English

• 1.   Introduction

  Difluoromethylated (hetero)arenes have gained increasing attention because of the unique properties of difluoromethyl group (CF₂H) that can function as a lipophilic hydrogen bond donor, and also as a bioisostere of hydroxyl and thiol groups.^[1] Hence, it is of great interest to develop new and efficient methods to synthesize difluoromethylated (hetero)arenes. Transition-metal-catalyzed direct difluromethylation of (hetero)aromatics has emerged as one of the most efficient strategies to access difluoromethylated (hetero)arenes.^[2] However, most of the difluoromethylation reagents used in these reported methods are expensive and additional step(s) are required to synthesize from fluoroalkyl halides, [2c, 3] thus limiting their widespread applications.

  In this regard, recently, we developed a palladium-catalyzed difluoromethylation of arylboronic acids with abundant and inexpensive industrial material chlorodifluoromethane (ClCF₂H) via a metal-difluorocarbene coupling (MeDiC), ^[4] which represents the first example of catalytic difluoromethylation from ClCF₂H.^[5] Later on, to replace the palladium with a base metal as a catalyst, we^[6] developed a nickel-catalyzed reductive cross-coupling between ClCF₂H and (hetero)aryl chlorides/bromides. Despite of the importance of these methods, the developing new methods to access valuable difluoromethylated (hetero)arenes remain highly desirable. Bromodifluoromethane (BrCF₂H) is a simple and readily available difluoromethyl source.^[7] Very recently, we^[8] and others^[9] reported a nickel-catalyzed cross-coupling of BrCF₂H with arylboronic acids, independently. However, the nickel-catalyzed reductive cross-coupling of BrCF₂H with (hetero)aryl halides has not been reported so far. To continue our research on catalytic fluoroalkylation reactions with inexpensive and readily available fluoroalkyl halides as fluoroalkyl sources, ^[10] herein, we disclose a nickel-catalyzed reductive cross- coupling of widely accessible (hetero)aryl bromides with BrCF₂H. The reaction proceeds under mild reaction conditions with broad substrate scope and excellent functional group tolerance without preformation of arylmetals.

  2.   Results and discussion

  Initially, 4-bromo-1, 1'-biphenyl (2a) was chosen as a coupling partner for this nickel-catalyzed difluoromethylation reaction (Table 1). However, only 16% yield of 3a was provided when the reaction was carried out with BrCF₂H (1, 1.0 equiv.) and 2a (2.5 equiv.) in the presence of NiBr₂•Diglyme (5 mol%) and bypyridyl (bpy) (5 mol%) in 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2(1H)-pyrimidinone (DMPU) at 80 ℃ by employing Zn as a reductant (Entry 1). The low yield of 3a is because of the formation of hydrodebrominated compound CF₂H₂ (4, 10% yield) and some other uncertain defluorinated by-products. To suppress these side reactions, a series of reaction parameters, such as ligand, solvent, and additive were examined (Entries 2~7). Among the tested ligands and solvents, the bpy ligand and DMPU were still the best choice. Other diamine ligands, such as 1, 10-phenanthroline (phen), 4, 4'-di^tBu-bpy, even the electron-rich ligand 4, 4'-diMeO-bpy, all provided lower yields. To our delight, the use of KI (0.4 equiv.)^[11] as an additive could afford 3a in 66% yield albeit formation of 5% yield of CF₂H₂ (Entry 6). The reaction was sensitive to the nickel catalysts (Entries 7~11) and Ni(PPh₃)₂Br₂ showed the highest reactivity (Entry 6). Finally, the optimum reaction conditions were identified by decreasing the reaction temperature to 60 ℃ with utility of 1.5 equiv. of 2a and 10 mol% Ni(PPh₃)₂Br₂/bpy, providing compound 3a in 91% yield upon isolation (Entry 13). No product 3a was observed without nickel or bpy, thus demonstrating the essential role of Ni/bpy in promotion of the reaction (Entries 14 and 15).

  Table 1

  

  Table 1.  Representative results for optimization of Ni-catalyzed difluoromethylation of 2a with BrCF₂H (1)^a

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  Entry	[Ni]	Zn/equiv.	Additive (equiv.)	Yieldb/% of 3a/4/1
  1	NiBr2•Diglyme	1.2	—	16/10/36
  2	NiBr2•Diglyme	1.2	LiI (0.2)	24/Trace/44
  3	NiBr2•Diglyme	1.2	NaI (0.2)	30/12/21
  4	NiBr2•Diglyme	1.2	KI (0.2)	45/Trace/25
  5	NiBr2•Diglyme	2.0	KI (0.2)	62/Trace/7
  6	NiBr2•Diglyme	2.0	KI (0.4)	66/5/0
  7	Ni(PPh3)2Br2	2.0	KI (0.4)	73/5/0
  8	Ni(PPh3)2Cl2	2.0	KI (0.4)	60/12/0
  9	Ni(dppe)Cl2	2.0	KI (0.4)	27/12/0
  10	NiCl2•DME	2.0	KI (0.4)	19/Trace/34
  11	Ni(cod)2	2.0	KI (0.4)	0/8/45
  12c	Ni(PPh3)2Br2	2.0	KI (0.4)	78/4/0
  13c, d	Ni(PPh3)2Br2	2.0	KI (0.4)	90 (91)/Trace/0
  14c, d	—	2.0	KI (0.4)	0/9/0
  15c, d, e	Ni(PPh3)2Br2	2.0	KI (0.4)	0/8/10
  a Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv.), 2a (0.75 mmol, 2.5 equiv.), DMPU (2 mL), 6 h. b Determined by 19F NMR using fluorobenzene as an internal standard and number in parenthesis is isolated yield. c Ni(PPh3)2Br2 (10 mol%), bpy (10 mol%), 60 ℃, 6 h. d 1 (0.3 mmol, 1.0 equiv.), 2a (0.45 mmol, 1.5 equiv.), DMPU (1.5 mL). e The reaction was run in the absence of bpy.

  With the viable reaction conditions in hand, a variety of aryl bromides were examined (Table 2). Generally, arylbromides bearing both electron-donating and electron-withdrawing substituents all showed good reactivity towards BrCF₂H, providing the corresponding difluoromethylated arenes in good to high yields (3c~3i). The reaction showed high functional group compatibility. Many important functional groups, including alkoxycarbonyl, enolizable ketone silyl and cyano are compatible with the reaction conditions (3f~3k), even towards alcohol (3l) and arylboronate (3m), thus demonstrating the advantage of present nickel-catalyzed process. Importantly, heteroaryl bromides were also amenable to the reaction. Pyridine-, quinoline-, isoquinoline-, benzothiazole-, and benzooxazole-containing substrates all underwent the reaction smoothly, leading to the corresponding difluoromethylated heteroarenes in good yields (3p~3w). Gram-scale synthesis of difluoromethylated quinoline 3t also proceeded efficiently with comparable yield (64%), thus demonstrating the reliability and practicability of this method. Furthermore, the utility of this method can also be demonstrated by the late-stage difluoromethylation of estrone- and ibuprofen-derived aryl bromides (3x and 3y), providing potential opportunities for discovering new interesting bioactive molecules.

  Table 2

  

  Table 2.  Ni-catalyzed reductive cross-coupling of bromodifluoromethane (1) with aryl bromides (2)^a

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  aReaction conditions (unless otherwise specified): 2 (0.9 mmol, 1.5 equiv.), 1 (0.6 mmol, 1.0 equiv.), DMPU (3.0 mL), 60 ℃, 6 h. Yields of isolated products are given. bNMR yield determined by 19F NMR. c2 (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh3)Br2 (5 mol%), 4, 4'-ditBu-bpy (5 mol%), 3Å MS (200 mg), 12 h. dGram-scale synthesis and reaction run for 12 h. e2 (1.5 equiv.), 6 (0.3 mmol, 1.0 equiv.), Ni(PPh3)Br2 (5 mol%), 4, 4'-ditBu-bpy (5 mol%), 3Å MS (400 mg), 12 h.

  To gain some mechanistic insights into the current nickel-catalyzed process, several experiments were conducted. Firstly, the reaction of BrCF₂H with Zn in DMPU was performed at 60 ℃ (Scheme 1a). It was found that the difluoromethyl zinc species [BrZnCF₂H] (A1) and [Zn(CF₂H)₂] (A2) could be generated in a high yield (A1+A2＝90% yield determined by ¹⁹F NMR)^[12] under this reaction condition. However, no desired product 3a was observed when the mixture of A1 and A2 was treated with aryl bromide 2a in the presence of Ni(PPh₃)₂Br₂ and bpy (Scheme 1a). In addition, the use of ¹⁹F NMR to monitor the reaction showed that A1 and A2 were not generated under standard reaction conditions (Scheme 1b). Thus, these results rule out the pathway that the production of difluoro-methylated arenes is originated from the cross-coupling of difluoroalkyl zinc species with aryl bromides. Secondly, the radical clock experiment by employing α-cyclopropyl- styrene 5 as a probe^[6] showed that a ring-expanded product 6 was obtained in 14% yield, demonstrating that a difluoromethyl radical exists in the reaction (Scheme 1c).

  Scheme 1

  

  Scheme 1.  Mechanistic studies

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  On the basis of these results and previous reports, ^{[6, 13]} two possible pathways were proposed for the current nickel-catalyzed process (Scheme 2). Path Ⅰ: The reaction begins the reaction of Ni(0) with aryl bromide to generate Ni(Ⅱ) complex [(Ar)Ni^I(L_n)Br] (A), which is subsequently reduced by Zn to give Ni(I) complex [(Ar)Ni^I(L_n)] (B) (Scheme 2a). B reacts with BrCF₂H via a radical cage rebound process to produce the key intermediate [(Ar)Ni^III-(L_n)(CF₂H)Br] (C). Finally, C undergoes reductive elimination to provide the difluoromethylated arene and [BrNi^I(L_n)] (D). Reduction of D by Zn regenerates the [Ni⁰(L_n)] species. Path Ⅱ: The difluoromethyl radical generated between [BrNi^I(L_n)] (D) and BrCF₂H diffuses to the solution to react with A to give the key intermediate C (Scheme 2b). Subsequently, reductive elimination of C provides the difluoromethylated arene. Finally, the resulting nickel(Ⅱ) complex [Ni^I(L_n)Br₂] is reduced by Zn to regenerate [Ni⁰(L_n)].

  Scheme 2

  

  Scheme 2.  Proposed reaction mechanisms

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  3.   Conclusions

  In conclusion, we have developed a nickel-catalyzed direct difluoromethylation of (hetero)aryl bromides with simple and readily available BrCF₂H via a reductive cross-coupling. The reaction proceeds under mild reaction conditions with high efficiency and good functional groups tolerance, providing a cost-efficient and straightforward route for the synthesis of difluoromethylated (hetero)arenes that are of great interest in medicinal chemistry.

  4.   Experimental section

  4.1   General information

  ¹H NMR and ¹³C NMR spectra were recorded on an Agilent MR 400 and Agilent MR 500 spectrometer. ¹⁹F NMR was recorded on an Agilent MR 400 spectrometer (CFCl₃ as an external standard and low field is positive). NMR yield was determined by ¹⁹F NMR using fluorobenzene as an internal standard before working up the reaction.

  All reagents were used as received from commercial sources, unless otherwise stated, or prepared as described in the literature. 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2(1H)-pyrimi- dinone (DMPU) was purchased from TCI and distilled from calcium hydride for twice before use.

  4.2   Preparation of BrCF2H stock solution

  1, 4-Dioxane (15 mL) was added to a Schlenk tube under argon. BrCF₂H gas was then bubbled through the 1, 4-dioxane until the total volume of the solution reach the maximum. The concentration of the BrCF₂H (3 mol•L^－1) stock solution was determined by ¹⁹F NMR spectrum using fluorobenzene as an internal standard.

  4.3   General procedure for Ni-catalyzed cross-coup- ling of 1 with 2

  To a 25 mL of Schlenk tube were added (hetero)arylbromide 2 (0.9 mmol, 1.5 equiv.), Ni(PPh₃)₂Br₂ (10 mol%), bpy (10 mol%), KI (0.4 equiv.), and Zn (2.0 equiv.) under air. The mixture was then evacuated and backfilled with argon for three times. DMPU (3 mL) and BrCF₂H (2.5 mol•L^－1 in 1, 4-dioxane, 240 μL, 0.6 mmol, 1.0 equiv.) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 ℃). After stirring for 6 h, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated, and the residue was washed with 10 mL of water, and extracted with organic solvent [V(petroleum ether):V(EtOAc)＝20:1] for three times. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified with silica gel chromatography to give product 3.

  4-(Difluoromethyl)-1, 1'-biphenyl (3a):^[4] The product (111 mg, 91% yield) was purified with silica gel chromatography (petroleum ether) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.72~7.68 (m, 2H), 7.64~7.59 (m, 4H), 7.52~7.47 (m, 2H), 7.44~7.49 (m, 1H), 6.71 (t, J＝56.4 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.3 (d, J＝56.5 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 143.7 (t, J＝2.0 Hz), 140.2, 133.2 (t, J＝22.4 Hz), 128.9, 127.9, 127.4, 127.2, 126.0 (t, J＝6.0 Hz), 114.7 (t, J＝238.5 Hz).

  1-(tert-Butyl)-4-(difluoromethyl)benzene (3b):^[4] The product (74% yield determined by ¹⁹F NMR) was purified with silica gel chromatography (petroleum ether) as a colorless oil. ¹H NMR (400 MHz, CDCl ) δ: 7.50~7.44 (m, 4H), 6.63 (t, J＝56.8 Hz, 1H), 1.35 (s, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －109.9 (d, J＝56.6 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 154.0 (t, J＝2.0 Hz), 131.5 (t, J＝22.4 Hz), 125.6, 125.3 (t, J＝6.0 Hz), 114.9 (t, J＝237.9 Hz), 34.8, 31.2.

  1-(Difluoromethyl)-4-methoxybenzene (3c):^[4] The product (55% yield determined by ¹⁹F NMR) as colorless oil was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝100:1). ¹H NMR (400 MHz, CDCl₃) δ: 7.44 (d, J＝8.6 Hz, 2H), 6.96 (d, J＝8.8 Hz, 2H), 6.60 (t, J＝56.7 Hz, 1H), 3.84 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －108.3 (d, J＝56.8 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 161.33, 127.1 (t, J＝6.0 Hz), 126.74 (t, J＝22.7 Hz), 114.9 (t, J＝237.3 Hz), 114.0, 55.3.

  1-(Difluoromethyl)-3-methoxybenzene (3d):^[4] The product (83% yield, determined by ¹⁹F NMR) was characterized by ¹⁹F NMR and GC-MS analysis. ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.3 (d, J＝37.6 Hz, 2F); GC-MS m/z (%): 158.0 (M⁺).

  1-(Difluoromethyl)-3, 5-dimethoxybenzene (3e):^[4] The product (63 mg, 56% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝30:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 6.68~6.62 (m, 2H), 6.56 (t, J＝56.4 Hz, 1H), 6.56~6.52 (m, 1H), 3.82 (s, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.9 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 161.0, 136.3 (t, J＝22.4 Hz), 114.5 (t, J＝239.4 Hz), 103.4 (t, J＝6.3 Hz), 102.6 (t, J＝1.8 Hz), 55.5.

  Ethyl 4-(difluoromethyl)benzoate (3f):^[4] The product (114 mg, 95% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (d, J＝8.2 Hz, 2H), 7.58 (d, J＝8.1 Hz, 2H), 6.69 (t, J＝56.1 Hz, 1H), 4.40 (q, J＝7.1 Hz, 2H), 1.41 (t, J＝7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.2 (d, J＝56.1 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 165.7, 138.3 (t, J＝22.4 Hz), 132.7 (t, J＝1.8 Hz), 129. 9, 125.6 (t, J＝6.1 Hz), 114.0 (t, J＝239.7 Hz), 61.3, 14.3.

  1-(4-(Difluoromethyl)phenyl)ethanone (3g):^[4] The product (94 mg, 92% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (d, J＝8.0 Hz, 2H), 7.61 (d, J＝7.9 Hz, 2H), 6.69 (t, J＝56.1 Hz, 1H), 2.64 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.3 (d, J＝56.1 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 197.3, 138.8 (t, J＝1.8 Hz), 138.5 (t, J＝22.4 Hz), 128.6, 125.9 (t, J＝6.0 Hz), 113.9 (t, J＝239.8 Hz), 26.8.

  1-(3-(Difluoromethyl)phenyl)ethanone (3h):^[4] The product (82 mg, 80% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.06 (s, 1H), 8.04 (d, J＝8.2 Hz, 1H), 7.69 (d, J＝7.7 Hz, 1H), 7.55 (t, J＝7.7 Hz, 1H), 6.68 (t, J＝56.2 Hz, 1H), 2.61 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.2 (d, J＝56.2 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 197.0, 137.4, 134.8 (t, J＝22.8 Hz), 130.4 (t, J＝1.7 Hz), 129.9 (t, J＝5.8 Hz), 129.1, 125.4 (t, J＝6.2 Hz), 114.1 (t, J＝239.4 Hz), 26.5.

  1-(Difluoromethyl)-4-(trifluoromethyl)benzene (3i):^[4] The product (77% yield, determined by ¹⁹F NMR) was characterized by ¹⁹F NMR and GC-MS analysis. ¹⁹F NMR (376 MHz, CDCl₃) δ: －113.6 (d, J＝37.6 Hz, 2F), －64.0 (s, 3F); GC-MS m/z (%): 196.0 (M⁺).

  (4-(Difluoromethyl)phenyl)trimethylsilane (3j):^[4] The product (90 mg, 75% yield) was purified with silica gel chromatography (petroleum ether) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.61 (d, J＝8.1 Hz, 2H), 7.48 (d, J＝7.8 Hz, 2H), 6.63 (t, J＝56.4 Hz, 1H), 0.28 (s, 9H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.9 (d, J＝56.5 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 144.0 (t, J＝1.7 Hz), 134.6 (t, J＝22.1 Hz), 133.6, 124.7 (t, J＝6.0 Hz), 114.8 (t, J＝238.5 Hz), －1.3.

  2-(4-(Difluoromethyl)phenyl)acetonitrile (3k): The product (73 mg, 73% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝20:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (d, J＝8.0 Hz, 2H), 7.42 (d, J＝8.0 Hz, 2H), 6.65 (t, J＝56.3 Hz, 1H), 3.79 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.0 (d, J＝56.3 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 134.2 (t, J＝22.7 Hz), 132.6 (t, J＝2.0 Hz), 128.2, 126.3 (t, J＝6.1 Hz), 117.3, 114.1 (t, J＝238.9 Hz), 23.4; IR (film) ν_max: 2965, 2253, 1621, 1425, 1328 cm^－1; MS (EI) m/z (%): 167 (M⁺), 116 (100); HRMS calcd for C₉H₇NF₂ 167.0547, found 167.0552.

  (4-(Difluoromethyl)phenyl)methanol (3l):^[4] The product (57 mg, 60% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J＝8.1 Hz, 2H), 7.41 (d, J＝8.0 Hz, 2H), 6.63 (t, J＝56.5 Hz, 1H), 4.69 (s, 2H), 2.48 (s, 1H); ¹⁹F NMR (376 MHz, C₆D₆) δ: －111.6 (d, J＝56.5 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 143.5 (t, J＝1.9 Hz), 133.5 (t, J＝22.4 Hz), 126.9, 125.7 (t, J＝6.1 Hz), 114.6 (t, J＝238.4 Hz), 64.5.

  2-(4-(Difluoromethyl)phenyl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (3m): The product (108 mg, 71% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝100:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (d, J＝7.7 Hz, 2H), 7.50 (d, J＝7.8 Hz, 2H), 6.65 (t, J＝56.4 Hz, 1H), 1.35 (s, 12H); ¹⁹F NMR (282 MHz, CDCl₃) δ: －111.9 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 136.8 (t, J＝22.1 Hz), 135.0, 126.0 (t, J＝6.1 Hz), 124.7 (t, J＝6.0 Hz), 114.7 (t, J＝239.0 Hz), 84.1, 24.9; IR (film) ν_max: 2984, 1742, 1374 cm^－1; MS (EI) m/z (%): 254 (M⁺), 239 (100); HRMS calcd. for C₁₃H₁₆¹⁰BO₂F₂ (M－H⁺) 252.1248, found 252.1247.

  1-(Difluoromethyl)naphthalene (3n):^[4] The product (64 mg, 60% yield) was purified with silica gel chromatography (Petroleum ether) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ: 8.20 (d, J＝8.0 Hz, 1H), 7.98 (d, J＝8.3 Hz, 1H), 7.93 (d, J＝8.0 Hz, 1H), 7.71 (d, J＝7.1 Hz, 1H), 7.67~7.44 (m, 3H), 7.15 (t, J＝55.1 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.9 (d, J＝55.1 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 133.7, 131.5 (t, J＝1.8 Hz), 129.7 (t, J＝2.9 Hz), 129.5 (t, J＝20.9 Hz), 128.7, 127.1, 126.3, 124.8 (t, J＝8.7 Hz), 124.6, 123.5 (t, J＝1.4 Hz), 115.4 (t, J＝238.3 Hz).

  2-(Difluoromethyl)naphthalene (3o):^[4] The product (85 mg, 84% yield) was purified with silica gel chromatography (petroleum ether) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.96~7.85 (m, 3H), 7.66~7.50 (m, 3H), 6.81 (t, J＝56.4 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －109.9 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 134.3 (t, J＝1.4 Hz), 132.5, 131.6 (t, J＝22.2 Hz), 128.9, 128.5, 127.9, 127.4, 126.8, 125.9 (t, J＝7.5 Hz), 122.0 (t, J＝4.8 Hz), 115.0 (t, J＝238.5 Hz).

  Ethyl 5-(difluoromethyl)nicotinate (3p):^[14] The reaction was carried out with ethyl 5-bromonicotinate (2.0 equiv), 1 (0.6 mmol, 1.0 equiv), Ni(PPh₃)Br₂ (5 mol%), 4, 4'-di^tBu- bpy (5 mol%), and molecular sieves (3 Å, 200 mg) in DMPU (3 mL) at 60 ℃ for 12 h. The product (81 mg, 67% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝8:1] as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 9.31 (s, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 6.76 (t, J＝55.6 Hz, 1H), 4.43 (q, J＝7.1 Hz, 2H), 1.41 (t, J＝7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.9 (d, J＝55.6 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 164.3, 152.8, 150.5 (t, J＝6.4 Hz), 134.4 (t, J＝5.7 Hz), 130.0 (t, J＝23.5 Hz), 126.4, 112.8 (t, J＝240.3 Hz), 61.9, 14.2; IR (film) ν_max: 3434, 2986, 1728, 1293, 1214, 1027 cm^－1; MS (EI) m/z (%): 201 (M⁺), 156(100); HRMS calcd for C₉H₉NO₂F₂ (M⁺) 201.0601, found 201.0605.

  5-(Difluoromethyl)-2-methoxypyridine (3q):^[6] The reaction was carried out with 5-bromo-2-methoxypyridine (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh₃)Br₂ (5 mol%), 4, 4-di^tBu-bpy (5 mol%), and molecular sieves (3 Å, 200 mg) in DMPU (3 mL) at 60 ℃ for 12 h. The product (67% yield, determined by ¹⁹F NMR) was characterized by ¹⁹F NMR and GC-MS analysis. ¹⁹F NMR (376 MHz, CDCl₃) δ: －109.6 (d, J＝56.4 Hz, 2F); GC-MS m/z (%): 159.0 (M⁺), 158 (100), 140, 129.

  2-(Benzyloxy)-5-(difluoromethyl)pyridine (3r):^[5] The reaction was carried out with 2-benzyloxy-5-bromopyridine (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh₃)Br₂ (5 mol%), 4, 4-di^tBu-bpy (5 mol%), and molecular sieves (3 Å, 200 mg) in DMPU (3 mL) at 60 ℃ for 12 h. The product (66 mg, 47% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (d, J＝1.6 Hz, 1H), 7.74 (dd, J＝8.6 Hz, 2.3 Hz, 1H), 7.46 (d, J＝7.1 Hz, 2H), 7.43~7.29 (m, 3H), 6.88 (d, J＝8.6 Hz, 1H), 6.65 (t, J＝56.0 Hz, 1H), 5.42 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －109.7 (d, J＝56.4 Hz, 2F); ¹³C NMR (126 MHz, CDCl₃) δ: 165.1 (t, J＝1.3 Hz), 145.2 (t, J＝7.5 Hz), 136.8, 135.9 (t, J＝4.5 Hz), 128.5, 128.0, 128.0, 123.6 (t, J＝23.4 Hz), 113.8 (t, J＝237.6 Hz), 111.7, 68.1; IR (film) ν_max: 2956, 1614, 1500, 1349, 1288, 1081, 1017 cm^－1; MS (EI) m/z (%): 235 (M⁺), 91(100); HRMS calcd. for C₁₃H₁₁NOF₂ 235.0809, found 201.0802.

  3-(Difluoromethyl)quinoline (3s):^[14] The product (67 mg, 62% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝8:1] as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 9.03 (d, J＝1.9 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J＝8.5 Hz, 1H), 7.89 (d, J＝8.2 Hz, 1H), 7.83~7.78 (m, 1H), 7.65~7.60 (m, 1H), 6.88 (t, J＝55.8 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.6 (d, J＝55.8 Hz, 2F). ¹³C NMR (125.7 MHz, CDCl₃) δ: 149.0 (t, J＝1.5 Hz), 147.1 (t, J＝5.3 Hz), 133.9 (t, J＝6.7 Hz), 131.0, 129.5, 128.3, 127.6, 127.1 (t, J＝22.8 Hz), 126.8, 113.7 (t, J＝239.5 Hz); IR (film) ν_max: 3420, 3061, 2964, 1625, 1500, 1180, 1089, 1032 cm^－1; MS (EI) m/z (%): 179 (M⁺), 179(100); HRMS calcd for C₁₀H₇NF₂ 179.0547, found 179.0541.

  6-(Difluoromethyl)-2-methylquinoline (3t):^[6] The product (76 mg, 66% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝8:1] as white solid (m.p. 48~50 ℃). ¹H NMR (400 MHz, CDCl₃) δ: 8.10~8.01 (m, 2H), 7.87 (s, 1H), 7.76 (d, J＝8.8 Hz, 1H), 7.31 (d, J＝8.4 Hz, 1H), 6.78 (t, J＝56.3 Hz, 1H), 2.74 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.2 (d, J＝56.4 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 160.7, 148.6 (t, J＝1.5 Hz), 136.5, 131.4 (t, J＝22.5 Hz), 129.6, 125.7 (t, J＝4.9 Hz), 125.7, 125.4 (t, J＝7.2 Hz), 122.8, 114.5 (t, J＝238.9 Hz), 25.4; IR (film) ν_max: 2997, 1631, 1604, 1484, 1086, 1019 cm^－1; MS (EI) m/z (%): 193 (M⁺), 193 (100); HRMS calcd. for C₁₁H₉NF₂ 193.0703, found 193.0695.

  6-(Difluoromethyl)isoquinoline (3u): The product (63 mg, 59% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝8:1] as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 9.29 (s, 1H), 8.59 (d, J＝5.7 Hz, 1H), 8.03 (d, J＝8.5 Hz, 1H), 7.93 (s, 1H), 7.68 (t, J＝6.6 Hz, 2H), 6.79 (t, J＝56.0 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.7 (d, J＝56.4 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 152.4, 143.9, 135.9 (t, J＝22.4 Hz), 135.1, 129.1, 128.6, 124.3 (t, J＝7.4 Hz), 123.5 (t, J＝4.9 Hz), 120.8, 114.1 (t, J＝239.8 Hz); IR (film) ν_max: 3393, 1591, 1352, 1179, 1034 cm^－1; MS (EI) m/z (%): 179 (M⁺), 179 (100); HRMS calcd. for C₁₀H₇NF₂ 179.0547, found 179.0545.

  2-(4-(Difluoromethyl)phenyl)benzo[d]thiazole (3v): The reaction was carried out with 1-(2-benzothiazolyl)-4-bromo- benzene (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh₃)Br₂ (5 mol%), 4, 4'-di^tBu-bpy (5 mol%), and molecular sieves (3 Å, 200 mg) in DMPU (3 mL) at 60 ℃ for 12 h. The product (116 mg, 74% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝ 5:1] as a white solid. m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.16 (d, J＝8.2 Hz, 2H), 8.09 (d, J＝8.1 Hz, 1H), 7.90 (d, J＝8.0 Hz, 1H), 7.62 (d, J＝8.1 Hz, 2H), 7.57~7.46 (m, 1H), 7.45~7.36 (m, 1H), 6.70 (t, J＝56.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.6 (d, J＝56.4 Hz, 2F); ¹³C NMR (125.7 MHz, CDCl₃) δ: 166.6, 154.0, 136.4 (t, J＝22.5 Hz), 135.7 (t, J＝2.0 Hz), 135.1, 127.7, 126.5, 126.2 (t, J＝6.1 Hz), 125.5, 123.4, 121.6, 114.1 (t, J＝239.4 Hz); IR (film) ν_max: 3054, 1484, 1376, 1073, 1015 cm^－1; MS (EI) m/z (%): 261 (M⁺), 261 (100); HRMS calcd for C₁₄H₉NSF₂ 261.0424, found 261.0422.

  2-(4-(Difluoromethyl)phenyl)benzo[d]oxazole (3w):^[5] The reaction was carried out with 2-(4-bromophenyl)-1, 3- benzoxazole (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh₃)- Br₂ (5 mol%), 4, 4'-di^tBu-bpy (5 mol%), and molecular sieves (3 Å, 200 mg) in DMPU (3 mL) at 60 ℃ for 12 h. The product (93 mg, 63% yield) was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝5:1] as a white solid. m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (d, J＝8.1 Hz, 2H), 7.85~7.75 (m, 1H), 7.66 (d, J＝8.1 Hz, 2H), 7.62~7.55 (m, 1H), 7.40~7.32 (m, 2H), 6.71 (t, J＝56.2 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.9 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 161.9 (t, J＝1.0 Hz), 150.8, 141.9, 137.0 (t, J＝22.5 Hz), 129.4 (t, J＝2.0 Hz), 127.8, 126.1 (t, J＝6.1 Hz), 125.5, 124.8, 120.2 (d, J＝1.0 Hz), 114.1 (t, J＝239.6 Hz), 110.7; IR (film) ν_max: 3064, 1557, 1454, 1073, 1053, 1015 cm^－1; MS (EI) m/z (%): 245 (M⁺), 245 (100); HRMS calcd for C₁₄H₉NOF₂ 245.0652, found 245.0653.

  (13S)-13-Methyl-17-oxo-7, 8, 9, 11, 12, 13, 14, 15, 16, 17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(difluoro- methyl)benzoate (3x): To a 25 mL Schlenk tube were added 2x (0.45 mmol, 1.5 equiv.), Ni(PPh₃)₂Br₂ (5 mol%), 4, 4'-di^tBu-bpy (5 mol%), zinc dust (2.0 equiv.), KI (0.4 equiv.) and 3 Å MS (400 mg). The mixture was evacuated and backfilled with argon for three times, then DMPU (1.5 mL) and BrCF₂H 1 (2.5 mol•L^－1 in 1, 4-dioxane, 0.3 mmol, 1.0 equiv.) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 ℃). After stirring overnight, the reaction mixture was cooled to room temperature and filtered with a pad of celite. The filtrate was concentrated, and the residue was purified with silica gel chromatography [V(petroleum ether):V(EtO-Ac)＝58:1] to give product 3x (64 mg, 50% yield) as a white solid. m.p. 140~143 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (d, J＝8.1 Hz, 2H), 7.66 (d, J＝8.1 Hz, 2H), 7.35 (d, J＝8.4 Hz, 1H), 6.99 (d, J＝8.4 Hz, 1H), 6.96 (s, 1H), 6.73 (t, J＝56.1 Hz, 1H), 2.99~2.92 (m, 2H), 2.57~2.47 (m, 1H), 2.47~2.40 (m, 1H), 2.37~2.27 (m, 1H), 2.22~1.94 (m, 4H), 1.71~1.42 (m, 6H), 0.93 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.4 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 220.7, 164.6, 148.6, 139.0 (t, J＝22.5 Hz), 138.2, 137.7, 131.9, 130.5, 126.5, 125.8 (t, J＝6.1 Hz), 121.6, 118.7, 113.9 (t, J＝239.9 Hz), 50.5, 47.9, 44.2, 38.0, 35.9, 31.6, 29.4, 26.3, 25.8, 21.6, 13.8; IR (film) ν_max: 2934, 2862, 1734, 1492, 1270, 1220, 1067 cm^－1; MS (EI) m/z (%): 424 (M⁺), 155 (100); HRMS calcd for C₂₆H₂₆O₃F₂ 424.1850, found 424.1855.

  4-(Difluoromethyl)benzyl 2-(4-isobutylphenyl) propanoate (3y): To a 25 mL Schlenk tube were added 2y (0.45 mmol, 1.5 equiv.), Ni(PPh₃)₂Br₂ (5 mol%), 4, 4'-di^tBu- bpy (5 mol%), zinc dust (2.0 equiv.), KI (0.4 equiv.) and 3 Å MS (400 mg). The mixture was evacuated and backfilled with argon for three times, then DMPU (1.5 mL) and BrCF₂H 1 (2.5 mol•L^－1 in 1, 4-dioxane, 0.3 mmol, 1.0 equiv.) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 ℃). After stirring overnight, the reaction mixture was cooled to room temperature and filtered with a pad of celite. The filtrate was concentrated, and the residue was purified with silica gel chromatography [V(petroleum ether):V(EtOAc)＝10:1] to give product 3y (64 mg, 62% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.44 (d, J＝7.9 Hz, 2H), 7.29 (d, J＝8.0 Hz, 2H), 7.21 (d, J＝8.0 Hz, 2H), 7.11 (d, J＝8.0 Hz, 2H), 6.62 (t, J＝56.4 Hz, 1H), 5.15 (s, 2H), 3.78 (q, J＝7.1 Hz, 1H), 2.47 (d, J＝7.2 Hz, 2H), 1.93~1.81 (m, 1H), 1.53 (d, J＝7.2 Hz, 3H), 0.92 (d, J＝6.6 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －110.7 (d, J＝56.4 Hz, 2F); ¹³C NMR (101 MHz, CDCl₃) δ: 174.3, 140.7, 138.9 (t, J＝2.0 Hz), 137.4, 134.0 (t, J＝22.4 Hz), 129.3, 127.7, 127.2, 125.7 (t, J＝6.1 Hz), 114.5 (t, J＝238.7 Hz), 65.5, 45.1, 45.0, 30.2, 22.3, 18.3; IR (film) ν_max: 2956, 2869, 1735, 1381, 1158, 1074, 1021 cm^－1; MS (EI) m/z (%): 346 (M⁺), 161 (100); HRMS calcd for C₂₁H₂₄O₂F₂ 346.1744, found 346.1741.

  4.4   Gram-scale synthesis of compound 3t

  To a 100 mL of Schlenk tube were added 6-bromo-2- methylquinoline (13.5 mmol, 1.5 equiv.), Ni(PPh₃)₂Br₂ (10 mol%), bpy (10 mol%), zinc dust (2.0 equiv.) and KI (0.4 equiv.). The mixture was evacuated and backfilled with argon for three times, DMPU (45 mL) and BrCF₂H 1 (2.5 mol•L^－1 in 1, 4-dioxane, 9 mmol, 1.0 equiv.) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 ℃). After stirring overnight, the reaction mixture was cooled to room temperature. The reaction mixture was filtered with a pad of celite. The filtrate was added into 50 mL of water. The aqueous layer was extracted with a mixture of petroleum ether and EtOAc (V:V＝5:1; 100 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and then evaporated under reduced pressure and the resulting crude product was purified by column chromatography with ethyl acetate and petroleum ether (V:V＝1:5) as eluent to give product 3t (1.12 g, 64%) as a white solid (m.p. 48~50 ℃).

  4.5   Radcial clock experiment

  To a 25 mL of Schlenk tube were added 2g (0.9 mmol, 1.5 equiv.), Ni(PPh₃)₂Br₂ (10 mol%), bpy (10 mol%), KI (0.4 equiv.), and Zn dust (2.0 equiv.) under air. The mixture was then evacuated and backfilled with Ar (3 times). Compound 5 (0.9 mmol, 1.5 equiv.), DMPU (3 mL) and BrCF₂H (2.5 mol•L^－1 in dioxane, 240 μL, 0.6 mmol, 1.0 equiv) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 ℃). After stirring for 6 h, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated, and the residue was washed with 10 mL of water, extracted with organic solvent [V(petroleum ether):V(EtOAc)＝20:1] for three times. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel (petroleum ether) to give compound 6^[6] (16 mg, 14% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.22~7.11 (m, 4H), 6.02 (t, J＝4.4 Hz, 1H), 5.91 (tt, J＝56.8, 4.8 Hz, 1H), 2.97 (td, J＝16.5, 3.8 Hz, 2H), 2.75 (t, J＝8.1 Hz, 2H), 2.28 (dd, J＝12.5, 8.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －114.0 (dt, J＝56.8, 16.5 Hz, 2F); MS (EI) m/z (%): 194 (M⁺), 129 (100); HRMS calcd for C₁₂H₁₂F₂ 194.0907, found 194.0909.

  Supporting Information    Optimization of the reaction conditions, mechanistic studies and copies of ¹H NMR, ¹⁹F NMR and ¹³C NMR spectra of compounds 3 and 6. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Scheme 1  Mechanistic studies

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  Scheme 2  Proposed reaction mechanisms

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  Table 1.  Representative results for optimization of Ni-catalyzed difluoromethylation of 2a with BrCF₂H (1)^a

  Entry	[Ni]	Zn/equiv.	Additive (equiv.)	Yieldb/% of 3a/4/1
  1	NiBr2•Diglyme	1.2	—	16/10/36
  2	NiBr2•Diglyme	1.2	LiI (0.2)	24/Trace/44
  3	NiBr2•Diglyme	1.2	NaI (0.2)	30/12/21
  4	NiBr2•Diglyme	1.2	KI (0.2)	45/Trace/25
  5	NiBr2•Diglyme	2.0	KI (0.2)	62/Trace/7
  6	NiBr2•Diglyme	2.0	KI (0.4)	66/5/0
  7	Ni(PPh3)2Br2	2.0	KI (0.4)	73/5/0
  8	Ni(PPh3)2Cl2	2.0	KI (0.4)	60/12/0
  9	Ni(dppe)Cl2	2.0	KI (0.4)	27/12/0
  10	NiCl2•DME	2.0	KI (0.4)	19/Trace/34
  11	Ni(cod)2	2.0	KI (0.4)	0/8/45
  12c	Ni(PPh3)2Br2	2.0	KI (0.4)	78/4/0
  13c, d	Ni(PPh3)2Br2	2.0	KI (0.4)	90 (91)/Trace/0
  14c, d	—	2.0	KI (0.4)	0/9/0
  15c, d, e	Ni(PPh3)2Br2	2.0	KI (0.4)	0/8/10
  a Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv.), 2a (0.75 mmol, 2.5 equiv.), DMPU (2 mL), 6 h. b Determined by 19F NMR using fluorobenzene as an internal standard and number in parenthesis is isolated yield. c Ni(PPh3)2Br2 (10 mol%), bpy (10 mol%), 60 ℃, 6 h. d 1 (0.3 mmol, 1.0 equiv.), 2a (0.45 mmol, 1.5 equiv.), DMPU (1.5 mL). e The reaction was run in the absence of bpy.

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  Table 2.  Ni-catalyzed reductive cross-coupling of bromodifluoromethane (1) with aryl bromides (2)^a

  aReaction conditions (unless otherwise specified): 2 (0.9 mmol, 1.5 equiv.), 1 (0.6 mmol, 1.0 equiv.), DMPU (3.0 mL), 60 ℃, 6 h. Yields of isolated products are given. bNMR yield determined by 19F NMR. c2 (2.0 equiv.), 1 (0.6 mmol, 1.0 equiv.), Ni(PPh3)Br2 (5 mol%), 4, 4'-ditBu-bpy (5 mol%), 3Å MS (200 mg), 12 h. dGram-scale synthesis and reaction run for 12 h. e2 (1.5 equiv.), 6 (0.3 mmol, 1.0 equiv.), Ni(PPh3)Br2 (5 mol%), 4, 4'-ditBu-bpy (5 mol%), 3Å MS (400 mg), 12 h.

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•