English

• 1.   Introduction

  In the past decades, fluorine-containing compounds have been widely used in various fields such as material chemistry, ^[1] medicinal chemistry, ^[2] and agrochemistry.^[3] The effect of incorporating one or several fluorine atoms into an organic substrate can have a vital effect on the physical, chemical, and biological properties of the molecule, which is exemplified by the growing number of pharmaceuticals and agrochemicals that contain fluorine atoms in their structure.^[4] Among organofluorinated molecules, difluoroethyl aryl ethers emerged as useful groups and were present in many bioactive substances due to high metabolic stability and significant lipophilicity of CF₂HCH₂O group (Scheme 1).^{[5, 6]}

  Scheme 1

  

  Scheme 1.  Representative structures of bioactive molecules containing difluoroethyl aryl ether moiety

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  Meanwhile, methods have been reported over the past decades for the assembling of difluoroethyl aryl ethers. The main method relies on the Williamson ether synthesis, which involves the nucleophilic addition of a phenol with a difluoroethyl electrophile, ^[7] such as difluoroethyl iodide or difluoroethyl mesylate. However, these strong alkylating agents are usually carcinogenic and therefore need extensive health and safety precautions (Scheme 1).^[8] Thus, the development of more general and applicable methods to prepare the difluoroethyl aryl ethers having been an important theme in organic chemistry and drug discovery. In this regard, palladium-catalyzed C—O coupling reactions have been an efficient method over traditional methods.^[9] For example, Singh and coworkers^[10] reported a palladium-catalyzed cross-coupling reaction of primary fluoroalkyl alcohols with activated aryl halides. However, the limitation of this method is that these procedures required the use of the precious metal Pd and phosphine ligands. Inspired by the achievements of the Cu-catalyzed C—O coupling reaction, ^[11] we assume that an alternative method that involves the copper-catalyzed arylated etherification reaction between aryl halide and commercial 2, 2-difluoro- ethanol would be feasible (Scheme 1).

  Generally speaking, traditional Ullmann-typed C—O coupling procedures suffered from drawbacks such as harsh reaction conditions, stoichiometric amounts of copper and restricted range of substrates.^[12] In the past two decades, important breakthroughs were reported for copper-catalyzed C—O coupling reaction with the use of appropriate ligands by the groups of Buchwald, Taillefer, Ma and Cai.^[13] Therefore, the methods for the coupling of aryl halides and 2, 2, 2-trifluoroethanol were also developed.^[14] However, there is no related report of the formation of difluoroethyl aryl ethers from 2, 2-difluoroethanol directly. Probably due to the weaker nucleophilicity of the 2, 2-di- fluoroethanol compared with the trifluoro one. Herein, we report the CuI catalyzed C—O coupling-type arylated etherification reaction for the preparation of difluoroethyl aryl ethers.

  2.   Results and discussion

  The reaction of 3-bromobenzotrifluoride (1a) and 2, 2-difluoroethanol (2) in the presence of K₃PO₄ was initially examined, using CuI as the catalyst precursor and 8-hydroxyquinoline as the ligand at 100 ℃. However, no desired product was observed under this reported procedure (Table 1, Entry 1).^[15] Then the results of replacing K₃PO₄ with Cs₂CO₃ were checked. To our delight, the reaction proceeded well to give the desired product 3a in 75% GC yield (Table 1, Entry 2). Encouraged by this, further optimization was first done with a survey of the ligand. Unfortunately, it was found that when using 1, 10-phenanthroline or ethyl 2-oxocyclohexanecarboxylate as ligand in the presence of Cs₂CO₃, the reaction proceeded sluggish to provide the target compound in trace yields (Table 1, Entries 3, 4). Given that the ligand/base can dramatically affect the yield, ^[16] a thorough screening of a range of base with 8-hydroxyquinoline has been carried out (Table 1, Entries 5~14). It was found that when EtONa, KOH, NaHCO₃, KHCO₃, KF, K₂HPO₄, or NaH was used as base, only trace product was formed. When NaOH or K₂CO₃ was used, little or moderate product was obtained (Table 1, Entries 5, 13). Gratifyingly, the desired product 3a was achieved in quantitative GC yield when t-BuOK was used as base after 12 h in the presence of 8-hydroxyquinoline (Table 1, Entry 14). As expected, when CF₃CH₂OH was used instead of CHF₂CH₂OH in this condition, the reaction proceeded well in nearly quantitative GC yield.^[14b]

  表 1

  

  表 1  Optimization of reaction conditions^a

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  Entry	Base	L	Yieldb/%
  1	K3PO4	8-Hydroxyquinoline	0
  2	Cs2CO3	8-Hydroxyquinoline	75
  3	Cs2CO3	1, 10-Phenanthroline	Trace
  4	Cs2CO3	Ethyl 2-oxocyclohexane carboxylate	Trace
  5	NaOH	8-Hydroxyquinoline	13
  6	C2H5ONa	8-Hydroxyquinoline	Trace
  7	KOH	8-Hydroxyquinoline	Trace
  8	NaHCO3	8-Hydroxyquinoline	Trace
  9	K2HPO4	8-Hydroxyquinoline	Trace
  10	KF	8-Hydroxyquinoline	Trace
  11	KHCO3	8-Hydroxyquinoline	Trace
  12	NaH	8-Hydroxyquinoline	Trace
  13	K2CO3	8-Hydroxyquinoline	58
  14	t-BuOK	8-Hydroxyquinoline	100
  a Reaction conditions: 1a (1.0 mmol), 2 (2 mL), base (2 equiv.), CuI (0.1 equiv.) and ligand (0.2 equiv.), 100 ℃ for 12 h. b GC yield.

  With the optimized reaction conditions in hand, the sub-strate generality of this copper-catalyzed arylated etherification of 2, 2-difluoroethanol with various aryl halides was explored. As shown in Scheme 2, the reactions of aryl bromides containing CF₃, methoxy or Cl group at meta-positions provided the desired product in good isolated yields (3a~3c). Further, when aryl bromides bearing electron-withdrawing or electron-donating groups at para-positions were used, the etherification reactions also proceeded smoothly to give the desired difluoroethyl aryl ethers in good yields (3d~3l). It is noted that when the aryl bromides containing two substituents at the 3, 4 or 3, 5 positions were used, the etherification reactions proceeded well with moderate to good yields (3m~3q). Particularly, tri-substituted 3, 4, 5-trimethoxybromobenzene was compatible with this method to furnish the corresponding ether with moderate yield (3r). In addition, 3-bromopyridine was well tolerated and the desired product (3v) was given in 73% isolated yield. However, the reactions of aryl bromides with orth-substituents gave the difluoroethyl aryl ethers in low yields owing to the steric effect (3s~3u).

  Scheme 2

  

  Scheme 2.  Two proposed pathways for the Cu catalyzed reaction of aryl bromide (1a) and 2, 2-difluoroethanol (2)

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  Next, the scope of aryl iodides was investigated for the CuI catalyzed C—O coupling in the presence of 8-hydro- xyquinoline/t-BuOK with 2, 2-difluoroethanol (Scheme 3). In general, various aryl iodides are suitable for this reac- tion. The steric and electronic effects of the substituents on yields are similar to aryl bromides. For example, aryl iodides with NO₂, CN at para-position or OMe, Cl, NO₂, CF₃ at meta-positon, were all smoothly coupled with 2, 2-difluoroethanol, giving desired products in excellent yields (5a~5g). While aryl iodides with NH₂ or CN at ortho-position only showed low reactivity with low to moderate yields (5h~5k). Though aryl iodides with NH₂ or CN at ortho-position only showed low reactivity (5h~5k), the corresponding products are valuable substrates for the hydrogen-borrowing reaction.^[17]

  表 2

  

  表 2  CuI/8-Hydroxyquinoine-catalyzed arylated etherification reaction of aryl bromides with 2, 2-difluoroethanol

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  表 3

  

  表 3  CuI/8-Hydroxyquinoine catalyzed coupling reaction of aryl iodides with 2, 2-difluoroethanol

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  Finally, we focused on elucidating the possible mechanism of this type of copper-catalyzed C—O cross coupling reaction. Based on previous reports, most studies support the initial formation of LCu(Ⅰ)Nu complex, then oxidative addition of aryl halide (ArBr) to the complex, followed by dissociation of HBr providing LCu(Ⅲ)Ar(OR), which regenerates the active Cu(Ⅰ) species and the desired product ArOR through reductive elimination. However, the detection of organometallic copper(Ⅲ) complexes has been very scarce under this catalytic Ullmann reaction conditions.^[18] In order to have a better insight of the reaction pathway, several mechanistic experiments were carried out. Firstly, when a stoichiometric amount of radical scavenger 2, 2, 6, 6- tetramethylpiperidine-1-oxyl (TEMPO) was added, the reaction was not suppressed and the difluoroethyl aryl ether 3a was delivered in 97% GC yield, which indicated that the reaction probably didn’t involve a radical process. Further, in situ ESI-MS analysis was carried out. A solution of 2, 2-difluoroethanol (5 equiv.), potassium tert- butoxide (2 equiv.), m-bromobenzotrifluo- ride (1 equiv.), CuI (10 mol%) and 8-hydroxyquinoline (20 mol%) was stirred at room temperature for 40 min. ESI-MS analysis (Figure 1) of the reaction solution showed the peak m/z 389.98 which is identified as [CuL₂]^－K⁺ and the peak of its dimer at m/z 743.01. Very fortunately, the peak at m/z 868.91 was observed, which is identified as the dimer of LCu(Ⅲ)Ar(OR). Obviously, it is the direct evidence for the existence of Cu(Ⅲ) intermediate during this difluoro- ethoxylation reaction.

  图 1

  

  图 1.  ESI-MS experiment on the CuI-catalyzed arylated etherification reaction between m-bromobenzotrifluoride and 2, 2- difluoroethanol

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  On the basis of above experimental results and the literature precedence as well as our density functional theory (DFT) calculations, ^[19] two plausible reaction pathways were proposed for this catalytic Ullmann-type arylated etherification reaction (Scheme 2). The path A begins with the coordination of the nucleophile CHF₂CH₂O^－ to the Cu(Ⅰ) center ([CuL₂]^－) to give [LCu-Nu]^－ (Int 1), which is followed by the oxidative addition with aryl bromide to form the LCu(Ⅲ)Ar(OR) species (Int 3). The subsequent reductive elimination gives the desired coupling product, together with the releasing of the Cu(Ⅰ) species. The path B would start with the oxidative addition of the [CuL₂]^－ intermediate with aryl bromide, then the rapid ligand substitution with nucleophile forms the detectable LCu(Ⅲ)- Ar(OR) (Int 3). Finally, reductive elimination from Int 3 would then produce the coupling product. As shown in Figure S2 and Figure S3 (see supporting information), the two Cu(Ⅰ) complexes [LCu-Nu]^－ and [CuL₂]^－ would perform the oxidative addition with aryl bromide as the rate-limiting step of the reaction. However, the free energy barrier for oxidative addition of [LCu-Nu]ˉ in path A is 89.6 kJ/mol, while the free energy barrier of [CuL₂]^－ in path B is only 70.3 kJ/mol. It was due to that electron- rich [CuL₂]^－ would be more reactive toward oxidative addition than [LCu-Nu]^－ complex. By comparison, the following reductive elimination is a facile step for both pathway with an energy barrier of 15.9 kJ/mol. Hence, the previous report suggested that the coordination of nucleophile to Cu(Ⅰ) may occur before activation of the aryl halide (path A). In our case, however, the path B involving oxidative addition/nucleophile substitution and reductive elimina- tion, is more reasonable.

  3.   Conclusions

  In summary, we have developed a general and efficient method for the construction of difluoroethyl aryl ethers through the C—O coupling-type arylated etherification reaction of aryl bromides or iodides with 2, 2-difluoroe- thanol. The reaction proceeded smoothly with CuI as a catalyst and 8-hydroxyquinoline as a ligand in the presence of t-BuOK under mild conditions. In addition, ESI-MS studies reveal that LCu(Ⅲ)Ar(OR) complex is involved in the reaction, and further DFT calculations support the new pathway of this C—O coupling reaction.

  4.   Experimental section

  4.1   General information

  Unless specifically stated, all reagents were commercially obtained and purified prior to use if appropriate. Flash column chromatography was performed over silica (100~200 mesh). ¹H NMR and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively on an Advance (Bruker) 400 MHz Nuclear Magnetic Resonance Spectromer, and were referenced to the internal solvent signals. EI and CI mass spectra were performed on a Trace DSQ GC/ MS spectrometer. High Resolution Mass Spectra (ESI- HRMS) were operated on a microOTOF-QII (Bruker). Thin layer chromatography was performed using Silica.

  4.2   General procedure for the coupling reaction of aryl bromides or aryl iodides with 2, 2-difluoroethanol

  To a solution of CuI (19 mg, 0.1 mmol), 8-hydroxy- quinoline (29 mg, 0.2 mmol) and t-BuOK (224 mg, 2 mmol) in 2, 2-difluoroethanol (2 mL) was added aryl bromide or aryl iodides (1 mmol). The mixture was heated at 100 ℃ for 12 h and then saturated NH₄Cl (30 mL) was added. The mixture was filtered through a pad of celite, and extracted with EtOAc (30 mL×3). The combined organic phase was dried over Na₂SO₄, concentrated in vacuo, and purified by flash column chromatograph on silica gel to give the corresponding coupling product.

  1-(2, 2-Difluoroethoxy)-3-(trifluoromethyl)benzene (3a): Light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.43 (t, J＝8.0 Hz, 1H), 7.31~7.25 (m, 1H), 7.16 (s, 1H), 7.10 (dd, J＝8.4, 2.0 Hz, 1H), 6.11 (tt, J＝54.8, 4.0 Hz, 1H), 4.22 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.0, 132.3 (q, J＝33 Hz), 130.4, 123.9 (q, J＝267 Hz), 118.9 (q, J＝4 Hz), 118.2, 113.5 (t, J＝240 Hz), 111.7 (q, J＝4 Hz), 67.6 (t, J＝30 Hz); HRMS (APCI) calcd for C₉H₇F₅O: 226.0412, found 226.0420.

  1-(2, 2-Difluoroethoxy)-3-methoxybenzene (3b): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:7.20 (t, J＝8.1 Hz, 1H), 6.62~6.54 (m, 1H), 6.54~6.44 (m, 2H), 6.07 (tt, J＝55.2, 4.4 Hz, 1H), 4.16 (td, J＝13.2, 4.4 Hz, 2H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.1, 159.1, 130.3, 113.8 (t, J＝240 Hz), 107.7, 106.6, 101.5, 67.4 (t, J＝30 Hz), 55.5; HRMS (APCI) calcd for C₉H₁₁F₂O₂ [M+H]⁺: 189.0722, found 189.0726.

  1-Chloro-3-(2, 2-difluoroethoxy)benzene (3c): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.23 (dd, J＝10.4, 2.4 Hz, 1H), 7.03~6.98 (m, 1H), 6.95~6.90 (m, 1H), 6.84~6.79 (m, 1H), 6.08 (tt, J＝54.8, 4.0 Hz, 1H), 4.16 (td, J＝13.2, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.5, 135.3, 130.6, 130.4, 122.4, 115.3, 113.6 (t, J＝240 Hz), 113.1, 67.5 (t, J＝30 Hz); HRMS (APCI) calcd for C₈H₇ClF₂O: 192.0148, found 192.0152.

  1-(2, 2-Difluoroethoxy)-4-methylbenzene (3d): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.02 (d, J＝8.3 Hz, 2H), 6.73 (d, J＝8.6 Hz, 2H), 5.98 (tt, J＝55.2, 4.0 Hz, 1H), 4.06 (td, J＝13.2, 4.0 Hz, 2H), 2.23 (s, J＝9.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 155.8, 131.4, 130.2, 114.7, 114.0 (t, J＝240 Hz), 67.6 (t, J＝30 Hz), 20.6; HRMS (APCI) calcd for C₉H₁₁F₂O [M+H]⁺: 173.0772, found 173.0779.

  1-(2-(2, 2-Difluoroethoxy)phenyl)ethanone (3e): Pale yellow solid, m.p. 48~50 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.99~7.93 (m, 2H), 6.96 (d, J＝8.9 Hz, 2H), 6.12 (tt, J＝54.8, 4.0 Hz, 1H), 4.25 (td, J＝12.8, 4.0 Hz, 2H), 2.57 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 196.7, 161.5, 131.6, 130.8, 114.4, 113.5 (t, J＝240 Hz), 67.3 (t, J＝30 Hz), 26.5; HRMS (APCI) calcd for C₁₀H₁₁F₂O₂ [M+H]⁺: 201.0722, found 201.0730.

  1-(2, 2-Difluoroethoxy)-4-fluorobenzene (3f): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.03~6.94 (m, 2H), 6.90~6.82 (m, 2H), 6.07 (tt, J＝55.2, 4.0 Hz, 1H), 4.14 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.3, 156.9, 154.0, 116.3 (d, J＝20 Hz), 116.0 (d, J＝8 Hz), 116.0, 113.8 (t, J＝240 Hz), 68.2 (t, J＝29 Hz); HRMS (APCI) calcd for C₈H₇F₃O: 176.0444, found 176.0447.

  4-(2, 2-Difluoroethoxy)biphenyl (3g): White solid, m.p. 87~89 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.57~7.51 (m, 4H), 7.42 (t, J＝7.6 Hz, 2H), 7.34 (s, 1H), 7.32 (t, J＝7.3 Hz, 1H), 6.11 (tt, J＝54.8, 4.0 Hz, 1H), 4.22 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 157.4, 140.6, 135.3, 128.9, 128.5, 127.1, 127.0, 115.1, 113.9 (t, J＝240 Hz), 67.57 (t, J＝30 Hz); MS (EI) m/z: 234, 215, 183, 169, 153, 76.

  1-tert-Butyl-4-(2, 2-Difluoroethoxy)benzene(3h): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.24 (d, J＝8.8 Hz, 2H), 6.77 (d, J＝8.8 Hz, 2H), 5.99 (tt, J＝55.6, 4.4 Hz, 1H), 4.08 (td, J＝13.2, 4.0 Hz, 2H), 1.22 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 155.7, 144.9, 126.6, 114.3, 114.0 (t, J＝240 Hz), 67.6 (t, J＝30 Hz), 34.3, 31.6; HRMS (APCI) calcd for C₁₂H₁₆F₂O: 214.1164, found 214.1150.

  4-(2, 2-Difluoroethoxy)benzonitrile (3i): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J＝8.9 Hz, 2H), 6.99 (d, J＝8.9 Hz, 2H), 6.11 (tt, J＝54.8, 4.0 Hz, 1H), 4.24 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.9, 134.3, 118.8, 115.4, 113.3 (t, J＝240 Hz), 105.7, 67.3 (t, J＝30 Hz); HRMS (APCI) calcd for C₉H₈F₂NO [M+H]⁺: 184.0568, found 184.0572.

  1-(2, 2-Difluoroethoxy)-4-(trifluoromethyl)benzene (3j): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J＝8.6 Hz, 2H), 6.99 (d, J＝8.6 Hz, 2H), 6.11 (tt, J＝54.8, 4.0 Hz, 1H), 4.22 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 127.3 (q, J＝4 Hz), 124.4 (q, J＝33 Hz), 124.4 (q, J＝70 Hz), 114.8, 113.5 (t, J＝240 Hz), 67.4 (t, J＝29 Hz); HRMS (APCI) calcd for C₉H₈F₅O: 226.0412, found 226.0420.

  1-(2, 2-Difluoroethoxy)-4-methoxybenzene (3k): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ: 6.89~6.80 (m, 4H), 6.05 (tt, J＝55.2, 4.0 Hz, 2H), 4.12 (td, J＝13.2, 4.0 Hz, 2H), 3.77 (d, J＝2.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 154.9, 152.1, 132.4, 116.0, 114.9, 114.0 (t, J＝240 Hz), 68.4 (t, J＝30 Hz), 55.8; HRMS (APCI) calcd for C₉H₁₁F₂O₂ [M+H]⁺: 189.0722, found 189.0731.

  4-(2, 2-Difluoroethoxy)-N, N-dimethylbenzenamine (3l): Purple black solid, m.p. 59~61 ℃; ¹H NMR (400 MHz, CDCl₃) δ:6.85~6.76 (m, 2H), 6.71 (d, J＝7.6 Hz, 2H), 5.98 (tt, J＝55.2, 4.0 Hz, 1H), 4.05 (td, J＝13.2, 4.0 Hz, 2H), 2.82 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ:116.1, 115.0, 114.1 (t, J＝240 Hz), 111.7, 100.2, 68.8 (t, J＝30 Hz), 41.9; HRMS (APCI) calcd for C₁₀H₁₄F₂NO [M+H]⁺: 202.1038, found 202.1045.

  4-(2, 2-Difluoroethoxy)-1, 2-dimethoxybenzene (3m): Pale yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ:6.76 (t, J＝8.9 Hz, 1H), 6.55 (d, J＝2.8 Hz, 1H), 6.39 (dd, J＝8.7, 2.8 Hz, 1H), 6.06 (tt, J＝55.2, 4.1 Hz, 1H), 4.13 (td, J＝13.2, 4.1 Hz, 2H), 3.84 (d, J＝6.5 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ:152.4, 150.1, 144.5, 113.8 (t, J＝240 Hz), 111.8, 104.1, 101.3, 68.0 (t, J＝30 Hz), 56.4, 55.9, 25.7; HRMS (APCI) calcd for C₁₀H₁₃F₂O [M+H]⁺: 219.0827, found 219.0833.

  1-(2, 2-Difluoroethoxy)-3, 5-dimethylbenzene (3n): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:6.58 (s, 1H), 6.46 (s, 2H), 5.98 (tt, J＝55.2, 4.4 Hz, 1H), 4.06 (td, J＝13.2, 4.8 Hz, 2H), 2.21 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ:157.9, 139.7, 123.8, 114.0 (t, J＝240 Hz), 112.5, 67.4 (t, J＝29 Hz), 21.5; HRMS (APCI) calcd for C₁₀H₁₃F₂O [M+H]⁺:187.0929, found 187.0922.

  1-(2, 2-Difluoroethoxy)-3, 5-dimethoxybenzene (3o): Co- lorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:6.13~6.14 (m, 1H), 6.08 (m, 2H), 6.07 (tt, J＝55.2, 4.4 Hz, 1H), 4.13 (td, J＝13.2, 4.0 Hz, 2H), 3.77 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ:161.7, 159.7, 113.7 (t, J＝240 Hz), 94.1, 93.6, 67.3 (t, J＝30 Hz), 55.5; HRMS (ESI) calcd for C₁₆H₂₅F₂O [M+H]⁺: 219.0827, found 219.0824.

  1, 3-Di-tert-butyl-5-(2, 2-Difluoroethoxy)benzene (3p): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:7.09 (t, J＝1.4 Hz, 1H), 6.77 (d, J＝1.5 Hz, 2H), 6.09 (tt, J＝55.2, 4.0 Hz, 1H), 4.18 (td, J＝13.2, 4.4 Hz, 2H), 1.30 (d, J＝7.8 Hz, 18H); ¹³C NMR (100 MHz, CDCl₃) δ:157.5, 152.8, 116.4, 114.1 (t, J＝240 Hz), 109.1, 67.5 (t, J＝30 Hz), 35.2, 31.6; HRMS (APCI) calcd for C₁₆H₂₅F₂O [M+H]⁺: 271.1868, found 271.1875.

  1-(2, 2-Difluoroethoxy)-3, 5-bis(trifluoromethyl)benzene (3q): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:7.55 (s, 1H), 7.35 (s, 2H), 6.13 (tt, J＝54.8, 4.0 Hz, 1H), 4.27 (tt, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:158.4, 133.4 (q, J＝33 Hz), 123.1 (q, J＝271 Hz), 115.8 (q, J＝4 Hz), 115.2, 113.1 (t, J＝240 Hz), 67.8 (t, J＝30 Hz); HRMS (APCI) calcd for C₁₀H₆F₈O: 294.0285, found 294.0292.

  5-(2, 2-Difluoroethoxy)-1, 2, 3-trimethoxybenzene (3r): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:6.21 (t, J＝4.0 Hz, 0.25H), 6.17 (s, 2H), 6.07 (t, J＝4.2 Hz, 0.5H), 5.94 (t, J＝4.2 Hz, 0.25H), 4.16 (td, J＝13.2, 4.0 Hz, 2H), 3.85 (s, 6H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ:154.5, 154.0, 133.4, 113.8 (t, J＝240 Hz), 92.8, 68.0 (t, J＝29 Hz), 61.2, 56.3; HRMS (APCI) calcd for C₁₁H₁₅F₂O₄ [M+H]⁺: 249.0933, found 249.0940.

  1-(2-(2, 2-Difluoroethoxy)phenyl)ethanone (3s): Pale yellow solid, m.p. 76~78 ℃; ¹H NMR (400 MHz, CDCl₃) δ:7.77 (dd, J＝7.6, 1.6 Hz, 1H), 7.53~7.43 (m, 1H), 7.09 (t, J＝8.0 Hz, 1H), 6.91 (d, J＝8.0 Hz, 1H), 6.16 (tt, J＝54.8, 4.0 Hz, 1H), 4.29 (td, J＝13.2, 4.0 Hz, 2H), 2.63 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ:199.3, 156.8, 133.8, 130.9, 128.9, 122.2, 113.3 (t, J＝240 Hz), 112.4, 67.6 (t, J＝29 Hz), 32.0; HRMS (APCI) calcd for C₁₀H₁₁F₂O₂ [M+H]⁺: 201.0722, found 201.0726.

  2-(2, 2-Difluoroethoxy)biphenyl (3t): Yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ:7.48~7.41 (m, 2H), 7.37~7.21 (m, 5H), 7.04 (td, J＝7.6, 0.8 Hz, 1H), 6.89 (d, J＝8.1 Hz, 1H), 5.88 (tt, J＝55.3, 4.2 Hz, 1H), 4.05 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:154.9, 138.0, 131.8, 131.4, 129.6, 128.8, 128.2, 127.3, 122.7, 113.9 (t, J＝240 Hz), 113.6, 68.4 (t, J＝30 Hz), 31.8, 29.8, 1.9; HRMS (APCI) calcd for C₁₄H₁₃F₂O [M+H]⁺: 235.0929, found 235.0935.

  1-(2, 2-Difluoroethoxy)-2-fluorobenzene (3u): Light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ:6.97~7.05 (m, 2H), 6.89~6.93 (m, 2H), 6.03 (tt, J＝56.0, 4.0 Hz, 1H), 4.05 (td, J＝12.0, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:153.0 (d, J＝245 Hz), 145.8 (d, J＝10 Hz), 124.5, 124.4, 123.0 (d, J＝7 Hz), 116.7 (t, J＝18 Hz), 113.6 (t, J＝240 Hz), 69.1 (t, J＝29 Hz); MS (EI) m/z: 176, 157, 125, 111, 95, 81, 65.

  3-(2, 2-Difluoroethoxy)pyridine (3v): Light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ:8.35 (s, 1H), 8.30 (m, 1H), 7.23~7.28 (m, 2H), 6.11 (tt, J＝56.0, 4.0 Hz, 1H), 4.24 (td, J＝16.0, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:154.0, 143.4, 137.9, 124.0, 121.5, 113.3 (t, J＝240 Hz), 67.4 (t, J＝30 Hz); MS (EI) m/z: 159, 108, 95, 91, 78, 73. HRMS (ESI) calcd for C₇H₈F₂NO [M+H]⁺: 160.0568, found 160.0568.

  1-(2, 2-Difluoroethoxy)-3-nitrobenzene (5c): Yellow solid, m.p. 41~43 ℃, ¹H NMR (400 MHz, CDCl₃) δ:7.91 (dd, J＝8.0, 1.8 Hz, 1H), 7.76 (t, J＝2.2 Hz, 1H), 7.49 (t, J＝8.2 Hz, 1H), 7.28 (dd, J＝8.4, 1.6 Hz, 1H), 6.13 (tt, J＝54.8, 4.0 Hz, 1H), 4.28 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:158.3, 149.4, 130.5, 121.8, 117.2, 113.3 (t, J＝240 Hz), 109.2, 67.8 (t, J＝30 Hz); HRMS (APCI) calcd for C₈H₈ F₂NO₃ [M+H]⁺: 204.0467, found 204.0472.

  1-(2, 2-Difluoroethoxy)-2-nitrobenzene (5f): Yellow solid, m.p. 50~52 ℃; ¹H NMR (400 MHz, CDCl₃) δ:7.87 (dd, J＝8.4, 1.6 Hz, 1H), 7.57 (td, J＝8.4, 1.6 Hz, 1H), 7.18~7.07 (m, 2H), 6.15 (tt, J＝54.8, 4.0 Hz, 1H), 4.32 (td, J＝12.8, 4.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:151.2, 140.7, 134.3, 126.0, 122.4, 115.8, 113.3 (t, J＝240 Hz), 69.2 (t, J＝30 Hz); HRMS (APCI) calcd for C₈H₈F₂NO₃ [M+H]⁺: 204.0467, found 204.0476.

  2-(2, 2-Difluoroethoxy)benzenamine (5h): Black oil. ¹H NMR (400 MHz, CDCl₃) δ:6.77 (td, J＝8.0, 1.6 Hz, 1H), 6.71~6.57 (m, 3H), 6.00 (tt, J＝55.2, 4.4 Hz, 1H), 4.10 (td, J＝13.2, 4.4 Hz, 2H), 3.72 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:145.4, 136.8, 122.9, 120.0, 118.5, 115.8, 113.8 (t, J＝240Hz), 112.6, 68.0 (t, J＝29 Hz); HRMS (APCI) calcd for C₈H₁₀F₂NO [M+H]⁺: 174.0725, found 174.0730.

  2-(2, 2-Difluoroethoxy)benzonitrile (5i): Colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ:7.49 (dd, J＝15.6, 7.6 Hz, 2H), 7.02 (dd, J＝7.6, 0.8 Hz, 1H), 6.91 (d, J＝8.3 Hz, 1H), 6.08 (tt, J＝54.8, 4.0 Hz, 1H), 4.23 (td, J＝12.8, 4.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:159.2, 134.6, 134.1, 122.3, 115.8, 113.3 (t, J＝240 Hz), 112.7, 102.7, 68.0 (t, J＝30 Hz); HRMS (APCI) calcd for C₉H₈F₂NO [M+H]⁺: 184.0568, found 184.0572.

  1-(2, 2-Difluoroethoxy)-4-nitrobenzene (5j): Light yellow solid, m.p. 87~88 ℃; ¹H NMR (400 MHz, CDCl₃) δ:788 (d, J＝1.6 Hz, 1H), 7.86~7.58 (m, 1H), 7.18~7.09 (m, 2H), 6.14 (tt, J＝54.8, 4.0 Hz, 1H), 4.29 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:162.5, 142.6, 126.2, 114.8, 113.2 (t, J＝240 Hz), 67.6 (t, J＝30 Hz); HRMS (APCl) calcd for C₈H₈F₂NO₃ [M+H]⁺ 204.0467, found 204.0475.

  1-(2, 2-Difluoroethoxy)naphthalene (5k): Brown liquid. ¹H NMR (400 MHz, CDCl₃) δ:8.22~8.14 (m, 1H), 7.74 (dd, J＝5.6, 2.4 Hz, 1H), 7.47~7.38 (m, 3H), 7.29 (t, J＝8.0 Hz, 1H), 6.72 (d, J＝7.6 Hz, 1H), 6.16 (tt, J＝55.2, 4.0 Hz, 1H), 4.28 (td, J＝12.8, 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:153.6, 134.7, 127.7, 126.9, 125.8, 125. 7, 125.6, 121.9, 121.8, 113.9 (t, J＝240 Hz), 105.3, 67.7 (t, J＝30 Hz); HRMS (APCI) calcd for C₁₂H₁₁F₂O [M+H]⁺: 209.0772, found 209.0780.

  Supporting Information NMR spectra for compounds, ESI-MS analysis of reaction intermediates, and DFT studies are available free of charge in the Supporting Information via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Scheme 1  Representative structures of bioactive molecules containing difluoroethyl aryl ether moiety

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  Scheme 2  Two proposed pathways for the Cu catalyzed reaction of aryl bromide (1a) and 2, 2-difluoroethanol (2)

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  图 1  ESI-MS experiment on the CuI-catalyzed arylated etherification reaction between m-bromobenzotrifluoride and 2, 2- difluoroethanol

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  表 1  Optimization of reaction conditions^a

  Entry	Base	L	Yieldb/%
  1	K3PO4	8-Hydroxyquinoline	0
  2	Cs2CO3	8-Hydroxyquinoline	75
  3	Cs2CO3	1, 10-Phenanthroline	Trace
  4	Cs2CO3	Ethyl 2-oxocyclohexane carboxylate	Trace
  5	NaOH	8-Hydroxyquinoline	13
  6	C2H5ONa	8-Hydroxyquinoline	Trace
  7	KOH	8-Hydroxyquinoline	Trace
  8	NaHCO3	8-Hydroxyquinoline	Trace
  9	K2HPO4	8-Hydroxyquinoline	Trace
  10	KF	8-Hydroxyquinoline	Trace
  11	KHCO3	8-Hydroxyquinoline	Trace
  12	NaH	8-Hydroxyquinoline	Trace
  13	K2CO3	8-Hydroxyquinoline	58
  14	t-BuOK	8-Hydroxyquinoline	100
  a Reaction conditions: 1a (1.0 mmol), 2 (2 mL), base (2 equiv.), CuI (0.1 equiv.) and ligand (0.2 equiv.), 100 ℃ for 12 h. b GC yield.

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  表 2  CuI/8-Hydroxyquinoine-catalyzed arylated etherification reaction of aryl bromides with 2, 2-difluoroethanol

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  表 3  CuI/8-Hydroxyquinoine catalyzed coupling reaction of aryl iodides with 2, 2-difluoroethanol

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•