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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 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].

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

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 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.

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

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

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 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 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 aryldifluoromethyl palladium complex [Ar-Pd(L n )-CF2H] is faster than that of aryltrifluoromethyl palladium complex [Ar-Pd(L n )-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.

Scheme 1.4 Copper-mediated oxidative difluoromethylation of heteroarenes.

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

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

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

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

Copper can also be used as the catalyst for the difluoromethylation. In 2016, Mikami and coworkers reported a ligand-free copper-catalyzed difluoromethylation 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].

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 systematically 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 bimolecular 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...