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Article

TBAB-Catalyzed 1,6-Conjugate Sulfonylation of para-Quinone Methides: A Highly Efficient Approach to Unsymmetrical gem-Diarylmethyl Sulfones in Water †

by
Zhang-Qin Liu
*,
Peng-Sheng You
,
Liang-Dong Zhang
,
Da-Qing Liu
,
Sheng-Shu Liu
and
Xiao-Yu Guan
*
Key Laboratory of Applied Chemistry of Chongqing Municipality, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
*
Authors to whom correspondence should be addressed.
†
Dedicated to Professor Jean-Marie Basset on the occasion of his 77th birthday.
Molecules 2020, 25(3), 539; https://doi.org/10.3390/molecules25030539
Submission received: 29 December 2019 / Revised: 21 January 2020 / Accepted: 24 January 2020 / Published: 26 January 2020
(This article belongs to the Special Issue Recent Advances in Carbon-Sulfur Bond Formation)
Browse Figures
Versions Notes

Abstract

:
A highly efficient sulfonylation of para-quinone methides with sulfonyl hydrazines in water has been developed on the basis of the mode involving a tetrabutyl ammonium bromide (TBAB)-promoted sulfa-1,6-conjugated addition pathway. This reaction provides a green and sustainable method to synthesize various unsymmetrical diarylmethyl sulfones, showing good functional group tolerance, scalability, and regioselectivity. Further transformation of the resulting diarylmethyl sulfones provides an efficient route to some functionalized molecules.

1. Introduction

As a class of sulfur-containing compounds, sulfones are widely used in organic synthesis, pharmaceuticals, agrochemicals, and materials science [1,2,3,4,5,6,7]. Among the sulfone family, diarylmethyl sulfones hold an essential position in biologically important compounds that show various biological activities, such as potassium channel inhibitory activity [8], as well as antidepressant [9] and anticancer properties (Figure 1) [10]. Additionally, diarylmethyl sulfones can be applied as useful intermediates for synthetic applications owing to the versatile reactivities of the sulfonyl group activated carbanions [1,11,12,13,14].
Although a number of methodologies have been developed for the synthesis of diarylmethyl sulfones, most of the reported methods suffer from the harsh reaction conditions, multi-step procedures, and requirements of expensive metal catalysts or potentially toxic organic solvents [15,16,17,18], which make them unsustainable and environmentally unfavorable.
Concerns about the environmental issues caused by the influence of human society have currently become prevalent and ubiquitous. Engagement on green and sustainable methods of chemical synthesis has emerged as a pioneering realm [19,20,21,22,23] garnering of enormous attention of chemists and biologists. Among them, chemical reactions “in water” [24] offered a novel way to green and sustainable synthesis. Water, compared to the traditional organic solvents, possesses distinctive properties such as safety, innocuousness, high heat capacity, extensive hydrogen bonding, and redox stability [24,25,26]. Consequently, water has been gradually accepted [27,28,29,30,31,32,33] as a desirable reaction medium since the first water-promoted Diels–Alder reaction reported by Breslow [34] in 1980.
The C-S bond formation reaction is still an intriguing field attributed to the versatile block-building usages [35,36] and the bioactive agents [37,38] of sulfur-containing compounds. Thus, substantial endeavors have been focused on the achievement of the efficient, expedient, and low-cost approach. With our keen interest in the sulfa-1,6-conjugated addition reaction [15,39,40], we try to combine the green and sustainable chemical synthetic concept and the C-S bonding formation reactions. Herein, we disclose a highly efficient tetrabutyl ammonium bromide (TBAB)-promoted sulfonylation of para-quinone methide (p-QM) with sulfonyl hydrazines to afford unsymmetrical gem-diarylmethyl sulfones via a sulfa-1,6-conjugated addition pathway. All these reactions were performed smoothly in water under mild conditions (Scheme 1).

2. Results and Discussion

2.1. Optimization of Reaction Conditions

In our preliminary study, the investigation of the reaction conditions was carried out with 4-methylbenzenesulfonohydrazide 1a and para-quinone methides (p-QM) 2a as model substrates (Table 1). Initially, the reaction was explored with different solvents in absence of a catalyst. When the reaction was carried out at 80 °C in tetrahydrofuran (THF), the desired 1,6-sulfa-conjugated adduct was obtained in mediate yield (50%). Other organic solvents including Et2O, toluene, dichloroethane (DCE), dioxane, and dimethylsulfoxide (DMSO) were proved to be unsuitable for the reaction (Table 1, entry 1–6). It was found that protic polar solvent had an obvious promotion effect on the reaction. When H2O and EtOH were employed, the yield was increased slightly to 61% and 73%, respectively (Table 1, entry 7–8). Although EtOH had a better effect than water, taking into consideration the “green and sustainable chemistry” perspective, we chose H2O as a solvent. Subsequently, we focused on catalyst screening to improve the yield of the water mediated C-S bond formation reaction. Unfortunately, heterogeneous transition metal nano-catalysts such as Pd/C, Pd/TiO2, Au/TiO2, and Pt/C had little promotion effect on the reaction (Table 1, entry 9–12). Inspired by the better result of EtOH, phase transfer catalysts were selected to improve the solubility of organic substrate 1a and 2a in water, which may have a positive influence on the reaction (Table 1, entry 13–17). To our delight, in presence of 10% mol tetrabutylammonium bromide (TBAB), the yield was improved sharply to 82% (Table 1, entry 16). Based on the result, we continuously investigated the effect of other reaction parameters including temperature, reaction time, and reactant ratio. We were pleased to find that the yield was markedly increased, as the reactant ratio of 2a:1a was increased from 1 to 1.5. Thus, the desired gem-diarylmethyl sulfone 3aa was obtained in 96% yield by performing the TBAB-catalyzed sulfonylation of 4-methylbenzenesulfonohydrazide 1a to p-QM 2a at 80 °C in 12 h (Table 1, entry 22). Given either a lower or higher temperature, the yields decreased (Table 1, entry 18–20).

2.2. Reaction Scope

Based on the optimized reaction conditions, the generality of this 1,6-conjugate sulfonylation reaction of sulfonyl hydrazines to para-quinone methides was investigated. Some of the results are summarized in Figure 2 and Figure 3.
A number of para-quinone methide derivatives 2 bearing different substituents were explored with 4-methylbenzenesulfonohydrazide 1a under standard reaction condition (Figure 2). Various substituent groups, such as electron-donating groups (-Me, -OMe), electron-withdrawing groups (-CF3, -NO2), and halogen atoms (F, Cl, Br), on the p-QM derivatives’ aryl ring at the ortho (2ab–2ag), meta (2ah–2al), and para (2am–2as) positions were well tolerated by the reaction to provide the corresponding sulfonylation adducts in good to excelled yields. Furthermore, non-substituted phenyl substrate 2aa, disubstituted 2,4-dichlorophenyl substrate 2at, polycyclic aromatic substrate 2av, heteroaromatic substrates 2au, and aliphatic substrate 2ay led to the desired product in 63–95% yields, implying the well-tolerated property of the substrates in this reaction. Moreover, p-QMs derived from 2,6-dimethylphenol 2aw and 2,6-diisopropylphenol 2ax were also compatible to afford the corresponding adducts, while the former was in lower yield (3aw, 63%) probably due to its small steric hindrance around the phenolic hydroxyl group.
Consequentially, we investigated the substitute effects of sulfonyl hydrazines by using 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dienone 2a as model substrate under optimized reaction condition (Figure 3). In general, a wide range of sulfonyl hydrazines 1 bearing meta and para substituent group including electron-donating groups (-Me, -OMe, -NHAc, -OCF3), electron-withdrawing groups (-CF3, -NO2), and halogen atom (F, Cl, Br) reacted smoothly with p-QM 2a, affording the adducts in 62–96% yields. In addition, phenyl 4aa, p-tert-butyl phenyl 4ab, 2-naphthyl 4ak, thienyl 4al and aliphatic benzyl substituted sulfonyl hydrazines were also tolerated by the reaction to produce the final products in 52–92% yields.

2.3. Proposed Mechanism

The chemical structure of diarylmethyl sulfones 3 and 4 were characterized by nuclear magnetic resonance spectroscopies (Supplementary Materials). Because there is another possible sulfinic ester adduct, the two potential products cannot be distinguished by NMR. To further identify the structure of the products, 4af was selected as a representative compound, and the sulfone structure was unequivocally confirmed by single crystal X-ray diffraction analysis, as shown in Figure 4 (CCDC No. 1531154).
On the basis of the above observations, we tentatively propose a plausible reaction mechanism (Scheme 2). First, the sulfonyl hydrazines 1 decomposed into sulfinyl anion 5 with the N2 released and hydronium generation under the heating condition. Intermediate 5 has a resonate equilibrium with sulfur-centered anion 6 in water. As a more reactive species, the sulfur-centered anion 6 attacks the electrophilic atom of the resonated structure of p-QM 2 with the help of tetrabutylammonium bromide (TBAB). Finally, driven by the aromatization force, the target product is obtained.

2.4. Derivatives of Products

To further demonstrate the synthetic utility of this protocol, the transformations of products were then explored (Scheme 3). A carbon-carbon bond formation between 3aa and indole led to the generation of unsymmetrical triarylmethane 7. Furthermore, base-promoted carbon-sulfur bond formation between 3aa and thiophenol proceeded to the facial delivery of unsymmetrical gem-diarylmethyl thioether 8. Moreover, the yield of products of both synthesis routines reached around 80%, implying the potential and feasibility of further application of 3aa.

3. Materials and Methods

3.1. General Information

1H-NMR, 13C-NMR spectra were obtained utilizing a Bruker 600 and 400 MHz instrument and reported in CDCl3 or DMSO(d6). 1H and 13CNMR chemical shifts are reported in ppm relative to either TMS (1H) (δ = 0 ppm) as an internal standard or the residual solvent peak as following: CDCl3 = 7.26 (1H-NMR), (CD3)2SO = 2.50 (1H-NMR), CDCl3 = 77.16 (13C-NMR), (CD3)2SO = 40.00 (13C-NMR). HRMS were performed on a Bruker Impact II 10200 instrument. Commercially available chemicals and solvents were purchased from Adamas-beta, Energy Chemical, Chongqing Chuandong Chemical, and Chengdu Kelong Chemical. The corresponding compounds were synthesized according to the methods reported in the literature. Analytical thin-layer chromatography (TLC) was performed on silicycle silica gel plates with F-254 indicator, and compounds were visualized by irradiation with UV light. Chromatography was carried out using silica gel 300–400 mesh.

3.2. Experiment

3.2.1. Representative Procedure for Synthesis of Gem-Diarylmethyl Sulfones

To a solution of corresponding 4-(arylmethylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (0.3 mmol) in 1 mL water, the corresponding arylsulfonohydrazide (0.2 mmol) and TBAB (0.02 mmol) were added. The mixture was stirred at 80°C. The reaction was monitored by TLC. After complete reaction, the mixture was extracted by ethyl acetate, dried over by anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was then purified by flash column chromatography on silica gel (gradient eluent of PE/EA = 30:1–10:1) to gain the corresponding product.
2,6-Di-tert-butyl-4-(phenyl(tosyl)methyl)phenol (3aa): [15] Pale yellow solid; 96% yield. 1H-NMR (600 MHz, CDCl3) δ 7.61 (d, J = 7.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.32 (dq, J = 14.2, 6.9 Hz, 3H), 7.16 (s, 2H), 7.13 (d, J = 7.9 Hz, 2H), 5.20 (s, 1H), 5.16 (s, 1H), 2.36 (s, 3H), 1.35 (s, 18H); 13C-NMR (151 MHz, CDCl3) δ 154.08 (s), 144.00 (s), 135.94 (s), 135.77 (s), 133.66 (s), 130.00 (s), 129.10 (s), 129.05 (s), 128.62 (s), 128.36 (s), 127.10 (s), 123.57 (s), 76.90 (s), 34.31 (s), 30.16 (s), 21.48 (s).
2,6-Di-tert-butyl-4-(o-tolyl(tosyl)methyl)phenol (3ab): [15] Pale yellow solid; 76% yield. 1H-NMR (600 MHz, CDCl3) δ 8.23 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.13 (s, 2H), 7.08 (d, J = 7.5 Hz, 1H), 5.43 (s, 1H), 5.21 (s, 1H), 2.37 (s, 3H), 2.17 (s, 3H), 1.34 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 153.99 (s), 143.87 (s), 138.20 (s), 135.84 (s), 130.49 (s), 129.84 (s), 129.33 (s), 129.09 (s), 128.99 (s), 127.03 (s), 123.75 (s), 76.67 (s), 34.28 (s), 30.13 (s), 21.47 (s), 21.09 (s).
2,6-Di-tert-butyl-4-((2-methoxyphenyl)(tosyl)methyl)phenol (3ac): [15] Pale yellow solid; 87% yield. 1H-NMR (600 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.22–7.25 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 5.93 (s, 1H), 5.19 (s, 1H), 3.60 (s, 3H), 2.36 (s, 3H), 1.36 (s, 18H). 13C-NMR (151 MHz) δ 156.98 (s), 153.95 (s), 143.67 (s), 136.30 (s), 135.69 (s), 129.86 (s), 129.39 (s), 129.08 (s), 128.82 (s), 127.36 (s), 123.53 (s), 122.54 (s), 120.69 (s), 110.79 (s), 66.98 (s), 55.56 (s), 34.30 (s), 30.17 (s), 21.46 (s).
2,6-Di-tert-butyl-4-((2-chlorophenyl)(tosyl)methyl)phenol (3ad): [15] Pale yellow solid; 75% yield. 1H-NMR (600 MHz, CDCl3) δ 8.35 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.16 (s, 3H), 7.15 (s, 1H), 5.88 (s, 1H), 5.23 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 153.20 (s), 143.25 (s), 134.90 (s), 134.72 (s), 133.87 (s), 131.18 (s), 129.10 (s), 128.80 (s), 128.38 (s), 128.17 (s), 128.01 (s), 126.25 (s), 126.05 (s), 121.54 (s), 70.08 (s), 33.28 (s), 29.11 (s), 20.52 (s).
4-((2-Bromophenyl)(tosyl)methyl)-2,6-di-tert-butylphenol (3ae): [15] Pale yellow solid; 82% yield. 1H-NMR (600 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.18 (s, 2H), 7.15 (m, 3H), 5.90 (s, 1H), 5.23 (s, 1H), 2.37 (s, 3H), 1.36 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.19 (s), 144.25 (s), 135.92 (s), 135.77 (s), 133.88 (s), 133.17 (s), 130.19 (s), 129.64 (s), 129.18 (s), 129.01 (s), 127.69 (s), 127.24 (s), 126.02 (s), 122.56 (s), 73.83 (s), 34.29 (s), 30.13 (s), 21.51 (s).
2,6-Di-tert-butyl-4-((2-fluorophenyl)(tosyl)methyl)phenol (3af): [15] Pale yellow solid; 74% yield. 1H-NMR (600 MHz, CDCl3) δ 8.21 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 13.2, 6.3 Hz, 1H), 7.27–7.22 (m, 1H), 7.16 (s, 3H), 7.15 (s, 1H), 6.96 (t, J = 9.1 Hz, 1H), 5.63 (s, 1H), 5.24 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 160.61 (d, JC-F = 247.4 Hz), 154.22 (s), 144.23 (s), 135.96 (s), 135.57 (s), 130.15 (d, JC-F = 1.6 Hz), 129.97 (d, JC-F = 8.6 Hz), 129.14 (s), 129.05 (s), 127.19 (s), 124.30 (d, JC-F = 3.6 Hz), 122.73 (s), 121.57 (d, JC-F =13.5 Hz), 115.50 (d, JC-F = 23.0 Hz), 67.18 (d, JC-F = 4.2 Hz), 34.29 (s), 30.10 (s), 21.50 (s).
2,6-Di-tert-butyl-4-(tosyl(2-(trifluoromethyl)phenyl)methyl)phenol (3ag): [15] Pale yellow solid; 89% yield. 1H-NMR (600 MHz, CDCl3) δ 8.61 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.44 (m, 3H), 7.15 (m, 4H), 5.59 (s, 1H), 5.23 (s, 1H), 2.36 (s, 3H), 1.34 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.20 (s), 144.34 (s), 135.87 (s), 135.59 (s), 133.00 (s), 131.99 (s), 130.47 (s), 129.18 (s), 129.10 (s), δ 129.64 – 128.96 (m), 128.25 (s), 127.10 (s), 126.45 (q, JC-F = 5.9 Hz), 124.12 (q, JC-F = 274.4 Hz).122.73 (s), 71.00 (s), 34.29 (s), 30.10 (s), 21.48 (s).
2,6-Di-tert-butyl-4-(m-tolyl(tosyl)methyl)phenol (3ah): [15] Pale yellow solid; 84% yield. 1H-NMR (600 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.39 (s, 1H), 7.28–7.19 (m, 1H), 7.13 (m, 5H), 5.20 (s, 1H), 5.12 (s, 1H), 2.35 (d, J = 9.0 Hz, 3H), 2.33 (s, 3H), 1.35 (s, 18H); 13C-NMR (151 MHz, CDCl3) δ 154.03 (s), 143.92 (s), 138.21 (s), 135.84 (s), 135.81 (s), 133.43 (s), 130.86 (s), 129.12 (s), 128.99 (s), 128.49 (s), 127.10 (s), 126.88 (s), 123.65 (s), 76.92 (s), 34.28 (s), 30.12 (s), 21.46 (s).
2,6-Di-tert-butyl-4-((3-methoxyphenyl)(tosyl)methyl)phenol (3ai): [15] Pale yellow solid; 81% yield. 1H-NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.8 Hz, 2H), 7.27–7.23 (m, 1H), 7.19 (d, J = 5.4 Hz, 2H), 7.17–7.11 (m, 4H), 6.86 (d, J = 8.0 Hz, 1H), 5.21 (s, 1H), 5.13 (s, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 159.65 (s), 154.08 (s), 143.99 (s), 135.87 (s), 135.74 (s), 134.93 (s), 129.53 (s), 129.11 (s), 129.03 (s), 127.07 (s), 123.45 (s), 122.39 (s), 115.33 (s), 114.42 (s), 76.78 (s), 55.22 (s), 34.29 (s), 30.13 (s), 21.47 (s).
4-((3-Bromophenyl)(tosyl)methyl)-2,6-di-tert-butylphenol (3aj): [15] Pale yellow solid; 77% yield. 1H-NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.10 (s, 2H), 5.24 (s, 1H), 5.11 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.24 (s), 144.32 (s), 136.08 (s), 135.82 (s), 135.35 (s), 133.15 (s), 131.46 (s), 130.07 (s), 129.16 (s), 129.10 (s), 128.34 (s), 127.02 (s), 122.90 (s), 122.55 (s), 76.15 (s), 34.31 (s), 30.10 (s), 21.49 (s).
2,6-Di-tert-butyl-4-((3-fluorophenyl)(tosyl)methyl)phenol (3ak): [15] Pale yellow solid; 78% yield. 1H-NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H), 7.41–7.36 (m, 2H), 7.31 (td, J = 8.0, 6.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.11 (s, 2H), 7.02 (tdd, J = 8.4, 2.5, 0.8 Hz, 1H), 5.25 (s, 1H), 5.15 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 162.67 (d, JC-F = 246.5 Hz), 154.23 (s), 144.24 (s), 136.06 (s), 135.91 (d, JC-F = 7.3 Hz), 135.46 (s), 130.02 (d, JC-F = 8.3 Hz), 129.13 (s), 129.08 (s), 127.01 (s), 125.71 (d, JC-F = 2.8 Hz), 123.04 (s), 117.05 (d, JC-F = 23.0 Hz), 115.35 (d, JC-F = 21.1 Hz), 76.22 (s), 34.29 (s), 30.10 (s), 21.43 (s).
2,6-Di-tert-butyl-4-(tosyl(3-(trifluoromethyl)phenyl)methyl)phenol (3al): [15] Pale yellow solid; 60% yield. 1H-NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 7.13 (s, 3H), 5.27 (s, 1H), 5.23 (s, 1H), 2.36 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.33 (s), 144.47 (s), 136.20 (s), 135.18 (s), 134.71 (s), 133.22 (s), 130.94 (q, JC-F = 32.5 Hz), 129.20 (s), 129.11 (d, JC-F =3.5 Hz), 127.20–126.83 (m), 125.29–125.02 (m), 123.90 (q, JC-F = 272.4 Hz).122.70 (s), 76.29 (s), 34.32 (s), 30.08 (s), 21.45 (s).
2,6-Di-tert-butyl-4-(p-tolyl(tosyl)methyl)phenol (3am): [15] Pale yellow solid; 80% yield. 1H-NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.2 Hz, 4H), 7.12 (d, J = 8.1 Hz, 2H), 5.19 (s, 1H), 5.13 (s, 1H), 2.36 (s, 3H), 2.33 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 153.99 (s), 143.87 (s), 138.20 (s), 135.84 (s), 130.49 (s), 129.84 (s), 129.33 (s), 129.09 (s), 128.99 (s), 127.03 (s), 123.75 (s), 76.67 (s), 34.28 (s), 30.13 (s), 21.47 (s), 21.09 (s).
2,6-Di-tert-butyl-4-((4-methoxyphenyl)(tosyl)methyl)phenol (3an): [15] Pale yellow solid; 79% yield. 1H-NMR (600 MHz, CDCl3) δ 7.53 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.15 (s, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.20 (s, 1H), 5.13 (s, 1H), 3.79 (s, 3H), 2.35 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 155.77 (s), 150.04 (s), 139.94 (s), 131.93 (s), 131.87 (s), 127.28 (s), 125.13 (s), 125.08 (s), 123.06 (s), 121.53 (s), 119.87 (s), 110.15 (s), 72.34 (s), 51.33 (s), 30.35 (s), 27.78–23.72 (m), 17.53 (s).
2,6-Di-tert-butyl-4-((4-chlorophenyl)(tosyl)methyl)phenol (3ao): [15] Pale yellow solid; 81% yield. 1H-NMR (600 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.09 (s, 2H), 5.23 (s, 1H), 5.14 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.18 (s), 144.23 (s), 136.05 (s), 135.45 (s), 134.54 (s), 132.16 (s), 131.25 (s), 129.15 (s), 129.07 (s), 128.82 (s), 126.96 (s), 123.10 (s), 76.05 (s), 34.30 (s), 30.10 (s), 21.50 (s).
4-((4-Bromophenyl)(tosyl)methyl)-2,6-di-tert-butylphenol (3ap): [15] Pale yellow solid; 79% yield. 1H-NMR (400 MHz, CDCl3) δ 7.54–7.45 (m, 4H), 7.42 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.09 (s, 2H), 5.24 (s, 1H), 5.13 (s, 1H), 2.37 (s, 3H), 1.34 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 154.20 (s), 144.28 (s), 136.02 (s), 135.35 (s), 132.67 (s), 131.79 (s), 131.54 (s), 129.17 (s), 129.06 (s), 126.95 (s), 122.98 (s), 122.76 (s), 76.08 (s), 34.30 (s), 30.10 (s), 21.53 (s).
2,6-Di-tert-butyl-4-((4-fluorophenyl)(tosyl)methyl)phenol (3aq): [15] Pale yellow solid; 70% yield. 1H-NMR (600 MHz, CDCl3) δ 7.60 (dd, J = 8.2, 5.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.12 (s, 2H), 7.04 (t, J = 8.5 Hz, 2H), 5.23 (s, 1H), 5.16 (s, 1H), 2.36 (s, 3H), 1.35 (s, 18H).13C-NMR (151 MHz, CDCl3) δ 162.79 (d, JC-F = 248.1 Hz), 154.13 (s), 144.15 (s), 136.03 (s), 135.54 (s), 131.73 (d, JC-F = 8.2 Hz), 129.44 (d, JC-F = 3.2 Hz), 129.11 (s), 129.06 (s), 126.97 (s), 123.33 (s), 115.57 (d, JC-F = 21.5 Hz), 75.98 (s), 34.30 (s), 30.11 (s), 21.47 (s).
2,6-Di-tert-butyl-4-(tosyl(4-(trifluoromethyl)phenyl)methyl)phenol (3ar): [15] Pale yellow solid; 77% yield. 1H-NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 (s, 2H), 5.25 (s, 1H), 5.22 (s, 1H), 2.37 (s, 3H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.29 (s), 144.41 (s), 137.69 (s), 136.17 (s), 135.29 (s), 130.55 (q, JC-F = 32.6 Hz), 130.28 (s), 129.18 (s), 129.07 (s), 126.97 (s), 125.53 (q, JC-F = 3.6 Hz), 123.96 (q, JC-F = 272.1 Hz). 122.83 (s), 76.32 (s), 34.30 (s), 30.08 (s), 21.49 (s).
2,6-Di-tert-butyl-4-((4-nitrophenyl)(tosyl)methyl)phenol (3as): [15] Pale yellow solid; 72% yield. 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.07 (s, 2H), 5.29 (s, 1H), 5.27 (s, 1H), 2.38 (s, 3H), 1.34 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 153.76 (s), 148.51 (d, J = 2.9 Hz), 147.13 (s), 143.63 (s), 137.22 (s), 136.63 (s), 129.98 (s), 129.55 (s), 128.21 (s), 127.26 (s), 124.18 (s), 123.50 (s), 61.32 (s), 34.31 (s), 30.04 (s), 21.45 (s).
2,6-Di-tert-butyl-4-((2,4-dichlorophenyl)(tosyl)methyl)phenol (3at): [15] Pale yellow solid; 68% yield. 1H-NMR (600 MHz, CDCl3) δ 8.29 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.10 (s, 2H), 5.79 (s, 1H), 5.25 (s, 1H), 2.39 (s, 1H), 1.35 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.31 (s), 144.50 (s), 136.06 (s), 135.56 (s), 135.47 (s), 134.79 (s), 130.90 (s), 130.83 (s), 129.62 (s), 129.29 (s), 128.99 (s), 127.44 (s), 127.08 (s), 122.18 (s), 70.63 (s), 34.29 (s), 30.09 (s), 21.53 (s).
2,6-Di-tert-butyl-4-((1,3-dihydroisobenzofuran-4-yl)(tosyl)methyl)phenol (3au): [15] Pale yellow solid; 68% yield. 1H-NMR (600 MHz, CDCl3) δ 7.43 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.95 (d, J = 3.4 Hz, 1H), 5.21 (s, 1H), 5.08 (s, 1H), 2.36 (s, 1H), 1.35 (s, 1H). 13C-NMR (151 MHz, CDCl3) δ 154.19 (s), 148.02 (s), 147.93 (s), 144.14 (s), 136.09 (s), 135.86 (s), 129.20 (s), 127.14 (s), 127.03 (s), 124.14 (s), 123.83 (s), 110.36 (s), 108.45 (s), 101.37 (s), 76.60 (s), 34.43 (s), 32.20–27.96 (m), 21.62 (s); HRMS calculated for [M + Na]+ C29H34O5SNa+, m/z 517.2019, found 517.2020.
2,6-Di-tert-butyl-4-(naphthalen-1-yl(tosyl)methyl)phenol (3av): [15] Pale yellow solid; 78% yield. 1H-NMR (600 MHz, CDCl3) δ 8.55 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.45–7.39 (m, 2H), 7.25 (s, 1H), 7.14 (s, 1H), 7.12 (d, J = 7.9 Hz, 2H), 6.05 (s, 1H), 5.19 (s, 1H), 2.33 (s, 3H), 1.31 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.12 (s), 144.09 (s), 136.00 (s), 135.77 (s), 134.12 (s), 131.79 (s), 129.79 (s), 129.16 (s), 129.13 (s), 128.92 (s), 127.32 (s), 126.85 (s), 126.50 (s), 125.49 (s), 125.32 (s), 123.36 (s), 122.37 (s), 71.18 (s), 34.24 (s), 30.08 (s), 21.46 (s).
2,6-Dimethyl-4-(phenyl(tosyl)methyl)phenol (3aw): [15] Pale yellow solid; 63% yield. 1H-NMR (600 MHz, CDCl3) δ 7.54–7.44 (m, 4H), 7.28 (m, 3H), 7.15 (m, 4H), 5.13 (s, 1H), 4.70 (s, 1H), 2.37 (s, 3H), 2.20 (s, 6H). 13C-NMR (151 MHz, CDCl3) δ 152.62 (s), 144.22 (s), 135.65 (s), 133.77 (s), 130.25 (s), 129.86 (s), 129.15 (s), 129.08 (s), 128.56 (s), 128.35 (s), 124.34 (s), 123.28 (s), 76.09 (s), 21.53 (s), 15.90 (s).
2,6-Diisopropyl-4-(phenyl(tosyl)methyl)phenol (3ax): [15] Pale yellow solid; 79% yield. 1H-NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.37–7.28 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 5.20 (s, 1H), 4.81 (s, 1H), 3.19–2.90 (m, 1H), 2.35 (s, 1H), 1.22 (d, J = 6.9 Hz, 1H), 1.14 (d, J = 6.8 Hz, 1H). 13C-NMR (151 MHz, CDCl3) δ 150.23 (s), 144.02 (s), 133.77 (s), 133.48 (s), 129.99 (s), 129.08 (s), 129.05 (s), 128.58 (s), 128.36 (s), 125.59 (s), 124.87 (s), 99.99 (s), 76.62 (s), 27.21 (s), 22.61 (s), 22.53 (s), 21.48 (s).
2,6-Di-tert-butyl-4-(1-tosylethyl)phenol (3ay): [15] Pale yellow solid; 80% yield. 1H-NMR (600 MHz,) δ 7.33 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.78 (s, 2H), 5.21 (s, 1H), 4.13 (q, J = 7.2 Hz, 1H), 2.38 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H), 1.32 (s, 18H). 13C-NMR (151 MHz,) δ 154.13 (s), 143.98 (s), 135.75 (s), 134.32 (s), 129.31 (s), 129.04 (s), 126.21 (s), 124.39 (s), 66.53 (s), 34.23 (s), 30.13 (s), 21.50 (s), 13.45 (s).
2,6-Di-tert-butyl-4-(phenyl(phenylsulfonyl)methyl)phenol (4aa): [16] Pale yellow solid; 92% yield. 1H-NMR (600 MHz, CDCl3) δ 7.62 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.34 (dd, J = 15.7, 8.5 Hz, 5H), 7.19 (s, 2H), 5.24 (s, 1H), 5.21 (s, 1H), 1.36 (s, 18H).13C-NMR (151 MHz, CDCl3) δ 154.15 (s), 138.65 (s), 135.97 (s), 133.45 (s), 133.13 (s), 130.00 (s), 129.08 (s), 128.67 (s), 128.47 (s), 128.44 (s), 127.10 (s), 123.29 (s), 34.34 (s), 30.18 (s).
2,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(phenyl)methyl)phenol (4ab): [16] Pale yellow solid; 77% yield. 1H-NMR (600 MHz, CDCl3) δ 7.63 (d, J = 7.1 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.38–7.30 (m, 5H), 7.12 (s, 2H), 5.21 (s, 1H), 5.18 (s, 1H), 1.34 (s, 18H), 1.29 (s, 9H). 13C-NMR (151 MHz, CDCl3) δ 157.07 (s), 154.04 (s), 135.85 (s), 135.59 (s), 133.66 (s), 129.96 (s), 129.01 (s), 128.60 (s), 128.33 (s), 127.13 (s), 125.42 (s), 123.57 (s), 76.88 (s), 35.12 (s), 34.29 (s), 31.04 (s), 30.16 (s).
2,6-Di-tert-butyl-4-(((4-methoxyphenyl)sulfonyl)(phenyl)methyl)phenol (4ac): [16] Pale yellow solid; 96% yield. 1H-NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.39–7.28 (m, 3H), 7.18 (s, 2H), 6.80 (d, J = 8.4 Hz, 2H), 5.23 (s, 1H), 5.16 (s, 1H), 3.81 (s, 3H), 1.36 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 154.29 (s), 137.65 (s), 136.11 (s), 133.01 (s), 131.68 (s), 130.54 (s), 129.95 (s), 128.78 (s), 128.65 (s), 128.53 (s), 127.08 (s), 122.89 (s), 76.97 (s), 34.32 (s), 30.13 (s).
N-(4-(((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl)methyl)sulfonyl)phenyl) acetamide (4ad): Pale yellow solid; 79% yield. 1H-NMR (600 MHz, DMSO(d6)) δ 10.28 (s, 1H), 7.61 (dd, J = 11.6, 8.3 Hz, 4H), 7.46 (d, J = 8.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.23 (s, 2H), 7.03 (s, 1H), 5.77 (s, 1H), 2.06 (s, 3H), 1.31 (s, 18H).13C-NMR (151 MHz, DMSO(d6)) δ 169.47 (s), 154.32 (s), 144.13 (s), 139.25 (s), 134.72 (s), 130.26 (s), 130.14 (s), 128.86 (s), 128.55 (s), 126.96 (s), 124.72 (s), 118.24 (s), 74.46 (s), 34.96 (s), 30.68 (s), 24.62 (s); HRMS (ESI): m/z calcd for C29H35NO4SNa [M + Na]+, 516.2178; found, 516.2179.
2,6-Di-tert-butyl-4-(((4-chlorophenyl)sulfonyl)(phenyl)methyl)phenol (4ae): [16] Pale yellow solid; 75% yield. 1H-NMR (600 MHz, DMSO(d6)) δ 7.64 (d, J = 7.3 Hz, 2H), 7.55 (dd, J = 22.6, 8.7 Hz, 4H), 7.39 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 6.8 Hz, 1H), 7.21 (s, 2H), 7.08 (s, 1H), 5.95 (s, 1H), 1.31 (s, 18H).13C-NMR (151 MHz, DMSO(d6)) δ 154.47 (s), 139.40 (s), 138.99 (s), 137.71 (s), 134.04 (s), 130.83 (s), 130.31 (s), 129.18 (s), 129.00 (s), 128.78 (s), 127.05 (s), 124.18 (s), 74.08 (s), 34.95 (s), 30.63 (s).
4-(((4-Bromophenyl)sulfonyl)(phenyl)methyl)-2,6-di-tert-butylphenol (4af): [16] Pale yellow solid; 81% yield. 1H-NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.7, 1.8 Hz, 2H), 7.50–7.45 (m, 2H), 7.42–7.40 (m, 1H), 7.40-7.32 (m, 4H), 7.17 (s, 2H), 5.26 (s, 1H), 5.17 (s, 1H), 1.37 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 154.29 (s), 137.65 (s), 136.11 (s), 133.01 (s), 131.68 (s), 130.54 (s), 129.95 (s), 128.78 (s), 128.65 (s), 128.53 (s), 127.08 (s), 122.89 (s), 76.97 (s), 34.32 (s), 30.13 (s).
2,6-Di-tert-butyl-4-(((4-fluorophenyl)sulfonyl)(phenyl)methyl)phenol (4ag): [16] Pale yellow solid; 62% yield. 1H-NMR (600 MHz, CDCl3) δ 7.60 (dd, J = 7.9, 1.2 Hz, 2H), 7.58–7.53 (m, 2H), 7.38–7.28 (m, 3H), 7.21 (s, 2H), 7.04–6.95 (m, 2H), 5.26 (s, 1H), 5.18 (s, 1H), 1.37 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 164.46 (d, J = 255.9 Hz), 153.21 (s), 135.05 (s), 133.62 (s), 132.21 (s), 130.79 (d, J = 9.5 Hz), 128.91 (s), 127.70 (s), 127.55 (s), 126.00 (s), 122.05 (s), 114.63 (d, J = 22.5 Hz), 75.99 (s), 33.30 (s), 29.12 (s).
2,6-Di-tert-butyl-4-(phenyl((4-(trifluoromethyl)phenyl)sulfonyl)methyl)phenol (4ah): [16] Pale yellow solid; 82% yield. 1H-NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.1 Hz, 2H), 7.65–7.57 (m, 4H), 7.40–7.33 (m, 3H), 7.17 (s, 2H), 5.27 (s, 1H), 5.21 (s, 1H), 1.35 (s, 18H). 13C-NMR (151 MHz, DMSO(d6)) δ 154.68 (s), 142.95 (s), 139.58 (s), 134.06–133.29 (m), 133.82 (s), 130.51 (s), 130.13 (s), 129.22 (s), 129.06 (s), 127.28 (s), 126.44–126.15 (m), 123.96 (q, J = 273.0 Hz), 123.98 (s), 74.06 (s), 35.07 (s), 30.72 (s).
2,6-Di-tert-butyl-4-(phenyl((4-(trifluoromethoxy)phenyl)sulfonyl)methyl)phenol (4ai): Pale yellow solid; 84% yield. 1H-NMR (600 MHz, CDCl3) δ 7.61 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.37–7.32 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 5.25 (s, 1H), 5.17 (s, 1H), 1.37 (s, 1H). 13C-NMR (151 MHz, DMSO(d6)) δ 154.48 (s), 152.04 (d, J = 2.0 Hz), 139.39 (s), 137.73 (s), 134.00 (s), 131.65 (s), 130.32 (s), 129.00 (s), 128.80 (s), 127.04 (s), 124.13 (s), 121.18 (s), 120.26 (q, J = 258.2 Hz).74.07 (s), 34.93 (s), 30.59 (s); HRMS (ESI): m/z calcd for C28H31F3O4SNa [M + Na]+, 543.1785; found, 543.1787.
2,6-Di-tert-butyl-4-(((3-nitrophenyl)sulfonyl)(phenyl)methyl)phenol (4aj): Pale yellow solid; 86% yield. 1H-NMR (600 MHz, CDCl3) δ 8.38–8.32 (m, 1H), 8.30 (t, J = 1.7 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 6.6 Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.42–7.33 (m, 3H), 7.23 (s, 2H), 5.30 (s, 1H), 5.24 (s, 1H), 1.36 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 154.56 (s), 147.81 (s), 140.94 (s), 136.49 (s), 134.26 (s), 132.33 (s), 129.99 (s), 129.66 (s), 128.97 (s), 128.93 (s), 127.49 (s), 127.07 (s), 124.48 (s), 122.32 (s), 77.12 (s), 34.35 (s), 30.14 (s); HRMS (ESI): m/z calcd for C27H31NO5SNa [M + Na]+, 504.1817; found, 504.1815.
2,6-Di-tert-butyl-4-((naphthalen-1-ylsulfonyl)(phenyl)methyl)phenol (4ak): [16] Pale yellow solid; 52% yield. 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.79 (dd, J = 8.1, 5.2 Hz, 2H), 7.67 (dd, J = 7.8, 1.6 Hz, 2H), 7.64–7.51 (m, 3H), 7.39–7.30 (m, 3H), 7.16 (s, 2H), 5.28 (s, 1H), 5.18 (s, 1H), 1.26 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 153.06 (s), 134.88 (s), 134.37 (s), 133.97 (s), 132.31 (s), 130.81 (s), 130.02 (s), 129.01 (s), 128.23 (s), 128.02 (s), 127.67 (s), 127.47 (s), 127.42 (s), 126.74 (s), 126.34 (s), 126.04 (s), 122.65 (s), 122.38 (s), 75.89 (s), 33.18 (s), 29.01 (s).
2,6-Di-tert-butyl-4-(phenyl(thiophen-2-ylsulfonyl)methyl)phenol (4al): [16] Pale yellow solid; 76% yield. 1H-NMR (600 MHz, CDCl3) δ 7.63 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 3.7 Hz, 1H), 7.40–7.30 (m, 3H), 7.28 (s, 3H), 7.01–6.89 (m, 1H), 5.30 (s, 1H), 5.26 (s, 1H), 1.38 (s, 18H). 13C-NMR (151 MHz, DMSO(d6)) δ 154.54 (s), 139.54 (s), 139.40 (s), 136.07 (s), 135.32 (s), 134.54 (s), 130.23 (s), 128.97 (s), 128.78 (s), 128.05 (s), 126.89 (s), 124.58 (s), 75.79 (s), 35.02 (s), 30.71 (s).
4-((Benzylsulfonyl)(phenyl)methyl)-2,6-di-tert-butylphenol (4am): [16] Pale yellow solid; 84% yield. 1H-NMR (600 MHz, CDCl3) δ 7.57 (dd, J = 5.2, 3.3 Hz, 2H), 7.42–7.29 (m, 8H), 7.17 (dd, J = 7.9, 1.3 Hz, 2H), 5.31 (s, 1H), 5.03 (s, 1H), 4.33–3.57 (m, 2H), 1.44 (s, 18H). 13C-NMR (101 MHz, CDCl3) δ 154.38 (s), 136.32 (s), 132.83 (s), 130.97 (s), 130.11 (s), 128.82 (s), 128.78 (s), 128.68 (d, J = 2.0 Hz), 128.07 (s), 126.88 (s), 122.93 (s), 71.81 (s), 58.13 (s), 34.48 (s), 30.30 (s).

3.2.2. Representative Procedure for General Reaction Procedure for Synthesis of Unsymmetrical Triarylmethane 7

To a solution of 2,6-di-tert-butyl-4-(phenyl(tosyl)methyl) phenol (45 mg, 0.10 mmol) in 1 mL DCE, KOH (5.6 mg, 0.10 mmol) and indole (14.06 mg, 0.12 mmol) were added. The mixture was stirred at 65 °C. The reaction was monitored by TLC. After complete reaction, the mixture was washed with water, dried over by anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was then purified by flash column chromatography on silica gel to afford the pure product 7.
2,6-Di-tert-butyl-4-((3a,7a-dihydro-1H-indol-3-yl)(phenyl)methyl)phenol (7): [41] Brown solid; 85% yield. 1H-NMR (600 MHz, CDCl3) δ 7.90 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 5.3 Hz, 4H), 7.22 (d, J = 8.1 Hz, 1H), 7.18 (qd, J = 5.3, 2.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.04 (s, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 23.9 Hz, 1H), 5.56 (s, 1H), 5.04 (s, 1H), 1.36 (s, 18H).13C-NMR (151 MHz, CDCl3) δ 152.91 (d, J = 2.9 Hz), 141.67 (s), 136.43 (d, J = 2.7 Hz), 135.80 (d, J = 2.2 Hz), 131.54 (s), 131.31 (s), 128.61 (d, J = 2.9 Hz), 128.43 (s), 127.04 (d, J = 2.6 Hz), 126.61 (d, J = 3.0 Hz), 125.21 (d, J = 2.8 Hz), 58.10 (s), 34.43 (s), 30.33 (s).

3.2.3. Representative Procedure for General Reaction Procedure for Synthesis of Unsymmetrical Gem-Diarylmethyl Thioether 8

To a solution of 2,6-di-tert-butyl-4-(phenyl(tosyl)methyl) phenol (45 mg, 0.1 mmol) in 1 mL methyl tert-butyl ether, Cs2CO3 (36 mg, 0.01 mmol) and TBAB (3.6 mg, 0.01 mmol) were added. Benzenethiol (13.68 μL, 0.12 mmol) was added to the solution dropwise, and the mixture was stirred at 80 °C. The reaction was monitored by TLC. After complete reaction, the mixture was concentrated in vacuo. The crude product was then purified by flash column chromatography on silica gel to afford the pure product 8.
2,6-Di-tert-butyl-4-(phenyl(phenylthio)methyl)phenol (8): [42] Colorless gummy liquid; 76% yield. 1H-NMR (600 MHz, CDCl3) δ 7.38 (d, J = 7.4 Hz, 2H), 7.20 (t, J = 7.3 Hz, 2H), 7.12 (t, J = 7.0 Hz, 3H), 7.10–7.00 (m, 5H), 5.35 (d, J = 23.3 Hz, 1H), 5.01 (d, J = 23.1 Hz, 1H), 1.29 (s, 18H). 13C-NMR (151 MHz, CDCl3) δ 152.00 (s), 144.65 (s), 136.75 (s), 135.42 (s), 135.29 (s), 134.46 (s), 128.95 (s), 128.09 (s), 127.19 (s), 125.92 (s), 125.54 (s), 123.80 (s), 121.92 (s), 120.11 (s), 119.23 (s), 110.89 (s), 48.84 (s), 34.35 (s), 30.40 (s).

4. Conclusions

In summary, we developed the TBAB-promoted sulfa-1,6-conjugated addition of para-quinone methides with sulfonyl hydrazines in water. This reaction provides a green and sustainable method for direct synthesis of various unsymmetrical diarylmethyl sulfones with good functional group tolerance, scalability, and regioselectivity. Further transformation of the resulting diarylmethyl sulfones provides an efficient route to some functionalized molecules.

Supplementary Materials

The following are available online, the 1H-NMR, 13C-NMR spectra of compounds 3aa–3ay and 4aa–4am, 7, 8; HRMS data of 4ad, 4ai and 4aj; crystal data of 4af are available as supporting data.

Author Contributions

Z.-Q.L. proposed the subject and designed the study, P.-S.Y. and D.-Q.L. carried out the chemical experiments, L.-D.Z. and S.-S.L. performed electrochemical data analysis, and X.-Y.G. wrote the article. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 21402159), the Fundamental Research Funds for the Central Universities (XDJK2019AA003), the Chongqing Postdoctoral Science Foundation (Xm2016110).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

THFTetrahydrofuran
DCEDichloroethane
DMSODimethylsulfoxide
CTABCetyltrimethyl Ammonium Bromide
TBAITetrabutyl Ammonium Iodide
TEBACTriethylbenzyl Ammonium Chloride
TBABTetrabutyl Ammonium Bromide
SDSSodium Dodecyl Sulfate
HRMSHigh Resolution Mass Spectroscopy

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Sample Availability: Samples of the compounds compounds 3aa–3ay and 4aa–4am are available from the authors.
Molecules 25 00539 g001 550
Figure 1. Representative biologically active diarylmethyl sulfone derivatives.
Figure 1. Representative biologically active diarylmethyl sulfone derivatives.
Molecules 25 00539 g001
Molecules 25 00539 sch001 550
Scheme 1. Synthesis of unsymmetrical gem-diarylmethyl sulfones via sulfa-1,6-conjugated addition in water.
Scheme 1. Synthesis of unsymmetrical gem-diarylmethyl sulfones via sulfa-1,6-conjugated addition in water.
Molecules 25 00539 sch001
Molecules 25 00539 g002 550
Figure 2. Tetrabutylammonium bromide (TBAB)-catalyzed 1,6-conjugate sulfonylation for synthesis of gem-diarylmethyl sulfones 3aa–3ay. a The reaction conditions: sulfonyl hydrazides 1a (0.20 mmol), p-QM 2 (0.30 mmol), TBAB (0.02 mmol) in 1 mL of H2O, 80 °C, 12 h, b Isolated yield base on 1a.
Figure 2. Tetrabutylammonium bromide (TBAB)-catalyzed 1,6-conjugate sulfonylation for synthesis of gem-diarylmethyl sulfones 3aa–3ay. a The reaction conditions: sulfonyl hydrazides 1a (0.20 mmol), p-QM 2 (0.30 mmol), TBAB (0.02 mmol) in 1 mL of H2O, 80 °C, 12 h, b Isolated yield base on 1a.
Molecules 25 00539 g002
Molecules 25 00539 g003 550
Figure 3. TBAB catalyzed 1,6-conjugate sulfonylation for synthesis of gem-diarylmethyl sulfones 4aa–4am. a The reaction conditions: sulfonyl hydrazides 1 (0.20 mmol), para-quinone methide (p-QM) 2a (0.30 mmol), TBAB (0.02 mmol) in 1 mL of H2O, 80°C, 12h, b isolated yield base on 1.
Figure 3. TBAB catalyzed 1,6-conjugate sulfonylation for synthesis of gem-diarylmethyl sulfones 4aa–4am. a The reaction conditions: sulfonyl hydrazides 1 (0.20 mmol), para-quinone methide (p-QM) 2a (0.30 mmol), TBAB (0.02 mmol) in 1 mL of H2O, 80°C, 12h, b isolated yield base on 1.
Molecules 25 00539 g003
Molecules 25 00539 g004 550
Figure 4. Crystal structure of diarylmethyl sulfone 4af and possible sulfinic ester.
Figure 4. Crystal structure of diarylmethyl sulfone 4af and possible sulfinic ester.
Molecules 25 00539 g004
Molecules 25 00539 sch002 550
Scheme 2. Probable mechanism of the sulfa-1,6-conjugate reactions in water.
Scheme 2. Probable mechanism of the sulfa-1,6-conjugate reactions in water.
Molecules 25 00539 sch002
Molecules 25 00539 sch003 550
Scheme 3. Synthetic utility of diarylmethyl sulfone 3aa.
Scheme 3. Synthetic utility of diarylmethyl sulfone 3aa.
Molecules 25 00539 sch003
Table
Table 1. Optimization of the reaction conditions for the 1,6-conjugate sulfonylation of 4-methylbenzenesulfonohydrazide 1a to p-QM 2aa.
Table 1. Optimization of the reaction conditions for the 1,6-conjugate sulfonylation of 4-methylbenzenesulfonohydrazide 1a to p-QM 2aa.
Molecules 25 00539 i001
EntryCatalystSolventT (°C)Time (h)Yield b (%)
1-Et2O40100
2-Toluene80100
3-THF701050
4-DCE8010trace
5-Dioxane8010trace
6-DMSO8010trace
7-H2O801061
8-EtOH801073
9Pd/CH2O801075
10Pd/TiO2H2O801053
11Au/TiO2H2O801043
12Pt/CH2O801070
13CTABH2O801051
14TBAIH2O801078
15TEBACH2O801080
16TBABH2O801082
17SDSH2O801018
18TBABH2O901081
19TBABH2O601063
20TBABH2O301015
21TBABH2O801290
22 cTBABH2O801296
a The reaction conditions: 1a (0.20 mmol), 2a (0.20 mmol), catalyst (0.02 mmol), solvent (1 mL), b isolated yield based on 1a, c 2a (0.3 mmol).

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Liu, Z.-Q.; You, P.-S.; Zhang, L.-D.; Liu, D.-Q.; Liu, S.-S.; Guan, X.-Y. TBAB-Catalyzed 1,6-Conjugate Sulfonylation of para-Quinone Methides: A Highly Efficient Approach to Unsymmetrical gem-Diarylmethyl Sulfones in Water. Molecules 2020, 25, 539. https://doi.org/10.3390/molecules25030539

AMA Style

Liu Z-Q, You P-S, Zhang L-D, Liu D-Q, Liu S-S, Guan X-Y. TBAB-Catalyzed 1,6-Conjugate Sulfonylation of para-Quinone Methides: A Highly Efficient Approach to Unsymmetrical gem-Diarylmethyl Sulfones in Water. Molecules. 2020; 25(3):539. https://doi.org/10.3390/molecules25030539

Chicago/Turabian Style

Liu, Zhang-Qin, Peng-Sheng You, Liang-Dong Zhang, Da-Qing Liu, Sheng-Shu Liu, and Xiao-Yu Guan. 2020. "TBAB-Catalyzed 1,6-Conjugate Sulfonylation of para-Quinone Methides: A Highly Efficient Approach to Unsymmetrical gem-Diarylmethyl Sulfones in Water" Molecules 25, no. 3: 539. https://doi.org/10.3390/molecules25030539

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