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

Subscriber access provided by University of Winnipeg Library

Article

Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process Gyoungwook Min, Jeongseob Seo, and Haye Min Ko J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01058 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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 [email protected]

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-(4-phenylpiperazin-1-yl)ethyl-containing molecules using arynes, 1,4diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a one-pot process.

Introduction The 1-ethyl-4-phenylpiperazine motif plays an important role and is an essential structure in m any compounds used in a variety of fields, such as material, agrochemical, and medicinal che mistry. Especially, bioactive molecules having these privileged heterocycles have found widespre ad applications as drug candidates or experimental drugs. 2-(4-Phenylpiperazin-1-yl)ethyl-containi ng derivatives are known to possess several bioactivities such as antitumor, anti-inflammatory, a ntiobesity, and cardiovascular activities (Figure 1).

1, 2

Despite their potential and usefulness, met

hods 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 1 963, required very high temperatures (around 150 °C), long reaction times (about 20 h), and el ectron-poor functional groups installed on the substrate to access the desired products. Another

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

synthetic strategy utilized pyridine-N-oxide as 1,4-diazabicyclo(2.2.2)octane (DABCO) activator a nd 2-bromopyridine for the ring-opening reaction via C‒N bond cleavage as shown in Figure 2

Figure 1. Representative bioactive molecules containing 1-ethyl-4-phenylpiperazine motifs.

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.

4

(a). Although these reactions involve new activators, a general and mild method for the synthesis of diversely substituted 2-(4-phenylpiperazin-1-yl)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 reactions 5 under transition-metal-free conditions. In particular,


Page 2 of 24

Page 3 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6

benzynes, which can be generated from o-silyl aryl triflates, are very reactive intermediates owing to a strained π-bond. Mono N-arylation7 of tertiary amines with arynes has recently been developed to 7

construct C‒N bonds via quaternary ammonium salts. However, to the best of our knowledge, extensive research of this reaction using DABCO to obtain 1-ethyl-4-phenylpiperazine-containing 4,8

derivatives has not been sufficiently explored.

Therefore, we decided to examine the reaction of

tertiary amines, such as N-methyl morpholine or DABCO with arynes (Figure 2 (b)).

Results and Discussion Table 1. Optimization of the reaction conditions

a

a

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

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 4phenylmorpholine 3a (Table 1, entry 1). However, 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

1:7.6 ratio, as determined from the H-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). Scheme 1. Substrate scope of benzyne precursors.

a

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

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-tohigh yields. Similarly, tert-butyl, methyl, or dimethyl substituted 2-(trimethylsilyl)phenyl triflates were


Page 4 of 24

Page 5 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 electronwithdrawing 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 63% 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, 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 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. Three-component 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%



Page 6 of 24

isolated yield.

Scheme 2. Three-component reaction of benzynes with DABCO and thiols.

a

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.)


Page 7 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


d

1

e

was used. Ratio of isomers (para : meta) determined by H-NMR spectroscopy. Isomeric mixture f Quinuclidine (2 equiv.) was used instead of DABCO 2a’.

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 d 1 CH3CN:Nu (1:1, 0.1 M) was used. Ratio of isomers (para : meta) determined by H-NMR spectroscopy.

Next, various sulfur nucleophiles were investigated for the three-component reaction to provide access to 1-ethyl-4-phenylpiperazine-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 towards oxygen, halogen, and carbon nucleophiles (Scheme 3). Although excess nucleophile was required (as much as that of the solvent), it was noted that methyl acrylate, allyl acetate, methyl acetate, fluoride, and 2,4-pentanedione participate in the ring-opening reaction of aryl DABCO ammonium salts to afford the



Page 8 of 24

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 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. Scheme 4. Proposed reaction mechanism. O

O

H3C 2a

OTf

1a

O

2a

N

N CH3

N -

OTf

H

F-

TMS

SR

O

N N

N -

2a'

N RS-H

3a

H3C CH3 N -OTf

3a'

N

SR

N OTf 5a'

H

5a

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 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. Based on 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-ethyl-4-phenylpiperazine derivatives 5a. 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. Based on this result, a three-component reaction with benzyne, DABCO, and a nucleophile


Page 9 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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-(4-phenylpiperazin-1-yl)ethyl moiety. Further investigations to expand the scope of nucleophiles are currently in progress. Experimental Section General. 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) w ere purchased from DAIHAN and dried in an oven overnight. Infrared spectra were recorded o n 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 are reported as +

+

m/z (relative intensity). Accurate masses are reported for the molecular ion [M+Na] , [M+H] , o r [M]+. Benzyne precursors and thiols were purchased from Sigma-Aldrich, TCI or Alfa Aesar. A ll reactions were run in flame- or oven-dried glassware under an atmosphere of N2 gas with p urchased dry solvents unless otherwise stated. Nuclear magnetic resonance spectra (1H NMR a nd

13

C NMR) were recorded with a Jeol (500 MHz, 1H at 500 MHz,

13

C at 125 MHz). For CD

Cl3 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). Couplin g constants are reported in Hertz (Hz). Data for 1H NMR spectra are reported as follows: che mical 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 doublet s, 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



Page 10 of 24

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 1

mmol, 84%) as colorless oil. Rf = 0.5 (EtOAc/Hexane=1/4). H 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 = 4.8Hz, 4H).

13

C 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). 1

4-methyl-4-phenylmorpholin-4-ium (3a'). H 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-


Page 11 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

3.83 (m, 4H), 3.12-3.10 (m, 4H). 3d' H 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), 3.861

3.84 (m, 4H), 3.14-3.12 (m, 4H), 1.29 (s, 9H). 3e' 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 13

(125 MHz, CDCl3) δ 148.9, 142.8, 126.0, 112.9, 67.0, 49.6, 34.0, 31.5. 3e' C 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, -1

+

1449, 1262, 1229, 1123, 958 cm ; 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), 3.113.01 (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-4-methyl-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



Page 12 of 24

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) 1

as a colorless oil in 46% yield (8.6 mg, 0.039 mmol). Rf = 0.4 (EtOAc/Hexane=1/4). H 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), 3.873.85 (m, 7H), 3.83 (s, 3H), 3.07-3.05 (m, 4H).

13

C 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, -1

+

1024, 970 cm ; 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)-1H-indol-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-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


Page 13 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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

1

(EtOAc/Hexane=1/4). H 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).

13

C 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, -1

+

2934, 2878, 2817, 1599, 1501, 1452, 1308, 1132, 1004 cm ; 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). 1

H 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), 13

2.19 (s, 3H). C 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, -1

+

1002, 961 cm ; 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).

13

C

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, -1

56.3, 55.9, 53.2, 50.7, 30.8. IR: v 2932, 2825, 1585, 1518, 1450, 1307, 1203, 1143, 1007, 912 cm ; HRMS (EI) calcd. for C20H26N2O2S [M]+: 358.1715. Found: 358.1718.



Page 14 of 24

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).

13

C 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, -1

30.8, 21.8, 20.5. IR: v 3054, 2936, 2878, 1601, 1583, 1493, 1376, 1289, 1165, 1090 cm ; 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, 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).

13

C 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,


Page 15 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

6H). 5f' H 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).

13

C 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, -1

+

1733, 1594, 1495, 1385, 1309, 1132 cm ; 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).

13

C

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). 1

H 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).

13

C 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).

Page 16 of 24

Compound

5i

was

synthesized

according to general procedure B using 2-(trimethylsilyl)naphthalen-1-yl trifluoromethanesulfonate (1i, 1

0.086 mmol) as colorless oil in 79% yield (23.7 mg, 0.068 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H 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).

13

C NMR

(125 MHz, CDCl3) δ 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, -1

+

1400, 1239, 1116, 922 cm ; 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


Page 17 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 7.317.24 (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).

13

C 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).

13

C 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/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).

Page 18 of 24

13

C 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, -1

+

2814, 1599, 1579, 1502, 1453, 1384, 1271, 1124 cm ; 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 1

colorless oil in 45% yield (12.6 mg, 0.045 mmol). Rf = 0.5 (EtOAc/Hexane=1/2). H 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).

13

C 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, -1

+

1163 cm ; 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).

13

C 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, -1

+

1730, 1598, 1501, 1402, 1335, 1269 cm ; 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 1

colorless oil in 85% yield (29.8 mg, 0.085 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H 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).

13

C 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,


Page 19 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


-1

+

1612, 1555, 1453, 1376, 1307, 1137 cm ; 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 1

mmol) as colorless oil in 93% yield (28.8 mg, 0.093 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H 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).

13

C 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 1

mmol) as colorless oil in 62% yield (22 mg, 0.062 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H 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).

13

C 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, 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

was

5u

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).

13

C 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



Page 20 of 24

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).

13

C 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, -1

+

2806, 1598, 1502, 1462, 1385, 1317, 1234 cm ; 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).

13

C 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, -1

+

1273, 1153, 1011 cm ; 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). 13

C NMR (125 MHz, CDCl3, 6b+6b', regioisomer mixture) δ 166.2, 151.4, 149.2, 138.8, 130.9, 129.7,


Page 21 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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). 1H 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).

13

C NMR (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 -1

2924, 2823, 1723, 1634, 1510, 1454, 1407, 1357, 1332, 1233 cm ; 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 4-fluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 1

mmol) as colorless oil in 13% yield (3.5 mg, 0.012 mmol). Rf = 0.5 (EtOAc only). H 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), 2.672.65 (m, 4H).

13

C 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). 1H 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).

13

C 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,



-1

+

1240, 1152 cm ; 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).

13

C 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).

1

Supporting Information. Copies of the H and

13

C NMR spectra for products 3-6. This material

is available free of charge via the Internet at http://pubs.acs.org.

Author Information Corresponding Author *E-mail: [email protected]

ORCID Haye Min Ko: 0000-0003-2807-9980 Notes The authors declare no competing financial interest. 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-


Page 22 of 24

Page 23 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2015R1C1A2A01051829, 2017R1A4A1015594).

References (1) For patents on the 1-thyl-4-phenylpiperazine motif and related compounds, see: (a) Chen, I. -J., Preparation of halogenated xanthine derivatives and precursors thereof for anti-cancer and antimetastasis 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-(4-phenyl-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 1aryl-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: OnePot 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 omegatrichloroalkyl phenyl ethers. Bull. Chem. Soc. Jpn. 2010, 83, 1238-1247. (d) Stephens, D.; Zhang, Y.;



Page 24 of 24

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

1,2-Elimination

of

O-

Trimethylsilylphenyl Triflate to Benzyne under Mild Conditions. Chem. Lett. 1983, 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.; Diesendruck, C. E. N-Arylation of Tertiary Amines under Mild Conditions. Org. Lett. 2016, 18, 980-983. (c) Zhang, J.; Chen, Z. -X.; Du, T.; Li, B.; Gu, Y.; Tian, S. -K. Aryne-Mediated [2,3]-Sigmatropic Rearrangement of Tertiary Allylic Amines. Org. Lett. 2016, 18, 4872-4875. (d) Liu, Z.; Larock, R. C. Facile N-Arylation of Amines and Sulfonamides. Org. Lett. 2003, 5, 4673-4675. (e) Zhang, L.; Geng, Y.; Jin, Z. Transition-Metal-Free Synthesis of N-Aryl Hydroxamic Acids via Insertion of Arynes. J. Org. Chem. 2016, 81, 3542-3552. (f) Lee, Y.-H.; Chen, Y.-C.; Hsieh, J. -C. Pyridine-Catalyzed Double C–N Coupling Reaction of an Isocyanate with Two Benzynes. Eur. J. Org. Chem. 2012, 2, 247-250. (g) Seo, J. H.; Ko, H. M. Transition-metal-free synthesis of aromatic amines via the reaction of benzynes with isocyanates. Tetrahedron Lett. 2018, 59, 671-674. (8) (a) Ross, S. P.; Hoye, T. R. Reactions of hexadehydro-Diels-Alder benzynes with structurally complex multifunctional natural products. Nat. Chem. 2017, 9, 523-530. (b) Ross, S. P.; Hoye, T. R. Multiheterocyclic Motifs via Three-Component Reactions of Benzynes, Cyclic Amines, and Protic Nucleophiles. Org. Lett. 2018, 20, 100-103. (9) (a) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Efficient Assembly of Chromone Skeleton from 2,3-

Allenoic Acids and Benzynes. Org. Lett. 2011, 13, 5196-5199. (b) Willoughby, P. H.; Niu, D.; Wang, T.; Haj, M. K.; Cramer, C. J.; Hoye, T. R. Mechanism of the Reactions of Alcohols with o-Benzynes. J. Am. Chem. Soc. 2014, 136, 13657-13665. (c) Im, G-. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. -Y.; Houk, K. N.; Garg, N. K. Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions. J. Am. Chem. Soc. 2010, 132, 17933-17944. (d) Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. The Role of Aryne Distortions, Steric Effects, and Charges in Regioselectivities of Aryne Reactions. J. Am. Chem. Soc. 2014, 136, 15798-15805.


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

Recommend Documents