[4 + 2] Cyclization of para-Quinone Methide Derivatives with Alkynes

Publication Date (Web): January 11, 2018 ... The first cyclization of para-quinone methide derivatives with alkynes was established by utilizing the [...
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Article Cite This: J. Org. Chem. 2018, 83, 1414−1421

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[4 + 2] Cyclization of para-Quinone Methide Derivatives with Alkynes Guang-Jian Mei,* Shao-Li Xu, Wen-Qin Zheng, Chen-Yu Bian, and Feng Shi* School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, China S Supporting Information *

ABSTRACT: The first cyclization of para-quinone methide derivatives with alkynes was established by utilizing the [4 + 2] reaction of ortho-hydroxyphenyl-substituted para-quinone methides with ynones or benzyne, which efficiently constructed the scaffolds of chromene and xanthene in high yields (up to 88%). This protocol has not only fulfilled the task of developing cyclization reactions of para-quinone methide derivatives but also provided an efficient method for constructing chromene and xanthene scaffolds.

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equivalents, pyrrole, thiol, and boronates (eq 1).4,5 In addition, p-QM-involved domino 1,6-addition/dearomatization reactions have also received increasing attention for the synthesis of spiro compounds (eq 2).6 However, designing p-QM derivatives as new building blocks and exploring their involved cyclizations are still underdeveloped (eq 3),7,8 although this strategy would provide an efficient method for constructing cyclic scaffolds. Until recently, the Enders group devised ortho-hydroxyphenyl-substituted p-QMs as a class of new building blocks and established an organocatalytic asymmetric cyclization of this reactant with methyleneindolinone via a cascade oxa-Michael/ 1,6-addition (Scheme 2, eq 4).7 Very recently, the Fan group utilized p-QM esters or amides to realize an intramolecular vinylogous Rauhut−Currier reaction in the presence of an organocatalyst (eq 5).8a In addition, the Zhao group also employed p-QM esters to perform a cascade cyclization with isocyanoacetate via Ag catalysis (eq 6).8b Despite these elegant approaches, cyclizations using p-QM derivatives as building blocks are still rather limited. Thus, it has become an urgent task to develop cyclization reactions of p-QM derivatives. To fulfill this task and as our continuous interests in developing QM-involved reactions for the synthesis of bioactive heterocyclic compounds,9 we considered using ortho-hydroxyphenyl-substituted p-QMs as building blocks to perform cyclizations (Scheme 3). Survey of the literature only revealed several cyclizations of this class of p-QM derivatives with alkenes or alkene precursors (eq 7),7,10 and the chemistry of cyclizations with alkynes still remains unknown (eq 8). Thus, we decided to establish the first cyclization of orthohydroxyphenyl-substituted p-QMs with alkynes such as ynones (eq 9) and benzyne (eq 10). This design will not only fulfill the task of developing cyclization reactions of p-QM derivatives but also provide easy access to structurally diversified chromenes and xanthenes, which are widely found in natural products and synthetic compounds with intriguing biological activities.11

INTRODUCTION

Quinone methides (QMs), as a privileged and unique class of conjugate addition acceptors, have proven to be versatile synthons in organic synthesis.1,2 Among them, ortho-quinone methides (o-QMs)1 and para-quinone methides (p-QMs)2 have aroused great interest in the chemistry community. Structurally, p-QMs are regarded as neutral molecules with zwitterionic resonance entities.3 Owing to their intrinsic electrophilic nature and the aromatization driving force of the cyclohexadiene moiety, p-QMs have been widely employed as 1,6-addition acceptors (Scheme 1), and great progress has been made in 1,6additions of p-QMs with a range of nucleophiles such as enolate Scheme 1. Profile of p-QM-Involved Reactions

Received: November 20, 2017 Published: January 11, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

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The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

Scheme 2. Limited Examples of p-QM Derivative-Involved Cyclizations

entry

base

solvent

additives

1 2 3 4 5 6 7 8 9 10 11 12

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

toluene MTBE DCE CH3CN EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc

4 4 4 4 4 4 4 4

Na2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

Å Å Å Å Å Å Å Å

MS MS MS MS MS MS MS MS

3 Å MS 5 Å MS MgSO4

yield (%)b 25 46 12 68 88 0 54 75 20 76 65 68

a

Unless indicated otherwise, the reaction was carried out at 0.05 mmol scale in a solvent (0.5 mL) at rt for 7 h, and the molar ratio of 1a:2a was 1:1.2. bIsolated yield.

although the yield of product 3aa was low (entry 1), which nevertheless demonstrated the feasibility of our design. Then, the screening of solvents (entries 1−5) indicated that ethyl acetate was the best solvent, affording the corresponding product 3aa in a good yield of 88% (entry 5). It was found that a base was necessary for this cyclization reaction (entry 6), and Cs2CO3 had a superior yield to those of Na2CO3 or K2CO3 (entry 5 vs 7−8). In addition, additives also played an important role in this cyclization because the reaction became very sluggish in the absence of additives (entry 9), and 4 Å molecular sieves (MS) were found to be the best additivs (entry 5 vs 9−12). Finally, the optimal reaction conditions were selected as those shown in entry 5 (1 equiv of Cs2CO3 as base, 4 Å MS as additives in ethyl acetate at rt for 7 h). Then, the generality of the [4 + 2] cyclization between pQMs 1 and alkynes 2 was investigated under the optimal reaction conditions. As shown in Table 2, p-QMs 1 bearing various substituents can be employed to the reaction with a series of terminal ynones, which delivered functionalized 4-arylchromenes 3 in generally acceptable to good yields (up to 88%). It seems that the position and electronic nature of the substituents had some delicate influence on the reaction. For instance, the C5-methoxyl-substituted substrate 1i generated product 3ia with a higher yield than those of the C4-methoxylsubstituted counterparts (3ia vs 3da). Moreover, in C5substituted substrates 1, p-QM bearing an electron-donating group was superior to its counterparts substituted with electron-withdrawing or -neutral groups (3ia vs 3ea, 3ha, and 3ja). Notably, a naphthyl-substituted p-QM could take part in the [4 + 2] cyclization and gave product 3ka in an acceptable yield. Finally, various aryl ynones were tolerated, and the corresponding products were obtained in acceptable to good yields (3ab−3ai). After we accomplished the [4 + 2] cyclization of p-QM derivatives 1 with ynones 2, we extended this protocol to benzyne under similar conditions. As shown in Table 3, this [4 + 2] cyclization of p-QM derivatives 1 with benzyne precursor 4 occurred smoothly, leading to the construction of 9-arylxanthene scaffold in acceptable to good yields (45−85%). The

Scheme 3. Design of Cyclizations of ortho-HydroxyphenylSubstituted p-QMs with Alkynes

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RESULTS AND DISCUSSION Initially, to test the feasibility of the designed formal [4 + 2] cycloaddition of ortho-hydroxyphenyl-substituted p-QMs with alkynes, the reaction of p-QM 1a with ynone 2a was employed as a model reaction for optimization of reaction conditions (Table 1). The [4 + 2] cyclization indeed occurred in toluene, 1415

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

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The Journal of Organic Chemistry Table 2. Substrate Scope of the [4 + 2] Cyclization of p-QMs 1 with Ynones 2a

Table 3. Substrate Scope of the [4 + 2] Cyclization of p-QMs 1 with Benzyne Precursor 4a

a

Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in ethyl acetate (1 mL) with KF (0.4 mmol), 18-crown-6 (0.4 mmol), and 4 Å MS (100 mg) for 7 h, and the molar ratio of 1:4 was 1:2. The yield referred to isolated yield.

nucleophilic addition, offering a transient intermediate B or D. Finally, the intermediate B or D underwent an intramolecular 1,6-addition to accomplish the [4 + 2] cyclization and afford products 3aa and 5a. To show the preliminary utility of the [4 + 2] cyclization, we performed a 1 mmol scale reaction of p-QM 1a with alkyne 2a, which smoothly afforded 4-aryl-chromene product 3aa in a good yield of 76% (Scheme 5, eq 11). Moreover, the tert-butyl groups in the structure of product 3aa could be efficiently removed to generate product 6 (eq 12), which indicated the preliminary utility of this [4 + 2] cyclization in organic synthesis.

a

Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale in ethyl acetate (1 mL) with Cs2CO3 (0.1 mmol) and 4 Å MS (100 mg) at room temperature for 7 h, and the molar ratio of 1:2 was 1:1.2. The yield referred to isolated yield.

electronic nature might have some impact on the yield. For example, electron-neutral group-substituted p-QMs gave higher yields than those of electron-rich or -deficient group-substituted ones (5a and 5h vs 5b−5g and 5i−5j). In addition, the naphthyl-substituted p-QM was also tolerated in this [4 + 2] cyclization with benzyne, which generated product 5k in an acceptable yield. The structures of all products 3 and 5 were unambiguously assigned by 1H and 13C NMR, IR, and HRMS. Moreover, the structures of products 3gb and 5a were further determined by single-crystal X-ray diffraction analysis (see the Supporting Information for details).12 On the basis of the experimental results, a possible reaction pathway was suggested (Scheme 4). As exemplified by the formation of products 3aa and 5a, the whole [4 + 2] cyclization was initiated by the deprotonation of p-QM derivative 1a under basic conditions, which generated an oxygen anion intermediate A possessing strong nucleophilicity. Then, intermediate A attacked ynone 2a or in situ-generated benzyne C via a

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CONCLUSIONS In summary, we have established the first cyclization of paraquinone methide derivatives with alkynes by utilizing the [4 + 2] reaction of ortho-hydroxyphenyl-substituted para-quinone methides with ynones or benzyne, which efficiently constructed the scaffolds of chromene and xanthene in high yields (up to 88%). This protocol has not only fulfilled the task of developing cyclization reactions of para-quinone methide derivatives13 but also provided an efficient method for constructing chromene and xanthene scaffolds.

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EXPERIMENTAL SECTION

1

H and 13C NMR spectra were measured at 400 and 100 MHz, respectively. The solvent used for NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was 1416

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

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The Journal of Organic Chemistry Scheme 4. Proposed Reaction Pathway

TOF) m/z [M + Na]+ calcd for C25H30O3Na 401.2087, found 401.2090. 1-(8-Chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen3-yl)ethan-1-one (3ba). In a flame-dried Schlenk tube under N2, pQM 1b (34 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ba (28 mg) was obtained in 68% yield as a yellowish solid. Mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.26 (dd, J = 7.8, 1.6 Hz, 1H), 7.08 (dd, J = 7.7, 1.1 Hz, 1H), 7.04−6.96 (m, 3H), 5.07 (s, 1H), 5.05 (s, 1H), 2.29 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.2, 152.5, 150.9, 145.5, 135.7, 128.5, 128.2, 127.3, 125.2, 124.3, 121.7, 121.3, 38.5, 34.3, 30.3, 25.6; IR (KBr) 2955, 1669, 1570, 1453, 1235, 1068, 978 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H29ClO3Na 435.1697, found 435.1695. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-8-methoxy-4H-chromen3-yl)(phenyl)methanone (3cb). In a flame-dried Schlenk tube under N2, p-QM 1c (34 mg, 0.1 mmol), alkynes 2b (16 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3cb (26 mg) was obtained in 56% yield as a white solid. Mp 139−140 °C; 1 H NMR (400 MHz, CDCl3) δ 7.67−7.61 (m, 2H), 7.56 (s, 1H), 7.55−7.49 (m, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.11 (s, 2H), 7.02 (t, J = 8.0 Hz, 1H), 6.84−6.77 (m, 2H), 5.26 (s, 1H), 5.04 (s, 1H), 3.94 (s, 3H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 194.7, 152.8, 152.5, 147.8, 138.8, 138.6, 136.0, 135.7, 131.7, 128.8, 128.3, 126.0, 124.7, 124.5, 121.7, 119.5, 109.6, 56.1, 38.9, 34.3, 30.3; IR (KBr) 2918, 1732, 1682, 1557, 1488, 1203, 983, 727 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H34O4Na 493.2349, found 493.2350. 1-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-7-methoxy-4H-chromen-3-yl)ethan-1-one (3da). In a flame-dried Schlenk tube under N2, p-QM 1d (34 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3da (24 mg) was obtained in 60% yield as a yellow solid. Mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.99 (s, 2H), 6.69−6.59 (m, 2H), 5.03 (s, 1H), 4.98 (s, 1H), 3.81 (s, 3H), 2.26 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.5, 158.9, 152.2, 151.3 150.1, 136.6, 135.5, 130.6, 124.3, 121.3, 117.5, 111.7,

Scheme 5. Preliminary Utility of the [4 + 2] Cyclization

determined by an HRMS/MS instrument. The X-ray source used for the single-crystal X-ray diffraction analysis of compounds 3gb and 5a was Mo Kα (λ = 0.71073 Å), and the thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were distilled before use. All starting materials commercially available were used directly. Substrates 1 and 2 were synthesized according to the literature method.7,14 General Procedure for the Synthesis of Products 3. In a flame-dried Schlenk tube under N2, p-QMs 1 (0.1 mmol), alkynes 2 (0.12 mmol), Cs2CO3 (0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel to obtain products 3. 1-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)ethan-1-one (3aa). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3aa (33 mg) was obtained in 88% yield as a yellowish solid. Mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.21−7.16 (m, 2H), 7.12−7.04 (m, 2H), 7.01 (s, 2H), 5.06−5.05 (m, 2H), 2.28 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 190.7, 147.5, 146.7, 144.8, 131.7, 130.8, 125.3, 122.7, 120.6, 120.4, 119.7, 116.3, 111.6, 33.5, 29.5, 25.5, 20.8; IR (KBr) 2963, 1732, 1698, 1557, 1456, 962, 715 cm−1; HRMS (ESI1417

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

Article

The Journal of Organic Chemistry

1-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-methoxy-4H-chromen-3-yl)ethan-1-one (3ia). In a flame-dried Schlenk tube under N2, p-QM 1i (34 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ia (30 mg) was obtained in 74% yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.07−6.96 (m, 3H), 6.74 (dd, J = 8.9, 3.0 Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 5.05 (s, 1H), 5.00 (s, 1H), 3.75 (s, 3H), 2.27 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.5, 156.6, 152.3, 151.8, 143.8, 136.2, 135.6, 126.2, 124.3, 120.2, 117.2, 114.1, 113.4, 55.6, 38.7, 34.3, 30.3, 25.6; IR (KBr) 2945, 1716, 1636, 1473, 1339, 1209, 741 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H32O4Na 431.2193, found 431.2194. 1-(6-(tert-Butyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)ethan-1-one (3ja). In a flame-dried Schlenk tube under N2, p-QM 1j (37 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ja (28 mg) was obtained in 65% yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.25−7.18 (m, 2H), 7.03−7.00 (m, 3H), 5.08 (s, 1H), 5.03 (s, 1H), 2.29 (s, 3H), 1.38 (s, 18H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 195.6, 152.2, 152.1, 147.9, 147.6, 136.0, 135.5, 126.6, 124.5, 124.1, 120.8, 115.8, 38.1, 34.3, 31.4, 30.3, 25.6; IR (KBr) 2925, 1716, 1661, 1521, 1496, 1338, 1260, 915 cm−1; HRMS (ESI-TOF) m/ z [M + Na]+ calcd for C29H38O3Na 457.2713, found 457.2714. 1-(1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1H-benzo[f ]chromen-2yl)ethan-1-one (3ka). In a flame-dried Schlenk tube under N2, p-QM 1k (36 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ka (22 mg) was obtained in 74% yield as a yellowish solid. Mp 117−118 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 7.84−7.71 (m, 3H), 7.53− 7.46 (m, 1H), 7.45−7.38 (m, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.11 (s, 2H), 5.72 (s, 1H), 4.99 (s, 1H), 2.33 (s, 3H), 1.34 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.2, 152.1, 151.2, 147.9, 135.3, 131.6, 131.5, 128.5, 128.3, 126.7, 125.0, 124.8, 123.7, 122.2, 117.9, 116.9, 34.7, 34.2, 30.3, 25.6; IR (KBr) 2924, 1867, 1716, 1635, 1540, 1456, 1263, 1079, 743 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H32O3Na 451.2244, found 451.2245. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)(phenyl)methanone (3ab). In a flame-dried Schlenk tube under N2, pQM 1a (31 mg, 0.1 mmol), alkynes 2b (16 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ab (33 mg) was obtained in 76% yield as a yellowish solid. Mp 76−77 °C; 1H NMR (400 MHz, CDCl3) δ 7.66−7.60 (m, 2H), 7.56−7.50 (m, 1H), 7.50− 7.41 (m, 3H), 7.24−7.17 (m, 2H), 7.13−7.04 (m, 4H), 5.28 (s, 1H), 5.05 (s, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 194.8, 153.3, 152.4, 149.2, 138.8, 136.3, 135.7, 131.5, 130.3, 128.8, 128.3, 127.5, 125.1, 125.0 124.5, 119.9, 116.4, 38.9, 34.3, 30.3; IR (KBr) 3011, 1942, 1791, 1553, 1395, 1224, 1079, 743 cm−1; HRMS (ESITOF) m/z [M + Na]+ calcd for C30H32O3Na 463.2244, found 463.2246. (2-Chlorophenyl)(4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)methanone (3ac). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2c (20 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was

101.3, 55.5, 37.7, 34.3, 30.3, 25.7; IR (KBr) 2945, 1698, 1575, 1486, 1394, 1203, 974 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H32O4Na 431.2193, found 431.2195. 1-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-fluoro-4H-chromen-3yl)ethan-1-one (3ea). In a flame-dried Schlenk tube under N2, p-QM 1e (33 mg, 0.1 mmol), alkynes 2a (8 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ea (24 mg) was obtained in 62% yield as a yellowish solid. Mp 126−127 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.06 (dd, J = 8.9, 4.7 Hz, 1H), 6.99 (s, 2H), 6.93−6.80 (m, 2H), 5.08 (s, 1H), 4.99 (s, 1H), 2.27 (s, 3H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.3, 152.5, 151.3, 145.6, 135.8, 135.7, 124.3, 120.1, 117.7 (J = 8 Hz), 116.2, 115.9, 114.5 (J = 24 Hz), 38.6, 34.3, 30.3, 25.6; 19F NMR (376 MHz, CDCl3) δ −117.6; IR (KBr) 2920, 2855, 1733, 1558, 1338, 672 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H29FO3Na 419.1993, found 419.1993. (6-Chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3yl)(phenyl)methanone (3fb). In a flame-dried Schlenk tube under N2, p-QM 1f (34 mg, 0.1 mmol), alkynes 2b (16 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3fb (33 mg) was obtained in 70% yield as a yellowish solid. Mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.0 Hz, 2H), 7.55−7.51 (m, 1H), 7.49−7.39 (m, 3H), 7.16−7.14 (m, 2H), 7.08 (s, 2H), 7.02 (d, J = 9.4 Hz, 1H), 5.21 (s, 1H), 5.09 (s, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 194.4, 152.6, 152.6, 147.8, 138.6, 135.9, 135.6, 131.7, 129.9, 129.8, 128.7, 128.4, 127.7, 126.6, 124.5, 119.6, 117.9, 39.0, 34.3, 30.3; IR (KBr) 2922, 1698, 1558, 1488, 1388, 1080 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H31ClO3Na 497.1854, found 497.1852. (6-Bromo-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3yl)(phenyl)methanone (3gb). In a flame-dried Schlenk tube under N2, p-QM 1g (39 mg, 0.1 mmol), alkynes 2b (16 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3gb (34 mg) was obtained in 65% yield as a yellowish solid. Mp 123−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 2H), 7.56−7.50 (m, 1H), 7.46−7.42 (m, 3H), 7.30 (d, J = 8.2 Hz, 2H), 7.07 (s, 2H), 6.96 (dd, J = 7.6, 1.5 Hz, 1H), 5.21 (s, 1H), 5.09 (s, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 194.4, 152.7, 152.5, 148.4, 138.6, 135.9, 135.6, 132.9, 131.7, 130.6, 128.7, 128.4, 127.1, 124.5, 119.7, 118.3, 117.4, 38.9, 34.3, 30.3; IR (KBr) 2923, 1748, 1652, 1557, 1488, 1260, 749 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H31BrO3Na 541.1349, found 541.1347. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-methyl-4H-chromen-3yl)(phenyl)methanone (3hb). In a flame-dried Schlenk tube under N2, p-QM 1h (32 mg, 0.1 mmol), alkynes 2b (16 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3hb (25 mg) was obtained in 55% yield as a yellowish solid. Mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 2H), 7.55−7.49 (m, 1H), 7.46−7.41 (m, 3H), 7.10 (s, 2H), 7.01−6.94 (m, 3H), 5.22 (s, 1H), 5.05 (s, 1H), 2.28 (s, 3H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 194.8, 153.5, 152.3, 147.3, 138.9, 136.4, 135.6, 134.5, 131.4, 130.4, 128.7, 128.3, 128.2, 124.5, 119.9, 116.1, 38.9, 34.3, 30.3, 20.9; IR (KBr) 2920, 1716, 1652, 1521, 1456, 1210, 973 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H34O3Na 477.2400, found 4377.2397. 1418

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

Article

The Journal of Organic Chemistry

45−46 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65−7.59 (m, 2H), 7.23−7.17 (m, 2H), 7.13 (dd, J = 4.9, 3.8 Hz, 1H), 7.11− 7.03 (m, 4H), 5.26 (s, 1H), 5.03 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 185.6, 152.4, 150.7, 149.1, 143.5, 135.9, 135.6, 132.4, 132.0, 130.1, 127.5, 127.4, 124.9, 124.8, 124.4, 119.9, 116.4, 39.2, 34.2, 30.3; IR (KBr) 3011, 1771, 1635, 1540, 1472, 1373, 974 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H30O3SNa 469.1808, found 469.1810. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)(naphthalen-1-yl)methanone (3ah). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2a (22 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ah (22 mg) was obtained in 46% yield as a yellowish solid. Mp 46−47 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.50−7.47 (m, 2H), 7.43−7.36 (m, 2H), 7.34 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.23−7.17 (m, 1H), 7.16−7.09 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 5.36 (s, 1H), 5.10 (s, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 196.2, 155.0, 152.5, 149.4, 136.9, 136.4, 135.8, 133.6, 130.7, 130.4, 130.1, 128.2, 127.5, 126.9, 126.3, 125.4, 125.3, 125.2, 124.9, 124.5, 124.5, 122.1, 116.5, 38.6, 34.3, 30.3; IR (KBr) 3011, 1771, 1635, 1540, 1472, 1373, 974 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C34H34O3Na 513.2400, found 513.2403. General Procedure for the Synthesis of Products 5. In a flame-dried Schlenk tube under N2, p-QMs 1 (0.1 mmol), benzyne precursor 4 (0.2 mmol), KF (0.4 mmol), 18-crown-6 (0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel to obtain products 5. 2,6-Di-tert-butyl-4-(9H-xanthen-9-yl)phenol (5a). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18-crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5a (28 mg) was obtained in 74% yield as a yellowish solid. Mp 117−118 °C; 1H NMR (400 MHz, CDCl3) δ 7.24−7.20 (m, 2H), 7.18−7.11 (m, 4H), 7.04− 7.00 (m, 2H), 6.97 (s, 2H), 5.17 (s, 1H), 5.07 (s, 1H), 1.38 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.4, 151.4, 136.8, 135.8, 129.5, 127.5, 125.5, 124.8, 123.1, 116.4, 44.4, 34.3, 30.3; IR (KBr) 2923, 1733, 1646, 1521, 1456, 1362, 1096, 881 cm−1; HRMS (ESI-TOF) m/ z [M + Na]+ calcd for C27H30O2Na 409.2138, found 409.2140. 2,6-Di-tert-butyl-4-(4-chloro-9H-xanthen-9-yl)phenol (5b). In a flame-dried Schlenk tube under N2, p-QM 1b (34 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5b (26 mg) was obtained in 62% yield as a yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.31−7.23 (m, 3H), 7.12 (d, J = 7.7 Hz, 1H), 7.07− 7.03 (m, 2H), 6.98−6.88 (m, 3H), 5.17 (s, 1H), 5.10 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 151.1, 147.4, 136.1, 135.9, 129.4, 128.3, 127.9, 127.8, 127.4, 125.0, 124.8, 123.7, 123.1, 121.5, 116.7, 44.5, 34.3, 30.2; IR (KBr) 2919, 1867, 1558, 1456, 1374, 1260, 879, 633 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H29ClO2Na 443.1748, found 443.1750. 2,6-Di-tert-butyl-4-(4-methoxy-9H-xanthen-9-yl)phenol (5c). In a flame-dried Schlenk tube under N2, p-QM 1c (34 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in

stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ac (33 mg) was obtained in 73% yield as a yellowish solid. Mp 89−90 °C; 1H NMR (400 MHz, CDCl3) δ 7.42−7.34 (m, 2H), 7.33−7.27 (m, 2H), 7.24− 7.17 (m, 3H), 7.13−7.05 (m, 4H), 5.20 (s, 1H), 5.06 (s, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 193.0, 155.3, 152.4, 149.2, 138.4, 135.9, 135.5, 131.1, 130.6, 130.3, 129.9, 128.6, 127.5, 126.5, 125.4, 124.9, 124.6, 120.7, 116.5, 38.3, 34.2, 30.3; IR (KBr) 2920, 1716, 1615, 1472, 1338, 1224, 918 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H31ClO3Na 497.1854, found 497.1855. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)(3fluorophenyl)methanone (3ad). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2d (18 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ad (25 mg) was obtained in 54% yield as a yellowish solid. Mp 135−136 °C; 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.45−7.37 (m, 2H), 7.32−7.28 (m, 1H), 7.25−7.17 (m, 3H), 7.12−7.05 (m, 4H), 5.25 (s, 1H), 5.06 (s, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 193.3, 162.4 (J = 247 Hz), 153.3, 152.4, 149.1, 140.9, 136.1, 135.7, 119.8, 118.4 (J = 21 Hz), 116.4, 115.7 (J = 22 Hz), 38.8, 34.2, 30.3; 19F NMR (376 MHz, CDCl3) δ −111.9; IR (KBr) 3011, 1716, 1652, 1507, 1456, 1338, 1079 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H31FO3Na 481.2149, found 481.2150. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)(mtolyl)methanone (3ae). In a flame-dried Schlenk tube under N2, pQM 1a (31 mg, 0.1 mmol), alkynes 2e (18 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ae (26 mg) was obtained in 58% yield as a yellow solid. Mp 47−48 °C; 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.43−7.41 (m, 2H), 7.36−7.29 (m, 2H), 7.23−7.16 (m, 2H), 7.13−7.04 (m, 4H), 5.27 (s, 1H), 5.04 (s, 1H), 2.41 (s, 3H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.0, 152.9, 152.3, 149.2, 138.8, 138.1, 136.2, 135.6, 132.2, 130.2, 129.3, 128.1, 127.4, 125.9, 125.0, 124.4, 119.9, 116.4, 38.9, 34.2, 30.3, 21.3; IR (KBr) 2955, 1791, 1635, 1435, 1362, 1079, 910 cm−1; HRMS (ESITOF) m/z [M + Na]+ calcd for C31H34O3Na 477.2400, found 477.2397. (4-Chlorophenyl)(4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)methanone (3af). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2f (20 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3af (29 mg) was obtained in 62% yield as a yellowish solid. Mp 45−46 °C; 1H NMR (400 MHz, CDCl3) δ 7.61−7.53 (m, 2H), 7.46−7.39 (m, 3H), 7.20− 7.18 (m, 2H), 7.13−7.05 (m, 4H), 5.25 (s, 1H), 5.05 (s, 1H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 193.5, 153.0, 152.4, 149.1, 137.8, 137.1, 136.1, 135.7, 130.2, 130.1, 128.6, 127.5, 125.2, 124.8, 124.4, 119.8, 116.4, 38.9, 34.3, 30.3; IR (KBr) 3004, 1716, 1635, 1457, 1374, 1260, 974 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H31ClO3Na 497.1854, found 497.1855. (4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)(thiophen-2-yl)methanone (3ag). In a flame-dried Schlenk tube under N2, p-QM 1a (31 mg, 0.1 mmol), alkynes 2g (18 mg, 0.12 mmol), Cs2CO3 (32 mg, 0.1 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica (PE/EA = 10:1); 3ag (24 mg) was obtained in 53% yield as a yellow solid. Mp 1419

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

Article

The Journal of Organic Chemistry dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5c (23 mg) was obtained in 56% yield as a yellowish solid. Mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 7.31−7.27 (m, 2H), 7.26−7.20 (m, 1H), 7.14−7.10 (m, 1H), 7.05−7.01 (m, 1H), 6.99−6.93 (m, 3H), 6.83 (dd, J = 8.1, 1.3 Hz, 1H), 6.76 (dd, J = 7.8, 0.7 Hz, 1H), 5.18 (s, 1H), 5.07 (s, 1H), 3.98 (s, 3H), 1.37 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 151.3, 147.9, 141.0, 136.8, 135.8, 129.5, 127.5, 126.4, 125.1, 124.7, 123.3, 122.7, 121.3, 116.7, 109.8, 56.2, 44.4, 34.3, 30.3; IR (KBr) 2921, 1661, 1575, 1418, 1338, 1235, 879, 688 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H32O3Na 439.2244, found 439.2245. 2,6-Di-tert-butyl-4-(2-fluoro-9H-xanthen-9-yl)phenol (5e). In a flame-dried Schlenk tube under N2, p-QM 1e (33 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5e (19 mg) was obtained in 47% yield as a yellowish solid. Mp 122−123 °C; 1H NMR (400 MHz, CDCl3) δ 7.25−7.20 (m, 1H), 7.15−7.07 (m, 3H), 7.05−6.99 (m, 1H), 6.96−6.88 (m, 3H), 6.80 (dd, J = 8.9, 2.8 Hz, 1H), 5.12 (s, 1H), 5.11 (s, 1H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.6, 151.3, 147.5, 136.1, 136.0, 129.5, 127.7, 124.7, 124.4, 123.2, 117.4 (J = 12 Hz), 116.3, 115.4 (J = 24 Hz), 114.4 (J = 23 Hz), 44.7, 34.3, 30.2; 19F NMR (376 MHz, CDCl3) δ −120.5; IR (KBr) 2924, 1867, 1558, 1456, 1374, 1263, 973 cm−1; HRMS (ESITOF) m/z [M + Na]+ calcd for C27H29FO2Na 427.2044, found 427.2046. 2,6-Di-tert-butyl-4-(2-chloro-9H-xanthen-9-yl)phenol (5f). In a flame-dried Schlenk tube under N2, p-QM 1f (34 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5f(32 mg) was obtained in 76% yield as a yellowish solid. Mp 133− 134 °C; 1H NMR (400 MHz, CDCl3) δ 7.26−7.20 (m, 1H), 7.20− 7.06 (m, 5H), 7.05−7.00 (m, 1H), 6.94 (s, 2H), 5.11 (s, 2H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.6, 151.0, 150.0, 136.2, 136.0, 129.5, 129.2, 127.7, 127.6, 127.0, 124.7, 124.7, 123.4, 117.7, 116.3, 44.4, 34.3, 30.2; IR (KBr) 2851, 1683, 1575, 1453, 1373, 1080, 634 cm −1 ; HRMS (ESI-TOF) m/z [M + Na] + calcd for C27H29ClO2Na 443.1748, found 443.1742. 4-(2-Bromo-9H-xanthen-9-yl)-2,6-di-tert-butylphenol (5g). In a flame-dried Schlenk tube under N2, p-QM 1g (39 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5g (36 mg) was obtained in 78% yield as a white solid. Mp 112−113 °C; 1 H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 8.7, 2.4 Hz, 1H), 7.26− 7.20 (m, 2H), 7.14−7.10 (m, 2H), 7.04−7.01 (m, 2H), 6.94 (s, 2H), 5.11 (s, 2H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.6, 151.0, 150.6, 136.3, 136.0, 132.1, 130.5, 129.5, 127.7, 127.5, 124.8, 124.6, 123.4, 118.2, 116.4, 115.2, 44.3, 34.3, 30.2; IR (KBr) 2924, 2853, 1652, 1540, 1456, 1374, 1338, 742 cm−1; HRMS (ESI-TOF) m/ z [M + Na]+ calcd for C27H29BrO2Na 487.1243, found 487.1245. 2,6-Di-tert-butyl-4-(2-methyl-9H-xanthen-9-yl)phenol (5h). In a flame-dried Schlenk tube under N2, p-QM 1h (32 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was

evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5h (36 mg) was obtained in 85% yield as a white solid. Mp 56−57 °C; 1H NMR (400 MHz, CDCl3) δ 7.24−7.18 (m, 1H), 7.15−7.12 (m, 2H), 7.07−6.92 (m, 6H), 5.11 (s, 1H), 5.07 (s, 1H), 2.28 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.6, 149.4, 137.1, 135.7, 132.4, 129.7, 129.5, 128.2, 127.4, 125.6, 125.0, 124.6, 122.9, 116.3, 116.1, 44.6, 34.3, 30.2, 20.8; IR (KBr) 2921, 2851, 1652, 1507, 1418, 1387, 1259, 625 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H32O2Na 423.2295, found 423.2291. 2,6-Di-tert-butyl-4-(2-methoxy-9H-xanthen-9-yl)phenol (5i). In a flame-dried Schlenk tube under N2, p-QM 1i (34 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5i (27 mg) was obtained in 65% yield as a yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.24−7.18 (m, 1H), 7.14−7.05 (m, 3H), 7.03−6.98 (m, 1H), 6.96 (s, 2H), 6.78 (dd, J = 8.9, 3.0 Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 5.12 (s, 1H), 5.07 (s, 1H), 3.75 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 155.2, 152.4, 145.7, 136.6, 135.8, 129.4, 127.5, 126.2, 125.0, 124.6, 122.9, 117.0, 116.3, 114.0, 113.3, 55.6, 44.9, 34.2, 30.3; IR (KBr) 2922, 1716, 1549, 1509, 1418, 1260, 742 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H32O3Na 439.2244, found 439.2247. 2,6-Di-tert-butyl-4-(2-(tert-butyl)-9H-xanthen-9-yl)phenol (5j). In a flame-dried Schlenk tube under N2, p-QM 1j (37 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5j (26 mg) was obtained in 60% yield as a yellow solid. Mp 55−56 °C; 1 H NMR (400 MHz, CDCl3) δ 7.27−7.11 (m, 5H), 7.08−7.03 (m, 2H), 6.94 (s, 2H), 5.17 (s, 1H), 5.06 (s, 1H), 1.37 (s, 18H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.2, 152.0, 149.5, 145.8, 136.1, 135.6, 129.4, 127.5, 126.0, 125.4, 124.8, 124.7, 124.5, 122.9, 116.3, 115.7, 44.4, 34.3, 31.4, 30.2; IR (KBr) 3011, 1646, 1557, 1496, 1338, 910 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H38O2Na 465.2764, found 465.2760. 4-(2-Bromo-9H-xanthen-9-yl)-2,6-di-tert-butylphenol (5k). In a flame-dried Schlenk tube under N2, p-QM 1k (36 mg, 0.1 mmol), benzyne precursor 4 (60 mg, 0.2 mmol), KF (23 mg, 0.4 mmol), 18crown-6 (106 mg, 0.4 mmol), and 4 Å MS (100 mg) were mixed in dry ethyl acetate (1 mL) at room temperature. Then, the resulting solution was stirred at the same temperature for 7 h. The solvent was evaporated under reduced pressure, and the crude products were purified by column chromatography on silica gel (PE/Tol = 4:1); 5k (20 mg) was obtained in 45% yield as a yellow solid. Mp 89−90 °C; 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.53−7.47 (m, 1H), 7.45−7.35 (m, 3H), 7.26−7.18 (m, 2H), 7.14−7.02 (m, 3H), 5.75 (s, 1H), 4.96 (s, 1H), 1.31 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.1, 150.9, 149.6, 136.7, 135.7, 131.8, 130.8, 129.2, 128.59, 128.4, 127.3, 126.4, 126.1, 123.9, 123.8, 123.6, 123.1, 117.9, 117.2, 116.5, 41.6, 34.2, 30.2; IR (KBr) 2920, 1716, 1636, 1521, 1395, 1079, 742 cm−1; HRMS (ESITOF) m/z [M + Na]+ calcd for C31H32O2Na 459.2295, found 459.2298. Procedure for the Synthesis of Product 6. Under a nitrogen atmosphere, the compound 3aa (38 mg, 0.1 mmol) was dissolved in 4 mL of dry toluene, and AlCl3 (133 mg, 1.0 mmol) was added. The resulting mixture was warmed to 35 °C and stirred for 16 h. Then, the reaction mixture was cooled to room temperature, and 4 mL of H2O was added and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel eluting with 1420

DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421

Article

The Journal of Organic Chemistry hexanes/ethyl acetate (2:1) to afford product 6 (18 mg) in 68% yield as a yellow solid. 1-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4H-chromen-3-yl)ethan-1-one (6). Yellow solid, mp 90−91 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.22−7.16 (m, 1H), 7.14−7.02 (m, 5H), 6.73−6.66 (m, 2H), 5.04 (s, 1H), 4.96 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 154.1, 151.4, 149.0, 138.3, 130.1, 129.2, 127.6, 125.2, 124.8, 120.5, 116.5, 115.3, 37.8, 25.4; IR (KBr) 2919, 1745, 1650, 1554, 1456, 1007, 668 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H14O3Na 289.0835, found 289.0830.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02942. Characterization data (including 1H and 13C NMR spectra) of products 3 and 5 (PDF) Crystallographic data for 3gb (CIF) Crystallographic data for 5a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Feng Shi: 0000-0003-3922-0708 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from National Natural Science Foundation of China (21772069 and 21702077), Natural Science Foundation of Jiangsu Province (BK20160003 and BK20170227), and Six Kinds of Talents Project of Jiangsu Province (SWYY-025).

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DOI: 10.1021/acs.joc.7b02942 J. Org. Chem. 2018, 83, 1414−1421