. of TMSCl at room temperature. An increase in temperature did not lead to the formation of any product. On the other hand, 3g was obtained with a better yield at 80 °C. The use of a milder acid as TMSCl in the case of pyrroles come from the high sensitivity of pyrroles to acidic condition’s, leading easily to polymerisation. Pyrrole 2t did not lead to the formation of the compound 3t, whatever the conditions. Also electron-rich aromatics, 3i and 3j were obtained with 80 % and 89 % yield respectively. Phenols as 2k and 2l needed a stronger acid to be activated, therefore leading to compounds 3k and 3l in presence of 1 equiv. of TfOH. Less electron-rich compounds as 2m and 2n gave their corresponding

PhSO2CF2S derivatives with lower yields, 30 % and 45 % respectively. Also in this case the use of a stronger acid as TfOH was necessary. When N-dimethylaniline reacted with 1a in presence of p-TsOH a peak at -81.56 ppm was detected in 19F NMR, which presumably corresponds to compound 3o. Unfortunately, we were not able to isolate compound 3o in order to have further evidences concerning its formation. Heteroaromatic compounds as benzothiophene 3p, benzodioxole 3q and dihydroimidazopyridines 3r-s did not give any formation of desired compounds, certainly due to their lower reactivity.

67 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.2.1.3 Electrophilic addition reactions on alkenes and alkynes

Protic or Lewis acid-mediated reaction between reagent 1a and alkenes were performed. In the case of trifluoromethanesulfenamides the best results were obtained in presence of a Lewis acid [118] and a tosylate salt. In the case of reagent 1a, the addition of SCF2SO2Ph to cyclohexene after activation of 1a by TsOH gave 5a in 77 % dosed yield whereas only 70% was obtained in Lewis acid conditions (Table 8, entries 1-2). An AB system was observed in 19F NMR corresponding to compound 5a, which was isolated with 61 % yield. An increase in temperature resulted in lower yields, 60 % when a protic acid was used and no product formation when a Lewis acid was used (Table 8, entries 3-4).

Table 8 Electrophilic addition on alkenes using 1a

SCF2SO2Ph H Nu N Acid, Nu + SCF2SO2Ph Solvent, Temp °C 15 h 4a 1a 5a Entry Acid / Nu (eq) Solvent T (°C) Yield (%)

1 p-TsOH 2.5 equiv. CH2Cl2 50 °C 77 %

2 BF3.Et2O / p-TsONa 5 / 1.5 equiv. CH2Cl2 50 °C 70 % 3 p-TsOH 2.5 equiv. DCE 80 °C 60 %

4 BF3.Et2O / p-TsONa 5 / 1.5 equiv. DCE 80 °C -

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

Whatever the conditions, only the trans product is formed, demonstrating the stereoselectivity of the reaction. With our best conditions in hand, we extended the scope to other alkenes. Addition to 1- dodecene gave compound 5b in a modest yield but as the only product based on 19F NMR analysis. As in the case of 5a the signal in 19F NMR is represented by an AB system and is the only signal we could observe. This demonstrates the high regioselectivity of this reaction, because only the Markovnikov product is observed.

68 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

SCF2SO2Ph TsO SCF2SO2Ph SCF2SO2Ph OTs OTs 5b 5a 5c (from (Z)-oct-4-ene) 61 % (77 %) 43 % (49 %) 54 % (62 %)

Figure 5 Electrophilic addition of SCF2SO2Ph to double bonds. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR

Electrophilic addition to (Z)-oct-4-ene led to the formation of 5c, and the trans conformation was obtained in a 54 % yield, confirming the stereoselectivity of the reaction. Only a single peak was observed in 19F NMR at -77.53 ppm as the sole formed peak after 15 h. Performing the same reaction using (E)-oct-4-ene, as a starting material only 30 % compound 5d was isolated, half respect to the Z enantiomer. However, only one diastereomer has been formed (the other one compare to Z-isomer) demonstrating the stereospecificity of the reaction. Furthermore, during the reaction, the allylic product 6d was also formed. It seems that the tosylate attack to the intermediate sulfenium is disfavoured due to steric hindrance and deprotonation in α-position is favoured, thus leading to the formation of the allylic compound 6d (Scheme 62, eq. a). Using an acid that has a less nucleophilic conjugate base as triflic acid, leads to the exclusive formation of the allylic compound with 58 % yield (Scheme 62, eq. b).

CF2SO2Ph CF2SO2Ph S R H R (a) S R N or SCF SO Ph + + TsOH 2 2 R R R 2.5 equiv. H H H H OTs OTs R= Et

35 % 30 %

(b) SCF2SO2Ph H TsO SCF2SO2Ph N R TfOH 2 eq SCF2SO2Ph + R R R R R CH2Cl2, 50 °C 16 h 6d 5d 58 %

Scheme 62 Mechanism involved in the formation of 5d and 6d

Based on the obtained results, we presume a mechanism involving the formation of a transient + episulfonium center. Protonation of 1a leads to the transfer of SCF2SO2Ph to form an episulfonium cation, which opens after the conjugated base (TsO- anion) approaches from back, to give the compound 5a with a trans configuration.

69 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

H TsO Ph NH3 N TsOH 2.5 eq SCF SO Ph + 2 2 + S TsO

4a 1a CF2SO2Ph

TsOH + Ph NH2

SCF2SO2Ph

OTs 5a Scheme 63 Mechanistic insight during the formation of the episulfonium intermediate

Considering the low nucleophilicity of weak conjugate bases as TfO-, the TfOH-mediated activation of 1a leads to the formation of compound 5e through an intramolecular cyclization reaction. Once the sulfonium intermediate is formed, the triflate anion is not enough nucleophilic to open it, thus the available electron pair of the aromatic ring attacks in α-position of the sulfenium intermediate, causing ring opening and giving compound 5e with a 71 % isolated yield (Scheme 64).

H N SCF SO Ph TfOH 2 eq + 2 2 CH2Cl2, 16 h SCF2SO2Ph 4e 1a 5e 71 % (75 %)

TfO S CF2SO2Ph Scheme 64 Intramolecular cyclization of terminal alkenes

After the encouraging results obtained in the acid-mediated addition of SCF2SO2Ph to alkenes, we performed the addition to alkynes using the same strategy. Contrary to alkenes, the use of a protic acid was less effective than a Lewis acid and the tosylate salt as a nucleophile. Adding 2.5 equiv. of p-TsOH to a mixture of 1a and alkyne at room temperature did not lead to the formation of the expected compound. Only the presence of starting material (1a) was observed after 48 h in 19F NMR spectroscopy (Table 9, entry 1). Increasing the temperature at 50 °C, a peak at -81.50 ppm was observed in 19F NMR, which corresponds to the desired compound, with

70 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions a dosed yield of 35 % (Table 9, entry 2). However, a further increase in temperature resulted deleterious for the reaction, giving the desired compound with only 15 % dosed yield (Table 9, entry 6). Fortunately, using boron trifluoride as a Lewis acid the reaction gave a yield of 26 % already at room temperature. Further increasing in temperature led to an improvement in yields, 44 % at 50 °C and 63 % at 80 °C (Table 9, entry 4-5).

Table 9 Addition to alkynes

H N OTs SCF2SO2Ph Acid, Nu R H + SCF2SO2Ph Solvent, T °C R Time h 1a R= C5H11 Entry Acid / Nu (eq) Solvent T (°C) Time h Yield (%)

1 p-TsOH 2.5 equiv. CH2Cl2 25 °C 48 h -

2 p-TsOH 2.5 equiv. CH2Cl2 50 °C 48 h 35 %

3 BF3.Et2O / p-TsONa 5 / 1.5 equiv. CH2Cl2 25 °C 48 h 26 %

4 BF3.Et2O / p-TsONa 5 / 1.5 equiv. CH2Cl2 50 °C 48 h 44 %

5 BF3.Et2O / p-TsONa 5 / 1.5 equiv. DCE 80 °C 24 h 63 % 6 p-TsOH 2.5 equiv. DCE 80 °C 24 h 15 %

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

The following reaction conditions were successfully applied to three different alkynes, 7a-c, obtaining single stereo- and regio-isomers 8a-c in modest to good yields

OTs OTs SCF2SO2Ph

SCF2SO2Ph SCF2SO2Ph OTs

8a 8b 8c 60 % (63 %) 42 % (46 %) 42 % (45 %) Figure 6 Electophilic addition to alkynes. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR

As in the case of alkenes, a transient episulfenium species is supposed as an intermediate leading to the final compounds by means of a nucleophilic attack mediated by the tosylate anion, which causes the opening of the sulfenium species.

II.2.1.4 Reductive desulfonylation: Access to SCF2H compounds

Difluoromethylthio (SCF2H) is an emerging group in fluorine chemistry, and there is still a lot of need for reagents and different ways to access difluoromethylthiolated molecules. As shown in

71 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions the bibliographic part, very recently there have been reported two shelf-stable reagents and other synthetic methodologies to access difluoromethylthiolated molecules. Thus, we thought of accessing difluoromethylthiolated compounds through a reductive desulfonylation reaction by taking advantage of the good capacity of phenylsulfone as a leaving group. Reductive desulfonylations are typically accomplished with metal amalgams. However, considering the difficulties in the preparation and use of the amalgams and the environmental hazards they do present there was a need to substitute such reductants with safer ones. Hu and coll. accessed to difluoromethylated carbonyl compounds by a magnesium metal-mediated desulfonylation reaction using AcOH/NaOAc as a proton source.[219] Based on already reported

[220] procedures we first tried a LiAlH4-mediated desulfonylation in THF. A typical doublet 19 corresponding to the SCF2H group appeared in the F NMR spectra between -93.54 ppm and -

93.75 ppm. Substituting the reductive system with Mg/I2 using MeOH as a proton donor and as a solvent the dosed yield improved to 89 %.

LiAlH4 (10 equiv.) THF, 0-55°C 4h (50%) OMe OMe SCF2H SCF2SO2Ph

MeO MeO 3i (89%) 9e Mg (30 equiv.) I2 (0.3 equiv.) MeOH, RT 4h Scheme 65 Reductive desulfonylation of compound 3e

Taking for granted the above reaction conditions as the best ones, we applied it to the different classes of compounds previously synthesized in order to access to various difluoromethylthiolated molecules. Compound 9a was isolated with a yield of 88 %. Also the indole and the pyrrole derivatives gave excellent isolated yields, 95 % and 82 % respectively. The intramolecular cyclization product 5e was also successfully reduced to 9e. In the case of compound 5a simultaneous desulfonylation and tosylate hydrolysis were obtained, leading to the compound 9d, in excellent yield. A further advantage of this methodology is that the final compounds were directly obtained after a simple work-up process, thus no need to use other purification techniques.

72 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

CO H OMe 2 SCF2H MeO SCF2H SCF2H N N MeO H H 9a 9b 9b 88% (89%) 95% (quant.) 82 %

SCF2H OH

SCF2H 9d 9e 92% 86% (94%) Figure 7 Reductive desulfonylation of different classes of compounds. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR

II.2.1.5 Reductive desulfonylation: Access to SCF2D compounds Deuterium is the stable isotope of the hydrogen, discovered by Harold Urey in 1932. Since is discovery, deuterium has been reported in a myriad of scientific publications. Nevertheless, the most common way to access deuterated compounds remains the isotope exchange methodology. Thus, the development of novel methods to access to such compounds is demanding considering also the recent interest of pharmaceutical companies towards deuterium. Being the stable isotope of hydrogen makes deuterium its best bioisostere without bringing any change on steric grounds. C-D bond is reported to be 6-10 times stronger than the C-H bond, thus an increase in stability towards oxidative processes has to be expected. As a consequence incorporation of deuterium into drugs could lead to drastic modifications to ADMET properties.[221] On late 2016 FDA approved the use of the first deuterated drug for the treatment of Huntington Disease, SD-809 (deutetrabenazine). Although head-to-head trials between deutetrabenazine and tetrabenazine has never been run, clinical data comparison suggested that SD-809 has a better safety profile respect to tetrabenazine.[222] Recently a deuterated version of the 18F rolipram analogue has been reported in order to avoid the defluorination in vivo, thus limiting the bone uptake of free 18F-fluoride.[223] With in mind the interest of deuterium we accessed to deuterated compounds by reductive desulfonylation using simply CD3OD as a source of deuterium.

73 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

OMe Mg (30 equiv.) OMe SCF SO Ph 2 2 I2 (0.3 equiv.) SCF2D

CD OD, 25 °C MeO 3 MeO 3e 4 h [D]9a (90 %) Scheme 66 Reductive desulfonylation in presence of a deuterium source

As shown in Figure 8, desulfonylation of different classes of products was obtained with good to excellent yields and in 19F NMR and 1H NMR spectroscopy only the formation of deuterated compounds has been observed. Desulfonylation of 5a led to [D]9d and only deuteration of difluoromethylthio moiety was observed based on GC-MS analysis. It should be noticed that these results constitute the first synthesis of DCF2S-molecules. SCF D OMe SCF2D SCF2D 2 SCF2D OH N N MeO H H [D]9a [D]9b [D]9d [D]10a 88% (90%) 81 % 87 % 86% (89%)

Figure 8 Reductive desulfonylation in presence of CD3OD as a deuterium source

II.2.1.6 Post-functionalization of phenylsulfonyl moiety

Several efforts have been made with the aim to fully exploit the post-functionalization capacity and the “chameleon like” character of the phenylsulfonyl moiety. Compound 3i was used as a starting material in post-functionalization reactions. In a Mg-mediated reductive desulfonylation followed by silylation in presence of TMSCl we obtained compound 11a with a 93 % yield. TMSCl is used both as a silylating reagent and as an Mg0 activator.

OMe Mg (2 equiv.) OMe TMSCl (5 equiv.) SCF2SO2Ph SCF2SiMe3 DMF 0 °C, 30 min MeO MeO 3i 11a 93 % (quant.)

Considering the recent interest toward SCF2 moiety and the lack of methodologies in forming C-

CF2S bonds, we decided to put our efforts in exploring such demanding chemistry. Starting from the results obtained by Olah and coll. in the t-BuOK-induced trifluoromethylation of carbonyl [29] compounds and disulfides using PhSO2CF3 as a trifluoromethylating source, we planned to extrapolate the above-mentioned conditions in order to access new difluoromethylthiolated compounds.

74 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Table 10 Post-functionalization reactions

OMe Starting material A OMe SCF2SO2Ph Additive SCF2R DMF, Temp °C MeO Time h MeO 3i Starting T (°C) Additive Entry Material Yield (%) S.M (%) Time (h) (equiv.) (equiv.) O

1 -50 °C – 25 °C t-BuOK n.r 100 % 16 h 2.5 equiv.

1 equiv. O

2 H -50 °C – 25 °C t-BuOK n.r 100 % 16 h 2 equiv.

3 equiv. O

3 0 °C t-BuOK n.r 50 % 4 h 3 equiv.

1 equiv. O

4 25 °C t-BuOK n.r - 4 h 3 equiv.

1 equiv. SeCl 5 25 °C Mg 2 equiv. n.r 50 %1 2 h 1 equiv.

SeCl 6 25 °C Mg/I2 n.r 100 %1 1.5 h 5/0.3 equiv. 1 equiv. 7 PhSSPh 25 °C Mg/I2 n.r 100 %1 2 h 5/0.3 equiv.

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. 1 No starting material was found when the reaction was run for 16 h.

Addition of a solution of t-BuOK in DMF to a mixture of acetophenone or benzaldehyde and compound 3i under stirring for 1 h at -50 °C and 15 h more hours at 25 °C did not result in the formation of any compound (Table 10, entries 1-2). Moreover, compound 3i was fully recovered after 15 h. When benzophenone was used as a starting material in DMF at 0 °C and 25 °C the formation of two new peaks was observed. First, an unknown compound corresponding to a peak at -50.48 ppm was observed by 19F NMR (Table 10, entries 3-4), but all the attempts to isolate this product failed. Second, a peak corresponding to the HCF2S-adduct, arising from a reductive

75 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions desulfonylation reaction was observed at 19F NMR spectroscopy. Neither reacting phenyldisulfide with 3i under Mg/I system conditions, led to the formation of the desired compound (Table 10, entry 7). As in the case of benzaldehydes and ketones only starting material was recovered. In the reaction between phenylselenyl chloride and 3i at DMF in presence of Mg a peak at -47 ppm, corresponding to an unknown compound, was observed in 19F NMR. Unfortunately, we could not isolate the preformed compounds by flash chromatography. When iodine was added to the reaction mixture such peak was not observed in 19F NMR (Table 10, entries 5-6).

Another way to access C-CF2S bond formation could be the substitution of phenylsulfonyl with an alkyl group. Using methyl iodide as a methylating agent in a Mg-mediated reaction in DMF no reaction was observed and after 16 h 3i was fully recovered (Table 11, entry 1). Methyl triflate was used as a methylating source in THF or as both reagent and solvent without success (Table

11, entries 2 and 5). Neither the use of other alkylating reagents as Me2SO4 and BF4OEt3 led to the formation of the desired product (Table 11, entries 3-4). Table 11 Alkylation reactions

OMe OMe R-CH3 SCF2SO2Ph Additive SCF2CH3 Solvent, 25 °C MeO 16 h MeO 3i Alkyl-R Additive Yield Starting material Entry Solvent (equiv.) (equiv.) (%) %

1 MeI Mg/I2 DMF - 100 % 3 equiv. 30/0.3 equiv.

2 MeOTf Mg/I2 THF - 65 % 3 equiv. 10/0.3 equiv.

3 Me2SO4 Mg/I2 CH2Cl2 - 75 % 3 equiv 10/0.3 equiv.

4 BF4OEt3 Mg/I2 CH3CN - 85 % 10/0.3 equiv.

5 MeOTf Mg/I2 MeOTf - - 10/0.3 equiv.

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

Compounds bearing a SCF2X group (X= Br, I) are interesting building blocks, especially for further use as starting materials in cross-coupling reactions. Thus, recently the demand for the synthesis of halogenated compounds has been increasing. The use of NBS as a halogenating agent in presence of Mg or t-BuOK did lead to the formation of the desired compound. Even after 16 h compound 3i was found to be quantitatively present in the reaction media (Table 12, entries 1-4). Dibromotetrachloroethane (Br2Cl4C2), diiodoethene (I2C2H2) and iodine (I2) were implied in halogenation reactions in presence of Mg in DMF at 25 °C and 80 °C without leading

76 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions to the formation of the desired compound even though consummation of starting material was observed (Table 12, entries 5-9). We explored also the replacement of the phenylsulfonyl group by fluorine; an interesting reaction especially for the development of novel methodologies for the synthesis 18F radiolabeled compounds. The use of Selectfluor as a fluorine source in presence of

AgNO3 or Mg did to lead to the formation of any compound (Table 12, entries 10-13).

Table 12 Desulfonative halogenation reactions

OMe R-X OMe SCF2SO2Ph Additive SCF2X Solvent, Temp °C MeO 16 h MeO 3i S. M Entry R-X Additive Solvent Temp Yield (equiv.) (equiv.) °C (%) %

1 NBS Mg DMF 25 °C - 100 % 5 equiv. 2 equiv.

2 NBS Mg/I2 DMF 25 °C - 100 % 2 equiv. 10/0.3

3 NBS t-BuOK DMF 25 °C - 100 % 5 equiv. 3 equiv.

4 NBS Mg/I2 CH3CN 25 °C - 100 % 5 equiv. 30/0.3 equiv.

5 I2 Mg/I2 DMF 25 °C - 100 % 5 equiv. 10/0.3 equiv.

6 Br2Cl4C2 Mg/I2 DMF 25 °C - 65 % 10 equiv. 30/0.3 equiv.

7 Br2Cl4C2 Mg/I2 DMF 80 °C - - 10 equiv. 30/0.3 equiv.

8 I2C2H2 Mg/I2 DMF 25 °C - 90 % 10 equiv. 30/0.3 equiv.

9 I2C2H2 Mg/I2 DMF 80 °C - 95 % 10 equiv. 30/0.3 equiv.

10 Selectfluor AgNO3 Acetone/H2O 55 °C - 40 % 5 equiv. 1 equiv.

11 Selectfluor Mg/I2 DMF 25 °C - 35 % 10 equiv. 20/0.3 equiv.

12 Selectfluor Mg/I2 DMF 25 °C - 75 % 10 equiv. 20/0.3 equiv.

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

77 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.3 (Methoxycarbonyl)difluoromethanesulfenamide: A new shelf- stable reagent

As reported above compound 1d also was prepared starting from the corresponding silane and DAST and the synthesis was scaled-up to 100 mmol of starting material without any change in the isolated yield. Herein, we disclose the last obtained results using reagent 1d as donor of + SCF2CO2Me in presence of various classes of compounds. The presence of CO2Me group could be exploited to access various compounds through a series of interesting post-functionalization reactions.

II.3.1.1 SEAr using compound 1d As in the case of 1a, reagent 1d was involved in electrophilic aromatic substitution reactions, in order to test its reactivity and access to compounds bearing an SCF2CO2Me group.

Table 13 SEAr using reagent 1d

SCF CO Me H F F 2 2 N O H+ or Lewis acid + S N CH Cl , 50 °C H O 2 2 N 16 h H 2a 1d 20a Entry Acid (equiv.) Yield (%) 1 TMSCl 1 equiv. 83 % 2 TMSCl 2 equiv. 100 % 3 TMSCl 30 mol % 50 % 4 p-TsOH 1 equiv. 40 % 5 p-TsOH 2.5 equiv. 65 % 6 p-TsOH 30 mol % 40 % 7 TfOH 1 equiv. 93 % Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

As shown in Table 13 both Lewis and protic acid can be activate reagent 1d. The use of p- toluenesulfonic acid in excess (2.5 eq.) led to the formation of the compound 20a with a yield of 65 % (Table 13, entry 5). Stoichiometric and catalytic quantities of p-toluenesulfonic acid gave the desired indole with a yield of 40 % in both cases (Table 13, entries 4 and 6). Using a stronger acid as TfOH increased the yield at 93 % (Table 13, entry 7). Nevertheless, the use of milder reaction conditions as activation of 1d by a Lewis acid results more advantageous and less complicated from a procedural point of view. Thus, employing TMSCl as an activator we observed the formation of compound 20a by both using excess, stoichiometric and catalytic

78 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions amounts of acid (Table 13, entries 1-3). However, the best result was obtained using 2 equiv. of TMSCl, which led to the formation of compound 20a with a 100 % dosed yield corresponding to a peak at -84.47 ppm observed by 19F NMR spectroscopy. Thus with the optimized reaction conditions in hand we extended the substrate scope to a wider number of electron-rich aromatic and heteroaromatic compounds. Compound 20a and 20c were isolated with good yields after activation of 1d by TMSCl. COOH SCF2CO2Me Br SCF CO Me 2 2 H2N

SCF2CO2Me N N SCF CO Me H N 2 2 H H N H 20b 20a 20c 20d (33 %) 80% (quant.) 94% (100%) (36%)b 63% (70%)b

SCF CO Me 2 2 SCF2CO2Me SCF2CO2Me I

SCF2CO2Me N N N N N N Ts H H 20e 20f 20g 20h (13 %) (50 %) (0%) (20 %) 89 % (89 %)

SCF CO Me OMe OH 2 2 SCF CO Me 2 2 SCF CO Me N 2 2 SCF2CO2Me

N N MeO H HO 20j 20l 20i 20k (41 %) 81 % (87%)b (0 %) 80% (83%)b 25 % (33 %) (33%), (17%)a OH OH OMe OMe

SCF2CO2Me

I SCF2CO2Me SCF2CO2Me SCF2CO2Me 20m 20n 20o 20p 66% (67%)b 83 % (84%)a (13%)a (12%)a

O BocHN OH NO2 HO HO OH

HO 20q 20r (9%)a (0%)b Figure 9 SEAr reactions of electron rich arenes and heteroarenes with reagent 1d. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR. a TfOH 1 equiv., 50 °C, CH2Cl2 15 h; b p-TsOH 2.5 equiv., 50 °C, CH2Cl2, 15 h.

On the other hand, to obtain compound 20b stronger conditions were needed as the use of p- TsOH. Using L-tryptophan as a starting material we could not access to compound 20d in a satisfactory yield, therefore the isolation of such compound was not possible. N-protected

79 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

indoles were also used in SEAr reactions. N-Tosyl indole gave compound 20e with only 13 % dosed yield, making vain the tentative for isolating the compound. This might be due to the electron-withdrawing properties of the tosyl group, which should deactivate the indole ring. Reacting N-methyl indole with 1d we could obtain compound 20f with 89 % yield. Compound 20g and 20h were not obtained when we reacted the proper azaindoles with reagent 1d. However, when compound 3-iodo-azaindole was used as a starting material, a peak at -84.79 ppm was observed in 19F NMR, which could correspond to compound 20h. Neither the reaction of an imidazolo-pyridine with the reagent 1d did lead to the formation of 20i. Compound 20j was obtained in a modest yield, enabling the access to an interesting class of compounds as substituted pyrroles. Also, electron-rich aromatics reacted with the reagent 1d, leading the desired compounds in a good yield. However, the best results in this case were obtained when the reaction was run in presence of a protic acid. Compounds 20k and 20l and 20m were obtained after reacting dimethoxybenzene, resorcinol and phenol with 1d in presence of p-TsOH with 80 %, 81 % and 66 % yield respectively. In the case of naphtol a stronger acid as triflic acid was needed to access compound 20n. Reacting less electron-rich adducts with the reagent 1d we could not isolate the compounds 20p and 20q due to the low dosed yields observed in 19F NMR. Neither the Boc-protected derivative of L-Dopa was able to give compound 20r.

II.3.1.2 Acid activation of α-ketones

Ketones are known as valuable building blocks and are also found in several natural products and biomolecules. Moreover, ketones have important physiological properties and are found in naturally occurring and synthetic steroid hormones. Cortisone, an anti-inflammatory agent has three ketone groups on its core. Thus, the association of fluorinated motifs to a ketone group into molecules could be of particular interest. Inspired by the previous works developed by us on the trifluoromethylthiolation of ketones in α-position using the trifluoromethanesulfenamide

[134] reagents we planned the insertion of SCF2CO2Me moiety through an acid-catalyzed reaction using 1d as a donor. Catalytic amounts of TMSCl in CH3CN already led to the formation of traces of the compound 21a, observed in 19F NMR (Table 14, entry 1). Using stoichiometric amounts of TMSCl the dosed yield increased to 20 % (Table 14, entry 2). An excess of the Lewis acid gave the desired compound with a 45 % yield in CH3CN (Table 14, entry 3). Increasing the amounts of 1d to 2.5 equiv. did not lead to any improvement in terms of yield (Table 14, entry 8). Changing the solvent to dichloroethane 21a gave rise to 25 % yield (Table 14, entry 4). Even when 2 equiv. of TMSCl were used at 50 °C in CH2Cl2 no formation of the compound was observed (Table 14, entry 5). However, replacing CH2Cl2 with CH3CN compound 21a the peak at -83.45 ppm corresponding to compound 21a was observed in 19F NMR (Table 14, entry 6).

80 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Substituting TMSCl with acetyl chloride (CH3COCl) and running the reaction in NMP at 25 °C in presence of 2. 5 equiv. of 1d, compound 21a was formed with a 35 % yield (Table 14, entry 7). Table 14 Acidic activation of ketones

O H O N SCF CO Me TMSCl SCF2CO2Me + 2 2 Solvent, Temp °C

15 1d 21a 1.2 equiv. Entry Acid (equiv.) Solvent T (°C) Yield (%)

1 TMSCl (0.3 equiv.) CH3CN 90 °C 5 %

2 TMSCl (1 equiv.) CH3CN 90 °C 20 %

3 TMSCl (2 equiv.) CH3CN 90 °C 45 % 4 TMSCl (2 equiv.) DCE 90 °C 25 %

5 TMSCl (2 equiv.) CH2Cl2 50 °C -

6 TMSCl (2 equiv.) CH3CN 50 °C 30 %

2 7 CH3COCl (3 equiv.) NMP 25 °C 35 %

2 8 TMSCl (2 equiv.) CH3CN 90 °C 45 %

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard. 2.5 equiv. of 1d were used

Taking for granted as best reaction conditions in entry 3, we extended the scope to a wider number of compounds. Acetophenone and 2-chloroacetophenone gave compound 21a and 21b in reasonable yields of 42 % and 40 % respectively. Surprisingly, the more hindered propiophenone gave 21d in a better yield of 52 %. The benzofuran derivative 21c was obtained with a yield of 46 %. Insertion of SCF2CO2Me in α-position of tetralone was successfully achieved with a dosed yield of 43 %. The new compound 21e was observed in 19F NMR represented by an AB system between -80.36 and -82.46 ppm. The synthesis of the chromanone derivative was less efficient and a lower yield was obtained. The formation of both compounds was confirmed by GC-MS but still not isolated. More complex structures as cholestenone did not lead to the formation of 21g although all the starting material has been consumed after 16 h. Several peaks were observed in 19F NMR nevertheless it was not possible to isolate any compound in order to get more insight on the reaction. Also β-ketoester 15g did not give compound 21g. As in the case of cholestenone several peaks were observed in 19F NMR and simultaneous consumption of 1d also. Reacting ketone 15h with the reagent 1d under the same reaction conditions did not lead to the desired product. An aldehyde also was tested, but unfortunately did not lead to the formation of compound 21j.

81 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

SCF CO Me O O O 2 2

SCF2CO2Me Cl SCF2CO2Me

O 21a 21b 21c 42% (45%) 40% (40%) 46% (55%)

O O O O

SCF2CO2Me SCF2CO2Me SCF CO Me 2 2 O 21d 21e 21f 52% (43 %) (26%)

O O O Ph N H OEt OEt

SCF2CO2Me Ph SCF2CO2Me H MeO2CF2CS 21g 21h H H (0 %) (0 %) O H 21i O (0%)

SCF2CO2Me

21j (0 %) Figure 10 Acid-catalyzed difluoroalkylation of ketones. Yields shown are of isolated products; values in parentheses are the yields as determined by 19F NMR.

II.3.1.3 Post-functionalization reactions

Several efforts were made in order to fully-exploit post-functionalization possibilities of

SCF2CO2Me and the SCF2COOH moieties in order to access interesting compounds. We decided to choose compound 20a and 20k as examples in post-functionalization reactions.

II.3.1.3.1 Post-Functionalization of the SCF2CO2Me moiety The first post-functionalization reactions were run with the aim to transform the ester moiety and 20a and 20k were chosen as starting materials. Hydroxyl (OH) is an important functional group in organic. Alcohol compounds find a wide use in science, medicine and industry as antifreeze, antiseptics, preservatives etc. Accessing compounds bearing a SCF2 group adjacent to the alcohol functionality could be of particular interest in modulating the properties of the molecules. Moreover, it could present a valuable synthetic procedure to access such compounds considering the lack of synthetic strategies. The use of lithium aluminium hydride (2 or 5 equiv.) to reduce the ester moiety into alcohol did not lead to the expected product (Table 15, entries 1 and 2). On the other hand, employing sodium borohydride as a reducing agent the desired product 22a was obtained in a quantitative yield (Table 15, entry 3).

82 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Performing an aminolysis reaction between benzylamine and compound 20k in MeOH in an aminolysis reaction gave the desired product 22b in a quantitative yield. Such reactions could be interesting as a starting point in the peptide-like coupling reactions employing aminoacids instead of the benzylamine (Table 15, entry 22b). Saponification of the ester using a 1M solution of

K2CO3 at room temperature led to the carboxylic acid derivative 22c with 87 % yield. Carboxylic acids are important motifs in organic chemistry and undergo facile post-functionalization.

Table 15 Post-funtctionalization reactions using 20k as a starting material

OMe OMe SCF CO Me SCF R 2 2 Additive 2 1 + R1 Solvent, Temp °C MeO MeO Time h 20k Time Temp Entry R1 (equiv.) Additive (equiv.) Solvent Yield (%) h C)

1 - LiAlH4 5 equiv. THF 2 h 0 °C – 25 °C n.r

2 - LiAlH4 5 equiv. THF 2 h 0 °C – 25 °C n.r

OMe

SCF2CH2OH

3 - NaBH4 2 equiv. MeOH 2 h 0 °C – 25 °C MeO 22a 99 % OMe O S NH2 C N Ph 4 - MeOH 3 h 25 °C F F H MeO 2 equiv. 22b 100 % OMe

SCF2COOH

5 - K2CO3 3 equiv. MeOH 3 h 25 °C MeO 22c 87 % (90 %)

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

The indole core bearing the SCF2CO2Me group was also subject to post-functionalization reactions. With the aim to demonstrate that the above-shown post-functionalization reactions are not substrate dependent and to access to new substrates we extended the scope to the indole family, choosing compound 20a as model substrate. NaBH4-mediated reduction to alcohol gave the expected compound 23a in a good yield (Table 16, entry 1). Also, the aminolysis reaction between benzylamine and the indole 20a led to the formation of the amide 23b with a 95 % isolated yield (Table 16, entry 2). Encouraged by the optimistic results obtained we tried to extend the scope to other primary amines. For instance, tryptophan was reacted with compound 20a without leading to the formation of the desired compound (Table 16, entry 3). As mentioned

83 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions before, the use of aminoacid derivatives in peptide-like coupling reactions could open the way to the synthesis of biologically active compounds that might find use in several fields. Unfortunately, neither reacting tert-butyl glycinate with 20a in MeOH the formation of the expected compound was observed. Neither performing the addition of an additive as AlMe3 we did not observe any formation of the expected compound (Table 16, entry 5). As in the case of the compound 22c, by means of a saponification reaction mediated by a 1M aqueous solution of

K2CO3, acid compound 23c was obtained

Table 16 Post-funtctionalization reactions using 20a as a starting material

SCF2CO2Me SCF2R1 Additive + R1 N Solvent, Temp °C N H Time h H 20a

Entry R1 Additive (equiv.) Solvent Temp (°C) Yield (%)

SCF2CH2OH

1 - NaBH4 2 equiv. MeOH 0 °C – 25 °C N H 23a 74 % (79 %) F F S NH2 NH 2 MeOH 25 °C O N 2 equiv. H 23b 95 % (100 %)

3 Tryptophane MeOH 25 °C n.r 2 equiv.

O 4 NH2 - MeOH 25 °C n.r O 2 equiv.

O NH2 5 AlMe3 3 equiv. MeOH 0 °C n.r O 2 equiv.

SCF2COOH

6 - K CO MeOH 25 °C 2 3 N H 23c 92 %

Crude yields were determined by 19F NMR spectroscopic analysis using PhOCF3 as an internal standard.

84 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

II.3.1.3.2 Post-Functionalization of the SCF2CO2H moiety Herein we report decarboxylative halogenation reactions and oxidative decarboxylation reaction to access SCF2-X bond formation and SCF2-C coupling respectively.

II.3.1.3.2.1 Decarboxylative halogenation reactions Carboxylic acids are pervasive in nature and find a wide use in industry in the production of pharmaceuticals, additives, polymers etc. Moreover, compounds bearing a carboxyl group can function as precursors to several molecules through post-functionalization of COOH motif. Decarboxylative halogenation reactions as Hunsdiecker reaction are well known in organic chemistry. Recently, decarboxylative halogenation in presence of adjacent fluorine atoms

(CF2COOH) has been reported. Gouverneur and coll. by means of an elegant procedure accessed trifluoromethylarenes through an electrophilic decarboxylation reaction in both cold and hot chemistry using Selectfluor as a fluoride source.[224] However, when we started this project such a reaction has never been performed in presence of a SCF2COOH group. Thus, it could be interesting to evaluate the influence of adjacent sulfur in this reaction. and explore the reaction 18 conditions that could be the first pass to access the radiolabeled [ F]CF3S moiety. Adaption of the reaction conditions reported by Gouverneur and coll., did not give the desired result. Although the entire starting material was consumed no trace of the trifluoromethylthiolated compounds was observed. However, multiple peaks were observed between -110 and -112 ppm in 19F NMR (Table 17, entry 1) suggesting an aromatic fluorination of our starting material. Neither increasing the amounts of AgNO3 (Table 17, entry 2), increasing the concentration of the reaction media (Table 17, entry 7), decreasing the reaction temperature to 25 °C and 5 °C (Table 17, entries 3-4), or changing the source of silver (Table 17, entries 5-6) we could access the expected compound. However, in all the cases full consumption of the starting material and presence of multiple peaks between -110 and -112 ppm was observed. Nevertheless, we could not isolate any of the by- products to further comprehend the reaction mechanism.

Another unexplored topic in fluorine chemistry is the synthesis of SCF2I group. The iododifluoromethylthio group is almost unknown to organic chemists and no evidence concerning its characterization was found in literature. Tentative for insertion of an iodine atom resulted unsuccessful, by using both I2 and NSI as iodine sources in presence of silver salt (Table

17, entries 8-9). Neither the addition of K2S2O8 or BHF4 to the reaction media gave the expected compound (Table 17, 10-11 and 19). Nor using the potassium salt as a starting material did not favor the formation of the desired compound (Table 17, 12-13), presumably due to steric hindrance and the less nucleophilic character of the iodine atom.

85 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Table 17 Decarboxylative halogenation reactions

OMe OMe SCF2COOH Additive 1 SCF2COOH + Halogen Source MeO Solvent, Temp °C MeO Addiitive 2, 16 h 22c Halogen Ag salt Additive Yield Entry Source Solvent T (°C) (equiv.) 2 (equiv.) (%) (equiv) 1 Selectfluor AgNO3 - (CH3)2CO/H2O 55 °C n.r 2 equiv. 20 mol % 1/1

2 Selectfluor AgNO3 - (CH3)2CO/H2O 55 °C n.r 2 equiv. 1 equiv. 1/1

3 Selectfluor AgNO3 - (CH3)2CO/H2O 25 °C n.r 2 equiv. 20 mol % 1/1

4 Selectfluor AgNO3 - (CH3)2CO/H2O 5°C n.r 2 equiv. 20 mol % 1/1

5 Selectfluor Ag2CO3 - (CH3)2CO/H2O 55 °C n.r 2 equiv. 20 mol % 1/1

6 Selectfluor Ag2OAc - (CH3)2CO/H2O 55 °C n.r 2 equiv. 20 mol % 1/1

71 Selectfluor AgNO3 - (CH3)2CO/H2O 55 °C n.r 2 equiv. 20 mol % 1/1

8 I2 AgNO3 - CH3CN 80 °C n.r 2 equiv. 20 mol %

9 NSI AgNO3 - CH3CN 80 °C n.r 2 equiv. 20 mol %

10 NSI AgNO3 K2S2O8 (CH3)2CO/H2O 55 °C n.r 1 equiv. 25 mol % 2 equiv. 1/1

11 I2 AgNO3 K2S2O8 (CH3)2CO/H2O 55 °C n.r 1 equiv. 25 mol % 2 equiv. 1/1

122 NSI AgNO3 K2S2O8 (CH3)2CO/H2O 55 °C n.r 2 equiv. 1 equiv. 2 equiv. 1/1

132 NSI AgNO3 K2S2O8 (CH3)2CO/H2O 55 °C n.r 2 equiv. 1 equiv. 2 equiv 1/1

14 NBS AgNO3 HBF4 CH2Cl2/H2O 80 °C 45 % 2 equiv. 20 mol % 3 equiv. 10/1

15 NBS AgNO3 HBF4 (CH3)2CO/H2O 55 °C n.r 2 equiv. 20 mol % 3 equiv. 1/1

16 NBS AgNO3 TfOH PhCF3/H2O 80 °C 1 % 3.5 equiv. 20 mol % 3 equiv. 10/1 NBS AgNO HBF CH Cl /H O 17 3 4 2 2 2 80 °C 20 % 2 equiv. 1 equiv. 3 equiv. 1/1 NBS AgNO HBF CH Cl /H O 18 3 4 2 2 2 80 °C 90 % 4 equiv. 20 mol % 3 equiv. 10/1 NSI AgNO CH Cl /H O 19 3 HBF 2 2 2 80 °C n.r 4 equiv. 20 mol % 4 10/1 Reactions were checked by 19F NMR after 4 h and 16 h. 1 Reaction was run at a [0.25M]. 2 The potassium salt of the acid was used as a starting material.

86 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

The decarboxylative bromination is also very appealing because could lead to precursor that can be used in coupling reactions. Such compounds can be used also as starting materials in a Ag- mediated halogen-exchange radiolabeling as demonstrated by Gouverneur and coll.[225] giving rise

18 to compounds bearing an [ F]CF3S group. Adapting very recently published conditions that has been used in decarboxylative fluorination [226] and substituting Selectfluor with NBS we observed 19 a peak at -23.05 ppm in F NMR, area corresponding to molecules bearing a SCF2Br group

(Table 17, entry 14). Choosing CH2Cl2/H2O as a solvent in a 10/1 ratio is crucial for the reaction trend. Using a 1/1 ratio of the same solvents the desired compound was formed only in 20 % yield Table 17, entry 17). Furthermore, substituting the solvent with a mixture of acetone/H2O or PhCF3/H2O no peaks or non-quantifiable signals were observed (Table 17, entry 15-16). When the amount of NBS was increased up to 4 equiv. correspondingly the dosed yield increased up to 90 % (Table 17, entry 18). Once the compound was isolated we realized that the observed 1H NMR spectra did not correspond to the expected compound. Hence, the peak corresponding to the hydrogen in meta respect SCF2Br group was missing. Considering the electron-rich character 22c a SEAr reaction took place simultaneously leading to the bromination of the arene ring. The structure of the new compound was confirmed by 1H NMR, 13C NMR and GC-MS (Scheme 67).

OMe OMe AgNO3 20 mol % SCF2COOH NBS 4 equiv. SCF2Br

HBF 3 equiv. MeO 4 MeO CH2Cl2/H2O 10/1 22c 80 °C, 16 h Br 24c 65 % (90 %) Scheme 67 Decarboxylative bromination reaction

II.3.1.3.2.2 Oxidative decarboxylation with SF2C-C bond formation

As mentioned before there is a great interest in developing SF2C-C coupling reactions, that could ease the way to access to SCF2-bridged molecules. As shown in Table 18, the reaction between aryl iodides or alkyl bromides and compound 22c in DMF in presence of CuI did not lead to the formation of any desired product (entries 1 and 3-4). Also, the potassium salt of compound 22c has been used as starting material, without success. However, after 16 hours no traces of starting material 22c were observed by 19F NMR.

87 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

Table 18 SF2C-C bond formation

OMe OMe SCF2COOH CuI SCF2R + X R MeO DMF, Temp °C 22c MeO Time h T (°C) Entry R-X (eq) Yield (%) Time (h)

I 170 °C 1 - OMe 16 h 1 equiv. I 170 °C 21 - OMe 16 h 1 equiv.

Br 80 °C 3 - 10 16 h 1 equiv.

Br 80 °C 4 - 10 16 h 2 equiv. 1 K salt was used instead of the carboxylic acid as starting material.

A last post-functionalization reaction that we tried is the oxidative decarboxylation in presence of EBX-TIPS to access difluoromethylthio alkynes, interesting building blocks that could lead to further structural modifications. To our knowledge, in literature there is only one example concerning the synthesis of difluoromethylthio alkynes, starting from a substituted benzyl thiol and a difluoropropargyl bromide.[227] Thus, with the last advances in the formation of difluoromethyl alkyne in mind and the interest of such motifs we adapted some existing procedures to our system.[228] Reacting 22c 19 with EBX-TIPS in presence of K2S2O8 we observed the formation of a peak at -58.80 ppm in F

NMR to our delight (Table 19, entry 1). Addition of AgNO3 to the reaction media improved the yield from 33 % to 60 % (Table 19, entry 2). Encouraged by the obtained results we planned the synthesis of various compounds by modifying the EBX reagent. The Ag-catalysed reaction between 22c and EBX-hexyne in acetone/H2O mixture did not give the expected results although no starting material was found in the reaction mixture (Table 19, entries 3-4). A peak at -58.18 ppm was observed in 19F NMR that could correspond to our compound although we do not have any evidence concerning to it. When the reaction was run in absence of AgNO3 40 % of the starting material was still found in the reaction media. The use of Ph-EBX led to the

88 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions formation of undefined complex mixtures also, and the starting material was consumed in both cases (Table 19, entries 5-6). Table 19 Decarboxylative oxidation hypervalent alkynyl iodines

OMe OMe R I O Catalyst SCF COOH Additive SCF2R 2 O + Solvent, Temp °C MeO MeO Time h Additive Entry R Catalyst Solvent Temp (°C) Yield (%) (equiv.) (equiv.) K S O 1 - 2 2 8 CH CN/H O 55 °C 25c 33 % TIPS 2 equiv. 3 2 AgNO K S O 2 3 2 2 8 (CH ) CO/H O 55 °C 25c 60 % TIPS 25 mol % 2 equiv. 3 2 2 R AgNO3 K2S2O8 3 (CH3)2CO/H2O 55 °C 25b 8 % 25 mol % 2 equiv.

R K2S2O8 4 - (CH3)2CO/H2O 55 °C n.r 2 equiv.

AgNO3 K2S2O8 5 Ph (CH ) CO/H O 55 °C Complex mixture 25 mol % 2 equiv. 3 2 2

AgNO3 K2S2O8 6 Ph CH CN/H O 55 °C Complex mixture 25 mol % 2 equiv. 3 2

Crude yields were determined by 19FNMR spectroscopic analysis using PhOCF3 as an internal standard.

TIPS-EBX was reacted in presence of indoles bearing a SCF2COOH group. In the case of the unprotected indole 23c, compound 25a was obtained with a modest yield of 13 %. N-methyl indole gave compound 25b with a 26 % yield.

TIPS F F S I O SCF2COOH AgNO3, 0.25 mol % K S O 2 equiv. O 2 2 8, TIPS + Acetone/H O, N N 2 55 °C, 24 h R R1 R= H, 25a 13% (19 %) R= CH3, 25b 26 % (33 %) Scheme 68 Alkylynation of indole-based molecules

89 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

III. Conclusions

At the beginning of this project no literature data concerning the direct insertion of SCF2FG group was present in literature. Thus, since the beginning we concentrated our efforts in the development and improvement of such chemistry. In the first chapter, we reported the synthesis of the first two sulfenamides-based reagents (1a and 1d) bearing a SCF2FG (FG= SO2Ph,

CO2Me) group. Both reagents were successfully used in electrophilic reactions as donors of + SCF2FG in presence of electron-rich (hetero) aryl compounds, alkenes, terminal alkynes and ketones. We have also exploited the post-functionalization capacity of the phenylsulfonyl,

CO2Me and COOH moieties to access differently substituting compounds. Among others, compounds bearing SCF2H and, for the first time, SCF2D were prepared after reductive desulfonylation of SO2Ph moiety. Substitution of SO2Ph with a SiMe3 also was performed.

Through post-functionalization of the SCF2CO2Me group we accessed to a different structure using different reactions as, reduction to alcohol, aminolysis and saponification reactions. More interestingly, decarboxylative halogenation and C-C bond formation by oxidative decarboxylation reactions were successfully performed leading to a new class of compounds.

90 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

IV. References:

[1] a) R. N. Haszeldine, B. Higginbottom, R. B. Rigby, A. E. Tipping, J. Chem. Soc., Perkin Trans. 1 1972, 155-159; b) R. N. Haszeldine, R. B. Rigby, A. E. Tipping, J. Chem. Soc., Perkin Trans. 1 1972, 2180-2182; c) R. N. Haszeldine, R. B. Rigby, A. E. Tipping, J. Chem. Soc., Perkin Trans. 1 1972, 159-161. [2] V. N. Boiko, Beilstein J. Org. Chem. 2010, 6, 880-921. [3] V. Soloshonok, V. Kukhar, Y. Pustovit, V. Nazaretyan, Synlett 1992, 657-658. [4] V. I. Popov, V. N. Boiko, L. M. Yagupolskii, J. Fluorine Chem. 1982, 21, 365-369. [5] V. G. Koshechko, L. A. Kiprianova, L. I. Fileleeva, Tetrahedron Lett. 1992, 33, 6677-6678. [6] H. Yasui, T. Yamamoto, E. Tokunaga, N. Shibata, J. Fluorine Chem. 2011, 132, 186-189. [7] A. Harsányi, É. Dorkó, Á. Csapó, T. Bakó, C. Peltz, J. Rábai, J. Fluorine Chem. 2011, 132, 1241-1246. [8] N. J. W. Straathof, B. J. P. Tegelbeckers, V. Hessel, X. Wang, T. Noel, Chem. Sci. 2014, 5, 4768-4773. [9] F. Sladojevich, E. McNeill, J. Börgel, S.-L. Zheng, T. Ritter, Angew. Chem. Int. Ed. 2015, 54, 3712-3716. [10] C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Commun. 1984, 793-794. [11] a) C. Wakselman, M. Tordeux, J.-L. Clavel, B. Langlois, J. Chem. Soc., Chem. Commun. 1991, 993-994; b) E. Anselmi, J.-C. Blazejewski, M. Tordeux, C. Wakselman, J. Fluorine Chem. 2000, 105, 41-44; c) E. Magnier, C. Wakselman, Synthesis 2003, 565-569. [12] B. Langlois, D. Montègre, N. Roidot, J. Fluorine Chem. 1994, 68, 63-66. [13] T. Billard, N. Roques, B. R. Langlois, J. Org. Chem. 1999, 64, 3813-3820. [14] a) T. Umemoto, A. Ando, Bull. Chem. Soc. Jpn. 1986, 59, 447-452; b) T. Umemoto, O. Miyano, Tetrahedron Lett. 1982, 23, 3929-3930. [15] N. V. Kondratenko, O. A. Radchenko, L. M. Yagupol'skii, Zh. Org. Khim. 1984, 20, 2250- 2251. [16] a) U. Teruo, I. Sumi, Tetrahedron Lett. 1990, 31, 3579-3582; b) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 1993, 115, 2156-2164. [17] T. Umemoto, Chem. Rev. 1996, 96, 1757-1778. [18] I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed. 2007, 46, 754-757. [19] R. Krishnamurti, D. R. Bellew, G. K. S. Prakash, J. Org. Chem. 1991, 56, 984-989. [20] M. Tordeux, C. Francese, C. Walkselman, J. Fluorine Chem. 1989, 43, 27-34. [21] V. N. Movchun, A. A. Kolomeitsev, Y. L. Yagupolskii, J. Fluorine Chem. 1995, 70, 255- 257. [22] a) T. Billard, B. R. Langlois, Tetrahedron Lett. 1996, 37, 6865-6868; b) T. Billard, S. Large, B. R. Langlois, Tetrahedron Lett. 1997, 38, 65-68. [23] C. E. Granger, C. P. Félix, H. P. Parrot-Lopez, B. R. Langlois, Tetrahedron Lett. 2000, 41, 9257-9260. [24] G. K. S. Prakash, P. V. Jog, P. T. D. Batamack, G. A. Olah, Science 2012, 338, 1324. [25] J. Russell, N. Roques, Tetrahedron 1998, 54, 13771-13782. [26] S. Large, N. Roques, B. R. Langlois, J. Org. Chem. 2000, 65, 8848-8856. [27] H. Kawai, Z. Yuan, E. Tokunaga, N. Shibata, Org. Biomol. Chem. 2013, 11, 1446-1450. [28] a) B. Quiclet-Sire, R. N. Saicic, S. Z. Zard, Tetrahedron Lett. 1996, 37, 9057-9058; b) N. Roques, J. Fluorine Chem. 2001, 107, 311-314. [29] G. K. S. Prakash, J. Hu, G. A. Olah, Org. Lett. 2003, 5, 3253-3256. [30] G. Blond, T. Billard, B. R. Langlois, Tetrahedron Lett. 2001, 42, 2473-2475. [31] D. Inschauspe, J.-B. Sortais, T. Billard, B. R. Langlois, Synlett 2003, 233-235. [32] M. V. Riofski, A. D. Hart, D. A. Colby, Org. Lett. 2013, 15, 208-211. [33] P. Cherkupally, P. Beier, Tetrahedron Lett. 2010, 51, 252-255.

91 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[34] a) C. Pooput, M. Medebielle, W. R. Dolbier, Org. Lett. 2004, 6, 301-303; b) C. Pooput, W. R. Dolbier, M. Médebielle, J. Org. Chem. 2006, 71, 3564-3568. [35] a) J. F. Harris, F. W. Stacey, J. Am. Chem. Soc. 1961, 83, 840-845; b) J. F. Harris, J. Am. Chem. Soc. 1962, 84, 3148-3153. [36] J. F. Harris, J. Org. Chem. 1967, 32, 2063-2074. [37] J. F. Harris, J. Org. Chem. 1966, 31, 931-935. [38] a) S. Munavalli, D. K. Rohrbaugh, F. J. Berg, L. R. McMahon, F. R. Longo, H. D. Durst, Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 1117-1125; b) D. K. Rohrbaugh, H. D. Durst, F. R. Longo, S. Munavalli, Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 2639- 2650; c) S. Munavalli, R. K. Rohrbaugh, G. W. Wagner, H. D. Durst, F. R. Longo, Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 1635-1643. [39] F. Yin, X.-S. Wang, Org. Lett. 2014, 16, 1128-1131. [40] K. Zhang, J.-B. Liu, F.-L. Qing, Chem. Commun. 2014, 50, 14157-14160. [41] C. Chen, X.-H. Xu, B. Yang, F.-L. Qing, Org. Lett. 2014, 16, 3372-3375. [42] N. Fuentes, W. Kong, L. Fernández-Sánchez, E. Merino, C. Nevado, J. Am. Chem. Soc. 2015, 137, 964-973. [43] Y.-F. Zeng, D.-H. Tan, Y. Chen, W.-X. Lv, X.-G. Liu, Q. Li, H. Wang, Org. Chem. Front. 2015, 2, 1511-1515. [44] Y.-F. Qiu, X.-Y. Zhu, Y.-X. Li, Y.-T. He, F. Yang, J. Wang, H.-L. Hua, L. Zheng, L.-C. Wang, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2015, 17, 3694-3697. [45] D.-P. Jin, P. Gao, D.-Q. Chen, S. Chen, J. Wang, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2016, 18, 3486-3489. [46] F. Hu, X. Shao, D. Zhu, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2014, 53, 6105-6109. [47] L. Candish, L. Pitzer, A. Gómez-Suárez, F. Glorius, Chem. Eur. J. 2016, 22, 4753-4756. [48] R. Honeker, R. A. Garza-Sanchez, M. N. Hopkinson, F. Glorius, Chem. Eur. J. 2016, 22, 4395-4399. [49] T. Yang, L. Lu, Q. Shen, Chem. Commun. 2015, 51, 5479-5481. [50] R. N. Haszeldine, J. M. Kidd, J. Chem. Soc. 1955, 3871-3880. [51] a) D. J. Adams, J. H. Clark, P. A. Heath, L. B. Hansen, V. C. Sanders, S. J. Tavener, J. Fluorine Chem. 2000, 101, 187-191; b) J. H. Clark, S. J. Tavener, J. Fluorine Chem. 1997, 85, 169-172; c) S. J. Tavener, D. J. Adams, J. H. Clark, J. Fluorine Chem. 1999, 95, 171-176; d) W. Dmowski, A. Haas, J. Chem. Soc., Perkin Trans. 1 1987, 2119-2124; e) W. Dmowski, A. Haas, J. Chem. Soc., Perkin Trans. 1 1988, 1179-1181. [52] E. H. Man, D. D. Coffman, E. L. Muetterties, J. Am. Chem. Soc. 1959, 81, 3575-3577. [53] G. A. R. Brandt, H. J. Emeleus, R. N. Haszeldine, J. Chem. Soc. 1952, 2198-2205. [54] A. I. Biggs, J. Baddiley, N. A. Hughes, A. L. James, K. B. L. Mathur, H. S. Mehra, F. S. H. Head, M. M. Williamson, A. F. Trotman-Dickenson, G. J. O. Verbeke, C. C. Barraclough, J. Lewis, R. S. Nyholm, I. R. Beattie, T. Gilson, M. D. Patel, J. M. Rowson, D. A. H. Taylor, J. R. B. Boocock, W. J. Hickinbottom, J. Davoll, K. A. Kerridge, A. R. Battersby, I. A. Greenock, J. R. Miller, A. G. Sharpe, J. Biggs, P. Sykes, H. J. Emeleus, D. E. MacDuffie, B. F. Cain, J. Chem. Soc. 1961, 2572-2600. [55] M. Hanack, F. W. Massa, Tetrahedron Lett. 1981, 22, 557-558. [56] M. Hanack, A. Kühnle, Tetrahedron Lett. 1981, 22, 3047-3048. [57] L. M. Yagupol'skii, O. D. Smirnova, Zh. Org. Khim. 1972, 8, 1990-1991. [58] M. Jiang, F. Zhu, H. Xiang, X. Xu, L. Deng, C. Yang, Org. Biomol. Chem. 2015, 13, 6935- 6939. [59] D. J. Adams, J. H. Clark, J. Org. Chem. 2000, 65, 1456-1460. [60] N. V. Kondratenko, V. P. Sambur, Ukr. Khim. Zh. (Russ. Ed.) 1975, 41, 516-519. [61] G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 7312-7314. [62] J. Xu, X. Mu, P. Chen, J. Ye, G. Liu, Org. Lett. 2014, 16, 3942-3945. [63] F. Xie, Z. Zhang, X. Yu, G. Tang, X. Li, Angew. Chem. Int. Ed. 2015, 54, 7405-7409. [64] P. Saravanan, P. Anbarasan, Adv. Synth. Catal. 2015, 357, 3521-3528.

92 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[65] W. Yin, Z. Wang, Y. Huang, Adv. Synth. Catal. 2014, 356, 2998-3006. [66] J.-B. Liu, X.-H. Xu, Z.-H. Chen, F.-L. Qing, Angew. Chem. Int. Ed. 2015, 54, 897-900. [67] K.-P. Wang, S. Y. Yun, P. Mamidipalli, D. Lee, Chem. Sci. 2013, 4, 3205-3211. [68] Q. Xiao, J. Sheng, Q. Ding, J. Wu, Eur. J. Org. Chem. 2014, 2014, 217-221. [69] D. C. Remy, K. E. Rittle, C. A. Hunt, M. B. Freedman, J. Org. Chem. 1976, 41, 1644-1646. [70] L. M. Yagupol'skii, N. V. Kondratenko, V. P. Sambur, Synthesis 1975, 721-723. [71] a) M. Hu, J. Rong, W. Miao, C. Ni, Y. Han, J. Hu, Org. Lett. 2014, 16, 2030-2033; b) E. Emer, J. Twilton, M. Tredwell, S. Calderwood, T. L. Collier, B. Liégault, M. Taillefer, V. Gouverneur, Org. Lett. 2014, 16, 6004-6007. [72] N. V. Kondratenko, A. A. Kolomeytsev, V. I. Popov, L. M. Yagupolskii, Synthesis 1985, 667-669. [73] A. A. Kolomeitsev, N. V. Kondratenko, V. I. Popov, L. M. Yagupolskii, Zh. Org. Khim. 1983, 19, 2631-2632. [74] S. Munavalli, A. Hassner, D. I. Rossman, S. Singh, D. K. Rohrbaugh, C. P. Ferguson, J. Fluorine Chem. 1995, 73, 7-11. [75] P. Kirsch, M. Lenges, D. Kühne, K.-P. Wanczek, Eur. J. Org. Chem. 2005, 2005, 797-802. [76] C. Rhode, J. Lemke, M. Lieb, N. Metzler-Nolte, Synthesis 2009, 2015-2018. [77] J. H. Clark, C. W. Jones, A. P. Kybett, M. A. McClinton, J. M. Miller, D. Bishop, R. J. Blade, J. Fluorine Chem. 1990, 48, 249-253. [78] D. J. Adams, A. Goddard, J. H. Clark, D. J. Macquarrie, Chem. Commun. 2000, 987-988. [79] M. Rueping, N. Tolstoluzhsky, P. Nikolaienko, Chem. Eur. J. 2013, 19, 14043-14046. [80] P. Nikolaienko, R. Pluta, M. Rueping, Chem. Eur. J. 2014, 20, 9867-9870. [81] Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem. Int. Ed. 2013, 52, 1548-1552. [82] Z. Wang, Q. Tu, Z. Weng, J. Organomet. Chem. 2014, 751, 830-834. [83] J. Tan, G. Zhang, Y. Ou, Y. Yuan, Z. Weng, Chin. J. Chem. 2013, 31, 921-926. [84] a) Q. Lin, L. Chen, Y. Huang, M. Rong, Y. Yuan, Z. Weng, Org. Biomol. Chem. 2014, 12, 5500-5508; b) D. Kong, Z. Jiang, S. Xin, Z. Bai, Y. Yuan, Z. Weng, Tetrahedron 2013, 69, 6046-6050. [85] J. H. Clark, H. Smith, J. Fluorine Chem. 1993, 61, 223-231. [86] a) Y. Huang, J. Ding, C. Wu, H. Zheng, Z. Weng, J. Org. Chem. 2015, 80, 2912-2917; b) C. Hou, X. Lin, Y. Huang, Z. Chen, Z. Weng, Synthesis 2015, 47, 969-975; c) P. Zhu, X. He, X. Chen, Y. You, Y. Yuan, Z. Weng, Tetrahedron 2014, 70, 672-677. [87] X. Wang, Y. Zhou, G. Ji, G. Wu, M. Li, Y. Zhang, J. Wang, Eur. J. Org. Chem. 2014, 2014, 3093-3096. [88] Q. Lefebvre, E. Fava, P. Nikolaienko, M. Rueping, Chem. Commun. 2014, 50, 6617-6619. [89] A. Kolomeitsev, M. Medebielle, P. Kirsch, E. Lork, G.-V. Roschenthaler, J. Chem. Soc., Perkin Trans. 1 2000, 2183-2185. [90] W. Tyrra, D. Naumann, B. Hoge, Y. L. Yagupolskii, J. Fluorine Chem. 2003, 119, 101-107. [91] M. M. Kremlev, W. Tyrra, D. Naumann, Y. L. Yagupolskii, Tetrahedron Lett. 2004, 45, 6101-6104. [92] C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012, 134, 183-185. [93] G. Yin, I. Kalvet, U. Englert, F. Schoenebeck, J. Am. Chem. Soc. 2015, 137, 4164-4172. [94] G. Yin, I. Kalvet, F. Schoenebeck, Angew. Chem. Int. Ed. 2015, 54, 6809-6813. [95] C.-P. Zhang, D. A. Vicic, Chem. Asian J. 2012, 7, 1756-1758. [96] C. Matheis, V. Wagner, L. J. Goossen, Chem. Eur. J. 2016, 22, 79-82. [97] K.-Y. Ye, X. Zhang, L.-X. Dai, S.-L. You, J. Org. Chem. 2014, 79, 12106-12110. [98] Q.-Y. Chen, J.-X. Duan, J. Chem. Soc., Chem. Commun. 1993, 918-919. [99] C. Chen, Y. Xie, L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing, Angew. Chem. Int. Ed. 2012, 51, 2492-2495. [100] C. Chen, L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 12454-12457.

93 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[101] J. Li, P. Wang, F.-F. Xie, X.-G. Yang, X.-N. Song, W.-D. Chen, J. Ren, B.-B. Zeng, Eur. J. Org. Chem. 2015, 2015, 3568-3571. [102] M. Rong, D. Li, R. Huang, Y. Huang, X. Han, Z. Weng, Eur. J. Org. Chem. 2014, 2014, 5010-5016. [103] Y. Huang, X. He, X. Lin, M. Rong, Z. Weng, Org. Lett. 2014, 16, 3284-3287. [104] J. Li, F.-F. Xie, P. Wang, Q.-Y. Wu, W.-D. Chen, J. Ren, B.-B. Zeng, Tetrahedron 2015, 71, 5520-5524. [105] a) X. Dai, D. Cahard, Synlett 2015, 26, 40-44; b) H.-B. Yang, X. Fan, Y. Wei, M. Shi, Org. Chem. Front. 2015, 2, 1088-1093. [106] S.-G. Li, S. Z. Zard, Org. Lett. 2013, 15, 5898-5901. [107] a) Q. Glenadel, M. Bordy, S. Alazet, A. Tlili, T. Billard, Asian J. Org. Chem. 2016, 5, 428- 433; b) Q. Glenadel, A. Tlili, T. Billard, Eur. J. Org. Chem. 2016, 2016, 1955-1957. [108] A. Haas, M. Lieb, Y. Zhang, J. Fluorine Chem. 1985, 30, 203-210. [109] a) S. Andreades, J. F. Harris, W. A. Sheppard, J. Org. Chem. 1964, 29, 898-900; b) A. Haas, V. Hellwig, J. Fluorine Chem. 1975, 6, 521-532; c) R. M. Scribner, J. Org. Chem. 1966, 31, 3671-3682. [110] a) A. Haas, U. Niemann, Chem. Ber. 1977, 110, 67-77; b) M. R. C. Gerstenberger, A. Haas, F. Liebig, J. Fluorine Chem. 1982, 19, 461-474; c) P. C. Belanger, J. G. Atkinson, C. S. Rooney, S. F. Britcher, D. C. Remy, J. Org. Chem. 1983, 48, 3234-3241; d) J. Mirek, A. Haas, J. Fluorine Chem. 1981, 19, 67-70; e) A. Hass, V. Hellwig, Chem. Ber. 1976, 109, 2475- 2484. [111] a) A. Haas, M. Lieb, J. Heterocycl. Chem. 1986, 23, 1079-1084; b) W. A. Sheppard, J. Org. Chem. 1964, 29, 895-898; c) A. Haas, U. Niemann, J. Fluorine Chem. 1978, 11, 509-518. [112] a) H. Bayreuther, A. Haas, Chem. Ber. 1973, 106, 1418-1422; b) M. Bauer, A. Haas, H. Muth, J. Fluorine Chem. 1980, 16, 129-136; c) A. Kolasa, J. Fluorine Chem. 1987, 36, 29-40; d) V. I. Popov, A. Haas, M. Lieb, J. Fluorine Chem. 1990, 47, 131-136. [113] K. Bogdanowicz-Szwed, B. e. Kawałek, M. Lieb, J. Fluorine Chem. 1987, 35, 317-327. [114] R. Honeker, J. B. Ernst, F. Glorius, Chem. Eur. J. 2015, 21, 8047-8051. [115] L. D. Tran, I. Popov, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 18237-18240. [116] L. Jiang, J. Qian, W. Yi, G. Lu, C. Cai, W. Zhang, Angew. Chem. Int. Ed. 2015, 54, 14965- 14969. [117] A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, J. Org. Chem. 2008, 73, 9362-9365. [118] A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, Angew. Chem. Int. Ed. 2009, 48, 8551-8555. [119] Q. Glenadel, S. Alazet, T. Billard, J. Fluorine Chem. 2015, 179, 89-95. [120] a) S. Alazet, T. Billard, Synlett 2015, 26, 76-78; b) M. Jereb, K. Gosak, Org. Biomol. Chem. 2015, 13, 3103-3115; c) S. Alazet, L. Zimmer, T. Billard, J. Fluorine Chem. 2015, 171, 78-81; d) A. Ferry, T. Billard, E. Bacqué, B. R. Langlois, J. Fluorine Chem. 2012, 134, 160-163. [121] a) F. Baert, J. Colomb, T. Billard, Angew. Chem. Int. Ed. 2012, 51, 10382-10385; b) S. Alazet, L. Zimmer, T. Billard, Angew. Chem. Int. Ed. 2013, 52, 10814-10817. [122] J. Sheng, J. Wu, Org. Biomol. Chem. 2014, 12, 7629-7633. [123] S. Alazet, K. Ollivier, T. Billard, Beilstein J. Org. Chem. 2013, 9, 2354-2357. [124] M. Jereb, D. Dolenc, RSC Advances 2015, 5, 58292-58306. [125] J. Liu, L. Chu, F.-L. Qing, Org. Lett. 2013, 15, 894-897. [126] Y. Yang, X. Jiang, F.-L. Qing, J. Org. Chem. 2012, 77, 7538-7547. [127] D.-Q. Chen, P. Gao, P.-X. Zhou, X.-R. Song, Y.-F. Qiu, X.-Y. Liu, Y.-M. Liang, Chem. Commun. 2015, 51, 6637-6639. [128] J. Sheng, C. Fan, J. Wu, Chem. Commun. 2014, 50, 5494-5496. [129] J. Sheng, S. Li, J. Wu, Chem. Commun. 2014, 50, 578-580. [130] Y. Li, G. Li, Q. Ding, Eur. J. Org. Chem. 2014, 2014, 5017-5022. [131] Q. Xiao, H. Zhu, G. Li, Z. Chen, Adv. Synth. Catal. 2014, 356, 3809-3815. [132] Q. Xiao, J. Sheng, Z. Chen, J. Wu, Chem. Commun. 2013, 49, 8647-8649. [133] W. Wu, X. Zhang, F. Liang, S. Cao, Org. Biomol. Chem. 2015, 13, 6992-6999.

94 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[134] S. Alazet, E. Ismalaj, Q. Glenadel, D. Le Bars, T. Billard, Eur. J. Org. Chem. 2015, 2015, 4607-4610. [135] Q. Glenadel, S. Alazet, A. Tlili, T. Billard, Chem. Eur. J. 2015, 21, 14694-14698. [136] H.-Y. Xiong, T. Besset, D. Cahard, X. Pannecoucke, J. Org. Chem. 2015, 80, 4204-4212. [137] C. P. Xu Jiabin, Ye Jinxing, Liu Guosheng, Acta Chim. Sinica 2015, 73, 1294-1297. [138] A. Tlili, S. Alazet, Q. Glenadel, T. Billard Chem. Eur. J. 2016, 22, 10230-10234. [139] Q. Glenadel, S. Alazet, F. Baert, T. Billard, Org. Process Res. Dev. 2016, 20, 960-964. [140] S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J. Berg, G. W. Wagner, H. D. Durst, Synth. Commun. 2000, 30, 2847-2854. [141] R. Pluta, P. Nikolaienko, M. Rueping, Angew. Chem. Int. Ed. 2014, 53, 1650-1653. [142] K. Kang, C. Xu, Q. Shen, Org. Chem. Front. 2014, 1, 294-297. [143] T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei, M. Rueping, Angew. Chem. Int. Ed. 2013, 52, 12856-12859. [144] M. Rueping, X. Liu, T. Bootwicha, R. Pluta, C. Merkens, Chem. Commun. 2014, 50, 2508- 2511. [145] R. Pluta, M. Rueping, Chem. Eur. J. 2014, 20, 17315-17318. [146] A. Haas, G. Möller, Chem. Ber. 1996, 129, 1383-1388. [147] C. Xu, Q. Shen, Org. Lett. 2014, 16, 2046-2049. [148] K. Liao, F. Zhou, J.-S. Yu, W.-M. Gao, J. Zhou, Chem. Commun. 2015, 51, 16255-16258. [149] S.-Q. Zhu, X.-H. Xu, F.-L. Qing, Eur. J. Org. Chem. 2014, 2014, 4453-4456. [150] X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 3457-3460. [151] E. V. Vinogradova, P. Müller, S. L. Buchwald, Angew. Chem. Int. Ed. 2014, 53, 3125-3128. [152] X. Shao, C. Xu, L. Lu, Q. Shen, J. Org. Chem. 2015, 80, 3012-3021. [153] X. Shao, T. Liu, L. Lu, Q. Shen, Org. Lett. 2014, 16, 4738-4741. [154] B. Ma, X. Shao, Q. Shen, J. Fluorine Chem. 2015, 171, 73-77. [155] T. Yang, Q. Shen, L. Lu, Chin. J. Chem. 2014, 32, 678-680. [156] X. Wang, T. Yang, X. Cheng, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 12860-12864. [157] Q.-H. Deng, C. Rettenmeier, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2014, 20, 93-97. [158] Y. Li, Z. Ye, T. M. Bellman, T. Chi, M. Dai, Org. Lett. 2015, 17, 2186-2189. [159] C. Xu, B. Ma, Q. Shen, Angew. Chem. Int. Ed. 2014, 53, 9316-9320. [160] Q. Wang, Z. Qi, F. Xie, X. Li, Adv. Synth. Catal. 2015, 357, 355-360. [161] Q. Wang, F. Xie, X. Li, J. Org. Chem. 2015, 80, 8361-8366. [162] J. Luo, Z. Zhu, Y. Liu, X. Zhao, Org. Lett. 2015, 17, 3620-3623. [163] C. Xu, Q. Shen, Org. Lett. 2015, 17, 4561-4563. [164] Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N. Shibata, J. Am. Chem. Soc. 2013, 135, 8782-8785. [165] Z. Huang, Y.-D. Yang, E. Tokunaga, N. Shibata, Org. Lett. 2015, 17, 1094-1097. [166] S. Arimori, M. Takada, N. Shibata, Dalton Trans. 2015, 44, 19456-19459. [167] Z. Huang, Y.-D. Yang, E. Tokunaga, N. Shibata, Asian J. Org. Chem. 2015, 4, 525-527. [168] S. Arimori, M. Takada, N. Shibata, Org. Lett. 2015, 17, 1063-1065. [169] X.-L. Zhu, J.-H. Xu, D.-J. Cheng, L.-J. Zhao, X.-Y. Liu, B. Tan, Org. Lett. 2014, 16, 2192- 2195. [170] H. Xiang, C. Yang, Org. Lett. 2014, 16, 5686-5689. [171] H.-Y. Xiong, X. Pannecoucke, T. Besset, Chem. Eur. J. 2016, n/a-n/a. [172] C. Ni, J. Hu, Synthesis 2014, 46, 842-863, 822 pp. [173] J. Hine, J. J. Porter, J. Am. Chem. Soc. 1957, 79, 5493-5496. [174] G. G. I. Moore, J. Org. Chem. 1979, 44, 1708-1711. [175] A. H. de Cat, R. K. van Poucke, R. Pollet, P. Schots, Bull. Soc. Chim. Belg. 1965, 74, 270- 280. [176] D. L. S. Brahms, W. P. Dailey, Chem. Rev. 1996, 96, 1585-1632. [177] B. R. Langlois, J. Fluorine Chem. 1988, 41, 247-261. [178] K. I. Petko, L. M. Yagupolskii, J. Fluorine Chem. 2001, 108, 211-214.

95 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[179] K. I. Petko, L. M. Yagupol'skii, Russ. J. Org. Chem. 2004, 40, 601-602. [180] A. M. Demchenko, K. G. Nazarenko, A. P. Andrushko, D. V. Fediyuk, A. N. Krasovsky, L. M. Yagupolsky, Chemistry of Heterocyclic Compounds 2003, 39, 965-969. [181] I. Rico, C. Wakselman, Tetrahedron 1981, 37, 4209-4213. [182] V. P. Mehta, M. F. Greaney, Org. Lett. 2013, 15, 5036-5039. [183] X.-Y. Deng, J.-H. Lin, J. Zheng, J.-C. Xiao, Chem. Commun. 2015, 51, 8805-8808. [184] K. Fuchibe, M. Bando, R. Takayama, J. Ichikawa, J. Fluorine Chem. 2015, 171, 133-138. [185] Y. Zafrani, G. Sod-Moriah, Y. Segall, Tetrahedron 2009, 65, 5278-5283. [186] F. Wang, W. Huang, J. Hu, Chin. J. Chem. 2011, 29, 2717-2721. [187] C. S. Thomoson, W. R. Dolbier, J. Org. Chem. 2013, 78, 8904-8908. [188] P. S. Fier, J. F. Hartwig, Angew. Chem. Int. Ed. 2013, 52, 2092-2095. [189] L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 2013, 52, 12390-12394. [190] W. Zhang, F. Wang, J. Hu, Org. Lett. 2009, 11, 2109-2112. [191] Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 2012, 134, 1494-1497. [192] C. Bottecchia, X.-J. Wei, K. P. L. Kuijpers, V. Hessel, T. Noël, J. Org. Chem. 2016, 81, 7301-7307. [193] G. K. S. Prakash, J. Hu, T. Mathew, G. A. Olah, Angew. Chem. Int. Ed. 2003, 42, 5216- 5219. [194] a) J. L. Howard, C. Schotten, S. T. Alston, D. L. Browne, Chem. Commun. 2016, 52, 8448- 8451; b) J.-B. Han, H.-L. Qin, S.-H. Ye, L. Zhu, C.-P. Zhang, J. Org. Chem. 2016, 81, 2506-2512. [195] Y.-m. Lin, W.-b. Yi, W.-z. Shen, G.-p. Lu, Org. Lett. 2016, 18, 592-595. [196] Y.-m. Lin, W.-b. Yi, W.-z. Shen, G.-p. Lu, Org. Lett. 2016, 18, 592-595. [197] D. Zhu, Y. Gu, L. Lu, Q. Shen, J. Am. Chem. Soc. 2015, 137, 10547-10553. [198] G. K. S. Prakash, S. Krishnamoorthy, S. Kar, G. A. Olah, J. Fluorine Chem. 2015, 180, 186- 191. [199] G. K. S. Prakash, Z. Zhang, F. Wang, C. Ni, G. A. Olah, J. Fluorine Chem. 2011, 132, 792- 798. [200] W. Zhang, J. Zhu, J. Hu, Tetrahedron Lett. 2008, 49, 5006-5008. [201] B. Bayarmagnai, C. Matheis, K. Jouvin, L. J. Goossen, Angew. Chem. Int. Ed. 2015, 54, 5753-5756. [202] M. V. Ivanova, A. Bayle, T. Besset, X. Pannecoucke, T. Poisson, Angew. Chem. Int. Ed. 2016, n/a-n/a. [203] K. Jouvin, C. Matheis, L. J. Goossen, Chem. Eur. J. 2015, 21, 14324-14327. [204] Y. Gu, D. Chang, X. Leng, Y. Gu, Q. Shen, Organometallics 2015, 34, 3065-3071. [205] J. Wu, Y. Gu, X. Leng, Q. Shen, Angew. Chem. Int. Ed. 2015, 54, 7648-7652. [206] J. Wu, Y. Liu, C. Lu, Q. Shen, Chem. Sci. 2016, 7, 3757-3762. [207] S. Arimori, O. Matsubara, M. Takada, M. Shiro, N. Shibata, Royal Society Open Science 2016, 3. [208] H.-Y. Xiong, A. Bayle, X. Pannecoucke, T. Besset, Angew. Chem. Int. Ed. 2016, 55, 13490- 13494. [209] K. M. Borys, M. D. Korzyński, Z. Ochal, Tetrahedron Lett. 2012, 53, 6606-6610. [210] F. Toulgoat, B. R. Langlois, M. Medebielle, J.-Y. Sanchez, J. Org. Chem. 2007, 72, 9046- 9052. [211] J. Liu, C. Ni, F. Wang, J. Hu, Tetrahedron Lett. 2008, 49, 1605-1608. [212] Y. Zhao, W. Huang, J. Zheng, J. Hu, Org. Lett. 2011, 13, 5342-5345. [213] B. M. Trost, Bull. Chem. Soc. Jpn. 1988, 61, 107-124. [214] R. Rajamuthiah, E. Jayamani, H. Majed, A. L. Conery, W. Kim, B. Kwon, B. B. Fuchs, M. J. Kelso, F. M. Ausubel, E. Mylonakis, Bioorg. Med. Chem. Lett. 2015, 25, 5203-5207. [215] W. Duan, J. Li, E. S. Inks, C. J. Chou, Y. Jia, X. Chu, X. Li, W. Xu, Y. Zhang, J. Med. Chem. 2015, 58, 4325-4338.

96 Chapter I. Synthesis of SCF2R derivatives and their application in electrophilic reactions

[216] A. Novakovic, L. Gojkovic-Bukarica, B. Beleslin-Cokic, N. Japundzic-Zigon, Z. Sajic, D. Nezic, M. Peric, B. Djukanovic, T. Kazic, J. Pharmacol. Sci. 2003, 92, 108-114. [217] S.-S. P. Chou, D.-J. Sun, H.-C. Lin, P.-K. Yang, Chem. Commun. 1996, 1045-1046. [218] S. Yuki, S. Hisahiro, K. Masato, I. Susumu, N. Kohei, K. Junji, Chem. Lett. 2016, 45, 283- 285. [219] C. Ni, J. Hu, Tetrahedron Lett. 2005, 46, 8273-8277. [220] a) X. Wang, G. Liu, X.-H. Xu, N. Shibata, E. Tokunaga, N. Shibata, Angew. Chem. Int. Ed. 2014, 53, 1827-1831; b) Y. Chernykh, B. Jurásek, P. Beier, J. Fluorine Chem. 2015, 171, 162- 168. [221] T. G. Gant, J. Med. Chem. 2014, 57, 3595-3611. [222] A. Mullard, Nat. Rev. Drug Discov. 2016, 15, 219-221. [223] D. Thomae, T. J. Morley, H. S. Lee, O. Barret, C. Constantinescu, C. Papin, R. M. Baldwin, G. D. Tamagnan, D. Alagille, J. Labelled Compd. Radiopharm. 2016, 59, 205-213. [224] S. Mizuta, I. S. R. Stenhagen, M. O’Duill, J. Wolstenhulme, A. K. Kirjavainen, S. J. Forsback, M. Tredwell, G. Sandford, P. R. Moore, M. Huiban, S. K. Luthra, J. Passchier, O. Solin, V. Gouverneur, Org. Lett. 2013, 15, 2648-2651. [225] T. Khotavivattana, S. Verhoog, M. Tredwell, L. Pfeifer, S. Calderwood, K. Wheelhouse, T. Lee Collier, V. Gouverneur, Angew. Chem. Int. Ed. 2015, 54, 9991-9995. [226] M. Zhou, C. Ni, Z. He, J. Hu, Org. Lett. 2016, 18, 3754-3757. [227] a) B. Xu, G. B. Hammond, Angew. Chem. Int. Ed. 2005, 44, 7404-7407; b) G. B. Hammond, J. Fluorine Chem. 2006, 127, 476-488. [228] a) X. Li, S. Li, S. Sun, F. Yang, W. Zhu, Y. Zhu, Y. Wu, Y. Wu, Adv. Synth. Catal. 2016, n/a-n/a; b) F. Chen, A. S. K. Hashmi, Org. Lett. 2016, 18, 2880-2882.

97 CHAPTER II

SYNTHESIS OF BENZYLFLUOROALKYLSELENIDE REAGENTS AND THEIR APPLICATION IN ELECTROPHILIC REACTIONS Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I. BIBLIOGRAPHY SECF3 AND SECF2R ...... 99

I.2 DIRECT INSERTION OF SECF3 GROUP ...... 104 I.2.1 Nucleophilic trifluoromethylselenolation reactions ...... 104 I.2.1.1 Trifluoromethyselenocopper ...... 105 I.2.1.2 Tetramethyl ammonium trifluoromethylselenate (0) ...... 107 I.2.2 Radical trifluoromethylselenolation reactions ...... 108 I.2.3 Electrophilic trifluoromethylselenolation reactions ...... 109 I.2.3.1 Trifluoromethaneselenyl chloride ...... 109

I.3 SE-CF2R BOND FORMATION; INDIRECT APPROACH ...... 111

I.3.1 Se-CF2R bond formation through a radical pathway ...... 111

I.3.1.1 HCF2Cl as difluorocarbene source ...... 111 I.3.1.2 Dibromodifluoromethane ...... 111 I.3.1.3 Sodium chlorodifluoroacetate ...... 112 I.3.1.4 Aryl difluoromethyl chlorides used as radical sources ...... 112

I.3.1.5 RFI used as perfluorinating reagent in radical perfluoroalkylations ...... 113

I.3.2 Se-CF2R bond formation through a nucleophilic pathway ...... 113 I.3.2.1 Hemiaminals and α-Difluorodiaroylmethanes ...... 113 I.3.2.2 Metal-catalyzed perfluoroalkylations ...... 114

II. RESULTS AND DISCUSSION: SECF2R INSERTION ...... 115 II.1 SYNTHESIS OF BENZYL FLUOROALKYL SELENIDES ...... 115

II.1.1 State of the art: Synthesis of the CF3SeCl ...... 115 II.1.2 Synthesis of benzyl fluoroalkyl selenides ...... 116

II.1.2.1 CF3SeCl: in situ preparation of the reactive species ...... 120

II.1.2.2 Benzyltrifluoromethyl selenide used as a CF3SeCl source in SEAr reactions ...... 121 II.1.2.3 Fluoroalkylselenolation of arenes ...... 123 II.1.3 Post-functionalization reactions ...... 126

III.CONCLUSIONS ...... 126

IV.REFERENCES: ...... 128

98 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

Herein we report the synthesis, characterization and the in-situ use of novel fluoroalkylselenolating pre-reagents. The generation of a well-known reactive species CF3SeCl in situ led to interesting results. Trifluoromethylselenolated molecules (SeCF3), superior homologs

(SeRF) as well as functionalized moieties (SeCF2FG) were obtained using different sources of

SeCF2R. The reported bibliographic data are prior October 2016. Results and discussion part is preceded by the bibliographic data concerning fluoroalkylselenolated compounds.

I. Bibliography SeCF3 and SeCF2R

Selenium was discovered in 1817 by Berzelius who named it in honor of the Greek moon goddess, Selene. This might be due to the similitudes he noticed with tellurium, named in honor of Tellus the Latin goddess of earth. However, selenium is far more similar to sulfur than tellurium, the previous chalcogen of the 16th group in the periodic table. Despite this, the interest towards selenium in organic chemistry remains still low in comparison to sulfur. Among various issues that limited the interest towards selenium might be also the awareness concerning its toxicity. However, selenium has been proven to be an essential oligoelement in living species. Selenium is found in the 21st proteinogenic discovered aminoacid selenocysteine,[1] which is integral part of several enzymes, as glutathione peroxidases, tetraiodothyronine 5’ iodinases, thioredoxin reductases etc. Scientists referred to selenium as the “essential poison” due to its small range between R.D.A (Recommended Dietary Allowance) (50μg/day) and toxic limit (800 μg/day). Despite the higher abundance of sulfur in nature, the presence of selenium is significant in different biological processes due to the ability of selenium to resist to permanent oxidation.[2] Thus, considering the importance of such element in natural processes, the development of synthetic methodologies and reagents to access fluoroalkylselenolated compounds appeared to be of interest. As mentioned above, the association of fluorine and selenium is less explored than in the case of the sulfur. Herein, you find a review of various synthetic pathways and reagents to access CF3Se and RCF2Se containing molecules. In the second part, we will report our recent results obtained in direct fluoroalkylselenolations.

99 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I.1 Introduction of CF3 group into Selenium-containing derivatives

Herein we report the most relevant works, to our knowledge, concerning the trifluoromethylation of Se-centers. Trifluoromethylation of Se-centers has been obtained through nucleophilic and radical reactions. Based on our bibliographic research, no electrophilic trifluoromethylation has been reported.

I.1.1 Radical trifluoromethylation of Se-centers

Radical trifluoromethylation of Se-centers is less developed respect to the trifluoromethylation of sulfur containing compounds. To our knowledge only a few reports has been published involving a couple of different CF3 sources.

I.1.1.1 Trifluoromethaneselenosulfonates and sodium trifluoromethanesulfinate

In late 90ies, trifluoromethaneselenosulfonates has been prepared in our labs reacting sodium trifluoromethanesulfinate with either selenyl chlorides or diselenides under oxidative conditions (Scheme 1).[3]

a) Ph-Se-Se-R/Br2

O b) F C S Ph-Se-Cl 3 Na R Se SO2CF3 O

R-Se-Se-R/PhI(OCOCF3)2 c) Scheme 1 Synthesis of trifluoromethaneselenosulfonates

Then phenyltrifluoromethaneselenosulfonate has been used as a CF3 radical source in the trifluoromethylation of diselenides. Trifluoromethylselenolated compound has been obtained through a SH2 reaction mechanism as reported by the authors. Taking in consideration the reaction sensitivity to light and formation of the various by-products further strengthens the conclusion of the authors concerning the reaction mechanism (Scheme 2).[3]

SeCF3 hv Se Ph Se Ph O O Se Se Se Se + S + + F C F3C 3 Se Ph CH2Cl2 58 % 3 % 4 % Scheme 2 Trifluoromethylalation of diselenides

Moreover the yield has been improved further up to 85 % adding two equiv. of diphenyl diselenide. In this case there is no need of irradiation. And the reaction proceeds through an SET

100 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions process with the phenyltrifluoromethaneselenosulfonate acting as an oxidant and the diselenide as a reducer as reported by the authors.[4]

Sodium trifluoromethanesulfinate, a well-known trifluoromethylating reagent developed in our labs, has been used in the radical trifluoromethylation of benzeneselenol compound. Cai and coll. reported the trifluoromethylation of only one example of seleno-containing compounds among various sulfur-centers. Mechanistic elucidations reveal that I2 released from iodine pentoxide generated the CF3 radical via a SET mechanism. Iodine also reacts with the benzeneselenol to form, in situ, Ph-Se-Se-Ph or Ph-SeI, which underwent trifluoromethylation in presence of the

[5] CF3 radical (Scheme 3).

SeH SeCF3 I2O5 + CF3SO2Na DMSO 75 % Scheme 3 Trifluoromethylation of benzeneselenol

I.1.1.2 Trifluoroiodomethane

CF3I is a colourless gas, part of the family of the halomethanes, which were proposed as a substitution of the environmentally hazardous CF3Br. Even though being a gas and facing several handling problems during its use, CF3I is one of the most used reagents as trifluoromethylating source. It has been used also in the trifluoromethylation of Se-centers through the formation of a

CF3 radical.

Magnier et al. reported the trifluoromethylation of diselenides in presence of CF3I, mediated by the use of sodium hydroxymethanesulfinate (Rongalite®) (Scheme 4, eq. a).[6] However, the methodology has been mostly applied to the synthesis of perfluoroalkyl selenides. As reported by

[6b] the authors, a SH2 (homolytic substitution) reaction mechanism or a SRN1 process involving a radical chain propagation could be involved.[6a]

b) a)

TDAE NaO2CH2OH R SeCF3 CF3I + RSeSeR R SeCF3 DMF DMF/H2O R= Me 90 % R= Ph 28 % R= Ph 99 % R= Bz 90 % Scheme 4 Use of trifluoroiodomethyl as a trifluoromethylating source

Later, Dolbier and coll. disclosed a new route for the trifluoromethylation of aryl and alkyl diselenides in excellent yields (Scheme 4, eq. b). CF3I/TDEA system gave the desired compounds in a high yield. Moreover, using the double of equiv. of CF3I they have reported the

101 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions trifluoromethylation of both parts of the diselenide thus obtaining almost 200 % of conversion respect to the moles of the diselenide.[7]

I.1.2 Nucleophilic trifluoromethylation of Se-centers

Nucleophilic trifluoromethylation of Se-centers is limited to a few papers as in the case of the radical trifluoromethylation. However, a wider range of trifluoromethylating sources has been used in these reactions. The use of Ruppert-Prakash reagent, fluoroform, trifluoromethylcopper and other reagents will be disclosed below.

I.1.2.1 Trifluoromethyl trimethylsilane

Trifluoromethyl trimethylsilane (CF3TMS), known also as Ruppert-Prakash reagent, is a very versatile and useful trifluoromethylating source. Since its discovery, it has been extensively used in trifluoromethylation reactions and very recently also in the difluoromethylation of C-,[8] N-[9] [10] and S-centers. Taking advantage of the high efficiency of CF3TMS as trifluoromethylating agent, its commercial availability and its easy-handling character, it was used in the trifluoromethylation of diselenides some years ago by our group. Thus, employing 2 equiv. of

TBAF as a desilylating agent in THF, (PhSe)2 was trifluoromethylated giving the desired compound in a 40 % isolated yield (Scheme 5, eq. a).[11] However, considering the low reaction yields obtained more efforts were made in order to increase it. Thus, using the selenocyanates as starting materials not only led to an improvement in terms of yield but also the amount of TBAF was reduced 10-fold (Scheme 5, eq. b). The released cyanide anion is also able to desilylate [12] CF3TMS, therefore explaining the use of TBAF in catalytic amounts.

b) a)

R-SeCN R-Se-Se-R TBAF cat. TBAF R SeCF TMSCF3 RSeCF 3 THF THF 3 58-75 % R= Ph 40 % Scheme 5 Ruppert-Prakash reagent as a trifluoromethylating source

Rueping and coll. reported the trifluoromethylation of a selenocyanates with TMSCF3 in presence of Cs2CO3 in good yield (Scheme 5, eq. a). However, the trifluoromethylation of the selenocyanates served as a starting point to the authors for the exploration of the best reaction conditions implied in the transformation of the diazonium salts into trifluoromethylselenolates (Scheme 6, eq. b).

102 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

SeCN

NH 2 MeO c) Cs2CO3 SeCN O2N a) CH CN 1. HBF4 ET2O 3 MeO i-AmONO SeCF3 84 % CH3CN TMSCF3 1.(Het)Ar N2BF4 O2N 2. CuCl/CuCl2 70 % 1,10-phen 10 mol % 2. CuCl/CuCl2 1,10-phen 10 mol % (Het)Ar SeCF3 KSeCN, CsCO b) 3 40-88 % CH3CN Scheme 6 In situ trifluoromethylation of selenocyanates

Therefore a CuI/CuII-mediated Sandmeyer type reaction involving the trifluoromethylselenolation of aryl and heteroaryl diazonium tetrafluoroborates has been successfully developed. The methodology tolerates various functional groups and works well with both electron-rich and electron poor substrates (Scheme 6, eq. b). The authors also reported the one pot trifluoromethylselenolation of the aniline (Scheme 6, eq. c).[13]

I.1.2.2 Trifluoromethane and hemiaminals of fluoral

As reported in the previous chapter, fluoroform is an industrial by-product in the production of Teflon, refrigerants, etc. Thus, a lot of effort has been made to transform this waste in a useful trifluoromethylating reagent in order to consume it. Among other reactions, fluoroform found use also in the trifluoromethylation of selenocyanates and diselenides. Fluoroform was used in the trifluoromethylation of carbonyl compounds, disulfides and also diselenides in the early 2000 in our labs. Trifluoromethylation occurs through the in situ formation of a tetrahedral DMF adduct arising from reaction of CF3H with DMF in presence of [14] a base. Such adduct acts as a reservoir-like source of CF3 (Scheme 7, eq. a).

R-SeCN b) R-Se-Se-R a) R-SeCF3 DMF (TMS)N /TBAF 80-95 % t-BuOK 3 CuCl or t-BuOK "CuCF3" HCF3 R SeCF3 R-Se-Se-R DMF 47 % R-SeCF3 DMF c) 95 % Scheme 7 Fluoroform as a trifluoromethylating source

Rozen and coll. accessed to alkyl, aryl and heteroaryl trifluomethylselenolated compounds starting from the corresponding selenocyanates and the fluoroform-derived CuCF3 (Scheme 7, eq. b). Similar reaction conditions have been applied also to diselenides leading to the desired products in high yields (Scheme 7, eq. c).[15]

103 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

Hemiaminals of fluoral has been developed in our labs in the early 2000 and could be easily prepared from fluoral or fluoroform. The trifluoromethylation ability of the hemiaminals has been successfully tested in presence of non-enolizable carbonyl compounds, disulfides and diselenides. Trifluoromethylselenolated compounds were obtained in a good yield starting from the proper diselenides and TBAT as fluoride source.[16]

OSiMe3 TBAT Ar-Se-Se-Ar + F C N N 3 Ar SeCF3 Ph Glyme H 80 % Scheme 8 Hemiaminal as a trifluoromethylating source

I.1.2.3 Diethyl trifluoromethylphosphonate

Diethyl trifluoromethylphosphate has been used as a trifluoromethylating reagent mostly in the trifluoromethylation of ketones and aldehydes. Nevertheless, Beier and coll. reported an example of the trifluoromethylation of diphenyl diselenide with a modest yield, using t-BuOK as a base.[17]

O t-BuOK EtO PCF3 + Ph-Se-Se-Ph Ph SeCF3 DMF OEt 34 % Scheme 9 Diethyl trifluoromethylphosphonate as a trifluoromethylating agent.

I.2 Direct insertion of SeCF3 group

Direct insertion of the trifluoromethylseleno group onto molecules remains the favorite approach with respect to the Se-CF3 bond formation, thus avoiding the pre-synthesis of selenolated compounds. Electrophilic and especially nucleophilic reactions are the most developed ways to access trifluoromethylselenolated compounds. Herein, we report the use of various reagents as well as the different synthetic pathways exploited to obtain SeCF2R adducts.

I.2.1 Nucleophilic trifluoromethylselenolation reactions

During recent years, interest has been increasing towards trifluoromethylselenolation through nucleophilic approach. Different research groups contributed to this field by developing new

¯ reagents that act as CF3Se donors as well as relevant synthetic strategies giving the possibility to access to a wide range of CF3Se containing compounds. Below we will report the most relevant synthetic procedures and use of different reagents that contributed in the improvement of this field.

104 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I.2.1.1 Trifluoromethyselenocopper

As in the case of nucleophilic trifluoromethylthiolation reactions, the association between organometallic chemistry and trifluoromethylseleno group led to important results. Hence, various classes of substrates have been trifluoromethylselenolated. Although the most used metal is Cu, trifluoromethylseleno adamantine has been prepared reacting iodoadamantine and [18] Hg(SeCF3)2.

One of the ways for preparing the CuSCF3 is reacting the trifluoromethyl diselenide with copper powder in DMF (Scheme 10). Yagupolskii and coll. reported the synthesis of trifluoromethylselenocopper in a quantitative yield. Nevertheless, CuSeCF3 could be isolated only as a complex containing one molecule of solvent.[19] Trifluoromethyl diselenide, itself, has been [20] prepared whether reacting mercury bis(trifluoromethyl) with SeBr4 or (CF3Se)3N with CF3SeBr (Scheme 10).[21]

Hg(CF3)2 + SeBr4

2 Cu F C Se Se 3 CF3 2 CuSeCF3 DMF 99 % + 2 (CF3Se)3N CF3SeBr

Scheme 10 Synthesis of CuSeCF3

They also described the synthesis of mono-, tri- and hexa-trifluoromethylselenolated arenes starting from the corresponding iodo-derivatives in presence of CuSeCF3 (Scheme 11). However, improved yields are reported running a one-pot reaction: in situ preformation of the complex and subsequent addition of the iodoarene.[19]

I F CSe SeCF SeCF3 I I 3 3 CuSeCF3 CuSeCF3 DMF O2N O2N NMP SeCF 95 % I 3 74 %

I SeCF3 I I F CSe SeCF CuSeCF3 3 3

I I NMP F3CSe SeCF3 I SeCF3 87 % Scheme 11 Trifluoromethylselenolation of arenes

Weng and coll. performed a catalytic Cu-mediated trifluoromethylselenolation of aryl, heteroaryl and alkyl halides in presence of elemental selenium, TMSCF3, KF, Ag2CO3 and phenantroline as a ligand in DMF (Scheme 12). The methodology seems to be compatible with a wide range of

105 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions functional groups. The presence of silver salt might to be involved in the formation of the active complex [(phen)Cu(SeCF3)]2, key intermediate in the reaction. Moreover, when catalytic amounts of CuI and phenantroline in absence of silver salt were used, the expected compound was obtained with 50 % yield. Furthermore, the use of the isolated of Cu complex as a reactive species, gave similar yields when compared to the in-situ formation of the complex.[22]

CuI, phen cat. Ag2CO3 + TMSCF + Se + KF R X 3 8 R SeCF3 DMF X= I, Br 53-94 % R= Alkyl, (Hetero)aryl Scheme 12 In situ C-Se-CF3 bond formation

Based on the results shown above and the previous works in Cu-catalyzed nucleophilic trifluoromethylthiolation of various starting materials, Weng and coll. also reported the synthesis

¯ of various Cu(I) trifluoromethylselenolate complexes and studied their reactivity as CF3Se donors towards various starting materials.

CuI + TMSCF3 + Se8 + KF

Het Br a) Het SeCF3 i) RX 14-95 % Dioxane bpy R SeCF3 b) 65-99% O

O R h) Cl c) Br Ar R (bpy)Cu(SeCF ) 3 2 SeCF3 CH3CN/Toluene SeCF3 DMF Ar 44-96 % 53-83 % g) d) R H DMP, KF R SeCF3 f) R Br DMF 57-87 % O R SeCF3 DMF 41-91 % R1 e) O R Br R R 1 SeCF CsF 3 CH CN/Xylene X 3 R 53-69 % SeCF R 3 31-94 % Scheme 13 CuI-catalyzednucluephilic triluoromethylselenolation of diverse starting materials

All the complexes has been prepared in a reaction involving CuI, TMSCF3, Se8, KF and [23] dinitrogen ligands in CH3CN (Scheme 13, eq. a).

106 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

Although all complexes led to high reaction yields (except the neocuprine coordinating complex) in presence of iodotoluene, the authors chose the [(bpy)Cu(SeCF3)]2 considering the ease in the preparation and being the most economically-advantageous as a source of SeCF3. Cu-mediated trifluoromethylselenolation of aryl and heteroaryl iodides and bromides as well as alkyl bromides have been successfully performed. The reaction conditions showed compatibility with various functional groups (Scheme 13, eq. b).[23] For instance, propargylic trifluoromethyl selenoethers has been prepared starting from the propargylic chloro derivatives in good yields. The same group reported also Cu-mediated trifluoromethylselenolation of allylic bromides (Scheme 13, eq. c and d).[24] Cu-mediated trifluoromethylselenolation of vinyl halides has been performed leading to vinyl trifluoromethyl selenoethers in good yields.[25] Trifluoromethylseleno-α,β-unsaturated carbonyl compounds have been prepared starting from the bromo derivatives (Scheme 13, eq. f).[26] Copper-mediated oxidative trifluoromethylselenolation of terminal alkynes has been reported in presence of DMP and KF (Scheme 13, eq. g).[27] In order to fully exploit the capacity of the previously prepared complex, the same group reported the Cu-mediated β-trifluoromethylseleno-α,β-unsaturated ketones starting from the brominated starting materials (Scheme 13, eq. h). The proposed reaction mechanism passes through the formation of an enolate between the Cu complex and the β-bromo ketone, leading to the desired product after bromide elimination.[28] Trifluoromethylselenolated heteroaromatics have been prepared reacting the bromo derivatives and the dimeric complex in presence of dioxane as a solvent (Scheme 13, eq. i).[29]

I.2.1.2 Tetramethyl ammonium trifluoromethylselenate (0)

Tetramethyl ammonium trifluoromethylselenolate (Me4N)SeCF3 has been firstly prepared by

Tyrra et al. reacting TMSCF3, elemental selenium (Se8) and Me4NF in THF or glyme with a yield of 70 % (Scheme 14, eq. a).[30] For instance, during the last few years the interest towards

(Me4N)SeCF3 has been continuously increasing and several groups used it as a SeCF3 source in nucleophilic trifluoromethylselenolation reactions. Rueping and coll. reported the Cu-mediated oxidative trifluoromethylselenolation of terminal alkynes by both using the isolated (Me4N)SeCF3 as well as preparing it in situ (Scheme 14, eq. b). However, the use of the preformed reagent gave higher yields. Also, the trifluoromethylselenolation of boronic acids as well as boronic pinacol esters has been successfully performed (Scheme 14, eq. c).[31] Goossen and coll. accessed to α- trifluoromethylseleno esters by means of a catalytic Cu-mediated method starting from the α- diazo esters (Scheme 14, eq. d).[32] Schoenebeck and coll. reported a straightforward Pd-mediated

107 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions coupling strategy for obtaining aryl and heteroaryl trifluoromethylselenolated adducts starting from the iodo-derivatives. A benchstable PdI-I dimer has been used as a catalyst, which I apparently leads to the in situ formation of Pd -SeCF3 dimer acting as a trifluoromethylselenolating species (Scheme 14, eq. e).[33]

TMSCF3 + Se8 + (NMe4)F

Ar I THF or glyme I 70 % tBu3P Pd Pd PBu3t R H I Cu(OTf)2, bpy cat. R SeCF Ar SeCF3 b) 3 TFH, O2 48-99 % Toluene e) 50-95 %

O Me4N SeCF3 R 1 OR c) R B(OH)2 N2 d) O R Bpin CuSCN cat. R 1 OR R SeCF3 DMF, O CH CN 2 58-84 % SeCF3 3 73-95 %

Scheme 14 Tetramethyl ammonium trifluoromethylselenolate as a SeCF3 source

I.2.2 Radical trifluoromethylselenolation reactions

On the contrary to nucleophilic trifluoromethylselenolation reactions, direct insertion of SeCF3 group into molecules through a radical pathway has not been extensively studied. To our knowledge only one recent publication has been reported using (Me4N)SeCF3 as a source of

SeCF3. Goossen and coll. accessed to trifluoromethylselenolated compounds in a Sandmeyer-type reaction starting from the aromatic and heteroaromatic diazonium salts in presence of catalytic amounts of copper thiocyanate. As expected, a single electron transfer mechanism is involved leading to the expected compounds (Scheme 15).[34]

Me NSeCF N BF 4 3 2 4 CuSCN cat. SeCF3 R R CH3CN 69-96 % Scheme 15 Sandmeyer trifluoromethylselenolation reaction

108 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I.2.3 Electrophilic trifluoromethylselenolation reactions

Electrophilic trifluoromethylselenolating reactions are far way less developed than nucleophilic trifluoromethylthiolating reactions. Thus, the development of new reagents as well as new synthetic approaches to access CF3Se-containing compounds through an electrophilic pathway would be highly desirable considering the advantages of this methodology.

I.2.3.1 Trifluoromethaneselenyl chloride

Trifluoromethaneselenyl chloride is the sole reagent used in electrophilic trifluoromethylselenolation reactions as a source of SeCF3. The first synthesis of CF3SeCl has been reported in the late 50ies by Emeleus and coll.[35] as well as Yarovenko and coll.[36] reacting trifluoromethyl diselenide with Cl2. Trifluoromethyl diselenide has been prepared by heating elemental selenium in presence of CF3I or trifluoromethylacetoxy silver (Scheme 16, eq. a). However, the synthetic pathway presents a low overall yield, especially due to the first synthetic step. In order to overcome such a problem, Magnier et al. reacted dibenzyldiselenide with CF3I in presence of sodium hydroxymethanesulfinate obtaining benzyl trifluoromethylselenide, which was reacted with sulfuryl chloride to give CF3SeCl with an overall yield of more than 90 % (Scheme 16).[6a] Despite the great steps forward in improving the synthesis, its good capacity in acting as trifluoromethylselenolating reagent has not been fully exploited and no novel reactions have been performed since then.

Se HOCH SO Na F3CSe 2 2 Se CF3I + DMF/H2O 90 %

95 % SO2Cl2 Se/ a) Δ CF3I 10-15 % Cl2 ClSeCF 3 CF3SeSeCF3 90 % Se/Δ O F C OAg 28 % 3 Scheme 16 Synthesis of trifluoromethaneselenyl chloride

Indeed, all the reactions performed with CF3SeCl date more than 30 years ago, when still the way to obtain such a highly volatile reagent was far way less advantageous. Yagupolskii and coll.

109 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

reported the trifluoromethylselenolation of aromatic amines through a SEAr reaction reacting [37] phenyl amines and CF3SeCl in Et2O (Scheme 17, eq. a). More electron-rich compounds as phenol gave a lack of selectivity leading to trifluoromethylseleno trisubstituted compounds (Scheme 17, eq. c).[38] Also few Grignard reagents have been successfully transformed to trifluoromethylselenolated compounds in diethyl ether (Scheme 17, eq. b). Haas and coll. reported [39] an acid mediated insertion of SeCF3 moiety to an aromatic core (Scheme 17, eq. d).

NH2 R R OMe 1 N N R 2 R R CF3SO3 NH3 SeCF3 1 H2N N OMe N OMe N OMe d) R2 a) H N N OMe CF3SO3H 2 Et2O OMe 65 % SeCF3 61-85 % ClSeCF3 OH MgBr c) OH SeCF3 F3CSe SeCF3 b)

Pyridine Et2O SeCF3 91 % quant. Scheme 17 Trifluoromethylselenolation reactions with trifluoromethaneselenyl chloride

110 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I.3 Se-CF2R bond formation; indirect approach

Concerning Se-CF2R (where R= FG, RF) containing molecules only the indirect approach has been reported to literature up to date. Herein we report the fluoroalkylation reactions as tools to access SeCF2R containing molecules.

I.3.1 Se-CF2R bond formation through a radical pathway

Herein we report the Se-CF2R bond formation through a radical pathway mechanism.

I.3.1.1 HCF2Cl as difluorocarbene source

As in the case of the thiolates, reactions involving difluorocarbene sources have been developed in order to access fluoroalkylselenolations. Chlorodifluoromethane, a restricted-use refrigerating gas is one of the first compounds used as a difluorocarbene source. Suzuki and coll. reported the difluoromethylation of preformed selenolates in presence of sodium hydroxide.[40]

1. LiAlH4, R 2. ClCF2H Se SeCF2H Se NaOH/H2O R R Dioxane or Benzene/EtOH 73-84 % Scheme 18 Chlorodifluoromethane as a difluorocarbene precursor

I.3.1.2 Dibromodifluoromethane

Dibromodifluoromethane is another well-known difluorocarbene precursor and it has been described in the previous chapter when used in the difluoromethylation of S-centers. Qing and coll. reported the synthesis of PhSeCF2Br, starting from selenophenol or diselenides in presence of CF2Br2 as a difluorocarbene precursor.

1. NaH, THF, 25 % a) 2. CF2Br2 1. NaH, THF, 86 % Ph SeH Ph SeCF Br 2. NaBH 2 b) 4 3. CF2Br2 c) 1. NaBH THF, 61 % Ph Se Se Ph 4, 2. CF2Br2 Scheme 19 Dibromodifluoromethane as a difluorocarbene source

The only use of NaH for deprotonating the selenophenol led to the expected compounds with a 25 % yield (Scheme 19, eq. a).[41] However, the authors improved the yield after addition of

111 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

NaBH4 to the reaction mixture in order to reduce PhSeSePh and other by-products to reactive [41] species (Scheme 19, eq. b). Also NaBH4-mediated reduction of the diselenide followed by subsequent addition of CF2Br2 led to the desired compound in a reasonable yield (Scheme 19, eq. c).[42]

I.3.1.3 Sodium chlorodifluoroacetate

SCDA (sodium chlorodifluoroacetate) has been also used as a difluorocarbene source in the difluoromethylation of thiols as shown above. However, only one example of difluoromethylation of selenols has been reported by the authors (Scheme 20).[43]

SeH O SeCF2H Cl K2CO3 + ONa F F DMF 65 % Scheme 20 SCDA as a difluorocarbene source

I.3.1.4 Aryl difluoromethyl chlorides used as radical sources

ArCF2Cl compounds were found to be radical sources in presence of light and underwent radical reactions in presence of a in situ preformed selenolate. ArCF2 radical has been formed after dissociation of C-Cl bond induced by light-mediated electron transfer from the selenolate. As expected, a radical chain propagation mechanism is involved leading to the expected selenolated compounds (Scheme 21).[44]

R 1. NaBH4 Se EtOH SeCF2Ar Se R R 2. ArCF2Cl hυ, DMF 84-93 %

Scheme 21 ArCF2Cl used as a difluorocarbene source

112 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

I.3.1.5 RFI used as perfluorinating reagent in radical perfluoroalkylations

C-RF and S-RF containing molecules have already been reported in literature and several ways to obtain them does already exist. In the case of perfluoroalkylselenides few data have been reported in literature.

a) NaO2SCH2OH

DMF, H2O 57-80 % + RSe RF RSeSeR RFI

TDAE b) DMF 98-99 % Scheme 22 Synthesis of prefluoroalkyl selenides

In the early 60ies, perfluoroalkyl selenolated derivatives has been firstly synthesized by Emeleus and coll. with the aim to compare their physico-chemical properties with the corresponding trifluoromethyl selenides.[45] Magnier et al. reported the synthesis of perfluoroalkyl selenides starting from the corresponding iodides and diselenides (Scheme 22, eq. a).[6] Later on, Dolbier and coll. accessed to perfluoroalkyl selenolated compounds using the TDAE/RFI methodology (Scheme 22, eq. b).[7a]

I.3.2 Se-CF2R bond formation through a nucleophilic pathway

Difluoroalkylation of Se-centres through a nucleophilic pathway has been even less explored respect to the already revisited radical pathway. Herein we report a short overview of the existing procedures in literature.

I.3.2.1 Hemiaminals and α-Difluorodiaroylmethanes

After using the hemiaminals of fluoral as trifluoromethylating reagents, our group studied also the possibility of using these compounds as difluoroalkylating reagents in presence of various electrophiles.

Cl Se NBn F OMe TMSOTf Se N F N THF F F O NBn 60 % Scheme 23 Use of hemiaminals in nucleophilic difluoroalkylation

113 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

Phenylselenyl chloride underwent difluoroalkylation leading to the desired compound in a good yield (Scheme 23).[16] The importance of such transformation should be also highlighted because it leads to adducts that can go post-functionalization.

Lu and coll. reported the synthesis of difluoromethyl phenyl selenide using α,α- difluorodibenzoylmethane as a difluoromethylating reagent. Nevertheless, only one substrate has been reported with only the dosed yield.[46]

O O

Cs2CO3 Ph Ph + PhSeSePh PhSeCF2H F F DMSO (95 %) Scheme 24 Diluoromethylation of diselenides

I.3.2.2 Metal-catalyzed perfluoroalkylations

As shown in the section above, Rueping and coll. reported the trifluoromethylation of the in situ formed selenocyanates starting from the diazonium salts. In the same paper also three perfluoroalkylations examples have been reported using the same methodology (Scheme 25).[13]

N BF 1. CuCl/CuCl2 SeC F 2 4 1,10-phen 10 mol % 2 5 R R KSeCN, Cs2CO3 CH CN 3 51-65 % 2. TMSC2F5 Scheme 25 Perfluoroalkylation reactions

A Pd-catalyzed cross-coupling reaction method has been used to obtain the superior homologs of CF3Se starting from selenyl stannanes and iodoperfluoroalkanes. Two examples have been reported with a good yield (Scheme 26).

Bu Se (PPh ) PdCl Se Sn Bu 3 2 2 RF +RI Bu F DMF 90 % Scheme 26 Perfluoroalkylation of selenyl stannates

114 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

II. Results and Discussion: SeCF2R insertion

As shown in the bibliographic part, most of the methodologies reporting the insertion the SeCF3 group insertion into molecules have been obtained through nucleophilic pathway. Various trifluoromethylselenolating reagents have already been reported. C-SeCF3 bond formation through a nucleophilic pathway led to different classes of compounds as (hetero)aromatics, propargyl, allyl, vinyl and alkyl as well as α,β-unsaturated carbonyl CF3Se-containing compounds. Up to the present time only a few examples of electrophilic substitution reactions have been reported. As a matter of fact, only CF3SeCl has been used with the aim to access CF3Se- containing compounds.

Concerning C-SeCF2R (where R= FG) bond formation no bibliographic data has been found up + to present time to our knowledge. Thus, the development of reagents acting as SeCF2R donors remains relevant.

II.1 Synthesis of benzyl fluoroalkyl selenides

Herein we report the synthesis of benzyl fluoroalkyl selenides, compounds that act as pre- reagents donating the SeCF2R group in presence of SO2Cl2 to form the reactive species CF3SeCl.

II.1.1 State of the art: Synthesis of the CF3SeCl

In the late 50ies two groups independently reported the synthesis of trifluoromethaneselenyl

[35-36] chloride reacting trifluoromethyl diselenide and chlorine. Indeed, CF3SeCl has been obtained with 90 % yield following this method during the last step of the synthesis. In spite of that, the synthetic method includes the use of gases as chlorine and the use of volatile and toxic starting materials as F3CSeSeCF3.

SO2Cl2 Cl2 SeCF3 ClSeCF3 CF3SeSeCF3 95 % 90 % Scheme 27 Synthesis of trifluoromethaneselenyl chloride

In order to overcome these drawbacks Magnier et al. reported an improved synthesis of CF3SeCl. Notably the use of more easy-to-handle starting materials, as trifluoromethyl benzyl selenide and sulfuryl chloride, was beneficial in both terms of manipulation and overall yield. Despite these steps forward, CF3SeCl still did not find any further use as trifluoromethylselenolating reagent. This might be due to the handling difficulties deriving from its highly volatile character considering that a boiling point between 31–31.5 °C has been reported in literature.[35-36] Another

115 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

important topic is the supposed toxicity of CF3SeCl (by analogy with CF3SCl), even if, up to the present time, no toxicity-related data have been reported to literature. As a result of what menationed above, its use has been rather limited to the synthesis a few examples reported in literature. Nevertheless, keeping in mind its good reactivity, efforts need to be done in order to revalorize such a reagent, minimizing the disadvantages. Therefore, the preparation of CF3SeCl and its in situ use could avoid the isolation and the direct contact with the reagent, rendering less essential the eventual toxicity of the reagent. Based on the results obtained by Magnier et al. the use of benzyl fluoroalkyl selenides as pre- reagents in presence of SO2Cl2 could be an attractive strategy. Thus, the CF3SeCl, in situ prepared, would react with the proper arenes leading to the formation of Ar-SeCF3 compounds.

II.1.2 Synthesis of benzyl fluoroalkyl selenides

Magnier et al. accessed to benzyl perfluoroalkyl selenides starting from dibenzyl diselenide and

CF3I as shown above. Furthermore, benzyl trifluoromethyl selenides were prepared in our laboratory years ago through a TBAF-catalyzed reaction between benzyl selenocyanates and

[12] TMSCF3 (Scheme 28). Benzyl selenocyanate itself can be easily obtained in a quantitative yield, starting from benzyl bromide and potassium selenocyanate.

TMSCF3 SeCN 2 equiv. SeCF3 TBAF cat. 70 % Scheme 28 Synthesis of benzyl trifluoromethyl selenide

Keeping in mind the willingness to access RCF2Se-containing molecules through an electrophilic pathway and considering the commercial availability of various fluoroalkylsilanes, we planned to synthesize different benzyl-SeCF2R (Scheme 29).

SeCF3 SeCF2Br SeCF2SO2Ph SeCF2CO2Me

2a 2b 2c 2d

SeCF2H SeCF2CF3 SeCF2CF2CF3

2e 2f 2g Scheme 29 Benzyl fluoroalkyl selenides

As mentioned above and with the previous obtained results in mind, we planned the synthesis of the pre-reagents 2a-g. Compound 2a was obtained reacting the Ruppert-Prakash reagent with Se1 in presence of catalytic amounts of TBAF. It should be noticed that the reaction was be 116 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions scaled-up with similar yield (Table 1, entry 1-3). Such a result emphasizes the robustness of the methodology. Compound 2b was obtained in a good yield in the same way reacting TMSCF2Br with BnSeCN and the synthesis scaled up to 20 mmol (Table 1, entry 4-5). Moreover, we could easily access to compounds 2d, 2f and 2g by using the previous reaction conditions and the proper silylated reagents. Additionally, in all of the cases good to excellent yields were obtained (Table 1, entry 10-13).

Table 1 Synthesis of benzyl fluoroalkyl selenides

SeCN F source + SeCF2R TMS CF2R Solvent,0-23 °C Time h Se1 2 equiv. 2a-g 1 equiv. - 1 2 Entry BnSeCN TMSCF2-R F source Solvent Time Yield (mmol) (2 equiv.) (equiv.) h (%) TBAF 2a 1 9.9 mmol CF THF 7 h 3 20 mol % 73 %

TBAF 2a 2 9.9 mmol CF3 THF 7 h 20 mol % 82 % TBAF 2a 3 70 mmol CF3 THF 7 h 20 mol % 70 % TBAF 2b 4 5 mmol CF2Br THF 4 h 20 mol % 80 % TBAF 2b 5 20 mmol CF2Br THF 4 h 20 mol % 88 % TBAF 2c 6 0.5 mmol CF2SO2Ph THF 15 h 20 mol % (6 %) CsF 2c 7 0.5 mmol CF2SO2Ph Diglyme 15 h 1 equiv. (40 %) CsF 2c 8 0.5 mmol CF2SO2Ph Diglyme 15 h 20 mol % (84 %) CsF 2c 9 5.5 mmol CF2SO2Ph Diglyme 15 h 20 mol % 80 % TBAF 2d 10 2 mmol CF2CO2Me THF 15 h 20 mol % 62 % TBAF 2f 11 4.5 mmol CF2CF3 THF 16 h 20 mol % 83 % TBAF 2f 12 14.2 mmol CF2CF3 THF 16 h 20 mol % 78% TBAF 2g 13 3.7 mmol CF2CF2CF3 THF 16 h 20 mol % 87% 1 A 1M solution of TBAF in THF was used. 2 Isolated yelds; In parentheses the 19 dosed yields determined by F NMR using PhOCF3 as an internal standard.

In contrast to other silanes, TMSCF2SO2Ph showed to be more stable considering that in presence of 0.2 equiv. of TBAF only 6 % of dosed yield was observed (Table 1, entry 6). The use

117 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions of a stronger fluoride source as CsF in diglyme led to compound 2c with a 40 % dosed yield with a stoichiometric amount (Table 1, entry 7). However, the optimal reaction conditions resulted to be catalytic amounts of CsF in diglyme. In this case compound 2c was obtained with 80 % isolated yield (Table 1, entry 9).

Considering the recent importance that have been given to the CF2H as a bioisostere in mimicking various endogenous functional groups and the recent advances in SCF2H chemistry, we came up with the idea of developing a pre-reagent that acts as a SeCF2H donor. To directly access compound 2e we reacted benzyl selenocyanate and difluoromethyl silane in presence of catalytic and excess amounts of TBAF.

Table 2 Synthesis of BnSeCF2H

SeCN + F source SeCF2H TMS CF2H Solvent,0 to 25 °C Time h Se1 2 equiv. 2e 1 equiv. F- source2 Temp Yield3 Entry Solvent (equiv.) °C (%) 1 TBAF 20 mol % THF 23 °C (2 %) 2 TBAF 2 equiv. THF 23 °C (7 %) 3 TBAF 2 equiv. THF 50 °C (12 %) 4 TBAF 20 mol % THF 65 °C (8 %) 5 TBAF 20 mol % DMF 120 °C (3 %) 6 CsF 20 mol % Diglyme 23 °C (3 %) 7 CsF 1 equiv. Diglyme 23 °C (28 %) 8 CsF 20 mol % DMF 23°C (16 %) 9 CsF 1 equiv. DMF 23°C (28 %) 10 CsF 3 equiv. DMF 23°C (12 %) 11 CsF 3 equiv. DMF 80 °C (12 %) 12 CsF 1 equiv. DMF 80 °C (9 %) 131 CsF 3 equiv. DMF 23°C (4 %) 14 CsF 1 equiv. DMF 23°C 19 % (33 %) 1 1 equiv. of CuSCN is added. 2 A 1M solution of TBAF in THF was used. 3 Isolated 19 yelds; In parentheses the dosed yields determined by F NMR using PhOCF3 as an internal standard.

Only low yields or traces of the expected compound were observed in contrast to the previously synthesized pre-reagents (Table 2, entry 1-5). This might be due to the more stable character of the TMSCF2H, as discussed above in this dissertation. CsF used in catalytic amounts gave 118 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions approximately the same results as in the case of TBAF (Table 2, entry 6 and 8). On the other hand, the use of stoichiometric amounts of CsF at 23 °C gave compound 2e with a 28 % dosed yield in diglyme as well as DMF (Table 2, entry 7 and 9). It was found that an excess of CsF as well as higher temperatures only hampers the reaction (Table 2, entry 8-12). Moreover, neither the use of CuSCN it was found beneficial for the reaction yield (Table 2, entry 13). Despite these efforts, compound 2e was finally obtained and isolated with a modest yield of 19 %. Regardless the low yield we should emphasize the fact that the first SeCF2H donor was developed in order to easily furnish SeCF2H containing molecules.

119 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

II.1.2.1 CF3SeCl: in situ preparation of the reactive species

In light of the results obtained by Magnier et al. we started exploring the best reaction conditions for the in situ preparation of CF3SeCl (2a’). By simply mixing equimolar amounts of benzyltrifluoromethyl selenide and sulfuryl chloride in THF the instant formation of trifluoromethaneselenyl chloride was observed (Table 3, entry 1 and 2). On the other hand, increasing the amount of SO2Cl2 gave a lower yield in the same period of time. This is related to the formation of a by-product CF3SeCl3 (2a″). Moreover, the formation of compound 2a″ increases proportionally with the time up to 4 hours (Table 3, entries 3-6).

Table 3 Formation of ClSeCF3

Solvent Ph SeCF3 + SO2Cl2 Cl SeCF3 + Cl3SeCF3 23 °C 2a 2a' 2a''

SO2Cl2 2a′ 2a″ Entry Solvent Time (equiv.) (%)1 (%)1 1 1 equiv. THF 4 min. (95 %) - 2 1 equiv. THF 15 min (95 %) - 3 2 equiv. THF 4 min. (82 %) (10 %) 4 2 equiv. THF 15 min (58 %) (40 %) 5 2 equiv. THF 1.5 h (46 %) (52 %) 6 2 equiv. THF 3 h (59 %) (41 %)

7 1 equiv. CH2Cl2 15 min (19 %) -

8 1 equiv. CH2Cl2 1.5 h (62 %) -

9 1 equiv. CH2Cl2 3 h (67 %)

10 1 equiv. CH2Cl2 4 h (67 %)

11 2 equiv. CH2Cl2 15 min (34 %)

12 2 equiv. CH2Cl2 1.5 h (83 %)

1 13 2 equiv. CH2Cl2 3 h (88 %)

1 19 In parentheses the dosed yields determined by F NMR using PhOCF3 as an internal standard.

Important to mention is the faster reaction rate in THF than in CH2Cl2 using 1 equiv. of SO2Cl2 (Table 3, entries 2 and 7). The slower product formation as well as the lower yield, 67 % after 3 h respect to 95 % after 4 minutes were observed in CH2Cl2. On the contrary to THF, use of 2 equivalents of SO2Cl2 in CH2Cl2 do not lead to the formation of by-products 2a”, but the yield of compound 2a′ increases up to 88 % in 3 hours.

120 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

As reported by Magnier et al., the mechanism could be supposed to start with the sulfuryl chloride dissociation in Cl2 and SO2. Generated chlorine attacks the selenium leading to the formation of a cationic intermediate which expels CF3SeCl through nucleophilic attack of chloride anion in benzylic position, generating also BnCl.[6b]

SO2Cl2

SO2 THF Cl SeCF3 Se Cl + Cl2 + Cl Cl SeCF2R + 23 °C CF3

Nu SeCF3

Scheme 30 Formation of ClSeCF2R

When 2 equiv. of SO2Cl2 were used in THF, a second equiv. of Cl2, coming from the excess of

SO2Cl2, reacts with CF3SeCl to give the unreactive species CF3SeCl3.

SO2Cl2 SO2Cl2

SO2 SO2 THF SeCF3 +Cl 2 Cl SeCF3 + Cl2 Cl3 SeCF3 23 °C Scheme 31 The use of 2 equiv.of sulfuryl difluoride

II.1.2.2 Benzyltrifluoromethyl selenide used as a CF3SeCl source in SEAr reactions

Herein we report the use of CF3SeCl (2a′) in SEAr reactions in presence of electron-rich arenes. Various compounds were prepared following such a straightforward strategy, thus enabling the scientific community to access CF3Se-compounds through easy-to-handle reagents.

After in situ formation of CF3SeCl, by action of SO2Cl2 onto BnSeCF3 in THF in 15 minutes, arenes or heteroarenes were added in reacting media (Scheme 32). The formation of corresponding trifluoromethylselenolated compounds was observed with electron-rich compounds. Good to excellent yields were obtained and the dosed yields were often quantitative (Scheme 32). Addition of dimethoxybenzene to the already-formed 2a′ after

15 minutes led to 40a with a yield of 80 %. Resorcinol and 1-naphtol reacted well with CF3SeCl leading to the formation of the desired compounds 40b and 40d with 85 % and 75 % yield respectively. Using 2.2 equiv. of both BnSeCF3 and SO2Cl2, with resorcinol led to the bis(trifluoromethylselenolated) compound 40c in a 75 % yield. Also, N-dimethylaniline reacted with the 2a′ giving compound 40e with 84 % yield. Less electron-rich compounds did not react

121 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

in the same conditions. In order to increase the reactivity of CF3SeCl we tried a Lewis acid- mediated reaction. Under these conditions, the use of catalytic amounts of BF3.Et2O gave compounds 40l and 40m with a yield of 60 % and 64 %. Nevertheless, compound 40k, arising from non electron-rich toluene, could be obtained with only 4% of yield. Also, the trifluoromethylselenolation of heteroaromatic compounds like pyrroles and indoles in presence of CF3SeCl was studied. The two classes of compounds find interest in pharmaceutical and agrochemical synthesis. Thus, could be of particular interest to obtain the trifluoromethylselenolated version of such compounds. Then, pyrrole 40f was synthesized with a good yield of 65 %. Trifluoromethylselenolated indoles (40h-j) were also obtained in excellent yields.

1) SO2Cl2 (1 equiv.), THF, 23°C, 15 min. Ph SeCF3 Ar SeCF3 2) ArH (30) (1 equiv.), THF, 0°C to 23°C 2a 40

SeCF SeCF 3 3 F3CSe SeCF3

MeO OMe HO OH HO OH 40a 40b 40c 80% (quant.) 85% (quant.) 93% (quant.)a N OH SeCF3

N H SeCF SeCF3 3 40f 40d 40e 67% (82%) 75% (quant.) 84% (88%) O SeCF SeCF Br 3 3 SeCF3 MeO N N N H H H 40h 40g 40j 80% (quant.) 91% (quant.) 89% (quant.)

SeCF3 SeCF3 SeCF3

MeO

40k 40l 40m b b (4%) 60% (74%) 64% (80%)b

Scheme 32 SEAr reactions using ClSeCF3. Yields shown are of isolated products; values in parentheses are yields as determined by 19F NMR spectroscopy using PhOCF3 as an internal standard. a2a (2.2 equiv), SO2Cl2 (2.2 equiv). b2a (1.2 equiv), SO2Cl2 (1.2 equiv), BF3. Et2O (0.3 equiv), ClCH2CH2Cl, 80 °C.

122 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

II.1.2.3 Fluoroalkylselenolation of arenes

As shown above the direct insertion of SeCF2R pre-functionalized groups into molecules has not been reported yet. With this in mind we planned the insertion of various fluoroalkylselenolated groups into molecules.

II.1.2.3.1 BrCF2SeCl used in SEAr reactions

Bromodifluoromethylselenolated arenes were prepared from the preformed reagent BrCF2SeCl 2b′ and the proper arenes. Up to date no literature data has been reported concerning the formation of BrCF2Se-molecules. Bromo derivatives find a wide use in synthesis as starting materials especially in cross-coupling reactions. Thus, the preparation of Ar-SeCF2Br compounds is of particular importance because would furnish pre-functionalized materials to use in further synthesis.

1) SO2Cl2 (1 equiv.), THF, 23°C, 30 min. Ph SeCF2Br Ar SeCF2Br 2) ArH (30) (1 equiv.), THF, 0°C to 23°C 2b 41

OH N SeCF2Br SeCF2Br

MeO OMe HO OH SeCF Br 41a 41b 2 SeCF2Br 80% (83%) 88% (quant.) 41d 41e 81% (93%) 72% (96%)

BrF CSe SeCF Br SeCF Br Br O 2 2 2 SeCF2Br SeCF2Br MeO N N H N N H H H 41g 41h 41i 41j 72% (96%)a 87% (96%) 76% (95%) 94% (quant.)

SeCF2Br SeCF2Br MeO

b 5l: (26%) 5m: (3%)b

Scheme 33 Synthesis of SeCF2Br containing compounds. Yields shown are of isolated products; values in parentheses are yields as determined by 19F NMR spectroscopy using PhOCF3 as an internal standard. a2b (2.2 equiv), SO2Cl2 (2.2 equiv). 2b (1.2 equiv), SO2Cl2 (1.2 equiv), BF3. Et2O (0.3 equiv), ClCH2CH2Cl, 80 °C. In general, the obtained yields are similar to the ones for the trifluoromethylselenolated adducts with electron-rich arenes. As in that case heterocyclic compounds were also

123 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions bromodifluoromethylselenolated. Pyrrole 30g gave only the compound 40g arising from bis- substitution. Less electron-rich did not react in these conditions and only low yields were observed when BF3.Et2O was used as an activator. As previously mentioned, such bromodifluoromethylselenolated molecules constitute important starting materials for further functionalization. For instance, Gouverneur and coll. reported the 18 - radiolabeling of BrCF2O and BrCF2S containing molecules with [ F]F through a nucleophilic halex-exchange mediated mechanism.[47] Consequently, the obtained molecules 41 could be used 18 to access, for the first-time, to [ F]CF3Se moiety. This application will be reported in Chapter 3.

II.1.2.3.2 RFSeCl used in SEAr reactions To our knowledge only one electrophilic perfluoroalkylselenolation reaction has been reported to literature. Magnier et al. reported the perfluorooctylselenolation of sodium diethylmalonate using [6b] C8F17SeCl.

(Et2OC)2CHNa + Cl-SeC8F17 BnCl (Et2OC)2CHSeC8F17 Et2O Scheme 34 Perfluoroalkylation performed in presence of sodium diethylmalonate

In our series of above reported pre-reagents, we reported the synthesis of two perfluoroalkylselenolated donors. Both these compounds would respectively give C2F5SeCl and

C3F7SeCl in presence of SO2Cl2. The in situ formed reactive species would react with electron-rich arenes to give the desired compounds as shown above in the case of SeCF3.

1) SO2Cl2 (1 equiv.), THF, 23°C, 15 min. Ph SeRF Ar SeRF RF= C2F5 42 2) ArH (30) (1 equiv.), THF, 0°C to 23°C RF= C H 43 2b 42 or 43 3 7

SeCF2CF3 SeCF2CF2CF3 SeCF2CF3 SeCF2CF2CF3

HO OH HO OH N N H H 42b 43b 42h 43h 86% (97%) 88% (quant.) 88% (91%) 89% (quant.) Scheme 35 Perfluoroalkylselenolation reactions. Yields shown are of isolated products; values in parentheses are yields as determined by 19F NMR spectroscopy using PhOCF3 as an internal standard For instance, resorcinol and indole were added to the reaction mixture containing the preformed

C2F5SeCl leading to compounds 42b and 42h with excellent yields. Likewise, using C3F7SeCl we could obtain compounds 43a and 43h with 88 % and 89 % yield respectively. Worth to mention,

124 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions that we reported the first direct fluoroalkylselenolations of arenes. For sure this methodology should be extended to other arenes in order to have a larger panel of ArSeRF compounds.

II.1.2.3.3 RCF2Se insertion through SEAr reactions.

As in the case of perfluoroalkylselenolation, direct RCF2Se (R= H, FG) insertion into molecules has not been reported. Herein, we report the synthesis of molecules bearing SeCF2H,

SeCF2CO2Me and SeCF2SO2Ph groups. As in the case of difluoromethylthiolated molecules, the

SeCF2H group could be of particular interest considering a possible H bonding donor character.

On the other hand, the presence of functional groups adjacent to the SeCF2 moiety could be valuable because leads to interesting compounds through post-functionalization reactions.

1) SO2Cl2 (1 equiv.), THF, 23°C, 30-45 min. Ph SeCF2R Ar SeCF2R R= H 44 2) ArH (30) (1 equiv.), THF, 0°C to 23°C CO2Me 45 2b 44-46 SO2Ph 46

SeCF2H SeCF2H

HO OH N H 44b 44h 86% (92%) 83% (92%)

SeCF2CO2Me SeCF2CO2Me

HO OH N H 45b 45h 60% (89%) 89% (quant.)

SeCF2SO2Ph SeCF2SO2Ph

HO OH N H 46b 46h 90% (quant.) 83% (quant.) Scheme 36 Fluoroalkylselenolation reactions. Yields shown are of isolated products; values in parentheses are yields as determined by 19F NMR spectroscopy using PhOCF3 as an internal standard

Thus, pre-reagents 2c, 2d and 2e in THF gave the corresponding reactive species 2c′-2e′, after the addition of SO2Cl2. The formation of HCF2SeCl (2e′) requires 45 minutes. After the addition of resorcinol or indole into the reaction media we obtained compounds 44b and 44h in good yields. The formation of the two other reactive species 2d′ and 2e′, requires also more time, 30

125 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions minutes for both. For instance, addition of arenes into reaction media after 30 minutes led to compounds 45 and 46 in good to excellent yields (Scheme 36). As reported above, those two functional groups have proved to be valuable in post- functionalization reactions in the chemistry of SCF2R. Thus, we could predict the same role in accessing post-functionalized CF2Se-containing molecules.

II.1.3 Post-functionalization reactions

Post-functionalization reactions occupy an important role in the first chapter. Through post- functionalization reactions we could access to various compounds that might find interest in organic synthesis or pharmaceuticals. An interesting transformation was obtained after a reductive desulfonylation in presence of a source of deuterium to access SCF2D compounds. Consequently, based on the recent interest towards deuterated molecules and our successful methodology to access DCF2S-containing compounds we decided to extend such a methodology to obtain, for the first time, DCF2Se adducts. Thus, adapting the reaction conditions previously used we accessed compound [D]47h with a 58 % yield.

SeCF2D SeCF2SO2Ph Mg (30 equiv.) I2 (0.3 equiv.)

CD OD, rt N 3 N H H 46h [D]47h 58% (61%)

Scheme 37 Synthesis of SeCF2D compound. Yields shown are of isolated products; values in parentheses are yields as determined by 19F NMR spectroscopy using PhOCF3 as an internal standard

III. Conclusions

As a conclusion, we came out with a new one-pot strategy to access various fluoroalkylselenolated compounds with good to excellent yields. The above reported results were obtained using a known source of fluoroalkylselenolating reagent. Thus, revalorization of an old reagent led to interesting results. We reported the synthesis of seven different pre-reagents 2a-2g, as sources of the corresponding reactive species generated in situ, 2a′-2g′. Only one of the above reported pre-reagents was known prior to literature. The preformed reactive species RCF2SeCl acted as fluoroalkylselenolating reagents in presence of arenes and heteroarenes. By means of the above described strategy, we reported the trifluoromethylselenolation of arenes and heteroarenes and most of the compounds were not reported in literature. Resorcinol and indole were used as starting material to access perfluoroalkylselenolation as well as difluoromethylselenolating

126 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions compounds for the first time in a direct insertion. Also, pre-functionalized molecules bearing

SeCF2Br, SeCF2SO2Ph and SeCF2CO2Me were reported. In the light of the results obtained in post-functionalization reactions reported in the first chapter we performed a Mg-mediated reductive desulfonylation reaction in CD3OD reporting the first procedure to access deuterodifluoromethylselenolated molecules.

127 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

IV. References:

[1] A. Böck, K. Forchhammer, J. Heider, W. Leinfelder, G. Sawers, B. Veprek, F. Zinoni, Mol. Microbiol. 1991, 5, 515-520. [2] H. J. Reich, R. J. Hondal, ACS Chem. Biol. 2016, 11, 821-841. [3] T. Billard, N. Roques, B. R. Langlois, J. Org. Chem. 1999, 64, 3813-3820. [4] T. Billard, B. R. Langlois, S. Large, Phosphorus, Sulfur Silicon Relat. Elem. 1998, 136, 521-524. [5] J.-J. Ma, W.-B. Yi, G.-P. Lu, C. Cai, Catal. Sci. Technol. 2016, 6, 417-421. [6] a) E. Magnier, C. Wakselman, Collect. Czech. Chem. Commun. 2002, 67, 1262-1266; b) E. Magnier, E. Vit, C. Wakselman, Synlett 2001, 1260-1262. [7] a) C. Pooput, W. R. Dolbier, M. Médebielle, J. Org. Chem. 2006, 71, 3564-3568; b) C. Pooput, M. Medebielle, W. R. Dolbier, Org. Lett. 2004, 6, 301-303. [8] K. Aikawa, K. Maruyama, J. Nitta, R. Hashimoto, K. Mikami, Org. Lett. 2016, 18, 3354- 3357. [9] G. K. S. Prakash, S. Krishnamoorthy, S. K. Ganesh, A. Kulkarni, R. Haiges, G. A. Olah, Org. Lett. 2014, 16, 54-57. [10] G. K. S. Prakash, S. Krishnamoorthy, S. Kar, G. A. Olah, J. Fluorine Chem. 2015, 180, 186- 191. [11] T. Billard, B. R. Langlois, Tetrahedron Lett. 1996, 37, 6865-6868. [12] T. Billard, S. Large, B. R. Langlois, Tetrahedron Lett. 1997, 38, 65-68. [13] P. Nikolaienko, M. Rueping, Chem. Eur. J. 2016, 22, 2620-2623. [14] S. Large, N. Roques, B. R. Langlois, J. Org. Chem. 2000, 65, 8848-8856. [15] S. Potash, S. Rozen, J. Org. Chem. 2014, 79, 11205-11208. [16] G. Blond, T. Billard, B. R. Langlois, Tetrahedron Lett. 2001, 42, 2473-2475. [17] P. Cherkupally, P. Beier, Tetrahedron Lett. 2010, 51, 252-255. [18] R. Feldhoff, A. Haas, M. Lieb, J. Fluorine Chem. 1994, 67, 245-251. [19] N. V. Kondratenko, A. A. Kolomeytsev, V. I. Popov, L. M. Yagupolskii, Synthesis 1985, 667-669. [20] E. A. Ganja, C. D. Ontiveros, J. A. Morrison, Inorg. Chem. 1988, 27, 4535-4538. [21] A. Haas, J. Fluorine Chem. 1986, 32, 415-439. [22] C. Chen, C. Hou, Y. Wang, T. S. A. Hor, Z. Weng, Org. Lett. 2014, 16, 524-527. [23] C. Chen, L. Ouyang, Q. Lin, Y. Liu, C. Hou, Y. Yuan, Z. Weng, Chem. Eur. J. 2014, 20, 657-661. [24] M. Rong, R. Huang, Y. You, Z. Weng, Tetrahedron 2014, 70, 8872-8878. [25] C. Wu, Y. Huang, Z. Chen, Z. Weng, Tetrahedron Lett. 2015, 56, 3838-3841. [26] P. Zhu, X. He, X. Chen, Y. You, Y. Yuan, Z. Weng, Tetrahedron 2014, 70, 672-677. [27] Y. Wang, Y. You, Z. Weng, Org. Chem. Front. 2015, 2, 574-577. [28] C. Hou, X. Lin, Y. Huang, Z. Chen, Z. Weng, Synthesis 2015, 47, 969-975. [29] Q. Tian, Z. Weng, Chin. J. Chem. 2016, 34, 505-510. [30] W. Tyrra, D. Naumann, Y. L. Yagupolskii, J. Fluorine Chem. 2003, 123, 183-187. [31] Q. Lefebvre, R. Pluta, M. Rueping, Chem. Commun. 2015, 51, 4394-4397. [32] C. Matheis, T. Krause, V. Bragoni, L. J. Goossen, Chem. Eur. J. 2016, 22, 12270-12273. [33] M. Aufiero, T. Sperger, A. S. K. Tsang, F. Schoenebeck, Angew. Chem. Int. Ed. 2015, 54, 10322-10326; Angew. Chem. 2015, 127, 10462-10466. [34] C. Matheis, V. Wagner, L. J. Goossen, Chem. Eur. J. 2016, 22, 79-82. [35] J. W. Dale, H. J. Emeleus, R. N. Haszeldine, J. Chem. Soc. 1958, 2939-2945. [36] N. N. Yarovenko, V. N. Shemanina, G. B. Gazieva, Zh. Obshch. Khim. 1959, 29, 942-945. [37] a) L. M. Yagupol'skii, V. G. Voloshchuk, Russ. J. Gen. Chem. 1966, 36, 173-174; b) V. G. Voloshchuk, L. M. Yagupol'skii, G. P. Syrova, V. P. Bystrov, Russ. J. Gen. Chem. 1967, 37, 105-108. [38] L. M. Yagupol'skii, V. G. Voloshchuk, Russ. J. Gen. Chem. 1968, 38, 2426-2429. 128 Chapter II. Synthesis of benzylfluoroalkyl selenide reagents: Application in SEAr ractions

[39] A. Haas, M. Lieb, B. Schwederski, Rev. Roum. Chim. 1987, 32, 1219-1224. [40] H. Suzuki, M. Yoshinaga, K. Takaoka, Y. Hiroi, Synthesis 1985, 497-499. [41] Y.-Y. Qin, X.-L. Qiu, Y.-Y. Yang, W.-D. Meng, F.-L. Qing, J. Org. Chem. 2005, 70, 9040- 9043. [42] a) Y.-Y. Qin, Y.-Y. Yang, X.-L. Qiu, F.-L. Qing, Synthesis 2006, 1475-1479; b) K. Uneyama, K. Maeda, Y. Tokunaga, N. Itano, J. Org. Chem. 1995, 60, 370-375. [43] V. P. Mehta, M. F. Greaney, Org. Lett. 2013, 15, 5036-5039. [44] M. Yoshida, A. Morishima, D. Suzuki, M. Iyoda, K. Aoki, S. Ikuta, Bull. Chem. Soc. Jpn. 1996, 69, 2019-2023. [45] H. J. Emeleus, N. Welcman, J. Chem. Soc. 1963, 1268-1271. [46] Y.-m. Lin, W.-b. Yi, W.-z. Shen, G.-p. Lu, Org. Lett. 2016, 18, 592-595. [47] T. Khotavivattana, S. Verhoog, M. Tredwell, L. Pfeifer, S. Calderwood, K. Wheelhouse, T. Lee Collier, V. Gouverneur, Angew. Chem. Int. Ed. 2015, 54, 9991-9995.

129 CHAPTER III

TRIFLUOROMETHYLCHALCOGENS; LATE-STAGE 18F-FLUORINATION OF SCF2R AND SeCF2R GROUPS Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

I. BIBLIOGRAPHY ...... 132

I.1 INTRODUCTION TO POSITRON EMISSION TOMOGRAPHY PRINCIPLES, NON-METALLIC

RADIONUCLIDES AND APPLICATIONS ...... 132

18 18 18 I.2 SYNTHESES OF SCF2 F, OCF2 F AND OCHF F COMPOUNDS BY NUCLEOPHILIC SUBSTITUTION REACTIONS: STATE OF ART ...... 134 18 I.2.1 [ F]-labeling of aryl-OCF2Br and aryl-OCHFBr compounds ...... 135 18 I.2.2 [ F]-labeling of aryl-SCF2Br compounds ...... 135

II. RESULTS AND DISCUSSION ...... 137 18 II.1 F-LABELING OF ARYL-SCF2FG SUBSTRATES ...... 137 18 II.2 F-LABELING OF ARYL-SECF2BR SUBSTRATES ...... 138

III.CONCLUSIONS ...... 140

IV.REFERENCES: ...... 141

131 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

As previously mentioned, part of our freshly synthesized compounds were used as starting materials in nucleophilic 18F-labeling. Herein we report the various efforts made to access 18 18 SCF2 F and SeCF2 F containing molecules. Results and Discussion part is preceded by a short overview of the data found in literature concerning radiolabeling of fluorochalcogen groups through 18F late-stage fluorination.

I. Bibliography

I.1 Introduction to Positron Emission Tomography principles, non- metallic radionuclides and applications

Nuclear medicine involves the application of radioactive substances in the detection and treatment of diseases. The most common techniques in nuclear imaging are single photon emission computed tomography (SPECT) and positron emission tomography (PET). Unlike SPECT imaging, positron emission tomography gives a higher resolution and a better quantification of the image. Positron emission tomography has been developed the last 40 years as a valuable imaging technique in detecting functional abnormalities at molecular levels. During the last years, PET imaging became an important diagnostic tool especially for physicians considering the facility to detect illnesses as brain disorders,[1] cancer[2] as well as heart diseases[3] at early stages. The non-invasive character of the PET imaging fits perfectly to the needs of the patients, which preferably would like to avoid invasive detection methods. Unlike structural imaging techniques as magnetic resonance imaging (MRI), computerized imaging (CT) or ultrasound (US), which provide useful anatomical information, PET gives a more detailed picture regarding the physiological and biological processes in living species by monitoring the distribution and concentration of the labeled probes over time. As a result, PET imaging could provide benefits to drug development, in vivo pharmacological imaging as well as in pre-clinical studies fields.[4] The development of PET radiotracers consists on the incorporation of radioactive isotopes into the molecule. Incorporation of low atomic mass elements as C, N and O into the molecules is advantageous due to their presence in most of the organic molecules. For instance, the labeling of radiotracers with these elements does not bring any structural modification within the molecule, thus no modification of the biological activity will be reported. Nevertheless, their short half-life remains the biggest drawback and needs an in situ radioisotope production, fast reaction synthesis and diagnostic tools in proximity.[5]

132 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

Tableau 1 Low atomic mass radionuclides used in PET.[5]

Half-life, (t ) Nuclear Decay Radionuclide 1/2 Target Product (min) reaction product

20 18 18 18 Ne(d,α) F Ne (+F2) [ F]F2 18 F 110 18 18 - O 18O (p,n) 18F [ O]H2O [ F]F

11 11 14 11 N2 (+O2) [ C]CO2 11 C 20.4 N(p,α) C 11 B N2 (+H2) [ C]CH4

13 13 16 13 H2O [ N]NOx 13 N 9.97 O(p,α) N 13 C H2O+EtOH [ N]NH3

15 15 15 15 15 O 2.04 N(d,n) O N2(+O2) [ O]O2 N

Another non-metallic radioisotope is 18F, which presents several advantages respect to the other radionuclides. Often fluorine-18 is referred as the radionuclide of choice due to the characteristics that confers to the radiotracer. Especially the longer half-life makes 18F the favorite radioisotope for clinical research as well as allowing to access 18F-radiolabeled tracers through a multistep synthesis. Moreover, its longer half-life permits to transport 18F also out of the site of production, thus not limiting the use only in sites equipped with a cyclotron. Other advantage is that multiple patients can be scanned with only one produced dose per day. Lately, the cold chemistry of fluorine has been expanding rapidly, allowing the access to various biologically active fluorinated molecules although the presence of fluorine in naturally occurring compounds is low. Furthermore, as previously said in introduction, the insertion of fluorine onto organic compounds modifies their properties then, often, enhancing the ADME (adsorption, distribution, metabolism and excretion) properties of the molecules.

[18F]fluodeoxyglucose ([18F]FDG) is the most used radiotracer in medical imaging. In the early beginnings [18F]FDG has been obtained through electrophilic fluorination of 3,4,6-tri-O-acetyl- 18 18 D-glucal with [ F]F2 gas (Figure 1). However, considering the low reported yields in F electrophilic fluorination, the radiotracer has been labeled through nucleophilic fluorination leading to higher radiochemical yield. The nucleophilic fluorination is the preferred way to access [18F]FDG starting from the acetylated sugar 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethane-sulfonyl-

18 - β-D-mannopyranose and [ F]F /K222.

133 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

Figure 1 From the synthesis of the radiotracer to the obtaining of PET image.

Once the radiotracer is prepared, it is administered to the patient by intravenous injection and decays in the body by positron emission. However, the emitted positron (β+) is not detected directly but travels into the tissues (a few mm) and collides with an electron. The collision between the positron and the electron results in an annihilation event that produces two γ ray photons with 511 keV energies that travels in opposite direction (180 °) to each other. The simultaneous detection of the two emissions that travels throughout the body (line of coincidence) by the PET scanner helps to locate the interested area in the body. The PET scanner consists of a crown of detectors that helps to identify various simultaneously occurring annihilation events in order to construct a PET image.

18 18 18 I.2 Syntheses of SCF2 F, OCF2 F and OCHF F compounds by nucleophilic substitution reactions: State of art

During the last few years the interest towards compounds containing fluorine has been growing rapidly. A plethora of methodologies to access organic compounds containing fluorine or a fluorinated group has already been reported. Fluoride itself and the trifluoromethyl group are the most common substituents in fluorine chemistry. However, the association of fluorine with other elements of the periodic table has been also explored. For example, fluorinated groups as OCF3 and SCF3 confer to the molecules a higher lipophilicity respect to their analog CF3. Thus, an

134 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling increase in lipophilicity represents an advantage for pharmaceuticals and agrochemicals. Despite the steps forward made in cold fluorine chemistry, 18F-labeled compounds are still challenging to be obtained. Herein we describe the only two works found in literature regarding the radiolabeling of SCF3, OCF3 as well as OCF2H with fluorine-18.

I.2.1 [18F]-labeling of aryl-OCF2Br and aryl-OCHFBr compounds

Among various groups involved in the 18F-radiolabeling of compounds, the group of Prof. Gouverneur gave a huge contribution in the development of different methodologies to access 18F-labeled molecules bearing various fluorinated groups. Recently Gouverneur and coll. reported

18 [6] the F-labeling of Ar-OCF2Br through a Ag-mediated halogen-exchange reaction. Thus, 18 various aryl-OCF2 F compounds have been synthesized (Scheme 1). Riluzole, the first drug approved for the treatment of amyotropic lateral sclerosis has been also radiolabeled.

[18F]KF/K 222 O 18F O Br AgOTf R F F R F F DCE

RCY 10-72 % (n= 4)

Scheme 1 18F-labeling of Ar-OCF2Br adducts

18 Also, aryl-OCF2 F compounds have been synthesized by using the same strategy. Nine substrates have been radiolabeled and good yields have been reported by the authors (Scheme 2).[6]

[18F]KF/K 222 O 18F O Br AgOTf R H R F H DCE F

RCY 67-79 % (n= 4)

Scheme 2 18F-labeLing of Ar-OCF2HCl adducts

I.2.2 [18F]-labeling of aryl-SCF2Br compounds

As described in the previous chapters, the F3CS-containing molecules are characterized by high lipophilicity (Hansch parameter π= 1.44), an important parameter in drug discovery in determining the transport of bioactive molecules through membranes. The last few years we have assisted to the development of a plethora methodologies to access direct SCF3 containing 18 molecules. Nevertheless, F-labeled SCF3 motifs have been reported only in two papers. 18 Gouverneur and coll. accessed for the first time the aryl-SCF2 F -containing adducts by a Ag- mediated halogen exchange nucleophilic fluorination reaction (Scheme 3). As in the case of OCF3

135 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

18 and OCF2H F-radiolabeled compounds, the strategy gave high yields and showed compatibility with various functional groups.[6]

18 [ F]KF/K222 S Br AgOTf S 18F R R F F DCM or DCE F F

RCY 12-81 % (n= 4)

Scheme 3 18F-labeling of Ar-SCF2Br adducts

At the same time Liang and coll. accessed to benzylic, allylic, aliphatic as well as heterocyclic [18F]

F3CS containing substrates starting from the corresponding halides. Difluoromethylene phosphobetaine (PDFA) has been employed as a difluorocarbene source and in presence of an

¯ ¯ external fluoride source forms CF3 anion. The anion reacts with S8 to give CF3S nucleophilic source, which gives the expected products through a nucleophilic substitution reaction.[7] Thus, in terms of scope the two reported methodologies could be considered complementary.

Ph O 18 Ph [ F]KF/K222 R-X + P + S 18 Ph O 8 R-SCF3[ F] DMF F F X= Br, I

Scheme 4 Synthesis of R-SCF3[18F] compounds

136 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

II. Results and discussion

As mentioned previously the association of CF3 and chalcogens increases the lipophilicity of the molecules. Both OCF3 and SCF3 are characterized of high lipophilicity with the respective Hansch parameters 1.04 and 1.44.[8] Following the same way of reasoning we have deduced that also SeCF3 motif confers a higher lipophilicity to the molecules. With this in mind and inspired by interesting results obtained from Gouverneur and coll., we decided to test the 18F-labeling of

SeCF2Br motif by halogen-exchange. 18 18 Also, the F-labeling of SCF2FG (FG= SO2Ph, CO2Me) to access [ F]F3CS labeled compounds was tested and a brief description will be reported below.

18 II.1 F-labeling of aryl-SCF2FG substrates

18 When we started this project, no F-labeling of SCF3 groups had been yet published. Because we had succeeded to achieve molecules bearing SCF2SO2Ph moieties, we decided to try to substitute 18 - the PhSO2 part by [ F]F , expecting the push-pull effect of sulfur atom would favor such reaction. However, whatever the tested conditions, no labelling has been observed.

OMe 18 OMe [ F]KF/K222 SCF2SO2Ph Additive SCF2SO2Ph

Diglyme, 150 °C MeO MeO 20 min Entry Additive RCYa (%)

1 CuOTf(CH3CN)4 n.r 2 AgOTf n.r 3 TfOH n.r 4 - n.r a RCY : radiochemical yield. Volume (300 μL).

Various works in decarboxylative fluorination has been reported in literature especially in cold chemistry. On the other hand, in hot chemistry only a few methods describing decarboxylative fluorination in presence of 18F has been reported. Gouverneur and coll. lately reported the Ag- 18 mediated F-labeling of ArCF2COOH compounds through decarboxylative fluorination using 18 18 [9] [ F]Selectfluor as a reagent accessing to [ F]F3CS-Ar substrates. Groves and coll. described a Mn-catalyzed decarboxylative fluorination of aliphatic carboxylic acids using nucleophilic [18F]F- as a fluoride source.[10] Based on the results obtained by Groves and coll. we tried to adapt their

137 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

18 optimal reaction conditions in order to access (hetero)aryl-SCF2 F substrates. For instance, using 2 mol % of Mn catalyst, and PhIO as an oxidant (Table 1, entry 1) we did not observe any formation of the 18F-labeled product after 10 min. Neither increasing the amounts of catalyst as well as the reaction times was beneficial to the reaction (Table 1, entry 2). Also, increasing the amounts of the oxidant as well as decreasing the volume of the solvent mixture did not lead to obtain the desired compound (Table 1, entry 3-5). Table 1 Decarboxylative fluorination using [18F]F-

OMe 18 OMe [ F]/KF.K222 SCF2COOH [Mn(tmp)Cl] SCF2COOH Oxidant, diglyme MeO 80 °C, time h MeO 20k 20ka Catalyst PhIO Time Volume Entry RCYa (%) (equiv.) (equiv.) (min) (μL) 1 2 mol % 0.33 equiv 10 400 n.r

2 1 0.33 equiv 50 400 n.r

3 1 0.33 equiv 20 300 n.r

4 1 1 15 300 n.r

5 1 1 15 400 n.r

a RCY : radiochemical yield.

18 II.2 F-labeling of aryl-SeCF2Br substrates

18 Herein we report the first Ag-mediated F-labeling of SeCF2Br compounds. Inspired by the results described by Gouverneur and coll. in the synthesis of [18F] di- and trifluoromethylethers and [18F] trifluoromethylthioethers we planned the 18F-labeling of trifluoromethylselenides by adapting the same reaction conditions. With the results obtained by Gouverneur and coll. in mind, we chose AgOTf as the best source of silver capable to promote the halex exchange at room temperature. Thus, as shown in Table 2 the best yield was obtained using 2 equiv. of AgOTf after 20 min in dichloromethane (entry 1). The reaction did not give the desired product in absence of AgOTf, thus confirming the importance of the silver in the reaction.

138 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

Table 2 Optimisation of the reaction conditions

OMe OMe [18F]/KF.K 222 18 SeCF2Br AgOTf 1eq SeCF2 F

CH2Cl2 300 μL MeO rt, 20 min MeO 41a 41aa Additive Entry RCYa (%) (equiv.) AgOTf 1 45% ± 4 % (n = 2) 1 equiv. AgOTf 2 35% ± 2 % (n = 2) 2 equiv. 3 - n.r a RCY : radiochemical yield.

With the optimized reaction conditions in hand, we tried to extend the 18F labeling methodology to a wider number of substrates. Indole substrates gave the expected compounds 41ha, 41ia and 41ja with a radiochemical yield of 20 %. Despite the modest radiochemical yield is worth to note that the radiolabeling of indoles was not reported in the case of the SCF2Br containing compounds.

OMe OH 18 OH SeCF2 F 18 18 SeCF2 F SeCF2 F MeO HO N 18 41aa SeCF2 F 45 ± 4 % (n = 2) 41ba 41da 41ea 0 % 14 ± 4 % (n = 2) 4 ± 0 % (n = 2) (+ 6 % by-product)

18 Br 18 O 18 SeCF2 F SeCF2 F SeCF2 F MeO N N N H H H 41ha 41ia 41ja 20 ± 1 % (n = 2) 20 % ± 2 % (n = 2) 20 ± 1 % (n = 2)

18 18 SeCF2 F SeCF2 F

50a 29 ± 1 % (n = 2) 50b n.d Figure 2

Aromatic substrates bearing acidic OH functional groups did not lead to the desired compounds or gave lower yields, probably due to deprotonation of OH by basic, naked, [18F]F-. No trace of the radiolabeled compound 41ba was observed after 20 minutes of reaction. On the other hand,

139 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

41d gave the radiolabeled compound with a 14% yield and also the formation of other by- products was observed. Also in the case of 41ea only traces of the radiolabeled adduct were observed.

18 Also, the F-labeling of SeCF2Br in benzylic and allylic position was reported. Surprisingly, bromodifluorobenzyl selenide gave compound 50a with a 29 % radiochemical yield. Thus, such a result is important because it shows that the halex-exchange methodology reported by Gouverneur and coll. is efficient also for 18F labeling in benzylic position. Compound 50b was not observed, only unidentified complex mixtures were formed.

III. Conclusions

To conclude, in this chapter we accessed for the first time to the radiolabeling of SeCF2Br containing molecules in collaboration with the University of Oxford. Nucleophilic 18F- fluorination of the substrates was obtained through Ag-mediated halex exchange reaction. We reported the first example of 18F-labeling over trifluoromethyl selenides, to our knowledge. However, experiments will be on-going in order to expand the substrate scope and improve the yield.

140 Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling

IV. References:

[1] a) F. F. Calabria, E. Calabria, V. Gangemi, G. L. Cascini, Hell. J. Nucl. Med. 2016, 19, 33- 41; b) H. F. Kung, Crit. Rev. Clin. Lab. Sci. 1991, 28, 269-286. [2] K. Kubota, T. Matsuzawa, Med. Philos. 1990, 9, 151-153. [3] A. Takalkar, A. Mavi, A. Alavi, L. Araujo, Radiol. Clin. North Am. 2005, 43, 107-119, xi. [4] a) V. J. Cunningham, C. A. Parker, E. A. Rabiner, A. D. Gee, R. N. Gunn, Drug Discovery Today: Technol. 2005, 2, 311-315; b) E. Fernandes, Z. Barbosa, G. Clemente, F. Alves, A. J. Abrunhosa, Curr. Radiopharm. 2012, 5, 90-98. [5] P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem., Int. Ed. 2008, 47, 8998-9033. [6] T. Khotavivattana, S. Verhoog, M. Tredwell, L. Pfeifer, S. Calderwood, K. Wheelhouse, T. Lee Collier, V. Gouverneur, Angew. Chem. Int. Ed. 2015, 54, 9991-9995. [7] J. Zheng, L. Wang, J.-H. Lin, J.-C. Xiao, S. H. Liang, Angew. Chem. Int. Ed. 2015, 54, 13236-13240. [8] a) C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165-195; b) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525-616. [9] S. Mizuta, I. S. R. Stenhagen, M. O’Duill, J. Wolstenhulme, A. K. Kirjavainen, S. J. Forsback, M. Tredwell, G. Sandford, P. R. Moore, M. Huiban, S. K. Luthra, J. Passchier, O. Solin, V. Gouverneur, Org. Lett. 2013, 15, 2648-2651. [10] X. Huang, W. Liu, J. M. Hooker, J. T. Groves, Angew. Chem. Int. Ed. 2015, 54, 5241-5245.

141 EXPERIMENTAL

PART Experimental Part

I. Generalities ...... 143

I.1 ANALYTIC TECHNIQUES ...... 143

I.2 WORKING PROCEDURES AND CONDITIONS ...... 144

II. Syntheses and characterization of the products ...... 145

II.1 SYNTHESIS AND CHARACTERIZATION OF REAGENT 1A AND THE PRECURSORS INVOLVED

II.1.3 Phenylsulfonyl reduction and access to SCF2H ...... 159 II.1.4 Post-functionalization of the phenylsulfonyl moiety ...... 162

II.2 SYNTHESIS AND CHARACTERIZATION OF REAGENT 1D ...... 164

II.2.1 SEAr reactions using reagent 1d ...... 164 II.2.2 Acid activation of α-ketones ...... 168

References: ...... 191

142 Experimental Part

I. Generalities

I.1 Analytic techniques

NMR spectra were recorded on Bruker AVL300 and AV400 at the “Centre Commun de RMN”, Universite Lyon1. All measurements were perfomed at room temperature if not otherwise mentioned. The internal standard is deuterated chloroform (CDCl3) if not otherwise mentioned. Chemical shifts are reported in parts per million (ppm) referred to TMS regarding 1H and 13C and

19 CF3Cl regarding F. Coupling constants are reported in Hertz. Multiplicity of the signals is h- given as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Dosed yields in 19F NMR were reported using trifluoromethoxybenzene as internal standard (PhOCF3, δ= -58.30, ppm, s). Nomenclature was assigned following the IUPAC nomenclature rules. Signal peak attribution was assigned after an arbitrary numeration of all the carbons found on the molecule using ChemBioDraw 14.0.

Melting points were measured using a Kofler bench apparatus with a temperature gradient between 45 °C-270 °C. Internal standards were used to calibrate the apparatus as reported in each case. The melting points were not corrected.

GC-MS analyses were measured using Agilent GC-MS mass spectra if reported.

143 Experimental Part

I.2 Working procedures and conditions

Commercally available compounds were purchased from different companies and used without any other further purification.

Dry solvents were purchased from Sigma-Aldrich and used without any other distillation.

Flash column chromatography was performed using silica gel 60M (0.04-0.063) as a stationary phase, from Macheray-Nagel company. The purification was carried out under compressed air pressure with the aim to fasten the purification process.

Thin layer chromatography was carried out on ALUGRAM SIL G/UV254 ready foils from Macheray-Nagel Company.

144 Experimental Part

II. Syntheses and characterization of the products

II.1 Synthesis and characterization of reagent 1a and the precursors involved in the preparation

[(bromodifluoromethyl)sulfanyl]benzene S1 Experimental procedure: Based on a slightly modified reaction procedure,[1] thiophenol (9.34ml, 100mmol) is slowly added to a suspension of NaH 60% (6 g, 150 mmol) in anhydrous DMF (100 mL) at 0 °C over a period of 30 min. The mixture is reported to room temperature and let stirring for 15 min. After 15 min. the reaction mixture is cooled to -35 °C (internal temp.), followed by the addition of CF2Br2 (27.4 mL, 300 mmol). The reaction mixture is stirred for 3h at -35 °C and 30 min from -35 °C to room temperature. The reaction flask is cooled in an ice-water bath and the excess of NaH quenched by dropwise addition of water (100mL). The aqueous phase is extracted with Et2O (3 x 100 mL) and the combined organic layers washed with water (3 x 100 mL), brine (100 mL), and dried over

MgSO4. Filtration and solvent evaporation left a crude product that was purified by distillation as reported in literature.

Identification: Yield Fractional distillation, b.p = 97 °C / 34 mmHG 60 % SCF Br 2 Colorless liquid

1 H NMR (300 MHz, CDCl3) δ = 7.66 (d, J = 6.8 Hz, 2H), 7.53–7.47 (m, S1 1H), 7.48 – 7.42 (m, 2H). 19 F NMR (282 MHz, CDCl3) δ = -22.13 (s, 2F)

Bromodifluoromethanesulfonylbenzene S2 Experimental procedure:

To a solution of bromodifluoromethylthiobenzene (S1) (19.2 g, 80 mmol) in dry CH2Cl2 (160 mL) was slowly added m-CPBA (598.9 g, 240 mmol) at 0 °C. The reaction is stirred at room temperature for 24 h. The reaction mixture is concentrated, dissolved in EtOAc (300 mL) and washed with NaOH 10 % (200 mL), saturated NaCl (200 mL) and dried over MgSO4. The solvent was removed in vacuo and the compound was purified via silica gel column chromatography.

145 Experimental Part

[2] Identification: In accordance with literature data Yield 93 % Flash column chromatography: CyHex/EtOAc: 9/1 O F F Colorless liquid S O Br 1 H NMR (300 MHz, CDCl3) δ = 7.66 (d, J = 6.8 Hz, 2H), 7.53–7.47 (m, S2 1H), 7.48–7.42 (m, 2H). 19 F NMR (282 MHz, CDCl3) δ -57.63 (s, 2F)

[(benzenesulfonyl)difluoromethyl]trimethylsilane Si1 Experimental procedure:

Following a slightly modified procedure, to the solution of PhSO2CF2Br (18.9 g, 70 mmol) and

TMSCl (22.2 mL, 175 mmol) in THF (210 mL) at -78 °C, under N2 atmosphere, n-BuLi (1.6M hexane solution, 96.3 mL, 154 mmol) is added. After the addition of n-BuLi (over a period of 1.5 h), the reaction mixture is stirred for 2 h more at -78 °C. Then the reaction mixture was carefully added into cold water. The mixture was extracted with Et2O (100mL x 3), and the combined organic phase was washed with brine, water, and then dried over Na2SO4. After the removal of the solvent under vacuum, the crude product was further fractionally distilled to afford the pure compound. Identification: In accordance with literature data[3] Fractional distillation b.p 96-97 °C / 1.3 mbar Yield= 80 % O F F Colorless liquid S 1 O Si H NMR (300 MHz, CDCl3) δ = 7.98–7.90 (m, 2H), 7.77–7.68 (m, 1H), Si1 7.64–7.55 (m, 2H), 0.43 (s, 9H). 19 F NMR (282 MHz, CDCl3) δ = -112.32 (s, 2F)

N-{[(benzenesulfonyl)difluoromethyl]sulfanyl}aniline 1a Experimental procedure:

In an oven-dried flask under N2 containing THF, DAST (9.15 mL, 66 mmol) is slowly added and the mixture is stirred for 10 min at room temperature. Silane (Si1) (15 gr, 60 mmol) is added to the solution and the reaction is stirred for 1 more hour. The reaction was quenched with aniline and left at room temperature over night. The reaction mixture was extracted with EtOAc (100 mL x 3) and the organic layers washed with water, brine and dried over Na2SO4. After the removal of the solvent under vacuum the compound was purified via silica gel column chromatography.

146 Experimental Part

Identification: Yield 60 % 5 4 Flash column chromatography: CyHex/EtOAc: 98/2 to 95/5 4 3 2 Brownish oil 3 1 NH 1 H NMR (400 MHz, CDCl3) δ =8–7.97(m, 2H8), 7.79–7.74(m, 1H10), S F 6 7.63–7.59 (m, 2H9), 7.28–7.24 (m, 2H4), 7.11–7.08(m, 2H3), 6.97–6.93 (m, O F S 1H5), 5.21 (s, 1H1). O 13 8 7 C NMR (101 MHz, CDCl3) δ = 145.5 (C2), 135.8 (C10), 132.4 (C7), 130.8 8 9 (C9), 129.6 (C8), 129.3 (C4), 127.5 (t, JC, F = 331.9 Hz, C6), 122.0 (C5), 115.5 9 (C ). 10 3 19 F NMR (376 MHz, CDCl ) δ = -89.84 (s, 2F). 1a 3

Elemental analysis calcd (%) C13H11F2NO2S2: C 49.51, H 3.52, N 4.44, S 20.34. Found: C 49.39, H 3.32, N 4.59, S 20.57

II.1.1 (Benzenesulfonyl)difluoromethylthiolation of aromatic and heteroaromatic compounds

II.1.1.1 General synthetic procedures

Experimental Procedure 1:

To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) in dry CH2Cl2 (1M), the nucleophile is added (0.5 mmol, 1 equiv.) and followed by the addition of P- toluenbenzensolfonic acid (1.25 mmol, 2.5 equiv.). After closing the reaction vessel hermetically, the mixture is left under stirring at 50 °C for 16 h. The reaction mixture was extracted with

EtOAc or Et2O (10 mL x 2). The fractions were collected together, washed with water and brine and dried over Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case. Experimental Procedure 2:

To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) in dry CH3CN, the nucleophile (0.5 mmol, 1 equiv.) is added. After the addition of TMSCl (0.5 mmol, 1 equiv.) the resulting mixture is stirred for 16 h at 25 °C or at 80 °C, depending on the substrate. The reaction mixture is quenched by addition of water and is extracted with EtOAc (10 mL x 2). The organic fractions are collected washed with water and dried over Na2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case.

Experimental Procedure 3:

To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) in dry CH2Cl2, the nucleophile (0.5 mmol, 1 equiv.) is added. After the addition of TfOH (0.5 mmol, 1 equiv.), the

147 Experimental Part resulting mixture is stirred for 16 h at 50 °C. The reaction mixture is quenched by the addition of water and extracted with EtOAc (10 mL x 2). The organic gfractions are collected washed with water and brine and dried over Na2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case.

3-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-1H-indole 3a

Identification: Exp. Proced. 1 Yield 85 % Eluent for flash column chromatography: CyHex/EtOAc: 8/2 2 1 6 3 Brown solid Melting point: 110 °C 5 4 1 8 H NMR (400 MHz, CDCl3) δ = 8.63 (bs, 1HNH), 7.98–7.95 (m, 2H12), HN S 7 7.77–7.75(m, 1H6), 7.73–7.69 (m, 1H14), 7.58–7.53 (m, 2H13), 7.52 (bd, J = O 10 F 2.7 Hz, 1H7), 7.38–7.35 (m, 1H3), 7.25–7.22 (m, 2H1, 2). 12 11 S F 13 13 O C NMR (101 MHz, CDCl3) δ = 136.3 (C4), 135.4 (C14), 134.1 (t, JC, F = 1.7 12 Hz, C7), 133.3 (C11), 130.9 (C12), 130.2 (C5), 129.4 (C13), 128.2 (t, JC, F = 325 14 13 Hz, C10), 123.5 (C1), 121.7 (C2), 119.6 (C6), 111.9 (C3), 94.2 (t, JC, F = 3.9 Hz, 3a C8). 19 F NMR (376 MHz, CDCl3) δ = -79.35 (s, 2F).

Elemental analysis calcd (%) C15H11F2NO2S2: C 53.09, H 3.27, N 4.13, S 18.90. Found: C 52.98, H 3.18, N 4.25, S 18.63.

2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-3-methyl-1H-indole 3b

Identification: Exp. Proced. 1 Yield 2 1 57 % Eluent for flash column chromatography: CyHex/EtOAc: 8/2 3 6 Redish solid Melting point: 116 °C 4 5 7 HN 8 1 9 H NMR (400 MHz, CDCl ) δ = 8.52 (bs, 1H, NH), 7.99–7.96 (m, 2H ), F 3 12 S 7.77–7.73(m, 1H ), 7.61–7.57 (m, 2H ), 7.39–7.35 (m, 1H ), 7.32–7.28 (m, F 14 6, 13 3 10 1H ), 7.17–7.13(m, 1H ), 2.45 (s, 3H ). O S O 1 2 8 11 13 12 12 C NMR (101 MHz, CDCl3) δ = 138.0 (C4), 135.7 (C14), 132.4 (C11), 131.0 (C ), 129.6 (C ), 128.2 (C ), 127.4 (t, J = 329 Hz, C ), 125.1 (C ), 125.0 13 13 12 13 5 C, F 10 7 14 (C1), 120.1 (C2), 120.0 (C6), 112.6 (t, JC, F = 4.5 Hz, C9), 111.5 (C3), 9.7 (C8). 3b 19 F NMR (376 MHz, CDCl3) δ = -80.47 (s, 2F).

Elemental analysis calcd (%) C16H13F2NO2S2: C 54.38, H 3.71, N 3.96, S 18.15. Found: C 54.63, H 3.44, N 4.21, S 18.01.

148 Experimental Part

2-(2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-5-methoxy-1H-indol-3-yl)acetic acid 3c Identification: Exp. Proced. 1 Yield 99 % 13 Flash column chromatography: Cyclohexane/EtOAc: 8/2 O 2 Brown solid Melting point: 152 °C 1 3 6 1H NMR (400 MHz, CD OD) δ = 7.97 (d, J = 7.6 Hz, 1H ), 7.85-7.77 4 5 3 13 8 (m, 1H ), 7.70-7.61 (m, 1H ), 7.26 (d, J = 8.9 Hz, 1H ), 7.02 (d, J = 2.4 HN 9 15 14 3 7 Hz, 1H ), 6.90 (dd, J = 8.9, 2.4 Hz, 1H ), 4.90 (s, 1H), 3.85 (s, 2H ), 3.80 (s, F 6 2 9 S CO2H 10 1H13). F 11 13 O S O C NMR (101 MHz, CD3OD) δ = 175.1 (C10), 155.6 (C1), 137.1 (C15), 12 13 13 134.8 (C4), 133.6 (C12), 131.9 (C13), 130.8 (C14), 128.8 (t, JC, F = 325.2 Hz, C ), 128.7 (C ), 120.7 (C ), 116.7 (C ), 114.3 (t, J = 3.3 Hz, C ), 113.5 14 14 11 5 8 2 C, F 7 15 (C3), 101.3 (C6), 56.0 (C9), 31.5 (C13). 3c 19 F NMR (376 MHz, CDCl3) δ = -76.18 (s, 2F).

Elemental analysis calcd (%) C18H15F2NO5S2: C 50.58, H 3.54, N 3.28 S 15.00. Found: C 50.52, H 3.81, N 3.12, S 14.88.

2-amino-3-(2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-1H-indol-3-yl)propanoic acid 3d

Identification: Exp. Proced. 1 Yield 80 % Flash column chromatography:CH2Cl2/MeOH: 9/1

1 White solid Melting point: 188 °C 6 2 5 9 11 1 8 10 CO H 3 2 H NMR (400 MHz, CD3OD) δ = 7.99–7.97 (m, 2H15), 7.86–7.82 (m, 4 1H ), 7.74–7.66 (m, 3H ), 7.41 (bd, J = 8.1 Hz, 1H ), 7.35–7.24 (m, HN H2N 17 3, 16 6 7 S F 1H1), 7.14 (bt, J = 7.5 Hz, 1H2), 4.15-4.07 (m, 1H10), 3.67 (dd, J = 15.0, 12 O F 5.4 Hz, 1H ), 3.42 (dd, J = 15.0, 8.5 Hz, 1H ). S 14 15 9 9 O 16 13 15 C NMR (101 MHz, CD3OD) δ = 173.0 (C11), 139.7 (C4), 137.3 (C17), 16 17 133.4 (C14), 131.9 (C15), 131.3 (C5), 130.9 (C16), 128.1 (t, JC, F = 345.0 Hz, C ), 125.6 (C ), 121.3 (C ), 120.9 (C ), 120.2 (C ), 115.4 (t, J = 3.4 Hz, 3d 12 1 2 8 3 C, F C7), 112.9 (C6), 55.7 (C10), 27.9 (C9). 19 F NMR (376 MHz, CDCl3) δ = -79.62 (s, 2F).

Elemental analysis calcd (%) C18H16F2N2O4S2: C 50.69, H 3.78, N 6.57 S 15.04. Found: C 50.97, H 4.06, N 6.79, S 14.91.

149 Experimental Part

3-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-6-bromo-1H-indole 3e

Identification: Exp. Proced. 1 Yield 86 % Br 1 Flash column chromatography: CyHex/EtOAc: 9/1 2 Yellow solid Melting point: 124 °C 3 6 4 5 1 H NMR (400 MHz, CDCl3) δ = 8.74 (s, 1HNH), 7.96–7.94(m, 2H11), 7.77 HN 8 S – 7.73 (m, 1H13), 7.64–7.57 (m, 3H6, 12), 7.54 (d, J = 2.8 Hz, 1H7), 7.49 (d, J 7 O 9 F = 1.6 Hz, 1H3), 7.33 (dd, J = 8.5, 1.7 Hz, 1H1). 11 S F 13C NMR (101 MHz, CDCl ) δ = 136.8 (C ), 135.7 (C ), 134.6 (t, J = 1.7 12 10 O 3 4 13 C, F 11 Hz, C7), 132.5 (C10), 130.8 (C11), 129.5 (C12), 128.9 (C5), 127.7(t, JC, F = 325.2 13 12 Hz, C9), 125.1 (C1), 120.9 (C6), 117.0 (C2), 114.9 (C3), 94.46 (t, JC, F = 4.1 Hz, C8). 3e 19 F NMR (376 MHz, CDCl3) δ = -79.93 (s, 2F).

Elemental analysis calcd (%) C15H10BrF2NO2S2: C 43.07, H 2.41, N 3.35, S 15.33, Br 19.10. Found: C 42.92, H 2.70, N 3.27, S 14.98, Br 19.33.

3-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-4-ethyl-2,5-dimethyl-1H-pyrrole

Identification: Exp. Proced. 2 Yield 58 % Flash column chromatography: CyHex/EtOAc: 95/5 to 9/1

13 14 Black solid Melting point: 118 - 120 °C

12 13 1 11 H NMR (400 MHz, CDCl3) δ = 8.15 (s, 1HNH), 7.98–7.95 (m, 1H12), O 12 S 7.77–7.71 (m, 1H14), 7.62–7.58 (m, 2H13), 2.37 (q, J = 7.6 Hz, 2H12), 2.20 7 S 10 O 8 3 2 F (s, 3H6), 2.09 (s, 3H5), 1.04 (t, J = 7.6 Hz, 3H8). F 13 C NMR (101 MHz, CDCl3) δ = 135.5 (C14), 132.4 (C11), 131.2 (C3), 4 1 6 5 N H 130.9 (C12), 130.1 (C1), 129.47 (C13), 126.90 (t, JC, F = 326.4 Hz, C10), 3f 123.14 (C4), 99.89 (t, JC, F = 4.5 Hz, C2), 18.1 (C7), 15.4 (C8), 11.6 (C5), 10.0 (C6). 19 F NMR (376 MHz, CDCl3) δ = -82.70 (s, 2F).

Elemental analysis calcd (%) C15H17F2NO2S2: C 52.16, H 4.96, N 4.05, S 18.57. Found: C 52.08, H 5.18, N 3.80, S 18.41.

3-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-2,5-dimethyl-1H-pyrrole 3g Identification: Exp. Proced. 2 Yield 84 % 11 Flash column chromatography: CyHex/EtOAc: 9/1 to 8/2 10 10 Brown solid Melting point: 113 °C 9 9 1 8 H NMR (400 MHz, CDCl3) δ = 8.03 (s, 1HNH), 8.00–7.97 (m, 2H9), 7.76– 14 O S O 13 7.71 (m, 1H11), 7.61–7.57 (m, 2H10), 5.95 (bs, 1H3), 2.31 (s, 3H6), 2.18 (s, 3H5). 7 F S F 13 2 C NMR (101 MHz, CDCl3) δ = 135.6 (C1), 135.3 (C11), 133.1 (C8), 130.8 3 6 (C ), 129.4 (C ), 128.01 (t, J = 323.3 Hz, C ), 126.8 (C ), 113.1 (C ), 96.02 (t, 1 9 10 C, F 7 4 3 4 NH JC, F = 3.7 Hz, C2), 13.1 (C6), 11.2 (C5). 5 19 F NMR (376 MHz, CDCl3) δ = -80.44 (s, 2F)

150 Experimental Part

Elemental analysis calcd (%) C13H13F2NO2S2: C 49.20, H 4.13, N 4.41, S 20.21. Found: C 49.07, H 4.32, N 4.33, S 20.56.

1-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-2,4-dimethoxybenzene 3i

Identification: Exp. Proced. 1 Yield 7 80 % O Flash column chromatography: CyHex/EtOAc: 9/1* 2 3 1 Brown solid Melting point: 113 °C

6 8 1 4 H NMR (500 MHz, CDCl3) δ = 7.98 (d, J = 7.1 Hz, 2H11), 7.73 (t, J = 7.5 5 O F Hz, 1H ), 7.61-7.54 (m, 3H ), 6.50 (dd, J = 8.5, 2.6 Hz, 1H ), 6.47 (d, J = S 13 4, 12 3 F 9 2.6 Hz, 1H1), 3.83 (s, 2H7), 3.83 (s, 1H8). 13 O S O C NMR (126 MHz, CDCl3) δ = 164.2 (C2), 162.9 (C6), 140.9 (C4), 135.4 10 (C ), 133.0 (C ), 130.9 (C ), 129.3 (C ), 128.1 (t, J = 325.4 Hz, C ), 105.7 11 11 13 10 11 12 C, F 9 (C3), 102.3 (C1), 99.3 (C5), 56.1 (C7), 55.7 (C8). 12 12 13 19 F NMR (471 MHz, CDCl3) δ = -79.61 (s, 2F). 3i

Elemental analysis calcd (%) C15H14F2O4S2: C 49.99, H 3.92, S 17.79. Found: C 50.12, H 4.09, S 17.96. *in order to avoid the purification via silica gel column chromatography, the crude was triturated in pentane and the solid was filtered off. The pure compound was washed with a minimal quantity of pentane and obtained with a 77 % yield.

4-{[(benzenesulfonyl)difluoromethyl]sulfanyl}benzene-1,3-diol 3j

Identification: Exp. Proced. 1 Yield 11 89 % 10 10 Flash column chromatography: CyHex/EtOAc: 8/2

9 9 Pale yellow solid Melting point: 150-152 °C 8 1 O S O H NMR (500 MHz, DMSO) δ = 10.20 (s, 1HOH), 9.98 (s, 1HOH), 8.01–7.99 7 F (m, 2H9), 7.92 (bt, J = 7.5 Hz, 1H11), 7.76 (bt, J = 7.9 Hz, 2H10), 7.16 (bd, J = S F 8.5 Hz, 1H4), 6.41 (bd, J = 2.6 Hz, 1H1), 6.27 (dd, J = 8.5, 2.5 Hz, 1H3). HO 5 4 13 6 C NMR (126 MHz, DMSO) δ = 162.1 (C2), 161.7 (C6), 140.1 (C4), 136.3 1 3 (C11), 131.7 (C8), 130.6 (C9), 130.0 (C10), 128.0 (t, JC, F = 323.6 Hz, C7), 108.2 2 (C3), 102.9 (C1), 96.2 (t, JC, F = 2.5 Hz, C5) OH 19 F NMR (471 MHz, DMSO) δ = -79.24 (s, 2F). 3j

Elemental analysis calcd (%) C13H10F2O2S2: C 46.98, H 3.03, S 19.30. Found: C 47.01, H 2.88, S 19.13.

151 Experimental Part

2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}naphthalen-1-ol 3k

Identification: Exp. Proced. 2 Yield 89 % OH Flash column chromatography: CyHex/EtOAc: 9/1 6 7 Pale brown solid Melting point: 134 °C 1 5 8 1H NMR (500 MHz, (CD ) CO) = 10.39 (s, 1H ), 8.32 (d, J = 8.4 Hz, 2 4 9 3 2 δ OH 3 10 F 1H6), 8.26 (d, J = 8.4 Hz, 1H3), 8.04 (d, J = 7.3 Hz, 2H13), 7.95 - 7.86 (m, S 11 F 1H15), 7.82 ) 7.69 (m, 3H9, 15), 7.62 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H1), 7.54 O S O (ddd, J = 8.2, 6.8, 1.2 Hz, 1H2), 7.03 (d, J = 8.0 Hz, 1H8). 12 13 C NMR (126 MHz, (CD3)2CO) δ = 158.4 (C7), 140.8 (C9), 138.0 (C4), 13 13 136.87 (C15), 133.34 (C12), 131.6 (C13), 130.6 (C14), 129.5 (t, JC, F = 324.5 14 14 Hz, C11), 128.8 (C1), 126.7 (C5), 126.2 (C2), 126.2 (C3), 123.7 (C6), 109.3 15 (C ), 109.12 (C ). 3k 8 10 19 F NMR (471 MHz, (CD3)2CO) δ = -79.27 (s, 2F).

4-{[(benzenesulfonyl)difluoromethyl]sulfanyl}phenol 3l

Identification: Exp. Proced. 3 Yield 11 84 % 10 10 Flash column chromatography: CyHex/EtOAc: 9/1 to 8/2

9 9 Pale yellow solid Melting point: 131-133 °C 8 1 O S O H NMR (400 MHz, CDCl3) δ = 7.98–7.96 (m, 2H9), 7.78–7.73 (m, 7 F 1H11), 7.63–7.58 (m, 2H10), 7.56 (d, J = 8.6 Hz, 2H2 4), 6.84 (d, J = 8.7 Hz, S 2H ). F 3 1, 5 4 13 2 C NMR (101 MHz, CDCl3) δ = 158.6 (C6), 139.5 (C2, 4), 135.7 (C11),

5 1 132.6 (C8), 130.9 (C9), 129.5 (C10), 128.1 (t, JC, F = 324.1 Hz, C7), 116.6 (C1, 6 5), 113.71 (t, JC, F = 3.2 H, (C13). OH 19 F NMR (376 MHz, CDCl ) δ = -78.25 (s, 2F). 3l 3

Elemental analysis calcd (%) C13H10F2O3S2: C 49.36, H 3.19, S 20.27. Found: C 49.21, H 3.46, S 20.13.

1-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-4-iodo-2-methoxybenzene 3m

Identification: Exp. Proced. 3 Yield 12 30 % 11 11 Flash column chromatography: CyHex/EtOAc: 9/1

10 10 Pale yellow solid Melting point: 96-98 °C 9 1 O S O H NMR (400 MHz, CDCl3) δ = 8.02 – 7.99(m, 2H10), 7.77–7.74 (m, 8 F 2H4, 12), 7.63–7.59 (m, 2H11), 7.47 (d, J = 2.7 Hz, 1H1), 6.91 (dd, J = 8.7, S

5 F 2.8 Hz, 1H3), 3.80 (s, 3H7). O 4 13 7 6 C NMR (101 MHz, CDCl3) δ = 161.8 (C6), 139.4 (C4), 135.6 (C12), 1 3 132.5 (C10), 131.1 (C9), 129.5 (C11), 128.2 (t, JC, F = 325.2 Hz, C8), 126.2 2 (C1), 120.1 (t, JC, F = 2.5 Hz, C5), 115.2 (C3), 111.0 (C2), 55.8 (C7). I 19 F NMR (376 MHz, CDCl ) = -79.13 (s, 2F). 3m 3 δ

Elemental analysis calcd (%) C14H11F2IO3S2: C 36.85, H 2.43, S 17.50. Found: C 37.07, H 2.51, S 17.23. 152 Experimental Part

4-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-2-nitrobenzene-1,3-diol 3n

Identification: Exp. Proced. 3 Yield 11 10 45 % Flash column chromatography: CyHex/EtOAc: 9/1 10 9 8 Redish solid Melting point: 116 °C 9 O S 14 F 1 O 7 H NMR (400 MHz, CDCl3) δ = 7.98–7.96 (m, 2H9), 7.77–7.72 (m, 1H11), F S 7.63–7.57 (m, 2H10), 7.45 (d, J = 8.1 Hz, 1H4), 6.68 (d, J = 8.1 Hz, 1H3). 5 4 6 13 HO 3 C NMR (101 MHz, CDCl3) δ = 159.4 (C2), 159.4 (C6), 139.2 (C4), 135.5 1 2 (C11), 132.8 (C9), 130.9 (C8), 129.4 (C10), 128.2 (t, JC, F = 324.8 Hz, C7), 124.9 O2N OH (C1), 115.9 (C3), 110.7 (C5). 19 F NMR (376 MHz, CDCl ) = -79.13 (s, 2F). 3n 3 δ

Elemental analysis calcd (%) C13H9F2NO6S2: C 41.38, H 2.40, N 3.71, S 17.00. Found: C 41.57, H 2.11, N 3.96, S 17.28.

II.1.2 Addition of (Benzenesulfonyl)difluoromethylthio moiety to alkenes and alkynes

II.1.2.1 General synthetic procedures

Experimental Procedure 1:

To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) in dry CH2Cl2 (1M), the nucleophile is added (0.5 mmol, 1 equiv.) followed by the addition of P-toluenbenzensolfonic acid (1.25 mmol, 2.5 equiv.). The reaction vessel is hermetically closed and the reaction is run overnight at 50 °C. The reaction is quenched with water and extracted with EtOAc or Et2O (10 mL x 2). The organic fractions were collected together, washed with water and brine and dried over Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case. Experimental Procedure 4: To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) and nucleophile (0.5 mmol, 1 equiv.) in dry DCE (1M), sodium tosylate is added (0.75 mmol, 1.5 equiv.). The resulting mixture is sirred vigorously for 5 min at room temperature. After 5 min of stirring, BF3.Et2O (2.5 mmol, 5 equiv.) is added dropwise, and the reaction left under stirring at 80 °C for 24 hours.

Et2O and water are added, followed by the extraction of the organic phase. The organic phases were collected together, washed with water and dried over Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case.

153 Experimental Part

(1R,2R)-2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}cyclohexyl 4-methylbenzene-1- sulfonate 5a

Identification: Exp. Proced. 1 Yield 45 % Flash column chromatography: CyHex/EtOAc: 9/1 Pale yellow oil

12 1 H NMR (400 MHz, CDCl3) δ = 7.97–7.92 (m, 2H9), 7.80–7.76 (m, 2H13), 10 F O 9 10 2 F 8 7.76–7.72 (m, 1H11), 7.60 (t, J = 7.9 Hz, 2H10), 7.30 (d, J = 8.0 Hz, 2H14), 1 S 11 7 3 S 9 4.52 (td, J = 6.6, 3.4 Hz, 1H5), 3.61–3.52 (m, 1H6), 2.40 (s, 3H16), 2.30–2.22 6 O 10 O 4 5 12 15 (m, 1H4), 2.06–2.02 (m, 1H1), 1.71–1.62 (m, 3H1, 3, 4), 1.50–1.38 (m, 3H2, 3). O S 16 13C NMR (101 MHz, CDCl ) δ = 144.8 (C ), 135.6 (C ), 134.1 (C ), O 13 14 3 15 11 12 5a 132.5 (C8), 130.9 (C9), 129.9 (C14), 129.5 (C10), 129.4 (t, JC, F = 325.1 Hz, C7), 128.0 (C13), 80.7 (C5), 46.3 (t, JC, F = 2.7 Hz, C6), 30.5 (C4), 29.7, 23.0 (C2), 21.6 (C16), 21.4 (C3). 19 F NMR (376 MHz, CDCl3) δ = -77.97 (d, JF, F = 207.0 Hz, AB system, 1F), -79.00 (d, JF, F = 207.0 Hz, AB system, 1F)

Elemental analysis calcd (%) C20H22F2O5S3: C 50.40, H 4.65, S 20.18. Found: C 50.56, H 4.93, S 20.04

1-{[(1-{[(benzenesulfonyl)difluoromethyl]sulfanyl}dodecan-2-yl)oxy]sulfonyl}-4- methylbenzene 5b

Identification: Exp. Proced. 1 Yield 1 43 % 2 Flash column chromatography: CyHex/EtOAc: 95/5 3 Redish oil 4 5 1 H NMR (400 MHz, CDCl3) δ = 7.98–7.96 (m, 2H15), 7.82-7.76(m, 3H17, 19), 22 6 21 20 7 7.65–7.61 (m, 2H16), 7.34 (dd, J = 8.6, 0.7 Hz, 2H20), 4.69 (t, J = 6.0 Hz, 1H11), 20 19 8 3.26 (ddd, J = 5.6, 4.3, 1.0 Hz, 2H12), 2.44 (s, 3H22), 1.71 (q, J = 6.1 Hz, 2H10), 9 19 18 O 1.33-1.16 (m, 16H2-9), 0.88 (t, J = 7.0 Hz, 3H1). S 10 O 13 O 11 C NMR (101 MHz, CDCl3) δ = 145.1 (C21), 135.8 (C17), 133.7 (C18), 132.1 12 (C ), 131.0 (C ), 130.0 (C ), 129.6 (C ), 129.1 (t, J = 324 Hz, C ), 128.1 5b 14 15 20 16 C, F 13 S F (C19), 81.0 (C11), 34.2 (t, JC, F = 3.6 Hz, C12), 33.5 (C10), 32.0 (C4), 29. 7 (C5), 29.6 13 O F (C ), 29.4 (C ), 29.2 (C ), 24.6 (C ), 22.8 (C ), 21.8 (C ), 14.3 (C ). S 6 7 8 9 3 2 1 15 14 O 19 16 15 F NMR (376 MHz, CDCl3) δ = -80.20 (d, JF, F = 210.0 Hz, AB system, 1F), - 80.95 (d, J = 210.0 Hz, AB system, 1F). 17 16 F, F

Elemental analysis calcd (%) C26H36F2O5S3: C 55.49, H 6.45, S 17.09. Found: C 55.31, H 6.55, S 17.20.

154 Experimental Part

1-({[(4R,5R)-5-{[(benzenesulfonyl)difluoromethyl]sulfanyl}octan-4-yl]oxy}sulfonyl)-4- methylbenzene 5c

Identification: Exp. Proced. 1 Yield 54 % Flash column chromatography: CyHex/EtOAc: 95/5 to 9/1 Yellow solid Melting point: 58 °C 18 1 17 H NMR (400 MHz, CDCl3) δ = 8.00 (d, J = 7.2 Hz, 2H11), 7.81–7.76 (m, 16 16 3H13, 15), 7.63 (t, J = 7.9 Hz, 2H12), 7.33 (d, J = 8.0 Hz, 2H16), 4.74 (dt, J = 15 15 14 9.0, 3.4 Hz, 1H1), 3.61 (ddd, J = 10.1, 4.5, 3.1 Hz, 1H2), 2.44 (s, 3H18), 1.80– O S O 3 1.68 (m, 2H3, 4), 1.58 (dd, J = 9.6, 4.8 Hz, 2H3, 5), 1.42–1.25 (m, 3H4, 5, 6), 7 O 5 1 1.13–1.09 (m, 1H ), 0.85 (t, J = 7.2 Hz, 3H ), 0.80 (t, J = 7.3 Hz, 3H ). 2 6 6 7 8 13 15 S 4 8 C NMR (101 MHz, CDCl3) δ = 145.0 (C17), 135.8 (C13), 133.9 (C14), 132.2 O 9 11 F 10 S (C10), 131.0 (C11), 129.9 (C16), 129.6 (C12), 129.6 (t, JC, F = 324 Hz, C9), 128.0 12 F 5c O (C ), 84.1 (C ), 48.2 (t, J = 2.1 Hz, C ) 31.7 (C ), 31.7 (C ), 21.8 (C ), 20.3 13 11 15 1 C, F 2 4 3 18 12 (C5), 18.8 (C6), 13.5 (C7, 8).

19 F NMR (376 MHz, CDCl3) δ = -80.20 (d, JF, F = 210.0 Hz, AB system, 1F), -80.95 (d, JF, F = 210.0 Hz, AB system, 1F).

Elemental analysis calcd (%) C22H28F2O5S3: C 52.15, H 5.57, S 18.99. Found: C 51.94, H 5.28, S 19.06.

1-({[(4R,5S)-5-{[(benzenesulfonyl)difluoromethyl]sulfanyl}octan-4-yl]oxy}sulfonyl)-4- methylbenzene 5d

Identification: Exp. Proced. 1 Yield 30 % Flash column chromatography: CyHex/EtOAc: 95/5 to 9/1 Yellow solid Melting point: 90 °C

13 1 12 12 H NMR (400 MHz, CDCl3) δ =7.98 – 7.96 (m, 2H11), 7.80 – 7.78 (m,

11 11 2H15), 7.77 – 7.75 (m, 1H13), 7.64 – 7.59 (m, 2H12), 7.30 (bd, J = 0.9 Hz, 10 27 O S O 2H16), 4.83 (ddd, J = 8.0, 5.6, 2.5 Hz, 1H1), 3.62 – 3.58 (m, 1H2), 2.43 (s, 9 F 3H18), 1.83 (dddd, J = 14.0, 10.1, 7.8, 5.1 Hz, 1H3), 1.69 – 1.19 (m, 7H3, 4, 5, S 3 F 6 7 5 1 6), 0.91 – 0.85 (m, 6H7, 8) 2 8 4 13 O C NMR (101 MHz, CDCl3) δ = 144.9 (C17), 135.7 (C13), 133.9 (C14), 15 O S 16 5d 132.3 (C ), 131.0 (C ), 129.8 (C ), 129.5 (C ), 129.4 (t, J = 324 Hz, C ), 14 O 10 11 16 15 C, F 9 17 15 128.1 (C12), 84.9 (C1), 49.5(t, JC, F = 2.2 Hz, C2), 34.0 (C3), 32.6 (d, JC, F = 1.5 18 16 Hz, C4), 21.8 (C18), 20.2 (C6), 18.6 (C5), 13.8 (C18), 13.7 (C7).

19 F NMR (376 MHz, CDCl3) δ -77.05 (d, JF, F = 207.0 Hz, AB system, 1F), -78.73 (d, JF, F = 207.0 Hz, AB system, 1F).

Elemental analysis calcd (%) C22H28F2O5S3: C 52.15, H 5.57, S 18.99. Found: C 52.01, H 5.80, S 19.25.

Experimental Procedure 5:

To an oven-dried flask containing a solution of 1a (0.5 mmol, 1 equiv.) in dry CH2Cl2, the nucleophile (0.5 mmol, 1 equiv.) is added following by the addition of TfOH (1 mmol, 2 equiv.). The resulting mixture is stirred for 16 h at 23 °C. Water is added and organic phase is extracted

155 Experimental Part with EtOAc (10 mL x 2). The organic fractions are collected , washed with water and dried over

Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography as specified in each case.

2-{[(benzenesulfonyl)difluoromethyl]sulfanyl}-1,2,3,4-tetrahydronaphthalene 5e

Identification: Exp. Proced. 5 Yield 71 % Flash column chromatography: CyHex/EtOAc: 9/1 to 8/2 2 1 Brown-redish oil 3 6 1 4 5 H NMR ((400 MHz, CDCl3) δ = 8.03 (d, J = 7.8 Hz, 2H13), 7.78 (t, J = 7.5 7 10 Hz, 1H15), 7.64 (t, J = 7.9 Hz, 2H14), 7.16–7.14 (m, 2H1, 2), 7.12–7.07 (m, 2H3, 6), 8 9 4.03–3.96 (m, 1H8), 3.33 (dd, J = 16.6, 5.2 Hz, 1H7), 3.04–2.95 (m, 3H2, 7), 2.35 S 14 F (dd, J = 13.4, 4.3 Hz, 1H3), 2.07–1.98 (m, 1H3). 11 O F 13 S C NMR (101 MHz, CDCl3) δ = 135.6 (C15), 134.9 (C4), 134.0 (C5), 132.5 13 12 O 16 (C12), 131.0 (C13), 130.2 (t, JC, F = 323.1 Hz C11), 129.5 (C14), 129.1 (C2), 129.0 14 13 (C1), 126.5 (C6), 126.2 (C3), 41.92 (t, JC, F = 2.6 Hz, C8), 37.26 (C7), 30.71 (C10),

15 14 28.06 (C9). 5e 19 F NMR (376 MHz, CDCl3) δ = -77.73 (d, JF, F = 209.0 Hz, AB system, 1F), - 78.32 (d, JF, F = 209.0 Hz, AB system, 1F).

Elemental analysis calcd (%) C17H16F2O2S2: C 57.61, H 4.55, S 18.09. Found: C 57.69, H 4.72, S 19.31.

Difluoro[(5E)-oct-5-en-4-ylsulfanyl]methanesulfonylbenzene 6d

Identification: Exp. Proced. 3 Yield 35 % Exp. Proced. 5 Yield (58 %)

Flash column chromatography: CyHex/EtOAc: 95/5 to 9/1 13 Colorless oil 12 12 1 11 H NMR (400 MHz, CDCl ) δ = 8.02–7.98 (m, 2H ), 7.78–7.74 (m, 1H ), 11 3 11 13 10 7.64–7.59 (m, 2H12), 5.73–5.65 (m, 1H3), 5.38 (ddt, J = 15.3, 9.0, 1.6 Hz, 1H1), O S O 4.05 (td, JC, F = 8.8, 5.9 Hz, 1H2), 2.03 (ddd, JC, F = 7.7, 6.4, 1.5 Hz, 2H5), 1.76– 9 F S 1.57 (m, 2H4), 1.44–1.38 (m, 2H6), 0.97 (t, J = 7.4 Hz, 3H8), 0.91 (t, J = 7.4 Hz, F 3H7). 1 2 4 6 13 7 C NMR (101 MHz, CDCl3) δ = 135.5 (C13), 135.5 (C3), 132.7 (C10), 131.0 3 6d (C11), (t, JC, F = 301.1 Hz, C9), 129.4 (C12), 128.8 (C1), 48.9 (t, JC, F = 2.0 Hz, C2), 5 37.6 (C4), 25.4 (C5), 20.3 (C6), 13.7 (C7), 13.4 (C8). 8 19 F NMR (376 MHz, CDCl3) = -75.94 (d, JF, F = 206.0 Hz, AB system, 1F), - 78.30 (d, JF, F = 206.0 Hz, AB system, 1F).

Elemental analysis calcd (%) C15H20F2O2S2: C 53.87, H 6.03, S 19.18. Found: C 53.74, H 5.75, S 18.85.

156 Experimental Part

({[(1E)-1-{[(benzenesulfonyl)difluoromethyl]sulfanyl}hept-1-en-2- yl]oxy}sulfonyl)benzene 8a

Identification: Exp. Proced. 4 Yield 60 % Flash column chromatography: CyHex/EtOAc: 95/5 Pale yellow oil 11 13 10 12 O 9 1 S 11 H NMR (400 MHz, CDCl3 δ = 7.98–7.95 (m, 2H15), 7.84–7.80 (m, 2H10), O 10 O 6 7.78– 7.75 (m, 1H ), 7.62–7.60 (m, 2H ), 7.38–7.34 (m, 2H ), 6.01 (s, 1H ), 7 17 16 11 7 5 4 F S 2.45 (s, 3H13), 2.41–2.37 (m, 2H5), 1.46–1.38 (m, 2H4), 1.30–1.15 (m, 4H2, 3), 3 8 F 2 O S O 0.83 (t, J = 7.0 Hz, 3H1). 1 14 15 15 13 C NMR (101 MHz, CDCl3) δ = = 159.3 (t, JC, F = 1.7 Hz, C6), 145.9 (C12), 16 16 17 135.9 (C17), 132.6 (C9), 132.0 (C14), 130.9 (C15), 130.1 (C11), 129.6 (C10), 128.5 8a (C16), 127.7 (t, JC, F J = 325.9 Hz C8), 103.7 (t, JC, F = 4.6 Hz C7), 31.2 (C5), 31.0 (C3), 25.8 (C4), 22.3 (C2), 21.8 (C13), 13.9 (C1). 9 F NMR (376 MHz, CDCl3) δ = -81.05 (s, 2F)

Elemental analysis calcd (%) C21H24F2O5S3: C 51.41, H 4.93, S 19.61. Found: C 51.27, H 5.01, S 19.83.

{[(E)-2-[(benzenesulfonyl)oxy]-2- cyclohexylethenyl]sulfanyl}difluoromethanesulfonylbenzene 8b

Identification: Exp. Proced. 4 Yield 42 % Flash column chromatography: CyHex/EtOAc: 95/5

F Pale yellow oil F 6 O 11 5 1 1 S 9 S 10 12 H NMR) δ = 7.99–7.97 (m, 2H11), 7.85–7.83 (m, 2H15), 7.81–7.77 (m, 4 O 2 8 1H ), 7.65–7.61 (m, 2H ), 7.38–7.36 (m, 2H ), 6.16 (s, 1H ), 2.84–2.77 3 7 11 13 13 12 16 8 O 12 (m, 1H4), 2.46 (s, 3H18), 1.72–1.60 (m, 4H3, 5), 1.50–1.42 (m, 2H1), 1.30– 25 O S O 24 14 8b 1.16 (m, 4H2, 6). 15 15 13 C NMR (101 MHz, CDCl3) δ = 162.9 (t, JC, F = 1.7 Hz, C7), 145.8 (C17), 16 16 17 135.8 (C13), 133.0 (C14), 132.2 (C10), 131.0 (C11), 130.0 (C16), 129.6 (C12), 18 128.6 (C15), 127.8 (t, JC, F = 325.6 Hz, C9), 98.89 (t, JC, F = 4.7 Hz, C8), 40.3 (C4), 29.1 (C2, 6), 25.7 (C3, 5), 25.5 (C4), 21.9 (C18). 19 F NMR (376 MHz, CDCl3) δ = -81.06 (s, 2F).

Elemental analysis calcd (%) C22H24F2O5S3: C 52.57, H 4.81, S 19.14. Found: C 52.51, H 5.01, S 19.51.

157 Experimental Part

{[(1E)-2-[(benzenesulfonyl)oxy]-4-phenylbut-1-en-1- yl]sulfanyl}difluoromethanesulfonylbenzene 8c

Identification: Exp. Proced. 4 Yield 42 % Flash column chromatography: CyHex/EtOAc: 100/95

18 20 Pale yellow oil 17 O 19 1H NMR (400 MHz, CDCl ) = 7.96–7.93 (m, 2H ), 7.86–7.84 (m, 12 S 16 18 3 δ 13 O 17 9 O 2H17), 7.8–7.76 (m, 1H15), 7.65–7.60 (m, 2H14), 7.40–7.37(m, 2H18), 7.28–

8 10 6 F 7.24 (m, 2H1, 3), 7.21–7.18 (m, 1H2), 7.12–7.09 (m, 2H4, 6), 5.99 (t, J = 1.0 7 S 1 5 11 F Hz, 1H10), 2.79–2.70 (m, 4H7, 8), 2.47 (s, 3H 20). 2 4 O S O 13 3 12 C NMR (101 MHz, CDCl3) δ = 158.1 (C9), 146.0 (C19), 139.8 (C5), 135.9 13 13 (C15), 132.6 (C18), 132.1 (C12), 131.0 (C13), 130.2 (C5), 129.6 (C14), 128.7 (C1, 14 14 15 3, 4, 6), 128.6 (C17), 127.6 (t, JC, F = 325.8 Hz, C11), 126.6 (C2), 105.0 (C10), 33.5 (C7), 32.4 (C8), 21.9 (C20). 19 F NMR (376 MHz, CDCl3) δ = -81.25 (s, 2F).

Elemental analysis calcd (%) C24H22F2O5S3: C 54.95, H 4.23, S 18.34. Found: C 54.83, H 4.16, S 18.26.

158 Experimental Part

II.1.3 Phenylsulfonyl reduction and access to SCF2H

Experimental Procedure 1

Catalytic I2 (30 mol %) was added to magnesium turnings (2.5 mmol, 10 equiv.) and heated up with a heat gun for 10 min under stirring. Then a solution of starting material (0.25 mmol, 1equiv.) in MeOH (2.5 mL) was added and the mixture was stirred for 1.5 h at room temperature. A second portion of Mg (5 mmol, 20 equiv.) was added and the reaction stirred for further 2.5 h. the reaction was quenched by the addition of NH4Cl (10 mL) reaction mixture and the organic phase was extracted with Et2O (15 x 3). The organic phases were collected, washed with water, brine and dried over MgSO4. Solvent removal under vacuum led to the pure final compounds without the need of any further purification if not specified differently.

Experimental Procedure 2: For the synthesis of deuterated molecules, we followed the above reported procedure step by stepby only substituting MeOH with CD3OD.

1-[(difluoromethyl)sulfanyl]-2,4-dimethoxybenzene 9a

Identification: Exp. Proced. 1 Yield 88 % Compound pure after work-up Colorless oil 9

O 7 1 6 H NMR (400 MHz, CDCl3) δ = 7.47–7.45 (m, 1H4), 6.80 (t, JH, F = 58.0 Hz, 1 SCF2H 5 1H7), 6.51–6.49 (m, 2H1, 3), 3.88 (s, 3H9), 3.83 (s, 3H8). 8 O 2 4 3 13 9a C NMR (101 MHz, CDCl3) δ = 163.2 (C2), 161.2 (C6), 139.0 (C4), 120.8 (t, JC, F = 275.1 Hz, C7), 105.5 (C3), 105.2 (C1), 99.4 (C5), 56.1 (C8), 55.7 (C9). 19 F NMR (376 MHz, CDCl3) δ = -93.16 (d, JF, H = 58.0 Hz).

Elemental analysis calcd (%) C9H10F2O2S: C 49.08, H 4.58, S 14.56. Found: C 49.18, H 4.84, S 14.83.

2-{2-[(difluoromethyl)sulfanyl]-5-methoxy-1H-indol-3-yl}acetic acid 9b

Identification: Exp. Proced. 1 Yield 95 % 12 Compound pure after work-up O 2 Black-brown solid Melting point: 92 °C 1 3 6 1 H NMR (400 MHz, CDCl3) δ = 8.40 (s, 1HOH), 7.23 (d, J = 8.8 Hz, 1H3), 6.99 4 5 HN (d, J = 2.4 Hz, 1H6), 6.95 – 6.92 (m, 1H2), 6.75 (t, JH, F = 57.3 Hz, 1H11), 3.91 (s, 7 8 9 2H9), 3.83 (s, 3H12). HF2CS CO2H 13 11 10 C NMR (101 MHz, CDCl3) δ = 177.1 (C10), 154.7 (C1), 132.4 (C4), 127.6 (C5), 9b 120.4 (t, JC, F = 278.4 Hz C11), 117.5 (t, JC, F = 4.0 Hz C7), 117.1 (C8), 115.6 (C2), 112.4 (C3), 100.57 (C6), 55.9 (C12), 30.8 (C9).

159 Experimental Part

19 F NMR (376 MHz, CDCl3) δ = -93.16 (d, J = 58.0 Hz).

Elemental analysis calcd (%) C9H10F2O2S: C 49.08, H 4.58, S 14.56. Found: C 49.18, H 4.84, S 14.83.

3-[(difluoromethyl)sulfanyl]-2,5-dimethyl-1H-pyrrole

Identification: Exp. Proced. 1 Yield 82 % Flash column chromatography: CyHex/EtOAc: 9/1 to 8/2 7 Redish oil SCF2H 3 2 1 H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1HNH), 6.58 (t, J = 57.8 Hz, 1H7), 6 1 5.92 (dd, J = 2.7, 1.2 Hz, 1H3), 2.30 (s, 3H6), 2.22 (s, 1H5). 5 4 N H 13C NMR (101 MHz, CDCl ) δ = 133.4 (C ), 126.6 (C ), 121.7 (t, J = 274.7 9b 3 1 4 C, F Hz, C7), 112.5 (C3), 98.9 (t, JC, F = 3.7 Hz, C2), 13.0 (C6), 11.4 (C5). 19 F NMR (376 MHz, CDCl3) δ = -92.83 (d, J = 57.4 Hz, 2F).

Elemental analysis calcd (%) C7H9F2NS: 47.44, H 5.12, N 7.90, S 18.09. Found: 47.58, H 5.05, N 7.68, S 18.24

(1R,2R)-2-[(difluoromethyl)sulfanyl]cyclohexan-1-ol

Identification: Exp. Proced. 1 Yield 92 % Compound pure after work-up Colorless oil 7 1 SCF2H H NMR (400 MHz, CDCl3) δ = 6.99 (dd, JH, F = 58.5, 55.7 Hz, 1H7), 3.42 (td, 6 1 5 OH J = 9.7, 4.5 Hz, 1H5), 2.89 (ddd, J = 12.3, 9.8, 4.1 Hz, 1H6), 2.51 (s, 1HOH), 2.19–2.08 (m, 2H1, 4), 1.79–1.69 (m, 2H2, 3), 1.51–1.47 (m, 1H4), 1.33–1.27 (m, 2 4 4H1, 2, 3). 3 9d 13 C NMR (101 MHz, CDCl3) δ = 121.0 (dd, JC, F = 274.1, 270.6 Hz, C7), 73.6 (C5), 50.5 (C6), 34.5 (C1), 33.49 (C4), 26.1 (C2), 24.2 (C3) 19 F NMR (376 MHz, CDCl3) δ = -88.96 (dd, JF, F = 245.6, 58.5 Hz, ABX system, 1F), -91.69 (dd, JF, F = 245.6, 55.7 Hz, ABX system, 1F).

Elemental analysis calcd (%) C7H12F2OS: C 46.14, H 6.64, S 17.60. Found: C 45.96, H 6.89, S 17.82.

160 Experimental Part

2-[(difluoromethyl)sulfanyl]-1,2,3,4-tetrahydronaphthalene 9e

Identification: Exp. Proced. 1 Yield 86 % Compound pure after work-up

11 Colorless oil SCF2H 8 1 9 H NMR (400 MHz, CDCl3) δ = 7.18–7.08 (m, 4H1, 2, 3, 6), 6.93 (t, JH, F = 56.2 10 7 Hz, 1H11), 3.71–3.64 (m, 1H8), 3.30–3.24 (m, 1H10), 3.02–2.93 (m, 3H7, 10), 2.33– 5 4 2.27 (m, 1H8), 2.02–1.93 (m, 1H8). 6 3 13 C NMR (101 MHz, CDCl3) δ = 135.2 (C4), 134.4 (C5), 129.1 (C6), 129.0 (C2), 1 2 126.4 (C1), 126.1 (C3), 121.0(t, JC, F = 272.5 Hz, C11), 38.3(t, JC, F = 2.5 Hz, C8), 9e 37.3 (C7), 30.7 (C9), 28.3 (C10). 19 F NMR (376 MHz, CDCl3) δ = -91.01 (dd, JF, F = 254.5, 56.2 Hz, ABX system, 1F), -91.55 (dd, JF, F = 254.5, 56.2 Hz, ABX system, 1F) Elemental analysis calcd (%) C11H12F2S: C 61.66, H 5.65, S 14.96. Found: C 61.84, H 5.48, S 15.11.

1-{[difluoro(D)methyl]sulfanyl}-2,4-dimethoxybenzene

Identification: Exp. Proced. 2 Yield 88 % Compound pure after work-up Colorless oil

7 O 9 1 6 SCF D H NMR (400 MHz, CDCl3) δ = 7.46–7.44 (m, 1H4), 6.50–6.48 (m, 2H1, 3), 1 2 5 3.87 (s, 3H7), 3.82 (s, 3H8). 4 8 O 2 3 13C NMR (101 MHz, CDCl ) δ = 163.1 (C ), 161.2 (C ), 138.9 (C ), 120.5 (tt, J [D]9a 3 2 6 4 C, F = 273.4 Hz, JC, D= 32.2 Hz, C9), 105.5 (C1), 105.2 (t, JC, F = 3.5 Hz, C5), 99.4 (C3), 56.1 (C8), 55.6 (C7). 19 F NMR (282 MHz, CDCl3) δ = -93.93 (t, JF, D = 9.1 Hz, 2F).

Elemental analysis calcd (%) C9H9DF2O2S: C 48.86, H 5.01, S 14.49. Found: C 48.67, H 5.28, S 14.54.

3-{[difluoro(D)methyl]sulfanyl}-2,5-dimethyl-1H-pyrrole

Identification: Exp. Proced. 2 Yield 81 % Compound pure after work-up

7 Redish oil SCF2D 1 2 3 H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1HNH), 5.92 (dd, J = 2.5, 1.2 Hz, 1H ), 2.29 (s, 3H ), 2.21 (s, 3H ). 1 6 3 6 5 4 N 5 13 H C NMR (101 MHz, CDCl3) δ = 133.4 (C1), 126.6 (C4), 121.3 (tt, JC, F = 273.6 [D]9c Hz, JC, D= 30.1 Hz, C7), 112.5 (C3), 98.9 (t, JC, F = 3.35 Hz, C2), 13.1 (C6), 11.4 (C5). 19 F NMR (282 MHz, CDCl3) δ = -93.65 (t, JF, D = 9.1 Hz, 2F).

Elemental analysis calcd (%) C7H8DF2NS: 47.17, H 5.65, N 7.86, S 17.99. Found: C 47.22, H 5.41, N 7.96, S 18.36.

161 Experimental Part

(1R,2R)-2-{[difluoro(D)methyl]sulfanyl}cyclohexan-1-ol

Identification: Exp. Proced. 2 Yield 81 % Compound pure after work-up

7 Redish oil SCF2D 1 6 H NMR (400 MHz, CDCl3) δ = 3.43 – 3.38 (m, 1H5), 2.88 (ddd, J = 12.3, 9.8, 1 5 OH 4.1 Hz, 1H6), 2.17–2.08 (m, 2H1, 4), 1.78–1.70 (m, 2H2, 3), 1.49 (ddd, J = 25.4, 2 4 12.4, 3.8 Hz, 1H4), 1.36–1.26 (m, 3H1, 2, 3). 3 13C NMR (101 MHz, CDCl ) δ = 120.7 (tt, J = 271.2 Hz, J = 31.4 Hz, C ), [D]9d 3 C, F C, D 7 73.6 (C5), 50.4 (C6), 34.5 (C1), 33.5 (C4), 26.1 (C2), 24.2 (C3). 19 F NMR (376 MHz, CDCl3) δ = -89.76 (dt, J = 246.3, JF, D= 8.5 Hz, ABX system, 1F), -91.69 (dt, J = 246,2, JD, F = 8.7 Hz, ABX system, 1F).

Elemental analysis calcd (%) C7H10D2F2OS: 45.63, H 7.66, S 17.40. Found: C 46.11, H 7.04, S 17.24.

3-{[difluoro(D)methyl]sulfanyl}-1H-indole

Identification: Exp. Proced. 2 Yield 86 % Compound pure after work-up brown oil 7 SCF D 6 2 1 H NMR (400 MHz, CDCl3) δ= 8.50 (s, 1HNH), 7.81–7.99 (m, 1H6), 7.47 (d, J 1 5 8 9 = 2.6 Hz, 1H7), 7.42 (dd, J = 7.9, 1.4 Hz, 1H3), 7.31–7.24 (m, 2H1, 2). 2 4 N 13 3 H C NMR (101 MHz, CDCl3) δ= 136.2 (C4), 132.0 (C7), 129.8 (C6), 123.3 (C1), [D]10a 121.4 (C2), 120.8 (tt, JC, F = 274.2 Hz, JC, D= 32.4 Hz, C9) 119.5 (C6), 111.7 (C3), 96.7 (t, J = 3.3 Hz, C8). 19 F NMR (282 MHz, CDCl3) δ = -92.84 (t, JD, F = 9.1 Hz, 2F).

Elemental analysis calcd (%) C9H6DF2NS: C 53.99, H 4.03, S 16.01, N 7.00. Found: C 54.25, H 4.29, S 16.29, N 7.23.

II.1.4 Post-functionalization of the phenylsulfonyl moiety

Experimental Procedure: To an oven-dried flask containing Mg turnings (12mg, 0.5mmol, 2 equiv.), TMSCl (159 µL, 1.25 mmol, 5 equiv.) is added added under N2 atmosphere and stirred for 2 minutes at 0 °C. Compound 3i dissolved in DMF (0.25M) is slowly added to the mixture and stirred for 30 minutes at 0 °C and 1.5 h at room temperature. To the reaction mixture Et2O and water is added and the organic layers are dried over Na2SO4. Solvent removal under vacuum led to the pure final compound without the need of any further purification.

162 Experimental Part

{[(2,4-dimethoxyphenyl)sulfanyl]difluoromethyl}trimethylsilane

Identification: Exp. Proced. 2 Yield 93 % Compound pure after work-up brown oil F F 10 S 7 Si 1 H NMR (400 MHz, CDCl3) δ= 7.51–7.49 (m, 1H4), 6.50 (m, 2H1, 3), 3.85 (s, 5 10 O 6 4 10 8 3H8), 3.81 (s, 3H9), 0.25 (s, 9H10). 1 3 11a 13 2 C NMR (101 MHz, CDCl3) δ= 162.8 (C2), 162.0 (C6), 140.1 (C4), 134.1 (t, J = O 9 300.6 Hz, C7), 105.2 (C3), 99.31 (C1), 99.0 (t, J = 8.4 Hz, C5), 56.1 (C9), 55.5 (C8), -4.1 (C10). 19 F NMR (376 MHz, CDCl3) δ = -87.51 (s, 2F).

Elemental analysis calcd (%) C12H18F2O2SSi: C 49.29, H 6.20, S 10.97, Si 9.60. Found: C 49.49, H 6.06, S 10.70, Si 9.26.

163 Experimental Part

II.2 Synthesis and characterization of reagent 1d

Methyl 2,2-difluoro-2-[(phenylamino)sulfanyl]acetate 1d Experimental Procedure

In an oven-dried flask under N2, DAST (8.7 mL, 66 mmol, 1.1 equiv.) is slowly added to a mixture of CH2Cl2 (120 mL) and DIPEA (11.5 mL, 66 mmol, 1.1 equiv.) and stirred for 20 min at – 25 °C. Methyl difluoro(trimethylsilyl)acetate (10.7 mL, 60 mmol, 1 equiv.) is slowly added to the solution and the reaction stirred for 1.5 hour.Aniline (5.47 mL, 60 mmol, 1 equiv.) is added to the mixture and the reaction is left under stirring for 16 hours at room temperature. The reaction mixture was extracted with Et2O (100 mL x 3). The organic fractions were collected and washed with water, brine and dried over Na2SO4. After the removal of the solvent under vacuum the compound was purified via silica gel column chromatography.

Identification: Yield 40 % 2 1 Flash chromatography: Pentane/Diethyl Ether: 100% to 95/5. 1 3 Redish oil 3 4 1 NH H NMR (400 MHz, CDCl3) δ = 7.27-7.22 (m, 2H1,), 7.05 (dt, J = 7.7, 1.1 Hz, S F 2H3), 6.92 (tt, J = 7.4, 1.1 Hz, 1H2), 5.12 (s, 1HNH), 3.71 (s, 3H7). 5 F 13 O 6 C NMR (101 MHz, CDCl3) δ = 162.4 (t, J = 32 H, C6), 145.5 (C4), 129.3 (C1), O 121.6 (C2), 120.0 (t, J = 290 Hz, C5), 115.2 (C3), 53.9 (C7) 19 7 F NMR (376 MHz, CDCl3) δ = -92.54 (s, 2F)

II.2.1 SEAr reactions using reagent 1d

Experimental Procedure 1:

To a flask containing a solution of reagent 1d (0.5 mmol, 1 equiv.) in dry CH2Cl2 (1M), the nucleophile (0.5 mmol, 1 equiv.) is added. TMSCl (1 mmol, 2 equiv.) is added to the resulting mixture and the solution was stirred for 16 h at 50 °C, depending on the substrate. The reaction mixture was extracted with Et2O (10 mL x 3). The organic fractions were collected and washed with water, brine and dried over Mg2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography. Experimental Procedure 2:

To a flask containing a solution of reagent 1d (0.5 mmol, 1 equiv.) in dry CH2Cl2 (1M), the nucleophile is added (0.5 mmol, 1 equiv.). P-TsOH (1.25 mmol, 2.5 equiv.) is added and the flask is heated at 50 °C overnight. The reaction mixture is quenched with water was extracted with

Et2O (10 mL x 3). The organic fractions were collected and washed with water, brine and dried

164 Experimental Part

over Mg2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where reported differently) Experimental Procedure 3:

To a flask containing a solution of 1d (0.5 mmol, 1 equiv.) in dry CH2Cl2 (1M), the nucleophile (0.5 mmol, 1 equiv.) is added. TfOH (0.5 mmol, 1 equiv.) is added to the resulting mixture and the solution is stirred for 16 h at at 50 °C. The reaction mixture is extracted with Et2O (10 mL x

3). The organic fractions were collected and washed with water, brine and dried over Mg2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where indicated differently).

Methyl 2,2-difluoro-2-(1H-indol-3-ylsulfanyl)acetate 20a

Identification: Exp. Proced. 1 Yield 80 % 10 Flash chromatography: Pentane/Diethyl Ether: 8/2. O Pale brown solid m.p. 82 °C, calibration substance: Acetanilid at 114.5 °C 9 F O 1 H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1HNH), 7.65 (dd, J = 6.1, 3.1 Hz, F 8 11 S 1H6), 7.27 (bd, J = 2.7 Hz, 1H11), 7.24-7.20 (m, 1H3), 7.17-7.13 (m, 2H1, 2), 3.60 7 NH (s, 3H10). 5 4 13C NMR (101 MHz, CDCl ) = 162.9 (t, J = 33 Hz, C ), 136.1 (C ), 133.3 6 3 3 δ 9 4 (C11), 129.6 (C5), 123.3 (C2), 121.5 (C1), 119.9 (t, J = 287 Hz, C8), 119.1 (C6), 1 2 20a 112.0 (C3), 94.93 (t, J = 4 Hz, C7), 53.9 (C10). 19 F NMR (376 MHz, CDCl3) δ = = -84.36 (s, 2F)

Methyl 2,2-difluoro-2-[(3-methyl-1H-indol-2-yl)sulfanyl]acetate 20b

Identification: Exp. Proced. 2 Yield 63 % 12 Flash chromatography: Pentane/Diethyl Ether: 8/2. Brown oil mp O O 11 1 F 10 H NMR (400 MHz, CDCl3) δ = 8.16 (s, 1HNH), 7.60 (dq, J = 8.0, 0.9 Hz, S F 1H6), 7.36-7.27 (m, 2H2, 3), 7.15 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H1), 3.79 (s, 1H12), 9 7 2.43 (s, 3H9). 8 NH 13 5 4 C NMR (101 MHz, CDCl3) δ = 162.3 (t, J = 32 Hz, C11), 137.6 (C4), 128.1 6 3 (C5), 124.7 (C1), 123.6 (C8), 121.27 (t, J = 289 Hz, C10), 120.0 (C2), 120.0 (C6), 113.7 (t, J = 3 Hz, C7), 111.2 (C3), 54.2 (C12), 9.6 (C9). 1 2 20b 19 F NMR (376 MHz, CDCl3) δ = -81.69 (s, 2F).

165 Experimental Part

Methyl 2-[(4-bromo-1H-indol-3-yl)sulfanyl]-2,2-difluoroacetate 20c

Identification: Exp. Proced. 1 Yield 94 % Flash chromatography: Pentane/Diethyl Ether: 9/1 to 8/2. 11 O Pale brown solid m.p. 132-134 °C, calibration substance: acetanilide at 114.5 F 10 °C O 1 1 F 9 7 H NMR (400 MHz, (CD3)2CO) δ = H NMR (400 MHz, (CD3)2CO) δ = 7.84 S 8 NH (s, 1H7), 7.58 (dd, J = 8.2, 0.9 Hz, 1H3), 7.37 (dd, J = 7.6, 0.9 Hz, 1H1), 7.12 (t, J 5 4 = 7.9, 1H2), 3.76 (s, 3H11). 13 3 Br 6 C NMR (101 MHz, (CD3)2CO) δ = 161.9 (t, J = 33 Hz, C10 ), 137.9 (C7), 1 2 137.3 (C4), 126.3 (C5), 125.9 (C2), 123.6 (C1), 119.2 (t, J = 285.8 Hz, C9), 113.3 20c (C6), 112.2 (C3), 94.2 (t, J = 3.8 Hz, C8), 53.3 (C11). 19 F NMR (376 MHz, (CD3)2CO) δ = -81.03 (s, 2F).

Methyl 2,2-difluoro-2-[(1-methyl-1H-indol-3-yl)sulfanyl]acetate 20f

Identification: Exp. Proced. 1 Yield 89 % Flash chromatography: Pentane/EtOAc: 85/15 to 8/2. 12 O Pale yellow solid m.p. 60°C, calibration substance: azobenzol at 68.0°C 10 F O 1 9 H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 7.5 Hz, 1H6), 7.29-7.16 (m, 4H2, 3, F 7 S 11 4, 7), 3.71 (s, 3H11), 3.62 (s, 3H12). 8 N 5 4 13 C NMR (101 MHz, CDCl3) δ = 162.7 (t, JC, F = 33 Hz, C10), 137.3 (C7), 137.2 6 3 (C4), 130.5 (C5), 122.9 (C1), 121.2 (C2), 119.8 (t, JC, F = 287 Hz, C9), 119.4 (C6), 1 2 20f 110.0 (C3), 93.0 (t, JC, F = 4 Hz, C8), 53.7 (C12), 33.3 (C11). 19 F NMR (376 MHz, CDCl3) δ = -84.14 (s, 2F).

Methyl 2-[(4-ethyl-2,5-dimethyl-1H-pyrrol-3-yl)sulfanyl]-2,2-difluoroacetate 2j

Identification: Exp. Proced. 1 Yield 25 % 11 Flash chromatography: Pentane/EtOAc: 100/0 to 9/1. O Black oil O 10 F 9 1H NMR (400 MHz, CDCl ) δ = 7.86 (s, 1H ), 3.79 (s, 3H ), 2.38 (q, J = 7.6 S F 3 NH 11 5 Hz, 2H ), 2.18 (s, 3H ), 2.07 (s, 3H ), 1.05 (t, J = 7.6 Hz, 3H ). 2 7 5 6 8 8 1 13C NMR (101 MHz, CDCl ) δ = 162.7 (t, J = 33 Hz, C ), 129.7 (C ), 129.5 7 3 NH 3 C, F 10 1 4 (C4), 123.2 (C3), 119.8 (t, JC, F = 288 Hz, C9), 101.6 (t, JC, F = 4 Hz, C2), 53.9 (C11), 6 18.1 (C7), 15.4 (C8), 11.5 (C5), 9.9 (C6). 20j 19 F NMR (376 MHz, CDCl3) δ = -84.20 (s, 2F).

166 Experimental Part

Methyl 2-[(2,4-dimethoxyphenyl)sulfanyl]-2,2-difluoroacetate 20k

Identification: Exp. Proced. 2 Yield 11 80 % Flash chromatography: Pentane/Et2O: 100/0 to 9/1. O O m.p. < 46°C, calibration substance: azobenzol at 10 Yellow solid 9 F 68.0°C S 1 F H NMR (400 MHz, CDCl3) δ = 7.49 (d, J = 8.4 Hz, 1H4), 6.52 (d, J = 2.5 Hz, O 5 4 1H ), 6.50 - 6.46 (m, 2H ), 3.85 (s, 3H ), 3.83 (s, 3H ), 3.81 (s, 3H ). 7 6 3 1 7 8 11 13 1 3 C NMR (101 MHz, CDCl3) δ = 163.9 (C2), 162.5 (t, JC, F = 33.3 Hz, C10), 2 162.3 (C ), 140.7 (C ), 119.5 (t, J = 287.2 Hz, (C ), 105.7 (C ), 103.6(t, J = 3 O 1 4 C, F 9 3 C, F 8 Hz, C5), 99.3 (C1), 56.1 (C7), 55.6 (C8), 53.7 (C11). 19 20k F NMR (376 MHz, CDCl3) δ = -84.10 (s, 2F).

Methyl 2-[(2,4-dihydroxyphenyl)sulfanyl]-2,2-difluoroacetate 20l

Identification: Exp. Proced. 2 Yield 9 81 % Flash chromatography: Pentane/Et2O: 100/0 to 8/2 to 7/3. O O Yellow solid m.p. 62-64 °C, calibration substance: azobenzol at 68.0°C 8 7 F 1 S H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 8.5 Hz, 1H4), 6.52 (d, J = 2.7 Hz, F 5 1H1), 6.44 (dd, J = 8.5, 2.6 Hz, 1H3), 3.84 (s, 3H9). HO 6 4 13 C NMR (101 MHz, CDCl3) δ = 162.1 (t, JC, F = 32.4 Hz, C8), 160.7 (C2), 159.7 1 3 (C6), 139.6 (C4), 119.7 (t, JC, F = 288.7 Hz, C7), 109.6 (C3), 102.8 (C1), 99.8 (t, JC, F 2 = 2.7 Hz, C ), 54.1 (C ). OH 5 9 19 20l F NMR (376 MHz, CDCl3) δ = -82.96 (s, 2F).

Methyl 2,2-difluoro-2-[(4-hydroxyphenyl)sulfanyl]acetate 20m

Identification: Exp. Proced. 2 Yield 66 % Flash chromatography: Pentane/Et2O: 100/0 to 8/2. OH Pale yellow solid 3 m.p. 58-60 °C, calibration substance: azobenzol at 68.0°C 1 1 20m 1 1 H NMR (400 MHz, CDCl3) δ = H NMR (300 MHz, CDCl3) δ = 7.47 (d, J = 2 2 4 O 8.9 Hz, 1H2), 6.84 (d, J = 8.8 Hz, 1H1), 3.83 (s, 1H7). 7 S 5 13 6 O C NMR (101 MHz, CDCl3) δ = 162.6 (t, JC, F = 33 Hz, C6), 158.2 (C3), 138.9 F F (C2), 120.2 (t, JC, F = 287 Hz, C5), 116.6 (C1), 115.2 (C4), 54.0 (C7). 19 F NMR (376 MHz, CDCl3) δ = -83.25 (s, 2F).

167 Experimental Part

Methyl 2,2-difluoro-2-[(1-hydroxynaphthalen-2-yl)sulfanyl]acetate 20n

Identification: Exp. Proced. 2 Yield 83 % Flash chromatography: Pentane/Et2O: 100/0 - 8/2. Pale yellow solid m.p. 132-134 °C, calibration substance: acetanilide at OH 68.0°C 6 5 7 1 1 8 H NMR (400 MHz, (CD3)2CO) δ = 9.92 (s, 1HOH), 8.41 (ddd, J = 8.6, 1.3, 0.7

2 4 9 Hz, 1H6), 8.34 (ddd, J = 8.4, 1.4, 0.7 Hz, 1H3), 7.78 (d, J = 7.9 Hz, 1H9), 7.69 10 3 F S (ddd, J = 8.4, 6.8, 1.4 Hz, 1H1), 7.58 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H2), 7.03 (d, J 11 F 12 13 = 7.9 Hz, 1H8), 3.68 (s, 3H13) O O 13C NMR (101 MHz, (CD ) CO) δ = 162.6 (t, J = 33 Hz, C ), 157.9 (C ), 20n 3 2 C, F 12 7 140.4 (C4), 137.8 (C9), 128.7 (C1), 126.6 (C5), 126.3 (C2), 126.3 (C3), 123.7 (C6), 121.2 (t, JC, F = 286 Hz, C11), 111.3 (t, JC, F = 3 Hz, C10), 109.3 (C8), 54.2 (C13). 19 F NMR (376 MHz, (CD3)2CO) δ = -83.85 (s, 2F).

II.2.2 Acid activation of α-ketones

Experimental Procedure 1:

To a flask containing a solution of reagent 1d (0.3 mmol, 1 equiv.) in dry CH3CN (0.5 M), the ketone is added (0.3 mmol, 1 equiv.). After stirring for 5 minutes, TMSCl (0.6 mmol, 2 equiv.) is slowly added and the flask is heated at 90 °C overnight. The reaction mixture is extracted with

Et2O (10 mL x 3). The organic fractions are collected and washed with water, brine and dried over Mg2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where reported differently).

Methyl 2,2-difluoro-2-[(2-oxo-2-phenylethyl)sulfanyl]acetate 21a

Identification: Yield

11 42 % Flash chromatography: Pentane/Et2O: 100/0 to 95/5. O O Pale yellow liquid 10 9 1 F H NMR (400 MHz, CDCl3) δ = 7.98-7.95 (m, 2H4, 6), 7.65-7.60 (m, 1H2), S F 7.53-7.48 (m, 2H1, 3), 4.47 (s, 2H8), 3.91 (s, 3H11). O 8 7 13C NMR (101 MHz, CDCl ) δ = 192.6 (C ), 162.2 (t, J = 33 Hz, C ) 135.2 5 3 7 C, F 10 6 4 (C5), 134.2 (C2), 129.1 (C1, 3), 128.6, (C4, 6) 120.1 (t, JC, F = 286.7 Hz, C9), 54.2 (C11), 37.3 (C8). 1 3 2 19F NMR (376 MHz, CDCl ) δ = -83.14 (s, 2F). 21a 3

168 Experimental Part

Methyl 2-{[2-(3-chlorophenyl)-2-oxoethyl]sulfanyl}-2,2-difluoroacetate 21b

Identification: Yield 40 % 11 Flash chromatography: Pentane/Et2O: 100/0 to 95/5.

O O Pale yellow liquid 10 9 F 1H NMR (400 MHz, CDCl ) δ = 7.93 (t, J = 1.9 Hz, 1H ), 7.83 (ddd, J = 7.8, S 3 6 F O 8 1.7, 1.0 Hz, 1H4), 7.60 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H2), 7.45 (t, J = 7.9 Hz, 1H3), 7 4.42 (d, J = 0.6 Hz, 2H8), 3.92 (s, 3H11). 5 13 6 4 C NMR (101 MHz, CDCl3) δ = 191.5 (C7), 162.1 (t, JC, F = 33.0 Hz, C10), 1 3 136.7 (C1), 135.5 (C5), 134.1 (C2), 130.4 (C3), 128.6 (C6), 126.7 (C4), 119.9 (t, JC, F Cl 2 = 287.0 Hz, C9), 54.28 (C11), 37.10 (t, JC, F = 3.0 Hz, C8). 21b 19 F NMR (282 MHz, CDCl3) δ = -83.10 (s, 2F).

Methyl 2-{[2-(1-benzofuran-3-yl)-2-oxoethyl]sulfanyl}-2,2-difluoroacetate 2c

Identification: Yield 46 % Flash chromatography: Pentane/EtOAc: 8/2 13 O O Brown oil 12 11 F 1 S H NMR (400 MHz, CDCl3) δ = 7.72 (ddd, J = 7.9, 1.3, 0.8 Hz, 1H6), 7.62 (d, F 10 O J = 1.0 Hz, 1H7), 7.60-7.56 (m, 1H3), 7.51 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H2), 7.33 9 8 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H ), 4.37 (d, J = 0.7 Hz, 2H ), 3.91 (s, 3H ). 6 5 1 10 13 7 13 1 C NMR (101 MHz, CDCl ) δ = 183.7 (C ), 162.0 (t, J = 33.0 Hz, C ), O 3 9 C, F 12 4 2 3 155.9 (C4), 150.9 (C8), 129.1 (C2), 126.9 (C5), 124.4 (C1), 123.7 (C6), 119.84 (t, JC, 21c F = 287.2 Hz, C11), 114.3 (C7), 112.6 (C3), 54.3 (C13), 36.06 (t, JC, F = 3.2 H, C10). 19 F NMR (376 MHz, CDCl3) δ = -82.99 (s, 2F).

2-[(1,1-difluoro-2-methoxyethyl)sulfanyl]-1-phenylpropan-1-one 2d

Identification: Yield 52 % Flash chromatography: Pentane/Et2O: 100/0 to 95/5. O 12 Pale yellow liquid 11 F 1 F 10 H NMR (400 MHz, CDCl3) δ = 8.22-7.83 (m, 2H 4, 6), 7.65-7.56 (m, 1H2), 7.53-7.45 (m, 2H ), 5.07 (q, J = 7.1 Hz, 1H ), 3.86 (s, 3H ), 1.68 (d, J = 7.1 8 S 1, 3 8 12 9 4 Hz, 2H ). 7 3 9 13 5 C NMR (101 MHz, CDCl3) δ = 196.9 (C7), 162.1 (t, JC, F = 32.8 Hz, C11), O 2 6 134.4 (C5), 134.0 (C2), 129.0 (C4, 6), 128.9 (C1, 3), 120.5 (t, JC, F = 287.5 Hz, C10), 1 21d 54.2 (C12), 43.1 (t, JC, F = 2.2 Hz, C8), 20.0 (C9). 19 F NMR (376 MHz, CDCl3) δ = -80.78 (d, J = 221.2 Hz, AB system 1F), - 81.61 (d, J = 221.2 Hz, AB system 1F)

169 Experimental Part

II.2.3 Post-functionalization of the SCF2CO2Me motif

II.2.3.1 Reduction od SCF2CO2Me to alcohol

Experimental Procedure: Compound 20k or 20f (0.5 mmol, 1 equiv.) was dissolved in dry MeOH (0.1 M) and followed by the addition of NaBH4 in portions at 0 °C. The reaction mixture is allowed to reach 25 °C and let under stirring overnight. After quenching the excess of NaBH4 with HCl 1M, the mixture was extracted with EtOAc (3x10). The organic layers were collected, washed with water and brine and dried over Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where reported differently).

2-[(2,4-dimethoxyphenyl)sulfanyl]-2-fluoroethan-1-ol 22a

Identification: Yield 99 % Pure compound after the work-up. OH 8 Pale yellow liquid 7 F S 1 F H NMR (400 MHz, CDCl3) δ = 7.68-7.40 (m, 1H4), 6.57-6.22 (m, 2H1, 3), 3.90 5 O 4 6 (s, 3H9), 3.83 (s, 3H10), 3.59 (t, JH, F = 11.4 Hz, 3H8). 9 1 3 13 2 22a C NMR (101 MHz, CDCl3) δ = 163.6 (C2), 161.52 (C6), 141.2 (C4), 129.2 (t, O J = 281.2 Hz, C ), 106.1 (C ), 105.2 (t, J = 3.9 Hz, C ), 99.4 (C ), 63.7 (t, J 10 C, F 7 3 C, F 5 1 C, F = 32.3 Hz, C8), 56.4 (C9), 55.7 (C10). 19 F NMR (376 MHz, CDCl3) δ = -86.25 (t, JF, H = 11.3 Hz, 2F).

2,2-difluoro-2-(1H-indol-3-ylsulfanyl)ethan-1-ol 23a

Identification: Flash chromatography: Pentane/EtOAc: 70/30 to 60/40. Yield 74 % Pure compound after the work-up. F OH F 10 Brown oil 9 S 1 8 H NMR (400 MHz, CDCl ) δ = 8.57 (bs, 1H ), 7.81 (m, 1H ), 7.44-7.38 (m, 7 3 NH 6 6 5 2H3, 7), 7.30-7.24 (m, 2H1, 2), 3.83 (t, JH, F = 12.2 Hz, 2H10), 2.39 (bs, 1HOH). NH 4 13 1 1 C NMR (101 MHz, CDCl3) δ = 136.2 (C4), 132.7 (C7), 129.9 (C5), 128.3 (t, JC, 2 3 F = 279.5 Hz, C9), 123.3 (C1), 121.5 (C2), 119.4 (C6), 111.8 (C3), 96.2 (m, C8), 23a 64.5 (t, JC, F = 30 Hz, C10). 19 F NMR (376 MHz, CDCl3) δ = -85.89 (t, JF, H = 12 Hz, 2F).

II.2.3.2 Aminolysis reactions

Experimental Procedure: Compound 20k or 20f (0.5 mmol, 1 equiv.) was dissolved in dry MeOH (0.1 M) and followed by the addition of benzylamine (1 mmol, 0.5 equiv.) the reaction was run at room temperature for 3

170 Experimental Part hours and 16 hours respectively. HCl 1M was added to the reaction mixture and the organic layers were extracted with EtOAc (3x10). The organic layers were collected, washed with water and brine and dried over Na2SO4 or MgSO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where reported differently)

N-benzyl-2-[(2,4-dimethoxyphenyl)sulfanyl]-2,2-difluoroacetamide

Identification: Yield

14 13 quant. Flash chromatography: Pentane/Et2O: 8/2. 15 12 Pale yellow solid 10 11 m.p. 96-98 °C, calibration substance: acetanilide at 114.5 °C 9 NH 1 H NMR (400 MHz, CDCl3) δ = 7.49 (d, J = 8.5 Hz, 1H4), 7.32-7.29 (m, 3H11, O 8 F 22b 7 13, 15 ), 7.19-7.17 (m, 2H12, 14,), 6.67 (s, 1HNH), 6.47 (dd, J = 8.6, 2.6 Hz, 1H3), 6.43 F S (d, J = 2.5 Hz, 1H1), 4.40 (d, J = 5.8 Hz, 2H9), 3.81 (s, 3H17), 3.73 (s, 3H16). 5 4 13C NMR (101 MHz, CDCl ) δ = 163.7 (C ), 162.1 (C ), 161.9 (C ), 140.5 (C ), O 3 3 8 2 6 4 6 2 136.6 (C10), 128.8 (C12, 14), 127.9 (C11, 15), 122.0 (t, JC, F = 288 Hz, C7), 105.6 (C3), 16 1 O 103.6 (t, JC, F = 3 Hz, C5), 99.3 (C1), 56.0 (C17), 55.7 (C16), 43.8 (C9). 19 17 F NMR (376 MHz, CDCl3) δ = -82.84 (s, 2F).

N-benzyl-2,2-difluoro-2-(1H-indol-3-ylsulfanyl)acetamide

Identification: Yield 17 95 % 16 Flash chromatography: Pentane/EtOAc: 75/25 to 65/35. 18 15 Brown oil 19 14 1 13 H NMR (400 MHz, CDCl3) δ = 9.15 (bs, 1HNH), 7.79 (d, J = 7.4 Hz, 1H6), HN 7.41 (d, J = 7.7 Hz, 1H3), 7.33 (bs, 1H7), 7.28-7.21 (m, 5H1, 2, 16, 17, 18), 6.98 (dd, J F 12 O = 6.6, 2.9 Hz, 2H15, 19), 6.38 (bs, 1HNH), 4.28 (d, J = 5.6 Hz, 2H13). F 11 13 7 C NMR (101 MHz, CDCl3) δ = 162.5 (t, JC, F = 29 Hz, C12), 136.3 (C14), 136.3 S 8 NH (C9), 133.5 (C7), 129.7 (C5), 128.9 (C16, 18), 128.0 (C17), 127.9 (C15, 19), 123.2 (C2), 5 4 122.4 (t, JC, F = 288 Hz, C11), 121.4 (C1), 119.2 (C6), 112.1 (C3), 95.0 (m, C8), 44.0 6 3 (C13). 1 2 19F NMR (376 MHz, CDCl ) δ = -84.39 (s, 2F). 23b 3

II.2.3.3 Saponification reactions

Experimental Procedure: To a flask are added the ester derivative (20c, 20k or 20f) (0.69 mmol, 1.0 equiv.), MeOH (2 mL) and a solution of K2CO3 1M in water (2.05 mL, 2.05 mmol, 3.0 equiv.). The reaction mixture is stirred at 23°C for 18 h. It is then partitioned between aqueous NaOH 2N and EtOAc. The organic layer is extracted with aqueous NaOH 2N and the combined aqueous layers are acidified with aqueous HCl 2N until pH 1-2. The aqueous layer is

171 Experimental Part extracted with EtOAc and the combined organic layers are washed with water, dried over

MgSO4, filtered and concentrated to dryness to afford the desired carboxylic acid.

2-[(2,4-dimethoxyphenyl)sulfanyl]-2,2-difluoroacetic acid 22c

Identification: Yield Flash chromatography: Pentane/EtOAc: 75/25 to 65/35. 87 % m.p. 74 °C, calibration substance: azobenzol at 68.0 15 Redish oil or redish solid 14 O OH °C 10 1 9 S F H NMR (400 MHz, CDCl3) δ = 9.27 (s, 1HOH), 7.50 (d, J = 8.4 Hz, 1H4), 7 O 5 F 6 6.52-6.33 (m, 2H1, 3), 3.82 (s, 3H7), 3.81 (s, 3H8). 4 1 13 3 2 22c C NMR (101 MHz, CDCl3) δ = 165.8 (t, JC, F = 34 Hz, C10), 164.0 (C2), 162.2 8 O (C6), 140.6 (C4), 118.9 (t, JC, F = 288 Hz, C9), 105.8 (C3), 103.3 (t, JC, F = 3 Hz, C5), 99.3 (C1), 56.0 (C7), 55.6 (C8). 19 F NMR (376 MHz, CDCl3) δ = -85.77 (s, 2F).

2,2-difluoro-2-(1H-indol-3-ylsulfanyl)acetic acid 23c

Identification: Yield Filtration in pentane 92 %

Brown solid m.p. 78-80 °C, calibration substance: azobenzol at 68.0°C 1 F F H NMR (300 MHz, (CD3)2CO) δ = 10.93 (bs, 1HOH), 9.24 (bs, 1HNH), 7.74- S 10 6 9 OH 5 8 7.71 (m, 2H ), 7.51 (m, 1H ), 7.25-7.16 (m, 2H ). 1 6, 7 3 1, 2 7 O 13 2 4 N 23c C NMR (101 MHz, (CD ) CO) = 163.1 (t, J ) = 32 Hz, C ), 137.7 (C ), 3 H 3 2 δ C, F 10 4 1 137.5 (C4), 135.0 (C7), 134.9 (C7), 130.9 (C5), 123.4 (C2), 121.6 (C1), 121.1 (t, J= 285 Hz, C9), 119.6 (C6), 113.0 (C3), 113.0 (C3), 94.6 (m, C8).

19 F NMR (376 MHz, (CD3)2CO) δ = -84.28 (s, 2F).

2,2-difluoro-2-[(1-methyl-1H-indol-3-yl)sulfanyl]acetic acid 23f

Identification: Yield Filtration in pentane 92 %

Brown solid m.p. 90-92 °C, calibration substance: azobenzol at 68.0°C F F 1 S 10 H NMR (300 MHz, (CD3)2CO) δ = 11.50 (s, 1HOH), 7.77 (d, J = 7.5 Hz, 1H6), 6 9 OH 5 8 1 7.61 (s, 1H7), 7.46 (d, J = 7.5 Hz, 1H3), 7.32-7.21 (m, 2H1, 2), 3.85 (s, 3H11). 7 O 2 4 N 13 3 C NMR (101 MHz, (CD3)2CO) δ = 163.3 (t, JC, F = 32Hz, C10), 138.5 (C4), 23f 11 138.3 (C7), 131.4 (C5), 123.3 (C1), 121.6 (C2), 121.0 (t, JC, F = 284 Hz, C9), 119.8 (C6), 111.0 (C3), 93.1 (bs), 33.3 (C11).

19 F NMR (376 MHz, (CD3)2CO) δ = -84.03 (s, 2F).

172 Experimental Part

II.2.3.4 Decarboxylative bromination reaction

Experimental Procedure:

In an oven-dried flask compound 23c (0.5 mmol, 1.0 equiv.), AgNO3 (0.1 mmol, 20 mol %),

Selectfluor II (1.75 mmol, 3.5 equiv.) is added. The flask is evacuated and backfilled with pure N2 for 3 times. Then dry CH2Cl2 (5.0 mL), water (0.5 mL) and HBF4 (50% aq.) (1.5 mmol, 3.0 equiv.) are added with syringe. The mixture is heated at 80 °C for 12 h. The reaction is quenched by addition of water and the organic phase is extracted with CH2Cl2 (3x10 mL). The combined organic phase is dried over Na2SO4. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography.

1-bromo-5-[(bromodifluoromethyl)sulfanyl]-2,4-dimethoxybenzen 24c

Identification: Yield Filtration in pentane 65 %

Brown solid m.p. 62 °C, calibration substance: azobenzol at 68.0 °C

8 1 H NMR (400 MHz, CDCl3) δ = 7.75 (s, 1H4), 6.50 (s, 1H1), 3.95 (s, 3H8), 3.91 O 6 5 S 7 Br (s, 3H9). 1 9 F F O 2 4 3 13 Br C NMR (101 MHz, CDCl3) δ = 161.8 (C2), 160.0 (C6), 142. (C4), 125.6 (C3) 24c 119.6 (t, JC, F = 340.3 Hz, C7), 107.3 (C3), 102.3 (C5), 96.6 (C1), 56.6 (C8), 56.51 (C9).

19 F NMR (376 MHz, CDCl3) δ = -22.56 (s, 2F).

II.2.3.5 Oxidative decarboxylation reactions

Synthesis of the Hypervalent iodonium reagents: All the hyperiodonium reagents and their precursors have been synthesized as following the procedures reported by Wasser and coll.[4] without any further modification, obtaining the same yields. General experimental procedure:

In an oven-dried flask, carboxylic acid 23 (0.2 mmol, 1 equiv.), AgNO3 (0.05 mmol, 25 mol %),

K2S2O8 (0.4 mmol, 2 equiv.), EBX reagent (0.2 mmol, 1 equiv.) and then H2O (1 mL), acetone (1 mL) was added. The reaction mixture is stirred at 50 °C for 16h. H2O and EtOAc are added to the reaction vessel and the organic layers were extracted with EtOAc (3x10 mL). The combined organic layer were washed with water and brine and dried with anhydrous Na2SO4 or MgSO4 and evaporated in vacuum. After the removal of the solvent under vacuum the compounds were purified via silica gel column chromatography (except where reported differently).

173 Experimental Part

{3-[(2,4-dimethoxyphenyl)sulfanyl]-3,3-difluoroprop-1-yn-1-yl}tris(propan-2-yl)silane 25c

Identification: Yield 60 % 17 16 Flash chromatography: Pentane/Et2O: 100 to 95/5. 18 14 19 Si 13 15 Brown solid 12 m.p. < 46 °C, calibration substance: azobenzol at 68.0 °C 11 20 1 10 H NMR (400 MHz, CDCl3) δ = 7.54-7.52 (m, 1H4), 6.51-6.48 (m, 2H1, 3), 3.86 9 F S (s, 3H6), 3.82 (s, 3H2), 1.06-1.03 (m, 21H12-20). F O 5 13 6 4 C NMR (101 MHz, CDCl3) δ = 163.6 (C6), 162.1 (C2), 140.3 (C4), 117.2 (t, JC, 7 1 3 F = 266 Hz, C9), 106.2 (C3), 105.5 (C5), 99.3 (C1), 97.1 (t, JC, F = 38 Hz, C10), 93.7 2 O (t, JC, F = 5 Hz, C11), 56.2 (C7), 55.6 (C8), 18.5 (C15-20), 11.0 (C12-14). 8 19 19 25c F NMR (376 MHz, (CD3)2CO) δ = F NMR (376 MHz, CDCl3) δ = -58.43 (s, 2F).

3-{[1,1-difluoro-3-(tri-tert-butylsilyl)prop-2-yn-1-yl]sulfanyl}-1H-indole 25a

Identification: Yield Flash chromatography: Pentane/EtOAc: 90/10 to 80/2. 13 % 17 16 18 Yellow solid 19 12 m.p. not determined. Si 14 15 1 13 11 H NMR (500 MHz, CDCl ) = 8.48 (bs, 1H ), 7.84 (m, 1H ), 7.51 (d, J = 20 3 δ NH 6 10 2.7 Hz, 1H7), 7.40 (m, 1H3), 7.28-7.22 (m, 2H1, 2), 1.03-1.01 (m, 21H12-20). 9 F 13 S F C NMR (126 MHz, CDCl3) δ = 136.2 (C4), 132.7 (C7), 130.0 (C5), 123.2 (C1), 8 6 5 7 121.5 (C2), 119.9 (C6), 116.9 (t, JC, F = 266 Hz, C9), 111.6 (C3), 98.4 (t, JC, F = 2 1 NH 4 Hz, C8), 97.1 (t, JC, F = 38 Hz, C10), 93.9 (t, JC, F = 5 Hz, C11), 18.5 (C15-20), 11.0 2 3 25a (C12-14). 19 F NMR (376 MHz, CDCl3) δ = -59.49 (s, 2F).

3-({1,1-difluoro-3-[tris(propan-2-yl)silyl]prop-2-yn-1-yl}sulfanyl)-1-methyl-1H-indole 25b

Identification: Yield Flash chromatography: Pentane/EtOAc: 98/2 to 95/5. 26 % 17 16 18 Yellow solid 19 12 m.p. 64 °C, calibration substance: azobenzol at 68.0 °C Si 14 15 1 13 11 H NMR (500 MHz, CDCl3) δ = 7.73 (d, J = 7.7 Hz, 1H6), 7.25-7.13 (m, 4H2, 1, 20 10 2, 3, 7), 3.71 (s, 3H21), 0.93 (massif, 21H12-20). 9 F 13 S F C NMR (126 MHz, CDCl3) δ = 137.3 (C4), 136.8 (C7), 130.8 (C5), 122.8 (C1), 8 6 5 7 121.1 (C2), 120.0 (C6), 117.1 (t, JC, F = 266 Hz, C9), 109.7 (C3), 97.2 (t, JC, F = 38 1 N 25b Hz, C ), 96.0 (t, J = 2 Hz, C ), 93.8 (t, J = 5 Hz, C ), 33.3 (C ), 18.5 (C 4 10 C, F 8 C, F 11 21 15- 2 3 21 20), 11.0 (C12-14). 19 F NMR (376 MHz, CDCl3) δ = -59.69 (s, 2F).

174 Experimental Part

II.3 Synthesis and characterization of pre-reagents 2a-g

{[(trifluoromethyl)selanyl]methyl}benzene 2a Experimental procedure: To an oven-dried flask equipped with a magnetic stirrer are added 2-phenylacetonitrile (70.0 mmol, 1.0 equiv.) and dry THF (140 mL). The flask is evacuated and refilled with nitrogen three times and TMSCF3 (20.7 mL, 140 mmol, 2.0 equiv.) is added. The reaction mixture is cooled to 0°C and TBAF in THF 1M (14.0 mL, 14.0 mmol, 0.2 equiv.) is added dropwise. After 10 minutes at 0°C under nitrogen, the reaction is allowed to warm to 20°C and stirred for 7 hours. The reaction mixture is then partitioned between water and pentane and the aqueous layer is extracted with pentane. The combined organic layers are washed with H2O, brine and dried over MgSO4, filtered through a pad of silica (rinsed with pentane) and concentrated to dryness (under moderate vacuum). After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

[5] Identification: As reported in literature Yield Flash chromatography: Pentane 100 % 70 %

SeCF3 Colorless liquid 1 2a H NMR (300 MHz, CDCl3) δ = 7.37-7.27 (m, 5H), 4.26 (s, 2H). 19 F NMR (282 MHz, CDCl3) δ = -34.47 (s, 3F).

{[(bromodifluoromethyl)selanyl]methyl}benzene 2b Experimental procedure: To an oven-dried flask equipped with a magnetic stirrer is added 2-phenylacetonitrile (1.08 gr, 10 mmol, 1.0 equiv.). The flask is evacuated and refilled with nitrogen three times before adding

THF (20 mL) and TMSCF2Br (3.1 mL, 20 mmol, 2.0 equiv.) to the reaction mixture. The reaction mixture is cooled to 0°C and TBAF in THF 1M (2 mL, 2 mmol, 0.2 equiv.) is added dropwise. After 10 minutes at 0°C under nitrogen, the reaction is allowed to warm to 20°C and stirred for 4 hours. The reaction mixture is then partitioned between water and pentane and the aqueous layer is extracted with pentane. The combined organic layers are washed with H2O, brine, dried over MgSO4 and concentrated to dryness (under moderate vacuum). After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

175 Experimental Part

Identification: Yield Flash chromatography: Pentane 100 % 88% % Colorless liquid F F 6 7 1 Se 1 5 8 Br H NMR (400 MHz, CDCl3) δ =7.36-7.28 (m, 5HAr), 4.31 (s, 2H7). 2 4 2b 13 3 C NMR (101 MHz, CDCl3) δ = 135.6 (C5), 129.3 (C4, 6), 129.0 (C1, 3), 127.9 (C2), 107.9 (t, JC, F = 355 Hz, C8), 32.7 (C7). 19 F NMR (282 MHz, CDCl3) δ = -34.47 (s, 3F). Elemental Analysis calcd (%) for C8H7BrF2Se: C, 32.03; H, 2.35; Br, 26.63; Se, 26.32. Found: C, 31.95; H, 2.47; Se, 26.11.

(benzylselanyl)difluoromethanesulfonylbenzene 2c Experimental procedure: To a flask equipped with a magnetic stirrer is added 2-phenylacetonitrile (1.08 gr, 5,5 mmol, 1.0 equiv.). The flask is evacuated and refilled with nitrogen three times before adding diglyme (11 mL), and TMSCF2SO2Ph (10 mmol, 2.0 equiv.) to the reaction mixture. The reaction mixture is cooled to 0°C and CsF (166 mg, 1.1 mmol, 0.2 equiv.) is carefully added. After 10 minutes at 0°C under nitrogen, the reaction is allowed to warm to 20°C and stirred for 15 hours. The reaction mixture is then partitioned between water and Et2O and the aqueous layer is extracted with Et2O.

The combined organic layers are washed with H2O, brine, dried over MgSO4 and concentrated to dryness. After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

Identification: Yield Flash chromatography: 9/1. 80% 10 9 12 White solid m.p. 64 °C, calibration substance: azobenzol 68 °C O 11 10 F S 1 9 H NMR (400 MHz, CDCl3) δ = 8.02 (dt, J = 8.5, 1.0 Hz, 2H9), 7.82 - 7.74 (m, F 8 O Se 1H ), 7.70 - 7.56 (m, 2H ), 7.41 - 7.27 (m, 5H ), 4.45 (s, 2H ). 7 12 10 Ar 7 13 5 2c C NMR (101 MHz, CDCl3) δ = 135.6 (C12), 131.9 (C11), 131.0 (C9), 129.5 6 4 (C10), 129.4 (C4, 6), 129.0 (C1, 3), 128.0 (C2), 126.01 (t, JC, F = 339 Hz, C8), 30.7 1 3 2 (C7). 19 F NMR (376 MHz, CDCl3) δ = -78.53 (s, 2F).

Elemental Analysis: calcd (%) for C14H12F2O2SSe: C, 46.55; H, 3.35; Se, 21.86, S 8.87. Found: C, 46.65; H, 3.58; Se, 21.64, S 9.07.

Methyl 2-(benzylselanyl)-2,2-difluoroacetate 2d Experimental procedure:

176 Experimental Part

To a flask equipped with a magnetic stirrer 2-phenylacetonitrile (980 mg, 5 mmol, 1.0 equiv.) is added. The flask is evacuated and refilled with nitrogen three times before adding THF (10 mL) and TMSCF2Br (1.77 mL, 10 mmol, 2.0 equiv.) to the flask. The reaction mixture is cooled to 0°C and TBAF in THF 1M (1 mL, 1 mmol, 0.2 equiv.) is added dropwise. After 10 minutes at 0°C under nitrogen, the reaction is allowed to warm to 20°C and stirred for 15 hours. The reaction mixture is then partitioned between water and EtOAc and the aqueous layer is extracted with

EtOAc. The combined organic layers are washed with H2O, brine, dried over MgSO4 and concentrated to dryness. After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

Identification: Yield 62% Flash chromatography: Pentane/Et2O 99/1 – 98/2 Pale yellow liquid

F 1 F 9 O 10 H NMR (400 MHz, CDCl3) δ = 7.36-7.24 (m, 5HAr), 4.24 (s, 2H7), 3.88 (s, 7 8 Se 3H10). 6 O 5 8 13 1 4 C NMR (101 MHz, CDCl3) δ = 163.0 (t, J = 31 Hz, C9), 136.4 (C5), 129.3 (C4, 2d 2 3 6), 128.9 (C1, 3), 127.7 (C2), 115.1 (t, JC, F = 302 Hz, C8), 54.0 (C10), 28.8 (t, JC, F = 3 Hz, C7). 19 F NMR (376 MHz, CDCl3) δ = -83.07 (s, 2F).

Elemental Analysis calcd (%) for C10H10F2O2Se: C, 43.03; H, 3.61; Se, 28.29. Found: C, 43.32; H, 3.92; Se, 28.10.

{[(difluoromethyl)selanyl]methyl}benzene 2e Experimental procedure: To a dry flask equipped with a magnetic stirrer 2-phenylacetonitrile (2.05 g, 10.45 mmol, 1.0 equiv.) and dry THF (21 mL) are added. The flask is evacuated and refilled with nitrogen three times and TMSCF2H (2.85 mL, 20.9 mmol, 2.0 equiv.) is added. The reaction mixture is cooled to 0°C and CsF (1.59 g, 10.45 mmol, 1.0 equiv.) is carefully added. After 30 minutes at 0°C under nitrogen, the reaction is allowed to warm to 20°C and stirred for 15 hours. The reaction mixture is then partitioned between water and pentane and the aqueous layer is extracted with pentane.

The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to dryness (under moderate vacuum). After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

177 Experimental Part

Identification: Yield 19 % Flash chromatography: Pentane/CH2Cl2 97/3 - 95/5 Pale yellow liquid F 6 F 5 1 1 7 Se 9 H H NMR (400 MHz, CDCl3) δ = 7.37-7.31 (m, 5HAr), 7.08 (t, JH, F = 55.2 Hz, 2 4 1H9), 4.12 (s, 2H7). 3 2e 13 C NMR (101 MHz, CDCl3) δ = 137.4 (C5), 129.1 (C4, 6), 128.9 (C1, 3), 127.5 (C2), 115.8 (t, JC, F = 287 Hz, C9, 26.4 (t, JC, F = 3 Hz, C7). 19 F NMR (376 MHz, CDCl3) δ = -92.95 (d, JF, H = 55.3 Hz, 2F).

Elemental Analysis calcd (%) for C8H8F2Se: C, 43.46; H, 3.65; Se, 35.71. Found: C, 43.29; H, 3.40; Se, 35.63.

{[(pentafluoroethyl)selanyl]methyl}benzene 2f Experimental procedure: To a flask equipped with a magnetic stirrer are added 2-phenylacetonitrile (2.8 g, 14.2 mmol, 1.0 equiv.) and dry THF (30 mL). The flask is evacuated and refilled with nitrogen three times and

TMSCF2CF3 (4.9 mL, 28.5 mmol, 2.0 equiv.) is added. The reaction mixture is cooled to 0°C and TBAF in THF 1M (2.8 mL, 2.8 mmol, 0.2 equiv.) is added dropwise. After 10 minutes at 0°C, the reaction is allowed to warm to 20°C and stirred for 16 hours. The reaction mixture is then partitioned between water and pentane and the aqueous layer is extracted with pentane. The combined organic layers are washed with brine, dried over MgSO4, filtered through a pad of silica (rinsed with pentane) and concentrated to dryness (under moderate vacuum). After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

Identification: Yield Flash chromatography: Pentane 100 % 83 % F F F 10 Colorless liquid F 9 F 1 Se H NMR (400 MHz, CDCl ) δ = 7.39-7.28 (m, 5H ), 4.28 (s, 2H ). 8 3 Ar 7 7 13 5 C NMR (101 MHz, CDCl3): δ = 135.5 (C5), 129.3 (C4, 6), 129.1 (C1, 3), 128.0 6 4 2f (C2), 119.1 (qt, JC, F = 285 Hz, JC, F = 35 Hz, C10), 116.5 (tq, JC, F = 303 Hz, JC, F =

1 3 43 Hz, C9), 28.6 (t, JC, F = 3 Hz, C7). 2 19F NMR (376 MHz, CDCl3): δ = -83.66 (t, JF, F = 4.3 Hz, 3F10), -91.75 (q, JF, F = 4.3 Hz, 2F9). Elemental Analysis Anal. calcd (%) for C9H7F5Se: C, 37.39; H, 2.44; Se, 27.31. Found: C, 37.54; H, 2.53; Se, 27.10.

{[(heptafluoropropyl)selanyl]methyl}benzene 2g Experimental procedure: To a flask equipped with a magnetic stirrer are added 2-phenylacetonitrile (720 mg, 3.7 mmol, 1.0 equiv.) and dry THF (7 mL) are added. The flask is evacuated and refilled with nitrogen three

178 Experimental Part

times and TMSCF2CF2CF3 (1.5 mL, 7.3 mmol, 2.0 equiv.) is added. The reaction mixture is cooled to 0°C and TBAF in THF 1M (0.73 mL, 0.73 mmol, 0.2 equiv.) is added dropwise. After 10 minutes at 0°C, the reaction is allowed to warm to 20°C and stirred for 16 hours. The reaction mixture is then partitioned between water and pentane and the aqueous layer is extracted with pentane. The combined organic layers are washed with brine, dried over MgSO4, filtered through a pad of silica (rinsed with pentane) and concentrated to dryness (under moderate vacuum). After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

Identification: Yield Flash chromatography: Pentane 100 % 87 % F F F Colorless liquid 10 11 F F 9 F 1 Se F H NMR (400 MHz, CDCl3) δ = 7.38-7.27 (massif, 5HAr), 4.30 (s, 2H7). 8 7 5 13 C NMR (101 MHz, CDCl3) δ = 135.5 (C5), 129.4 (C4, 6), 129.1 (C1, 3), 128.1 6 4 2g (C2), 119.4 (tt, JC, F) = 304 Hz, JC, F = 38 Hz, C9), 117.8 (qt, JC, F = 288 Hz, JC, F = 1 3 35 Hz, C ), 108.9 (tsex, J = 262 Hz, J = 36 Hz, C ), 28.6 (m, C ). 2 11 C, F C, F 10 7 19 F NMR (376 MHz, CDCl3): δ = -79.78 (t, JF, F = 9.3 Hz, 3F11), -87.74 (m, 2F9), -122.77 (bs, 2F10).

Elemental Analysis Calcd (%) for C10H7F7Se: C, 35.42; H, 2.08; Se, 23.28. Found: C, 35.18; H, 2.23; Se, 23.13.

II.3.1 Fluoroalkylselenolationation reactions

General experimental procedure 1: To a flask equipped with a magnetic stirrer are added the pre-reagent 2a-g (0.5 mmol, 1.0 equiv.), sulfuryl chloride (0.5 mmol, 1.0 equiv.) and dry THF (0.5 mL, 1M). The reaction mixture is stirred at 23°C for 15 minutes, it is then cooled to 0°C followed by the addition of the nucleophile (0.5 mmol, 1.0 equiv.). The reaction mixture is stirred for 10 minutes at 0°C until complete conversion of the intermediate ClSeCF3. The reaction mixture is then partitioned between water and Et2O and the aqueous layer is extracted with Et2O. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to dryness. After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography (if not differently indicated).

Experimental procedure 2: To a flask equipped with a magnetic stirrer were added 1 (0.6 mmol, 1.2 equiv.), sulfuryl chloride (0.6 mmol, 1.2 equiv.), and dry DCE (0.5 mL, 1 M). The reaction mixture was stirred at 23 °C for

3.5 h followed by the addition of 3 (0.5 mmol, 1.0 equiv.) and BF3·Et2O (0.15 mmol, 30 mol %).

179 Experimental Part

The reaction mixture was heated to 80 °C for 15 h. The reaction mixture was then partitioned between water and pentane, and the aqueous layer was extracted with pentane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography (if not differently indicated).

2,4-dimethoxy-1-[(trifluoromethyl)selanyl]benzene 40a

[6] Identification: Exp. Proced. 1:In accordance with literature data Yield 80 % F Flash chromatography: Pentane/toluene: 90/10 to 85/15. F F Colorless liquid Se 1 H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 8.1 Hz, 1H), 6.52-6.48 (m 2H), O O 3.87 (s, 3H), 3.84 (s, 3H). 40a 19 F NMR (282 MHz, CDCl3): δ = -36.54 (s, 3F).

4-[(trifluoromethyl)selanyl]benzene-1,3-diol 40b

Identification: Exp. Proced. 1: Yield Flash chromatography: Pentane/Acetone: 80/20. 85 % F F F White solid m.p. 69 °C, calibration substance: azobenzol at 68.0 °C 7 6 1 1 5 Se H NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.5 Hz, 1H6), 6.58 (d, J = 2.7 4 Hz, 1H3), 6.45 (dd, J = 8.5, 2.7 Hz, 1H1), 6.25 (bs, 1HOH), 5.44 (bs, 1HOH). 2 13 HO 3 OH C NMR (101 MHz, CDCl3) δ = 160.6 (C2), 158.8 (C4), 140.3 (C6), 121.9 (q, 40b JC, F = 336 Hz, C7), 109.8 (C1), 102.7 (C3), 100.3 (C5). 19 F NMR (376 MHz, CDCl3) δ = -36.74 (s, 3F).

Elemental Analysis calcd (%) for C7H5F3O2Se: C, 32.71; H, 1.96; Se, 30.72. Found: C, 32.59; H, 1.91; Se, 30.48.

4,6-bis[(trifluoromethyl)selanyl]benzene-1,3-diol 40c

a Identification: Exp.Proced. 1: 2a (2.2 equiv), SO2Cl2 (2.2 equiv) Yield 93 % Flash chromatography: Pentane/Acetone: 80/20

7 6 8 White solid 1 m.p. 65 °C, calibration substance: azobenzol at 68.0 °C F3CSe 5 SeCF3 1 4 2 H NMR (400 MHz, CDCl3) δ = 8.01 (s, 1H6), 6.84 (s, 1H3), 6.47 (bs, 2HOH). HO OH 3 13 40c C NMR (101 MHz, CDCl3) δ = 162.1 (C2, 4), 149.3 (C6), 121.7 (q, JC, F = 336 Hz, C7, 8), 102.6 (C3), 101.9 (bs C1, 5). 19 F NMR (376 MHz, CDCl3) δ = -36.47 (s, 6F).

Elemental Analysis calcd (%) for C8H4F6O2Se2: C, 23.78; H, 1.00; Se, 39.09. Found: C, 23.67; H, 0.89; Se, 39.14.

180 Experimental Part

4-[(trifluoromethyl)selanyl]naphthalen-1-ol 40d

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc 95/5 to 85/15. 75 %

Brown solid m.p. 64-66 °C, calibration substance: azobenzol at 68.0°C OH 1 6 10 H NMR (400 MHz, CDCl ) = 8.46 (d, J = 8.4 Hz, 1H ), 8.26 (ddd, J = 8.3, 5 3 δ 3 1 9 1.4, 0.7 Hz, 1H6), 7.91 (d, J = 7.8 Hz, 1H8), 7.66 (ddd, J = 8.4, 6.8, 1.4 Hz, 8 1H ), 7.57 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H ), 6.80 (d, J = 7.8 Hz, 1H ), 5.84 (bs, 2 4 2 1 9 3 7 1HOH). SeCF3 13 11 40d C NMR (101 MHz, CDCl3) δ = 154.8 (C10), 139.4 (C8), 136.8 (C4), 128.3 (C2), 128.3 (C3), 126.1 (C1), 125.3 (C5), 122.7 (q, JC, F = 335 Hz, C11), 122.4 (C6), 113.2 (q, JC, F = 2 Hz, C7), 108.9 (C9). 19 F NMR (376 MHz, CDCl3) δ = -36.38 (s, 3F). Elemental Analysis calcd (%) for C11H7F3OSe: C, 45.38; H, 2.42; Se, 27.12. Found: C, 45.59; H, 2.65; Se, 27.31.

N,N-dimethyl-4-[(trifluoromethyl)selanyl]aniline 40e

[6] Identification: Exp.Proced. 1: In accordance with the literature data Yield N 84 % Brown solid m.p. 64-66 °C, calibration substance: azobenzol at 68.0°C 1 H NMR (300 MHz, CDCl3) d = 7.57 (m, 2H), 6.68 (m, 2H), 3.01 (s, 6H). SeCF3 19 F NMR (282 MHz, CDCl3) d = -37.84 (s, 3F). 40e

3-ethyl-2,5-dimethyl-4-[(trifluoromethyl)selanyl]-1H-pyrrole 40f

Identification: Exp.Proced. 1: Yield 67 % Flash chromatography: Pentane/Et2O: 100/0 to 98/2. Dark brown liquid 8 7 SeCF 9 3 2 3 1 H NMR (400 MHz, CDCl3) δ = 7.85 (bs, 1HNH), 2.44 (q, J = 7.6 Hz, 2H8), 1 2.24 (s, 3H ), 2.16 (s, 3H ), 1.10 (t, J = 7.6 Hz, 3H ). 5 4 6 5 9 N 6 13 H C NMR (101 MHz, CDCl3) d = 129.6 (C1), 129.4 (C4), 123.0 (C3), 122.3 (q, 40f JC, F = 338 Hz, C7), 100.5 (q, JC, F = 2 Hz, C2), 18.2 (C8), 15.4 (C9), 11.4 (C6), 10.8 (C5). 19 F NMR (376 MHz, CDCl3) d = -38.58 (s, 3F).

Elemental Analysis calcd (%) for C9H12F3NSe: C, 40.01; H, 4.48, N 5.18; Se, 29.23. Found: C, 39.76; H, 4.71, N 5.46; Se, 29.52.

181 Experimental Part

3-[(trifluoromethyl)selanyl]-1H-indole 40h

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc: 90/10 to 85/15. 67 %

10 Brown solid m.p. 64 °C, calibration substance: azobenzol at 68.0 °C SeCF 6 3 1 1 5 8 H NMR (400 MHz, CDCl3) δ = 8.44 (bs, 1HNH), 7.82 (m, 1H6), 7.48 (d, J = 7 2.7 Hz, 1H7), 7.43 (m, 1H3), 7.36-7.30 (m, 2H1, 2). 2 4 N 13 3 H C NMR (101 MHz, CDCl3) d = 136.1 (C4), 133.0 (C7), 130.1 (C5), 123.4 (C1), 40h 122.4 (q, JC, F = 335 Hz, C10), 121.6 (C2), 120.1 (C6), 111.7 (C3), 93.2 (q, JC, F = 2 Hz, C8). 19F NMR (376 MHz, CDCl3) d = -37.54 (s, 3F). Elemental Analysis calcd (%) for C H F NSe: C, 40.93; H, 2.29, N 5.30; Se, 29.90. Found: C, 9 6 3 41.02; H, 2.48, N 5.13; Se, 29.74.

4-bromo-3-[(trifluoromethyl)selanyl]-1H-indole 40g

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc: 85/15 to 80/20. 91 %

9 Brown solid Br m.p. 98-100°C, calibration substance: azobenzol at 68.0°C SeCF3 6 8 1 5 1 H NMR (400 MHz, CDCl3): d = 8.65 (bs, 1HNH), 7.56 (d, J = 2.8 Hz, 1H7), 7 7.43-7.38 (m, 2H ), 7.10 (t, J = 7.9 Hz, 1H ). 2 1, 3 2 4 N 13 3 H C NMR (101 MHz, CDCl3): d = 137.1 (C4), 135.5 (C7), 126.6 (C5), 126.2 (C ), 124.2 (C ), 122.0 (q, J = 335 Hz, C ), 115.0 (C ), 111.3 (C ), 93.3 (q, J 40g 1 2 C, F 9 6 3 C, F = 2 Hz, C8). 19 F NMR (376 MHz, CDCl3): d = -38.70 (s, 3F). Elemental Analysis calcd (%) for C H BrF NSe: C, 31.51; H, 1.47, Br 23.30, N 4.08; Se, 23.02. 9 5 3 Found: C, 31.70; H, 1.70, Br 23.22, N 4.21; Se, 22.96.

Methyl 3-[(trifluoromethyl)selanyl]-1H-indole-5-carboxylate 40j

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc: 80/20 to 70/30. 89 %

Pale pink solid m.p. 170°C, calibration substance: benzanilid at 163.0°C 9 O 1 6 SeCF3 1 5 8 H NMR (400 MHz, (CD3)2CO) δ = 11.34 (bs, 1HNH), 8.42 (s, 1H6), 7.95-7.92 MeO 10 12 7 (m, 2H2, 7), 7.64 (d, J = 8.9 Hz, 1H3), 3.91 (s, 3H12). 2 4 N 3 H 13 40j C NMR (101 MHz, (CD3)2CO) δ = 167.8 (C10), 140.3 (C4), 137.1 (C7), 130.6 (C5), 124.7 (C2), 124.2 (C1), 123.4 (q, JC, F = 334 Hz, C9), 122.6 (C6), 113.1 (C3), 93.5 (C8), 52.2 (C12). 19 F NMR (376 MHz, (CD3)2CO) δ = -38.93 (s, 3F).

Elemental Analysis calcd (%) for C11H8F3NO2Se: C, 41.01; H, 2.50, N 4.35; Se, 24.51. Found: C, 40.88; H, 2.66, N 4.16; Se, 24.81.

182 Experimental Part

1-methyl-4-[(trifluoromethyl)selanyl]benzene 40l

[6] Identification: Exp.Proced. 1: In accordance to literature Yield Flash chromatography: Cyclohexane/toluene 98/2. 60 %

SeCF3 Pale pink solid MeO 1 40l H NMR (300 MHz, CDCl3) δ = 7.66 (m, 2H), 6.91 (m, 2H), 3.83 (s, 3H) 19 F NMR (282 MHz, CDCl3) δ = −37.18 (s, 3F)

1,3,5-trimethyl-2-[(trifluoromethyl)selanyl]benzene 40l

[7] Identification: Exp.Proced. 1: In accordance to literature data. Yield Flash chromatography: Pentane 100 % 64 % SeCF3 1 H NMR (300 MHz, CDCl3) δ = 7.05 (s, 2H), 2.60 (s, 6H), 2.34 (s, 3H). 19 F NMR (282 MHz, CDCl ) δ = −35.16 (s, 3F). 40l 3

1-[(bromodifluoromethyl)selanyl]-2,4-dimethoxybenzene 41a

1 Identification: Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation Yield Flash chromatography: Cyclohexane/Toluene: 9/1. 80 %

Off white solid m.p. < 46°C, calibration substance: azobenzol at 68.0°C 9 6 5 SeCF Br 1 2 1H NMR (400 MHz, CDCl ) = 7.63 (m, 1H ), 6.52-6.49 (m, 2H ), 3.86 (s, 4 3 δ 6 1, 3 MeO 2 OMe 3H ), 3.84 (s, 3H ). 7 3 8 8 7 41a 13 C NMR (101 MHz, CDCl3) δ = 163.8 (C2), 161.2 (C4), 140.5 (C6), 109.3 (t, JC, F = 359 Hz, C9), 106.9 (C1), 105.8 (C3), 99.2 (C5), 56.2 (C8), 55.6 (C7). 19 F NMR (376 MHz, CDCl3) δ = -18.20 (s, 2F).

Elemental Analysis calcd (%) for C9H9BrF2O2Se: C, 31.24; H, 2.62, Br 23.09; Se, 22.82. Found: C, 31.49; H, 2.92, Br 23.17; Se, 22.96.

4-[(bromodifluoromethyl)selanyl]benzene-1,3-diol 41b

1 Identification: Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation Yield Flash chromatography: Cyclohexane/Toluene: 9/1. 88 %

Pale yellow solid m.p. 116-118 °C, calibration substance: acetanilide 114.5°C 6 7 5 SeCF2Br 1 1 H NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.5 Hz, 1H6), 6.58 (dd, J = 2.7,

HO 2 4 OH 0.5 Hz, 1H ), 6.45 (ddd, J = 8.5, 2.7, 0.5 Hz, 1H ), 6.27 (bs, 1H ), 5.52 (bs, 3 3 1 OH 41b 1HOH). 13 C NMR (101 MHz, CDCl3) δ = 161.0 (C2), 158.8 (C4), 140.3 (C6), 109.7 (C1), 108.8 (t, JC, F = 359 Hz, C7), 104.4 (C3), 102.7 (C5). 19 F NMR (376 MHz, CDCl3) δ = -18.20 (s, 2F).

Elemental Analysis calcd (%) for C7H5BrF2O2Se: C, 26.44; H, 1.59, Br 25.13; Se, 24.83. Found: C, 26.53; H, 1.87, Br 25.39; Se, 24.97.

183 Experimental Part

4-[(bromodifluoromethyl)selanyl]naphthalen-1-ol 41d

1 Identification: Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation Yield Flash chromatography: Cyclohexane/EtOAc: 95/5. 81 %

Brown solid m.p. 96°C, calibration substance: azobenzol at 68.0°C OH 1H NMR (400 MHz, CDCl ) = 8.46 (bd, J = 8.5 Hz, 1H ), 8.26 (ddd, J = 6 10 3 δ 3 1 5 9 8.2, 1.4, 0.7 Hz, 1H6), 7.92 (d, J = 7.8 Hz, 1H8), 7.65 (ddd, J = 8.5, 6.8, 1.4 Hz,

8 1H2), 7.56 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H1), 6.82 (d, J = 7.8 Hz, 1H9), 5.99 (bs, 2 4 7 3 1HOH). SeCF2Br 13 41d 11 C NMR (101 MHz, CDCl3) δ = 155.1 (C10), 139.5 (C8), 136.7 (C4), 128.4 (C5), 128.3 (C2), 126.1 (C1), 125.3 (C5), 122.4 (C6), 117.2 (C7), 109.4 (t, JC, F = 359 Hz, C11), 108.9 (C9). 19 F NMR (376 MHz, CDCl3) δ = -18.09 (s, 2F).

Elemental Analysis Calcd (%) for C11H7BrF2OSe: C, 37.53; H, 2.00, Br 22.70; Se, 22.43. Found: C, 37.28; H, 1.87, Br 22.82; Se, 22.73.

4-[(bromodifluoromethyl)selanyl]-N,N-dimethylaniline 41e

1 Identification: Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation Yield 72 % Purification: Trituration in a small quantity of pentane and filtration 9 10 N Yellow solid m.p. 76-78°C, calibration substance: azobenzol at 68.0°C 6 1 5 1 41e H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.5 Hz, 2H2, 4), 6.74 (d, J = 8.5 2 4 Hz, 2H1, 5), 3.02 (s, 6H9, 10). 3 13 C NMR (101 MHz, CDCl3) δ = 151.7 (C6), 138.8 (C2, 4), 112.6 (C1, 5), 111.4 SeCF2Br 8 (C3), 109.9 (t, JC, F = 357 Hz, C8), 40.2 (C9, 10). 19 F NMR (376 MHz, CDCl3) δ = -19.35 (s, 2F).

Elemental Analysis calcd (%) for C9H10BrF2NSe: C, 32.85; H, 3.06, Br 24.28, N 4.26; Se, 24.00. Found: C, 32.69; H, 3.11, Br 24.20, N 4.35; Se, 23.79.

3,4-bis[(bromodifluoromethyl)selanyl]-2,5-dimethyl-1H-pyrrole 41g

1 2 Identification: Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation . 2b (2.2 equiv), SO Cl (2.2 equiv). Yield 2 2 76 % Flash chromatography: Cyclohexane/EtOAc: 9/1.

8 7 BrF CSe SeCF Br Yellow pale oil 2 3 2 2 4 6 5 N 1 1H NMR (400 MHz, CDCl3) δ = 8.53 (bs, 1HNH), 2.45 (s, 6H5, 6). H 13 C NMR (101 MHz, CDCl3) δ = 136.1 (C1, 4), 110.2 (t, JC, F = 359 Hz, C7, 8), 41g 109.3 (C2, 3), 13.5 (C5, 6). 19 F NMR (376 MHz, CDCl3) δ = -18.97 (s, 4F).

Elemental Analysis calcd (%) for C8H7Br2F4NSe2: C, 18.81; H, 1.38, Br 31.28, N 2.74; Se, 30.91. Found: C, 19.05; H, 1.57, Br 31.33, N 2.59; Se, 30.98.

184 Experimental Part

3-[(bromodifluoromethyl)selanyl]-1H-indole 41h

Identification: 1 Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation. Yield Flash chromatography: Cyclohexane/EtOAc: 9/1 - 8/2. 87 %

9 Brown solid m.p. 50°C, calibration substance: azobenzol at 68.0°C SeCF Br 6 2 8 1 1 5 H NMR (400 MHz, CDCl ) δ = 8.54 (bs, 1H ), 7.81 (m, 1H ), 7.53 (d, J = 7 3 NH 6 2 4 N 2.7 Hz, 1H3), 7.44 (m, 1H3), 7.34-7.27 (m, 2H1, 2). 3 H 13C NMR (101 MHz, CDCl ) δ = 136.1 (C ), 133.2 (C ), 130.0 (C ), 123.5 (C ), 41h 3 4 7 5 1 121.7 (C2), 120.3 (C6), 111.6 (C3), 109.9 (t, JC, F = 359 Hz, C9), 98.0 (C8). 19 F NMR (376 MHz, CDCl3) δ = -18.92 (s, 2F). Elemental Analysis Calcd (%) for C9H6BrF2NSe: C, 33.26; H, 1.86, Br 24.58, N 4.31 Se 24.29. Found: C, 33.18; H, 2.02, Br 24.90, N 4.49; Se, 24.21.

4-bromo-3-[(bromodifluoromethyl)selanyl]-1H-indole 41i

Identification: 1 Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation. Yield Flash chromatography: Cyclohexane/EtOAc: 8/2. 76 %

Br 9 Dark brown solid m.p. 90-92°C, calibration substance: azobenzol at 68.0°C SeCF2Br 6 5 8 1 1 H NMR (400 MHz, CDCl ) = 8.67 (bs, 1H ), 7.60 (d, J = 2.8 Hz, 1H ), 7 3 δ NH 7 2 4 N 7.44-7.40 (m, 2H1, 3), 7.11 (t, J = 7.9 Hz, 1H2). 3 H 13C NMR (101 MHz, CDCl ) = 137.0 (C ), 135.8 (C ), 126.7 (C ), 126.2 (C ), 41i 3 δ 4 7 1 5 124.2 (C2), 115.1 (C6), 111.3 (C3), 109.7 (t, JC, F = 359 Hz C9), 98.0 (C8). 19 F NMR (376 MHz, CDCl3) δ = -20.24 (s, 2F). Elemental Analysis calcd (%) for C9H5Br2F2NSe: C, 26.76; H, 1.25, Br 39.57, N 3.47 Se 19.55. Found: C, 26.52; H, 1.07, Br 39.83, N 3.24; Se, 19.87.

Methyl 3-[(bromodifluoromethyl)selanyl]-1H-indole-5-carboxylate

Identification: 1 Exp.Proced. 1: 30 min. needed for BrF2CSeCl formation. Yield Purification: Trituration in a small quantity of pentane and filtration 94 %

Pale pink solid m.p. 188-190°C, calibration substance: salophen at 191.0°C 1 9 H NMR (400 MHz, CDCl3) δ = 8.83 (bs, 1HNH), 8.51 (bs, 1H6), 8.01 (dd, J = O SeCF Br 6 8 2 1 5 MeO 10 8.5, 1.6 Hz, 1H2), 7.64 (d, J = 2.6 Hz, 1H7), 7.48 (d, J = 8.5 Hz, 1H3), 3.96 (s, 11 7 2 4 N 3H ). 3 H 11 13 C NMR (101 MHz, CDCl3) δ = 167.9 (C10), 138.8 (C4), 134.5 (C7), 129.8 (C5), 124.9 (C2), 124.0 (C1), 123.2 (C6), 111.5 (C3), 109.5 (t, JC, F = 359 Hz, C9), 99.5 (C8), 52.3 (C11). 19 F NMR (376 MHz, CDCl3) δ = -19.07 (s, 2F).

Elemental Analysis calcd (%) for C11H8BrF2NO2Se: C, 34.49; H, 2.11, Br 20.86, N 3.66 Se 20.61. Found: C, 34.37; H, 2.34, Br 21.05, N 3.75; Se, 20.85.

185 Experimental Part

4-[(pentafluoroethyl)selanyl]benzene-1,3-diol 42b

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/Acetone: 80/20. 86 %

White solid m.p. 92°C, calibration substance: benzil at 95.0°C

7 8 1 6 SeCF CF H NMR (400 MHz, CDCl3) δ= 7.49 (d, J = 8.5 Hz, 1H6), 6.58 (d, J = 2.7 Hz, 1 5 2 3 4 1H3), 6.44 (dd, J = 8.5, 2.7 Hz, 1H1), 6.22 (bs, 1HOH), 5.42 (bs, 1HOH). HO 2 OH 3 13C NMR (101 MHz, CDCl ) δ = 160.7 (C ), 159.2 (C ), 140.8 (C ), 118.7 (qt, 42b 3 2 4 6 JC, F = 286 Hz, JC, F = 34 Hz, C8), 115.4 (tq, JC, F = 305 Hz, JC, F = 42 Hz, C7), 109.8 (C1), 102.7 (C3), 99.2 (t, JC, F = 3 Hz, C5). 19 F NMR (376 MHz, CDCl3) δ = -82.80 (t, JF, F = 3.8 Hz, 3F8), -91.61 (q, JF, F = 3.8 Hz, 2F7).

Elemental Analysis calcd (%) for C8H5F5O2Se: C, 31.29; H, 1.64; Se, 25.71. Found: C, 31.19; H, 1.77; Se, 26.03.

4-[(heptafluoropropyl)selanyl]benzene-1,3-diol 43b

Identification: Exp.Proced. 1: Yield 88 % OH Flash chromatography: Pentane/Acetone: 80/20. 2 3 1 White solid m.p., 72°C, calibration substance: azobenzol at 68.0°C 4 1 6 H NMR (400 MHz, CDCl ) = 7.50 (d, J = 8.5 Hz, 1H ), 6.58 (s, J = 2.7 HO 5 3 δ 6 F Se Hz, 1H3), 6.45 (dd, J = 8.5, 2.7 Hz, 1H1), 6.23 (s, 1HOH), 5.51 (s, 1HOH). 7 F 13 C NMR (101 MHz, CDCl3) δ = 160.8 (C2), 159.3 (C4), 141.0 (C6), 118.2 (tt, F 9 F 8 JC, F = 306 Hz, JC, F = 40 Hz, C7), 117.5 (qt, JC, F = 289 Hz, JC, F = 35 Hz, C9), F F F 109.8 (C1), 108.8 (tsex, JC, F = 263 Hz, JC, F = 38 Hz, C8), 102.7 (C3), 99.1 (C5). 43b 19 F NMR (376 MHz, CDCl3) δ = -79.85 (t, JF, F = 9.2 Hz, 3F9), -87.57 (m, 2F7), -122.28 (s, 2F8). Elemental Analysis calcd (%) for C H F O Se: C, 30.27; H, 1.41; Se, 22.11. Found: C, 30.50; 9 5 7 2 H, 1.71; Se, 22.33.

3-[(pentafluoroethyl)selanyl]-1H-indole

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc: 90/10. 88 %

Pale pink solid m.p. 74-76°C, calibration substance: azobenzol at 68.0°C F F 1H NMR (400 MHz, CDCl ) = 8.51 (bs, 1H ), 7.79 (m, 1H ), 7.50 (d, J = Se 9 3 δ NH 6 6 F 5 8 10 1 2.7 Hz, 1H7), 7.43 (m, 1H3), 7.34-7.28 (m, 2H1, 2). F F 7 13C NMR (101 MHz, CDCl ) δ = 136.1 (C ), 133.6 (C ), 130.4 (C ), 123.4 (C ), 2 4 N 42h 3 4 7 5 1 3 H 121.7 (C2), 120.2 (C6), 119.1 (qt, JC, F = 286 Hz, JC, F = 35 Hz, C10), 115.4 (tq, JC, F = 304 Hz, JC, F = 41 Hz, C9), 111.6 (C3), 92.1 (t, JC, F = 4 Hz, C8). 19 F NMR (376 MHz, CDCl3) δ = -82.75 (t, JF, F = 3.9 Hz, 3F10), -92.62 (q, JF, F = 3.9 Hz, 2F9). Elemental Analysis calcd (%) for C11H6F7NSe: C, 36.28; H, 1.66, N 3.85; Se, 21.69. Found: C, 36.14; H, 1.49, N 4.12; Se, 21.51

186 Experimental Part

3-[(heptafluoropropyl)selanyl]-1H-indole

Identification: Exp.Proced. 1: Yield Flash chromatography: Pentane/EtOAc: 90/10. 89 % F F Redish solid F 11 F m.p. 46-48°C, calibration substance: azobenzol at 68.0°C 10 F 1 F 9 H NMR (400 MHz, CDCl3) δ= 8.49 (bs, 1HNH), 7.82 (m, 1H6), 7.48 (d, J = F Se 2.7 Hz, 1H7), 7.42 (m, 1H3), 7.36-7.30 (m, 2H1, 2). 6 13 5 8 1 C NMR (101 MHz, CDCl3) δ = 136.2 (C4), 133.8 (C7), 130.5 (C5), 123.4 (C1), 7 121.7 (C2), 120.2 (C6), 118.1 (tt, JC, F = 305 Hz, JC, F = 38 Hz, C9), 117.7 (qt, JC, F 2 4 N = 289 Hz, JC, F = 35 Hz, C11), 111.7 (C3), 109.0 (tsex, JC, F = 263 Hz, JC, F = 38 3 H Hz, C ), 92.1 (t, J = 4 Hz, C ). 43h 10 C, F 8 19 F NMR (282 MHz, CDCl3) δ = -79.87 (t, JF, F) = 9.1 Hz, 3F11), -88.46 (qt, JF, F = 9.1 Hz, JF, F = 3.4 Hz, 2F9), -122.42 (bs, 2F10). Elemental Analysis Calcd (%) for C10H6F5NSe: C, 38.24; H, 1.93, N 4.46; Se, 25.14. Found: C, 38.13; H, 2.14, N 4.71; Se, 25.34.

Experimental procedure 3: To a flask equipped with a magnetic stirrer is added 2e (0.4 mmol, 1.0 equiv) and dry THF (0.2 mL). The solution is cooled to 0 °C, followed by the addition of sulfuryl chloride (0.4 mmol, 1.0 equiv) and dry THF (0.2 mL). The reaction mixture was stirred at 0 °C for 45 min, and the nucleophile (0.4 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 0 °C until complete conversion of the intermediate 2e (the conversion takes around 2 h; it was checked by

19F NMR with PhOCF3 as internal standard). The reaction mixture was then partitioned between water and Et2O, and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography (if not differently indicated).

4-[(difluoromethyl)selanyl]benzene-1,3-diol 44b

Identification: Exp.Proced. 3: Yield Flash chromatography: Pentane/EtOAc: 90/10 – 85/15. 83 %

Pale yellow oil 7 6 1 5 SeCF H 1 2 H NMR (400 MHz, CDCl3) δ = 7.46 (d, J = 8.5 Hz, 1H6), 6.95 (t, JH, F = 55.2 Hz, 1H7), 6.57 (d, J = 2.6 Hz, 1H3), 6.43 (dd, J = 8.5, 2.6 Hz, 1H1), 6.37 (bs, HO 2 4 OH 3 1HOH), 5.75 (bs, 1HOH). 44b 13 C NMR (101 MHz, CDCl3) δ = 159.9 (C2), 158.5 (C4), 140.0 (C6), 116.4 (t, JC, F = 292 Hz, C7), 109.6 (C3), 102.5 (C1), 100.5 (t, JC, F = 3 Hz, C5). 19 F NMR (282 MHz, CDCl3) δ = -90.05 (d, JF, F = 55.4 Hz).

Elemental Analysis Calcd (%) for C7H6F2O2Se: C, 35.17; H, 2.53; Se, 33.03. Found: C, 34.94; H, 2.62; Se, 32.88.

187 Experimental Part

3-[(difluoromethyl)selanyl]-1H-indole

Identification: Exp.Proced. 3: Yield Flash chromatography: Pentane/EtOAc: 75/25. 83 % Pale yellow oil 9 SeCF H 6 2 1 5 8 H NMR (400 MHz, CDCl3) δ = 8.44 (bs, 1HNH), 7.79 (m, 1H6), 7.44-7.41 (m, 1 7 2H3, 7), 7.33-7.26 (m, 2H1, 2), 7.00 (t, J = 55.7 Hz, 1H9). 2 4 N 13 3 H C NMR (101 MHz, CDCl3) δ = 136.2 (C4), 132.2 (C7), 130.4 (C5), 123.3 (C1), 44h 121.3 (C2), 120.2 (C6), 117.2 (t, JC, F = 290 Hz, C9), 111.6 (C3), 93.4 (t, JC, F = 4 Hz, C8). 19 F NMR (282 MHz, CDCl3) δ = -90.60 (d, JF, H = 54.9 Hz).

Elemental Analysis Calcd (%) for C9H7F2NSe: C, 43.92; H, 2.87, N 5.69; Se, 32.08. Found: C, 43.75; H, 3.12, N 5.74; Se, 32.28.

Methyl 2-[(2,4-dihydroxyphenyl)selanyl]-2,2-difluoroacetate 45b

Identification: Exp.Proced. 3: Yield Flash chromatography: Cyclohexane/EtOAc: 8/2. 60 %

Yellow oil O 1 4 H NMR (400 MHz, CDCl3) δ = 7.40 (d, J = 8.5Hz, 1H4), 6.53 (d, J = 2.6Hz, 5 Se 7 3 8 O 9 6 F F 1H1), 6.40 (dd, J =8.5, 2.6Hz, 1H3), 6.45 - 6.35 (m, 2HOH), 3.78 (s, 3H9). 2 HO 1 OH 13 45b C NMR (101 MHz, CDCl3) δ = 162.8 (t, JC, F = 30 Hz, C8), 160.8 (C2), 158.8 (C6), 140.4 (C4), 115.9 (t, JC, F = 304 Hz, C7), 109.8 (C3), 102.6 (C1), 100.5 (t, JC, F = 3 Hz, C5), 54.3 (C9). 19 F NMR (282 MHz, CDCl3) δ = -82.73 (s, 2F).

Elemental Analysis Calcd (%) for C9H8F2O4Se: C, 36.38; H, 2.71; Se, 26.58. Found: C, 36.63; H, 2.89; Se, 26.48.

Methyl 2,2-difluoro-2-(1H-indol-3-ylselanyl)acetate 45h

Identification: Exp.Proced. 3: Yield 89 % 11 Flash chromatography: Pentane/EtOAc 80/20 to 75/25 14 O Redish solid 10 O mp 94−96 °C, calibration substance: benzil at 95.0 °C F 9 1H NMR (400 MHz, CDCl ) δ = 8.67 (bs, 1H ), 7.71 (m, 1H ), 7.35−7.31 F Se 3 NH 6 6 − 5 (m, 2H3, 7), 7.27 7.23 (m, 2H1, 2), 3.62 (s, 3H11). 1 8 13 7 C NMR (101 MHz, CDCl3) δ = 163.2 (t, JC, F = 30 Hz, C10), 136.2 (C4), 133.4 2 4 N (C7), 130.2 (C5), 123.2 (C1), 121.3 (C2), 119.8 (C6), 115.7 (t, JC, F = 302 Hz, C9), 3 H 111.8 (C3), 93.1 (t, JC, F = 3 Hz, C8), 53.7 (C11). 45h 19 F NMR (282 MHz, CDCl3) δ = −84.47 (s, 2F).

Elemental Analysis Calcd (%) for C11H9F2NO2Se: C, 43.44; H, 2.98, N 4.61; Se, 25.96. Found C 43.60; H, 3.22, N 4.36; Se, 26.06.

188 Experimental Part

4-{[(benzenesulfonyl)difluoromethyl]selanyl}benzene-1,3-diol

Identification: Exp.Proced. 3: Yield 11 Purification: Trituration in a small quantity of pentane and filtration 90 % 10 10 mp 149−151 °C, calibration substance: acetanilide at 114.5 9 9 Off white solid 8 °C 14 O S O 1 H NMR (400 MHz, CDCl3) δ = 7.97 (m, 2H9), 7.81 (m, 1H11), 7.67 (m, 7 F Se 2H ), 7.35 (d, J = 8.5 Hz, 1H ), 6.39 (d, J = 2.6 Hz, 1H ), 6.28 (dd, J = 8.5, 2.6 F 10 4 1 5 HO 6 Hz, 1H3). 4 13 C NMR (101 MHz, CDCl3) δ = 163.2 (C2), 162.0 (C6), 142.0 (C4), 136.8 1 3 2 (C11), 133.5 (C8), 131.9 (C9), 130.6 (C10), 126.4 (t, JC, F = 340 Hz C7), 109.3 (C3), OH 103.6 (C3), 99.5 (t, JC, F = 2 Hz, C5). 46b 19 F NMR (282 MHz, CDCl3) δ = −75.51 (s, 2F).

Elemental Analysis calcd (%) for C13H10F2O4SSe: C, 41.17; H, 2.66, S 8.45 Se 20.82. Found: C, 41.27; H, 2.90, S 8.25; Se, 20.96.

3-{[(benzenesulfonyl)difluoromethyl]selanyl}-1H-indole

Identification: Exp.Proced. 3: Yield Purification: Trituration in a small quantity of pentane and filtration 90 % 13 12 12 mp 122−124 °C, calibration substance: acetanilide at 114.5 11 Pale brown solid 10 11 °C O 1 S O H NMR (400 MHz, CDCl3) δ = 8.75 (bs, 1HNH), 7.95 (d, J = 7.7 Hz, 2H11), F 9 7.79 (m, 1H13), 7.74 (t, J = 7.7 Hz, 1H12), 7.57 (t, J = 7.7 Hz, 2H6), 7.52 (m, 6 F Se 5 8 1H7), 7.41 (m, 1H3), 7.29−7.25 (m, 2H1, 2). 1 13 7 C NMR (101 MHz, CDCl3) δ = 136.1 (C4), 135.5 (C13), 134.2 (C7), 132.0 2 4 N 3 H (C10), 130.8 (C11), 130.5 (C5), 129.4 (C12), 124.9 (t, JC, F = 342 Hz, C9), 123.2 (C ), 121.5 (C ), 120.2 (C ), 111.8 (C ), 92.3 (m, C ). 46h 1 2 6 3 8 19 F NMR (282 MHz, CDCl3) δ = −78.03 (s, 2F).

Elemental Analysis calcd (%) for C15H11F2NO2SSe: C, 46.64; H, 2.87, N 3.63, S 8.30 Se 20.44. Found: C, 46.43; H, 2.74, N 3.71, S 8.14; Se, 20.27.

3-{[difluoro(D)methyl]selanyl}-1H-indole Experimental procedure: To a flask are added magnesium turnings (93 mg, 3.9 mmol, 10 equiv) and iodine (14.8 mg, 0.12 mmol, 30 mol %.), and is heated up with a heat gun for 10 min under stirring. The flask is evacuated and refilled with nitrogen three times before adding a solution of 46h (150 mg, 0.38 mmol, 1 equiv) in CD3OD (3.8 mL, 0.1 M). The mixture is stirred for 1.5 h at 23 °C, then a second portion of magnesium (187 mg, 7.8 mmol, 20 equiv) is added and the reaction is stirred for a further 2 h. A saturated aqueous solution of NH4Cl (10 mL) is added, and the reaction mixture is extracted with Et2O (15 mL × 3). The combined organic layers are washed with water

189 Experimental Part

and brine, dried over MgSO4, filtered, and concentrated to dryness. . After the removal of the solvent under vacuum the crude residue is purified via silica gel column chromatography.

Identification: Exp.Proced. 3: Yield Flash chromatography: Pentane/EtOAc 85/15 to 75/25 58 %

Yellow oil 9 1 SeCF2D δ − 6 8 H NMR (400 MHz, CDCl3) = 8.43 (bs, 1HNH), 7.79 (m, 1H6), 7.44 7.41 5 1 − 7 (m, 2H3, 7), 7.33 7.26 (m, 2H1, 2). 2 13 4 N C NMR (101 MHz, CDCl3) δ = 136.2 (C4), 132.2 (C7), 130.4 (C5), 123.3 (C1), 3 H 121.3 (C2), 120.2 (C6), 116.9 (tt, JC, F = 289 Hz, JC, D = 32 Hz, C9), 111.6 (C3), 93.3 (t, JC, F = 4 Hz, C8). 19 F NMR (282 MHz, CDCl3) δ = −91.33 (t, JF, D = 8.5 Hz, 2F)

Elemental Analysis calcd (%) for C9H6DF2NSe: C, 43.74; H, 3.26, N 5.67; Se, 31.95. Found: C, 43.54; H, 2.98, N 5.80; Se, 32.06.

190 Experimental Part

References:

[1] F. Toulgoat, B. R. Langlois, M. Medebielle, J.-Y. Sanchez, J. Org. Chem. 2007, 72, 9046- 9052. [2] N. Surapanich, C. Kuhakarn, M. Pohmakotr, V. Reutrakul, Eur. J. Org. Chem. 2012, 2012, 5943-5952. [3] J. Liu, C. Ni, F. Wang, J. Hu, Tetrahedron Lett. 2008, 49, 1605-1608. [4] a) J. P. Brand, J. Charpentier, J. Waser, Angew. Chem., Int. Ed. 2009, 48, 9346-9349; b) J. P. Brand, C. Chevalley, R. Scopelliti, J. Waser, Chem. Eur. J. 2012, 18, 5655-5666. [5] T. Billard, S. Large, B. R. Langlois, Tetrahedron Lett. 1997, 38, 65-68. [6] P. Nikolaienko, M. Rueping, Chem. Eur. J. 2016, 22, 2620-2623. [7] C. Chen, L. Ouyang, Q. Lin, Y. Liu, C. Hou, Y. Yuan, Z. Weng, Chem. Eur. J. 2014, 20, 657-661.

191 English Abstract: During the last years a lot of progress has been done in the fluorine field. Various groups contributed by developing methodologies or fluorinated reagents that find a wide use nowadays within the scientific community. Among them, we were concentrated in exploiting the association of fluorine with heteroatoms. Such an interest is totally comprehensible considering the changes that fluorine is able to induce to organic compounds. Fluorine is well known for increasing the lipophilicity of the compounds bearing it and one of the most lipophilic motifs is

SCF3. During the last years we have developed three bench-stable trifluoromethylthiolating reagents that were used in synthetic chemistry from us and other groups as well. Starting from the results obtained in this field, recently we expanded our interest towards the development of reagents that act as fluoroalkylthiolating reagents in electrophilic reactions. Thus, two reagents bearing a SCF2FG (FG= functional group) motif were developed and successfully used in various reactions. Thus, such reagents not only opened the way to access functionalized new fluoroalkylthiolated molecules, but also the obtained compounds could be post-transformed. In this dissertation we also studied the association of fluorine with another chalcogen, namely Selenium. Fluoroalkylselenolated compounds are less studied respect to the thiolated analogs. Herein, we report a new one-pot strategy to access various trifluoromethylselenolated compounds through in situ formation of CF3SeCl starting from the easy-to-handle pre-reagent trifluoromethyl benzyl selenide. Also analogs and homologs of the reagent were synthesized and successfully used in reactions leading RCF2Se-adducts. Some of the synthesized compounds were also used as starting materials in nucleophilic 18F- 18 labeling reactions. Thus we accessed for the first time to SeCF2 F molecules opening the way to selenium in 18F radiolabeled products. Key words : (benzenesulfonyl)difluoromethanesulfenamide, difluoromethylthiolation, 18F- labeling, trifluoromethylselenolation, fluoroalkylselenolation, trifluoromethaneselenyl chloride.

French Abstract : Au cours des dernières années, de nombreux progrès ont été réalisés dans le domaine de la chimie du fluor. Diverses équipes ont contribué au développement de nouvelles méthodologies ainsi qu’à la mise au point de réactifs de fluoration trouvant de larges applications au sein de la communauté scientifique. Au cours de ces travaux, nous nous sommes intéressés à l’association du fluor à des hétéroatomes. Cet intérêt s’explique par les propriétés de ces groupements. En effet, ils permettent ainsi d’augmenter la lipophilie des molécules sur lesquelles ils sont introduits, en particulier le motif SCF3. Durant les dernières années, nous avons développé trois réactifs de Chapter III. Trifluoromethylchalcogens; Late-stage [18F]F- radiolabeling trifluorométhylthiolation stables qui ont pu être par la suite utilisé en synthèse aussi bien par notre groupe que par d’autres équipes. A partir de ces résultats, nous avons récemment étendu cette thématique vers le développement de réactifs de fluoroalkylthiolation en conditions électrophiles. Ainsi, deux réactifs portant le motif SCF2FG (FG=groupe fonctionnel) ont été développés et utilisés avec succès dans diverses réactions. Aux vues de ces résultats, ces réactifs permettent l’accès à de nouvelles molécules fluoroalkylthiolées fonctionnalisées ; mais également à leur post-transformation. Nous avons également étudié l’association du fluor avec un autre élément de la famille des chalcogènes ; le sélénium. Les composés fluoroalkylséléniés sont moins étudiés que leurs analogues soufrés. Dans ces travaux, nous reportons une nouvelle stratégie monotopique pour accéder à diverses molécules trifluorométhylséléniés via la formation in situ de l’intermédiaire

CF3SeCl à partir d’un pré-réactif facile à manipuler, le trifluorométhylséléniure de benzyle. Des analogues et homologues de ce pré-réactif ont été synthétisés et utilisés pour conduire à des composés SeCF2R. Certains des produits synthétisés ont été employés comme réactifs de départ dans des réactions nucléophiles de radiomarquage au fluor-18. Ainsi, nous avons pu accéder pour 18 la première fois à des molécules comportant le groupement SeCF2 F offrant la possibilité d’utiliser le sélénium dans des molécules marquées au fluor-18.