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1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes 3 1 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 syn- thesis 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‐cata- lyzed cross‐coupling difluoromethylation is one of the most efficient strategies to access this class of compounds. Over the past few years, impressive achieve- ments 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 syn- thetic 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. c01.indd 3 14-03-2020 20:52:44 4 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes 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 aro- matics. 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 elec- tron‐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 trans- metalation between n‐Bu3SnCF2H and CuI to generate CuCF2H species was pro- posed. 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 c01.indd 4 14-03-2020 20:52:44 1.2 Difluoromethylation of (Hetero)aromatics 5 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 stoi- chiometric amount of copper salts were required. A more efficient and attractive alternative is the catalytic difluoromethylation. In 2010, Buchwald and cowork- ers reported the first example of palladium‐catalyzed trifluoromethylation of aryl chlorides with TESCF3 [13]. Direct adaptation of this strategy to difluoro- methylation resulted in inefficient transmetalation between the palladium c01.indd 5 14-03-2020 20:52:44 6 1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes 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). c01.indd 6 14-03-2020 20:52:45 1.2 Difluoromethylation of (Hetero)aromatics 7 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 pal- ladium catalysis (Scheme 1.6) [16]. The use of electron‐rich monophosphine ligands [BrettPhos and P(t‐Bu)3] allowed difluoromethylation of a series of elec- tron‐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 S 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 difluo- romethylation 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 difluoromethyla- tion of benzoic acid chlorides (Scheme 1.8) [18].
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