1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Difluoromethylation and Difluoroalkylation of (Hetero) Arenes: Access to Ar(Het)–CF2H and Ar(Het)–CF2R Yu‐Lan Xiao and Xingang Zhang

Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, CAS Key Laboratory of Organofluorine Chemistry, 345 Lingling Road, Shanghai 200032, China

1.1 Introduction

The difluoromethylation of arenes has been given increasing attention due to the unique properties of the difluoromethyl group (CF2H), which is considered as a bioisostere of hydroxyl and thiol groups and also as a lipophilic hydrogen bond donor [1]. Thus, the incorporation of CF2H into an aromatic ring has become an important strategy in medicinal chemistry [2]. Conventional method for the synthesis of difluoromethylated arenes relies on the deoxyfluorination of aromatic aldehydes with diethylaminosulfur trifluoride (DAST) [3]. However, this method has a modest functional group tolerance and high cost. Transition‐metal‐catalyzed cross‐coupling difluoromethylation is one of the most efficient strategies to access this class of compounds. Over the past few years, impressive achievements have been made in this field [4]. In this chapter, we describe three modes of difluoromethylation of aromatics: nucleophilic difluoromethylation, catalytic metal difluorocarbene‐involved coupling reaction (MeDIC), and radical difluoromethylation.

1.2 Difluoromethylation of (Hetero)aromatics

1.2.1 Transition‐Metal‐Mediated/Catalyzed Nucleophilic Difluoromethylation of (Hetero)aromatics

Copper is the first transition metal that has been used for mediating nucleophilic difluoromethylation of (hetero)aromatics. In 1990, Burton et al. synthesized the first difluoromethyl copper complex by metathesis reaction between [Cd(CF2H)2] and CuBr [5]. However, the instability of this complex restricts its further synthetic applications [6]. In 2012, Hartwig and coworker found that using TMSCF2H (5.0 equiv) as source of fluorine to generate difluoromethyl copper in situ could

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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CuI (1.0 equiv) CsF (3.0 equiv) I CF2H TMSCF2H (5.0 equiv) R R NMP, 120°C, 24 h

R = EDG 30–91%

Me CF2H CF H 2 MeO CF2H CF2H O Ph Me Br 88% 81% 48% 77% (a)

CuCl (1.2 equiv) 1,10-phen (1.2 equiv) I CF2H TMSCF2H (2.4 equiv) R R t-BuOK (2.4 equiv) DMF, rt R = EWG 70–93%

CF H 2 CF2H CF2H CF2H

EtO C 2 O2N NC Cl N (b) 80% 78% 82% 74%

Scheme 1.1 Copper‐mediated difluoromethylation of aryl iodides with TMSCF2H.

lead to the difluoromethylation of aryl iodides efficiently (Scheme 1.1a) [7], representing the first example of copper‐mediated difluoromethylation of aromatics. In this reaction, however, only electron‐rich and ‐neutral aryl iodides − were suitable substrates. A difluoromethylcuprate species [Cu(CF2H)2] was proposed in the reaction. To overcome this limitation, Qing and coworkers reported a 1,10‐phen‐promoted copper‐mediated difluoromethylation of electron‐deficient (hetero)aryl iodides with TMSCF2H (Scheme 1.1b) [8]. The role of the ligand is to stabilize the difluoromethyl copper species. In 2012, Prakash et al. also reported a copper‐mediated difluoromethylation of aryl iodides, employing n‐Bu3SnCF2H, instead of TMSCF2H, as the difluoromethylation reagent (Scheme 1.2) [9]. This method allowed difluoromethylation of electron‐deficient (hetero)aryl iodides, but electron‐rich partners produced low yields. A transmetalation between n‐Bu3SnCF2H and CuI to generate CuCF2H species was proposed. Using similar strategy, Goossen and coworkers reported a Sandmeyer‐type copper‐mediated difluoromethylation of (hetero)arenediazonium salts with TMSCF2H (Scheme 1.3) [10]. In addition to the difluoromethylation of prefunctionalized aromatics, the copper‐mediated direct C─H bond difluoromethylation of heteroaromatics has also been reported, representing a more straightforward and atom/step‐ economic approach. Inspired by the oxidative trifluoromethylation reaction of

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CuI (1.3 equiv) KF (3.0 equiv) I CF2H nBu3SnCF2H (5.0 equiv) R R X DMA, 100–120°C, 24 h X

X = CH, N 32–82%

CF H CF2H CF2H 2 N CF2H

CHO MeO2C Br 53% 82% 78%75%

DFT calculations

CH3 H C DMF F 3 – H C Sn Sn F H C F –3.6 CH3 Cu I 3 3 H C CH3 –48.6 H C Sn CF H 3 Sn CF H 3 CH3 2 2 I CF2H H C F– +3.6 H C +31.8 3 CH3 3 F Cu DMF + Cu CF2H FMD + I–

Scheme 1.2 Copper‐mediated difluoromethylation of (hetero)aryl iodides with n‐Bu3SnCF2H.

TMSCF2H (2.5 equiv) CuSCN (1.0 equiv) DMF CsF (3.0 equiv) 40°C, 1 h

t-BuONO + – NH2 N2 BF4 Cu–CF H CF2H HBF4 2 R R R DMF, rt, 12 h 34–86%

CF H CF H CF2H CF H 2 2 O 2

Ph NC N N H 81% 67% 76% 54%

Scheme 1.3 Copper‐mediated difluoromethylation of (hetero)arenediazoniums.

heteroaromatics [11], Qing and coworkers reported a copper‐mediated direct oxidative difluoromethylation of C─H bonds on electron‐deficient heteroarenes with TMSCF2H (Scheme 1.4) [12]. The use of 9,10‐phenanthrenequinone (PQ) as an oxidant was essential for the reaction. Regioselective difluoromethylation was favorable to the more acidic C─H bond, which was readily deprotonated by t‐BuOK base, to provide the desired products. These copper‐mediated difluoromethylation reactions paved a new way to access difluoromethylated arenes. In these reactions, however, more than stoichiometric amount of copper salts were required. A more efficient and attractive alternative is the catalytic difluoromethylation. In 2010, Buchwald and coworkers reported the first example of palladium‐catalyzed trifluoromethylation of aryl chlorides with TESCF3 [13]. Direct adaptation of this strategy to difluoromethylation resulted in inefficient transmetalation between the palladium

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CuCN (3.0 equiv) PQ (1.8 equiv) Y X TMSCF2H (3 equiv) X Y R H R CF2H Z t-BuOK (4.5 equiv) Z NMP, rt, 6 h O O 46–87% PQ

N N N N NC N CF2H CF2H CF2H O O CF2H O NC N MeO NC Me I 87% 77% 56% 48%

Scheme 1.4 Copper‐mediated oxidative difluoromethylation of heteroarenes.

catalyst and TMSCF2H. In 2014, Shen and coworkers developed a cooperative dual palladium/silver catalytic system with both bidentate phosphine 1,1′‐ bis(diphenylphosphino)ferrocene (dppf) and N‐heterocyclic carbene (NHC) SIPr as the ligands (Scheme 1.5a) [14]. This system enabled difluoromethylation of electron‐rich and electron‐deficient aryl bromides and iodides with TMSCF2H

Pd(dba)2 (5 mol%), DPPF (10 mol%) [(SIPr)AgCI] (20 mol%) i-Pr i-Pr Br/I TMSCF2H (2 equiv) CF2H R R N N t-BuONa (2 equiv) dioxane or toluene, 80 °C, 4–6 h 58%~96% i-Pr i-Pr SIPr

CF2H CF2H CF2H BnO CF2H

Ph t-BuO2C BnO N 86% 76% 84% 58% (a)

Proposed mechanism

CF2H Pd(dppf) (SIPr)Ag CF2H Ar Ar-CHF2H TMSCF2H t-BuONa (dppf)Pd(0)

Ar-X X Pd(dppf) (SIPr)Ag X Ar

i-Pr i-Pr Pd(dba) (5 mol%) X 2 CF2H N N DPEPhos (10 mol%) Het R Het R + Toluene, 80 °C, 6 h Ag i-Pr i-Pr 54%~95% X = Cl, Br, I CF2H

(b) (SIPr)Ag(CF2H)

Scheme 1.5 Palladium‐catalyzed difluoromethylation of aryl halides with (SIPr)Ag(CF2H).

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efficiently. An in situ generated difluoromethyl silver complex (SIPr)Ag(CF2H) was found to promote the transmetalation step and facilitate the catalytic cycle. Stoichiometric reaction showed that the reductive elimination of aryldifluoro- methyl palladium complex [Ar–Pd(Ln)–CF2H] is faster than that of aryltrifluoro- methyl palladium complex [Ar–Pd(Ln)–CF3], suggesting the different electronic effect between CF3 and CF2H. The method can also be extended to heteroaryl halides [15] and triflates (Scheme 1.5b) [15b], including pharmaceutical and agrochemical derivatives. Very recently, Sanford and coworkers demonstrated that the use of TMSCF2H can also lead to difluoromethylated arenes under palladium catalysis (Scheme 1.6) [16]. The use of electron‐rich monophosphine ligands [BrettPhos and P(t‐Bu)3] allowed difluoromethylation of a series of electron‐rich (hetero)aryl chlorides and bromides.

Cl/Br Conditions CF2H R + TMSCF2H R

Yields up to 87%

OMe Condition B:

Pd(Pt-Bu3)2 (5 mol%), CsF (2 equiv), MeO PCy dioxane, 100–120 °C, 16–36 h 2 i-Pr i-Pr

Condition A: Pd(dba) (3 mol%), BrettPhos (4.5 mol%), 2 i-Pr CsF (2 equiv), dioxane, 100 °C, 16–36 h BrettPhos

CF H CF HCF H 2 2 O 2 CF2H

Ph N O 87% 60% 60% 38% N

Scheme 1.6 Palladium‐catalyzed difluoromethylation of aryl halides with TMSCF2H.

Using more reactive transmetalating zinc reagent (TMEDA)2Zn(CF2H)2 as fluorine source, Mikami and coworkers developed a palladium‐catalyzed difluoromethylation of (hetero)aryl iodides and bromides (Scheme 1.7) [17]. Similar to Shen’s work, dppf was employed as the ligand in the reaction. This method exhibited broad substrate scope, where both electron‐rich and electron‐deficient aryl iodides were suitable substrates. Besides the aryl halides, benzoic acid chlorides were also a competent coupling partner. With (DMPU)2Zn(CF2H)2 as the difluoromethylating reagent, Ritter and coworkers developed a palladium‐catalyzed decarbonylative difluoromethylation of benzoic acid chlorides (Scheme 1.8) [18]. This reaction proceeded under

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PPh2 Pd(dba)2 (5 mol%), dppf (10 mol%) Br/I CF2H (TMEDA)Zn(CF2H)2 (2 equiv) Fe R R 1,4-Dioxane, 120 °C, 6 h PPh2 39–99% DPPF

Cl N CF2H CF2H CF2H N AcO N O N Cl N CF2H 2 MeO O 80% 86% 82% AcO OAc 61%

Scheme 1.7 Palladium‐catalyzed difluoromethylation of aryl bromides/chlorides with (TMEDA)Zn(CF2H)2.

mild reaction conditions with good functional group tolerance. The use of monophosphine ligand RuPhos is critical in promoting the decarbonylation and subsequent difluoromethylation.

O Pd(dba) (5 mol%), RuPhos (6 mol%) 2 CF2H Cl (DMPU)2Zn(CF2H)2 (1 equiv) R R Dioxane, 23 °C, 1 h 63–93%

Me Me O N CF2H CF2H Me CF2H CF H N 2 Ph Ph F Me Me 91% 72% 82% 93%

Proposed mechanism O (RuPhos)Pd(0) Ar Cl ArCF2H

O Ar (RuPhos)Pd(II) Ar (RuPhos)Pd(II) Cl CF2H

(DMPU)22 Zn(CF H)X

X = CF2H or Cl

CO O Ar (RuPhos)Pd(II) (DMPU)2ZnClX CF2H

Scheme 1.8 Palladium‐catalyzed decarbonylative difluoromethylation of benzoic acid chlorides with (DMPU)2Zn(CF2H)2.

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Copper can also be used as the catalyst for the difluoromethylation. In 2016, Mikami and coworkers reported a ligand‐free copper‐catalyzed difluoromethyl- − ation of (hetero)aryl iodides (Scheme 1.9), in which a cuprate [Cu(CF2H)2] species may be involved in the reaction [19], in agreement with Hartwig’s hypothesis [7].

CuI (2–10 mol%) I CF2H (DMPU)2Zn(CF2H)2 (2 equiv) R R DMPU, 60 °C, 24 h 5–94%

CF2H CF2H N CF2H CF2H N CO2Et CN Br MeO 92% 60% 91% 5%

Proposed mechanism

L2Zn(CF2H)2 + L2Zn(CF2H)I Ar–CF H CuI 2 L = DMPU

L2Zn(CF2H)I + L2ZnI2

[O] – – CuCF2H [Cu(CF2H)2] [Cu(CF2H)4] 19 I CF H Detected by F NMR Inactive Cu 2 Ar HF2C  CF2HH+ FC  CFH

Ar–I

Scheme 1.9 Copper‐catalyzed difluoromethylation of aryl iodides with (DMPU)2Zn(CF2H)2.

For all these copper‐mediated or catalyzed difluoromethylation reactions, a difluoromethyl copper species was proposed as the key intermediate. However, the nature and properties of the unstable copper species have not been system- atically investigated. In 2017, Sanford and coworkers reported the synthesis, reactivity, and catalytic applications of an isolable (IPr)Cu(CF2H) complex (Scheme 1.10) [20]. Unlike the previous supposition [5, 6], this complex is stable in solution at room temperature for at least 24 hours, suggesting that the bimo- lecular decomposition pathway is relatively slow. A variety of aryl electrophiles could react with this (IPr)Cu(CF2H) complex to furnish the corresponding difluoromethylated arenes smoothly. Based on this fundamental research, a copper‐catalyzed difluoromethylation of aryl iodides with TMSCF2H has been developed by employing IPrCuCl as the catalyst. Although palladium‐ and copper‐catalyzed nucleophilic difluoromethylation reactions have been developed, the development of fluoroalkylation catalyzed by earth‐abundant transition metals remains appealing. In 2016, Vicic and coworker reported a nickel‐catalyzed difluoromethylation of (hetero)aryl iodides,

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NN NN NN R R t-BuONa R R TMSCF2H R R Cu –NaCl Cu –TMSOt-Bu Cu

CI Ot-Bu CF2H From (IPr)CuCl 51% From (SIPr)CuCl 82%

IPrCuCI (10 mol%) i-Pr i-Pr TMSCF H (2 equiv) I 2 CF H NN CsF (3 equiv) 2 R R i-Pr i-Pr Dioxane/toluene 3 : 1 Cu 120 °C, 20 h Yields up to 92% CI IPrCuCI

CF2H CF2H Br CF2H CF2H

NC PhO N 64% 66% 71% 78%

Scheme 1.10 (NHC)CuCl‐catalyzed difluoromethylation of aryl iodides with TMSCF2H.

bromides, and triflates with (DMPU)2Zn(CF2H)2 (Scheme 1.11) [21]. This is the first example to use (DMPU)2Zn(CF2H)2 as the difluoromethylation reagent. The reaction underwent difluoromethylation smoothly with electron‐deficient substrates, but electron‐rich aryl iodides or aryl bromides were not applicable to the reaction.

CF H X CF2H (dppf)Ni(COD) (15 mol%) 2 R (DMPU)2Zn R CF2H DMSO, 25 °C, 24 h X = Cl, Br, I Yields up to 91%

CF2H CF2H CF2H CF2H

Ph NC S N X = Br 78% X = Br 79% X = Br 65% X = Br 53% X = I 74% X = I 91% X = I 51% X = I 60%

Scheme 1.11 Nickel‐catalyzed difluoromethylation of aryl halides with (DMPU)2Zn(CF2H)2.

1.2.2 Catalytic Metal‐Difluorocarbene‐Involved Coupling (MeDIC) Reaction

Difluorocarbene is an electrophilic ground‐state singlet carbene. As an important intermediate, difluorocarbene has privileged applications in various areas [22]. However, the intrinsic electrophilic nature of difluorocarbene limits its reaction types [23]. Usually, difluorocarbene is used to react with heteroatom nucleophiles (O, S, N, P) to produce heteroatom‐substituted difluoromethylated compounds [24] or to react with alkenes/alkynes to prepare gem‐difluorocyclopropanes

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/gem‐difluorocyclopropenes [25]. The use of transition metal to tune the reactivity of difluorocarbene would provide a promising strategy to develop new types of difluorocarbene transfer reaction. However, because of the inherently low reactivity of known isolated metal‐difluorocarbene complexes compared to their non- fluorinated counterparts [26], it is of great challenge to apply metal‐difluorocarbene to the catalytic cross‐coupling. The catalytic MeDIC reaction had not been reported until Zhang and coworkers reported a palladium‐catalyzed difluoromethylation of arylboronic acids with BrCF2CO2Et in 2015 (Scheme 1.12) [27]. This reaction represents the first example of a catalytic MeDIC reaction by exhib- iting excellent functional group tolerance (even toward bromide and hydroxyl groups) and being compatible with both electron‐rich and electron‐deficient arylboronic acids. Compared to the catalytic nucleophilic difluoromethylation of aromatics, the advantages of this reaction are broad substrate scope and the use of inexpensive and readily available fluorine source without requiring a multistep synthetic procedure. The combination of bidentate phosphine ligand Xantphos and additive hydroquinone is essential for reaction efficiency. Kinetic studies showed that a potassium salt BrCF2CO2K was generated in situ at the initial stage, which served as a difluorocarbene precursor in the reaction. Mechanistic studies revealed that an aryl group migration to the palladium difluorocarbene carbon pathway was not involved in the reaction. Inspired by this palladium‐catalyzed MeDIC reaction, Zhang and coworkers employed ClCF2H as the fluorine source for the difluoromethylation (Scheme 1.13) [28]. ClCF2H is an inexpensive and abundant industrial chemical used for the production of fluorinated polymers [22], representing an ideal and the most straightforward difluoromethylating reagent. The reaction allowed difluoromethylation of a wide range of (hetero)arylboronic acids and esters and was used for difluoromethylation of a series of biologically active molecules, including pharmaceuticals, agrochemicals, and natural products. Most remarkably, the late‐stage difluoromethylation of biologically active molecules through a sequential C–H/C–CN borylation [29] and difluoromethylation process proceeded smoothly, thus providing a straightforward route for applications in drug discov- ery and development. Deuterium‐labeling experiments demonstrated that arylboronic acids, hydroquinone, ClCF2H, and even water were the proton donors. Xiao and coworkers reported a difluoromethylation of arylboronic acids with + − Ph3P CF2COO (PDFA), but electron‐deficient arylboronic acids were not suitable substrates (Scheme 1.14) [30]. A palladium(0) difluorocarbene trimer [Pd(CF2)(PPh3)]3 was isolated. Stoichiometric reaction of this [{Pd(CF2)(PPh3)}3] complex with arylboronic acid demonstrated that this palladium difluorocarbene cluster was not an active species in the reaction.

1.2.3 Transition‐Metal‐Catalyzed Radical Difluoromethylation of (Hetero)aryl Metals/Halides and Beyond

Owning to the electron‐withdrawing effect of fluorine atom, perfluoroalkyl halides can be readily initiated by a low‐valent transition metal to generate a radical via a single electron transfer (SET) pathway [31]. A nickel‐catalyzed perfluoroalkylation of aromatics with perfluoroalkyl iodides was reported in

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PdCI2(PPh3)2 (5 mol%) Xantphos (7.5 mol%) Me Me OH Hydroquinone (2.0 equiv) B(OH)2 CF H Fe(acac)3 (3.5 mol%) 2 R BrCF2CO2Et R Styrene (20 mol%) O (2 equiv) K CO , dioxane, 80 °C PPh2 PPh2 OH R = EDG, EWG 2 3 33–87% Xantphos Hydroquinone :CF2 via: LnPdCF2

CF2H OH CF2H MeO CF2H CF2H F EtO TMS N O OMe O 80% 73% 72% 58% F

Scheme 1.12 Palladium‐catalyzed difluoromethylation of arylboronic acids with bromodifluoroacetate via a difluorocarbene pathway. 14-03-2020 20:52:46 c01.indd 13

Pd2(dba)3 (2.5 mol%) Xantphos (7.5 mol%) CF H B Hydroquinone (2.0 equiv) 2 R ClCF2H R via: LnPdCF2 (10 equiv) K2CO3 (4.0 equiv) Dioxane, 110 °C 45–95%

R = EDG, EWG :CF2 • B = B(OH)2, Beg, Bneop KOH, B(Oi-Pr)3Li

O CF2H CF2H Me Me OMe CF H O 2 O Me Me O CF2H N O N Me O O Me S O MeO N N OEt CO2Me O Me MeO Me 72% 80% 45% 72% Gram scale

F CN F CF2H CF2H H

O O (1) C–H borylation (1) C–CN borylation Me Me Me Me O (2) C–B difluoromethylation O (2) C–B difluoromethylation O O O O Me NHBoc Me NHBoc On-Bu On-Bu Me Me

Scheme 1.13 Palladium‐catalyzed difluoromethylation of aryl borons with chlorodifluoromethane via a difluorocarbene pathway. 14-03-2020 20:52:47 c01.indd 14

Pd(PPh3)4 (20 mol%) 1,3-Cyclopentadione (1 equiv) B(OH)2 CF2H H2O (2.5 equiv), Ca(OH)2 (4 equiv) R Ph P+CF CO – R 3 2 2 p-Xylene, 90 °C, 3 h O O PDFA (5 equiv) R = EDG 23–86% 1,3-Cyclopentadione via: LnPdCF2 :CF2

CF H 2 CF2H CF2H CF2H MeO O

83% 78% 86% 68%

Scheme 1.14 Palladium‐catalyzed difluoromethylation of arylboronic acids with PDFA via a difluorocarbene pathway. 14-03-2020 20:52:47 1.2 Difluoromethylation of (Hetero)aromatics 15

1989 by Huang and coworker [32]. A radical initiated by nickel(0) was involved in the reaction, but no fluoroalkyl nickel species was generated. A nickel‐catalyzed radical difluoromethylation of aromatics (Scheme 1.15a) was reported in 2018 by Zhang and coworkers [33] on the basis of their previous work on the nickel‐ catalyzed difluoroalkylation of arylboronic acids with difluoroalkyl halides [34]. The reaction exhibited high functional group tolerance and allowed difluoromethylation of a variety of arylboronic acids with simple and readily available bromodifluoromethane (BrCF2H) as the fluorine source. A combined (2 + 1) ligand system [34b,c] (a bidentate ligand and a monodentate ligand) was employed to promote the relatively low reactivity of BrCF2H and facilitate catalytic cycle. Radical inhibition, radical clock, and electron paramagnetic resonance (EPR)

Ni(PPh3)2Br2 (5 mol%) bpy (10 mol%), DMAP (5 mol%) B(OH)2 CF2H K2CO3 (4.0 equiv) R BrCF2H R THF, 80 °C, 17 h N N 37–93% bpy

CF2H MeO CF2H CF2H CF2H

EtO TMS N OMe O Ph (a) 85% 83% 80% 70%

Proposed mechanism

ArCF2H I ArB(OH)2 Ni Ln

Ar HF C NiIIIL I 2 n Ar–Ni Ln Br

• Single electron transfer CF2H + II BrCF 2H Ar–Ni (Ln)Br

Ni(OTf)2 (5 mol%) t-Bu t-Bu ditBuBpy (5 mol%), PPh3 (10 mol%) B(OH)2 CF2H K2CO3 (3.0 equiv) R BrCF2H R Dioxane, 80 °C, 24 h N N ditBuBpy 51–92%

CF2H CF2H CF2H O O CF2H EtO Ph PhO O (b) 92% 86% 69% 53%

Scheme 1.15 Nickel‐catalyzed difluoromethylation of arylboronic acids with bromodifluoromethane.

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experiments demonstrated that a difluoromethyl radical was involved in the reaction. Based on the mechanistic studies and previous reports [35], a Ni(I/III) catalytic cycle involving a radical was proposed. Similar to Zhang’s studies, Wang and coworkers reported a nickel‐catalyzed cross‐coupling of BrCF2H with arylboronic acids using PPh3 as the co‐ligand (Scheme 1.15b) [36]. Later on, Zhang and coworkers extended this (2 + 1) ligand system to the nickel‐catalyzed cross‐coupling between (hetero)aryl chlorides/bromides and ClCF2H [37], representing the first example of nickel‐catalyzed reductive cross‐ coupling between organoelectrophiles and fluoroalkyl halides (Scheme 1.16). The reaction exhibited remarkably broad substrate scope, including a range of pharmaceuticals, without preformation of aryl metals. The reaction can be scaled up to 10 g scale without loss of reaction efficiency, providing a practical application of ClCF2H in life and materials sciences. Radical clock and control experiments revealed that a difluoromethyl radical generated by direct cleavage of C─Cl bond in ClCF2H was involved in the reaction. Stoichiometric reaction of aryl nickel complex [ArNi(ditBuBpy)X] with ClCF2H and reaction of difluoromethyl nickel complex [HCF2Ni(ditBuBpy)X] with aryl chloride showed that the reaction started from the oxidative addition of aryl halides to Ni(0). This is in

NiCI2 (10 mol%) Ligand (5 mol%) H2N NH2 CI CF H DMAP (20 mol%) 2 R Het CICF2H R Het MgCI2 (4.0 equiv) N N (6.5 equiv) Zn (3.0 equiv) Ligand 3Å MS, DMA, 60 °C Yields up to 92%

Me O O CO Me N Me 2 O Me O N CF H N 2 H NBoc N CF H 2 H OH CF2H 72% 84% 76% O N 91%, 10.5 g CF2H Me

Proposed mechanism

Zn [Ni0] Ar–Cl Zn [Ni0] Ar–Cl

[NiI] [Ar–NiII–Cl] [NiII] [Ar–NiII–Cl]

CF2H Ar–CF2H Zn

ClCF2H III [Ar–NiI] [NiI] III [Ar–Ni –CF2H] [Ar–Ni –CF2H]

ClCF2H [Ar–NiII–Cl] + CF2H Ar–CF2H a. Radical-Cage rebound process b. Radical chain mechanism

Ni(PPh3)2Br2 (10 mol%) bpy (10 mol%) Br CF H KI (0.4 equiv) 2 R Het BrCF2H R Het Zn (2.0 equiv) (1.0 equiv) DMPU, 60 °C, 6 h Yields up to 91%

Scheme 1.16 Nickel‐catalyzed reductive difluoromethylation of aryl chlorides and bromides.

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contrast to palladium‐catalyzed difluoromethylation of arylboronic acids and esters with ClCF2H, in which a difluorocarbene pathway is involved in the reaction [28]. This nickel‐catalyzed reductive process can also be applied to BrCF2H with high efficiency and good functional group tolerance (Scheme 1.16) [38]. The nickel‐catalyzed reductive difluoromethylation has also been extended to photoredox catalysis. Recently, McMillan and coworkers reported a method to access difluoromethylated (hetero)arenes through cross‐coupling of (hetero)aryl bromides with BrCF2H by combining nickel catalysis (NiBr2·4,4′‐di‐tert‐ butyl‐2,2′‐bipyridine [dtbbpy]) with iridium photocatalysis {[Ir(dF(CF3) ppy)2(dtbbpy)]PF6} (Scheme 1.17) [39]. A pathway involving silyl radical‐medi-

CF3 – Ir photocatalyst (1 mol%) F PF6 NiBr2 dtbbpy (5 mol%) N tBu (TMS) SiH (1.05 equiv) 3 N Br 2,6-Lutidine (2.0 equiv) CF2H F F Ir R BrCF2H R N DME, blue LEDs, 18 h X X (1–2 equiv) N tBu 45–85% F CF3 Ir photocatalyst

O NH2 S CF H O 2 OMe CF2H O NNO N N N S Me MeO N O F3C Me CF2H CO2Me 66% 64% MeO 82%

Proposed mechanism Formation of difluoromethyl radical:

(TMS)3SiH BrCF2H Br (TMS)3Si (TMS)3SiBr + CF2H –HBr hv Ar–Br visible light excitation

0 IrIII (dtbbpy)Ni Ln Br NNiII Ar N

SET CF2H *IrIII

CF 2H II I NNiIII–Ar Br Ir (dtbbpy)Ni Ln N

Br Ar–CF2H

Scheme 1.17 Metallaphotoredox difluoromethylation of aryl bromides with bromodifluoromethane.

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ated halogen abstraction to generate difluoromethyl radical was proposed. One advantage of this method is that various N‐containing heteroaromatics were applicable to the reaction, providing an alternative access to difluoromethylated (hetero)aromatics. The nickel‐catalyzed difluoromethylation of arylmetals with difluoromethyl halides has also been applied to the cross‐coupling between arylmagnesium bromides and difluoroiodomethane (ICF2H) (Scheme 1.18) [40]. In contrast to the previous difluoromethylation via a Ni(I/III) catalytic cycle [33], a Ni(0/II) catalytic cycle was proposed by Mikami and coworkers [40] to be likely involved in the reaction. This plausible mechanism was supported by the stoichiometric reaction of a difluoromethyl nickel(II) complex with PhMgBr. Radical clock experiment showed that the free difluoromethyl radical was unlikely involved in the reaction. They also used ICF2H as the difluoromethylating reagent and developed a palladium‐catalyzed difluoromethylation of arylboronic acids with ICF2H (Scheme 1.19) [41]. Preliminary mechanistic studies revealed that the reaction started from the oxidative addition of ICF2H to Pd(PPh3)4; the resulting square‐planar trans‐(PPh3)2Pd(II)(CF2H)I complex underwent transmetalation to provide cis‐(PPh3)2Pd(CF2H)Ph, which subsequently underwent a ligand

Ni(cod)2 (2.5 mol%) MgBr TMDEA (2.5 mol%) CF2H R + ICF H R 2 THF, 0 °C to rt, 1 h

(1.5 equiv) 42–99%

CF2H CF2H EtO2C CF2H NC CF2H

Ph MeS 89% 82% 79% 33%

Proposed mechanism Oxidative addition N ICF H I 2 Ni N CF2H

Ar–MgBr N Ni0 N

MgBrI

N Ar Transmetalation Ar–CF2H Ni N CF2H Reductive elimination

Scheme 1.18 Nickel‐catalyzed difluoromethylation of aryl magnesium reagents with iododifluoromethane.

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Pd(PPh3)4 (10 mol%) DPEphos (10 mol%) B(OH)2 CF2H K3PO4 (2 equiv) R + ICF2H R O Toluene/H2O = 10 : 1 PPh2 PPh2 (1.5 equiv) 60 °C, 24 h 33–98% DPEphos

CF2H CF2H CF2H CF2H Ph TMS NH2 O 89% 90% 29% 68%

Me Me Pd (dba) (5 mol%) Zn 2 3 CF H Xantphos (11 mol%) 2 R + ICF2H R 2 THF, rt, 20 h O (1.5 equiv) 12–97% PPh2 PPh2 Xantphos

CF2H MeO CF2H CF2H CF2H

EtO2C CN 97% 67% 49% 52%

Scheme 1.19 Palladium‐catalyzed difluoromethylation of arylboronic acids or aryl zinc reagents.

exchange with DPEphos, followed by reductive elimination to produce the difluoromethylated aromatics. In addition to the nickel‐catalyzed radical difluoromethylation, the use of inexpensive, nontoxic, and environmentally benign iron as the catalyst has also been given increasing attention. In 2018, Hu and coworkers reported an iron‐catalyzed difluoromethylation of arylzinc reagents with difluoromethyl 2‐pyridyl sulfone (Scheme 1.20a) [42]. Generally, moderate to high yields were obtained with electron‐rich substrates, but less reactivity was showed by electron‐deficient substrates. Preliminary mechanistic studies showed that a difluoromethyl radical, generated via SET pathway from difluoromethyl 2‐pyridyl sulfone, was involved in the reaction. In the same year, Zhang and coworkers also developed an iron‐catalyzed difluoromethylation (Scheme 1.20b) [43], in which a bulky diamine ligand with a butylene group substituted at one carbon atom of ethylene backbone in N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) was used to promote the reaction. During the reaction/catalysis process, the corresponding iron complex can be changed from five‐coordinate to more electron‐deficient four‐coordinate, thus improving its catalytic efficiency. This iron‐catalyzed difluoromethylation has later been extended to ICF2H by Mikami and coworkers (Scheme 1.20c) [44]. In contrast, no ligand was required in this reaction, mainly owing to the different reactivity between BrCF2H and ICF2H.

1.2.4 Radical C─H Bond Difluoromethylation of (Hetero)aromatics The direct C─H bond difluoromethylation of (hetero)aromatics represents a more straightforward alternative. Over the past a few years, important progress has been made in this field, providing synthetically convenient routes for

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O O Fe(acac)3 (20 mol%) S H TMEDA (2.0 equiv) Ar2Zn Ar CF2H N F F THF, –40 °C to rt, 2 h 36–96%

Me N CF2H CF2H O MeO F3C

F CF2H CF2H (a) 88% 68% 92% 80%

FeBr2 (10 mol%) MgBr L1 (10 mol%) CF2H + R R BrCF2H Me2N THF/dioxane, rt, 90 min NMe2 L1 41–91%

CF2H CF2H MeO CF2H CF2H

Ph F3C TMS OMe (b) 85% 91% 63% 65%

CF H MgBr Fe(acac)3 (2.5 mol%) 2 R + ICF2H R THF, –20 °C, 30 min 16–94%

CF2H CF2H CF2H CF2H EtO Ph PhO O N (c) 84% 85% 55% 53%

Scheme 1.20 Iron‐catalyzed difluoromethylation of aryl zinc reagents or aryl magnesium reagents.

applications in organic synthesis. In 2012, Baran and coworkers developed a new difluoromethylating reagent Zn(SO2CF2H)2 (DMFS) that allowed difluoromethylation of a range of N‐containing heteroarenes in the presence of t‐BuOOH via a radical pathway (Scheme 1.21) [45]. Regiochemical comparisons showed that the difluoromethylation preferred to occur at relatively more electron‐deficient carbon, suggesting a nucleophilic character of the difluoromethyl radical generated from DMFS. The use of inexpensive and readily available difluoromethylating reagents via the C─H bond difluoromethylation would be more attractive in terms of cost efficiency. In 2017, Maruoka and coworkers developed a hypervalent iodine reagent with readily available difluoroacetic acid as the ligand (Scheme 1.22) [46]. Upon irradiation of this difluoromethylating reagent with UV, a series of N‐heteroarenes can be difluoromethylated at relatively more electron‐deficient carbons via a difluoromethyl radical process. The regioselectivity of this reaction

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Zn(SO2CF2H)2 (2.0–4.0 equiv) t-BuOOH (4.0–6.0 equiv) TFA (1.0 equiv) Het H Het CF2H CH2CI2:H2O (2.5 : 1), 23 °C 30–90%

O OEt O O O 4 4 H OMe Me N MeO MeO N CF2H CF2H CF2H 2 6 6 N 2 N O N N CF2H 45% 79% Me 66% C2 : C4 : C6 C2 : C4 : C6 90% 1.5 : 1.5 : 2 1 : 1 : 2

CF3 H H 5 Zn(SO2CF2H)2 5 N 5 N N NaSO2CF3 t-BuOOH HN HN HN (50%) CH2CI2/H2O 2 N 2 H N 2 H N CF H C5 : C2 4 : 1 (50%) 2

Scheme 1.21 Radical difluoromethylation of heteroarenes with Zn(SO2CF2H)2.

ArI(OCOCF2H)2 (2.0 equiv) hv (400 nm) Het H Het CF2H CDCl3, rt, 14 h 20–77%

O Me O OEt O Me Me N Me CF H N N N 2 N CF2H O N O N Cl HF2C N CF H CO Me Me 2 Me 2 48% 47% 55% 22%

Scheme 1.22 Radical difluoromethylation of heteroarenes with ArI(OCOCF2H)2.

is same as that of Baran’s method [45], implying the same nucleophilic character of difluoromethyl radical generated from these two new reagents. However, only low to moderate yields were obtained. The direct use of difluoroacetic acid as the difluoromethylating reagent has also been reported almost contemporaneously. Nielsen and coworkers employed AgNO3/K2S2O8 as the oxidants to generate difluoromethyl radical from difluoroacetic acid (Scheme 1.23) [47]. This process allowed difluoromethylation at electron poor carbons adjacent to the nitrogen atom in N‐heteroarenes. Similarly, low to moderate yields were obtained. Further investigation showed that a bis‐ difluoromethylation could also be occurred by increasing the reaction temperature. In parallel to Nielsen’s work, Qing and coworkers described a direct difluoromethylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H (Scheme 1.24) [48]. The reaction used PhI(OCOCF3)2 or N‐Chlorosuccinimide (NCS) as the oxidant, and silver salt as the additive, providing the corresponding difluoromethylated heteroarenes in low to moderate yields. A pathway was pro-

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CF2HCOOH (2 equiv) AgNO3 (0.5 equiv), K2S2O8 (5 equiv) Het Het CH3CN/H2O: 2/1, 50 °C, 5–24 h N H N CF2H

OPh CN CF2H N Cl N

N CF2H N CF2H N CF2H 62% 61% 32% 36%

Proposed mechanism 2– 2– S2O8 SO4

Ag2+ Ag+

CF2HCOOH CF2HCOO

+ H –CO2

+ + [H ] CF2H (1) –H H (2) –H N H N H N N CF2H CF2H H H

Scheme 1.23 Radical difluoromethylation of heteroarenes with HCF2COOH.

TMSCF2H (3.0 equiv) t-BuOK (3.0 equiv), silver salt (1.0 equiv) R Oxidant (3.0 equiv), rt R

N Silver salt: AgOAc or AgCl N H Oxidant: PhI(TFA)2 or NCS CF2H

Cl Cl MeO

N N N N N N CF2H CF2H CF2H CF2H 63% 58% 67%32%

Scheme 1.24 Oxidative difluoromethylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H.

posed for the reaction to involve a nucleophilic addition of difluoromethyl anion to the heteroarenes, followed by aromatization process, but a difluoromethyl radical pathway cannot be ruled out.

1.3 Difluoroalkylation of Aromatics

In addition to difluoromethylated aromatics, other difluoroalkylated aromatics also have important applications in medicinal chemistry and materials science due to the unique properties of difluoromethylene group (CF2). The incorporation of CF2 at the benzylic position not only can improve the metabolic stability

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of biologically active molecules but also can enhance the acidity of its neighbor- ing groups [49]. However, except for the conventional difluorination of ketoaromatics with DAST, general and efficient methods for highly selective introduction of CF2R into organic molecules to access these valuable compounds had been less explored before 2012 [4]. The transition‐metal‐catalyzed cross‐ coupling difluoroalkylation would be an attractive strategy, as it can directly con- struct (Het)Ar─CF2R bonds in an efficient and controllable manner. In particular, this strategy can enable late‐stage difluoroalkylation of biologically active molecules without the need of multistep synthesis. Nevertheless, the difficulty in selectively controlling the catalytic cycle to access the desired difluoroalkylated aromatics posed problems with such strategy. Difluoroalkylated metal species have a different instability compared with their non‐fluorinated counterparts due to decomposition or protonation to generate by‐products [50]; this has increased attention on the subject and impressive achievements have been made over the past a few years [4]. Here, we specifically focus on the transition‐metal‐ catalyzed difluoroalkylation of aromatics, including phosphonyldifluoromethylation and difluoroacetylation. The direct difluoroalkylation of C─H bond via a radical process will not be discussed in this session, as comprehensive reviews have been described previously [4].

1.3.1 Transition‐Metal‐Catalyzed Phosphonyldifluoromethylation of (Hetero)aromatics

Phosphonyldifluoromethyl groups (CF2PO(OR)2) have important applications in medicinal chemistry and chemical biology because CF2 is a bioisopolar and bioisostere of oxygen and replacing the oxygen atom of phosphoryl ester with CF2 results in a phosphate mimic that can protect against hydrolysis. For instance, an aromatic ring bearing this functional group can act as a protein tyrosine phosphatase (PTPase) inhibitor with significant bioactivity [51]. However, only a few methods to access aryldifluoromethylphosphonates have been developed before 2012 [52]. In 1996, Burton and coworker reported the first example of copper‐mediated phosphonyldifluoromethylation of aryl iodides with bromocadmiumdifluoromethylphosphate (BrCdCF2PO(OEt)2) (Scheme 1.25a) [52a]. The reaction was carried out under mild conditions and exhibited good functional group compatibility. However, the use of excessive toxic

CuI (1.16 equiv) I CF P(O)(OEt) BrCdCF2P(O)(OEt)2 (1.66 equiv) 2 2 R R DMF, rt, 3 h (a) 65–88%

CuBr (2.0 equiv) I CF P(O)(OEt) BrZnCF2P(O)(OEt)2 (2.0 equiv) 2 2 R R DMF, rt, 7–150 h (b) 17–99%

Scheme 1.25 Copper‐mediated phosphonyldifluoromethylation of aryl iodides with difluoromethylphosphonyl cadmium or zinc reagents.

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cadmium reagents restricts its widespread synthetic applications. In this context, Shibuya and coworkers replaced BrCdCF2PO(OEt)2 with a zinc analogue (BrZnCF2PO(OEt)2) reagent and furnished the corresponding Ar–CF2PO(OEt)2 smoothly (Scheme 1.25b) [52b]. This reaction required 2.0 equiv of copper salt due to the instability of the difluoromethylphosphonate copper–zinc complex. To overcome this limitation, in 2012 Zhang and coworkers reported the first example of copper‐catalyzed cross‐coupling of iodobenzoates with BrZnCF2PO(OEt)2 (Scheme 1.26) [53]. To stabilize the difluoromethylphosphonate copper–zinc complex, 1,10‐phenanthroline (Phen) was used as the ligand and an ester group was employed as a chelating group ortho to the iodide to facilitate the oxidative addition of copper to the Ar─I bond. The reaction showed high reaction efficiency and excellent functional group tolerance. A Cu(I/III) catalytic cycle was proposed for this reaction, which was further supported by computational studies by Jover [54], in which the Zn(II) salt can act as a linker to connect both the chelating group and the copper catalyst. When replacing the ester on aromatic ring with a removable and versatile triazene group, the aryl bromides were also suitable substrates for this reaction. The resulting triazene‐containing products could serve as a good platform for diversity‐oriented synthesis, providing a wide range of Ar–CF2PO(OEt)2 that are otherwise difficult to prepare (Scheme 1.27) [55].

CO2Me CuI (0.1 equiv) CO2Me I Phen (0.2 equiv) CF2P(O)(OEt)2 + BrCF P(O)(OEt) R 2 2 Zn (2.0 equiv) R Dioxane, 60 °C 24-48 h 53–95%

CO2Me CO2Me CO2Me CO2Me CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2

MeO Me OMe NO2 95% 80% 54% 60%

Proposed mechanism

BrCF2P(O)(OEt)2 DG CF P(O)(OEt) Zn 2 2 R Cu(I) BrZnCF2P(O)(OEt)2

DG . X2Zn CuCF2P(O)(OEt)2 R CuCF2P(O)(OEt)2 I DG DG I R MCF2P(O)(OEt)2 R I

Scheme 1.26 Copper‐catalyzed cross‐coupling of bromozinc‐difluorophosphonate with 2‐iodobenzoates.

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CuCN (10 mol%) Me Me N N N N N Ligand (20 mol%) N R + BrCF2P(O)(OEt)2 R Me Me Zn (3.0 equiv) I/Br CF2P(O)(OEt)2 N N Dioxane, 60 °C 40–91% Ligand

CF3 Pd(OAc)2 (5 mol%) Pd(OAc)2 (5 mol%) . N N . BF3 Et2O N BF3 Et2O

4-CF3-C6H4B(OH)2 3-Me-C6H4B(OH)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 85% 97% (1) MeI, 100 °C Pd(OAc)2 (10 mol%) (2) PdCl2(PPh3)2 (10 mol%) . Styrene, BF3. Et2O CuI (0.1 equiv), Et3N BF3 Et2O TMS

TMS H Ph

CF P(O)(OEt) CF2P(O)(OEt)2 CF2P(O)(OEt)2 2 2 82% 2 steps 83% 93%

Scheme 1.27 Copper‐catalyzed cross‐coupling of bromozinc‐difluorophosphonate with iodo/bromo‐aryl triazenes and further transformations. 14-03-2020 20:52:50 26 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Chelating group free transition‐metal‐catalyzed phosphonyldifluoromethylation of (hetero)aromatics would be a more attractive strategy. In 2014, Zhang and coworkers developed a palladium‐catalyzed cross‐coupling of BrCF2PO(OEt)2 with arylboronic acids (Scheme 1.28) [56], representing the first example of catalytic difluoroalkylation of organoborons. The use of bidentate ligand Xantphos was essential in the promotion of the reaction probably due to the wide bite angle of Xantphos. This method paved a new way for the selective difluoroalkylation of aromatics. The reaction allowed the preparation of a variety of Ar–CF2PO(OEt)2, including a PTPase inhibitor. Preliminary mechanistic studies showed that a difluoroalkyl radical generated via an SET pathway was involved in the reaction. Recently, Poisson and coworkers also reported a palladium‐catalyzed phosphonyldifluoromethylation to prepare Ar–CF2PO(OEt)2 (Scheme 1.29) [57]. The reaction employed aryl iodides as the coupling partner, and stoichiometric amount of phosphonyldifluoromethyl copper (CuCF2PO(OEt)2) was needed. As an alternative, Qing and coworkers reported a copper‐mediated oxidative cross‐coupling between arylboronic acids and TMSCF2PO(OEt)2 (Scheme 1.30) [58]. Stoichiometric copper complex CuTc and excess of Ag2CO3 were needed. This strategy can also be extended to oxidative cross‐coupling of PhSO2CF2Cu with arylboronic acids [59]. Later on, Poisson and coworkers employed (hetero) aryl iodonium and aryl diazonium salts as the coupling partners, enabling the phosphonyldifluoromethylation (Scheme 1.31) [60]. Vinyl and alkynyl iodonium salts were also suitable substrates, thus demonstrating the generality of this method. In 2018, Amii and coworkers replaced (hetero)aryl iodonium salts with (hetero)aryl iodides and developed a copper‐mediated cross‐coupling between (hetero)aryl iodides and TMSCF2PO(OEt)2 (Scheme 1.32) [61]. They investigated the catalytic phosphonyldifluoromethylation, but only three electron‐deficient (hetero)aryl iodides with 42–69% yields were obtained by using 0.1–0.2 equiv CuI.

1.3.2 Transition‐Metal‐Catalyzed Difluoroacetylation of (Hetero) aromatics and Beyond

The versatile synthetic utility of ester moiety led to the increased attention on the difluoroacetylation of aromatics. In 1986, Kobayashi and coworkers reported the first example of copper‐mediated difluoroacetylation of aryl halides with difluoroacetate iodide (Scheme 1.33a) [62]. The reaction underwent difluoroacetylation under mild conditions with good functional group compatibility. Several copper‐mediated difluoroacetylations of various aryl halides and aryl boronic acids have been reported [63]. However, excess of copper was needed. Later on, Amii and coworkers reported a copper‐catalyzed cross‐coupling of aryl iodides with TMSCF2CO2Et (Scheme 1.33b) [64]. The reaction facilitated the synthesis of difluoroacetylated arenes in 40–71% yields but was limited to electron‐deficient substrates. The resulting difluoroacetylated arenes were further used to prepare difluoromethylated arenes by sequential hydrolysis and decarboxylation. To overcome the substrate scope limitation of Amii’s method, Hartwig and coworker employed α‐silyldifluoroamides as the coupling partners and 18‐crown‐6 as the additive, enabling the efficient synthesis of aryl difluoroacetamides (Scheme 1.34) [65]. Both electron‐rich and electron‐deficient aryl iodides were

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Pd(PPh3)4 (5 mol%) CF P(O)(OEt) B(OH)2 Xantphos (10 mol%) 2 2 R R + BrCF2P(O)(OEt)2 O K2CO3 (2.0 equiv) PPh PPh Dioxane, 80 °C 44–86% 2 2 Xantphos

CF P(O)(OEt) CF2P(O)(OEt)2 2 2 CF2P(O)(OEt)2 CO2Me NHBoc O EtO2C (EtO)2(O)PF2C O 41% 86% 70% 80% (with 3 Å MS) PTPase inhibitor

Proposed mechanism

Ar –CF R 0 BrCF2R 2 Pd Ln

1 2 R = PO(OEt)2, CO2Et, CONR R

II I ArPd LnCF2R BrPd Ln + CF2R

Base

II ArB(OH)2 BrPd LnCF2R

Scheme 1.28 Palladium‐catalyzed phosphonyldifluoromethylation of arylboronic acids with bromodifluorophosphonate. 14-03-2020 20:52:50 28 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

PdCl2(PPh3)2 (5 mol%) I CF P(O)(OEt) CuCF2P(O)(OEt)2 (1.0 equiv) 2 2 R Het R Het CH3CN, 40 °C, 16 h 38–80%

CF2P(O)(OEt)2 CF2P(O)(OEt)2 N CF2P(O)(OEt)2 N CF2P(O)(OEt)2

MeO MeO2C Br N 64% 58% 69%46%

Scheme 1.29 Palladium‐catalyzed phosphonyldifluoromethylation of aryl iodides with difluorophosphonyl copper reagents.

CuTc (1.0 equiv) B(OH)2 Phen (1.0 equiv) CF2P(O)(OEt)2 R TMSCF2P(O)(OEt)2 R Ag2CO3 (1.5 equiv), pyridine 4 Å MS, DMF, 45 °C 31–81%

CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 MeO2C MeO S 72% 54% 40%31%

Scheme 1.30 Copper‐mediated oxidative phosphonyldifluoromethylation of arylboronic acids with TMSCF2PO(OEt)2.

CuSCN (1.0 equiv) X CsF (3.0 equiv) CF2PO(OEt)2 R + TMSCF2P(O)(OEt)2 R (2.5 equiv) MeCN/DMF, 0 °C to rt

X = I(Ar)OTf/BF4 Yield up to 76% + – N2 BF4

CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2 CF2P(O)(OEt)2

OMe MeO2C 71% 60% 51% Br 45%

Scheme 1.31 Copper‐mediated phosphonyldifluoromethylation of aryl hypervalent iodides or aryl diazoniums with TMSCF2PO(OEt)2.

CuI (0.2 equiv) I CsF (1.2 equiv) CF2P(O)(OEt)2 R + TMSCF2P(O)(OEt)2 R THF, 60 °C, 24 h (1.2 equiv)

CF2P(O)(OEt)2 N CF2P(O)(OEt)2 N CF2P(O)(OEt)2

NC 50% 42% 69%

Scheme 1.32 Copper‐catalyzed phosphonyldifluoromethylation of (hetero)aryl iodides with TMSCF2PO(OEt)2.

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Cu powder X (4.0 equiv) CF2CO2Me + R ICF2CO2Me R (3.0 equiv) DMSO, rt to 60 °C X = Br, I 21–88% (a) CuI (20 mol%) I CF COOEt KF (1.2 equiv) 2 R + TESCF COOEt R 2 DMSO, 60 °C (b) 40–71% (19F NMR)

CF2COOEt CF2COOEt Cl CF2COOEt N CF2COOEt

NC EtO2C Cl 71% 40% 42%67%

Preparation of difluoromethylated arenes via a decarboxylation process KF (or CsF) CF COOEt CF2COOH CF H 2 K2CO3 DMF or NMP 2 R R R MeOH/H2O 170–200 °C rt, 1–2 h 2–48 h

CF2COOEt CF2COOEt CF2COOEt N CF2COOEt

NC EtO2C Br 84% 74%59% 89%

Scheme 1.33 Copper‐mediated/catalyzed difluoroacetylation of aryl iodides/bromides and applications in the synthesis of difluoromethylated arenes.

CuOAc (20 mol%) R1 KF (1.2 equiv) 1 I F F F F R 18-crown-6 (1.2 equiv) + N 2 N R TMS R R2 Toluene, 100 °C R O O 71–97%

Bn F F O F F O F F O F F N N N N Bn O O O N O MeO t-BuO2C 85% 92% 73% 75%

Scheme 1.34 Copper‐catalyzed cross‐coupling of aryl iodides with α‐silyldifluoroamides.

applicable to the reaction, providing an alternative access to difluoroacetylated arenes. The copper‐catalyzed C─H bond difluoroacetylation of furans and benzofurans with difluoroacetate bromide has also been reported by Poisson and coworkers (Scheme 1.35) [66]. A Cu(I/III) catalytic cycle was proposed based on no inhibition of the reaction by addition of radical inhibitor (tert‐butylhy- droxytoluene) or scavenger tetramethylpiperidinooxy (TEMPO) to the reaction.

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R1 R1 CuI (10 mol%), phen (12 mol%) CF CO Et R H + BrCF2CO2Et R 2 2 O K2CO3 ( 2 equiv), DMF, 80 °C O 36–65% Ph CF CO Et CF CO Et 2 2 2 2 CF2CO2Et CF CO Et O AcO O 2 2 O O 52% (60 °C) 63% (60 °C) 50% 67%

Proposed mechanism

CF CO Et 2 2 I BrCF CO Et O Cu X 2 2

CF2CO2Me CuIII Br III Cu CF2CO2Me O X X

Base • HX

H O CF2CO2Me Base + CuIII X O

Scheme 1.35 Copper‐catalyzed difluoroacetylation of furans and benzofurans with bromodifluoroacetates and the possible mechanism. 14-03-2020 20:52:52 1.3 Difluoroalkylation of Aromatics 31

The first example of palladium‐catalyzed difluoroacetylation of aromatics was reported by Zhang and coworkers in 2014 (Scheme 1.36) [56]. The combination of Pd(PPh3)4/Xantphos with CuI provided an efficient catalytic system to prepare difluoroacetylated arenes from arylboronic acids and difluoroacetate bromide. The reaction allowed difluoroacetylation of a variety of arylboronic acids with excellent functional group tolerance. Mechanistic studies revealed that a dif- luoroacetyl radical via an SET pathway was involved in the reaction. This strategy can also be extended to (hetero)aryl bromides. Later on, Hartwig and coworkers developed a palladium cross‐coupling of α‐trimethylsilyldifluoroacetamides with (hetero)aryl halides (Scheme 1.37a) [67]. Contrary to Zhang’s method, a palladacyclic complex containing PCy(t‐Bu)2 was used as the pre‐catalyst in this reaction. The mechanistic studies of the reductive elimination from arylpalla- dium difluoroacetate complexes showed that Xantphos with a wide bite angle facilitates the reductive elimination [68]. Recently, Liao, Hartwig, and coworkers also developed a palladium‐catalyzed cross‐coupling of aryl electrophiles with difluoroacetylzinc generated in situ from the reaction of BrCF2CO2Et with zinc (Scheme 1.37b) [69], providing an alternative route for applications in the synthesis of aryl difluoroacetates.

Pd(PPh ) (5 mol%) 3 4 2 B(OH)2 Xantphos (10 mol%) CF2COR 1 2 1 R + BrCF2COR R CuI (5 mol%) K2CO3 (4.0 equiv) Dioxane, 80 °C 53–95%

O CO2Me MeO CF2CO2Et CF CO Et F F 2 2 H H HN OHC H O OMe t-Bu EtO2CF2C 77% 74% 71% 91% Estrone derivative

Scheme 1.36 Palladium‐catalyzed cross‐coupling of arylboronic acids with bromodifluoroacetate and bromodifluoroacetamides.

In addition to palladium‐catalyzed difluoroacetylation of prefunctionalized (hetero)arenes, Buchwald and coworker described a palladium‐catalyzed intramolecular C─H bond difluoroalkylation from chlorodifluoroacetamides with BrettPhos as the ligand (Scheme 1.38) [70]. An intermolecular ruthenium‐catalyzed C–H difluoroacetylation of aromatics was reported by Ackermann and coworkers in 2017 (Scheme 1.39a) [71], in which a cooperative phosphine and carboxylate ligand system was used to promote the C–H difluoroacetylation. The reaction showed high meta‐selectivity with pyridine as the directing group. Mechanistic studies showed that an ortho C–H metalation was the initial step. Subsequently, the resulting ruthenium(II) complex reacted with the difluoroa- cetyl radical generated via an SET pathway from Ru(II) species to provide meta‐ difluoroacetylated arenes. Simultaneously to Ackermann’s work, Wang and

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[Pd] (1–3 mol%) Br CF CONEt KF (3.0 equiv) 2 2 R + TMSCF CONEt R 2 2 Toluene/dioxane (1:1) H N Pd Cl 100 °C, 30 h 2 62–95% [Pd] PCy(tBu)2

F F F F F F F F NEt2 O NEt2 N NEt2 NEt2

O O O O O F3C N 82% 81% 62% 67% (a)

[Pd(π-cinnamyl)Cl]2 (5 mol%) Xantphos (15 mol%) X Zn (1.5 equiv), TBAT (0.380–0.75 equiv) CF2CO2Et R + BrCF CO Et R 2 2 THF, 60 °C, 24 h

X = Br, OTf 42–96% (b)

Scheme 1.37 Palladium‐catalyzed difluoroacetylation of aryl bromides/triflates. 14-03-2020 20:52:52 1.3 Difluoroalkylation of Aromatics 33

OMe F Pd2dba3 (2 mol%) F O MeO PCy2 R1 BrettPhos (8 mol%) R1 O i-Pr i-Pr N CF2Cl K2CO3 (1.5 equiv) N 2 CPME, 120 °C, 20 h R R2 52–95% i-Pr BrettPhos

OMe O F F F F F F MeO MeO N O O O N n-Pr t-Bu N N Bn O N MeO N F Me F O MeO Me2N 76% 66% 68% 70% Regioisomeric ratio: 5.6:1

Scheme 1.38 Palladium‐catalyzed intramolecular C─H bond difluoroalkylation with the aid of chlorodifluoroacetamides.

coworkers developed a ruthenium and palladium co‐catalyzed meta‐selective difluoroacetylation (Scheme 1.39b) [72]. Similarly, the ortho C–H metalation by ruthenium(II) was the initial step, but Pd(PPh3)4 was used as the radical initiator for the SET process (Scheme 1.40). Recently, a para‐selective difluoroacetylation of arenes has been reported by Zhao and coworkers with aniline derivatives as the coupling partners, in which a radical process was also involved in the reaction (Scheme 1.41) [73]. Although impressive achievements have been made in copper‐ and palladium‐ catalyzed trifluoromethylation and difluoroalkylation of aromatics, the use of earth‐abundant nickel as a catalyst has been less explored due to the thermal stability of arylnickel(II) fluoroalkyl complexes [74]. In 2014, Zhang and coworkers reported the first example of a nickel‐catalyzed difluoroacetylation of arylboronic acids with Cl/BrCF2CO2Et (Scheme 1.42) [34a]. The reaction exhibited broad substrate scope including drug derivatives and excellent functional tolerance, with inexpensive Ni(NO3)2⋅6H2O as the catalyst and readily available bipyridine (bpy) as the ligand. Notably, a wide range of difluoroalkyl bromides 1 2 1 (BrCF2R, R = CO2Et, CONR R , COAr, COR , HetAr) were applicable to the reaction. A Ni(I/III) catalytic cycle was proposed for the reaction, in which a nickel(III) facilitates the reductive elimination of the arylnickel(III) fluoroalkyl complex. Recently, Sanford and coworkers confirmed that arylnickel(III) trifluo- romethyl complexes [(Ar)(CF3)Ni(III)LnX] are favorable for reductive elimination [75]. Compared to the palladium‐ and copper‐catalyzed difluoroalkylation, the advantage of nickel‐catalyzed process is more general in terms of the substrate scope of difluoroalkyl halides and functional group tolerance. This strategy has also been applied to the nickel‐catalyzed cross‐coupling of bromodifluoroacetamides with arylzinc reagents by using bisoxazoline as the ligand (Scheme 1.43) [76]. In addition to the nickel‐catalyzed difluoroacetylation, the cobalt‐catalyzed cross‐coupling of arylzinc reagents with bromodifluoroacetate has also been reported by Inoue and coworker(Scheme 1.44) [77].

c01.indd 33 14-03-2020 20:52:52 c01.indd 34

DG DG [Ru] (10 mol%) Me i-Pr P(4-C6H4CF3)3 (20 mol%) + BrCF2CO2Et Ru Na CO (2.0 equiv) O H 2 3 CF COEt MesCO 1,4-Dioxane 2 2 O Mes 60 °C, 18 h 31–89% [Ru]

CF2CO2Et N N N

CF2CO2Et CF2CO2Et N CF2CO2Et N N OMe CO2Me F N N 50% 82% 75% n-Bu (a) 78%

[RuCl (p-cymene)] (5 mol%) DG 2 2 DG Pd(PPh3)4 (10 mol%) Na2CO3 (2.0 equiv) + BrCF2CO2Et Ba(OAc) (0.15 equiv) H 2 CF COEt 1,4-Dioxane 2 90 °C, 24 h 53–84%

N N N CF CO Et CF CO Et CF2CO2Et N CF2CO2Et 2 2 N 2 2 N OMe Br 76% 55% 79% 53% (b)

Scheme 1.39 Directing‐group promoted ruthenium‐catalyzed meta‐difluoroacetylation of arenes. 14-03-2020 20:52:52 1.3 Difluoroalkylation of Aromatics 35

[RuCl (p-cymene)] 2 2 H N R2 N R2 Ba(OAc)2 R1 R1 BaCl2 CF2CO2Et H Na2CO3 Na2CO3, Ba(OAc)2, L RuCl(OAc)(p-cymene)

NaHCO3, NaOAc NaOAc, BaCl2, NaHCO3

Me i-Pr Me i-Pr

Ru L Ru Cl N R2 N R2

R1 R1

CF2CO2Et H Pd(0) NaHCO3, NaBr L SET Ligand exchange

Pd(I)Br, Na2CO3 Cl–

Me i-Pr Me i-Pr

Ru L Ru L N R2 N R2

1 1 R H R CF2CO2Et H

F F F F SET OEt OEt Br O Pd(I) Pd(0) O

Scheme 1.40 Possible mechanism of ruthenium/palladium co‐catalyzed meta‐ difluoroacetylation of arenes with direction groups.

O O Pd(PPh3)4 (5 mol%) KOAc (4 equiv), AgF (30 mol%) + BrCF2CO2Et PPh3 (30 mol%), Ar H (X) n-Hexane or 1,4-dioxane CF2CO2Et (X) 140 °C, 20 h 36–84%

O O OMe O CO2Me

Me OH S EtO CF C EtO CF C 2 2 2 2 EtO2CF2C 74% 63% 52%

Scheme 1.41 Palladium‐catalyzed para‐selective C─H bond difluoroacetylation of aryl ketones.

c01.indd 35 14-03-2020 20:52:53 36 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Ni(NO3)2 • 6H2O (2.5–5.0 mol%) B(OH)2 bpy (2.5–5.0 mol%) CF2R 1 + R1 R XCF2R K2CO3 (2.0 equiv) X = Br, Cl 1,4-Dioxane, 60–80 °C

CF2CO2Et CF2CO2Et CF2CO2Et CF2CO2Et

MeO EtO2C Br X = Br, 87% X = Br, 81% X = Br, 96% X = Br, 95% X = Cl, 76%a X = Cl, 62%a X = Cl, 40%a O

F F H F F H H N N H O O O F F X = Br, 88% X = Br, 93% X = Br, 56%

a 5 mol% PPh3 was added.

Proposed mechanism ArB(OH) ArCF2R XNi(I)Ln 2

Ar Ar Ni(I)Ln LnNi(III) CF2R X

BrCF2R CF2R + Ar–Ni(II)(Ln)Br

Scheme 1.42 Nickel‐catalyzed cross‐coupling of arylboronic acids with functionalized difluoroalkyl bromides and chlorides.

NiCl DME ( 5 mol%) F F 2 O O ZnCl Ligand (6 mol%) NR2 R + BrCF2CONR2 R N N TMEDA (1.6 equiv) O THF, 0 °C Ph Ph 20–96% Ligand

O F F O F F O F F O F F N N N N

O O O H O MeO F 91% 91% 96% O 72%

Scheme 1.43 Nickel‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetamides.

c01.indd 36 14-03-2020 20:52:53 1.3 Difluoroalkylation of Aromatics 37

CoCl2 (5 mol%) ZnCl NMe Ligand (5 mol%) CF2CO2Et 2 R ·TMEDA + BrCF CO Et R 2 2 THF, rt NMe2 48–79% Ligand

CF CO Et CF2CO2Et CF2CO2Et CF CO Et 2 2 O 2 2

F MeO 53% 74% 70% 79%

Scheme 1.44 Cobalt‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetates.

Pd(OAc)2 (5 mol%) t-Bu P (10 mol%) Br F OTMS 3 CF COPh SnBu F (3.0 equiv) 2 R + 3 R F Ph Toluene, 85 °C, 8 h 70–91%

CF2COPh CF2COPh CF2COPh CF2COPh

MeO NC O2N 91% 84% 90% 76%

Scheme 1.45 Palladium‐catalyzed cross‐coupling of aryl bromides with difluoroenol silyl.

1.3.3 Other Catalytic Difluoroalkylations of (Hetero)aromatics

In 2007, Shreeve and coworker reported the first example of a palladium‐catalyzed cross‐coupling between aryl bromides and difluoroenol silyl ether with a bulky electron‐rich monophosphine P(tBu)3 as the ligand (Scheme 1.45) [78]. However, toxic tin reagent was needed to promote the reaction and the substrate scope was relatively limited. In this context, Qing and coworkers developed a palladium‐catalyzed cross‐coupling of difluoromethyl phenyl ketone with aryl bromides in the presence of a base (Scheme 1.46a) [79]. This method is synthetically convenient: no need to prepare difluoroenol silyl ether and use toxic tin reagent. Hartwig and coworkers found that the use of a cyclopalladium species as the catalyst could enable the difluoroalkylation with high efficiency and broad scope, even aryl chlorides were suitable substrates (Scheme 1.46b) [80]. Notably, the method can also be used for the preparation of difluoromethylated arenes by debenzoylation of the resulting products ArCF2COPh (Scheme 1.46). In addition to the preparation of ArCF2COAr, the catalytic gem‐difluoroallylation of aromatics has also been reported. In 2014, Zhang and coworkers developed a palladium‐catalyzed highly α‐selective gem‐difluoroallylation of arylboronic acids and esters with bromodifluoromethylated alkenes

c01.indd 37 14-03-2020 20:52:54 38 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Pd(OAc)2 (10 mol%) rac-BINAP (20 mol%) Br O CF2COAr Cs2CO3 (2.0 equiv) R + R HF2C Ar Xylene, 130 °C, 8–12 h (2.0 equiv) 52–90%

OMe F F F F F F F F

O O O O MeO F3C 88% 53% 68% 63% (a)

[Pd] (0.5–2 mol%) Cs CO (2.0 equiv) O 2 3 X CF2COAr or K3PO4(H2O) (4 equiv) R + R HF2C Ar Toluene, 100 °C, 24 h HN.Pd P(tBu)Cy2 Cl (2.0 equiv) (1.0 equiv) 65–93% [Pd]

F F F F F F F F

O O EtO O O MeO N X = Br, 93% X = Br, 84% O X = Br, 86% X = Br, 80% X = Cl, 88% X = Cl, 81% X = Cl, 77% X = Cl, 80%

One-pot synthesis of difluoromethylated arenes (1) [Pd] (1 mol%)

K3PO4(H2O) (4 equiv) X O Toluene, 100 °C, 30 h CF2H R + R HF2C Ph (2) KOH/H2O, 100 °C, 2 h (1.0 equiv) (2.0 equiv) 63–99%

O CF2H CF2H CF2H CF2H

O TMS EtO2C N X = Br, 92% X = Br, 95% X = Br, 83% X = Br, 77% X = Cl, 82% X = Cl, 94% X = Cl, 79% (b)

Scheme 1.46 Palladium‐catalyzed cross‐coupling of aryl bromides/chlorides with α,α‐ difluoroketones and one‐pot synthesis of difluoromethylated arenes.

(Scheme 1.47) [81]. Contrary to previous works using BrCF2PO(OEt)2 and BrCF2CO2Et as the coupling partners, this reaction was presumed to occur via a formal electrophilic difluoroalkylation pathway, probably because of stabilization of palladium intermediate by coordination with alkene, thus facili- tating the oxidative addition step via a two‐electron transfer process. The high α‐regioselectivity of this reaction (α/γ > 37 : 1) may be ascribed to the strong electron withdrawing effect of the CF2 group, which strengthens the Pd─CF2R bond. Remarkably, even when the Pd catalyst loading was decreased to 0.02 mol%, high α‐regioselectivity and good yield of gem‐difluoroallylated arene was still obtained on the 10 g scale reaction, thus demonstrating the good practicality of this protocol. This reaction can also be extended to gem‐difluoropropargylation

c01.indd 38 14-03-2020 20:52:54 1.4 Outlook 39

F F B(OH) 1 Pd2(dba)3 (0.01–0.4 mol%) 2 R 2 K2CO3 (3.0 equiv) R R + R2 R BrF C R1 2 H2O (0.48 equiv) Dioxane, 80 °C 60–93%

F F F F Me F F F F F F EtO2C

HO Ph t-Bu BnO Me Me

80% (10:1) 87% (28:1) 78% (17:1) 68% (19:1) 53% (15:1) 10-gram scale

Scheme 1.47 Palladium‐catalyzed gem‐difluoroallylation of organoborons with bromodifluoromethylated alkenes.

of arylboronic acids and esters with high efficiency and regioselectivity (Scheme 1.48) [82]. Since carbon–carbon double bond and triple bond are synthetically versatile functional groups, these resulting difluoroalkylated arenes could serve as useful building blocks for diversity‐oriented synthesis, thus offer- ing good opportunities for applications in the organic synthesis and related chemistry. Although impressive progress has been made in the catalytic difluoroalkylation of aromatics, a π‐system adjacent to CF2 is required to activate the difluoro- alkylating reagents [4a, 83]. In 2013, Baran and coworkers developed a type of sodium α,α‐difluoroalkylsulfinate (NaSO2CF2alkyl) reagents for direct difluoroalkylation of heteroarenes (Scheme 1.49) [84]. Similar to the difluoromethylating reagent DMFS, the reaction required tBuOOH to furnish the difluoroalkylated heteroarenes via a radical process. Zinc chloride was found to be critical for the reaction. The advantage of this protocol is the synthetic simplicity. However, the modest regioselectivity of this approach restricts its widespread synthetic applications. In 2016, Zhang and coworkers reported a nickel‐catalyzed difluoroalkylation of (hetero)arylboronic acids with unactivated difluoroalkyl bromides (BrCF2–alkyl) (Scheme 1.50a) [34b]. A combined (2 + 1) ligand system was used to facilitate the formal oxidative addition of nickel to the BrCF2–alkyl. The reaction showed broad substrate scope with high efficiency. A nickel‐catalyzed reductive cross‐ coupling between (hetero)aryl bromides and BrCF2–alkyl [85] and an iron‐catalyzed cross‐coupling of arylmagnesiums with BrCF2–alkyl have been reported by the same group (Scheme 1.50b,c) [43]. In 2018, Baran and coworkers also reported nickel‐catalyzed difluoroalkylation of arylzincs with difluoroalkyl sulfones, providing an alternative access to difluoroalkylated arenes (Scheme 1.51) [86].

1.4 Outlook

We have comprehensively summarized the transition‐metal‐mediated/catalyzed difluoromethylation and difluoroalkylation of (hetero)aromatics. Several new types of difluoroalkylation reactions were developed and provided synthetically

c01.indd 39 14-03-2020 20:52:54 c01.indd 40

F F F F Condition A or B Ar[B] + Br Ar R R

Condition A: Pd2(dba)3 (0.1–2.5 mol%), P(o-Tol)3 (0.6–15 mol%), K2CO3 or Cs2CO3 (3.0 equiv), dioxane or toluene, 80 °C, 24 h [B] = B(OH)2 [B] = Bpin F F F F F F F F

TIPS Br TIPS TIPS 5 EtO2C O O 80%, gram scale 48% 57% 60%

Condition B: NiCl2·dppe (2.5 mol%), bpy (2.5 mol%), K2CO3 (2.0 equiv), dioxane, 80 °C, 24 h

[B] = B(OH)2

F F F F F F F F

TIPS TIPS TIPS TIPS EtO2C Br NC 92% 77% 39% O 82%

Scheme 1.48 Palladium‐ or nickel‐catalyzed gem‐difluoropropargylation of arylboronic reagents. 14-03-2020 20:52:54 1.4 Outlook 41

DAAS-Na (3.0 equiv) O ZnCl (1.5 equiv) 2 S N t-BuOOH (5.0 equiv) NaO 3 Het Het CF (CH ) N 5 H 2 2 6 3 FF TsOH·H2O or TFA (1.0 equiv) CH2Cl2:H2O or DMSO:H2O (2.5:1) DAAS-Na

CF2(CH2)6N3 CF2(CH2)6N3 CF2(CH2)6N3 O N N N Me N N NMe O 2 2 AcO OAc 42% Et 82% 50% OH O Camptothecin Acridine orange Bisacodyl MeO O 8% H Me MeO NH MeO 17% 9% N 9% N N N MeO H H H H 16% Nevirapine Papaverine

Scheme 1.49 C─H bond difluoroalkylation of heteroarenes with DAAS‐Na.

NiCl2·DME (5–10 mol%) ditBuBpy (5–10 mol%) t-Bu t-Bu B(OH) CF Alkyl 2 DMAP (20 mol%) 2 R R + BrCF2Alkyl K2CO3 (2.0 equiv) N N Triglyme, 80 °C 32–95% ditBuBpy

F F NBoc F F F Ph F Ph F 3 F OH Ph F 3 F 4 N

N SO Me Ac 2 F 92% 78% 72% 46% 83%a

a HetArB(OiPr)3Li was used. (a)

NiBr2·diglyme (5 mol%) L (5 mol%) MeO OMe Br 2 CF Alkyl NaI (80 mol%) 2 R + BrCF Alkyl R 2 Zn (1.2 equiv) N N 3 Å MS, DMPU, 80 °C 35–88% (b) L2

FeI (10 mol%) Br 1 CF Alkyl L (5 mol%) 2 R 1 R + BrCF2Alkyl THF/dioxane, rt, 90 min Me2N NMe2 (c) 24–90% L1

Scheme 1.50 Nickel‐ or iron‐catalyzed difluoroalkylation of aromatics with unactivated difluoroalkyl bromides.

c01.indd 41 14-03-2020 20:52:55 42 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Ph Ni(acac) ·xH O (5 mol%) ZnCl O O 2 2 CF R2 R2 S N bpy (5.5 mol%) 2 R1 + R1 N THF/NMP, rt FF N N

F F F F MsN Me OO NBoc F FF N OiPr 55% 41% 44% O

Scheme 1.51 Nickel‐catalyzed difluoroalkylation of aryl zinc reagents with difluoroalkylated sulfones.

convenient and cost‐efficient methods to prepare difluoroalkylated arenes that are of great interest in life and materials sciences. In particular, a new mode of difluoromethylation reaction, i.e. catalytic MeDIC, has been developed, which expands our understanding of metal difluorocarbene chemistry, and should influ- ence future thinking in the field. Mechanistic studies on difluoroalkylation reactions showed the differences between organofluorine chemistry and classical C–H chemistry, and thus it is imperative to develop new chemistry for fluoroalkylation reactions. In future works, the development of environmental benign, cost‐efficient, and highly regioselective difluoroalkylation reactions from inexpensive fluorine sources remains necessary. In particular, the direct C–H difluoroalkylation of heteroarenes with high regioselectivity and broad substrate scope should be considered in pharmaceutical, agrochemical, and advanced mate- rial applications. To meet the increasing demand from life science, such as design of bioactive peptides, protein engineering, probes for the investigation of enzyme kinetics, diagnosing neurodegenerative diseases and so on, the development of biocompatible fluoroalkylations, including site-selective fluoroalkylation of peptides, proteins, oligocarbohydrates and DNA, would be a promising research area.

References

1 (a) Erickson, J.A. and McLoughlin, J.I. (1995). J. Org. Chem. 60: 1626–1631. (b) Meanwell, N.A. (2011). J. Med. Chem. 54: 2529–2591. (c) Zafrani, Y., Yeffet, D., Sod‐Moriah, G. et al. (2017). J. Med. Chem. 60: 797–804. 2 Wang, J., Sanchez‐Rosello, M., Acen, J.L. et al. (2014). Chem. Rev. 114: 2432–2506. 3 (a) Markovskij, L.N., Pashinnik, V.E., and Kirsanov, A.V. (1973). Synthesis 1973: 787–789. (b) Middleton, W.J. (1975). J. Org. Chem. 40: 574–578. (c) Lal, G.S., Pez, G.P., Pesaresi, R.J. et al. (1999). J. Org. Chem. 64: 7048–7054. 4 (a) Feng, Z., Xiao, Y.‐L., and Zhang, X. (2018). Acc. Chem. Res. 51: 2264–2278. (b) Ni, C., Zhu, L., and Hu, J. (2015). Acta Chim. Sinica 73: 90–115. (c) Yerien, D.E., Barata‐Vallejo, S., and Postigo, A. (2017). Chem. Eur. J. 23: 14676–14701. (d) Belhomme, M.‐C., Besset, T., Poisson, T., and Pannecoucke, X. (2015). Chem. Eur. J. 21: 12836–12865. (e) Chen, B. and Vicic, D.A. (2014). Top. Organomet. Chem. 52: 113–142.

c01.indd 42 14-03-2020 20:52:55 References 43

5 Burton, D.J., Hartgraves, G.A., and Hsu, J. (1990). Tetrahedron Lett. 31: 3699–3702. 6 Burton, D.J. and Hartgraves, G.A. (2007). J. Fluorine Chem. 128: 1198–1215. 7 Fier, P.S. and Hartwig, J.F. (2012). J. Am. Chem. Soc. 134: 5524–5527. 8 Jiang, X.‐L., Chen, Z.‐H., Xu, X., and Qing, F.‐L. (2014). Org. Chem. Front. 1: 774–776. 9 Prakash, G.S.K., Ganesh, S.K., Jones, J.‐P. et al. (2012). Angew. Chem. Int. Ed. 51: 12090–12094. 10 Matheis, C., Jouvin, K., and Goossen, L.K. (2014). Org. Lett. 16: 5984–5987. 11 Chu, L. and Qing, F.L. (2014). Acc. Chem. Res. 47: 1513–1522. 12 Zhu, S.‐Q., Liu, Y.‐L., Li, H. et al. (2018). J. Am. Chem. Soc. 140: 11613–11617. 13 Cho, E.J., Senecal, T.D., Kinzel, T. et al. (2010). Science 328: 1679–1681. 14 Gu, Y., Leng, X., and Shen, Q. (2014). Nat. Commun. 5: 5405. 15 (a) Lu, C., Gu, Y., Wu, J. et al. (2017). Chem. Sci. 8: 4848–4852. (b) Lu, C., Lu, H., Wu, J. et al. (2018). J. Org. Chem. 83: 1077–1083. 16 Ferguson, D.M., Malapit, C.A., Bour, J.R., and Sanford, M.S. (2019). J. Org. Chem. 84: 3735–3740. 17 Aikawa, K., Serizawa, H., Ishii, K., and Mikami, K. (2016). Org. Lett. 18: 3690–3693. 18 Pan, F., Boursalian, G.B., and Ritter, T. (2018). Angew. Chem. Int. Ed. 57: 16871–16876. 19 Serizawa, H., Ishii, K., Aikawa, K., and Mikami, K. (2016). Org. Lett. 18: 3686–3689. 20 Bour, J.R., Kariofillis, S.K., and Sanford, M.S. (2017). Organometallics 36: 1220–1223. 21 Xu, L. and Vicic, D.A. (2016). J. Am. Chem. Soc. 138: 2536–2539. 22 Hudlicky, M. and Pavlath, A.E. (1995). Chemistry of Organic Fluorine Compounds II. American Chemical Society. 23 (a) Brahms, D.L.S. and Dailey, W.P. (1996). Chem. Rev. 96: 1585–1632. (b) Ni, C.F. and Hu, J. (2014). Synthesis 46: 0842–0863. 24 (a) Hine, J. and Porter, J.J. (1957). J. Am. Chem. Soc. 79: 5493–7496. (b) Miller, T.G. and Thanassi, J.W. (1960). J. Org. Chem. 25: 2009–2012. (c) Moore, G.G.I. (1979). J. Org. Chem. 44: 1708–1711. (d) Nawrot, E. and Jonczyk, A. (2007). J. Org. Chem. 72: 10258–10260. (e) Obayashi, M., Ito, E., Matsui, K., and Kondo, K. (1982). Tetrahedron Lett. 23: 2323–2326. (f) Metcalf, B.W., Bey, P., Danzin, C. et al. (1978). J. Am. Chem. Soc. 100: 2551–2553. 25 Dolbier, W.R. Jr. and Battiste, M.A. (2003). Chem. Rev. 103: 1071–1098. 26 (a) Brothers, P.J. and Roper, W.R. (1988). Chem. Rev. 88: 1293–1326. (b) Trnka, T.M., Day, M.W., and Grubbs, R.H. (2001). Angew. Chem. Int. Ed. 40: 3441–3444. (c) Harrison, D.J., Gorelsky, S.I., Lee, G.M. et al. (2013). Organometallics 32: 12–15. (d) Harrison, D.J., Daniels, A.L., Korobkov, I., and Baker, R.T. (2015). Organometallics 34: 5683–5686. (e) Takahira, Y. and Morizawa, Y. (2015). J. Am. Chem. Soc. 137: 7031–7034. 27 Feng, Z., Min, Q.‐Q., and Zhang, X. (2015). Org. Lett. 18: 44–47. 28 Feng, Z., Min, Q.‐Q., Fu, X.‐P. et al. (2017). Nat. Chem. 9: 918–923. 29 (a) Ishiyama, T., Takagi, J., Ishida, K. et al. (2002). J. Am. Chem. Soc. 124: 390–391. (b) Tobisu, M., Kinuta, H., Kita, Y. et al. (2012). J. Am. Chem. Soc. 134: 115–118.

c01.indd 43 14-03-2020 20:52:55 44 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

30 Deng, X.‐Y., Lin, J.‐H., and Xiao, J.‐C. (2016). Org. Lett. 18: 4384–4387. 31 (a) Chen, Q.Y. and Yang, Z.Y. (1985). Acta Chim. Sinica. (Engl. Ed.) 44: 1118. (b) Chen, Q.‐Y., Yang, Z.‐Y., Zhao, C.‐X., and Qiu, Z.‐M. (1988). J. Chem. Soc., Perkin Trans. 1: 563–567. 32 Zhou, Q.‐L. and Huang, Y.‐Z. (1989). J. Fluorine Chem. 43: 385–392. 33 Fu, X.‐P., Xiao, Y.‐L., and Zhang, X. (2018). Chin. J. Chem. 36: 143–146. 34 (a) Xiao, Y.‐L., Guo, W.‐H., He, G.‐Z. et al. (2014). Angew. Chem. Int. Ed. 53: 9909–9913. (b) Xiao, Y.‐L., Min, Q.‐Q., Xu, C. et al. (2016). Angew. Chem. Int. Ed. 55: 5837–5841. (c) An, L., Xiao, Y.‐L., Min, Q.‐Q., and Zhang, X. (2015). Angew. Chem. Int. Ed. 54: 9079–9083. 35 (a) Wilsily, A., Tramutola, F., Owston, N.A., and Fu, G.C. (2012). J. Am. Chem. Soc. 134: 5794–5979. (b) Zultanski, S.L. and Fu, G.C. (2013). J. Am. Chem. Soc. 135: 624–627. (c) Jones, G.D., Martin, J.L., McFarland, C. et al. (2006). J. Am. Chem. Soc. 128: 13175–13183. (d) Gutierrez, O., Tellis, J.C., Primer, D.N. et al. (2015). J. Am. Chem. Soc. 137: 4896–4899. 36 Sheng, J., Ni, H.‐Q., Bian, K.‐J. et al. (2018). Org. Chem. Front. 5: 606–610. 37 Xu, C., Guo, W.‐H., He, X. et al. (2018). Nat. Commun. 9: 1170. 38 Gao, X., He, X., and Zhang, X. (2019). Chin. J. Org. Chem. 39: 215–222. 39 Bacauanu, V., Cardinal, S., Yamauchi, M. et al. (2018). Angew. Chem. Int. Ed. 57: 12543–12548. 40 Motohashi, H. and Koichi, M. (2018). Org. Lett. 20: 5340–5343. 41 (a) Hori, K., Motohashi, H., Saito, D., and Mikami, K. (2019). ACS Catal. 9: 417–421. (b) Nitta, J., Motohashi, H., Aikawa, K., and Mikami, K. (2019). Asian. J. Org. Chem. 8: 698–701. 42 Miao, W.J., Zhao, Y., Ni, C. et al. (2018). J. Am. Chem. Soc. 140: 880–883. 43 (a) An, L., Xiao, Y.‐L., and Zhang, X. (2018). Angew. Chem. Int. Ed. 57: 6921–6925. (b) An, L., Tong, F.‐F., and Zhang, X. (2018). Acta Chim. Sinica 76: 977–982. 44 Motohashi, H., Kato, M., and Mikami, K. (2019). J. Org. Chem. 84: 6483–6490. 45 Fujiwara, Y., Dixon, J.A., Rodriguez, R.A. et al. (2012). J. Am. Chem. Soc. 134: 1494–1497. 46 Sakamoto, R., Kashiwagi, H., and Maruoka, K. (2017). Org. Lett. 19: 5126–5129. 47 Tung, T.T., Christensen, S.B., and Nielsen, J. (2017). Chem. Eur. J. 23: 18125–18128. 48 Zhu, S.‐Q., Xu, X.‐H., and Qing, F.‐L. (2017). Chem. Commun. 53: 11484–11487. 49 (a) Muller, K., Faeh, C., and Diederich, F. (2007). Science 317: 1881–1886. (b) O’Hagan, D. (2008). Chem. Soc. Rev. 37: 308–319. 50 (a) Yokomatsu, T., Suemune, K., Murano, T., and Shibuya, S. (1996). J. Org. Chem. 61: 7207–7211. (b) Eujen, R., Hoge, B., and Brauer, D.J. (1996). J. Organomet. Chem. 519: 7–20. (c) Hu, J., Zhang, W., and Wang, F. (2009). Chem. Commun. 2009: 7465–7478. 51 Zhang, Z.‐Y. (2003). Acc. Chem. Res. 36: 385–392. 52 (a) Qiu, W. and Burton, D.J. (1996). Tetrahedron Lett. 37: 2745–2748. (b) Yokomatsu, T., Murano, T., Suemune, K., and Shibuya, S. (1997). Tetrahedron 53: 815–822. 53 Feng, Z., Chen, F., and Zhang, X. (2012). Org. Lett. 14: 1938–1941.

c01.indd 44 14-03-2020 20:52:55 References 45

54 Jover, J. (2018). Organometallics 37: 327–336. 55 Feng, Z., Xiao, Y.‐L., and Zhang, X. (2014). Org. Chem. Front. 1: 113–116. 56 Feng, Z., Min, Q.‐Q., Xiao, Y.‐L. et al. (2014). Angew. Chem. Int. Ed. 53: 1669–1673. 57 Ivanova, M.V., Besset, T., Pannecoucke, X., and Poisson, T. (2018). Synthesis 50: 778–784. 58 Jiang, X., Chu, L., and Qing, F.‐L. (2013). New J. Chem. 37: 1736–1741. 59 Li, X., Zhao, J., Hu, M. et al. (2016). Chem. Commun. 52: 3657–3660. 60 (a) Ivanova, M.V., Bayle, A., Besset, T. et al. (2015). Angew. Chem. Int. Ed. 54: 13406–13410. (b) Bayle, A., Cocaud, C., Nicolas, C. et al. (2015). Eur. J. Org. Chem. 2015: 3787–3792. 61 Komoda, K., Iwamoto, R., Kasumi, M., and Amii, H. (2018). Molecules 23: 3292. 62 Taguchi, T., Kitagawa, O., Morikawa, T. et al. (1986). Tetrahedron Lett. 27: 6103–6107. 63 (a) Sato, K., Kawata, R., Ama, F. et al. (1999). Chem. Pharm. Bull. 47: 1013–1016. (b) Sato, K., Omote, M., Ando, A., and Kumadaki, I. (2004). J. Fluorine Chem. 125: 509–515. (c) Ashwood, M.S., Cottrell, I.F., Cowden, C.J. et al. (2002). Tetrahedron Lett. 43: 9271–9273. (d) Kitagawa, O., Taguchi, T., and Kobayashi, Y. (1989). Chem. Lett. 18: 389. (e) Zhu, J., Zhang, W., Zhang, L. et al. (2010). J. Org. Chem. 75: 5505–5512. (f) Qi, Q., Shen, Q., and Lu, L. (2012). J. Am. Chem. Soc. 134: 6548–6551. 64 (a) Fujikawa, K., Fujioka, Y., Kobayashi, A., and Amii, H. (2011). Org. Lett. 13: 5560–5563. (b) Fujikawa, K., Kobayashi, A., and Amii, H. (2012). Synthesis 44: 3015–3018. 65 Arlow, S.I. and Hartwig, J.F. (2016). Angew. Chem. Int. Ed. 55: 4567–4572. 66 Belhomme, M.C., Bayle, A., Poisson, T., and Pannecoucke, X. (2015). Eur. J. Org. Chem. 2015: 1719–1726. 67 Ge, S., Arlow, S.I., Mormino, M.G., and Hartwig, J.F. (2014). J. Am. Chem. Soc. 136: 14401–14404. 68 Arlow, S.I. and Hartwig, J.F. (2017). J. Am. Chem. Soc. 139: 16088–16091. 69 Xia, T., He, L., Liu, Y.A. et al. (2017). Org. Lett. 19: 2610–2613. 70 Shi, S.‐L. and Buchwald, S.L. (2015). Angew. Chem. Int. Ed. 54: 1646–1650. 71 Ruan, Z., Zhang, S.‐K., Zhu, C. et al. (2017). Angew. Chem. Int. Ed. 56: 2045–2049. 72 Li, Z.‐Y., Li, L., Li, Q.‐L. et al. (2017). Chem. Eur. J. 23: 3285–3290. 73 (a) Yuan, C., Zhu, L., Zeng, R. et al. (2018). Angew. Chem. Int. Ed. 57: 1277– 1281. (b) Tu, G., Yuan, C., Li, Y. et al. (2018). Angew. Chem. Int. Ed. 57: 15597–15601. 74 Dubinina, G.G., Brennessel, W.W., Miller, J.L., and Vicic, D.A. (2008). Organometallics 27: 3933–3938. 75 Bour, J.R., Camasso, N.M., Meucci, E.A. et al. (2016). J. Am. Chem. Soc. 138: 16105–16111. 76 Tarui, A., Shinohara, S., Sato, K. et al. (2016). Org. Lett. 18: 1128–1131. 77 Araki, K. and Inoue, M. (2013). Tetrahedron 69: 3913–3918. 78 Guo, Y. and Shreeve, J.M. (2007). Chem. Commun. 2007: 3583–3585.

c01.indd 45 14-03-2020 20:52:55 46 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

79 Guo, C., Wang, R.‐W., and Qing, F.‐L. (2012). J. Fluorine Chem. 143: 135–142. 80 Ge, S., Chaładaj, W., and Hartwig, J.F. (2014). J. Am. Chem. Soc. 136: 4149–4152. 81 Min, Q.‐Q., Yin, Z., Feng, Z. et al. (2014). J. Am. Chem. Soc. 136: 1230–1233. 82 (a) Yu, Y.‐B., He, G.‐Z., and Zhang, X. (2014). Angew. Chem. Int. Ed. 53: 10457– 10461. (b) Xiao, Y.‐L., Pan, Q., and Zhang, X. (2015). Acta Chim. Sinica 73: 383–387. 83 (a) Xiao, Y.‐L., Zhang, B., Feng, Z., and Zhang, X. (2014). Org. Lett. 16: 4822–4825. (b) Gu, J.‐W., Guo, W.‐H., and Zhang, X. (2015). Org. Chem. Front. 2: 38–41. 84 (a) Zhou, Q., Gui, J., Pan, C.‐M. et al. (2013). J. Am. Chem. Soc. 135: 12994–12997. (b) Zhou, Q., Ruffoni, A., Gianatassio, R. et al. (2013). Angew. Chem. Int. Ed. 52: 3949–3952. 85 He, X., Gao, X., and Zhang, X. (2018). Chin. J. Chem. 36: 1059–1062. 86 Merchant, R.R., Edwards, J.T., Qin, T. et al. (2018). Science 360: 75–80.

c01.indd 46 14-03-2020 20:52:55