Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process

Article abstract of DOI:10.1021/acs.joc.8b01058

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-excell

Full text of DOI:10.1021/acs.joc.8b01058

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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
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Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process
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Gyoungwook Min, Jeongseob Seo and Haye Min Ko*
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Department of BioꢀNano Chemistry, Wonkwang University, 460 Iksandaeꢀro, Iksan, Jeonbuk, 54538,
Republic of Korea
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hayeminko@wku.ac.kr
ABSTRACT
An unprecedented threeꢀcomponent 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 goodꢀtoꢀexcellent yields. Expansively, this reaction can
produce biologically important 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethylꢀcontaining molecules using arynes, 1,4ꢀ
diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a oneꢀpot process.
Introduction
The 1ꢀethylꢀ4ꢀphenylpiperazine 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. 2ꢀ(4ꢀPhenylpiperazinꢀ1ꢀyl)ethylꢀcontaini
ng derivatives are known to possess several bioactivities such as antitumor, antiꢀinflammatory, 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 electronꢀwithdrawing 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
ectronꢀpoor functional groups installed on the substrate to access the desired products. Another
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synthetic strategy utilized pyridineꢀNꢀoxide as 1,4ꢀdiazabicyclo(2.2.2)octane (DABCO) activator a
nd 2ꢀbromopyridine for the ringꢀopening reaction via C‒N bond cleavage as shown in Figure 2
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Figure 1. Representative bioactive molecules containing 1ꢀethylꢀ4ꢀphenylpiperazine motifs.
Figure 2. Ringꢀopening reaction of an aryl DABCO ammonium salt through C‒N bond cleavage for
the synthesis of 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethylꢀcontaining derivatives.
(a).4 Although these reactions involve new activators, a general and mild method for the synthesis of
diversely substituted 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethylꢀcontaining derivatives is still required. To
overcome the synthetic difficulty and limitation of structural diversity, we focused our attention on
aryneꢀmediated threeꢀcomponent reactions5 under transitionꢀmetalꢀfree conditions. In particular,
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benzynes, which can be generated from oꢀsilyl aryl triflates,6 are very reactive intermediates owing to
a strained πꢀbond. Mono Nꢀarylation7 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 1ꢀethylꢀ4ꢀphenylpiperazineꢀcontaining
derivatives has not been sufficiently explored.4,8 Therefore, we decided to examine the reaction of
tertiary amines, such as Nꢀmethyl morpholine or DABCO with arynes (Figure 2 (b)).
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Results and Discussion
Table 1. Optimization of the reaction conditionsa
aReaction conditions: oꢀsilyl aryl triflate 1a (0.1 mmol), 4ꢀmethylmorpholine 2a (2 equiv.), CsF (1
b
c
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equiv.), CH3CN (0.2 M), 100 °C, 9 h. Isolated yield. Ratio determined by HꢀNMR spectroscopy of
crude product.
Initially, we attempted the reaction of benzyne precursor 1a (1 equiv.) with 4ꢀmethyl morpholine 2a (2
equiv.) in the presence of one equivalent of CsF in MeCN at room temperature to obtain 4ꢀ
phenylmorpholine 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
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1:7.6 ratio, as determined from the HꢀNMR 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
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3a in 88% yield (entry 7).
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Scheme 1. Substrate scope of benzyne precursors.
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aReaction conditions: oꢀsilyl aryl triflate 1a (0.1 mmol), 4ꢀmethylmorpholine 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
instead of 4ꢀmethylmorpholine 2a. cNꢀMethyl piperidine (2 equiv.) was used instead of 4ꢀ
d
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e
methylmorpholine 2a. Ratio of isomers (para : meta) determined by HꢀNMR spectroscopy. Yield
determined by 1HꢀNMR 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 electronꢀwithdrawing functional
groups such as fluoride or chloride afforded the corresponding products (3b, 3c, and 3d) in goodꢀtoꢀ
high yields. Similarly, tertꢀbutyl, methyl, or dimethyl substituted 2ꢀ(trimethylsilyl)phenyl triflates were
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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
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in some cases, where the regioisomeric ratio (para:meta), measured by HꢀNMR spectroscopy, was
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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 4ꢀsubstituted benzynes. Whereas electronꢀ
withdrawing group dominated nucleophilic attack at the para position, electronꢀdonating 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 3,4ꢀpyridine
precursor with 4ꢀmethyl 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 4ꢀmethyl morpholine. NꢀMethyl
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 1HꢀNMR spectroscopy using mesitylene as internal standard.
Encouraged by these interesting results, we next focused our attention on the threeꢀcomponent
reaction with benzyne, DABCO, and a nucleophile (Scheme 2.). The ringꢀopening 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 goodꢀtoꢀhigh 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. Threeꢀcomponent 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%
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isolated yield.
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Scheme 2. Threeꢀcomponent reaction of benzynes with DABCO and thiols.a
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aReaction conditions: oꢀsilyl 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. Thiophenol (excess) was used. Thiophenol (1 equiv.)
b
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d
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e
was used. Ratio of isomers (para : meta) determined by HꢀNMR spectroscopy. Isomeric mixture
fQuinuclidine (2 equiv.) was used instead of DABCO 2a’.
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Scheme 3. Threeꢀcomponent reactions of benzynes with DABCO and nucleophiles.
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aReaction conditions: oꢀsilyl aryl triflate 1a (0.1 mmol), DABCO 2a’ (2 equiv.), and CsF (1 equiv.) in
b
CH3CN:methyl acrylate (1:1, 0.1 M) at 100 °C, 18 h. KF (30 equiv.) was used instead of CsF.
cCH3CN:Nu (1:1, 0.1 M) was used. dRatio of isomers (para : meta) determined by 1HꢀNMR
spectroscopy.
Next, various sulfur nucleophiles were investigated for the threeꢀcomponent reaction to provide
access to 1ꢀethylꢀ4ꢀphenylpiperazineꢀcontaining derivatives. As shown in Scheme 2, various sulfur
nucleophiles were suitable partners to deliver the desired products. Thiols containing a 2ꢀnaphthyl, pꢀ
methylphenyl, 2,6ꢀdimethylphenyl, and acetyl group reacted to provide products 5k, 5l, 5m, and 5n in
goodꢀtoꢀhigh 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
2,4ꢀpentanedione participate in the ringꢀopening reaction of aryl DABCO ammonium salts to afford the
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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 2,4ꢀpentanedione, generating the targeted molecules 6e and 6f in
yields of 45% and 23%, respectively.
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Scheme 4. Proposed reaction mechanism.
O
O
O
2a
H3C
N
H
N
N
2a
ꢀOTf
3a'
CH3
3a
CH3
N
H3C
ꢀOTf
OTf
Fꢀ
O
TMS
SR
1a
SR
N
N
N
N
N
N
H
ꢀOTf
2a'
5a
5a'
RSꢀH
A possible mechanism for the formation of 4ꢀphenylmorpholine 3a from oꢀsilyl aryl triflates 1a via a
C‒N bond cleavage reaction of morpholine is illustrated in Scheme 4.7aꢀb The benzyne generated from
1a is attacked by a nucleophile such as 4ꢀmethylmorpholine 2a to generate intermediate ammonium
salt 3a’. Ammonium salt 3a’ is directly converted to 3a through the release of 4,4ꢀdimethyl
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 ringꢀopening reaction with the
aid of another nucleophile (Nu) would follow to afford 1ꢀethylꢀ4ꢀphenylpiperazine derivatives 5a.
Conclusion
In conclusion, we have demonstrated a new synthetic method utilizing benzyne, DABCO, and a
nucleophile for the construction of 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethylꢀcontaining derivatives via a oneꢀpot
process. This work represents the inert C‒N bond cleavage of tertiary amines activated by diverse
benzynes. Based on this result, a threeꢀcomponent reaction with benzyne, DABCO, and a nucleophile
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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 2,4ꢀpentanedione 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 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethyl moiety. Further investigations to
expand the scope of nucleophiles are currently in progress.
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Experimental Section
General.
Analytical thinꢀlayer 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 IRPrestigeꢀ21 from SHIMADZU. Highꢀresolution 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 SigmaꢀAldrich, TCI or Alfa Aesar. A
ll reactions were run in flameꢀ or ovenꢀdried glassware under an atmosphere of N2 gas with p
urchased dry solvents unless otherwise stated. Nuclear magnetic resonance spectra (1H NMR a
1
nd 13C NMR) were recorded with a Jeol (500 MHz, H at 500 MHz, 13C 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 4ꢀmethylmorpholine (22.0 ꢁL, 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
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filtered and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel to give the desired 4ꢀ(3,4ꢀdifluorophenyl)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 = 4.8Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 150.7 (dd, 1C, JCꢀF = 244.3, 13.1
Hz), 148.5 (dd, 1C, JCꢀF = 7.3, 2.3 Hz), 144.5 (dd, 1C, JCꢀF = 238.9, 12.8 Hz), 117.4 (d, 1C, JCꢀF = 17.6
Hz), 111.2 (q, 1C, JCꢀF = 2.9 Hz), 105.1 (d, 1C, JCꢀF = 20.2 Hz), 66.8, 49.7. IR: v 2962, 2855, 1601,
1518, 1451, 1380, 1305, 1230, 1145, 885 cmꢀ1; HRMS (EI) calcd. for C10H11F2NO [M]+: 199.0809.
Found: 199.0810.
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4-phenylmorpholine (3a). Compound 3a was synthesized according to general procedure A using 2ꢀ
(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), 4.18ꢀ4.07 (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 4ꢀfluoroꢀ2ꢀ(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
6.99ꢀ6.96 (m, 2H), 6.86ꢀ6.85 (m, 2H), 3.89ꢀ3.83 (m, 4H), 3.11ꢀ3.05 (m, 4H).
4-(3-fluorophenyl)morpholine (3b'). Compound 3b' was synthesized according to general
procedure A using 4ꢀfluoroꢀ2ꢀ(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), 6.59ꢀ6.54 (m, 2H), 3.87ꢀ3.82
(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 4ꢀchloroꢀ2ꢀ(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 7.23ꢀ7.20 (m, 2H), 6.84ꢀ6.81 (m, 2H), 3.85ꢀ
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3.83 (m, 4H), 3.12ꢀ3.10 (m, 4H). 3d' 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 8.0 Hz, 1H), 6.86ꢀ6.85
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(m, 1H), 6.84ꢀ6.81 (m, 1H), 6.78ꢀ6.76 (m, 1H) 3.85ꢀ3.83 (m, 4H) 3.15ꢀ3.13 (m, 4H).
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synthesized according to general procedure
A
using 4ꢀ(tertꢀbutyl)ꢀ2ꢀ(trimethylsilyl)phenyl
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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 7.32ꢀ7.28 (m, 2H), 6.88ꢀ6.85 (m, 2H), 3.86ꢀ
3.84 (m, 4H), 3.14ꢀ3.12 (m, 4H), 1.29 (s, 9H). 3e' 1H NMR (500 MHz, CDCl3) δ 7.22 (t, J = 7.9 Hz, 1H),
6.98ꢀ6.93 (m, 2H), 6.75ꢀ6.72 (m, 1H), 3.89ꢀ3.86 (m, 4H), 3.17ꢀ3.15 (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 cmꢀ1; 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 4ꢀmethylꢀ2ꢀ(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), 3.87ꢀ3.85 (m, 4H), 3.11ꢀ
3.01 (m, 4H), 2.27 (s, 3H). 3f' 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 6.74ꢀ6.71 (m, 3H),
3.87ꢀ3.85 (m, 4H), 3.16ꢀ3.14 (m, 4H), 2.32 (s, 3H).
4-(3-bromo-5-methylphenyl)morpholine (3g). Compound 3g was synthesized according to general
procedure A using 2ꢀbromoꢀ4ꢀmethylꢀ6ꢀ(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 4,5ꢀdimethylꢀ2ꢀ(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 2ꢀ(trimethylsilyl)naphthalenꢀ1ꢀyl 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
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procedure A using 2ꢀmethoxyꢀ6ꢀ(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).
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4-(3,4-dimethoxyphenyl)morpholine (3k). Compound 3k was synthesized according to general
procedure A using 4,5ꢀdimethoxyꢀ2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1k, 0.084 mmol)
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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), 3.87ꢀ
3.85 (m, 7H), 3.83 (s, 3H), 3.07ꢀ3.05 (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 cmꢀ1; 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 3ꢀ(trimethylsilyl)pyridinꢀ4ꢀyl 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 4ꢀ(trimethylsilyl)ꢀ1Hꢀindolꢀ5ꢀyl 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 4ꢀ(trimethylsilyl)ꢀ1Hꢀindolꢀ5ꢀyl 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 2ꢀ
(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 2ꢀ
(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
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temperature. Thiol (20.0 ꢁL, 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 1ꢀphenylꢀ4ꢀ(2ꢀ
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(phenylthio)ethyl)piperazine 5a (27 mg, 0.090 mmol, 84%) as colorless oil. Rf
=
0.4
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(EtOAc/Hexane=1/4). 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 5.2, 3.1 Hz, 2H), 7.31ꢀ7.25 (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 cmꢀ1; 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 4,5ꢀdimethylꢀ2ꢀ(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 cmꢀ1; 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
4,5ꢀdimethoxyꢀ2ꢀ(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 7.37ꢀ7.33 (m, 2H), 7.30ꢀ7.25 (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), 3.12ꢀ3.07 (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 cmꢀ1;
HRMS (EI) calcd. for C20H26N2O2S [M]+: 358.1715. Found: 358.1718.
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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 4ꢀmethylꢀ2ꢀ(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 7.38ꢀ7.35 (m, 2H), 7.29 (t, J = 7.8 Hz, 2H),
7.20ꢀ7.14 (m, 1H), 6.87ꢀ6.83 (m, 2H), 6.74 (d, J = 8.6 Hz, 2H), 3.17 (t, J = 5.0 Hz, 4H), 3.10 (t, J = 7.5
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Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.66ꢀ2.63 (m, 4H), 2.27 (s, 3H). 5d' H NMR (500 MHz, CDCl3) δ
7.38ꢀ7.35 (m, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.20ꢀ7.14 (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), 2.66ꢀ2.63 (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 cmꢀ1; 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 4ꢀ(tertꢀbutyl)ꢀ2ꢀ
(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), 7.31ꢀ7.26 (m, 2H), 7.21ꢀ7.16 (m, 1H), 6.99ꢀ6.97 (m, 2H), 6.88ꢀ6.85 (m, 2H), 3.22ꢀ3.16 (m,
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4H), 3.12ꢀ3.08 (m, 2H), 2.73ꢀ2.69 (m, 2H), 2.68ꢀ2.63 (m, 4H), 1.28 (s, 9H). 5e' H NMR (500 MHz,
CDCl3) δ 7.36 (td, J = 2.7, 1.6 Hz, 2H), 7.31ꢀ7.26 (m, 3H), 7.21ꢀ7.16 (m, 2H), 6.92 (d, J = 7.7 Hz, 1H),
6.74 (dd, J = 7.5, 2.5 Hz, 1H), 3.22ꢀ3.16 (m, 4H), 3.12ꢀ3.08 (m, 2H), 2.73ꢀ2.69 (m, 2H), 2.68ꢀ2.63 (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 cmꢀ1; 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 4ꢀchloroꢀ2ꢀ(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), 7.21ꢀ7.13 (m, 3H), 6.87ꢀ6.75 (m, 2H), 3.24ꢀ3.15 (m, 4H), 3.11 (t, J = 6.5 Hz, 2H), 2.75ꢀ2.62 (m,
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6H). 5f' 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.21ꢀ7.13 (m,
2H), 6.87ꢀ6.75 (m, 3H), 3.24ꢀ3.15 (m, 4H), 3.11 (t, J = 6.5 Hz, 2H), 2.75ꢀ2.62 (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 cmꢀ1; HRMS (EI) calcd. for C18H21ClN2S [M]+: 332.1114. Found:
332.1116.
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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 4ꢀfluoroꢀ2ꢀ
(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), 7.30ꢀ7.27 (m, 2H), 7.20ꢀ7.15 (m, 1H), 6.98ꢀ6.92 (m, 2H), 6.89ꢀ6.84 (m, 2H), 3.21ꢀ3.18 (m,
1
2H), 3.14ꢀ3.07 (m, 4H), 2.72ꢀ2.67 (m, 2H), 2.66ꢀ2.60 (m, 4H). 5g' H NMR (500 MHz, CDCl3) δ 7.35
(td, J = 2.9, 1.7 Hz, 2H), 7.30ꢀ7.27 (m, 2H), 7.20ꢀ7.15 (m, 2H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.57 (td,
J = 12.4, 2.4 Hz, 1H), 6.54ꢀ6.50 (m, 1H), 3.14ꢀ3.07 (m, 6H), 2.72ꢀ2.67 (m, 2H), 2.66ꢀ2.60 (m, 4H). 13
C
NMR (125 MHz, CDCl3, 5g+5g', regioisomer mixture) δ 163.9 (d, 1C, JCꢀF = 241.6 Hz), 157.3 (d, 1C,
JCꢀF = 237.3 Hz), 153.0 (d, 1C, JCꢀF = 10.0 Hz), 148.0 (d, 1C, JCꢀF = 2.3 Hz), 136.4, 136.3, 130.2 (d, 1C,
J
CꢀF = 10.0 Hz), 129.26, 129.23, 129.0, 126.14, 126.12, 118.0 (d, 1C, JCꢀF = 7.6 Hz), 115.6 (d, 1C, JCꢀF
= 21.9 Hz), 111.2 (d, 1C, JCꢀF = 2.4 Hz), 105.9 (d, 1C, JCꢀF = 21.4 Hz), 102.8 (d, 1C, JCꢀF = 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 cmꢀ1; 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 2ꢀmethoxyꢀ6ꢀ(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), 3.12ꢀ3.07 (m, 2H), 2.72ꢀ2.67 (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 cmꢀ1; HRMS (EI)
calcd. for C19H24N2OS [M]+: 328.1609. Found: 328.1612.
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1-(naphthalen-2-yl)-4-(2-(phenylthio)ethyl)piperazine (5i). Compound 5i was synthesized
according to general procedure B using 2ꢀ(trimethylsilyl)naphthalenꢀ1ꢀyl trifluoromethanesulfonate (1i,
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0.086 mmol) as colorless oil in 79% yield (23.7 mg, 0.068 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H
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NMR (500 MHz, CDCl3) δ 7.73ꢀ7.67 (m, 3H), 7.40ꢀ7.36 (m, 3H), 7.32ꢀ7.24 (m, 4H), 7.19 (t, J = 7.3 Hz,
1H), 7.11 (d, J = 2.0 Hz, 1H), 3.33ꢀ3.28 (m, 4H), 3.12 (t, J = 7.7 Hz, 2H), 2.74ꢀ2.69 (m, 6H). 13C 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 cmꢀ1; HRMS (EI) calcd. for C22H24N2S [M]+: 348.1660. Found: 348.1656.
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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
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oil in 74% yield (22.3 mg, 0.037 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H NMR (500 MHz, CDCl3,
regioisomer mixture) δ 7.50ꢀ7.47 (m, 1H), 7.46 (d, J = 8.8 Hz, 0.3H), 7.39ꢀ7.35 (m, 4H), 7.30 (q, J =
8.4 Hz, 5.5H), 7.21ꢀ7.17 (m, 2H), 7.10ꢀ7.04 (m, 2.3H), 6.98ꢀ6.94 (m, 1.3H), 6.91 (d, J = 1.7 Hz, 0.5H),
6.87ꢀ6.84 (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 cmꢀ1; 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 2ꢀ(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 7.81ꢀ7.74 (m, 4H), 7.50ꢀ7.42 (m, 3H), 7.29ꢀ7.25 (m, 2H), 6.95ꢀ6.91 (m, 2H), 6.87 (t, J =
7.3 Hz, 1H), 3.23ꢀ3.19 (m, 6H), 2.78ꢀ2.73 (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 cmꢀ1;
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
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procedure B using 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as colorless oil in
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76% yield (24 mg, 0.076 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H NMR (500 MHz, CDCl3) δ 7.31ꢀ
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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), 2.70ꢀ2.62 (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 cmꢀ1; HRMS (EI) calcd. for C19H24N2S [M]+: 312.1660.
Found: 312.1661.
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1-(2-((2,6-dimethylphenyl)thio)ethyl)-4-phenylpiperazine (5m). Compound 5m was synthesized
according to general procedure B using 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1
1
mmol) as colorless oil in 63% yield (20.7 mg, 0.063 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H NMR
(500 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 2H), 7.12ꢀ7.09 (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), 2.60ꢀ2.56 (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 cmꢀ1; 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 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as
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colorless oil in 75% yield (19.9 mg, 0.075 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H NMR (500 MHz,
CDCl3) δ 7.28ꢀ7.23 (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 cmꢀ1; 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 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as
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colorless oil in 47% yield (14.2 mg, 0.047 mmol). Rf = 0.5 (EtOAc/Hexane=1/2). H NMR (500 MHz,
CDCl3) δ 8.43ꢀ8.41 (m, 1H), 7.48ꢀ7.44 (m, 1H), 7.28ꢀ7.24 (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),
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3.23ꢀ3.20 (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 cmꢀ1; HRMS (EI) calcd. for C17H21N3S [M]+:
299.1456. Found: 299.1458.
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1-(2-(tert-butylthio)ethyl)-4-phenylpiperazine (5p). Compound 5p was synthesized according to
general procedure B using 2ꢀ(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 7.28ꢀ7.24 (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),
2.74ꢀ2.69 (m, 2H), 2.68ꢀ2.61 (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 cmꢀ1; 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 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as
1
colorless oil in 93% yield (28.6 mg, 0.093 mmol). Rf = 0.5 (EtOAc/Hexane=1/2). H NMR (500 MHz,
CDCl3) δ 7.34 (dd, J = 5.3, 1.2 Hz, 1H), 7.27ꢀ7.24 (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 cmꢀ1; 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 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1 mmol) as
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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), 7.45ꢀ7.40 (m, 1H), 7.29ꢀ7.25 (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,
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1612, 1555, 1453, 1376, 1307, 1137 cmꢀ1; HRMS (EI) calcd. for C21H23N3S [M]+: 349.1613. Found:
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2-((2-(4-phenylpiperazin-1-yl)ethyl)thio)-4,5-dihydrothiazole (5s). Compound 5s was synthesized
according to general procedure B using 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1a, 0.1
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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). 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
cmꢀ1; 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 2ꢀ(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), 7.43ꢀ7.39 (m, 1H), 7.31ꢀ7.24 (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, 1131, 993 cmꢀ1; 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 2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate
1
(1a, 0.1 mmol) as colorless oil in 46% yield (16.5 mg, 0.046 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H
NMR (500 MHz, CDCl3) δ 7.28ꢀ7.23 (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), 2.72ꢀ2.58 (m, 8H), 2.04 (s, 3H), 1.86 (d, J = 2.6 Hz, 6H), 1.71ꢀ1.64 (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 cmꢀ1; 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
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colorless oil in 46% yield (13.8 mg, 0.046 mmol). Rf = 0.5 (EtOAc/Hexane=1/4). H NMR (500 MHz,
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(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), 1.69ꢀ1.55 (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 cmꢀ1; HRMS (EI) calcd. for C19H23NS [M]+: 297.1551.
Found: 297.1552.
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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 2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)ethyl acrylate 6a (10.8 mg,
0.041 mmol, 41%) as colorless oil. Rf = 0.5 (EtOAc only). 1H NMR (500 MHz, CDCl3) δ 7.28ꢀ7.23 (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 cmꢀ1; 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 4ꢀmethylꢀ2ꢀ(trimethylsilyl)phenyl
trifluoromethanesulfonate (1f, 0.096 mmol) as colorless oil in 33% yield (8.7 mg, 0.032 mmol). Rf =
1
0.5 (EtOAc only). 6b H 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), 2.71ꢀ2.66 (m, 4H), 2.31 (s, 3H).
6b' 1H NMR (500 MHz, CDCl3) δ 7.15 (t, J = 7.7 Hz, 1H), 6.76ꢀ6.71 (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), 2.71ꢀ2.66 (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,
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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 cmꢀ1; HRMS (EI) calcd. for C16H22N2O2
[M]+: 274.1681. Found: 274.1678.
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2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl acrylate (6c). Compound 6c was synthesized according to
general procedure C using 4ꢀfluoroꢀ2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1b, 0.095 mmol)
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as colorless oil in 20% yield (5.4 mg, 0.019 mmol). H NMR (500 MHz, CDCl3) δ 6.97ꢀ6.93 (m, 2H),
6.88ꢀ6.85 (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), 3.12ꢀ3.10 (m, 4H), 2.74 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.0 Hz,
4H). 13C NMR (125 MHz, CDCl3) δ 166.1, 157.3 (d, 1C, JCꢀF = 237.4 Hz), 148.0 (d, 1C, JCꢀF = 2.4 Hz),
130.9, 128.4, 117.1 (d, 2C, JCꢀF = 7.6 Hz), 115.6 (d, 2C, JCꢀF = 22.0 Hz), 62.0, 56.6, 53.4, 50.2. IR: v
2924, 2823, 1723, 1634, 1510, 1454, 1407, 1357, 1332, 1233 cmꢀ1; 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 4ꢀfluoroꢀ2ꢀ(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), 3.20ꢀ3.18 (m, 4H), 2.73 (t, J = 6.0 Hz, 2H), 2.67ꢀ
2.65 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 166.1, 164.0 (d, 1C, JCꢀF = 241.6 Hz), 153.0 (d, 1C, JCꢀF
9.6 Hz), 130.9, 130.2 (d, 1C, JCꢀF = 9.8 Hz), 128.4, 111.2 (d, 1C, JCꢀF = 2.4 Hz), 105.9 (d, 1C, JCꢀF
=
=
21.4 Hz), 102.7 (d, 1C, JCꢀF = 24.9 Hz), 62.0, 56.6, 53.2, 48.6. IR: v , 2952, 2848, 1724, 1633, 1581,
1495, 1407, 1357, 1294 cmꢀ1; 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 4ꢀmethylꢀ2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (1f, 0.096 mmol) as
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colorless oil in 32% yield (8 mg, 0.030 mmol). Rf = 0.4 (EtOAc only). H NMR (500 MHz, CDCl3) δ
7.29ꢀ7.23 (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), 2.72ꢀ2.64 (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,
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1240, 1152 cmꢀ1; HRMS (EI) calcd. for C14H20N2O2 [M]+: 248.1525. Found: 248.1525.
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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 2ꢀ(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 7.29ꢀ7.24 (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 cmꢀ1;
HRMS (EI) calcd. for C17H24N2O2 [M]+: 288.1838. Found: 288.1840.
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1-(2-fluoroethyl)-4-phenylpiperazine (6e). Compound 6e was synthesized according to general
procedure C using 2ꢀ(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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Supporting Information. Copies of the H and 13C NMR spectra for products 3ꢀ6. This material
is available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: hayeminko@wku.ac.kr
ORCID
Haye Min Ko: 0000ꢀ0003ꢀ2807ꢀ9980
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 (NRFꢀ
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2015R1C1A2A01051829, 2017R1A4A1015594).
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