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Article

1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6

by
Dingben Chen
1,2,
Ling Huang
1,
Mingyu Liang
1,
Xiaojing Chen
1,
Dongdong Cao
1,
Pan Xiao
2,3,
Chuanfa Ni
2 and
Jinbo Hu
2,3,*
1
School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, China
2
Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
3
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(12), 2905; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29122905
Submission received: 2 April 2024 / Revised: 6 June 2024 / Accepted: 14 June 2024 / Published: 19 June 2024
(This article belongs to the Special Issue Advances in Modern Fluorine Chemistry)
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Abstract

:
The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of para-quinone methides (p-QMs) with Me3SiRf (Rf = CF2H, CF3, CF2CF3, CF2COOEt, and CF2SPh) under mild conditions are described. Although Me3SiCF2H shows lower reactivity than Me3SiCF3, it can react with p-QMs promoted by CsF/18-Crown-6 to give structurally diverse difluoromethyl products in good yields. The products can then be further converted into fluoroalkylated para-quinone methides and α-fluoroalkylated diarylmethanes.

1. Introduction

Organofluorine compounds have been widely applied in various fields, including pharmaceuticals, agrochemicals, materials, surfactants, and catalysis, thanks to the unique properties of fluorine [1,2,3,4,5,6,7,8,9]. The incorporation of fluorine atoms or fluorinated moieties is recognized for its ability to significantly enhance the metabolic stability, lipophilicity, and binding properties of bioactive organic molecules [10,11,12,13]. Among the various fluorinated moieties, the di- and trifluoromethyl groups have garnered considerable attention due to their utilization in numerous drugs and pesticides, such as efavirenz (HIV-RT inhibitor), mefloquine (antimalarial), eflornithine (ODC inhibitor), roflumilast (drug for COPD), fluxapyroxad (fungicide), and thiazopyr (herbicide) [3,14,15,16,17]. Consequently, developing new methods for the efficient introduction of di- and trifluoromethyl groups into organic molecules holds significant synthetic interest.
Nucleophilic fluoroalkylation has proven to be a convenient method for preparing fluorinated compounds [18,19,20,21]. Among the various nucleophilic fluoroalkylating agents, Ruppert–Prakash reagent (Me3SiCF3) is the most popular trifluoromethylating agent, widely employed for direct nucleophilic trifluoromethylation of aldehyde, ketone, imine, ester, and amide substrates, etc. [22,23]. However, compared with Me3SiCF3, the silane reagent Me3SiCF2H exhibits lower reactivity due to the relatively weak electron-withdrawing ability of the CF2H group, which makes cleavage of the Si-CF2H bond more difficult than that of the Si-CF3 bond [24]. Therefore, the synthetic application of Me3SiCF2H in nucleophilic difluoromethylation has been largely retarded [25,26,27,28,29,30,31,32,33,34,35,36].
In 2011, our group first demonstrated the effectiveness of utilizing Me3SiCF2H in nucleophilic difluoromethylation activated by CsF or tBuOK under mild conditions [25]. This discovery made people realize that Me3SiCF2H could be used as an efficient difluoromethylation reagent. Subsequently, in 2016, our group conducted in-depth research on the 1,2-addition of Me3SiCF2H to enolizable ketones. We found that CsF/18-crown-6 acts as an initiation system to produce a pentavalent silicon reactive intermediate [(18-crown-6)Cs]+[(CH3)3Si(CF2H)2]−, which serves as a temporary reservoir for the difluoromethyl anion, playing a pivotal role in the success of the difluoromethylation in enolizable ketones [37]. In recent years, other strong basic initiators, such as tBu-P4 and t-AmOK, among others, have been developed for various difluoromethylations with TMSCF2H [26,30,31]. However, identifying appropriate initiators to facilitate the difluoromethylation of base-sensitive substrates with Me3SiCF2H remains a formidable challenge.
Due to the hard nature of fluoroalkyl anions, the direct regioselective 1,4-nucleophilic fluoroalkylation of α,β-unsaturated carbonyl compounds is a challenging task [38,39,40,41], and 1,4-nucleophilic fluoroalkylations are often accompanied with a 1,2-addition reaction [39,40]. Moreover, 1,4-trifluoromethylation of Me3SiCF3 activated by AcONa or TBAF [38] is mainly limited to electron-deficient olefins containing two electron-withdrawing groups. However, weak basic initiators struggle to cleave the Si-CF2H bond of Me3SiCF2H, and using Me3SiCF2H to engage in 1,4-/1,6-nucleophilic addition of α,β-unsaturated carbonyl compounds is difficult and has not been reported previously. para-Quinone methides (p-QMs), often used as excellent receptors in Michael reactions, can be used as a potentially unique raw material for the synthesis of natural and bioactive diarylmethane compounds [42,43,44,45,46]. The radical reactions of p-QMs with fluoroalkylation reagents have been reported [47,48,49,50,51]; for instance, Song et al. reported the radical 1,6-hydrodifluoroacetylation of p-QMs with difluoroalkyl bromides and bis(pinacolato) diboron (B2pin2) via copper catalysis (Equation (1), Scheme 1) [47]. Liu et al. described the radical tri-/difluoromethylation of p-QMs using sodium tri-/difluoromethanesulfinate via organic photoredox catalysis (Equation (2)) [49]. In addition, Zhou et al. developed the Fe(III)-catalyzed 1,6-conjugate addition of p-QMs with fluorinated silyl enol ethers toward β,β-diaryl α-fluorinated ketones (Equation (3)) [52]. However, to the best of our knowledge, there are no reports on the 1,6-nucleophilic difluoromethylation of p-QMs with less reactive Me3SiCF2H. Herein, we report CsF/18-crown-6 facilitated 1,6-nucleophilic difluoromethylation of p-QMs under mild conditions, and the trifluoromethylation and difluoroalkylation of p-QMs are also presented.

2. Results

We initiated the study by optimizing the reaction conditions, including the choice of initiators, temperature, and solvents, using 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (1a) as the model substrate and Me3SiCF2H as the difluoromethylation reagent (Table 1). We first performed the reaction under the previously reported conditions for the direct nucleophilic difluoromethylation of enolizable ketones, which involved using 0.2 equiv. of CsF/18-crown-6 (1:1) and THF as the solvent at room temperature [37]. However, we did not observe any product (entry 1). Then, by gradually increasing the temperature from −15 °C to room temperature and using DMF as the solvent, along with 0.2 equiv. of TBAF, CsF, or TMAF as the initiator, the product 2,6-di-tert-butyl-4-(2,2-difluoro-1-phenethyl) phenol 2a was obtained in approximately 30% yield (entries 2, 3, and 5). When 0.2 equiv. of TBAF was used as the initiator, the yield of the product was significantly low, irrespective of the temperature (entries 4 and 7). Similarly, using KF as the initiator only yielded trace amounts of product (entry 6). In contrast, when 0.2 equiv. of CsF, 0.1 equiv. of 18-crown-6, and DMF were employed, the yield increased to 42% at −30 °C (entry 10). With 1.0 equiv of CsF/18-crown-6 (1:1), the yield of product reached 60% within a temperature range of −15 °C to room temperature (entry 12). Further, when 1.5 equiv. of CsF/18-crown-6 (1:1) was used, the yield increased up to 70% (entry 13). However, 2.0 equiv. of the initiator CsF/18-crown-6 (1:1) caused a decrease in the yield (60%, entry 14). A 1.5 equiv. amount of KF/18-crown-6 (1:1) was also not suitable for the reaction (12%, entry 15). Therefore, the optimum conditions for this experiment were 1.0 equiv. of 1a, 2.0 equiv. of Me3SiCF2H, 1.5 equiv. of CsF/18-crown-6 (1:1), and running the reaction in DMF at temperatures ranging from −15 °C to room temperature overnight.
We next investigated the substrate scope of the direct nucleophilic difluoromethylation between Me3SiCF2H and 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dien-1-one derivatives (Table 2). Using the above optimized conditions, as shown in Table 2, most of the substrates examined provided good yields. A series of p-QMs bearing electron-donating groups (R = 4-Me, 4-tBu, and 4-OMe) (2d and 2i–2j) produced the corresponding products in somewhat lower yields than p-QMs bearing electron-withdrawing groups (R = 4-F, 4-Cl, and 4-Br) (2e, 2f, and 2k). Among them, the 4-Cl substituted product 2,6-di-tert-butyl-4-[1-(4-chlorophenyl)-2,2-difluoroethyl]phenol (2f) was obtained in the highest yield of 86%. Among the o-, m-, and p-Me-substituted substrates examined in the reaction (2b–2d), the substrate with the o-Me substituent gave the corresponding product in the highest yield (70%). Additionally, when the benzene ring was replaced by naphthalene, tert-butyl, and pyridine moiety, the corresponding products were generated with yields of 61%, 23%, and 62%, respectively (2l–2n).
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3). A comparison of Table 2 with Table 3 indicates that there are some differences between the di- and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b–3d) in higher yields than the difluoromethyl products (Table 2, 2b–2d). As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h–3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a–3d and 3f). The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.
The nucleophilic di-/trifluoromethylation reactions of other p-QMs with Me3SiRf (Rf = CF2H or CF3) were also investigated (Scheme 2). 4-Benzylidene-2-(tert-butyl)-6-methylcyclohexa-2,5-dien-1-one (1n) gave the corresponding di-/trifluoromethyl products 4a and 4b in 45–47% yields, which are significantly lower than those obtained with 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (1a). 2,6-Di-tert-butyl-4-(9H-fluoren-9-ylidene) cyclohexa-2,5-dien-1-one (1o) could be engaged in reactions with Me3SiRf (Rf = CF2H or CF3) to form di- and trifluoromethyl products containing quaternary carbon centers. The yield of the trifluoromethyl product 4d was much higher than that of the difluoromethyl product 4c, indicating that Me3SiCF3 is more reactive than Me3SiCF2H.
In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60–88% yields. It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).
Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3). Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield. De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield. Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54]. Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1-trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55]. Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.

3. Materials and Methods

3.1. General Information

All reactions were carried out in oven-dried glassware under nitrogen atmosphere. Commercially available reagents were used without further purification. para-Quinone methides were prepared according to the reported literature [56]. The solvent DMF was dried over CaH2 and distilled under reduced pressure. Column chromatography was performed with 300–400 mesh silica gel. All melting points are uncorrected. 1H, 13C, and 19F NMR spectra were recorded on a 400 MHz NMR spectrometer (Brucker, Karlsruhe, Germany). TLC was carried out with 0.2-millimeter-thick silica gel plates (GF254). Visualization was accomplished by UV light. Mass spectra were obtained on a mass spectrometer. High-resolution mass data were recorded on a high-resolution mass spectrometer in ESI positive ion mode (Q Exactive HF Orbitrap, Thermo Fisher Scientific, Waltham, MA, USA).

3.2. General Procedure

3.2.1. Experimental Procedures for the Synthesis of 2–5

Under nitrogen atmosphere, para-quinone methide 1 (0.4 mmol), CsF (91.14 mg, 0.6 mmol), and 18-crown-6 (158.6 mg, 0.6 mmol) were added into a Schlenk tube. The Schlenk tube was placed in a cold bath and stirred at −15 °C, and then DMF (2 mL) and TMSCF2H (100 mg, 107 μL, 0.80 mmol), TMSCF3 (114 mg, 118 μL, 0.80 mmol), or TMSCF2R (0.80 mmol) were added. The reaction mixture was gradually warmed to room temperature and stirred overnight. Subsequently, HCl aq. (1.0 M, 1.0 mL) was added at room temperature and the above mixture was stirred for another 15 min. Finally, the mixture was extracted with methyl tert-butyl ether (3 × 20 mL). The organic phase was washed with brine and then dried over anhydrous Na2SO4. After filtration and evaporation under vacuum, the residue was subjected to silica gel column chromatography using hexane/dichloromethane (4:1-1:1, v/v) as an eluent to give products 2–5.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-phenylethyl)phenol (2a) [49]: 97 mg, 70% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.34–7.32 (m, 4H), 7.30–7.26 (m, 1H), 7.09 (s, 2H), 6.25 (td, J = 56.1, 4.4 Hz, 1H), 5.16 (s, 1H), 4.30 (td, J = 16.2, 4.3 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.1, 137.6 (t, J = 3.4 Hz), 135.9, 129.1, 128.5, 127.6 (t, J = 3.8 Hz), 127.2, 125.6, 117.3 (t, J = 244.5 Hz), 55.1 (t, J = 20.4 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −117.13 (ddd, J = 276.9, 56.1, 15.6 Hz, 1F), −118.28 (ddd, J = 276.9, 56.1, 17.0 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H27F2O, 345.2030; found, 345.2039.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(o-tolyl)ethyl)phenol (2b): 101 mg, 70% yield. Yellow solid. M.p.: 75–76 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 7.17 (d, J = 4.1 Hz, 2H), 7.04 (s, 2H), 6.30 (td, J = 56.2, 5.0 Hz, 1H), 5.14 (s, 1H), 4.53–4.45 (m, 1H), 2.29 (s, 3H), 1.38 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.9, 136.7, 136.4 (t, J = 3.2 Hz), 135.7, 130.8, 127.3, 127.0, 126.9 (td, J = 4.3, 2.8 Hz), 126.0, 125.8, 117.6 (t, J = 243.8 Hz), 50.7 (t, J = 20.8 Hz), 34.3, 30.2, 20.0. 19F NMR (376 MHz, CDCl3): δ −116.62 (dd, J = 56.2, 14.4 Hz, 1F), −118.63 (ddd, J = 276.1, 56.1, 16.5 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H29F2O, 359.2186; found, 359.2187.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(m-tolyl)ethyl)phenol (2c): 66 mg, 46% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 7.8 Hz, 1H), 7.14–7.12 (m, 2H), 7.12–7.08 (m, 3H), 6.24 (td, J = 56.2, 4.5 Hz, 1H), 5.17 (s, 1H), 4.25 (td, J = 16.1, 4.5 Hz, 1H), 2.34 (s, 3H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.0, 138.1, 137.5 (t, J = 3.4 Hz), 135.8, 129.9, 128.4, 128.0, 127.6 (t, J = 3.8 Hz), 125.8, 125.6, 117.3 (t, J = 244.5 Hz), 55.1 (t, J = 20.4 Hz), 34.3, 30.2, 21.5. 19F NMR (376 MHz, CDCl3): δ (−116.75)–(−117.65) (m, 1F), (−117.66)–(−118.5) (m, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H29F2O, 359.2186; found, 359.2187.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(p-tolyl)ethyl)phenol (2d) [49]: 71 mg, 49 yield. Yellow solid. M.p.: 62–63 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 (s, 2H), 6.23 (td, J = 56.2, 4.4 Hz, 1H), 5.16 (s, 1H), 4.26 (td, J = 16.3, 4.3 Hz, 1H), 2.33 (s, 3H),1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.0, 136.8, 135.8, 134.5 (t, J = 3.4 Hz), 129.2, 128.9, 127.8 (t, J = 3.7 Hz), 125.6, 117.3 (t, J = 244.4 Hz), 54.7 (t, J = 20.4 Hz), 34.3, 30.2, 21.0. 19F NMR (376 MHz, CDCl3) δ −117.44 (dd, J = 56.2, 15.6 Hz, 1F), −118.01 (dd, J = 56.3, 17.0 Hz. 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H29F2O, 359.2186; found, 359.2187.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(4-fluorophenyl)ethyl)phenol (2e): 114 mg, 78% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.29 (dd, J = 7.8, 5.7 Hz, 2H), 7.06 (s, 2H), 7.03 (t, J = 8.6 Hz, 2H), 6.22 (td, J = 56.1, 4.1 Hz, 1H), 5.20 (d, J = 1.2 Hz, 1H), 4.30 (d, J = 6.4 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.0 (d, J = 245.9 Hz), 153.1, 136.0, 133.2 (q, J = 3.2 Hz), 130.7 (d, J = 8.0 Hz), 127.3 (t, J = 3.6 Hz), 125.5, 117.0 (t, J = 244.7 Hz), 115.4 (d, J = 21.3 Hz), 54.2 (t, J = 20.5 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ (−115.45)–(−115.52) (m, 1F), −116.83 (ddd, J = 277.4, 56.0, 14.8 Hz, 1F), −119.06 (ddd, J = 277.5, 56.2, 18.1 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26F3O, 363.1936; found, 363.1941.
2,6-Di-tert-butyl-4-(1-(4-chlorophenyl)-2,2-difluoroethyl)phenol (2f) [49]: 131 mg, 86% yield. Yellow solid. M.p.: 64–65 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.5 Hz,2H), 7.25 (d, J = 8.5 Hz, 2H), 7.05 (s, 2H), 6.22 (td, J = 56.0, 4.1 Hz, 1H), 5.20 (s, 1H), 4.28 (td, J = 18.3, 14.6, 4.0 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.2, 136.0, 135.9 (t, J = 3.1 Hz), 133.2, 130.5, 128.6, 127.1 (t, J = 4.4 Hz), 125.5, 116.9 (t, J = 244.7 Hz), 54.3 (t, J = 20.5 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −116.73 (ddd, J = 277.9, 55.9, 14.5 Hz, 1F), −119.09 (ddd, J = 278.0, 56.1, 18.2 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26ClF2O, 379.1640; found, 379.1642.
4-(1-(4-Bromophenyl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (2g): 109 mg, 63% yield. Yellow solid. M.p.: 95–96 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.06 (s, 2H), 6.22 (tdd, J = 56.1, 4.0, 1.4 Hz, 1H), 5.20 (d, J = 1.6 Hz, 1H), 4.27 (t, J = 14.4 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.2, 136.5 (t, J = 3.0 Hz), 136.0, 131.6, 130.8, 127.0 (t, J = 3.6 Hz), 125.5, 121.3, 116.9 (t, J = 244.8 Hz), 54.4 (t, J = 20.5 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −116.66 (ddd, J = 278.1, 55.8, 14.4 Hz, 1F), −119.07 (ddd, J = 278.0, 56.1, 18.1 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26BrF2O, 423.1135; found, 423.1139.
4-(1-(3-Bromophenyl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (2h): 115 mg, 68% yield. Yellow solid. M.p.: 86–87 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.42–7.40 (m, 1H), 7.25 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.06 (s, 2H), 6.22 (td, J = 55.9, 4.1 Hz, 1H), 5.21 (s, 1H), 4.26 (td, J = 18.3, 14.6, 4.1 Hz, 1H), 1.42 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.3, 139.7 (t, J = 3.2 Hz), 136.1, 132.3, 130.4, 130.0, 127.7, 126.8 (t, J = 3.8 Hz), 125.5, 122.5, 116.8 (t, J = 244.9 Hz), 54.7 (t, J = 20.6 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −116.78 (ddd, J = 278.2, 55.9, 14.6 Hz, 1F), −118.85 (ddd, J = 278.1, 56.1, 17.9 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26BrF2O, 423.1135; found, 423.1139.
2,6-Di-tert-butyl-4-(1-(4-tert-butylphenyl)-2,2-difluoroethyl)phenol (2i): 97 mg, 60% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.11 (s, 2H), 6.23 (td, J = 56.3, 4.4 Hz, 1H), 5.16 (s, 1H), 4.26 (td, J = 16.4, 4.3 Hz, 1H), 1.41 (s, 18H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.0, 150.0, 135.8, 134.5 (t, J = 3.3 Hz), 128.6, 127.7 (t, J = 3.7 Hz), 125.6, 125.4, 117.4 (t, J = 244.5 Hz), 54.7 (t, J = 20.4 Hz), 34.4, 34.3, 31.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −116.93 (ddd, J = 276.0, 56.2, 15.7 Hz, 1F), −118.29 (ddd, J = 276.0, 56.3, 17.0 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C26H35F2O, 401.2656; found, 401.2663.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(4-methoxyphenyl)ethyl)phenol (2j): 60 mg, 40% yield. Yellow solid. M.p.: 75–76 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.7 Hz, 2H), 7.09 (s, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.21 (td, J = 56.3, 4.3 Hz, 1H), 5.17 (s, 1H), 4.33–4.12 (m, 1H), 3.78 (s, 3H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 158.7, 153.0, 135.8, 130.1, 129.6 (t, J = 3.5 Hz), 127.9 (t, J = 3.7 Hz), 125.5, 117.3 (t, J = 244.4 Hz), 113.9, 55.2, 54.2 (t, J = 20.4 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −116.96 (ddd, J = 276.2, 56.2, 15.3 Hz, 1F), −118.55 (ddd, J = 276.3, 56.3, 17.4 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H29F2O2, 375.2136; found, 375.2143.
2,6-Di-tert-butyl-4-(1-(2,4-dichlorophenyl)-2,2-difluoroethyl)phenol (2k): 111 mg, 67% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.45–7.40 (m, 2H), 7.29–7.24 (m, 1H), 7.08 (s, 2H), 6.26 (td, J = 55.8, 4.1 Hz, 1H), 5.19 (s, 1H), 4.85 (td, J = 16.3, 4.0 Hz, 1H), 1.40 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.3, 136.0, 135.3, 134.3 (t, J = 3.2 Hz), 133.6, 130.5, 129.8, 127.2, 125.9 (t, J = 3.2 Hz), 125.7, 116.7 (t, J = 245.2 Hz), 50.2 (t, J = 21.1 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ (−117.38)–(−118.21) (m, 1F), (−118.27)–(−118.69) (m, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26Cl2F2O, 413.1251; found, 413.1261.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(naphthalen-2-yl)ethyl)phenol (2l): 97 mg, 61% yield. Orange solid. M.p.: 104–105 °C. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.1 Hz, 1H), 7.51–7.46 (m, 3H), 7.15 (s, 2H), 6.43 (td, J = 56.0, 4.6 Hz, 1H), 5.13 (s, 1H), 1.37 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.1, 135.7, 134.1, 133.8 (t, J = 3.7 Hz), 131.8, 128.9, 127.9, 127.1 (t, J = 3.6 Hz), 126.3, 125.8, 125.6, 125.4, 125.2, 123.4, 117.6 (t, J = 244.3 Hz), 50.0 (t, J = 20.9 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ –115.55 (ddd, J = 275.9, 56.1, 13.6 Hz), –118.53 (ddd, J = 276.0, 56.0, 17.2 Hz). HRMS (ESI) m/z: [M − H]+ calcd. for C26H29F2O, 395.2186; found, 395.2192.
2,6-Di-tert-butyl-4-(1,1,1,3,3-pentafluoropropan-2-yl)phenol (2m): 30 mg, 23% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 3:1, v/v). 1H NMR (400 MHz, CDCl3): δ 6.99 (s, 2H), 6.17 (td, J = 56.0, 3.8 Hz, 1H), 5.11 (s, 1H), 2.72 (ddd, J = 21.9, 15.1, 3.8 Hz, 1H), 1.43 (s, 18H), 0.98 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.7, 135.0, 126.8, 118.3 (t, J = 243.2 Hz), 58.9 (t, J = 17.7 Hz), 34.2, 33.6–32.7 (m), 30.4, 28.9. 19F NMR (376 MHz, CDCl3): δ (−114.45)–(−115.41) (m, 1F), (−115.41)–(−116.36) (m, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C20H31F2O, 325.2343; found, 325.2348.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-(pyridin-2-yl)ethyl)phenol (2n): 86 mg, 62% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 20:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.65–8.50 (m, 1H), 7.60 (td, J = 7.7, 1.8 Hz, 1H), 7.24–7.12 (m, 4H), 6.59 (td, J = 56.3, 6.3 Hz, 1H), 5.17 (s, 1H), 4.37 (ddd, J = 14.0, 11.6, 6.3 Hz, 1H), 1.40 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 158.4 (d, J = 7.8 Hz), 153.4, 149.2, 136.7, 136.0, 126.9 (d, J = 7.0 Hz), 125.8, 124.1, 122.1, 117.9 (t, J = 243.3 Hz), 57.1 (t, J = 21.7 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3) δ −117.08 (dd, J = 54.5, 11.9 Hz, 1F), −122.47 (dd, J = 56.8, 14.3 Hz, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C21H27F2NO, 348.2139; found, 348.2146.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-phenyl-ethyl)-phenol (3a) [49]: 96 mg, 66% yield. Yellow solid. M.p.: 64–65 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.40–7.29 (m, 5H), 7.15 (s, 2H), 5.19 (s, 1H), 4.56 (q, J = 10.2 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.4, 136.0, 135.9, 129.0, 128.6, 127.9 (q, J = 280.5 Hz), 127.6, 125.9, 125.8, 55.5 (q, J = 27.3 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −65.96 (d, J = 10.1 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H26F3O, 363.1936; found, 363.1931.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-o-tolyl-ethyl)-phenol (3b): 129 mg, 85% yield. Yellow solid. M.p.: 112–114 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.7 Hz, 1H), 7.29–7.13 (m, 3H), 7.11 (s, 2H), 5.17 (s, 1H), 4.79 (q, J = 10.2 Hz, 1H), 2.30 (s, 3H), 1.39 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.3, 135.5, 134.7, 133.5, 129.8, 126.5, 126.4, 126.4, 125.7 (q, J = 280.78 Hz), 125.2, 125.1, 49.8 (q, J = 27.1 Hz), 33.3, 29.2, 19.1. 19F NMR (376 MHz, CDCl3): δ −65.24 (d, J = 10.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H28F3O, 377.2092; found, 377.2108.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-m-tolyl-ethyl)-phenol (3c): 92 mg, 61% yield. Yellow solid. M.p.: 68–70 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.23–7.19 (m, 3H), 7.16 (s, 2H), 7.10 (d, J = 6.4 Hz, 1H), 5.19 (s, 1H), 4.51 (q, J = 10.2 Hz, 1H), 2.34 (s, 3H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.4, 137.2, 134.8, 134.7, 128.9, 127.4, 127.3, 125.5 (q, J = 280.5 Hz), 124.9, 124.8, 124.7, 54.5 (q, J = 27.1 Hz), 33.3, 29.2, 20.4. 19F NMR (376 MHz, CDCl3): δ −65.93 (d, J = 10.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H28F3O, 377.2092; found, 377.2101.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-p-tolyl-ethyl)-phenol (3d) [49]: 124 mg, 82% yield. Yellow solid. M.p.: 92–94 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.28–7.24 (m, 2H), 7.15–7.13 (m, 4H), 5.18 (s, 1H), 4.52 (q, J = 10.2 Hz, 1H), 2.33 (s, 3H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.3, 136.3, 134.8, 132.0, 128.3, 127.8, 125.5 (q, J = 280.4 Hz), 125.1, 124.7, 54.2 (q, J = 27.2 Hz), 33.3, 29.2, 20.0. 19F NMR (376 MHz, CDCl3): δ −65.24 (d, J = 10.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H28F3O, 377.2092; found, 377.2098.
2,6-Di-tert-butyl-4-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethyl]-phenol (3e) [49]: 87 mg, 57% yield. Yellow solid. M.p.: 84–85 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.35 (dd, J = 8.3, 5.4 Hz, 2H), 7.12 (s, 2H), 7.03 (t, J = 8.7 Hz, 2H), 5.22 (s, 1H), 4.56 (q, J = 10.0 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.4, 161.0, 153.5, 136.0, 131.9, 130.7 (d, J = 8.1 Hz), 126.3 (q, J = 281.2, 280.7 Hz), 125.7, 115.5 (d, J = 21.5 Hz), 54.7 (q, J = 27.4 Hz), 30.2, 18.4. 19F NMR (376 MHz, CDCl3): δ −66.24 (d, J = 10.3 Hz), −114.72 (ddd, J = 13.6, 8.6, 5.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H25F4O, 381.1842; found, 381.1851.
4-[1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethyl]-2,6-di-tert-butyl-phenol (3f) [49]: 152 mg, 86% yield. Yellow solid. M.p.: 93–95 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.03 (s, 2H), 5.15 (s, 1H), 4.45 (q, J = 10.0 Hz, 1H), 1.33 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.5, 135.0, 134.0, 130.7, 129.7, 125.1 (q, J = 280.7 Hz), 124.6, 124.3, 120.8, 53.9 (q, J = 27.5 Hz), 33.3, 29.2. 19F NMR (376 MHz, CDCl3): δ −66.08 (d, J = 10.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H25BrF3O, 441.1041; found, 441.1044.
2,6-Di-tert-butyl-4-[1-(2,4-dichloro-phenyl)-2,2,2-trifluoro-ethyl]-phenol (3g): 105 mg, 61% yield. Yellow solid. M.p.: 99–100 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.28 (dd, J = 8.5, 2.1 Hz, 1H), 7.12 (s, 2H), 5.23 (s, 1H), 5.17 (q, J = 10.0 Hz, 1H), 1.40 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.7, 136.0, 135.3, 134.1, 132.8, 129.9, 129.8, 127.4, 126.1 (q, J = 280.6 Hz), 125.9, 124.2, 50.5 (q, J = 28.2 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −65.57 (d, J = 9.5 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H24Cl2F3O, 431.1156; found, 431.1151.
2,6-Di-tert-butyl-4-[1-(4-tert-butyl-phenyl)-2,2,2-trifluoro-ethyl]-phenol (3h) [50]: 76 mg, 45% yield. Yellow solid. M.p.: 83–85 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.37-7.31 (m, 4H), 7.17 (s, 2H), 5.18 (s, 1H), 4.52 (q, J = 10.3 Hz, 1H), 1.41 (s, 18H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.4, 150.5, 135.9, 133.0, 128.6, 128.0 (q, J = 280.6 Hz), 126.2, 125.8, 125.5, 55.2 (q, J = 27.1 Hz), 34.5, 34.4, 31.3, 30.3. 19F NMR (376 MHz, CDCl3): δ −66.04 (d, J = 10.2 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C26H34F3O, 419.2562; found, 419.2552.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)phenol (3i) [49]: 87 mg, 55% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.4 Hz, 2H), 7.14 (s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.19 (s, 1H), 4.52 (q, J = 10.2 Hz, 1H), 3.79 (s, 3H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.0, 153.3, 135.9, 130.2, 128.2, 128.0 (q, J = 280.5 Hz), 126.2, 125.6, 55.2, 54.7 (q, J = 27.2 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −66.24 (d, J = 2.7 Hz), −66.27 (d, J = 2.7 Hz). HRMS (ESI) m/z: [M − H]+ calcd. for C23H28F3O2, 393.2041; found, 393.2044.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-naphthalen-2-yl-ethyl)-phenol (3j) [49]: 129 mg, 78% yield. Yellow solid. M.p.: 145–147 °C. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.3 Hz, 1H), 7.90–7.74 (m, 3H), 7.57–7.43 (m, 3H), 7.21 (s, 2H), 5.44 (q, J = 9.9 Hz, 1H), 5.17 (s, 1H), 1.37 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.4, 135.8, 134.1, 131.7, 131.6, 129.1, 128.4, 126.9 (q, J = 286.4 Hz), 126.5, 126.0, 125.8, 125.7, 125.6, 125.5, 125.2, 123.1, 50.3 (q, J = 27.3 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −64.83 (d, J = 9.7 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C26H28F3O, 413.2092; found, 413.2091.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)phenol (3k): 43 mg, 30% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.62 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.69 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.26–7.19 (m, 3H), 5.23 (s, 1H), 4.79 (q, J = 9.9 Hz, 1H), 1.41 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 155.9 (d, J = 1.9 Hz), 153.7, 149.6, 136.8, 135.9, 126.2,126.0 (q, J = 280.2 Hz), 123.3, 122.6, 57.8 (q, J = 27.1 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3) −66.14 (d, J = 8.7 Hz, 3F). HRMS (ESI) m/z: [M + H]+ calcd. for C21H26F3NO, 366.2045; found, 366.2049.
2-Tert-butyl-4-(2,2-difluoro-1-phenylethyl)-6-methylphenol (4a): 55 mg, 45% yield. Orange solid. M.p.: 104–105 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.33–7.11 (m, 5H), 6.99 (s, 1H), 6.85 (s, 1H), 6.17 (td, J = 56.1, 4.4 Hz, 1H), 4.67 (s, 1H), 4.21 (td, J = 16.1, 4.1 Hz, 1H), 2.12 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.0, 137.6 (t, J = 3.4 Hz), 135.8, 129.0, 128.9, 128.6, 128.3 (t, J = 3.7 Hz), 127.3, 126.0, 123.2, 117.2 (t, J = 244.3 Hz), 54.7 (t, J = 20.6 Hz), 34.6, 29.7, 16.1. 19F NMR (376 MHz, CDCl3): δ (−116.71)–117.77 (m, 1F), (−117.78)–(−118.82) (m, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C19H21F2O, 303.1560; found, 303.1566.
2-(Tert-butyl)-6-methyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (4b) [50]: 61 mg, 47% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.41–7.22 (m, 5H), 7.12 (s, 1H), 7.00 (s, 1H), 4.79 (s, 1H), 4.56 (q, J = 10.1 Hz, 1H), 2.21 (s, 3H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.3, 135.9, 135.8, 128.9, 128.9, 128.6 (q, J = 280.5 Hz), 127.8, 127.7, 126.5, 126.2, 123.2, 55.2 (q, J = 27.3 Hz), 34.6, 29.6, 16.1. 19F NMR (376 MHz, CDCl3): δ −65.98 (d, J = 10.1 Hz, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C19H20F3O, 321.1466; found, 321.1474.
2,6-Di-tert-butyl-4-(9-(difluoromethyl)-9H-fluoren-9-yl)phenol (4c): 50 mg, 30% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 20:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.22 (s, 2H), 6.08 (t, J = 56.0 Hz, 1H), 5.13 (s, 1H), 1.35 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 153.1, 144.91 (t, J = 3.5 Hz), 141.3, 135.6, 128.5, 127.6, 126.7, 124.5, 120.2, 117.8 (t, J = 233.1 Hz), 62.4 (t, J = 19.8 Hz), 34.5, 30.2. 19F NMR (377 MHz, CDCl3) −119.21 (d, J = 56.2 Hz, 2F),. HRMS (ESI) m/z: [M − H]+ calcd. for C28H30F2O, 419.2186; found, 419.2191.
2-(Tert-butyl)-6-methyl-4-(9-(trifluoromethyl)-9H-fluoren-9-yl)phenol (4d): 109 mg, 62% yield. Yellow solid. M.p.: 156–158 °C. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 7.1 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.28–7.08 (m, 4H), 5.07 (s, 1H), 1.25 (s, 20H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.2, 142.9, 140.2, 134.5, 127.8, 126.6, 126.3, 125.3, 124.7 (q, J = 282.4 Hz), 123.3, 119.2, 62.5 (q, J = 26.5, 26.1 Hz), 33.4, 29.1. 19F NMR (376 MHz, CDCl3): δ −66.72 (s, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C28H28F3O, 437.2092; found, 437.2092.
2,6-Di-tert-butyl-4-(2,2,3,3,3-pentafluoro-1-phenylpropyl)phenol (5a): 146 mg, 88% yield. Yellow solid. M.p.: 70–72 °C. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.46–7.45 (m, 2H), 7.39–7.26 (m, 3H), 7.21 (s, 2H), 5.19 (s, 1H), 4.45 (t, J = 18.0 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.5, 135.9, 135.8, 129.3, 128.7, 127.8, 126.0, 125.6 (d, J = 3.3 Hz), 121.1–112.9 (m, CF2CF3), 53.3 (t, J = 20.7 Hz), 34.4, 30.2. 19F NMR (376 MHz, CDCl3): δ −81.12 (s, 3F), −114.93 (qd, J = 270.8, 18.3 Hz, 2F). HRMS (ESI) m/z: [M − H]+ calcd. for C27H35F5O, 413.1904; found, 413.1913.
Ethyl 3-(4-(tert-butyl)phenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoropropanoate (5b) [47]: 112 mg, 67% yield. Brown oil. Purification by column chromatography (hexane/dichloromethane = 4:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 7.34–7.25 (m, 3H), 7.18 (s, 2H), 5.17 (s, 1H), 4.64 (t, J = 18.5 Hz, 1H), 4.11 (qt, J = 7.1, 3.6 Hz, 2H), 1.40 (s, 18H), 1.02 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.1 (t, J = 32.4 Hz), 153.4, 136.1 (d, J = 3.8 Hz), 135.8, 129.6, 128.5, 127.6, 126.3, 125.9 (d, J = 4.1 Hz), 116.1 (t, J = 255.7 Hz), 62.6, 55.5 (t, J = 21.8 Hz), 34.3, 30.3, 13.6. 19F NMR (376 MHz, CDCl3): δ (−105.34)–(−107.42) (m, 2F). HRMS (ESI) m/z: [M − H]+ calcd. for C29H40F2O3, 417.2241; found, 417.2243.
2,6-Di-tert-butyl-4-(2,2-difluoro-1-phenyl-2-(phenylthio)ethyl)phenol (5c): 127 mg, 70% yield. Yellow solid. M.p.: 99–111 °C. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.53–7.51 (m, 2H), 7.46–7.45 (m, 2H), 7.36–7.25 (m, 6H), 7.22 (s, 2H), 5.15 (s, 1H), 4.55 (t, J = 15.3 Hz, 1H), 1.41 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.2, 137.6 (d, J = 2.2 Hz), 136.2, 135.6, 130.2 (t, J = 284.6 Hz), 129.7, 129.5, 128.9, 128.4, 127.5, 127.4, 127.3, 126.4, 59.9 (t, J = 22.1 Hz), 34.4, 30.3. 19F NMR (376 MHz, CDCl3): δ −72.36 (dd, J = 204.7, 15.0 Hz, 1F), −73.06 (dd, J = 204.8, 15.7 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C28H31OSF2, 452.2064; found, 453.2065.
2,6-Di-tert-butyl-4-((2,2,3,3,3-pentafluoro-1-(furan-2-yl)propy)phenol (5d): 118 mg, 73% yield. Yellow solid. M.p.: 112–114 °C. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, 1H), 7.24 (s, 2H), 6.39–6.33 (m, 2H), 5.24 (s, 1H), 4.61 (dd, J = 19.1, 14.8 Hz, 1H), 1.43 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.9, 148.4 (d, J = 6.1 Hz), 142.6, 135.9, 126.4, 122.8 (d, J = 2.8 Hz), 120.9–111.1 (m, CF2CF3), 110.5, 109.3, 47.2 (dd, J = 23.6, 20.9 Hz), 34.3, 30.2. 19F NMR (376 MHz, CDCl3): δ −81.93 (s, 3F), −115.62 (dd, J = 269.2, 14.6 Hz, 1F), −117.41 (dd, J = 269.3, 19.3 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C21H24O2F5, 403.1696; found, 403.1699.
Ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-3-(furan-2-yl)propanoate (5e): 98 mg, 60% yield. Brown oil. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.38 (dd, J = 1.8, 0.9 Hz, 1H), 7.19 (s, 2H), 6.37–6.33 (m, 2H), 5.22 (s, 1H), 4.75 (t, J = 16.8 Hz, 1H), 4.17 (qd, J = 7.2, 5.5 Hz, 2H), 1.42 (s, 18H), 1.15 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.79 (t, J = 32.3 Hz), 153.81, 149.43 (d, J = 6.2 Hz), 142.4, 135.8, 126.6, 123.2 (d, J = 2.6 Hz), 114.9 (t, J = 256.5 Hz), 110.4, 109.1, 62.7, 49.7 (t, J = 23.3 Hz), 34.3, 30.2, 13.7. 19F NMR (376 MHz, CDCl3): δ −108.07 (dd, J = 253.3, 15.9 Hz, 1F), −109.06 (dd, J = 253.5, 17.8 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C23H29F2O4, 407.2034; found, 407.2040.

3.2.2. Experimental Procedures for the Synthesis of 2,6-Di-tert-butyl-4-(1-(4-chlorophenyl)-2,2-difluoroethylidene)cyclohexa-2,5-dien-1-one (6a)

K3[Fe(CN)6] (395 mg, 1.2 mmol) and KOH (71 mg, 1.26 mmol) in water (3 mL) were added in one portion to a solution of 2f (114 mg, 0.3 mmol) in hexane (3 mL) under N2 in a 25-milliliter round-bottom flask equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 5 h. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the solution was concentrated by rotary evaporation. The residue was purified by silica gel flash column chromatography using petroleum ether to afford 6a (88.5 mg, 78%).
2,6-Di-tert-butyl-4-(1-(4-chlorophenyl)-2,2-difluoroethylidene)cyclohexa-2,5-dien-1-one (6a): 118 mg, 78% yield. Yellow solid. M.p.: 125–127 °C. Purification by column chromatography using hexane. 1H NMR (400 MHz, CDCl3): δ 7.48–7.42 (m, 2H), 7.41–7.37 (m, 1H), 7.25 (d, J = 9.0 Hz, 2H), 6.98 (t, J = 54.9 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 1.34 (s, 9H), 1.15 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 186.1, 150.5, 150.4, 139.9 (t, J = 20.6 Hz), 135.4, 133.5 (t, J = 7.5 Hz), 131.7, 131.7, 129.8, 128.6, 125.3, 111.7 (t, J = 237.9 Hz), 35.8, 35.5, 29.5, 29.3. 19F NMR (376 MHz, CDCl3): δ −109.91 (d, J = 54.7 Hz, 2F). HRMS (ESI) m/z: [M − H]+ calcd. for C22H24ClF2O, 377.1484; found, 377.1482.

3.2.3. Experimental Procedures for the Synthesis of 4-(1-(4-Chlorophenyl)-2,2-difluoroethyl) Phenol (6b)

A 10-milliliter sealed tube equipped with a magnetic stir bar was charged with 2f (114 mg, 0.3 mmol) and dry toluene (3 mL). The solution was added with concentrated H2SO4 (1 drop) and heated at 120 °C (oil bath temperature) for 18 h with vigorous stirring. After cooling to room temperature, water (20 mL) was poured into the reaction mixture, and then the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using petroleum ether-ethyl acetate (5:1-1:1, v/v) as an eluent to afford the product 6b (65.0 mg, 81%).
4-(1-(4-Chlorophenyl)-2,2-difluoroethyl)phenol (6b): 87 mg, 81% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.34–7.27 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.17–7.07 (m, 2H), 6.87–6.71 (m, 2H), 6.22 (td, J = 55.8, 4.1 Hz, 1H), 5.14 (s, 1H), 4.32 (td, J = 16.1, 4.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.1, 135.7 (t, J = 3.3 Hz), 133.4, 130.4, 130.2, 128.8, 128.7, 116.6 (t, J = 244.7 Hz), 115.7, 53.5 (t, J = 20.8 Hz). 19F NMR (376 MHz, CDCl3): δ −117.75 (ddd, J = 279.3, 55.8, 15.6 Hz, 1F), −118.89 (ddd, J = 280.0, 56.8, 17.0 Hz, 1F). HRMS (ESI) m/z: [M − H]+ calcd. for C14H10ClF2O, 267.0388; found, 267.0390.

3.2.4. General Experimental Procedure for the Synthesis of 1-Ethoxy-4-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)benzene (7b)

A 30-milliliter sealed tube equipped with a magnetic stir bar was charged with 3i (236 mg, 0.6 mmol) and dry toluene (5 mL). The solution was added with concentrated H2SO4 (2 drops) and heated at 120 °C (oil bath temperature) for 18 h with vigorous stirring. After cooling to room temperature, water (20 mL) was poured into the reaction mixture, and then the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using petroleum ether-ethyl acetate (5:1–1:1, v/v) as an eluent to afford the intermediate 7a (127.0 mg, 75%).
A 25-milliliter round-bottom flask was charged with a magnetic stir bar, the intermediate 7a (84.5 mg, 0.3 mmol), Cs2CO3 (71 mg, 0.6 mmol), CH3CN (10 mL), and iodoethane (93.5 mg, 0.6 mmol). The reaction mixture was stirred for about 24 h at 90 °C (oil bath temperature) and then cooled to room temperature and filtered. The solvent was evaporated under vacuum. The residue was subjected to silica gel column chromatography using petroleum ether–ethyl acetate (10:1, v/v) as an eluent to give the product 7b (82.8 mg, 89% yield).
4-(2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl)phenol (7a): 85 mg, 75% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 5:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.82–6.73 (m, 2H), 5.21– 5.17 (m, 1H), 4.56 (q, J = 10.0 Hz, 1H), 3.79 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.1, 155.2, 130.4, 130.1, 128.0, 127.8, 126.4 (q, J = 280.3 Hz), 115.5, 114.1, 55.3, 53.9 (q, J = 27.6 Hz). 19F NMR (376 MHz, CDCl3): δ −66.38 (s, 3F). HRMS (ESI) m/z: [M − H]+ calcd. for C15H12F3O2, 281.0789; found, 281.0793.
1-Ethoxy-4-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)benzene (7b): 110 mg, 89% yield. Yellow oil. Purification by column chromatography (hexane/dichloromethane = 10:1, v/v). 1H NMR (400 MHz, CDCl3): δ 7.28–7.24 (m, 4H), 7.04–6.44 (m, 4H), 4.57 (q, J = 9.8 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.1, 158.5, 130.1, 130.1, 129.2 (q, J = 280.4 Hz), 127.9 (d, J = 1.4 Hz), 127.6 (d, J = 1.3 Hz), 114.6, 114.1, 63.4, 55.2, 54.0 (q, J = 27.5 Hz), 14.8. 19F NMR (376 MHz, CDCl3): δ −66.38 (s). MS (EI, m/z, %): 213 (46.74), 241 (100.00), 310 (M+, 36.84).

4. Conclusions

In summary, we have developed a direct method for the 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of p-QMs using Me3SiRf (Rf = CF2H, CF3, CF2CF3, CF2COOEt, and CF2SPh) as a reagent, promoted by CsF/18-crown-6, within a temperature range of −15 °C to room temperature. The nucleophilic reaction is suitable for p-QMs with various substituents, giving the corresponding products in satisfactory to good yields. The synthetic utility of the approach has been exemplified by the formation of fluoroalkylated p-quinone methide (via oxidation) and α-fluoroalkyl diarylmethane (via de-tert-butylation).

Supplementary Materials

The following supporting information can be downloaded at: https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/molecules29122905/s1. The NMR spectra of all products are included in.

Author Contributions

Methodology, D.C. (Dingben Chen), L.H., M.L., X.C. and P.X.; software, D.C. (Dingben Chen), L.H., M.L., X.C. and P.X.; validation, D.C. (Dingben Chen), L.H., M.L., X.C. and P.X.; formal analysis, D.C. (Dingben Chen), L.H., M.L., X.C. and P.X.; writing—original draft preparation, D.C. (Dingben Chen); writing—review and editing, D.C. (Dongdong Cao), M.L., C.N. and J.H.; supervision, J.H. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the National Key Research and Development Program of China (2021YFF0701700), the National Natural Science Foundation of China (22261132514, 22271299, and 22301308), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0590000), the Natural Science Foundation of Shandong Province (ZR2021LFG006 and ZR2023LFG003), and the Natural Science Foundation of Zhejiang Province (LY18B020003).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 29 02905 sch001
Scheme 1. The reactions between p-QMs and different fluorine reagents.
Scheme 1. The reactions between p-QMs and different fluorine reagents.
Molecules 29 02905 sch001
Molecules 29 02905 sch002
Scheme 2. Direct nucleophilic di-/trifluoromethylation reactions of other p-QMs with Me3SiCF2H/Me3SiCF3.
Scheme 2. Direct nucleophilic di-/trifluoromethylation reactions of other p-QMs with Me3SiCF2H/Me3SiCF3.
Molecules 29 02905 sch002
Molecules 29 02905 sch003
Scheme 3. Synthetic applications of di- and trifluoromethylated p-quinone methides.
Scheme 3. Synthetic applications of di- and trifluoromethylated p-quinone methides.
Molecules 29 02905 sch003
Table 1. Optimization of reaction conditions between p-QMs 1a and Me3SiCF2H a.
Table 1. Optimization of reaction conditions between p-QMs 1a and Me3SiCF2H a.
Molecules 29 02905 i001
EntryInitiator (equiv)T (°C)SolventYield (%) b
1CsF (0.2)/18-crown-6 (0.2)rtTHF0
2TBAF (0.2)−15 to rtDMF30
3CsF (0.2)−15 to rtDMF33
4TBAF (0.2)−30DMF17
5TMAF (0.2)−15 to rtDMF30
6KF (0.2)−30DMFtrace
7TBAF (0.2)rtDMF20
8CsF(1.0)−30DMF36
9CsF (1.0)/18-crown-6 (0.2)−30DMF51
10CsF (0.2)/18-crown-6 (0.1)−30DMF42
11CsF (0.2)/18-crown-6 (0.1)−15 to rtDMF52
12CsF (1.0)/18-crown-6 (1.0)−15 to rtDMF60
13CsF (1.5)/18-crown-6 (1.5)−15 to rtDMF70
14CsF (2.0)/18-crown-6 (2.0)−15 to rtDMF60
15KF (1.5)/18-crown-6 (1.5)−15 to rtDMF12
a In all entries, Me3SiCF2H (0.4 mmol, 2 equiv) and 1a (0.2 mmol, 1.0 equiv) were used. b Yields were determined by 19F NMR analysis using PhCF3 as an internal standard.
Table 2. Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b.
Table 2. Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b.
Molecules 29 02905 i002
Molecules 29 02905 i003Molecules 29 02905 i004Molecules 29 02905 i005Molecules 29 02905 i006Molecules 29 02905 i007
2a, 70%2b, 70%2c, 46%2d, 49%2e, 78%
Molecules 29 02905 i008Molecules 29 02905 i009Molecules 29 02905 i010Molecules 29 02905 i011Molecules 29 02905 i012
2f, 86%2g, 63%2h, 68%2i, 60%2j, 40%
Molecules 29 02905 i013Molecules 29 02905 i014Molecules 29 02905 i015Molecules 29 02905 i016
2k, 67%2l, 61%2m, 23%2n, 62%
a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used. b Isolated yields were given.
Table 3. Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b.
Table 3. Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b.
Molecules 29 02905 i017
Molecules 29 02905 i018Molecules 29 02905 i019Molecules 29 02905 i020Molecules 29 02905 i021Molecules 29 02905 i022
3a, 66%3b, 85%3c, 61%3d, 82%3e, 57%
Molecules 29 02905 i023Molecules 29 02905 i024Molecules 29 02905 i025Molecules 29 02905 i026Molecules 29 02905 i027
3f, 86%3g, 61%3h, 45%3i, 55%3j, 78%
Molecules 29 02905 i028
3k, 30%
a Me3SiCF3 (0.8 mmol, 2.0 equiv) and 1 (0.4 mmol, 1.0 equiv) were used. b Isolated yields were given.
Table 4. Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b.
Table 4. Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b.
Molecules 29 02905 i029
Molecules 29 02905 i030Molecules 29 02905 i031Molecules 29 02905 i032Molecules 29 02905 i033Molecules 29 02905 i034
5a, 88%5b, 67%5c, 70%5d, 73%5e, 60%
a Me3SiRf (0.8 mmol, 2.0 equiv) and 1 (0.4 mmol, 1.0 equiv) were used. b Isolated yields are given.
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Chen, D.; Huang, L.; Liang, M.; Chen, X.; Cao, D.; Xiao, P.; Ni, C.; Hu, J. 1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6. Molecules 2024, 29, 2905. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29122905

AMA Style

Chen D, Huang L, Liang M, Chen X, Cao D, Xiao P, Ni C, Hu J. 1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6. Molecules. 2024; 29(12):2905. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29122905

Chicago/Turabian Style

Chen, Dingben, Ling Huang, Mingyu Liang, Xiaojing Chen, Dongdong Cao, Pan Xiao, Chuanfa Ni, and Jinbo Hu. 2024. "1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6" Molecules 29, no. 12: 2905. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29122905

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