Nickel-Catalyzed Selective Decarbonylation of α-Amino Acid Thioester: Aminomethylation of Mercaptans

Article abstract of DOI:10.1021/acs.joc.1c01480

The nickel-catalyzed aminomethylation of mercaptans has been disclosed that offers efficient and expedient access to synthesize α-aminosulfides. The intramolecular fragment coupling shows excellent chemoselectivity. This transformation shows good functional-group compatibility, tolerates a wide range of electron-withdrawing, electron-neutral, and electron-donating substituents in this process, and can serve as a powerful synthetic tool for the synthesis of α-aminosulfides at a gram scale. Thus, the newly developed methodology enables a facile route for C-S bond formation in a straightforward fashion.

Full text of DOI:10.1021/acs.joc.1c01480

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Article
Nickel-Catalyzed Selective Decarbonylation of α‑Amino Acid
Thioester: Aminomethylation of Mercaptans
Jing-Ya Zhou, Rui Tian, and Yong-Ming Zhu*
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ABSTRACT: The nickel-catalyzed aminomethylation of mercap-
tans has been disclosed that offers efficient and expedient access to
synthesize α-aminosulfides. The intramolecular fragment coupling
shows excellent chemoselectivity. This transformation shows good
functional-group compatibility, tolerates a wide range of electron-
withdrawing, electron-neutral, and electron-donating substituents
in this process, and can serve as a powerful synthetic tool for the
synthesis of α-aminosulfides at a gram scale. Thus, the newly
developed methodology enables a facile route for C−S bond
formation in a straightforward fashion.
decarbonylation reaction has been extensively explored by
various research groups.17 In 2018, Szostak’s group18 reported
the use of a stable and inexpensive nickel source as a catalyst in
the intramolecular decarbonylation of thioesters to form C−S
bonds (Scheme 1a). In the same year, Rueping et al.19 have
reported a new cross-coupling reaction of esters and amides
with mercaptans as coupling partners (Scheme 1b). In recent
years, our research group20 has successfully constructed C−S
bonds by decarbonylation using carboxylic acid derivatives,
such as aryl carboxylic acids and aryl anhydrides as the source
of aryl groups (Scheme 1b). In 2020, Sanford et al.21 described
a nickel-catalyzed decarbonylative reaction for the synthesis of
fluoroalkyl thioethers (RFSR) from the corresponding
thioesters (Scheme 1c). This method leverages readily
available fluorocarboxylic acids as commercial and stable
fluoroalkyl sources. Therefore, we consider using α-amino acid
thioesters as the starting materials to synthesize α-amino-
sulfides by intramolecular decarbonylation under the catalysis
of nickel to realize the aminomethylation of mercaptans
(Scheme 1d).
INTRODUCTION
■
α-Aminosulfides are an important structural motif found in
many pharmaceutical1 and heterocycles such as 4-thiazolidi-
nones.2 Among many S-benzamidomethyl derivatives, there
are reports that S-benzamidomethyl-L-cysteine is used in
peptide synthesis.3 Interestingly, benzamidomethyl aryl thio-
ethers can act as useful synthetic intermediates in organic
synthesis.4 For instance, they can be used as intermediates in
the synthesis of benzothiazines.5 Furthermore, α-amidosulfides
constitute an interesting stable masked form of N-acyl- and N-
carbamoylimines (or iminium ions) in the presence of a soft
Lewis acid.6 In 1973, Sekiya et al.7 reported the reaction of N-
(α-dialkylaminobenzyl)amides with sulfides to form α-amino-
sulfides. Popovski et al.8 successfully achieved the benzamido-
methylation of phenol, mercaptans, carboxylic acids, and
amines using (benzamidomethyl)triethylammonium chloride.
Moreover, some other groups9 have successfully synthesized α-
aminosulfides using N-acylimines as starting materials or
intermediates. In addition, with the continuous in-depth
study of photocatalytic reactions,10 chemists have also applied
this method for the synthesis of α-aminosulfides.11 For
example, Fu’s group12 has developed a novel and efficient
visible-light photoredox decarboxylative arylthiation. Recently,
Zheng’s group13 has developed a novel method for the
construction of α-aminosulfides via visible-light-induced
photoredox catalysis of redox-active esters with disulfides.
Because α-Aminosulfides have synthetic utilities, they are of
great significance to develop a universal and simple synthetic
method.
RESULTS AND DISCUSSION
■
We selected S-(p-tolyl) 2-benzamidoethanethioate (1a) as the
model reaction (Table 1) for the nickel-catalyzed intra-
molecular decarbonylation of α-amino acid thioesters reaction.
In the presence of 10 mol % NiCl2, 20 mol % dppp and 0.2
Received: June 23, 2021
In the last few decades, the application of metal-catalyzed
decarbonylation has attracted much attention.14 Nickel
catalysis has attracted much attention from chemists owing
to its properties of easier oxidative addition,15 abundance, and
economic advantages.16 In particular, the nickel-catalyzed
https://doi.org/10.1021/acs.joc.1c01480
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© XXXX American Chemical Society
A

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Scheme 1. Decarbonylative Synthesis of Sulfides
ab
Table 1. Optimization of Reaction Conditions
entry
Ni cat.
NiCl2
ligand
base
additive
solvent
yield
1
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
PPh3
PCy3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
none
71%
65%
trace
none
none
27%
34%
none
none
none
69%
54%
20%
trace
58%
47%
86%
2
3
4
5
6
7
8
9
Ni(dppp)Cl2
Ni(OAc)2·4H2O
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(PPh3)Cl2
Ni(PCy3)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
c
d
10
11
12
13
14
15
dppp
dppp
dppp
dppp
dppp
dppp
dppp
e
f
Zn
Zn
Mn
Mn
Mn
g
h i
16 ,
i j
17 ,
h i
18 ,
a
General conditions: thioester (0.5 mmol), catalyst (10 mol %), ligand (20 mol %), base (0.2 equiv), Mn (0.5 mmol), and toluene (2.0 mL), N2,
b
c
d
e
f
g
h
i
160 °C, 12 h. Isolated yields. Na2CO3 (0.5 equiv). Na2CO3 (1.5 equiv). dppp (40 mol %). Zn (1 equiv). Zn (2.0 equiv). Mn (1 equiv). 150
°C. Mn (2.5 equiv).
j
equiv Na2CO3 reacted in toluene solution at 160 °C for 12 h.
Unfortunately, the target product 2a was not found to be
formed (Table 1, entry 1). The change in nickel sources such
as Ni(dppp)Cl2 and Ni(OAc)2·4H2O proved successful in this
coupling reaction with a high reactivity (Table 1, entries 2−3).
Switching bases to NaHCO3, K2CO3, or Cs2CO3 resulted in
B
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ab
Table 2. Substrate Scope I
a
General conditions: thioester (0.5 mmol), Ni (dppp)Cl2 (10 mol %), dppp (20 mol %), Mn (0.5 mmol), and toluene (2.0 mL), N2, 150 °C, 12 h.
b
Isolated yields.
little or no desired products (Table 1, entries 4−6). At the
thioesters, the target decarbonylation compounds can be
obtained with good yields. This may be due to steric hindrance
resulting in a decrease in yield. Additionally, the heterocycles
also performed well in this reaction and obtained the product
with a good yield (Table 2, 2l, 2m). Very encouragingly,
aliphatic α-amino acid compounds were also workable,
providing the desired compounds in moderate to good yields
(Table 2, 2n, 2o).
At the same time, we also investigated the substitution of
other groups to expand the scope of substrates (Table 3).
What excited us was that acetyl, methyl ester, and Boc groups
were well tolerated in this reaction (Table 3, 4a−4c).
Substitution with other acyl groups, such as naphthoyl, p-
chlorobenzoyl, p-methoxybenzoyl, and phenylacetyl, could
yield the target compounds with good yields (Table 3, 4d−
4g). By the use of 2-(1,3-dioxoisoindolin-2-yl)acetic acid
derivative, the desired compound was obtained in excellent
yield (Table 3, 4h). Moreover, by the use of α-monosub-
stituted amino acid thioester, certain target compounds could
also be obtained under our reaction conditions, but due to the
influence of steric hindrance, the yields were decreased (Table
3, 4i-4l). In addition, we were surprised to find that α-
disubstituted amino acid thioester formed a lactone under the
reaction conditions and stopped the reaction (Table 3, 4n′). If
both the hydrogen atoms on the N atom and on the methylene
same time, we also investigated the amount of base under
identical reaction conditions and found that increasing the
amount of base resulted in a dramatically decreased yield
(Table 1, entries 7−8). Regarding the role of the supporting
ligand, replacement of bidentate phosphine ligand by another
monodentate or no ligand under identical reaction conditions
did not yield the target compound (Table 1, entries 9−11). By
switching the solvent, such as dioxane, still resulted in a similar
yield (Table 1, entry 12). Notably, increasing the dppp loading
to 40 mol % decreased the yield to 54% (Table 1, entry 13).
Further optimizations were performed by screening different
equivalents of Zn, but they all provided unsatisfactory (Table
1, entries 14, 15). When the reaction temperature was 150 °C,
the utilization of Mn instead of Zn as a reaction additive can
achieve moderate yields (Table 1, entries 16, 17). We added 1
equiv of Mn without the addition of Na2CO3, and the yield
was dramatically increased to 86% (Table 1, entry 18).
With the optimized conditions in hand, the generality of the
reaction was subsequently investigated. The reaction exhibits
broad substrate scope (Table 2). As shown, a wide range of α-
amino acid thioesters that incorporate electron-neutral,
electron-donating, and electron-withdrawing substituents
were readily tolerated (Table 2, 2a−2k). Except that the
yield of 2f is slightly lower, with the other α-amino acid
C
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ab
Table 3. Substrate Scope II
a
General conditions: thioester (0.5 mmol), Ni (dppp)Cl2 (10 mol %), dppp (20 mol %), Mn (0.5 mmol), and toluene (2.0 mL), N2, 150 °C, 12 h.
b
Isolated yields.
Scheme 2. Large-Scale Synthesis
group were replaced at the same time, the target compound
could be smoothly obtained, such as 4m.
3a). Furthermore, this protocol also tolerates β-amino acid
thioester. However, the expected decarbonylation compound
was not obtained, but a rearrangement occurred, resulting in
the same product as α-alanine thioester (Scheme 3b).
To prove the practicality of this method, we next performed
a gram-scale reaction of S-(p-tolyl) 2-benzamidoethanethioate.
When the model reaction was performed on a 4.0 mmol scale,
the yield of the desired product 2a was obtained in 79%
(Scheme 2), thus demonstrating the scalability of this strategy.
With the completion of the substrate expansion, we
performed some mechanism control experiments (Scheme
3). We have synthesized (L)-alanine thioester using N-benzoyl-
L-alanine as a starting material, and reacted under standard
conditions to obtain the target product. We conducted chiral
tests on the α-alanine thioester and the target product and
found that the chiral α-amino acid thioesters racemized under
our reaction conditions to obtain the racemic product (Scheme
Based on the previous literature reports17a,19,22 and
mechanistic experiments, the elementary steps involved in
the present nickel-catalyzed α-amino acid thioester decarbon-
ylation aminomethylation is postulated in Scheme 4. Initially,
oxidative addition of [Ni0] and compound A occurs to
generate the acyl-nickel (II) intermediate B. The decarbon-
ylation process is accessed through the extrusion of carbon
monoxide from intermediate B to obtain the five-membered
ring intermediate C, and then the sulfide ion can attack the
intermediate C from the front and back; subsequent reductive
elimination releases the desired product.
D
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Scheme 3. Mechanistic Experiments
1
with a digital melting-point apparatus. H (400 or 300 MHz) and
13C(101 MHz) NMR spectra were obtained from solutions in CDCl3
Scheme 4. Proposed Reaction Mechanism
or with tetramethylsilane as an internal standard using 400 MHz
spectrometers. High-resolution mass spectra (HRMS) analyses were
carried out on electron spray ionization, chemical ionization, or
electron impact ion source (ESI, CI, or EI) apparatus using time-of-
flight (TOF) mass spectrometry.
General Procedure for Amino Acid Acylation Synthesis.23
Glycine (20 mmol) was added to a solution of H2O (20 mL) and
NaOH (40 mmol) at room temperature. The reaction mixture was
then warmed to 70−80 °C and acid chloride (20 mmol) was added
portionwise over a 10−20 min period. After the addition was
complete, the reaction mixture was stirred with warming for an
additional 15−30 min. The solution was then cooled (ice bath) and
acidified to pH 1 with concentrated HCl. The resultant precipitate
was isolated by filtration, washed with water (25−50 mL), and
recrystallized.
General Procedure for Acylation of Mercaptan.24 A solution
of N,N′-dicyclohexylcarbodiimide (1.3 g, 6 mmol) in dichloro-
methane (5 cm3) was added to a solution of the appropriate
mercaptan (5 mmol) in the same solvent (20−30 cm3). Air was
displaced by nitrogen and the mixture was shaken for 16 h and then
filtered. The solvent was removed under vacuum. The residue was
purified on a silica gel column to give the pure target product.
General Procedure for Decarbonylation of α-Amino Acid
Thioester. Thioester (0.5 mmol), Ni(dppp)Cl2 (27 mg, 0.05 mmol),
dppp (41 mg, 0.1 mmol), and Mn (28 mg, 0.5 mmol) were
successively added into a 15 mL sealed tube, using anhydrous toluene
(2.0 mL) as solvent. The mixture was stirred in a 150 °C oil bath
under nitrogen for 12 h. Upon completion of the reaction as indicated
by TLC, the mixture was diluted with EtOAc, and then filtered
through a pad of Celite. The solvent was removed under vacuum. The
residue was purified on a silica gel column to give the pure target
product.
CONCLUSIONS
■
In conclusion, we have developed the first nickel-catalyzed
selective decarbonylation of α-amino acid thioester to achieve
aminomethylation of mercaptans. The broad substrate scope,
high reactivity, and scalability of the method suggest that this
protocol can provide a new route for the aminomethylation of
mercaptans. Intramolecular decarbonylation shows that the
reaction has certain chemical selectivity. The process provides
a synthetic entry to the biologically relevant α-aminosulfides
functional group exploiting abundant amino acid as ultimate
cross-coupling precursors.
S-(p-Tolyl) 2-Benzamidoethanethioate (1a).25 White solid. Mp:
136.5−137.4 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H),
7.46−7.35 (m, 4H), 7.13 (d, J = 7.7 Hz, 2H), 6.45 (s, 1H), 4.83 (d, J
= 6.0 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
196.1, 167.4, 140.2, 134.7, 133.6, 132.0, 130.3, 128.7, 127.1, 122.5,
49.4, 21.3.
EXPERIMENTAL SECTION
■
S-(4-Methoxyphenyl) 2-Benzamidoethanethioate (1b). White
solid. Mp: 156.1−157.5 °C. EtOAc/petroleum ether = 1:8. 1H
NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.2
Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.95 (d, J
= 8.6 Hz, 2H), 6.84 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 196.6, 167.4, 161.0, 136.3,
General Information. Reactants and reagents were purchased
from commercial suppliers and used without further purification. All
anhydrous solvents used in the reactions were dried and freshly
distilled. All reactions were carried out in sealed tubes (including
large-scale experiments), and blast shields were also used. TLC was
performed on silica HSGF254 plates. Melting points were determined
E
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133.6, 132.0, 128.7, 127.1, 116.6, 115.1, 55.4, 49.3. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C16H16NO3S, 302.0845; found,
302.0841.
(ESI-TOF) m/z [M + H]+ calcd for C16H13F3NO2S, 340.0614; found,
340.0610.
(3,4-Difluorophenyl) 2-Benzamidoethanethioate (1k). White
solid. Mp: 117.3−118.2 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.87−7.80 (m, 2H), 7.55 (t, J = 6.9 Hz,
1H), 7.49−7.42 (m, 2H), 7.29−7.25 (m, 1H), 7.24−7.12 (m, 2H),
7.05−6.89 (m, 1H), 4.52−4.46 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 195.0, 167.8, 152.7 (dd, JC‑F = 11.1, 12.5 Hz), 150.2 (dd,
S-(4-(tert-Butyl)phenyl) 2-Benzamidoethanethioate (1c). White
solid. Mp: 139.1−140.5 °C. EtOAc/petroleum ether = 1:10. 1H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 7.0 Hz, 2H), 7.58−7.50 (m, 1H),
7.49−7.40 (m, 4H), 7.36 (d, J = 7.8 Hz, 2H), 6.78 (s, 1H), 4.52 (d, J
= 4.8 Hz, 2H), 1.33 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
196.0, 167.4, 153.2, 134.4, 133.6, 132.0, 128.7, 127.1, 126.6, 122.6,
49.4, 34.8, 31.2. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C19H22NO2S, 328.1366; found, 328.1360.
J
C‑F = 11.0, 12.5 Hz), 133.3, 132.2, 131.3 (q, JC‑F = 6.6, 3.8 Hz), 128.7,
127.1, 123.8 (d, JC‑F = 18.2 Hz), 122.4 (t, JC‑F = 4.9 Hz), 118.1 (d, JC‑F
= 17.8 Hz), 49.4. 19F{1H} (377 MHz, CDCl3) δ −134.6 (d, J = 20.9
Hz), −135.2 (d, J = 20.9 Hz). HRMS (ESI-TOF) m/z [M + H]+
calcd for C15H12F2NO2S, 308.0551; found, 308.0551.
S-(4-Isopropylphenyl) 2-Benzamidoethanethioate (1d). White
1
solid. Mp: 84.5−85.2 °C. EtOAc/petroleum ether = 1:10. H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 6.8 Hz,
1H), 7.42 (t, J = 7.0 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H), 7.26 (d, J = 7.5
Hz, 2H), 7.09 (s, 1H), 4.46 (d, J = 4.7 Hz, 2H), 2.90 (dd, J = 13.0, 6.3
Hz, 1H), 1.24 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 196.2, 167.6, 150.8, 134.6, 133.5, 131.9, 128.6, 127.6, 127.1, 122.9,
49.3, 33.9, 23.7. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C18H20NO2S, 314.1209; found, 314.1205.
S-(Naphthalen-2-yl) 2-Benzamidoethanethioate (1e). White
solid. Mp: 139.6−140.2 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.80 (d, J = 7.5 Hz, 2H),
7.75 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.54 (d, J = 8.4 Hz,
1H), 7.48 (s, 3H), 7.38 (t, J = 7.2 Hz, 2H), 6.51 (s, 1H), 4.98 (d, J =
5.6 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.8, 167.5,
134.8, 133.6, 133.53, 133.48, 132.0, 130.9, 129.1, 128.7, 128.0, 127.8,
127.4, 127.1, 126.7, 123.4, 49.5. HRMS (ESI-TOF) m/z [M + H]+
calcd for C19H16NO2S, 322.0896; found, 322.0890.
S-(o-tolyl) 2-Benzamidoethanethioate (1f). White solid. Mp:
112.2−113.4 °C. EtOAc/petroleum ether = 1:8. 1H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 6.3 Hz, 2H), 7.52 (d, J = 5.9 Hz, 1H), 7.49−
7.38 (m, 3H), 7.38−7.28 (m, 2H), 7.23 (s, 1H), 6.91 (s, 1H), 4.50 (s,
2H), 2.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.1, 167.5,
142.3, 136.0, 133.6, 131.9, 130.9, 130.5, 128.7, 127.1, 126.8, 125.6,
49.5, 20.7. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H16NO2S,
286.0896; found, 286.0892.
S-(2-Methoxyphenyl) 2-Benzamidoethanethioate (1g). White
solid. Mp: 133.1−134.3 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.3 Hz, 2H), 7.53 (t, J = 7.0
Hz, 1H), 7.49−7.37 (m, 4H), 7.01 (t, J = 9.5 Hz, 2H), 6.79 (s, 1H),
4.53 (d, J = 5.0 Hz, 2H), 3.86 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 195.0, 167.3, 159.3, 136.9, 133.7, 132.2, 131.9, 128.7, 127.1,
121.3, 114.2, 111.7, 56.0, 49.3. HRMS (ESI-TOF) m/z [M + H]+
calcd for C16H16NO3S, 302.0845; found, 302.0840.
S-(4-Chlorophenyl) 2-Benzamidoethanethioate (1h). White
solid. Mp: 166.4−167.3 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.0 Hz, 2H), 7.51 (t, J = 6.8
Hz, 1H), 7.47−7.37 (m, 4H), 7.29 (s, 2H), 6.47 (s, 1H), 4.88 (d, J =
5.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.1, 167.5,
136.3, 135.9, 133.4, 132.1, 129.7, 128.8, 127.1, 124.6, 49.4. HRMS
(ESI-TOF) m/z [M + H]+ calcd for C15H13ClNO2S, 306.0350;
found, 306.0343.
S-(4-Fluorophenyl) 2-Benzamidoethanethioate (1i). White solid.
Mp: 139.7−140.5 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 2H), 7.55−7.45 (m, 3H), 7.42 (t,
J = 7.5 Hz, 2H), 7.02 (t, J = 8.3 Hz, 2H), 6.47 (s, 1H), 4.83 (d, J = 6.2
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.6, 167.5, 165.0 (d,
S-(Thiophen-2-yl) 2-Benzamidoethanethioate (1l). White solid.
Mp: 123.4−124.5 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 5.3 Hz, 1H),
7.54 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 3.5 Hz,
1H), 7.15−7.10 (m, 1H), 6.81 (s, 1H), 4.51 (d, J = 5.6 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 195.9, 167.5, 136.5, 133.4,
132.5, 132.1, 128.7, 128.1, 127.1, 122.8, 49.1. HRMS (ESI-TOF) m/z
[M + H]+ calcd for C13H12NO2S2, 278.0304; found, 278.0300.
S-(2-Methylfuran-3-yl) 2-Benzamidoethanethioate (1m). White
1
solid. Mp: 101.3−102.1 °C. EtOAc/petroleum ether = 1:5. H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.4 Hz,
1H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 1.9 Hz, 1H), 6.82 (s, 1H),
6.34 (d, J = 1.8 Hz, 1H), 4.48 (d, J = 5.5 Hz, 2H), 2.28 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 195.5, 167.5, 156.7, 141.4,
133.5, 132.0, 128.7, 127.1, 114.7, 102.4, 49.2, 12.0. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C14H14NO3S, 276.0689; found,
276.0689.
S-Dodecyl 2-Benzamidoethanethioate (1n). Yellow solid. Mp:
1
82.3−83.1 °C. EtOAc/petroleum ether = 1:10. H NMR (300 MHz,
CDCl3) δ 7.83 (d, J = 7.3 Hz, 2H), 7.54 (t, 1H), 7.46 (t, J = 7.4 Hz,
2H), 6.77 (s, 1H), 4.42 (d, J = 5.5 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H),
1.65−1.52 (m, 4H), 1.34−1.25 (m, 16H), 0.88 (t, J = 6.6 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 197.0, 167.4, 133.7, 131.9,
128.7, 127.1, 49.6, 31.9, 29.6, 29.59, 29.55, 29.4, 29.3, 29.1, 28.8, 22.7,
14.1. HRMS (CI-TOF) m/z [M + H]+ calcd for C21H34NO2S,
364.2310; found, 364.2311.
S-Benzyl 2-Benzamidoethanethioate (1o).26 White solid. Mp:
102.6−103.5 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.81 (d, J = 7.4 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H),
7.44 (t, J = 7.5 Hz, 2H), 7.31−7.27 (m, 4H), 7.26−7.22 (m, 1H),
6.77 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.18 (s, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 196.5, 167.5, 136.8, 133.5, 132.0, 128.9, 128.7,
127.5, 127.1, 49.4, 33.0.
N-((p-Tolylthio)methyl)benzamide (2a).27 White solid (115 mg,
86%). Mp: 113.8−114.6 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.0
Hz, 1H), 7.47−7.34 (m, 4H), 7.13 (d, J = 7.3 Hz, 2H), 6.44 (s, 1H),
4.83 (d, J = 5.7 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.9, 137.9, 133.9, 132.1, 131.8, 130.0, 129.9, 128.6, 126.9,
44.9, 21.1.
N-(((4-Methoxyphenyl)thio)methyl)benzamide (2b). White solid
(116 mg, 85%). Mp: 134.8−135.6 °C. EtOAc/petroleum ether = 1:8.
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.4 Hz, 2H), 7.54−7.47
(m, 1H), 7.48−7.36 (m, 4H), 6.86 (d, J = 8.2 Hz, 2H), 6.44 (s, 1H),
4.76 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.9, 159.8, 135.0, 133.9, 131.7, 128.5, 126.9, 123.8, 114.8,
55.3, 45.8. HRMS (EI-TOF) m/z [M]+ calcd for C15H15NO2S,
273.0824; found, 273.0827.
J
C‑F = 251.7 Hz), 136.8 (d, JC‑F = 8.6 Hz), 133.5, 132.1, 128.7, 127.1,
121.4 (d, JC‑F = 3.5 Hz), 116.8 (d, JC‑F = 22.5 Hz), 49.3. 19F{1H}
NMR (377 MHz, CDCl3) δ −110.4. HRMS (ESI-TOF) m/z [M +
H]+ calcd for C15H13FNO2S, 290.0646; found, 290.0639.
S-(4-(Trifluoromethyl)phenyl) 2-Benzamidoethanethioate (1j).
White solid. Mp: 141.6−142.5 °C. EtOAc/petroleum ether = 1:10.
1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.3 Hz, 2H), 7.68 (d, J =
7.7 Hz, 2H), 7.56 (d, J = 7.6 Hz, 3H), 7.48 (t, J = 7.2 Hz, 2H), 6.79
(s, 1H), 4.54 (d, J = 5.3 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 194.4, 167.6, 134.8, 133.3, 132.2, 131.6 (d, JC‑F = 33.0 Hz), 131.0
N-(((4-(tert-Butyl)phenyl)thio)methyl)benzamide (2c). White
solid (114 mg, 76%). Mp: 120.5−121.3 °C. EtOAc/petroleum
ether = 1:10. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.3 Hz, 2H),
7.54−7.46 (m, 1H), 7.46−7.36 (m, 4H), 7.34 (d, J = 7.4 Hz, 2H),
6.45 (s, 1H), 4.85 (d, J = 5.3 Hz, 2H), 1.30 (s, 9H). 13C{1H} NMR
(101 MHz, CDCl3) δ 167.0, 150.9, 134.0, 131.8, 131.6, 130.1, 128.6,
126.9, 126.3, 44.6, 34.6, 31.2. HRMS (EI-TOF) m/z [M]+ calcd for
C18H21NOS, 299.1344; found, 299.1346.
(d, J = 1.1 Hz), 128.8, 127.1, 126.1 (q, J = 3.6 Hz), 122.3 (d, JC‑F
=
273.4 Hz), 49.5. 19F{1H} NMR (377 MHz, CDCl3) δ −62.9. HRMS
F
https://doi.org/10.1021/acs.joc.1c01480
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
N-(((4-Isopropylphenyl)thio)methyl)benzamide (2d). White solid
(123 mg, 86%). Mp: 109.8−110.3 °C. EtOAc/petroleum ether =
1:10. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.4 Hz, 2H), 7.50 (t,
J = 7.1 Hz, 1H), 7.46−7.35 (m, 4H), 7.18 (d, J = 7.6 Hz, 2H), 6.45 (s,
1H), 4.84 (d, J = 5.7 Hz, 2H), 2.96−2.81 (m, 1H), 1.23 (d, J = 6.8
Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 148.7, 134.0,
132.0, 131.8, 130.3, 128.6, 127.5, 126.9, 44.8, 33.7, 23.8. HRMS (EI-
TOF) m/z [M]+ calcd for C17H19NOS, 285.1187; found, 285.1181.
N-((o-Tolylthio)methyl)benzamide (2e). White solid (101 mg,
NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.2
Hz, 1H), 7.46−7.40 (m, 3H), 7.20 (d, J = 3.5 Hz, 1H), 7.04−6.99 (m,
1H), 6.68 (s, 1H), 4.69 (d, J = 6.5 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.8, 135.3, 133.8, 131.9, 131.7, 130.9, 128.6, 128.0,
127.0, 47.8. HRMS (EI-TOF) m/z [M]+ calcd for C12H11NOS2,
249.0282; found, 249.0280.
N-(((2-Methylfuran-3-yl)thio)methyl)benzamide (2m). Yellow
solid (101 mg, 82%). Mp: 84.5−88.9 °C. EtOAc/petroleum ether =
1:5. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.4 Hz, 2H), 7.51 (t,
J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 3H), 7.29 (s, 1H), 6.48 (s, 1H),
6.38 (s, 1H), 4.59 (d, J = 6.4 Hz, 2H), 2.31 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.7, 156.0, 141.0, 133.9, 131.8, 128.7, 126.8,
115.1, 108.4, 45.2, 11.8. HRMS (EI-TOF) m/z [M]+ calcd for
C13H13NO2S, 247.0667; found, 247.0666.
1
79%). Mp: 92.0−92.7 °C. EtOAc/petroleum ether = 1:10. H NMR
(400 MHz, CDCl3) δ 7.74−7.62 (m, 2H), 7.48 (d, J = 7.3 Hz, 1H),
7.46−7.34 (m, 3H), 7.24−7.19 (m, 1H), 7.19−7.11 (m, 2H), 6.49 (s,
1H), 4.85 (d, J = 5.5 Hz, 2H), 2.43 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.9, 137.9, 133.9, 132.1, 131.8, 130.0, 129.9, 128.6,
126.9, 44.9, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for C15H15NOS,
257.0874; found, 257.0876.
N-((Dodecylthio)methyl)benzamide (2n). Yellow solid (91 mg,
1
54%). Mp: 60.5−61.8 °C. EtOAc/petroleum ether = 1:10. H NMR
N-(((2-Methoxyphenyl)thio)methyl)benzamide (2f). White solid
(90 mg, 66%). Mp: 103.9−104.7 °C. EtOAc/petroleum ether = 1:8.
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 6.1 Hz, 2H), 7.55−7.35
(m, 4H), 7.34−7.27 (m, 1H), 6.96−6.85 (m, 2H), 6.66 (s, 1H), 4.84
(d, J = 3.4 Hz, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 167.0, 158.7, 134.2, 133.9, 131.7, 129.6, 128.6, 126.9, 121.4, 121.3,
111.2, 56.0, 43.5. HRMS (EI-TOF) m/z [M]+ calcd for C15H15NO2S,
273.0824; found, 273.0825.
(400 MHz, CDCl3) δ 7.79 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.3 Hz,
1H), 7.43 (t, J = 7.5 Hz, 2H), 6.62 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H),
2.64 (t, J = 7.3 Hz, 2H), 1.68−1.56 (m, 2H), 1.41−1.33 (m, 2H),
1.30−1.23 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 167.2, 133.9, 131.7, 128.6, 126.9, 41.6, 31.9, 31.3,
29.6, 29.58, 29.57, 29.54, 29.46, 29.3, 29.1, 28.8, 22.6, 14.1. HRMS
(EI-TOF) m/z [M]+ calcd for C20H33NOS, 335.2283; found,
335.2287.
N-((Naphthalen-2-ylthio)methyl)benzamide (2g).28 White solid
(111 mg, 76%). Mp: 114.0−114.8 °C. EtOAc/petroleum ether =
N-((Benzylthio)methyl)benzamide (2o).28 Yellow oil (103 mg,
1
80%). EtOAc/petroleum ether = 1:10. H NMR (400 MHz, CDCl3)
1
1:10. H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.80 (d, J = 7.5
δ 7.59 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.39 (t, 4H), 7.31
(t, J = 7.4 Hz, 2H), 7.26−7.22 (m, 1H), 6.29−6.13 (m, 1H), 4.57 (d,
J = 6.1 Hz, 2H), 3.86 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.0, 138.7, 133.7, 131.7, 128.9, 128.8, 128.5, 127.2, 126.9, 42.0,
36.3.
S-(p-Tolyl) 2-Acetamidoethanethioate (3a). White solid. Mp:
106.3−107.1 °C. EtOAc/petroleum ether = 1:5. 1H NMR (400 MHz,
CDCl3) δ 7.29 (d, J = 7.0 Hz, 2H), 7.23 (d, J = 6.2 Hz, 2H), 6.26 (s,
1H), 4.28 (s, 2H), 2.38 (s, 3H), 2.06 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 196.0, 170.3, 140.1, 134.6, 130.2, 122.6, 49.0, 22.9,
21.3. HRMS (EI-TOF) m/z [M+Na]+ calcd for C11H13NO2SNa,
246.0559; found, 246.0560.
Hz, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.54 (d, J
= 8.4 Hz, 1H), 7.48 (s, 3H), 7.38 (t, J = 7.2 Hz, 2H), 6.51 (s, 1H),
4.98 (d, J = 5.6 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.1,
133.8, 133.7, 132.4, 131.8, 131.0, 130.0, 129.0, 128.6, 128.5, 127.7,
127.4, 126.9, 126.7, 126.3, 44.2.
N-(((4-Chlorophenyl)thio)methyl)benzamide (2h).27 White solid
(111 mg, 80%). Mp: 141.7−142.8 °C. EtOAc/petroleum ether =
1:10. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.0 Hz, 2H), 7.55−
7.48 (m, 1H), 7.47−7.37 (m, 4H), 7.32−7.27 (m, 2H), 6.47 (s, 1H),
4.88 (d, J = 5.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0,
133.72, 133.67, 132.7, 132.1, 131.9, 129.4, 128.7, 126.9, 44.4.
N-(((4-Fluorophenyl)thio)methyl)benzamide (2i). White solid
(110 mg, 84%). Mp: 115.5−116.5 °C. EtOAc/petroleum ether =
1:10. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 2H), 7.54−
7.45 (m, 3H), 7.42 (t, J = 7.5 Hz, 2H), 7.02 (t, J = 8.3 Hz, 2H), 6.47
(s, 1H), 4.83 (d, J = 6.2 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 166.9, 162.7 (d, JC‑F = 249.5 Hz), 134.5 (d, JC‑F = 8.3 Hz), 133.8,
131.9, 128.7, 128.5 (d, JC‑F = 3.3 Hz), 126.9, 116.4 (d, JC‑F = 21.9
Hz), 45.3. 19F{1H} NMR (377 MHz, CDCl3) δ −113.4. HRMS (EI-
TOF) m/z [M]+ calcd for C14H12FNOS, 261.0624; found, 261.0629.
N-(((4-(Trifluoromethyl)phenyl)thio)methyl)benzamide (2j).
White solid (110 mg, 71%). Mp: 120.1−121.2 °C. EtOAc/petroleum
ether = 1:10. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.3 Hz, 2H),
7.60−7.48 (m, 5H), 7.43 (t, J = 7.1 Hz, 2H), 6.50 (s, 1H), 5.01 (d, J =
5.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.2, 139.1 (d,
S-(p-Tolyl) 2-((Methoxycarbonyl)amino)ethanethioate (3b).
1
White solid. Mp: 85.5−86.7 °C. EtOAc/petroleum ether = 1:10. H
NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.0
Hz, 2H), 5.31 (s, 1H), 4.20 (d, J = 6.0 Hz, 2H), 3.74 (s, 3H), 2.38 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 196.4, 156.8, 140.1, 134.6,
130.2, 122.7, 52.7, 50.5, 21.3. HRMS (EI-TOF) m/z [M + H]+ calcd
for C11H14NO3S, 240.0689; found, 240.0687.
S-(p-Tolyl) 2-((tert-Butoxycarbonyl)amino)ethanethioate (3c).
1
White solid. Mp: 74.5−75.5 °C. EtOAc/petroleum ether = 1:12. H
NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.7
Hz, 2H), 5.29 (s, 1H), 4.11 (d, J = 5.5 Hz, 2H), 2.36 (s, 3H), 1.47 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.1, 155.5, 139.8, 134.5,
130.0, 123.0, 80.3, 50.1, 28.2, 21.2. HRMS (EI-TOF) m/z [M+Na]+
calcd for C14H19NO3SNa, 304.0978; found, 304.0980.
J
C‑F = 1.2 Hz), 133.5, 132.1, 129.4, 129.0, 128.7, 126.9, 126.0 (q, JC‑F
= 3.7 Hz), 123.9 (d, JC‑F = 273.0 Hz), 43.0. 19F{1H} NMR (377 MHz,
CDCl3) δ −62.6. HRMS (EI-TOF) m/z [M]+ calcd for
C15H12F3NOS, 311.0592; found, 311.0596.
S-(p-Tolyl) 2-(2-Naphthamido)ethanethioate (3d). White solid.
Mp: 186.5−187.3 °C. EtOAc/petroleum ether = 1:10. 1H NMR (300
MHz, CDCl3) δ 8.34 (s, 1H), 7.99−7.77 (m, 4H), 7.62−7.47 (m,
2H), 7.32 (d, J = 8.0 Hz, 2H), 7.26−7.20 (m, 2H), 7.04 (s, 1H), 4.55
(d, J = 5.4 Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 196.2, 167.5, 140.2, 134.9, 134.7, 132.5, 130.7, 130.3, 129.0, 128.6,
127.9, 127.79, 127.75, 126.9, 123.5, 122.5, 49.5, 21.3. HRMS (EI-
TOF) m/z [M + H]+ calcd for C20H18NO2S, 336.1053; found,
336.1053.
N-(((3,4-Difluorophenyl)thio)methyl)benzamide (2k). White solid
(114 mg, 82%). Mp: 101.5−102.8 °C. EtOAc/petroleum ether =
1:10. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.4 Hz, 2H), 7.52 (t,
J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.36−7.30 (m, 1H), 7.24−
7.19 (m, 1H), 7.15−7.06 (m, 1H), 6.57 (s, 1H), 4.86 (d, J = 6.3 Hz,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 151.4 (dd, JC‑F
=
S-(p-Tolyl) 2-(4-Chlorobenzamido)ethanethioate (3e). White
solid. Mp: 199.5−200.7 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5
Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.73 (s,
1H), 4.49 (d, J = 5.5 Hz, 2H), 2.39 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 195.9, 166.4, 140.4, 138.3, 134.7, 131.9, 130.3, 129.0,
128.5, 122.4, 49.3, 21.4. HRMS (EI-TOF) m/z [M + H]+ calcd for
C16H15ClNO2S, 320.0507; found, 320.0507.
12.9, 4.8 Hz), 148.9 (dd, JC‑F = 12.9, 3.2 Hz), 133.6, 132.0, 129.9 (q,
JC‑F = 5.6, 4.2 Hz), 128.7, 128.3 (q, JC‑F = 6.1, 3.7 Hz), 126.9, 121.0
(d, JC‑F = 17.9 Hz), 118.0 (d, JC‑F = 17.7 Hz), 45.0. 19F{1H} NMR
(377 MHz, CDCl3) δ −135.7 (d, J = 20.8 Hz), −138.0 (d, J = 21.3
Hz). HRMS (EI-TOF) m/z [M]+ calcd for C14H11F2NOS, 279.0529;
found, 279.0527.
N-((Thiophen-2-ylthio)methyl)benzamide (2l). White solid (100
1
mg, 80%). Mp: 87.1−88.9 °C. EtOAc/petroleum ether = 1:10. H
G
https://doi.org/10.1021/acs.joc.1c01480
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
S-(p-Tolyl) 2-(4-Methoxybenzamido)ethanethioate (3f). White
solid. Mp: 142.3−143.4 °C. EtOAc/petroleum ether = 1:8. H NMR
S-(p-Tolyl) 3-Benzamidopropanethioate (3n). White solid. Mp:
124.3−125.7 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.1 Hz, 1H),
7.41 (t, J = 7.3 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 8.1 Hz,
2H), 6.76 (s, 1H), 3.77 (d, J = 5.4 Hz, 2H), 3.01 (t, J = 5.2 Hz, 2H),
2.38 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.6, 167.3,
140.1, 134.5, 134.2, 131.5, 130.2, 128.5, 126.9, 123.5, 42.7, 35.7, 21.3.
N-((p-Tolylthio)methyl)acetamide (4a).29 White solid (70 mg,
1
(400 MHz, CDCl3) δ 7.79 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.0 Hz,
2H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.84 (t, J = 4.7
Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.84 (s, 3H), 2.37 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 196.40, 166.97, 162.54, 140.14,
134.65, 130.21, 128.99, 125.76, 122.65, 113.86, 55.40, 49.35, 21.31.
HRMS (EI-TOF) m/z [M + H]+ calcd for C17H18NO3S, 316.1002;
found, 316.1004.
1
72%). Mp: 95.3−96.7 °C. EtOAc/petroleum ether = 1:5. H NMR
(400 MHz, CDCl3) δ 7.33 (d, J = 6.1 Hz, 2H), 7.14 (d, J = 6.2 Hz,
2H), 5.80 (s, 1H), 4.62 (s, 2H), 2.34 (s, 3H), 1.94 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 169.6, 137.7, 131.7, 130.2, 130.0, 44.1,
23.2, 21.1.
S-(p-Tolyl) 2-(2-Phenylacetamido)ethanethioate (3g). White
solid. Mp: 117.5−118.1 °C. EtOAc/petroleum ether = 1:5. 1H
NMR (400 MHz, CDCl3) δ 7.39−7.33 (m, 2H), 7.30 (t, J = 3.2 Hz,
2H), 7.28 (d, J = 5.1 Hz, 2H), 7.25 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H),
6.05 (s, 1H), 4.24 (d, J = 5.7 Hz, 2H), 3.65 (s, 2H), 2.36 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 195.7, 171.1, 140.2, 134.6,
134.1, 130.2, 129.6, 129.1, 127.6, 122.5, 48.9, 43.5, 21.3. HRMS (EI-
TOF) m/z [M + H]+ calcd for C17H18NO2S, 300.1053; found,
300.1056.
S-(p-Tolyl) 2-(1,3-Dioxoisoindolin-2-yl)ethanethioate (3h). White
solid. Mp: 127.1−128.7 °C. EtOAc/petroleum ether = 1:10. 1H NMR
(400 MHz, CDCl3) δ 7.91 (s, 2H), 7.77 (d, J = 2.0 Hz, 2H), 7.32 (d, J
= 7.4 Hz, 2H), 7.21 (d, J = 7.5 Hz, 2H), 4.67 (s, 2H), 2.36 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 192.7, 167.3, 140.2, 134.7,
134.4, 131.9, 130.2, 123.7, 122.2, 46.3, 21.3. HRMS (EI-TOF) m/z
[M + H]+ calcd for C17H14NO3S, 312.0689; found, 312.0691.
S-(p-Tolyl) 2-Benzamido-3-phenylpropanethioate (3i). White
solid. Mp: 160.4−161.2 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.78−7.65 (m, 2H), 7.49 (d, 1H), 7.45−
7.36 (m, 2H), 7.31 (d, J = 5.3 Hz, 3H), 7.26−7.18 (m, 6H), 6.65 (d, J
= 6.2 Hz, 1H), 5.31 (s, 1H), 3.28 (s, 2H), 2.36 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 198.7, 167.0, 139.9, 135.4, 134.5, 133.6,
131.9, 130.1, 129.4, 128.7, 128.6, 127.3, 127.0, 123.2, 59.6, 38.3, 21.3.
HRMS (EI-TOF) m/z [M + H]+ calcd for C23H22NO2S, 376.1366;
found, 376.1365.
S-(p-Tolyl) 2-Benzamido-4-methylpentanethioate (3j). White
solid. Mp: 175.9−176.7 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.3
Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (d, J
= 8.0 Hz, 2H), 6.49 (d, J = 8.6 Hz, 1H), 5.16−5.03 (m, 1H), 2.37 (s,
3H), 1.92−1.83 (m, 1H), 1.83−1.73 (m, 1H), 1.73−1.65 (m, 1H),
1.00 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 199.6,
167.2, 139.9, 134.6, 133.8, 131.9, 130.1, 128.7, 127.1, 123.3, 57.8,
42.1, 25.0, 23.1, 21.7, 21.3. HRMS (EI-TOF) m/z [M + H]+ calcd for
C20H24NO2S, 342.1522; found, 342.1526.
S-(p-Tolyl) 2-Benzamidopropanethioate (3k). White solid. Mp:
158.7−159.8 °C. EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 7.7 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H),
7.46 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz,
2H), 6.66 (d, J = 7.1 Hz, 1H), 5.12−5.01 (m, 1H), 2.38 (s, 3H), 1.60
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 199.6, 166.9, 140.0,
134.6, 133.8, 131.9, 130.1, 128.7, 127.1, 123.0, 55.2, 21.3, 19.2.
HRMS (EI-TOF) m/z [M + H]+ calcd for C17H18NO2S, 300.1053;
found, 300.1053.
Methyl ((p-Tolylthio)methyl)carbamate (4b). White solid (95 mg,
1
90%). Mp: 55.5−56.7 °C. EtOAc/petroleum ether = 1:10. H NMR
(400 MHz, CDCl3) δ 7.35 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.8 Hz,
2H), 5.13 (s, 1H), 4.56 (d, J = 6.4 Hz, 2H), 3.65 (s, 3H), 2.33 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.2, 137.8, 132.5, 129.9,
128.5, 52.4, 46.9, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for
C10H13NO2S, 211.0667; found, 211.0668.
tert-Butyl ((p-Tolylthio)methyl)carbamate (4c). White solid (50
1
mg, 40%). mp: 47.6−48.8 °C. EtOAc/petroleum ether = 1:12. H
NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.9
Hz, 2H), 4.89 (s, 1H), 4.53 (d, J = 6.4 Hz, 2H), 2.33 (s, 3H), 1.40 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.9, 137.6, 132.4, 130.0,
129.9, 80.1, 46.4, 28.3, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for
C13H19NO2S, 253.1137; found 253.1135.
N-((p-Tolylthio)methyl)-2-naphthamide (4d). White solid (124
1
mg, 81%). mp: 99.8−101.1 °C. EtOAc/petroleum ether = 1:10. H
NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 7.84 (d, J = 7.3 Hz, 3H),
7.74 (d, J = 8.2 Hz, 1H), 7.62−7.46 (m, 2H), 7.40 (d, J = 7.4 Hz,
2H), 7.12 (d, J = 7.1 Hz, 2H), 6.71 (s, 1H), 4.87 (d, J = 5.8 Hz, 2H),
2.31 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 137.8,
134.8, 132.5, 132.2, 131.1, 130.0, 129.9, 128.9, 128.5, 127.8, 127.7,
127.5, 126.8, 123.4, 45.0, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for
C19H17NOS, 307.1031; found, 307.1027.
4-Chloro-N-((p-tolylthio)methyl)benzamide (4e).31 White solid
(108 mg, 74%). Mp: 93.7−94.8 °C. EtOAc/petroleum ether = 1:10.
1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.45−7.30
(m, 4H), 7.13 (d, J = 7.7 Hz, 2H), 6.46 (s, 1H), 4.80 (d, J = 6.0 Hz,
2H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.9, 138.1,
138.0, 132.3, 132.2, 130.1, 129.7, 128.9, 128.3, 45.0, 21.1.
4-Methoxy-N-((p-tolylthio)methyl)benzamide (4f).30 White solid
(110 mg, 77%). Mp: 102.2−103.5 °C. EtOAc/petroleum ether = 1:8.
1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 9H), 7.37 (d, J =
8.1 Hz, 8H), 7.26 (s, 6H), 7.13 (d, J = 7.8 Hz, 7H), 6.90 (d, J = 8.8
Hz, 7H), 6.36 (s, 4H), 4.82 (d, J = 6.1 Hz, 8H), 3.84 (s, 11H), 2.33
(s, 11H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 162.4, 137.8,
132.1, 130.0, 128.8, 126.2, 113.8, 55.4, 44.9, 21.1.
2-Phenyl-N-((p-tolylthio)methyl)acetamide (4g). White solid
(110 mg, 81%). Mp: 71.5−72.5 °C. EtOAc/petroleum ether = 1:5.
1H NMR (400 MHz, CDCl3) δ 7.35−7.32 (m, 1H), 7.32−7.28 (m,
2H), 7.19 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 1.8 Hz, 1H), 7.14 (s, 1H),
7.07 (s, 1H), 7.05 (s, 1H), 5.67 (s, 1H), 4.54 (d, J = 6.2 Hz, 2H), 3.52
(s, 2H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.4,
137.9, 134.3, 132.6, 129.9, 129.44, 129.41, 129.1, 127.4, 44.4, 43.7,
21.1. HRMS (EI-TOF) m/z [M]+ calcd for C16H17NOS, 271.1031;
found, 271.1034.
S-(p-Tolyl) 2-Acetamido-4-methylpentanethioate (3l). White
1
solid. Mp: 74.5−75.5 °C. EtOAc/petroleum ether = 1:10. H NMR
(400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.1 Hz,
2H), 5.82 (d, J = 8.6 Hz, 1H), 4.92−4.81 (m, 1H), 2.37 (s, 3H), 2.07
(s, 3H), 1.81−1.66 (m, 2H), 1.58−1.51 (m, 1H), 0.97 (t, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 199.6, 170.1, 139.8, 134.5,
130.0, 123.4, 57.5, 41.7, 24.8, 23.1, 23.0, 21.6, 21.3. HRMS (EI-TOF)
m/z [M+Na]+ calcd for C15H21NO2SNa, 302.1185; found, 302.1182.
S-(p-Tolyl) 2-(1,3-Dioxoisoindolin-2-yl)-2-methylpropanethioate
2-((p-Tolylthio)methyl)isoindoline-1,3-dione (4h).31 White solid
(133 mg, 94%). Mp: 109.8−110.5 °C. EtOAc/petroleum ether =
1
1:10. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.7 Hz, 2H), 7.72
(s, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H), 5.00 (s,
2H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.9, 138.3,
134.2, 133.2, 131.9, 129.8, 129.4, 123.5, 42.7, 21.2.
1
(3m). Colorless oil. EtOAc/petroleum ether = 1:10. H NMR (300
N-(2-Phenyl-1-(p-tolylthio)ethyl)benzamide (4i). White solid (34
1
MHz, CDCl3) δ 7.90−7.82 (m, 2H), 7.78−7.70 (m, 2H), 7.32 (d, J =
8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H), 1.94 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 199.4, 168.4, 139.7, 134.9,
134.2, 131.8, 130.0, 123.5, 123.3, 66.9, 24.9, 21.3. HRMS (EI-TOF)
m/z [M + H]+ calcd for C19H18NO3S, 340.1002; found, 340.1002.
mg, 20%). Mp: 73.5−74.4 °C. EtOAc/petroleum ether = 1:10. H
NMR (400 MHz, CDCl3) δ 7.55 (d, J = 6.5 Hz, 2H), 7.46 (d, J = 5.8
Hz, 1H), 7.43−7.33 (m, 4H), 7.34−7.26 (m, 5H), 7.07 (d, J = 6.6 Hz,
2H), 6.23 (d, J = 8.0 Hz, 1H), 5.85 (s, 1H), 3.33−3.10 (m, 2H), 2.28
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 138.1, 136.4,
H
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
134.0, 133.3, 131.6, 129.8, 129.6, 128.8, 128.53, 128.50, 127.1, 126.7,
58.1, 41.8, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for C22H21NOS,
347.1344; found, 347.1351.
REFERENCES
■
́
(1) (a) Sohár, P.; Kövesdi, I.; Szabo, J.; Katócs, A.; Fodor, L.; Szucs,
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N-(3-Methyl-1-(p-tolylthio)butyl)benzamide (4j). Colorless oil
(67 mg, 43%). EtOAc/petroleum ether = 1:10. 1H NMR (400
MHz, CDCl3) δ 7.62 (d, J = 7.3 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H),
7.42−7.34 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 6.13 (d, J = 9.5 Hz,
1H), 5.69−5.59 (m, 1H), 2.29 (s, 3H), 1.90−1.79 (m, 1H), 1.75−
1.66 (m, 2H), 0.98 (dd, J = 6.5, 4.1 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.2, 138.1, 134.2, 133.8, 131.6, 129.7, 128.5, 126.8,
55.9, 45.0, 25.6, 23.0, 22.5, 22.2, 21.1. HRMS (EI-TOF) m/z [M]+
calcd for C19H23NOS, 313.1500; found, 313.1506.
N-(1-(p-Tolylthio)ethyl)benzamide (4k). White solid (85 mg,
63%). Mp: 101.5−102.4 °C. EtOAc/petroleum ether = 1:10. 1H
NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 6.8
Hz, 1H), 7.44−7.31 (m, 4H), 7.10 (d, J = 7.3 Hz, 2H), 6.22 (s, 1H),
5.75−5.60 (m, 1H), 2.30 (s, 3H), 1.60 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.2, 138.2, 134.1, 133.6, 131.6, 129.8, 128.63,
128.55, 126.8, 53.1, 22.3, 21.1. HRMS (EI-TOF) m/z [M]+ calcd for
C16H17NOS, 271.1031; found, 271.1030.
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1
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mg, 54%). Mp: 78.0−79.1 °C. EtOAc/petroleum ether = 1:10. H
NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.8
Hz, 2H), 5.48 (s, 1H), 5.46−5.39 (m, 1H), 2.33 (s, 3H), 1.86 (s, 3H),
1.82−1.73 (m, 1H), 1.65−1.53 (m, 2H), 0.95 (s, 3H), 0.93 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 138.0, 133.6, 129.7,
128.7, 25.5, 23.2, 22.5, 22.1, 21.1. HRMS (EI-TOF) m/z [M]+ calcd
for C14H21NOS, 251.1344; found, 251.1346.
2-(2-(p-Tolylthio)propan-2-yl)isoindoline-1,3-dione (4m). Color-
1
less oil (50 mg, 32%). EtOAc/petroleum ether = 1:5. H NMR (300
MHz, CDCl3) δ 7.81−7.73 (m, 2H), 7.73−7.66 (m, 2H), 7.22 (d, J =
7.7 Hz, 2H), 6.99 (d, J = 7.6 Hz, 2H), 2.28 (s, 3H), 2.08 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 139.6, 136.8, 134.0,
131.6, 129.6, 122.9, 68.7, 29.9, 21.2. HRMS (EI-TOF) m/z [M]+
calcd for C18H17NO2S, 311.0980; found, 311.0986.
́
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̈
E.; Bernáth, G.; Tamás, J. Synthesis and conformational analysis of
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ASSOCIATED CONTENT
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sı
* Supporting Information
Dombi, G.; Gunther, G.; Bernáth, G.; Fodor, L. Ring-closure reaction
̈
of N-arylthiomethylaroylamides to 1, 3-benzothiazines. J. Heterocycl.
Chem. 1992, 29, 1321−1324.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01480.
1H, 13C, 19F NMR spectra; HRMS spectra; and chiral
HPLC spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
Yong-Ming Zhu − College of Pharmaceutical Sciences,
Soochow University, Suzhou 215123, China; orcid.org/
0000-0002-7078-7908; Email: zhuyongming@suda.edu.cn
(7) Sakai, H.; Ito, K.; Sekiya, M. Reaction of N-(Dialkylamino-
methyl) amides and N-(α-Dialkylaminobenzyl) amides with Sulfides
and Cyanide. Chem. Pharm. Bull. 1973, 21, 2257−2264.
Authors
Jing-Ya Zhou − College of Pharmaceutical Sciences, Soochow
University, Suzhou 215123, China
Rui Tian − College of Pharmaceutical Sciences, Soochow
University, Suzhou 215123, China
̌
́
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triethylammonium chloride. 2. A simple method for benzamidome-
thylation of thiols, amines and carboxylic acids. Molecules 2000, 5,
927−936.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01480
(9) (a) Wang, H. Y.; Zhang, J. X.; Cao, D. D.; Zhao, G.
Enantioselective addition of thiols to imines catalyzed by thiourea-
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L. X.; Zhang, B. H.; Zhang, J. N.; Shi, X. X.; Guo, R. X. One-pot
multicomponent asymmetric synthesis of α-amidosulfides from
thiophenol and N-acylimines generated in situ from α-amidosulfones.
Monatsh. Chem. Chem. Mon. 2017, 148, 375−379.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support by
PAPD (A Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions).
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