Molecular Iodine-Mediated Difunctionalization of Alkenes with Nitriles and Thiols Leading to β-Acetamido Sulfides

Article abstract of DOI:10.1021/acs.joc.5b02579

A direct difunctionalization protocol of alkenes with nitriles and thiols toward β-acetamido sulfide derivatives has been proposed under metal-free synthesis conditions. The present protocol provides the facile and highly efficient synthesis of various β-acetamido sulfides in a scaled-up manner with good to excellent yields simply using inexpensive molecular iodine as a catalyst, DMSO as a mild oxidant, and readily available thiols as thiolating reagents.

Full text of DOI:10.1021/acs.joc.5b02579

Article
pubs.acs.org/joc
Molecular Iodine-Mediated Difunctionalization of Alkenes with
Nitriles and Thiols Leading to β‑Acetamido Sulfides
Huanhuan Cui, Xiaoxia Liu, Wei Wei,* Daoshan Yang, Chenglong He, Tiantian Zhang, and Hua Wang*
The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine,
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong China
S
* Supporting Information
ABSTRACT: A direct difunctionalization protocol of alkenes
with nitriles and thiols toward β-acetamido sulfide derivatives
has been proposed under metal-free synthesis conditions. The
present protocol provides the facile and highly efficient
synthesis of various β-acetamido sulfides in a scaled-up
manner with good to excellent yields simply using inexpensive
molecular iodine as a catalyst, DMSO as a mild oxidant, and
readily available thiols as thiolating reagents.
Scheme 1. Methods for the Synthesis of β-Acetamido Sulfide
Derivatives
INTRODUCTION
■
The synthetic pursuit of sulfur-containing compounds has been
strong among chemists in both academic and industrial
communities due to their extensive applications in organic
synthesis,1 the pharmaceutical industry,2 and materials science.3
The introduction of a sulfanyl group to an unsaturated carbon−
carbon bond represents one of most powerful and reliable
procedures for the synthesis of organosulfur compounds.4 In
particular, the difunctionalization of alkenes with thiolation
agents and other functional groups could provide rapid and
concise access to diverse sulfur-containing organic materials in a
single pot operation.5−9 Over the past several years, some
useful organosulfur compounds have been successfully
synthesized through the difunctionalization of alkenes, such
as alkoxythiolation,5 hydroxythiolation,6 acetoxythiolation,7
sulfamination,8 and disulfidation.9 However, there is still great
demand for the development of some convenient and efficient
difunctionalization reaction systems to afford structurally
diverse functional sulfur compounds of great importance.
β-Acetamido sulfides, an important class of sulfur-containing
molecules, are widely presented in various biologically active
compounds and natural products.10 Furthermore, they can also
serve as versatile building blocks for various organic trans-
formations toward many useful compounds.11 Generally, the
acetamidosulfidation of alkenes with nitriles and preformed
benzenesulfenanilides or disulfides can give β-acetamido sulfide
derivatives in the presence of a stoichiometric amount of a
transition-metal catalyst or strong acid (Scheme 1, (1)).12 An
alternative method for the synthesis of β-acetamido sulfide
derivatives from oxiranes, PhSNa, and nitrile has also been
developed (Scheme 1, (2)).13 Nevertheless, most of these
reactions might suffer from certain limitations, such as the need
for prefunctionalized thiolating reagents, limited substrate
scope, harsh reaction conditions, low atom economy, poor
regioselectivity, or toxic metal catalysts. Therefore, it remains a
challenging but attractive task to develop more direct,
economic, efficient, and environmentally benign methods to
construct β-acetamido sulfide derivatives.
From a synthetic standpoint, the direct use of thiols as
thiolating reagents for the functionalization of olefins is an ideal
method for constructing β-acetamido sulfides because it offers
the advantages of easy availability, low cost, and high atom
economy.14 With our continuous interest in metal-free
difunctionalization of alkenes,15 we wish to report here a
simple, economic, and efficient method for the selective
synthesis of β-acetamido sulfide compounds via direct metal-
free difunctionalization of alkenes with various thiols and
nitriles (Scheme 1, (3)). A series of biologically important β-
acetamido sulfide derivatives were selectively synthesized with
Received: November 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02579
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good to excellent yields in a simple way use inexpensive
molecular iodine as a catalyst, DMSO as a mild oxidant, and
commercially available thiols as thiolating reagents.
temperature proved that 80 °C was appropriate for this
reaction (entries 8 and 20−22). Finally, the desired product
was obtained in 93% yield when the model reaction was
performed in dry nitriles, suggesting that anhydrous reagents
have no obvious impact on the reaction efficiency (entry 23).
Under the optimized conditions, the scope of the
difunctionalization reaction of styrene with acetonitrile and
various thiols was explored with the results summarized in
Table 2. In general, aryl thiols containing electron-rich or -poor
groups on the aryl rings could readily participate in the
reactions, affording the desired products in good to excellent
yields (4aa−4ak). It was found that the reaction was not
significantly affected by the steric effect. The sterically
congested ortho- or meta-substituted aryl thiols were also
effectively reacted with styrene and acetonitrile to achieve
products 4ad−4ah in good yields. 2-Naphthalenethiol could
also be used in the reactions to give expected product 4al in
88% yield. Notably, various alkyl thiols, such as phenyl-
methanethiol, 2-phenylethanethiol, and thiols with long
aliphatic chains, could also be compatible with the reactions
to deliver corresponding products 4am−4ar in good yields.
Moreover, the participation of various alkenes and nitriles in
this protocol was examined (Table 3). The reactions also
proceeded well using aromatic alkenes with an electron-
donating or -withdrawing group on the aromatic ring to give
the desired products in moderate to good yields (4ba−4ha). As
expected, 2-vinylnaphthalene was also compatible with the
reactions with the desired product 4ia obtained in 64% yield. It
is noteworthy that aliphatic alkenes (i.e., cyclooctane, 1-hexene,
and 1-octene) were all tolerated in the reactions, yet they might
obtain the corresponding products (4ka−4oa) in moderate
yields. Moreover, the difunctionalization reaction proceeded
with excellent stereoselectivity when internal alkenes were used
in the present reaction system. For example, (E)-β-methylstyr-
ene gave 4la in 40% yield with good stereoselectivity, and
cyclooctane, (E)-oct-4-ene, and (Z)-oct-4-ene gave the
corresponding stereospecific products 4ka−4ma in moderate
to good yields, respectively. The scope of this difunctionaliza-
tion reaction was further expanded to a variety of nitriles. In
addition to 3a, herein a series of substituted nitriles containing
long aliphatic chains or aromatic ring group were all suitable
substrates, generating the corresponding products 4aab−4aag
in good yields.
RESULTS AND DISCUSSION
■
Initially, the reaction of styrene (1a), 4-methylbenzenethiol
(2a), and CH3CN (3a) was selected as the model reaction to
optimize various reaction conditions. In the absence of a
transition-metal catalyst, various iodide-containing reagents
were investigated using DMSO as the oxidant. As shown in
Table 1, none of the desired product was detected when KI,
a
Table 1. Optimization of the Reaction Conditions
iodine reagent
(mol %)
T
(°C)
yield
b
entry
oxidant (equiv)
(%)
1
KI (20)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
PhI(AcO)2 (1.5)
K2S2O8 (1.5)
H2O2 (1.5)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
25
60
100
80
0
0
2
NaI (20)
TBAI (20)
I2 (20)
3
0
4
83
0
5
6
I2 (5)
34
58
94
92
94
71
53
72
62
42
<10
74
25
0
7
I2 (10)
I2 (30)
I2 (40)
I2 (50)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Oxone (1.5)
C12H25S(O)Me (1.5)
O2
DMSO (1.0)
DMSO (0.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
DMSO (1.5)
trace
84
92
c
93
Furthermore, the potential synthetic applicability of this
method was investigated on a gram scale using the model
reaction. As shown in Scheme 2, the reaction could afford 2.51
g of 4aa in 88% yield without any significant loss of its
efficiency, demonstrating the potential applications of the
present method for a large scale synthesis of β-acetamido
sulfide derivatives.
a
Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), iodine
reagent (0−50% equiv), oxidant (0−1.5 equiv), CH3CN 3a (2 mL,
b
47.8 mmol), 25−100 °C, 24 h. Isolated yields based on 1a. TBAI =
c
(n-Bu)4NI; DMSO = dimethyl sulfoxide. Dry CH3CN 3a (2 mL, 47.8
mmol).
For further insights into this reaction to be obtained, two
control experiments were newly carried out under the standard
conditions (Scheme 3). When thiophenol 2b was added
independently under the standard conditions, the correspond-
ing diphenyl sulfide (5b) was isolated in 90% yield at 2 h
(Scheme 3, (a)). Furthermore, when styrene (1a), diphenyl
sulfide (5b), and CH3CN (3a) reactions were conducted under
the standard conditions in the presence of H2O (1.5 equiv),
desired product 4ab was isolated in 92% (Scheme 3, (b)). The
above result suggested that diphenyl sulfide might be an
intermediate in the present reaction system.
NaI, or TBAI was separately used as the catalyst (entries 1−3).
To our delight, desired β-acetamido sulfide 4aa was obtained in
83% yield when the reaction was carried out by employing
molecular iodine (20 mol %) (entry 4). Further optimization of
catalyst loading demonstrated that 30 mol % of iodine was the
best choice, affording product 4aa in 94% yield (entry 8).
Moreover, no conversion was observed when the reaction was
performed in the absence of molecular iodine (entry 5). The
use of other oxidants did not improve the reaction efficiency
(entries 11−16). In addition, the reaction efficiency was
obviously low with decreasing DMSO loading, and no reaction
occurred in the absence of DMSO (entries 17−19).
Subsequent investigation on the effect of the reaction
A possible reaction pathway was thus proposed as Scheme 4
for this difunctionalization of alkenes. Initially, the interaction
B
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a
Table 2. Results for the Molecular-Iodine Mediated Difunctionalization of Styrene with Acetonitrile and Various Thiols
a
Reaction conditions: 1a (0.25 mmol), 2 (0.375 mmol), 3a (2.0 mL, 47.8 mmol), I2 (30 mol %, 0.075 mmol), DMSO (1.5 equiv, 0.375 mmol), 80
°C, 24−30 h. Isolated yields based on 1a.
of molecular iodine with thiol 2 generated disulfide 5 with the
concomitant formation of HI.16a,d Formed disulfide 5 reacted
with iodine to give electrophilic species R3−SI 6.16
Furthermore, the electrophilic attack of R3−SI 6 to alkene 1
gave thiiranium ion intermediate 7.17 Next, intermediate 7 was
selectively attacked by nitrile 3, followed by hydrolysis (Ritter-
type reaction) to produce the desired β-acetamido sulfide
derivatives with the release of HI.12a,c,d It should be noted that
the ring opening of a thiiranium ion by an attack of iodide ion
followed by displacement of nitrile via an SN2 reaction might
also be involved in this transformation to some extent. Finally,
DMSO would oxidize two equiv of HI into molecular iodine to
participate in the catalytic cycle along with the generation of
water and dimethyl sulfide with a bad smell.18
CONCLUSIONS
■
In conclusion, a facile and atom-economical method has been
successfully developed for the synthesis of β-acetamido sulfides
through the metal-free direct difuctionalization of alkenes with
thiols and nitriles. A series of structurally diverse β-acetamido
sulfide derivatives could be effectively obtained from various
readily available starting materials in the I2/DMSO system by
mild heating. The difunctionalization reactions proceeded with
good regioselectivity, and no regioisomers were observed in the
present reaction system. Taking into account the combination
of some desirable features, such as operation simplicity, atom
efficiency, good tolerance to scale-up synthesis, good
regioselectivity and stereoselectivity, as well as readily available
catalyst and oxidant of low toxicity, this synthesis procedure
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Table 3. Results for the Molecular Iodine-Mediated Difunctionalization of Various Alkenes with Nitriles and 4-
ab
,
Methylbenzenethiol
a
Reaction conditions: 1 (0.25 mmol), 2a (0.375 mmol), 3 (2 mL: 3a, 47.8 mmol; 3b, 23.0 mmol; 3c, 22.0 mmol; 3d, 19.1 mmol; 3e, 16.5 mmol; 3f,
b
19.6 mmol; 3g, 16.7 mmol), I2 (30 mol %, 0.075 mmol), DMSO (1.5 equiv, 0.375 mmol), 80 °C, 24−36 h. Isolated yields based on 1; the value of
dr was determined by H NMR. From (E)-β-methylstyrene. From (Z)-hex-3-ene. From (E)-hex-3-ene.
c
d
e
1
Scheme 2. Gram Scale Reaction
D
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Scheme 3. Control Experiments
N-(1-Phenyl-2-(phenylthio)ethyl)acetamide (4ab). Compound
4ab14 was obtained in 87% yield (58.7 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow oil. H
Scheme 4. Postulated Reaction Pathway
1
NMR (CDCl3, 400 MHz): δ 7.41−7.38 (m, 2H), 7.37−7.33 (m, 2H),
7.32−7.28 (m, 5H), 7.24−7.20 (m, 1H), 6.19 (d, J = 7.2 Hz, 1H), 5.21
(q, J = 6.9 Hz, 1H), 3.42 (dd, J1 = 7.0 Hz, J2 = 13.6 Hz, 1H), 3.32 (dd,
J1 = 6.3 Hz, J2 = 13.6 Hz, 1H), 1.96 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 169.6, 140.3, 135.6, 129.8, 129.1, 128.8, 127.9, 126.7, 126.5,
53.0, 39.8, 23.3. HRMS calcd for C16H18NOS [M + H]+, 272.1109;
found, 272.1112.
N-(2-(4-Methoxyphenylthio)-1-phenylethyl)acetamide (4ac).
Compound 4ac14 was obtained in 99% yield (74.6 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white
1
solid; mp 98.7−99.7 °C. H NMR (CDCl3, 400 MHz): δ 7.38−7.35
(m, 2H), 7.33−7.32 (m, 2H), 7.29−7.24 (m, 3H), 6.87−6.84 (m, 2H),
6.17 (d, J = 7.4 Hz, 1H), 5.12 (q, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.28−
3.19 (m, 2H), 1.98 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.5,
159.3, 140.6, 133.7, 128.7, 127.7, 126.6, 125.5, 114.8, 55.4, 53.0, 41.8,
23.3. HRMS calcd for C17H20NO2S [M + H]+, 302.1215; found,
302.1217.
would serve as a practical and efficient protocol to synthesize β-
acetamido sulfide derivatives.
EXPERIMENTAL SECTION
■
N-(1-Phenyl-2-(o-tolylthio)ethyl)acetamide(4ad). Compound
4ad14 was obtained in 87% yield (62.4 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white solid; mp
General. Chemicals were commercially available and used without
further purification unless otherwise stated. All solvents were used as
received without further purification unless otherwise stated. 1H NMR
and 13C NMR spectra were obtained in CDCl3 with TMS as
1
97.1−99.0 °C. H NMR (CDCl3, 400 MHz): δ 7.42−7.29 (m, 6H),
theinternal standard (400 or 500 MHz H and 100 or 125 MHz 13C)
1
7.20−7.14 (m, 3H), 6.15 (d, J = 7.2 Hz, 1H), 5.21 (q, J = 7.1 Hz, 1H),
3.39 (dd, J1 = 7.2 Hz, J2 = 13.4 Hz, 1H), 3.28 (dd, J1 = 6.3 Hz, J2 =
13.4 Hz, 1H), 2.37 (s, 3H), 1.98 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 169.6, 140.5, 138.3, 134.8, 130.3, 129.3, 128.8, 127.9, 126.7,
126.6, 126.5, 53.0, 39.2, 23.3, 20.5. HRMS calcd for C17H20NOS [M +
H]+, 286.1266; found, 286.1269.
at room temperature; the chemical shifts (δ) were expressed in ppm,
and J values were given in Hz. The following abbreviations are used to
indicate the multiplicity: singlet (s), doublet (d), triplet (t), quartet
(q), doublet of doublets (dd), doublet of triplets (dt), doublet of
quartets (dq), and multiplet (m). All first order splitting patterns were
assigned on the basis of the appearance of the multiplet. Splitting
patterns that could not be easily interpreted were designated as
multiplet (m). In a few cases, the number of signals in the 13C NMR
spectrum is less than expected, which may be caused by the
superimposition of signals. HRMS data were obtained by ESI on a
TOF mass analyzer. Column chromatography was performed on silica
gel (200−300 mesh).
N-(2-(2,4-Dimethylphenylthio)-1-phenylethyl)acetamide (4ae).
Compound 4ae was obtained in 84% yield (62.5 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a
yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.37−7.33 (m, 2H), 7.32−
7.27 (m, 4H), 7.03 (s, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.20 (d, J = 7.3
Hz, 1H), 5.15 (q, J = 7.3 Hz, 1H), 3.30 (dd, J1 = 7.4 Hz, J2 = 13.4 Hz,
1H), 3.30 (dd, J1 = 6.1 Hz, J2 = 13.4 Hz, 1H), 2.36 (s, 3H), 2.31 (s,
3H), 1.98 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.5, 140.7,
138.8, 136.8, 131.3, 130.9, 130.8, 128.7, 127.7, 127.4, 126.6, 53.0, 39.9,
23.3, 20.9, 20.5. HRMS calcd for C18H22NOS [M + H]+, 300.1422;
found, 300.1425.
General Experimental Procedures. To a 25 mL round-
bottomed flask was added alkene 1 (0.25 mmol), thiol 2 (0.38
mmol), nitrile 3 (2.0 mL), I2 (30 mol %, 0.075 mmol), and DMSO
(1.5 equiv, 0.38 mmol). The reaction vessel was allowed to stir at 80
°C for 24−36 h. After the reaction, the solvent was removed under a
vacuum. The residue was purified by flash column chromatography
using a mixture of petroleum ether and ethyl acetate as eluent to give
desired product 4. Caution! Thiols and byproduct dimethylsulfide have a
bad smell, and ventilation should be used while carrying out this reaction.
N-(1-Phenyl-2-(p-tolylthio)ethyl)acetamide (4aa). Compound
4aa14 was obtained in 94% yield (67.0 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow solid; mp
N-(1-Phenyl-2-(m-tolylthio)ethyl)acetamide (4af). Compound 4af
was obtained in 88% yield (62.8 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow oil. H
NMR (CDCl3, 400 MHz): δ 7.37−7.33 (m, 2H), 7.31−7.28 (m, 3H),
7.20−7.17 (m, 3H), 7.04−7.02 (m, 1H), 6.26 (d, J = 7.2 Hz, 1H), 5.22
(q, J = 6.9 Hz, 1H), 3.42−3.37 (dd, J1 = 7.0 Hz, J2 = 13.5 Hz, 1H),
3.34−3.29 (dd, J1 = 6.2 Hz, J2 = 13.5 Hz, 1H), 2.34 (s, 3H), 1.97 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 169.6, 140.5, 138.9, 135.4,
130.4, 128.9, 128.7, 127.8, 127.4, 126.8, 126.7, 53.0, 39.8, 23.2, 21.3.
HRMS calcd for C17H20NOS [M + H]+, 286.1266; found, 286.1271.
N-(2-(2-Chlorophenylthio)-1-phenylethyl)acetamide (4ag). Com-
pound 4ag14 was obtained in 89% yield (67.7 mg) according to the
general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow
oil. 1H NMR (CDCl3, 400 MHz): δ 7.48 (dd, J1 = 1.5 Hz, J2 = 7.8 Hz,
1
72.4−74.1 °C. H NMR (CDCl3, 400 MHz): δ 7.35−7.26 (m, 7H),
7.12 (d, J = 8.1 Hz, 2H), 6.36 (d, J = 7.3 Hz, 1H), 5.16 (q, J = 7.2 Hz,
1H), 3.36−3.24 (m, 2H), 2.34 (s, 3H), 1.96 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 169.7, 140.6, 136.8, 131.7, 130.7, 129.9, 128.7,
127.7, 126.6, 53.0, 40.6, 23.2, 21.0. HRMS calcd for C17H20NOS [M +
H]+, 286.1266; found, 286.1263.
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1H), 7.39−7.30 (m, 6H), 7.23 (dt, J1 = 1.4 Hz, J2 = 7.5 Hz, 1H), 7.15
(dt, J1 = 1.6 Hz, J2 = 7.8 Hz, 1H), 6.24 (d, J = 7.2 Hz, 1H), 5.22 (q, J =
6.8 Hz, 1H), 3.48−3.43 (dd, J1 = 6.8 Hz, J2 = 13.6 Hz, 1H), 3.36−3.31
(dd, J1 = 6.7 Hz, J2 = 13.5 Hz, 1H), 2.00 (s, 3H). 13C NMR (CDCl3,
100 MHz): δ 169.7, 140.0, 134.7, 134.3, 130.2, 129.8, 128.8, 128.0,
127.4, 127.3, 126.7, 52.7, 38.6, 23.3. HRMS calcd for C16H17ClNOS
[M + H]+, 306.0719; found, 306.0721.
5H), 7.20 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.2 Hz, 2H), 6.08 (s, 1H),
5.17 (q, J = 6.4 Hz, 1H), 3.00−2.91 (m, 2H), 2.82 (t, J = 7.7 Hz, 2H),
2.67−2.64 (m, 2H), 2.03 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ
169.6, 140.7, 140.2, 128.8, 128.5, 128.5, 127.8, 126.5, 126.4, 52.5, 38.1,
36.2, 33.9, 23.4. HRMS calcd for C18H22NOS [M + H]+, 300.1422;
found, 300.1427.
N-(2-(Butylthio)-1-phenylethyl)acetamide (4ao). Compound 4ao
N-(2-(3-Chlorophenylthio)-1-phenylethyl)acetamide (4ah). Com-
pound 4ah was obtained in 88% yield (67.1 mg) according to the
general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow
was obtained in 70% yield (43.7 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow oil. H
NMR (CDCl3, 400 MHz): δ 7.37−7.28 (m, 5H), 6.30 (d, J = 7.2 Hz,
1H), 5.18 (q, J = 6.5 Hz, 1H), 2.99−2.90 (m, 2H), 2.42 (t, J = 7.3 Hz,
2H), 2.03 (s, 3H), 1.54−1.48 (m, 2H), 1.39−1.33 (m, 2H), 0.89 (t, J =
7.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.6, 140.9, 128.7,
127.7, 126.5, 52.5, 38.1, 32.2, 31.6, 23.3, 21.9, 13.6. HRMS calcd for
C14H22NOS [M + H]+, 252.1422; found, 252.1425.
1
oil. H NMR (CDCl3, 400 MHz): δ 7.38−7.28 (m, 6H), 7.26−7.15
(m, 3H), 6.12 (d, J = 7.2 Hz, 1H), 5.22 (q, J = 6.8 Hz, 1H), 3.50−3.45
(dd, J1 = 6.5 Hz, J2 = 13.5 Hz, 1H), 3.33−3.28 (dd, J1 = 6.8 Hz, J2 =
13.6 Hz, 1H), 2.00 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.6,
139.8, 137.9, 134.7, 130.0, 128.9, 128.8, 128.1, 127.2, 126.7, 126.4,
53.0, 39.2, 23.3. HRMS calcd for C16H17ClNOS [M + H]+, 306.0719;
found, 306.0723.
N-(2-(Pentylthio)-1-phenylethyl)acetamide (4ap). Compound 4ap
was obtained in 76% yield (50.2 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow oil. H
N-(2-(4-Chlorophenylthio)-1-phenylethyl)acetamide (4ai). Com-
pound 4ai was obtained in 92% yield (70.3 mg) according to the
general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow
solid; mp 118.3−119.9 °C. 1H NMR (CDCl3, 400 MHz): δ 7.37−7.33
(m, 2H), 7.32−7.24 (m, 7H), 6.18 (d, J = 7.3 Hz, 1H), 5.17 (q, J = 7.0
Hz, 1H), 3.42 (dd, J1 = 6.8 Hz, J2 = 13.6 Hz, 1H), 3.27 (dd, J1 = 6.8
Hz, J2 = 13.6 Hz, 1H), 1.98 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
169.6, 140.0, 134.1, 132.5, 131.1, 129.2, 128.8, 128.0, 126.7, 53.0, 39.8,
23.3. HRMS calcd for C16H17ClNOS [M + H]+, 306.0719; found,
306.0721.
N-(2-(4-Bromophenylthio)-1-phenylethyl)acetamide (4aj). Com-
pound 4aj was obtained in 90% yield (78.4 mg) according to the
general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow
solid; mp 134.7−137.1 °C. 1H NMR (CDCl3, 400 MHz): δ 7.42−7.38
(m, 2H), 7.37−7.31 (m, 3H), 7.28−7.23 (m, 4H), 6.13 (d, J = 7.4 Hz,
1H), 5.17 (q, J = 6.9 Hz, 1H), 3.43 (dd, J1 = 6.7 Hz, J2 = 13.5 Hz, 1H),
3.27 (dd, J1 = 6.8 Hz, J2 = 13.6 Hz, 1H), 1.99 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 169.6, 140.0, 134.8, 132.1, 131.2, 128.9, 128.1,
126.7, 120.4, 52.9, 39.5, 23.3. HRMS calcd for C16H17BrNOS [M +
H]+, 350.0214; found, 350.0217.
NMR (CDCl3, 500 MHz): δ 7.34 (t, J = 7.2 Hz, 2H), 7.30−7.26 (m,
3H), 6.04 (d, J = 6.5 Hz, 1H), 5.18 (q, J = 6.4 Hz, 1H), 2.99−2.92 (m,
2H), 2.39 (t, J = 6.9 Hz, 2H), 2.05 (s, 3H), 1.54−1.49 (m, 2H), 1.29−
1.26 (m, 4H), 0.88 (t, J = 6.5 Hz, 3H). 13C NMR (CDCl3, 125 MHz):
δ 169.6, 140.8, 128.7, 127.7, 126.5, 52.5, 38.0, 32.5, 31.0, 29.3, 23.3,
22.2, 14.0. HRMS calcd for C15H24NOS [M + H]+, 266.1579; found,
266.1581.
N-(2-(Hexylthio)-1-phenylethyl)acetamide (4aq). Compound 4aq
was obtained in 66% yield (46 mg) according to the general procedure
(acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow oil. 1H NMR
(CDCl3, 500 MHz): δ 7.34 (t, J = 7.4 Hz, 2H), 7.30−7.26 (m, 3H),
6.04 (d, J = 6.2 Hz, 1H), 5.18 (q, J = 6.3 Hz, 1H), 3.00−2.92 (m, 2H),
2.39 (t, J = 7.4 Hz, 2H), 2.05 (s, 3H), 1.52−1.50 (m, 2H), 1.30−1.23
(m, 6H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 125 MHz): δ
169.5, 140.8, 128.7, 127.7, 126.5, 52.4, 38.1, 32.6, 31.4, 29.5, 28.5, 23.4,
22.5, 14.0. HRMS calcd for C16H26NOS [M + H]+, 280.1735; found,
280.1739.
N-(2-(Octylthio)-1-phenylethyl)acetamide (4ar). Compound 4ar
was obtained in 70% yield (53.6 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow oil. H
N-(1-Phenyl-2-(4-(trifluoromethyl)phenylthio)ethyl)acetamide
(4ak). Compound 4ak was obtained in 79% yield (66.6 mg) according
to the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a
white solid; mp 104.7−105.3 °C. 1H NMR (CDCl3, 500 MHz): δ 7.42
(d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.28−7.19 (m, 5H), 6.03
(s, 1H), 5.12 (q, J = 6.8 Hz, 1H), 3.49 (dd, J1 = 6.2 Hz, J2 = 13.6 Hz,
1H), 3.24 (dd, J1 = 7.3 Hz, J2 = 13.5 Hz, 1H), 1.91 (s, 3H). 13CNMR
(CDCl3, 125 MHz): δ 169.8, 141.2, 139.5, 129.0, 128.3, 128.0, 126.8,
125.7 (q, J = 4.1 Hz), 124.1 (q, J = 298.9 Hz), 53.0, 38.0, 23.3. HRMS
calcd for C17H17F3NOS [M + H]+, 340.0983; found, 340.0984.
N-(2-(Naphthalen-2-ylthio)-1-phenylethyl)acetamide (4al). Com-
pound 4al was obtained in 88% yield (70.4 mg) according to the
general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow
oil. 1H NMR (CDCl3, 500 MHz): δ 7.73 (s, 1H), 7.70−7.65 (m, 3H),
7.40−7.32 (m, 3H), 7.26−7.17 (m, 5H), 6.11 (s, 1H), 5.17 (q, J = 6.6
Hz, 1H), 3.44 (dd, J1 = 6.8 Hz, J2 = 13.6 Hz, 1H), 3.31 (dd, J1 = 6.4
Hz, J2 =13.6 Hz, 1H), 1.86 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ
169.8, 140.2, 133.8, 133.0, 131.9, 128.8, 128.6, 128.0, 127.7, 127.6,
127.5, 127.2, 126.7, 126.7, 125.9, 53.1, 39.4, 23.3. HRMS calcd for
C20H20NOS [M + H]+, 322.1266; found, 322.1269.
N-(2-(Benzylthio)-1-phenylethyl)acetamide (4am). Compound
4am14 was obtained in 72% yield (51.6 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow solid; mp
108.1−109.3 °C. 1H NMR (CDCl3, 500 MHz): δ 7.35−7.29 (m, 5H),
7.26−7.23 (m, 5H), 5.91 (d, J = 6.2 Hz, 1H), 5.17 (q, J = 6.7 Hz, 1H),
3.61−3.54 (m, 2H), 2.89−2.80 (m, 2H), 1.99 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 169.7, 140.8, 138.0, 129.0, 128.7, 128.6, 127.7,
127.2, 126.5, 52.2, 37.2, 36.4, 23.3. HRMS calcd for C17H20NOS [M +
H]+, 286.1266; found, 286.1269.
NMR (CDCl3, 500 MHz): δ 7.34 (t, J = 7.3 Hz, 2H), 7.30−7.26 (m,
3H), 6.07 (d, J = 5.2 Hz, 1H), 5.18 (q, J = 6.5 Hz, 1H), 2.99−2.92 (m,
2H), 2.39 (t, J = 7.4 Hz, 2H), 2.04 (s, 3H), 1.52−1.48 (m, 2H), 1.29−
1.25 (m, 10H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 125
MHz): δ 169.5, 140.8, 128.7, 127.7, 126.5, 52.4, 38.1, 32.6, 31.8, 29.5,
29.2, 29.1, 28.8, 23.4, 22.7, 14.1. HRMS calcd for C18H30NOS [M +
H]+, 308.2048; found, 308.2051.
N-(1-p-Tolyl-2-(p-tolylthio)ethyl)acetamide (4ba). Compound
4ba was obtained in 64% yield (47.8 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow oil. H
NMR (CDCl3, 400 MHz): δ 7.30 (d, J = 8.2 Hz, 2H), 7.19−7.11 (m,
6H), 6.09 (d, J = 7.4 Hz, 1H), 5.14 (q, J = 6.9 Hz, 1H), 3.36 (dd, J1 =
7.0 Hz, J2 = 13.5 Hz, 1H), 3.26 (dd, J1 = 6.3 Hz, J2 = 13.5 Hz, 1H),
2.35 (s, 3H), 2.34 (s, 3H), 1.96 (m, 3H). 13C NMR (CDCl3, 100
MHz): δ 169.5, 137.5, 137.4, 136.7, 131.8, 130.6, 129.9, 129.4, 126.5,
52.7, 40.4, 23.3, 21.1, 21.0. HRMS calcd for C18H22NOS [M + H]+,
300.1422; found, 300.1423.
N-(1-m-Tolyl-2-(p-tolylthio)ethyl)acetamide (4ca). Compound
4ca was obtained in 91% yield (68.0 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a yellow solid; mp
1
87.0−89.0 °C. H NMR (CDCl3, 400 MHz): δ 7.31 (d, J = 8.2 Hz,
2H), 7.24 (t, J = 7.8 Hz, 1H), 7.13−7.07 (m, 5H), 6.07 (d, J = 7.4 Hz,
1H), 5.13 (q, J = 7.1 Hz, 1H), 3.35 (dd, J1 = 6.2 Hz, J2 = 13.6 Hz, 1H),
3.27 (dd, J1 = 7.2 Hz, J2 = 13.6 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H),
1.98 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.5, 140.4, 138.4,
136.8, 131.8, 130.7, 129.9, 128.6, 128.6, 127.4, 123.6, 53.0, 40.5, 23.3,
21.5, 21.0. HRMS calcd for C18H22NOS [M + H]+, 300.1422; found,
300.1425.
N-(2-(Phenethylthio)-1-phenylethyl)acetamide (4an). Compound
N-(1-(4-Chlorophenyl)-2-(p-tolylthio)ethyl)acetamide (4da).
Compound 4da was obtained in 86% yield (68.9 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a
4an was obtained in 77% yield (57.5 mg) according to the general
1
procedure (acetonitrile: 2 mL, 47.8 mmol; 30 h) as a yellow oil. H
1
NMR (CDCl3, 500 MHz): δ 7.34 (t, J = 7.5 Hz, 2H), 7.29−7.26 (m,
yellow oil. H NMR (CDCl3, 400 MHz): δ 7.29−7.27 (m, 4H), 7.19
F
DOI: 10.1021/acs.joc.5b02579
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.22 (d, J = 7.2 Hz, 1H),
5.10 (q, J = 7.0 Hz, 1H), 3.30−3.20 (m, 2H), 2.34 (s, 3H), 1.97 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 169.6, 139.1, 137.2, 133.5,
131.2, 130.9, 130.0, 128.8, 128.0, 52.4, 40.6, 23.2, 21.0. HRMS calcd
for C17H19ClNOS [M + H]+, 320.0876; found, 320.0877.
109.6 °C. H NMR (CDCl3, 400 MHz): δ 7.33 (d, J = 8.1 Hz, 2H),
7.13 (d, J = 7.9 Hz, 2H), 5.66 (d, J = 8.5 Hz, 1H), 4.06−3.99 (m, 1H),
3.23−3.18 (m, 1H), 2.34 (s, 3H), 2.11−2.05 (m, 1H), 1.93 (s, 3H),
1.90−1.75 (m, 4H), 1.69−1.61 (m, 4H), 1.52−1.42 (m, 3H). 13C
NMR (CDCl3, 100 MHz): δ 169.3, 137.3, 132.7, 131.3, 129.8, 53.9,
53.2, 31.6, 30.4, 26.2, 26.1, 25.6, 24.9, 23.5, 21.1. HRMS calcd for
C17H26NOS [M + H]+, 292.1735; found, 292.1733.
N-(1-(3-Chlorophenyl)-2-(p-tolylthio)ethyl)acetamide (4ea).
Compound 4ea was obtained in 73% yield (58.4 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white
N-(4-(p-Tolylthio)hexan-3-yl)acetamide (4la). Compound 4la was
obtained in 62% yield (41.1 mg) according to the general procedure
(acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white solid; mp 79.6−81.0
°C. 1H NMR (CDCl3, 500 MHz): δ 7.36 (d, J = 8.2 Hz, 2H), 7.12 (d,
J = 7.9 Hz, 2H), 5.54 (d, J = 9.0 Hz, 1H), 4.21−4.16 (m, 1H), 3.10−
3.06 (m, 1H), 2.35 (s, 3H), 2.01 (s, 3H), 1.72−1.65 (m, 1H), 1.64−
1.53 (m, 3H), 1.11 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C
NMR (CDCl3, 125 MHz): δ 169.6, 137.1, 132.2, 132.1, 129.8, 56.7,
54.0, 26.6, 26.4, 23.4, 21.1, 12.4, 10.8. HRMS calcd for C15H24NOS [M
+ H]+, 266.1579; found, 266.1580.
N-(4-(p-Tolylthio)hexan-3-yl)acetamide (4ma). Compound 4ma
was obtained in 58% yield (38.4 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a light yellow oil.
1H NMR (CDCl3, 500 MHz): δ 7.32 (d, J = 8.2 Hz, 2H), 7.11 (d, J =
7.9 Hz, 2H), 5.57 (d, J = 8.9 Hz, 1H), 4.17−4.11 (m, 1H), 3.22−3.19
(m, 1H), 2.33 (s, 3H), 1.81 (s, 3H), 1.72−1.63 (m, 3H), 1.49−1.42
(m, 1H), 1.10 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 125 MHz): δ 169.7, 136.8, 133.1, 131.5, 129.9, 58.2, 53.9,
26.7, 23.2, 22.4, 21.0, 12.4, 10.8. HRMS calcd for C15H24NOS [M +
H]+, 266.1579; found, 266.1583.
1
solid; mp 97−99.6 °C. H NMR (CDCl3 , 400 MHz): δ 7.30−7.27
(m, 2H), 7.25−7.23 (m, 3H), 7.15−7.11 (m, 3H), 6.25 (d, J = 7.3 Hz,
1H), 5.10 (q, J = 7.0 Hz, 1H), 3.28−3.20 (m, 2H), 2.34 (s, 3H), 1.98
(s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.7, 142.8, 137.2, 134.6,
131.1, 131.1, 131.1, 130.0, 129.9, 127.8, 126.7, 124.9, 52.6, 40.7, 23.2,
21.0. HRMS calcd for C17H19ClNOS [M + H]+, 320.0876; found,
320.0879.
N-(1-(2-Chlorophenyl)-2-(p-tolylthio)ethyl)acetamide (4fa).
Compound 4fa was obtained in 74% yield (59.1 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white
solid; mp 158.7−159.7 °C. 1H NMR (CDCl3, 400 MHz): δ 7.34−7.29
(m, 4H), 7.25−7.18 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.36 (d, J = 7.2
Hz, 1H), 5.48−5.43 (m, 1H), 3.37 (q, J = 5.6 Hz, 1H), 3.36 (dd, J1 =
5.6 Hz, J2 = 13.8 Hz, 1H), 3.27 (dd, J1 = 7.8 Hz, J2 = 13.8 Hz, 1H),
2.34 (s, 3H), 1.99 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.5,
137.8, 137.0, 132.7, 131.1, 131.0, 130.0, 129.9, 128.8, 128.2, 127.0,
51.1, 38.9, 23.2, 21.1. HRMS calcd for C17H19ClNOS [M + H]+,
320.0876; found, 320.0879.
N-(1-(4-Bromophenyl)-2-(p-tolylthio)ethyl)acetamide (4ga).
Compound 4ga was obtained in 60% yield (54.5 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol, 36 h) as a white
solid; mp 116.1−118.4 °C. 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J
= 8.4 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 7.14−7.11 (m, 4H), 6.14 (d, J
= 7.2 Hz, 1H), 5.09 (q, J = 7.0 Hz, 1H), 3.31−3.20 (m, 2H), 2.34 (s,
3H), 1.98 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.6, 139.6,
137.2, 131.8, 131.2, 131.0, 130.0, 128.3, 121.6, 52.5, 40.5, 23.2, 21.1.
HRMS calcd for C17H19BrNOS [M + H]+, 364.0371; found, 364.0374.
N-(1-(4-Fluorophenyl)-2-(p-tolylthio)ethyl)acetamide (4ha).
Compound 4ha was obtained in 86% yield (64.9 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a
N-(1-((p-Tolylthio)methyl)pentyl)acetamide (4na). Compound
4na was obtained in 60% yield (39.8 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white solid; mp
1
89.3−89.4 °C. H NMR (CDCl3, 400 MHz): δ 7.32 (d, J = 8.2 Hz,
2H), 7.12 (d, J = 8.0 Hz, 2H), 5.47 (d, J = 8.1 Hz, 1H), 4.18−4.13 (m,
1H), 3.14−3.05 (m, 2H), 2.33 (s, 3H), 1.88 (s, 3H), 1.68−1.61 (m,
1H), 1.55−1.47 (m, 1H), 1.33−1.25 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H).
13C NMR (CDCl3, 100 MHz): δ 169.6, 136.5, 132.6, 130.2, 129.8,
49.1, 39.4, 33.2, 28.1, 23.3, 22.5, 21.0, 13.9. HRMS calcd for
C15H24NOS [M + H]+, 266.1579; found, 266.1581.
N-(1-((p-Tolylthio)methyl)heptyl)acetamide (4oa). Compound
4oa was obtained in 58% yield (42.7 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white solid; mp
1
yellow solid, mp 86.1−87.4 °C. H NMR (CDCl3, 400 MHz): δ 7.28
(d, J = 8.2 Hz, 2H), 7.25−7.21 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H),
7.03−6.99 (m, 2H), 6.21 (d, J = 7.2 Hz, 1H), 5.12 (q, J = 7.0 Hz, 1H),
3.33−3.21 (m, 2H), 2.34 (s, 3H), 1.97 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 169.6, 162.2 (d, J = 244.7 Hz), 137.1, 136.4 (d, J = 3.2 Hz),
131.4, 130.8, 129.9, 128.3 (d, J = 8.1 Hz), 115.5 (d, J = 8.1 Hz), 52.4,
40.7, 23.2, 21.0. HRMS calcd for C17H19FNOS [M + H]+, 304.1171;
found, 304.1177.
1
89.1−89.4 °C. H NMR (CDCl3, 400 MHz): δ 7.31 (d, J = 8.2 Hz,
2H), 7.12 (d, J = 8.0 Hz, 2H), 5.47 (d, J = 8.4 Hz, 1H), 4.18−4.12 (m,
1H), 3.14−3.05 (m, 2H), 2.33 (s, 3H), 1.88 (s, 3H), 1.67−1.60 (m,
1H), 1.52−1.49 (m, 1H), 1.32 −1.26 (m, 8H), 0.89 (t, J = 6.6 Hz,
3H). 13C NMR (CDCl3, 100 MHz): δ 169.6, 136.5, 132.6, 130.2,
129.8, 49.1, 39.3, 33.5, 31.7, 29.1, 25.9, 23.3, 22.6, 21.0, 14.0. HRMS
calcd for C17H28NOS [M + H]+, 294.1892; found, 294.1894.
N-(1-(Naphthalen-2-yl)-2-(p-tolylthio)ethyl)acetamide (4ia).
Compound 4ia was obtained in 64% yield (53.6 mg) according to
the general procedure (acetonitrile: 2 mL, 47.8 mmol; 24 h) as a
N-(1-Phenyl-2-(p-tolylthio)ethyl)butyramide (4aab). Compound
4aab was obtained in 94% yield (73.8 mg) according to the general
procedure (butyronitrile: 2 mL, 23 mmol; 24 h) as a white solid; mp
1
yellow oil. H NMR (CDCl3, 400 MHz): δ 7.84−7.80 (m, 3H), 7.72
1
(s, 1H), 7.50−7.48 (m, 2H), 7.37 (dd, J1 = 1.8 Hz, J2 = 8.5 Hz, 1H),
7.31 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.31 (d, J = 7.6 Hz,
1H), 5.34 (q, J = 7.0 Hz, 1H), 3.45−3.33 (m, 2H), 2.33 (s, 3H), 2.00
(s, 3H). 13C NMR (CDCl3, 100 MHz): δ 169.7, 137.9, 136.9, 133.3,
132.9, 131.6, 130.8, 129.9, 128.6, 127.9, 127.7, 126.3, 126.1, 125.5,
124.6, 53.1, 40.5, 23.3, 21.0. HRMS calcd for C21H22NOS [M + H]+,
336.1422; found, 336.1425.
87.0−88.1 °C. H NMR (CDCl3, 400 MHz): δ 7.35−7.27 (m, 7H),
7.12 (d, J = 7.9 Hz, 2H), 6.15 (d, J = 7.4 Hz, 1H), 5.18 (q, J = 7.2 Hz,
1H), 3.37−3.26 (m, 2H), 2.34 (s, 3H), 2.16 (t, J = 7.0 Hz, 2H), 1.70−
1.61 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δ 172.5, 140.7, 136.8, 131.7, 130.7, 129.9, 128.7, 127.7, 126.6, 52.7,
40.7, 38.6, 21.0, 19.1, 13.8. HRMS calcd for C19H24NOS [M + H]+,
314.1579; found, 314.1583.
N-(1-Phenyl-2-(p-tolylthio)propyl)acetamide (4ja). Compound
4ja was obtained in 40% yield (29.9 mg) according to the general
procedure (acetonitrile: 2 mL, 47.8 mmol, 36 h) as a yellow solid; mp
136.2−138.9 °C. 1H NMR (CDCl3, 500 MHz): δ 7.35−7.32 (m, 4H),
7.29−7.27 (m, 3H), 7.13 (d, J = 7.1 Hz, 2H), 6.21 (d, J = 6.2 Hz, 1H),
5.15(dd, J1 = 4.4 Hz, J2 = 6.3 Hz, 1H), 3.64−3.55 (m, 1H), 2.33 (s,
3H), 2.00 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H). 13C NMR (CDCl3, 125
MHz): δ 169.3, 138.7, 137.7, 132.8, 131.0, 130.0, 128.4, 127.7, 127.4,
56.5, 49.9, 23.4, 21.1, 17.9. HRMS calcd for C18H22NOS [M + H]+,
300.1422; found, 300.1426.
N-(1-Phenyl-2-(p-tolylthio)ethyl)isobutyramide (4aac). Com-
pound 4aac was obtained in 87% yield (68.5 mg) according to the
general procedure (isobutyronitrile: 2 mL, 22.0 mmol; 24 h) as a white
solid; mp 144.5−146.7 °C. 1H NMR (CDCl3, 400 MHz): δ 7.35−7.26
(m, 7H), 7.12 (d, J = 8.0 Hz, 2H), 6.06 (d, J = 7.0 Hz, 1H), 5.16 (q, J
= 7.0 Hz, 1H), 3.39−3.27 (m, 2H), 2.42−2.35 (m, 1H), 2.34 (s, 3H),
1.18 (d, J = 6.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3,
100 MHz): δ 176.3, 140.7, 136.8, 131.7, 130.7, 129.9, 128.7, 127.7,
126.5, 52.5, 40.7, 35.7, 21.0, 19.6, 19.5. HRMS calcd for C19H24NOS
[M + H]+, 314.1579; found, 314.1581.
N-(2-(p-Tolylthio)cyclooctyl)acetamide (4ka). Compound 4ka was
obtained in 50% yield (36.4 mg) according to the general procedure
(acetonitrile: 2 mL, 47.8 mmol; 24 h) as a white solid; mp 108.7−
N-(1-Phenyl-2-(p-tolylthio)ethyl)pentanamide (4aad). Com-
pound 4aad was obtained in 94% yield (76.6 mg) according to the
general procedure (pentanenitrile: 2 mL, 19.1 mmol; 24 h) as a white
G
DOI: 10.1021/acs.joc.5b02579
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1
solid; mp 58.5−59.1 °C. H NMR (CDCl3, 400 MHz): δ 7.36−7.27
(c) Block, E. Reactions of Organosulfur Compounds; Academic Press:
New York, 1978. (d) Patai, S., Rappoport, Z., Eds. The Chemistry of
Organic Selenium and Tellurium Compounds; Wiley: New York, 1986−
1987; Vols. 1−2. (e) Zyk, N. V.; Beloglazkina, E. K.; Belova, M. A.;
Dubinina, N. S. Russ. Chem. Rev. 2003, 72, 769. (f) Sizov, A. Y.;
Kovregin, A. N.; Ermolov, A. F. Russ. Chem. Rev. 2003, 72, 357.
(g) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev.
2004, 104, 2239.
(m, 7H), 7.12 (d, J = 8.0 Hz, 2H), 6.10 (d, J = 7.4 Hz, 1H), 5.18 (q, J
= 7.1 Hz, 1H), 3.38−3.26 (m, 2H), 2.34 (s, 3H), 2.18 (t, J = 7.5 Hz,
2H), 1.64−1.57 (m, 2H), 1.40−1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 100 MHz): δ 172.6, 140.7, 136.8, 131.7, 130.7,
129.9, 128.7, 127.7, 126.6, 52.7, 40.6, 36.5, 27.7, 22.4, 21.0, 13.8.
HRMS calcd for C20H26NOS [M + H]+, 328.1735; found, 328.1733.
N-(1-Phenyl-2-(p-tolylthio)ethyl)hexanamide (4aae). Compound
4aae was obtained in 81% yield (69.2 mg) according to the general
procedure (hexanenitrile: 2 mL, 16.5 mmol; 24 h) as a white solid; mp
(2) (a) Blair, L. M.; Sperry, J. J. Nat. Prod. 2013, 76, 794.
(b) Gademann, K.; Portmann, C.; Blom, J. F.; Zeder, M.; Juttner, F. J.
̈
1
93.4−96.0 °C. H NMR (CDCl3, 400 MHz): δ 7.32 (t, J = 7.0 Hz,
Nat. Prod. 2010, 73, 980. (c) Halim, M.; Yee, D. J.; Sames, D. J. Am.
Chem. Soc. 2008, 130, 14123. (d) Li, J.; Pan, L.; Deng, Y.;
2H), 7.28−7.24 (m, 5H), 7.09 (d, J = 7.9 Hz, 2H), 5.97 (d, J = 6.4 Hz,
1H), 5.15 (q, J = 6.9 Hz, 1H), 3.35−3.25 (m, 2H), 2.31 (s, 3H), 2.14
(t, J = 7.5 Hz, 2H), 1.62−1.57 (m, 2H), 1.31−1.26 (m, 4H), 0.88 (t, J
= 6.8 Hz, H). 13CNMR (CDCl3, 100 MHz): δ 172.6, 140.6, 136.8,
131.7, 130.7, 129.9, 128.7, 127.7, 126.6, 52.7, 40.6, 36.7, 31.5, 25.3,
22.4, 21.0, 14.0. HRMS calcd for C21H28NOS [M + H]+, 342.1892;
found, 342.1897.
MunozAcuna, U.; Yuan, C.; Lai, H.; Chai, H.; Chagwedera, T. E.;
̃
̃
Farnsworth, N. R.; Carcache de Blanco, E. J.; Li, C.; Soejarto, D. D.;
Kinghorn, A. D. J. Org. Chem. 2013, 78, 10166. (e) Pedras, M. S. C.;
Zaharia, I. L. Org. Lett. 2001, 3, 1213. (f) Pedras, M. S. C.; Zheng, Q.-
A.; Strelkov, S. J. Agric. Food Chem. 2008, 56, 9949. (g) Wilson, A. J.;
Kerns, J. K.; Callahan, J. F.; Moody, C. J. J. Med. Chem. 2013, 56, 7463.
(3) (a) Lauterbach, C.; Fabian, J. Eur. J. Inorg. Chem. 1999, 1999,
1995. (b) Hope, E. G.; Levason, W. Coord. Chem. Rev. 1993, 122, 109.
(c) Clemenson, P. I. Coord. Chem. Rev. 1990, 106, 171. (d) Baumann,
R. P.; Ishiguro, K.; Penketh, P. G.; Shyam, K.; Zhu, R.; Sartorelli, A. C.
Biochem. Pharmacol. 2011, 81, 1201.
N-(1-Phenyl-2-(p-tolylthio)ethyl)benzamide (4aaf). Compound
4aaf was obtained in 72% yield (62.2 mg) according to the general
procedure (benzonitrile: 2 mL, 19.6 mmol; 24 h) as a white solid; mp
156.1−157.5 °C. 1H NMR (CDCl3, 400 MHz): δ 7.72−7.70 (m, 2H),
7.53−7.49 (m, 1H), 7.43−7.40 (m, 2H), 7.37−7.29 (m, 7H), 7.12 (d, J
= 7.9 Hz, 2H), 6.79 (d, J = 7.1 Hz, 1H), 5.37 (q, J = 7.0 Hz, 1H),
3.49−3.40 (m, 2H), 2.34 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
166.9, 140.6, 137.0, 134.2, 131.6, 131.5, 130.9, 130.0, 128.8, 128.5,
127.8, 127.0, 126.6, 53.5, 40.8, 21.1. HRMS calcd for C22H22NOS [M
+ H]+, 348.1422; found, 348.1423.
(4) (a) Taniguchi, N. J. Org. Chem. 2006, 71, 7874. (b) Yang, F.-L.;
Tian, S.-K. Angew. Chem., Int. Ed. 2013, 52, 4929. (c) Zhao, X.; Zhang,
L.; Li, T.; Liu, G.; Wang, H.; Lu, K. Chem. Commun. 2014, 50, 13121.
(d) Zhao, X.; Zhang, L.; Lu, X.; Li, T.; Lu, K. J. Org. Chem. 2015, 80,
2918 and references cited therein..
4-Methyl-N-(1-phenyl-2-(p-tolylthio)ethyl)benzamide (4aag).
Compound 4aag was obtained in 60% yield (54.1 mg) according to
the general procedure (4-methylbenzonitrile: 2 mL, 16.7 mmol; 24 h)
as a white solid; mp 129.0−130.0 °C. 1H NMR (CDCl3, 400 MHz): δ
7.62 (d, J = 8.2 Hz, 2H), 7.36−7.30 (m, 7H), 7.21 (d, J = 8.0 Hz, 2H),
7.12 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 7.1 Hz, 1H), 5.36 (q, J = 7.0 Hz,
1H), 3.49−3.39 (m, 2H), 2.42 (s, 3H), 2.34 (s, 2H). 13C NMR
(CDCl3, 100 MHz): δ 166.8, 142.0, 140.7, 137.0, 131.6, 131.4, 130.9,
130.0, 129.2, 128.8, 127.7, 127.0, 126.6, 53.4, 40.8, 21.5, 21.0. HRMS
calcd for C23H24NOS [M + H]+, 362.1579; found, 362.1581.
(5) (a) Wang, H.; Huang, D.; Cheng, D.; Li, L.; Shi, Y. Org. Lett.
2011, 13, 1650. (b) Guan, H.; Wang, H.; Huang, D.; Shi, Y.
Tetrahedron 2012, 68, 2728. (c) Gao, X.; Pan, X.; Gao, J.; Jiang, H.;
Yuan, G.; Li, Y. Org. Lett. 2015, 17, 1038. (d) Yang, F.-L.; Wang, F.-X.;
Wang, T.-T.; Wang, Y.-J.; Tian, S.-K. Chem. Commun. 2014, 50, 2111.
(e) Yu, J.; Gao, C.; Song, Z.; Yang, H.; Fu, H. Org. Biomol. Chem.
2015, 13, 4846. (f) Vieira, A.; Azeredo, J. B.; Godoi, M.; Santi, C.; da
Silva Junior, E. N.; Braga, A. L. J. Org. Chem. 2015, 80, 2120.
́
(6) (a) Yadav, L. D. S.; Awasthi, C. Tetrahedron Lett. 2009, 50, 3801.
(b) Movassagh, B.; Navidi, M. Tetrahedron Lett. 2008, 49, 6712.
(c) Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R. J. Org.
Chem. 2006, 71, 5819. (d) Kamal, A.; Reddy, D. R. J. Mol. Catal. A:
Chem. 2007, 272, 26. (e) Keshari, T.; Yadav, V. K.; Srivastava, V. P.;
Yadav, L. D. S. Green Chem. 2014, 16, 3986. (f) Xi, H.; Deng, B.; Zong,
Z.; Lu, S.; Li, Z. Org. Lett. 2015, 17, 1180. (g) Yadav, V. K.; Srivastava,
V. P.; Yadav, L. D. S. Tetrahedron Lett. 2015, 56, 2892.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02579.
1H and 13C NMR spectra for all compounds (PDF)
(7) (a) Taniguchi, N. J. Org. Chem. 2006, 71, 7874. (b) Muangkaew,
C.; Katrun, P.; Kanchanarugee, P.; Pohmakotr, M.; Reutrakul, V.;
Soorukram, D.; Jaipetch, T.; Kuhakarn, C. Tetrahedron 2013, 69, 8847.
(8) (a) Li, L.; Wang, H.; Huang, D.; Shi, Y. Tetrahedron 2012, 68,
9853. (b) Li, L.; Li, Z.; Huang, D.; Wang, H.; Shi, Y. RSC Adv. 2013, 3,
4523.
(9) (a) Usugi, S.-i.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Org.
Lett. 2004, 6, 601. (b) Matsumoto, K.; Fujie, S.; Suga, S.; Nokami, T.;
Yoshida, J.-i. Chem. Commun. 2009, 5448. (c) Caserio, M. C.; Fisher,
C. L.; Kim, J. K. J. Org. Chem. 1985, 50, 4390. (d) Wang, X.-R.; Chen,
F. Tetrahedron 2011, 67, 4547.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: weiweiqfnu@163.com; tel.: +86 537 4458317; fax:
+86 537 4458317.
■
*E-mail: huawang_qfnu@126.com; website: http://wang.qfnu.
edu.cn.
Notes
The authors declare no competing financial interest.
(10) (a) Newton, G. L.; Av-Gay, Y.; Fahey, R. C. Biochemistry 2000,
39, 10739. (b) Nicholas, G. M.; Kovac, P.; Bewley, C. A. J. Am. Chem.
Soc. 2002, 124, 3492. (c) Nogle, L. M.; Gerwick, W. H. Org. Lett.
2002, 4, 1095. (d) Lee, S.; Rosazza, J. P. N. Org. Lett. 2004, 6, 365.
(e) Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.; Muller, H.; Benet-
Buchholz, J.; Gantner, F.; Tichy, H.-V.; Reinemer, P.; Bacon, K. B. J.
Nat. Prod. 2007, 70, 246. (f) Singh, S. B.; Zink, D. L.; Dorso, K.;
Motyl, M.; Salazar, O.; Basilio, A.; Vicente, F.; Byrne, K. M.; Ha, S.;
Genilloud, O. J. Nat. Prod. 2009, 72, 345. (g) Wang, X.; Shaaban, K.
A.; Elshahawi, S. I.; Ponomareva, L. V.; Sunkara, M.; Zhang, Y.;
Copley, G. C.; Hower, J. C.; Morris, A. J.; Kharel, M. K.; Thorson, J. S.
J. Nat. Prod. 2013, 76, 1441.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21302109, 21302110, and
21375075), the Taishan Scholar Foundation of Shandong
Province, and the Natural Science Foundation of Shandong
Province (ZR2015JL004).
REFERENCES
■
(1) For selected examples, see: (a) Block, E. Reactions of Organosulfur
Compounds; Academic Press: New York, 1978. (b) Bernardi, F.,
Csizmadia, I. G., Mangini, A., Eds. Organic Sulfur Chemistry. Theoretical
and Experimental Advances; Elsevier: Amsterdam, 1985; Vol. 19.
(11) (a) Yu, L.; Dennis, E. A. J. Am. Chem. Soc. 1992, 114, 8757.
(b) Kakule, T. B.; Lin, Z.; Schmidt, E. W. J. Am. Chem. Soc. 2014, 136,
H
DOI: 10.1021/acs.joc.5b02579
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
17882. (c) Kakule, T. B.; Zhang, S.; Zhan, J.; Schmidt, E. W. Org. Lett.
2015, 17, 2295.
(12) (a) Bewick, A.; Mellor, J. M.; Owton, W. M. J. Chem. Soc., Perkin
Trans. 1 1985, 1039. (b) Benati, L.; Montevecchi, P. C. J. Chem. Soc.,
Perkin Trans. 1 1987, 2815. (c) Tiecco, M.; Tingoli, M.; Testaferri, L.;
Balducci, R. J. Org. Chem. 1992, 57, 4025. (d) Lucchini, V.; Modena,
G.; Pasquato, L. J. Chem. Soc., Chem. Commun. 1994, 1565.
(13) (a) Toshimitsu, A.; Hirosawa, C.; Tanimoto, S. Tetrahedron Lett.
1991, 32, 4317. (b) Toshimitsu, A.; Hirosawa, C.; Tamao, K.
Tetrahedron 1994, 50, 8997. (c) Toshimitsu, A.; Hirosawa, C.;
Nakano, K.; Mukai, T. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120,
355.
(14) After the experiments and while preparing this manuscript, Xu
and Mao presented NaI-mediated acetamidosulfenylation of alkenes
with nitriles and disulfides or thiolphenols leading to β-acetamido
sulfides at 100 °C by using (NH4)2S2O8 as the stoichiometric oxidant,
see: Zheng, Y.; He, Y.; Rong, G.; Zhang, X.; Weng, Y.; Dong, K.; Xu,
X.; Mao, J. Org. Lett. 2015, 17, 5444.
(15) (a) Wei, W.; Wen, J.; Yang, D.; Du, J.; You, J.; Wang, H. Green
Chem. 2014, 16, 2988. (b) Wei, W.; Wen, J.; Yang, D.; Liu, X.; Guo,
M.; Dong, R.; Wang, H. J. Org. Chem. 2014, 79, 4225. (c) Wei, W.;
Liu, X.; Yang, D.; Dong, R.; Cui, Y.; Yuan, F.; Wang, H. Tetrahedron
Lett. 2015, 56, 1808. (d) Liu, C.; Zhu, M.; Wei, W.; Yang, D.; Cui, H.;
Liu, X.; Wang, H. Org. Chem. Front. 2015, 2, 1356.
(16) (a) Liao, Y.; Jiang, P.; Chen, S.; Qi, H.; Deng, G.-J. Green Chem.
2013, 15, 3302. (b) Ge, W.; Zhu, X.; Wei, Y. Adv. Synth. Catal. 2013,
355, 3014. (c) Ge, W.; Wei, Y. Green Chem. 2012, 14, 2066.
(d) Parumala, S. K. R.; Peddinti, R. K. Green Chem. 2015, 17, 4068.
(e) Azeredo, J. B.; Godoi, M.; Martins, G. M.; Silveira, C. C.; Braga, A.
L. J. Org. Chem. 2014, 79, 4125. (f) Vieira, A. A.; Azeredo, J. B.; Godoi,
M.; Santi, C.; da Silva Junior, E. N.; Braga, A. L. J. Org. Chem. 2015, 80,
́
2120.
(17) (a) Rasteikiene, L.; Greiciute, D.; Lin’kova, M. G.; Knunyants, I.
L. Russ. Chem. Rev. 1977, 46, 548. (b) Schmid, G. H.; Garratt, D. G.
Tetrahedron Lett. 1983, 24, 5299.
(18) (a) Tamres, M.; Bhat, S. N. J. Am. Chem. Soc. 1972, 94, 2577.
(b) Lo, S. J.; Tamres, M. Can. J. Chem. 1983, 61, 1933.
I
DOI: 10.1021/acs.joc.5b02579
J. Org. Chem. XXXX, XXX, XXX−XXX