Three-Component Reactions of Arynes, Amines, and Nucleophiles via

Jul 3, 2018 - Gyoungwook Min , Jeongseob Seo , and Haye Min Ko*. Department of Bio-Nano Chemistry, Wonkwang University , 460 Iksandae-ro, Iksan ...
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Article Cite This: J. Org. Chem. 2018, 83, 8417−8425

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Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process Gyoungwook Min, Jeongseob Seo, and Haye Min Ko* Department of Bio-Nano Chemistry, Wonkwang University, 460 Iksandae-ro, Iksan, Jeonbuk 54538, Republic of Korea

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S Supporting Information *

ABSTRACT: An unprecedented three-component reaction of arynes, tertiary amines, and nucleophiles has been demonstrated through ammonium salt intermediates. This protocol allows access to tertiary aniline derivatives containing the piperazine motif in good-to-excellent yields. Expansively, this reaction can produce biologically important 2-(4phenylpiperazin-1-yl)ethyl-containing molecules using arynes, 1,4-diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a one-pot process.

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INTRODUCTION

The 1-ethyl-4-phenylpiperazine motif plays an important role and is an essential structure in many compounds used in a variety of fields, such as material, agrochemical, and medicinal chemistry. Especially, bioactive molecules having these privileged heterocycles have found widespread applications as drug candidates or experimental drugs. 2-(4-Phenylpiperazin1-yl)ethyl-containing derivatives are known to possess several bioactivities such as antitumor, anti-inflammatory, antiobesity, and cardiovascular activities (Figure 1).1,2 Despite their potential and usefulness, methods to construct this scaffold have been extremely limited. Up to now, only one method using nucleophilic aromatic substitution reactions involving electron-withdrawing groups, such as NO2, has been developed (Figure 2 (a)).3 This SNAr reaction, developed by Manuel Finkelstein in 1963, required very high temperatures (around

Figure 2. Ring-opening reaction of an aryl DABCO ammonium salt through C−N bond cleavage for the synthesis of 2-(4-phenylpiperazin-1-yl)ethyl-containing derivatives.

150 °C), long reaction times (about 20 h), and electron-poor functional groups installed on the substrate to access the desired products. Another synthetic strategy utilized pyridineN-oxide as 1,4-diazabicyclo(2.2.2)octane (DABCO) activator and 2-bromopyridine for the ring-opening reaction via C−N bond cleavage as shown in Figure 2 (a).4 Although these reactions involve new activators, a general and mild method for the synthesis of diversely substituted 2-(4-phenylpiperazin-1yl)ethyl-containing derivatives is still required. To overcome the synthetic difficulty and limitation of structural diversity, we focused our attention on aryne-mediated three-component reactions5 under transition-metal-free conditions. In particular, benzynes, which can be generated from o-silyl aryl triflates,6 are very reactive intermediates owing to a strained π-bond. Mono Figure 1. Representative bioactive molecules containing 1-ethyl-4phenylpiperazine motifs. © 2018 American Chemical Society

Received: April 26, 2018 Published: July 3, 2018 8417

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

Article

The Journal of Organic Chemistry N-arylation7 of tertiary amines with arynes has recently been developed to construct C−N bonds via quaternary ammonium salts.7 However, to the best of our knowledge, extensive research of this reaction using DABCO to obtain 1-ethyl-4phenylpiperazine-containing derivatives has not been sufficiently explored.4,8 Therefore, we decided to examine the reaction of tertiary amines, such as N-methyl morpholine or DABCO with arynes (Figure 2 (b)).

Scheme 1. Substrate Scope of Benzyne Precursors

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RESULTS AND DISCUSSION Initially, we attempted the reaction of benzyne precursor 1a (1 equiv) with 4-methyl morpholine 2a (2 equiv) in the presence of one equivalent of CsF in MeCN at room temperature to obtain 4-phenylmorpholine 3a (Table 1, entry 1). However, Table 1. Optimization of the Reaction Conditionsa

entry

variation from standard conditions

1 2 3 4 5 6 7 8

r.t., instead of 100 °C 65 °C, instead of 100 °C 85 °C, instead of 100 °C none 12 h, instead of 9 h 0.1 M CH3CN 5 equiv 2a, 0.1 M CH3CN 1 equiv 2a

3a:3a′ ratioc 1:7.6 12:1 25:1

1.3:1

yield (%)b 0 − − 79 77 37 88 23

a

Reaction conditions: o-silyl aryl triflate 1a (0.1 mmol), 4methylmorpholine 2a (2 equiv), CsF (1 equiv), CH3CN (0.2 M), 100 °C, 9 h. bIsolated yield. cRatio determined by 1H NMR spectroscopy of crude product.

a

Reaction conditions: o-silyl aryl triflate 1a (0.1 mmol), 4methylmorpholine 2a (2 equiv), and CsF (1 equiv) in CH3CN (0.2 M) at 100 °C, 9 h. bN,N,N′,N′-Tetramethylethylenediamine (2 equiv) was used instead of 4-methylmorpholine 2a. cN-Methyl piperidine (2 equiv) was used instead of 4-methylmorpholine 2a. d Ratio of isomers (para:meta) determined by 1H NMR spectroscopy. e Yield determined by 1H NMR spectroscopy using mesitylene as internal standard.

neither the desired product 3a nor intermediates 3a′ were present. Increasing the reaction temperature to 65 °C generated 3a and intermediates 3a′ in a 1:7.6 ratio, as determined from the 1H NMR spectrum of the crude product (entry 2). At 85 °C the 3a:3a′ ratio increased to 12:1 (entry 3) and to 25:1 at 100 °C, where 3a was isolated in 79% yield (entry 4). To further optimize the reaction conditions, the concentration of the reaction (0.1 M) and number of equivalents of 2a were varied (entries 6−8). Ultimately, an excess of 2a (5 equiv) afforded 3a in 88% yield (entry 7). On the basis of the above results, C−N bond cleavage could be triggered by a tertiary amine, which reacted with the quaternary ammonium salt produced by C−N bond formation. Having established the optimal reaction conditions, which involved the formation of an intermediate aryne, we studied the scope of benzyne precursors (Scheme 1). Benzyne precursors with electron-withdrawing functional groups such as fluoride or chloride afforded the corresponding products (3b, 3c, and 3d) in good-to-high yields. Similarly, tert-butyl, methyl, or dimethyl substituted 2-(trimethylsilyl)phenyl triflates were tolerated, and generated the desired products 3e, 3f, and 3h in yields of 73%, 73%, and 68%, respectively. In the case of disubstituted benzyne precursors 1g and 1i, the reaction led to formation of 3g and 3i in yields of 74%, and 62% yield, respectively. The para regioisomer was obtained, except in some cases, where the regioisomeric ratio (para:meta), measured by 1H NMR spectroscopy, was approximately 1:0.6 for 3b, 1:0.75 for 3d, 0.6:1 for 3e and 3f. These results

were attributed to electronic effects rather than steric effects due to 4-substituted benzynes. Whereas electron-withdrawing group dominated nucleophilic attack at the para position, electron-donating group favored nucleophilic attack at the meta position.9 The corresponding products 3b, 3d, 3e, 3f were isolated as mixtures of regioisomers. Compounds 3j and 3k bearing a methoxy substituent were obtained in moderate yields. In the case of an heteroaromatic compound, the reaction of Garg 3,4-pyridine precursor with 4-methyl morpholine 2a produced 3l in 39% yield. The reaction of indolyne precursor 1m gave rise to a mixture of regioisomers, 3m and 3m′, in a combined yield of 63%. Furthermore, we investigated the reaction using different tertiary amines instead of 4-methyl morpholine. N-Methyl piperidine, which is a cyclic amine with a conformation similar to morpholine, was converted to 3p in 64% yield. In contrast, the reaction with linear amine N,N,N′,N′-tetramethylethylenediamine gave 3o in 40% yield, as determined by 1H NMR spectroscopy using mesitylene as internal standard. Encouraged by these interesting results, we next focused our attention on the three-component reaction with benzyne, 8418

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

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gave 5a in yields of 90% and 96%, respectively. Then, a variety of benzyne precursors as well as thiols were reacted under the optimized reaction conditions, which afforded the desired products in good-to-high yields. Utilizing disubstituted benzyne precursors as substrates, the corresponding products 5b, 5c, 5h, and 5i were obtained as single regioisomers in yields of 81%, 47%, 64%, and 79%, respectively. Threecomponent adducts 5d, 5e, 5f, and 5g were produced as mixtures of regioisomers (approximately 1:1 for 5d and 5f, 0.6:1 for 5e, and 1:0.3 for 5g). The reaction of benzyne precursor 1j′, DABCO, and thiophenol gave an isomeric mixture of 5j in 74% isolated yield. Next, various sulfur nucleophiles were investigated for the three-component reaction to provide access to 1-ethyl-4phenylpiperazine-containing derivatives. As shown in Scheme 2, various sulfur nucleophiles were suitable partners to deliver the desired products. Thiols containing a 2-naphthyl, pmethylphenyl, 2,6-dimethylphenyl, and acetyl group reacted to provide products 5k, 5l, 5m, and 5n in good-to-high yields (63−76%). The reaction with heterocyclic thiols led to the formation of the corresponding products 5q, 5r, and 5s in excellent yields (93%, 85%, and 93%, respectively), whereas products 5t and 5o were obtained in moderate yields (62% and 47%, respectively). In the case of alkyl thiols the corresponding products 5p and 5u were obtained in moderate yields (45% and 46%, respectively). Note that the reaction using quinuclidine instead of DABCO proceeded to give product 5v in 98% yield. In terms of expanding the nucleophile scope, we then focused on the reactivity toward oxygen, halogen, and carbon nucleophiles (Scheme 3). Although excess nucleophile was

DABCO, and a nucleophile (Scheme 2). The ring-opening reaction of the aryl DABCO ammonium salt was initially performed under the standard condition using thiophenol as a nucleophile. Surprisingly, the desired product 5a was successfully obtained in 66% yield when the reaction was conducted using only one equivalent of thiophenol for 18 h. Increasing the number of equivalents of nucleophile to two and excess Scheme 2. Three-Component Reaction of Benzynes with DABCO and Thiols

Scheme 3. Three-Component Reactions of Benzynes with DABCO and Nucleophiles

a Reaction conditions: o-silyl aryl triflate 1a (0.1 mmol), DABCO 2a′ (2 equiv), and CsF (1 equiv) in CH3CN:methyl acrylate (1:1, 0.1 M) at 100 °C, 18 h. bKF (30 equiv) was used instead of CsF. c CH3CN:Nu (1:1, 0.1 M) was used. dRatio of isomers (para:meta) determined by 1H NMR spectroscopy.

required (as much as that of the solvent), it was noted that methyl acrylate, allyl acetate, methyl acetate, fluoride, and 2,4pentanedione participate in the ring-opening reaction of aryl DABCO ammonium salts to afford the expected products. When methyl acrylate was used as a nucleophile, the desired products 6a, 6b, and 6c were prepared from the corresponding benzynes in modest yields (41%, 33%, and 33%, respectively), although compounds 6b and 6c were obtained as mixtures of

a

Reaction conditions: o-silyl aryl triflate 1a (0.1 mmol), DABCO 2a′ (2 equiv), thiol (2 equiv), and CsF (1 equiv) in CH3CN (0.1 M) at 100 °C, 18 h. bThiophenol (excess) was used. cThiophenol (1 equiv) was used. dRatio of isomers (para:meta) determined by 1H NMR spectroscopy. eIsomeric mixture. fQuinuclidine (2 equiv) was used instead of DABCO 2a′. 8419

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are reported as m/z (relative intensity). Accurate masses are reported for the molecular ion [M + Na]+, [M + H]+, or [M]+. Benzyne precursors and thiols were purchased from Sigma-Aldrich, TCI or Alfa Aesar. All reactions were run in flame- or oven-dried glassware under an atmosphere of N2 gas with purchased dry solvents unless otherwise stated. Nuclear magnetic resonance spectra (1H NMR and 13C NMR) were recorded with a Jeol (500 MHz, 1H at 500 MHz, 13C at 125 MHz). For CDCl3 solutions the chemical shifts are reported as parts per million (ppm) referenced to residual protium or carbon of the solvents; CHCl3 δ H (7.26 ppm) and CDCl3 δ C (77.16 ppm). Coupling constants are reported in Hertz (Hz). Data for 1H NMR spectra are reported as follows: chemical shift (ppm, referenced to protium; s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublet of doublets, m = multiplet, coupling constant (Hz), and integration). 4-(3,4-Difluorophenyl)morpholine (3c). General procedure A: Benzyne precursor 1c (30 mg, 0.090 mmol) and 4-methylmorpholine (22.0 μL, 0.2 mmol) and cesium fluoride (15 mg, 0.1 mmol) added to 4 mL vial in acetonitrile (0.5 mL). The solution was heated at 100 °C for 9 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired 4-(3,4-difluorophenyl)morpholine 3c (16.8 mg, 0.084 mmol, 84%) as colorless oil. Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.04 (dd, J = 19.1, 9.1 Hz, 1H), 6.68 (ddd, J = 13.3, 6.8, 3.0 Hz, 1H), 6.57 (dtd, J = 9.0, 3.2, 1.6 Hz, 1H), 3.84 (t, J = 4.7 Hz, 4H), 3.07 (t, J = 4.8 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 150.7 (dd, 1C, JC−F = 244.3, 13.1 Hz), 148.5 (dd, 1C, JC−F = 7.3, 2.3 Hz), 144.5 (dd, 1C, JC−F = 238.9, 12.8 Hz), 117.4 (d, 1C, JC−F = 17.6 Hz), 111.2 (q, 1C, JC−F = 2.9 Hz), 105.1 (d, 1C, JC−F = 20.2 Hz), 66.8, 49.7. IR v 2962, 2855, 1601, 1518, 1451, 1380, 1305, 1230, 1145, 885 cm−1; HRMS (EI) calcd. for C10H11F2NO [M]+: 199.0809, found 199.0810. 4-Phenylmorpholine (3a). Compound 3a was synthesized according to general procedure A using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as a colorless oil in 79% yield (12.9 mg, 0.079 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 4-Methyl-4-phenylmorpholin-4-ium (3a′). 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.9 Hz, 2H), 7.65 (t, J = 7.9 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 4.37 (d, J = 12.2 Hz, 2H), 4.18−4.07 (m, 4H), 3.83 (ddd, J = 13.9, 10.9, 6.6 Hz, 2H), 3.61 (s, 3H). 4-(4-Fluorophenyl)morpholine (3b). Compound 3b was synthesized according to general procedure A using 4-fluoro-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol) as colorless oil in 53% yield (8.1 mg, 0.050 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 3b 1H NMR (500 MHz, CDCl3) δ 6.99−6.96 (m, 2H), 6.86−6.85 (m, 2H), 3.89−3.83 (m, 4H), 3.11−3.05 (m, 4H). 4-(3-Fluorophenyl)morpholine (3b′). Compound 3b′ was synthesized according to general procedure A using 4-fluoro-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol) as colorless oil in 31% yield (4.8 mg, 0.029 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 3b′ 1H NMR (500 MHz, CDCl3) δ 7.20 (dd, J = 15.2, 8.2 Hz, 1H), 6.66 (dd, J = 8.3, 2.3 Hz, 1H), 6.59−6.54 (m, 2H), 3.87−3.82 (m, 4H), 3.15 (dd, J = 5.7, 4.0 Hz, 4H). 4-(4-Chlorophenyl)morpholine (3d+3d′ Regioisomer Mixture). Compounds 3d, 3d′ (1:0.75) were synthesized according to general procedure A using 4-chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1d, 0.090 mmol) as colorless oil in 72% yield (12.8 mg, 0.065 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 3d 1H NMR (500 MHz, CDCl3) δ 7.23−7.20 (m, 2H), 6.84−6.81 (m, 2H), 3.85−3.83 (m, 4H), 3.12−3.10 (m, 4H). 3d′ 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 8.0 Hz, 1H), 6.86−6.85 (m, 1H), 6.84−6.81 (m, 1H), 6.78−6.76 (m, 1H) 3.85−3.83 (m, 4H) 3.15−3.13 (m, 4H). 4-(4-(tert-Butyl)phenyl)morpholine (3e+3e′, Regioisomer Mixture). Compounds 3e, 3e′ (0.6:1) were synthesized according to general procedure A using 4-(tert-butyl)-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1e, 0.085 mmol) as a colorless oil in 73% yield (13.4 mg, 0.061 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 3e 1H NMR (500 MHz, CDCl3) δ 7.32−7.28 (m, 2H), 6.88−6.85 (m, 2H), 3.86−3.84 (m, 4H), 3.14−3.12 (m, 4H), 1.29 (s, 9H). 3e′

regioisomers. Using either allyl or methyl acetate to form a carbon−oxygen bond through the C−N bond cleavage in the aryl DABCO ammonium salt, produced 6d in yields of 18% and 32%, respectively. Importantly, carbon−fluoride and carbon−carbon bond formations were successfully achieved using different nucleophiles, such as KF and 2,4-pentanedione, generating the targeted molecules 6e and 6f in yields of 45% and 23%, respectively. A possible mechanism for the formation of 4-phenylmorpholine 3a from o-silyl aryl triflates 1a via a C−N bond cleavage reaction of morpholine is illustrated in Scheme 4.7a,b The Scheme 4. Proposed Reaction Mechanism

benzyne generated from 1a is attacked by a nucleophile such as 4-methylmorpholine 2a to generate intermediate ammonium salt 3a′. Ammonium salt 3a′ is directly converted to 3a through the release of 4,4-dimethyl morpholinium salt. On the basis of this feasible route, aryl DABCO ammonium salt 5a′ would be formed via the nucleophilic attack of DABCO to the benzyne intermediate, and the ring-opening reaction with the aid of another nucleophile (Nu) would follow to afford 1-ethyl4-phenylpiperazine derivatives 5a.

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CONCLUSION In conclusion, we have demonstrated a new synthetic method utilizing benzyne, DABCO, and a nucleophile for the construction of 2-(4-phenylpiperazin-1-yl)ethyl-containing derivatives via a one-pot process. This work represents the inert C−N bond cleavage of tertiary amines activated by diverse benzynes. On the basis of this result, a three-component reaction with benzyne, DABCO, and a nucleophile was developed via an aryl DABCO ammonium salt. Various benzynes and nucleophilic thiols are effective and tolerated under these mild conditions. This reaction not only allows the C−S bond formation with thiols but also the C−O, C−C, and C−F bond formation by employing methyl acrylate, allyl acetate, methyl acetate, fluoride, and 2,4-pentanedione as nucleophiles. The exemplified diversity of the carbon− heteroatom bond formation of this synthetic strategy provides a new route to potential drug candidates containing a 2-(4phenylpiperazin-1-yl)ethyl moiety. Further investigations to expand the scope of nucleophiles are currently in progress.

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EXPERIMENTAL SECTION

General Methods. Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm commercial silica gel plates (silica gel 60, F254, EMD chemical). The vials (Wheaton Standard Scintillation Vials) were purchased from DAIHAN and dried in an oven overnight. Infrared spectra were recorded on a IRPrestige-21 from SHIMADZU. High-resolution mass spectra (EI) were obtained on a Jeol JMS 700 HRMS at the Korea Basic Science Center (KBSI), Daegu, Korea and 8420

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

Article

The Journal of Organic Chemistry H NMR (500 MHz, CDCl3) δ 7.22 (t, J = 7.9 Hz, 1H), 6.98−6.93 (m, 2H), 6.75−6.72 (m, 1H), 3.89−3.86 (m, 4H), 3.17−3.15 (m, 4H), 1.31 (s, 9H). 3e 13C NMR (125 MHz, CDCl3) δ 148.9, 142.8, 126.0, 112.9, 67.0, 49.6, 34.0, 31.5. 3e′ 13C NMR (125 MHz, CDCl3) δ 152.2, 151.2, 128.8, 117.6, 115.4, 113.5, 67.1, 49.8, 34.9, 31.4. IR v 2959, 2923, 2853, 1600, 1517, 1449, 1262, 1229, 1123, 958 cm−1; HRMS (EI) calcd. for C14H21NO [M]+: 219.1623, found 219.1622. 4-(p-Tolyl)morpholine (3f+3f′ Regioisomer Mixture). Compounds 3f, 3f′ (0.6:1) were synthesized according to general procedure A using 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1f, 0.096 mmol) as colorless oil in 73% yield (12.4 mg, 0.070 mmol). Rf = 0.4 (EtOAc/Hexane = 1/4). 3f 1H NMR (500 MHz, CDCl3) δ 7.09 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.87−3.85 (m, 4H), 3.11−3.01 (m, 4H), 2.27 (s, 3H). 3f′ 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 6.74−6.71 (m, 3H), 3.87−3.85 (m, 4H), 3.16−3.14 (m, 4H), 2.32 (s, 3H). 4-(3-Bromo-5-methylphenyl)morpholine (3g). Compound 3g was synthesized according to general procedure A using 2-bromo-4methyl-6-(trimethylsilyl)phenyl trifluoromethanesulfonate (1g, 0.077 mmol) as colorless oil in 74% yield (14.5 mg, 0.057 mmol). Rf = 0.4 (EtOAc/Hexane = 1/4). 4-(3,4-Dimethylphenyl)morpholine (3h). Compound 3h was synthesized according to general procedure A using 4,5-dimethyl-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1h, 0.091 mmol) as colorless oil in 68% yield (12 mg, 0.062 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 4-(Naphthalen-2-yl)morpholine (3i). Compound 3i was synthesized according to general procedure A using 2-(trimethylsilyl)naphthalen-1-yl trifluoromethanesulfonate (1i, 0.086 mmol) as colorless oil in 62% yield (11.4 mg, 0.053 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 4-(3-Methoxyphenyl)morpholine (3j). Compound 3j was synthesized according to general procedure A using 2-methoxy-6(trimethylsilyl)phenyl trifluoromethanesulfonate (1j, 0.091 mmol) as colorless oil in 57% yield (10.1 mg, 0.052 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 4-(3,4-Dimethoxyphenyl)morpholine (3k). Compound 3k was synthesized according to general procedure A using 4,5-dimethoxy-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1k, 0.084 mmol) as a colorless oil in 46% yield (8.6 mg, 0.039 mmol). Rf = 0.4 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 2.7 Hz, 1H), 6.44 (dd, J = 8.7, 2.7 Hz, 1H), 3.87− 3.85 (m, 7H), 3.83 (s, 3H), 3.07−3.05 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 149.7, 146.3, 143.8, 112.3, 107.7, 102.6, 67.1, 56.4, 55.9, 50.9. IR v 2955, 2922, 2852, 1517, 1448, 1256, 1202, 1168, 1024, 970 cm−1; HRMS (EI) calcd. for C12H17NO3 [M]+: 223.1208, found 223.1206. 4-(Pyridin-3-yl)morpholine (3l). Compound 3l was synthesized according to general procedure A using 3-(trimethylsilyl)pyridin-4-yl trifluoromethanesulfonate (1l, 0.1 mmol) as colorless oil in 39% yield (6.4 mg, 0.039 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 4-(1H-Indol-5-yl)morpholine (3m). Compound 3m was synthesized according to general procedure A using 4-(trimethylsilyl)-1Hindol-5-yl trifluoromethanesulfonate (1m, 0.085 mmol) as colorless oil in 42% yield (7.3 mg, 0.036 mmol). Rf = 0.5 (EtOAc/Hexane = 1/ 4). 4-(1-Methyl-1H-indol-4-yl)morpholine (3m′). Compound 3m′ was synthesized according to general procedure A using 4(trimethylsilyl)-1H-indol-5-yl trifluoromethanesulfonate (1m, 0.085 mmol) as colorless oil in 21% yield (3.9 mg, 0.018 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). N,N-Dimethylaniline (3o). Compound 3o was synthesized according to general procedure A using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as a colorless oil in 40% yield (4.9 mg, 0.040 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1-Phenylpiperidine (3p). Compound 3p was synthesized according to general procedure A using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as a colorless oil in 64% yield (10.4 mg, 0.064 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1

1-Phenyl-4-(2-(phenylthio)ethyl)piperazine (5a). General procedure B: Benzyne precursor 1a (30 mg, 0.1 mmol) and DABCO (22.5 mg, 0.2 mmol) and cesium fluoride (15 mg, 0.1 mmol) added to 4 mL vial in acetonitrile (1 mL, 0.1 M). The reaction was kept stirring for a few hours at room temperature. Thiol (20.0 μL, 0.185 mmol) was added after checked the TLC and the reaction was heated at 100 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired 1-phenyl-4-(2-(phenylthio)ethyl)piperazine 5a (27 mg, 0.090 mmol, 84%) as colorless oil. Rf = 0.4 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 5.2, 3.1 Hz, 2H), 7.31−7.25 (m, 4H), 7.19 (dd, J = 10.3, 4.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.86 (td, J = 7.3, 3.7 Hz, 1H), 3.21 (t, J = 5.0 Hz, 4H), 3.11 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 151.3, 136.4, 129.23, 129.20, 129.0, 126.1, 119.8, 116.2, 57.8, 53.1, 49.1, 30.9. IR v 3056, 2934, 2878, 2817, 1599, 1501, 1452, 1308, 1132, 1004 cm−1; HRMS (EI) calcd. for C18H22N2S [M]+: 298.1504, found 298.1501. 1-(3,4-Dimethylphenyl)-4-(2-(phenylthio)ethyl)piperazine (5b). Compound 5b was synthesized according to general procedure B using 4,5-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1h, 0.091 mmol) as colorless oil in 81% yield (24.3 mg, 0.074 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 8.3, 1.1 Hz, 2H), 7.29 (dd, J = 10.5, 4.9 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.2, 2.6 Hz, 1H), 3.17 (t, J = 5.0 Hz, 4H), 3.12 (t, J = 7.7 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 5.0 Hz, 4H), 2.23 (s, 3H), 2.19 (s, 3H).13C NMR (125 MHz, CDCl3) δ 149.6, 137.1, 136.3, 130.2, 129.2, 129.0, 128.2, 126.1, 118.2, 113.9, 57.7, 53.2, 49.7, 30.8, 20.2, 18.8. IR v 3055, 2918, 2811, 1613, 1503, 1453, 1337, 1131, 1002, 961 cm−1; HRMS (EI) calcd. for C20H26N2S [M]+: 326.1817, found 326.1818. 1-(3,4-Dimethoxyphenyl)-4-(2-(phenylthio)ethyl)piperazine (5c). Compound 5c was synthesized according to general procedure B using 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1k, 0.084 mmol) as colorless oil in 47% yield (14.1 mg, 0.039 mmol). Rf = 0.4 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.37−7.33 (m, 2H), 7.30−7.25 (m, 2H), 7.18 (dd, J = 11.6, 4.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 6.44 (dd, J = 8.7, 2.7 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.12−3.07 (m, 6H), 2.72 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 149.5, 146.3, 143.6, 136.4, 129.1, 129.0, 126.1, 112.0, 108.0, 103.0, 57.7, 56.3, 55.9, 53.2, 50.7, 30.8. IR v 2932, 2825, 1585, 1518, 1450, 1307, 1203, 1143, 1007, 912 cm−1; HRMS (EI) calcd. for C20H26N2O2S [M]+: 358.1715, found 358.1718. 1-(2-(Phenylthio)ethyl)-4-(p-tolyl)piperazine (5d+5d′, Regioisomer Mixture). Compounds 5d, 5d′ (1:1) were synthesized according to general procedure B using 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1f, 0.096 mmol) as colorless oil in 73% yield (21.9 mg, 0.070 mmol). Rf = 0.4 (EtOAc/Hexane = 1/4). 5d 1H NMR (500 MHz, CDCl3) δ 7.38−7.35 (m, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.20−7.14 (m, 1H), 6.87−6.83 (m, 2H), 6.74 (d, J = 8.6 Hz, 2H), 3.17 (t, J = 5.0 Hz, 4H), 3.10 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.66−2.63 (m, 4H), 2.27 (s, 3H). 5d′ 1H NMR (500 MHz, CDCl3) δ 7.38−7.35 (m, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.20− 7.14 (m, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.69 (t, J = 7.5 Hz, 1H), 3.22 (t, J = 5.0 Hz, 4H), 3.10 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.66−2.63 (m, 4H), 2.32 (s, 3H). 13C NMR (125 MHz, CDCl3, 5d +5d’, regioisomer mixture) δ 151.4, 149.2, 138.8, 136.4, 129.73, 129.72, 129.4, 129.22, 129.21, 129.0, 126.1, 120.7, 117.0, 116.5, 113.3, 57.8, 53.2, 49.7, 49.2, 30.8, 21.8, 20.5. IR v 3054, 2936, 2878, 1601, 1583, 1493, 1376, 1289, 1165, 1090 cm−1; HRMS (EI) calcd. for C19H24N2S [M]+: 312.1660, found 312.1658. 1-(4-(tert-Butyl)phenyl)-4-(2-(phenylthio)ethyl)piperazine (5e +5e′, Regioisomer Mixture). Compounds 5e, 5e′ (0.6:1) were synthesized according to general procedure B using 4-(tert-butyl)-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1e, 0.085 mmol) as colorless oil in 62% yield (18.7 mg, 0.053 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 5e 1H NMR (500 MHz, CDCl3) δ 7.36 (td, J = 2.7, 1.6 Hz, 2H), 7.31−7.26 (m, 2H), 7.21−7.16 (m, 1H), 6.99−6.97 (m, 8421

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

Article

The Journal of Organic Chemistry

149.1, 136.4, 134.6, 129.2, 129.0, 128.7, 128.6, 127.4, 126.8, 126.3, 126.1, 123.4, 119.4, 110.3, 57.8, 53.1, 49.5, 31.0. IR v 3054, 2923, 2818, 1627, 1597, 1453, 1308, 1219, 1129, 1024 cm−1; HRMS (EI) calcd. for C22H24N2S [M]+: 348.1660, found 348.1656. 4,4′-Bis(4-(2-(phenylthio)ethyl)piperazin-1-yl)-1,1′-biphenyl (5j, Regioisomer Mixture). Compounds 5j (regioisomer mixture) were synthesized according to general procedure B using 3,3′-bis(trimethylsilyl)-[1,1′-biphenyl]-4,4′-diyl bis(trifluoromethanesulfonate) (1j′, 0.050 mmol) as colorless oil in 74% yield (22.3 mg, 0.037 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3, regioisomer mixture) δ 7.50−7.47 (m, 1H), 7.46 (d, J = 8.8 Hz, 0.3H), 7.39−7.35 (m, 4H), 7.30 (q, J = 8.4 Hz, 5.5H), 7.21−7.17 (m, 2H), 7.10−7.04 (m, 2.3H), 6.98−6.94 (m, 1.3H), 6.91 (d, J = 1.7 Hz, 0.5H), 6.87−6.84 (m, 0.4H), 3.27 (dd, J = 9.6, 5.4 Hz, 8H), 3.16 (t, J = 7.5 Hz, 4H), 2.73 (dd, J = 15.1, 7.5 Hz, 12H). 13C NMR (125 MHz, CDCl3, regioisomer mixture) δ 151.59, 151.55, 150.4, 142.9, 142.0, 136.22, 136.20, 136.1, 133.0, 129.4, 129.3, 129.0, 127.9, 127.2, 126.2, 119.2, 118.6, 116.4, 116.2, 115.4, 115.1, 114.7, 114.5, 57.7, 53.1, 53.0, 49.1, 49.0, 48.8, 30.7. IR v 2921, 2846, 2528, 1597, 1519, 1439, 1400, 1239, 1116, 922 cm−1; HRMS (EI) calcd. for C36H42N4S2 [M]+: 594.2851, found 594.2849. 1-(2-(Naphthalen-2-ylthio)ethyl)-4-phenylpiperazine (5k). Compound 5k was synthesized according to general procedure B using 2(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 74% yield (26 mg, 0.074 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.81−7.74 (m, 4H), 7.50−7.42 (m, 3H), 7.29−7.25 (m, 2H), 6.95−6.91 (m, 2H), 6.87 (t, J = 7.3 Hz, 1H), 3.23−3.19 (m, 6H), 2.78−2.73 (m, 2H), 2.67 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 151.3, 133.9, 133.8, 131.8, 129.2, 128.5, 127.8, 127.4, 127.1, 126.9, 126.7, 125.7, 119.8, 116.2, 57.7, 53.1, 49.1, 30.8. IR v 3052, 2923, 2818, 1623, 1598, 1501, 1377, 1268, 1132, 1069 cm−1; HRMS (EI) calcd. for C22H24N2S [M]+: 348.1660, found 348.1661. 1-Phenyl-4-(2-(p-tolylthio)ethyl)piperazine (5l). Compound 5l was synthesized according to general procedure B using 2(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 76% yield (24 mg, 0.076 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.31−7.24 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 3.22 (t, J = 5.0 Hz, 4H), 3.06 (t, J = 7.8 Hz, 2H), 2.70−2.62 (m, 6H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 151.3, 136.3, 132.5, 130.1, 129.8, 129.2, 119.8, 116.1, 57.9, 53.1, 49.1, 31.5, 21.1. IR v 3021, 2921, 2878, 2817, 1599, 1493, 1384, 1307, 1269, 1132 cm−1; HRMS (EI) calcd. for C19H24N2S [M]+: 312.1660, found 312.1661. 1-(2-((2,6-Dimethylphenyl)thio)ethyl)-4-phenylpiperazine (5m). Compound 5m was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 63% yield (20.7 mg, 0.063 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 2H), 7.12−7.09 (m, 3H), 6.91 (d, J = 8.7 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 3.18 (t, J = 5.0 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.60−2.56 (m, 12H). 13C NMR (125 MHz, CDCl3) δ 151.3, 143.1, 133.4, 129.1, 128.2, 128.1, 119.7, 116.1, 58.2, 53.1, 49.1, 32.4, 22.2. IR v 3056, 2916, 2848, 1738, 1599, 1502, 1454, 1352, 1269, 1132 cm−1; HRMS (EI) calcd. for C20H26N2S [M]+: 326.1817, found 326.1815. S-(2-(4-Phenylpiperazin-1-yl)ethyl)ethanethioate (5n). Compound 5n was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 75% yield (19.9 mg, 0.075 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.28−7.23 (m, 2H), 6.92 (d, J = 7.9 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 3.22 (t, J = 5.0 Hz, 4H), 3.08 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 5.0 Hz, 4H), 2.63 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 195.7, 151.3, 129.1, 119.8, 116.1, 57.5, 53.0, 49.1, 30.6, 26.3. IR v 3359, 3059, 2940, 2818, 1927, 1691, 1599, 1578, 1501, 1376 cm−1; HRMS (EI) calcd. for C14H20N2OS [M]+: 264.1296, found 264.1294. 1-Phenyl-4-(2-(pyridin-2-ylthio)ethyl)piperazine (5o). Compound 5o was synthesized according to general procedure B using 2(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 47% yield (14.2 mg, 0.047 mmol). Rf = 0.5 (EtOAc/

2H), 6.88−6.85 (m, 2H), 3.22−3.16 (m, 4H), 3.12−3.08 (m, 2H), 2.73−2.69 (m, 2H), 2.68−2.63 (m, 4H), 1.28 (s, 9H). 5e’ 1H NMR (500 MHz, CDCl3) δ 7.36 (td, J = 2.7, 1.6 Hz, 2H), 7.31−7.26 (m, 3H), 7.21−7.16 (m, 2H), 6.92 (d, J = 7.7 Hz, 1H), 6.74 (dd, J = 7.5, 2.5 Hz, 1H), 3.22−3.16 (m, 4H), 3.12−3.08 (m, 2H), 2.73−2.69 (m, 2H), 2.68−2.63 (m, 4H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3, 5e+5e’, regioisomer mixture) δ 152.1, 151.2, 148.9, 142.5, 136.4, 129.4, 129.2, 129.0, 128.7, 126.1, 125.9, 117.4, 115.9, 114.0, 113.4, 57.8, 57.7, 53.26, 53.24, 49.6, 49.3, 34.9, 34.0, 31.5, 31.4, 30.9. IR v 3054, 2916, 2818, 1732, 1600, 1580, 1480, 1362, 1265, 1089 cm−1; HRMS (EI) calcd. for C22H30N2S [M]+: 354.2130, found 354.2132. 1-(4-Chlorophenyl)-4-(2-(phenylthio)ethyl)piperazine (5f+5f′, Regioisomer Mixture). Compounds 5f, 5f′ (1:1) were synthesized according to general procedure B using 4-chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1d, 0.090 mmol) as colorless oil in 73% yield (21.9 mg, 0.066 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 5f 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.21−7.13 (m, 3H), 6.87−6.75 (m, 2H), 3.24−3.15 (m, 4H), 3.11 (t, J = 6.5 Hz, 2H), 2.75−2.62 (m, 6H). 5f’ 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.21−7.13 (m, 2H), 6.87−6.75 (m, 3H), 3.24−3.15 (m, 4H), 3.11 (t, J = 6.5 Hz, 2H), 2.75−2.62 (m, 6H). 13C NMR (125 MHz, CDCl3, 5f+5f’, regioisomer mixture) δ 147.5, 145.1, 130.3, 125.4, 124.5, 124.35, 124.33, 121.5, 114.7, 112.7, 111.2, 109.2, 52.92, 52.90, 48.2, 48.1, 44.2, 43.8, 26.0. IR v 3054, 2938, 2880, 2820, 1733, 1594, 1495, 1385, 1309, 1132 cm−1; HRMS (EI) calcd. for C18H21ClN2S [M]+: 332.1114, found 332.1116. 1-(4-Fluorophenyl)-4-(2-(phenylthio)ethyl)piperazine (5g+5g′, Regioisomer Mixture). Compounds 5g, 5g′ (1:0.3) were synthesized according to general procedure B using 4-fluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol) as colorless oil in 65% yield (19.5 mg, 0.062 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 5g 1H NMR (500 MHz, CDCl3) δ 7.35 (td, J = 2.9, 1.7 Hz, 2H), 7.30−7.27 (m, 2H), 7.20−7.15 (m, 1H), 6.98−6.92 (m, 2H), 6.89− 6.84 (m, 2H), 3.21−3.18 (m, 2H), 3.14−3.07 (m, 4H), 2.72−2.67 (m, 2H), 2.66−2.60 (m, 4H). 5g′ 1H NMR (500 MHz, CDCl3) δ 7.35 (td, J = 2.9, 1.7 Hz, 2H), 7.30−7.27 (m, 2H), 7.20−7.15 (m, 2H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.57 (td, J = 12.4, 2.4 Hz, 1H), 6.54−6.50 (m, 1H), 3.14−3.07 (m, 6H), 2.72−2.67 (m, 2H), 2.66− 2.60 (m, 4H). 13C NMR (125 MHz, CDCl3, 5g+5g′, regioisomer mixture) δ 163.9 (d, 1C, JC−F = 241.6 Hz), 157.3 (d, 1C, JC−F = 237.3 Hz), 153.0 (d, 1C, JC−F = 10.0 Hz), 148.0 (d, 1C, JC−F = 2.3 Hz), 136.4, 136.3, 130.2 (d, 1C, JC−F = 10.0 Hz), 129.26, 129.23, 129.0, 126.14, 126.12, 118.0 (d, 1C, JC−F = 7.6 Hz), 115.6 (d, 1C, JC−F = 21.9 Hz), 111.2 (d, 1C, JC−F = 2.4 Hz), 105.9 (d, 1C, JC−F = 21.4 Hz), 102.8 (d, 1C, JC−F = 24.9 Hz), 100.0, 57.7, 53.1, 52.9, 50.1, 48.6, 30.9. IR v 3052, 2940, 2820, 1733, 1612, 1509, 1454, 1354, 1309, 1179 cm−1; HRMS (EI) calcd. for C18H21FN2S [M]+: 316.1409, found 316.1408. 1-(3-Methoxyphenyl)-4-(2-(phenylthio)ethyl)piperazine (5h). Compound 5h was synthesized according to general procedure B using 2-methoxy-6-(trimethylsilyl)phenyl trifluoromethanesulfonate (1j, 0.091 mmol) as colorless oil in 64% yield (19.2 mg, 0.059 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 9.5 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.17 (dd, J = 15.9, 7.8 Hz, 2H), 6.53 (dd, J = 8.2, 2.3 Hz, 1H), 6.45 (t, J = 2.3 Hz, 1H), 6.42 (dd, J = 8.1, 2.3 Hz, 1H), 3.78 (s, 3H), 3.22 (t, J = 5.0 Hz, 4H), 3.12−3.07 (m, 2H), 2.72−2.67 (m, 2H), 2.64 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 160.6, 152.7, 136.3, 129.8, 129.2, 129.0, 126.1, 108.9, 104.5, 102.6, 57.7, 55.2, 53.0, 49.0, 30.8. IR v 3056, 2923, 2849, 1732, 1600, 1495, 1376, 1309, 1202, 1170 cm−1; HRMS (EI) calcd. for C19H24N2OS [M]+: 328.1609, found 328.1612. 1-(Naphthalen-2-yl)-4-(2-(phenylthio)ethyl)piperazine (5i). Compound 5i was synthesized according to general procedure B using 2-(trimethylsilyl)naphthalen-1-yl trifluoromethanesulfonate (1i, 0.086 mmol) as colorless oil in 79% yield (23.7 mg, 0.068 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.73− 7.67 (m, 3H), 7.40−7.36 (m, 3H), 7.32−7.24 (m, 4H), 7.19 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 3.33−3.28 (m, 4H), 3.12 (t, J = 7.7 Hz, 2H), 2.74−2.69 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 8422

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

Article

The Journal of Organic Chemistry

1131, 993 cm−1; HRMS (EI) calcd. for C19H21N3S2 [M]+: 355.1177, found 355.1178. 1-(2-((3s,5s,7s)-Adamantan-1-ylthio)ethyl)-4-phenylpiperazine (5u). Compound 5u was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 46% yield (16.5 mg, 0.046 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.28−7.23 (m, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 3.24 (t, J = 5.0 Hz, 4H), 2.72−2.58 (m, 8H), 2.04 (s, 3H), 1.86 (d, J = 2.6 Hz, 6H), 1.71−1.64 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 151.3, 129.1, 119.8, 116.1, 59.2, 53.2, 49.1, 44.3, 43.6, 36.3, 29.7, 22.9. IR v 2912, 2847, 2818, 1599, 1501, 1452, 1300, 1236, 757, 691 cm−1; HRMS (EI) calcd. for C22H32N2S [M]+: 356.2286, found 356.2286. 1-Phenyl-4-(2-(phenylthio)ethyl)piperidine (5v). Compound 5v was synthesized according to general procedure B using 2(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 46% yield (13.8 mg, 0.046 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.35−7.33 (m, 2H), 7.32−7.24 (m, 4H), 7.21−7.16 (m, 1H), 6.95 (d, J = 7.8 Hz, 2H), 6.85−6.82 (m, 1H), 3.70 (d, J = 12.5 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.69 (dt, J = 12.2, 2.5 Hz, 2H), 1.84 (d, J = 12.5 Hz, 2H), 1.69− 1.55 (m, 3H), 1.38 (qd, J = 12.2, 3.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 151.9, 136.8, 129.1, 129.0, 128.9, 125.9, 119.4, 116.6, 50.0, 35.8, 34.9, 31.9, 31.0. IR v 3056, 2916, 2847, 2806, 1598, 1502, 1462, 1385, 1317, 1234 cm−1; HRMS (EI) calcd. for C19H23NS [M]+: 297.1551, found 297.1552. 2-(4-Phenylpiperazin-1-yl)ethyl acrylate (6a). General procedure C: Benzyne precursor 1a (30 mg, 0.1 mmol) and DABCO (22.5 mg, 0.2 mmol) and cesium fluoride (15 mg, 0.1 mmol) added to 4 mL vial in acetonitrile: Nucleophile (0.5 mL: 0.5 mL, 0.2 M) was heated at 100 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired 2-(4-phenylpiperazin-1-yl)ethyl acrylate 6a (10.8 mg, 0.041 mmol, 41%) as colorless oil. Rf = 0.5 (EtOAc only). 1H NMR (500 MHz, CDCl3) δ 7.28−7.23 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 7.5 Hz, 1H), 6.42 (dd, J = 17.3, 1.4 Hz, 1H), 6.15 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J = 10.4, 1.4 Hz, 1H), 4.33 (t, J = 6.0 Hz, 2H), 3.23 (t, J = 5.0 Hz, 4H), 2.74 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 166.2, 151.3, 130.9, 129.1, 128.4, 119.8, 116.1, 62.0, 56.7, 53.5, 49.1. IR v 2924, 2822, 1723, 1599, 1501, 1407, 1383, 1273, 1153, 1011 cm−1; HRMS (EI) calcd. for C15H20N2O2 [M]+: 260.1525, found 260.1525. 2-(4-(p-Tolyl)piperazin-1-yl)ethyl acrylate (6b+6b′, Regioisomer Mixture). Compounds 6b, 6b′ (0.8:1) were synthesized according to general procedure C using 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1f, 0.096 mmol) as colorless oil in 33% yield (8.7 mg, 0.032 mmol). Rf = 0.5 (EtOAc only). 6b 1H NMR (500 MHz, CDCl3) δ 7.07 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 6.42 (d, J = 17.3 Hz, 1H), 6.15 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J = 10.4, 1.3 Hz, 1H), 4.33 (td, J = 6.0, 1.5 Hz, 2H), 3.20 (t, J = 5.0 Hz, 4H), 3.16 (t, J = 5.0 Hz, 2H), 2.71−2.66 (m, 4H), 2.31 (s, 3H). 6b′ 1H NMR (500 MHz, CDCl3) δ 7.15 (t, J = 7.7 Hz, 1H), 6.76−6.71 (m, 2H), 6.68 (d, J = 7.5 Hz, 1H), 6.42 (d, J = 17.3 Hz, 1H), 6.15 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J = 10.4, 1.3 Hz, 1H), 4.33 (td, J = 6.0, 1.5 Hz, 2H), 3.16 (t, J = 5.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 4H), 2.71− 2.66 (m, 4H), 2.26 (s, 3H). 13C NMR (125 MHz, CDCl3, 6b+6b′, regioisomer mixture) δ 166.2, 151.4, 149.2, 138.8, 130.9, 129.7, 129.3, 129.0, 128.4, 120.7, 117.0, 116.5, 113.2, 99.9, 62.0, 56.7, 53.5, 49.7, 49.2, 21.8, 20.4. IR v 2921, 2822, 1726, 1678, 1634, 1602, 1515, 1494, 1407, 1382 cm−1; HRMS (EI) calcd. for C16H22N2O2 [M]+: 274.1681, found 274.1678. 2-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl acrylate (6c). Compound 6c was synthesized according to general procedure C using 4-fluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol) as colorless oil in 20% yield (5.4 mg, 0.019 mmol). 1 H NMR (500 MHz, CDCl3) δ 6.97−6.93 (m, 2H), 6.88−6.85 (m, 2H), 6.41 (dd, J = 17.3, 1.4 Hz, 1H), 6.14 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J = 10.4, 1.4 Hz, 1H), 4.33 (t, J = 5.7 Hz, 2H), 3.12−3.10 (m, 4H), 2.74 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.0 Hz, 4H). 13C NMR

Hexane = 1/2). 1H NMR (500 MHz, CDCl3) δ 8.43−8.41 (m, 1H), 7.48−7.44 (m, 1H), 7.28−7.24 (m, 2H), 7.18 (d, J = 8.1 Hz, 1H), 6.97 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 3.37 (t, J = 7.5 Hz, 2H), 3.23−3.20 (m, 4H), 2.76 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 158.8, 151.4, 149.5, 135.9, 129.1, 122.4, 119.7, 119.4, 116.1, 57.9, 53.1, 49.1, 27.0. IR v 3039, 2924, 2814, 1599, 1579, 1502, 1453, 1384, 1271, 1124 cm−1; HRMS (EI) calcd. for C17H21N3S [M]+: 299.1456, found 299.1458. 1-(2-(tert-Butylthio)ethyl)-4-phenylpiperazine (5p). Compound 5p was synthesized according to general procedure B using 2(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 45% yield (12.6 mg, 0.045 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/2). 1H NMR (500 MHz, CDCl3) δ 7.28−7.24 (m, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 3.23 (t, J = 5.2 Hz, 4H), 2.74−2.69 (m, 2H), 2.68−2.61 (m, 6H), 1.33 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 151.3, 129.1, 119.8, 116.1, 58.6, 53.2, 49.1, 42.1, 31.0, 25.6. IR v 2956, 2924, 2853, 2818, 1600, 1501, 1455, 1363, 1235, 1163 cm−1; HRMS (EI) calcd. for C16H26N2S [M]+: 278.1817, found 278.1813. 1-Phenyl-4-(2-(thiophen-2-ylthio)ethyl)piperazine (5q). Compound 5q was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 93% yield (28.6 mg, 0.093 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/2). 1H NMR (500 MHz, CDCl3) δ 7.34 (dd, J = 5.3, 1.2 Hz, 1H), 7.27−7.24 (m, 2H), 7.14 (dd, J = 3.5, 1.1 Hz, 1H), 6.97 (dd, J = 5.3, 3.5 Hz, 1H), 6.92 (d, J = 7.9 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 3.21 (t, J = 5.0 Hz, 4H), 2.98 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 151.3, 134.4, 133.7, 129.3, 129.2, 127.6, 119.8, 116.1, 57.9, 53.1, 49.1, 35.8. IR v 3060, 3035, 2918, 1817, 1730, 1598, 1501, 1402, 1335, 1269 cm−1; HRMS (EI) calcd. for C16H20N2S2 [M]+: 304.1068, found 304.1067. 2-((2-(4-Phenylpiperazin-1-yl)ethyl)thio)quinolone (5r). Compound 5r was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 85% yield (29.8 mg, 0.085 mmol). Rf = 0.5 (EtOAc/ Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.72 (dd, J = 8.0, 1.1 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.45−7.40 (m, 1H), 7.29−7.25 (m, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.8 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 3.54 (t, J = 7.8 Hz, 2H), 3.27 (t, J = 5.0 Hz, 4H), 2.85 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 158.8, 151.4, 148.4, 135.4, 129.7, 129.2, 128.0, 127.7, 126.0, 125.3, 121.1, 119.8, 116.2, 57.8, 53.1, 49.2, 26.5. IR v 3056, 2922, 2851, 2818, 1612, 1555, 1453, 1376, 1307, 1137 cm−1; HRMS (EI) calcd. for C21H23N3S [M]+: 349.1613, found 349.1615. 2-((2-(4-Phenylpiperazin-1-yl)ethyl)thio)-4,5-dihydrothiazole (5s). Compound 5s was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 93% yield (28.8 mg, 0.093 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.25 (t, J = 7.5 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 4.20 (t, J = 8.0 Hz, 2H), 3.38 (t, J = 8.0 Hz, 2H), 3.30 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 4.7 Hz, 4H), 2.75 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 165.5, 151.3, 129.1, 119.8, 116.2, 64.3, 57.2, 52.9, 49.1, 35.6, 30.0. IR v 3036, 2923, 2819, 1598, 1501, 1452, 1376, 1306, 1270, 1142 cm−1; HRMS (EI) calcd. for C15H21N3S2 [M]+: 307.1177, found 307.1176. 2-((2-(4-Phenylpiperazin-1-yl)ethyl)thio)benzo[d]thiazole (5t). Compound 5t was synthesized according to general procedure B using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in 62% yield (22 mg, 0.062 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.43−7.39 (m, 1H), 7.31−7.24 (m, 3H), 6.93 (d, J = 7.8 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 3.59 (t, J = 7.0 Hz, 2H), 3.24 (t, J = 5.0 Hz, 4H), 2.90 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 5.0 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 167.0, 153.3, 151.3, 135.3, 129.2, 126.1, 124.3, 121.5, 121.0, 119.8, 116.2, 57.1, 53.0, 49.1, 30.9. IR v 3058, 2923, 2818, 1598, 1501, 1427, 1353, 1272, 8423

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

The Journal of Organic Chemistry

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(125 MHz, CDCl3) δ 166.1, 157.3 (d, 1C, JC−F = 237.4 Hz), 148.0 (d, 1C, JC−F = 2.4 Hz), 130.9, 128.4, 117.1 (d, 2C, JC−F = 7.6 Hz), 115.6 (d, 2C, JC−F = 22.0 Hz), 62.0, 56.6, 53.4, 50.2. IR v 2924, 2823, 1723, 1634, 1510, 1454, 1407, 1357, 1332, 1233 cm−1; HRMS (EI) calcd. for C15H19FN2O2 [M]+: 278.1431, found 278.1431. 2-(4-(3-Fluorophenyl)piperazin-1-yl)ethyl acrylate (6c′). Compound 6c′ was synthesized according to general procedure C using 4fluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol) as colorless oil in 13% yield (3.5 mg, 0.012 mmol). Rf = 0.5 (EtOAc only). 1H NMR (500 MHz, CDCl3) δ 7.17 (dd, J = 15.2, 8.2 Hz, 1H), 6.66 (dd, J = 8.3, 2.3 Hz, 1H), 6.57 (td, J = 12.4, 2.3 Hz, 1H), 6.51 (dt, J = 8.2, 2.3 Hz, 1H), 6.41 (dd, J = 17.3, 1.4 Hz, 1H), 6.14 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J = 10.4, 1.4 Hz, 1H), 4.32 (t, J = 5.8 Hz, 2H), 3.20−3.18 (m, 4H), 2.73 (t, J = 6.0 Hz, 2H), 2.67−2.65 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 166.1, 164.0 (d, 1C, JC−F = 241.6 Hz), 153.0 (d, 1C, JC−F = 9.6 Hz), 130.9, 130.2 (d, 1C, JC−F = 9.8 Hz), 128.4, 111.2 (d, 1C, JC−F = 2.4 Hz), 105.9 (d, 1C, JC−F = 21.4 Hz), 102.7 (d, 1C, JC−F = 24.9 Hz), 62.0, 56.6, 53.2, 48.6. IR v, 2952, 2848, 1724, 1633, 1581, 1495, 1407, 1357, 1294 cm−1; HRMS (EI) calcd. for C15H19FN2O2 [M]+: 278.1431, found 278.1431. 2-(4-Phenylpiperazin-1-yl)ethyl acetate (6d). Compound 6d was synthesized according to general procedure C using 4-methyl-2(trimethylsilyl)phenyl trifluoromethanesulfonate (1f, 0.096 mmol) as colorless oil in 32% yield (8 mg, 0.030 mmol). Rf = 0.4 (EtOAc only). 1 H NMR (500 MHz, CDCl3) δ 7.29−7.23 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 4.23 (t, J = 5.8 Hz, 2H), 3.24 (t, J = 4.8 Hz, 4H), 2.72−2.64 (m, 6H), 2.08 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 171.1, 151.3, 129.1, 119.8, 116.1, 61.8, 56.7, 53.5, 49.1, 21.1. IR v 2920, 2850, 1774, 1600, 1502, 1454, 1373, 1306, 1240, 1152 cm−1; HRMS (EI) calcd. for C14H20N2O2 [M]+: 248.1525, found 248.1525. 4-Hydroxy-3-(2-(4-phenylpiperazin-1-yl)ethyl)pent-3-en-2-one (6f). Compound 6f was synthesized according to general procedure C using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.01 mmol) as colorless oil in 23% yield (6.7 mg, 0.023 mmol). Rf = 0.4 (EtOAc only). 1H NMR (500 MHz, CDCl3) δ 7.29−7.24 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 5.47 (s, 1H), 3.95 (t, J = 5.8 Hz, 2H), 3.23 (t, J = 5.0 Hz, 4H), 2.80 (t, J = 5.7 Hz, 2H), 2.73 (t, J = 5.0 Hz, 4H), 2.29 (s, 3H), 2.16 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 197.0, 171.8, 151.3, 129.2, 119.9, 116.1, 100.1, 66.2, 56.6, 53.7, 49.2, 32.1, 19.9. IR v 3345, 3060, 3037, 2916, 2847, 2246, 1729, 1679, 1580, 1232 cm−1; HRMS (EI) calcd. for C17H24N2O2 [M]+: 288.1838, found 288.1840. 1-(2-Fluoroethyl)-4-phenylpiperazine (6e). Compound 6e was synthesized according to general procedure C using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as a colorless oil in 45% yield (9.4 mg, 0.045 mmol). Rf = 0.5 (EtOAc/Hexane = 1/4).

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ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A2A01051829, 2017R1A4A1015594).

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REFERENCES

(1) For patents on the 1-ethyl-4-phenylpiperazine motif and related compounds, see: (a) Chen, I.-J. Preparation of halogenated xanthine derivatives and precursors thereof for anti-cancer and anti-metastasis activity and preparing method thereof. U.S. Patent 0118464, 2011. (b) McLure, K. G.; Young, P. R. Preparation of quinazolin-4(3H)-one derivatives and for the treatment of diseases by epigenetic regulation. U.S. Patent 0281399, 2013. (c) Zhou, Y.; Zhang, L.; Zhou, J.; Zhou, X. Preparation of benzo fused five-membered azaheterocyclic piperazine or piperidine derivatives. PCT Int. Appl. (2014), WO 2014079155. (d) Bottegoni, G.; De Simone, A.; Ruda, G. F.; Cavalli, A.; Bandiera, T.; Piomelli, D. Preparation of phenyl carbamates as inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR). PCT Int. Appl. (2015), WO 2015007615. (e) Xu, X.; Wang, X.; Mao, L.; Zhao, L.; Xi, B. Preparation of pyrimidine compounds as Btk and Jak kinase inhibitors. PCT Int. Appl. (2015), WO 2015006754. (2) Chae, E.; Yi, H.; Choi, Y.; Cho, H.; Lee, K.; Moon, H. Synthesis and pharmacological evaluation of carbamic acid 1-phenyl-3-(4phenyl-piperazine-1-yl)-propyl ester derivatives as new analgesic agents. Bioorg. Med. Chem. Lett. 2012, 22, 2434−2439. (3) (a) Ross, S.; Finkelstein, M. Nucleophilic Displacement Reactions in Aromatic Systems. VII. The ortho:para Ratio in the Reactions of Nitrochlorobenzenes with Piperidine and with 1,4Diazabicyclo(2.2.2)octane. J. Am. Chem. Soc. 1963, 85, 2603−2607. (b) Gladstone, S. G.; Earley, W. G.; Acker, J. K.; Martin, G. S. Efficient microwave-assisted three-component one-pot preparation of 1-aryl-4-(2-acetoxyethyl)piperazines and 1-aryl-4-(2-acetoxyethyl)piperidines. Tetrahedron Lett. 2009, 50, 3813−3816. (4) (a) Zhu, Q.; Yuan, Q.; Chen, M.; Guo, M.; Huang, H. Multicomponent Reactions with Cyclic Tertiary Amines Enabled by Facile C-N Bond Cleavage. Angew. Chem. Int. Ed. 2017, 56, 5101− 5105. (b) Bugaenko, D. I.; Yurovskaya, M. A.; Karchava, A. V. Quaternary N-(2-Pyridyl)-DABCO Salts: One-Pot in Situ Formation from Pyridine-N-oxides and Reactions with Nucleophiles: A Mild and Selective Route to Substituted N-(2-Pyridyl)-N′-ethylpiperazines. J. Org. Chem. 2017, 82, 2136−2149. (5) For selected reports of aryne-mediated three-component reactions, see: (a) Okuma, K.; Fukuzaki, Y.; Nojima, A.; Shioji, K.; Yokomori, Y. Novel tandem reaction of benzyne with cyclic ethers and active methines: synthesis of ω-trichloroalkyl phenyl ethers. Tetrahedron Lett. 2008, 49, 3063−3066. (b) Okuma, K.; Hino, H.; Sou, A.; Nagahora, N.; Shioji, K. Cascade Approach to Trichloroalkyl Phenyl Ethers from Benzyne, Epoxides, and Chloroform. Chem. Lett. 2009, 38, 1030−1031. (c) Okuma, K.; Fukuzaki, Y.; Nojima, A.; Sou, A.; Hino, H.; Matsunaga, N.; Nagahora, N.; Shioji, K.; Yokomori, Y. Three component reaction of arynes with cyclic ethers and active methines: synthesis of omega-trichloroalkyl phenyl ethers. Bull. Chem. Soc. Jpn. 2010, 83, 1238−1247. (d) Stephens, D.; Zhang, Y.; Cormier, M.; Chavez, G.; Armana, H.; Larionov, O. V. Three-component reaction of small-ring cyclic amines with arynes and acetonitrile. Chem. Commun. 2013, 49, 6558−6560. (e) Roy, T.; Baviskar, D. R.; Biju, A. T. Synthesis of N-Aryl β-Amino Alcohols by Trifluoroacetic Acid Promoted Multicomponent Coupling of Aziridines, Arynes, and Water. J. Org. Chem. 2015, 80, 11131−11137. (6) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-Induced 1,2Elimination of O-Trimethylsilylphenyl Triflate to Benzyne under Mild Conditions. Chem. Lett. 1983, 12, 1211−1214. (7) (a) Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Employing Arynes in Transition-Metal-Free Monoarylation of Aromatic Tertiary Amines. Org. Lett. 2013, 15, 5452−5455. (b) Hirsch, M.; Dhara, S.;

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Haye Min Ko: 0000-0003-2807-9980 Notes

The authors declare no competing financial interest. 8424

DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425

Article

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DOI: 10.1021/acs.joc.8b01058 J. Org. Chem. 2018, 83, 8417−8425