Synthesis of carbamothioate derivatives via a copper catalyzed thiocarboxamidation of aryl iodides

Article abstract of DOI:10.1007/s00706-020-02613-6

Abstract: A catalytic route to carbamothioate derivatives through a reaction involving isocyanides, elemental sulfur, and aryl iodides has been developed. The reaction scope has been examined using a range of isocyanides and aryl iodides. The reactions involve two consecutive C–S bond formations. Control experiment revealed that the reaction proceeds through an iminium species. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-020-02613-6

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02613-6
ORIGINAL PAPER
Synthesis of carbamothioate derivatives via a copper catalyzed
thiocarboxamidation of aryl iodides
Mehdi Khalaj1
Received: 24 February 2020 / Accepted: 27 April 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
A catalytic route to carbamothioate derivatives through a reaction involving isocyanides, elemental sulfur, and aryl iodides has
been developed. The reaction scope has been examined using a range of isocyanides and aryl iodides. The reactions involve
two consecutive C–S bond formations. Control experiment revealed that the reaction proceeds through an iminium species.
Graphic abstract
Keywords Cross-coupling reaction · Carbamothioate · Isocyanide · Copper catalysis · Aryl iodide
Introduction
[17]. Wang’s laboratory developed a versatile method for the
synthesis of sulfone skeletons using cross-coupling strategy
[18]. Consecutive cross-coupling/C–H functionalization has
been utilized to form a wide range of 2-(phenylthio)phe-
nols [19]. Jiang has developed tandem C–S bond formation/
condensation of 2-haloanilides with metal sulfdes to access
benzothiazoles skeletons [20].
Metal catalyzed cross-coupling reactions play a signifcant
role in syntheses of C–C and C–heteroatom bonds [1–3].
Of the cross-coupling reactions, the methods for C–S bond
formations are prominence due to the importance of C–S
bond in pharmaceutical agents and materials science [4–6].
Since the pioneering work of Migita in cross-coupling reac-
tion of aryl halides and thiols with Pd(PPh3)4 [7, 8], many
reports have been developed to circumvent the problems of
the transformation such as lack the efciency and tolerance
of functional groups [9, 10].
In this context, Zheng’s report on-palladium catalyzed
cross-coupling of thiophenols and aryl trifates serves as a
useful procedure for the synthesis of aryl sulfde skeletons
[21]. Sulfde salts have been also used as sulfur source for
synthesis of C–S bond [22]. Copper-catalyzed thioetherif-
cation of aryl halides with thiourea provides a complemen-
tary route to produce aryl sulfde derivatives [23]. Based on
previous reports, the reaction of isocyanides with elemental
aforded isothiocyanate derivatives via a nitrile sulfde inter-
mediate [24, 25].
The frst mechanistic study in carbon–sulfur bond for-
mation advanced by Hartwig’s group [11]. Subsequently,
a great number of reports by Buchwald, Venkataraman,
and Li have been developed [12–16]. Particularly, Buch-
wald described an interesting protocol to form C–S bond
which tolerated an exceptional level of functional-groups
The carbamothioate motif is important skeleton, which
exhibited a broad range of activities such as antiviral, bac-
tericidal, anesthetic, and pesticidal [26–28]. There are many
reports in literature featuring synthesis of this important
class of organosulfur compounds with reactions involv-
ing isocyanides are among the most documented methods
* Mehdi Khalaj
khalaj_mehdi@yahoo.com; m.khalaj@buiniau.ac.ir
1
Department of Chemistry, Buinzahra Branch, Islamic Azad
University, Buinzahra, Iran
Vol.:(0123456789)
1 3

M. Khalaj
Table 1 Optimization of the reaction conditions
Entry
Catalyst
Ligand
Solvent
Yield/%
1
2
3
4
5
6
7
8
CuI
CuOTf
CuOAc
Cu2O
CuBr
CuCl
CuCl2·2H2O
Cu(OAc)2·H2O
–
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
Toluene
THF
Dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
44
34
53
21
17
29
86
78
N.R
53
Trace
Trace
34
79
34
51
69
9
10
11
12
13
14
15
16
17
18
19
20
21
22
35
17
L1
L1
L1
57a
71b
48c
Reaction conditions for all entries except stated otherwise: 1a (1.2 mmol), 2a (0.2 equiv.), 3a (1.0 mmol), copper salt (0.1 mmol), ligand
(0.1 mmol), NMP (1.5 mmol), 3.0 cm3 solvent, 80 °C for 22 h
a0.05 mmol of CuCl2·2H2O was used
b18 h
cNMP (1.0 mmol)
[29–32]. Previous method in cross-coupling reactions
[33–35] encouraged us to evaluate the reactivity of iso-
cyanides, elemental sulfur, and aryl iodides in preparation
of carbamothioate skeletons through C-S cross-coupling
reaction.
Results and discussion
The reaction was initially conducted with cyclohexyl iso-
cyanide (1a), elemental sulfur (2), and iodobenzene (3a)
as substrates, CuI as the catalyst, and 1,10-phenanthroline
1
(Phen) as the ligand in MeCN at 80 °C. H NMR spectra
1 3

Synthesis of carbamothioate derivatives via a copper catalyzed thiocarboxamidation of aryl…
Table 2 Reaction scope with isocyanides and aryl iodides
Entry
Isocyanide, R1
Aryl iodide, R2
4, Yield/%
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
3a
3b
3c
3d
3e
3f
Phenyl
o-Tolyl
m-Tolyl
p-Tolyl
1-Naphthyl
4-MeO-C6H4
4-Br-C6H4
4-NO2-C6H4
4-CH3OCO-C6H4
3-CF3-C6H4
4-CN-C6H4
2-Thienyl
Phenyl
4a, 86
4b, 54
4c, 81
4d, 83
4e, 71
4f, 57
4g, 81
4h, 93
4i, 89
4j, 96
4k, 61
4l, 75
4m, 81
3g
3h
3i
9
10
11
12
13
3j
3k
3l
1,1,3,3-Tetrameth-
3a
ylbutyl
14
15
16
17
18
1c
1d
1e
1f
tert-Butyl
Benzyl
Phenyl
2,6-Dimethylphenyl
2-Naphthyl
3a
3a
3a
3a
3a
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4n, 80
4o, 83
4p, 72
4q, 51
4r, 74
1g
Reaction conditions: 1 (1.2 mmol), 2 (0.2 equiv.), 3 (1.0 mmol), CuCl2 (0.1 mmol), Phen (0.1 mmol), NMP (1.5 mmol), 3.0 cm3 DMF, 80 °C for
22 h
ligand screen proved the essential presence of L1 for success
of the crude reaction mixture indicated that the reaction is
of the transformation (Table 1, entries 15–19). Additionally,
not productive even at elevated temperatures and for a pro-
the reaction also shows a great dependence on the amount
longed time (not shown in Table 1). A literature surveying
of the catalyst (Table 1, entry 20). It is also noted that the
revealed that N-methylpiperidine (NMP) efectively reacts
reduction of the reaction time and additive amount resulted
with cyclooctasulfur, afording an active electrophile sulfur
in inferior yields (Table 1, entries 21, 22).
source. Accordingly, the use of NMP as the additive led to
The generality of this transformation was then evaluated
a promising 44% yield of the desired product together with
with diferent aryl iodides and isocyanides and the results
isothiocyanate cyclohexane in 21% yield (Table 1, entry 1).
are shown in Table 2. Iodobenzene (3a) reacted efciently
Whit this result, a range of catalysts have been examined to
and gave the desired product 4a in good yield (entry 1).
further improve the reaction yield. The copper screen indi-
As expected, steric hindrance of aryl synthon afected the
cated that the choice of copper salt has great impact on the
reaction yield; as 1-iodo-2-methylbenzene (3b) resulted in
reaction outcome (Table 1, entries 1–8). CuCl2 represented
diminished yield (entry 2). 3- and 4-methyl substituted iodo-
the optimum choice of catalyst for the reaction (Table 1,
benzenes 3c, 3d also aforded the corresponding product
entry 7). Meanwhile, Cu(OAc)2 also provided a good yield
in good yields (entries 3, 4). 1-Iodonaphthalene (3e) was
(Table 1, entry 8). As expected, the targeted product did
also tolerated however, the yield was slightly lower (entry
not obtain without the copper catalyst (Table 1, entry 9).
5). The presence of electron-donating group like methoxy
To further develop the reaction conditions, the reaction was
adversely afected the yield presumably duo to the inter-
conducted in various solvents (Table 1, entries 10–14). Polar
fering of methoxy group in coordination of copper catalyst
solvents were more productive in this transformation. A
and the lower electrophilicity of the substrate (entry 6). The
1 3

M. Khalaj
Scheme 1
Scheme 2
chemoselectivity of the proposed reaction was also exam-
ined using 1-bromo-4-iodobenzene (3g) and only the prod-
uct derived from cross-coupling at 4-position is detected
in crude reaction mixture analysis (entry 7). Gratefully, the
chemoselectivity in cross-coupling reaction gives further
advantage to the current work from a synthetic point of view.
Electron-defcient aryl iodides 3h–3k were also subjected to
the proposed cross-coupling reaction and the correspond-
ing carbamothioate products were achieved in good yields
however, the presence of CN- group on aryl ring resulted
in lower yield (entries 8–11). Heteroaromatic substrate 3l
aforded the desired product in reasonable yield (entry 12).
To further develop the scope of the proposed transformation
a range of alkyl and aryl isocyanides were also examined.
The study indicated that alkyl isocyanides were more ef-
cient than those of aryl isocyanides (entries 13–18).
To get insight on the reaction pathway, the reaction was
conducted with isothiocyanate cyclohexane 5. This experi-
ment revealed that the reaction did not proceed through
isothiocyanate intermediate (Scheme 1). Additionally, the
reaction was conducted in DMF:EtOH (1:1, 4.0 cm3) provid-
ing corresponding imidothioate 6 in 71% yield. This study
clearly indicated that the reaction proceeds through active
nitrilium species 11 (see Scheme 2).
Based on our experimental results and previous reports
[24, 25], the possible reaction pathway is depicted in
1 3

Synthesis of carbamothioate derivatives via a copper catalyzed thiocarboxamidation of aryl…
Scheme 2. Initially, ring opening activation of elemental
sulfur with NMP aforded active species 7 which further
reacted with isocyanide 1a to give intermediate 8. In par-
allel reaction, iodobenzene oxidatively added to copper
catalyst to form active intermediate 9. Ligand exchange of
intermediate 9 with species 8 gives intermediate 10 which
further transferred to C–S coupling intermediate 11 via a
reductive elimination sequence. Finally, 11 is hydrolyzed
during the aqueous work-up to aford the targeted product
4a (Scheme 2).
S‑Phenyl cyclohexylcarbamothioate (4a, C13H17NOS) The
crude product was purified by column chromatography
(SiO2, hexane/EtOAc 3/1, Rf: 0.24) afording 0.20 g (86%)
of 4a. IR (KBr): ̄ꢀ = 3311, 3036, 2959, 1653, 1461, 1243,
1
1067 cm−1; H NMR (500.1 MHz, CDCl3): δ = 1.23–1.99
(10H, m, 5 CH2), 3.87–3.93 (1H, m, CH), 6.73 (1H, d,
3J=5.8 Hz, NH), 7.25 (1H, t, 3J=7.3 Hz, CH), 7.31 (2H, t,
3J=7.3 Hz, 2 CH), 7.41 (2H, t, 3J=7.3 Hz, 2 CH) ppm; 13
C
NMR (125.7 MHz, CDCl3): δ=25.3 (2 CH2), 26.6 (CH2),
34.9 (2 CH2), 56.1 (CH), 126.1 (CH), 128.7 (2 CH), 130.1
(2 CH), 137.2 (C), 170.4 (C) ppm; EI-MS (70 eV): m/z
(%)=235 (M+, 2), 152 (13), 126 (34), 83 (81), 77 (100).
Conclusion
S‑(o‑Tolyl) cyclohexylcarbamothioate (4b, C14H19NOS) The
crude product was purified by column chromatography
(SiO2, hexane/EtOAc 3/1, Rf: 0.23) afording 0.15 g (54%)
4b. IR (KBr): ̄ꢀ = 3327, 3043, 2968, 1651, 1412, 1304,
In conclusion, we have developed a catalytic system for
direct thiocarboxamidation of aryl iodides using commer-
cially available substrates. A decent range of aryl iodides
and isocyanides were tolerated, providing the corresponding
products in reasonable yields.
1
1087 cm−1; H NMR (500.1 MHz, CDCl3): δ = 1.27–1.96
(10H, m, 5 CH2), 2.38 (3H, s, Me), 3.78–3.83 (1H, m, CH),
6.89 (1H, d, 3J=5.5 Hz, NH), 7.21 (1H, t, 3J=7.8 Hz, CH),
7.35 (1H, d, 3J=7.8 Hz, CH), 7.44 (1H, t, 3J=7.8 Hz, CH),
7.56 (1H, d, 3J=7.7 Hz, CH) ppm; 13C NMR (125.7 MHz,
CDCl3): δ = 23.9 (Me), 26.0 (2 CH2), 28.5 (CH2), 36.1 (2
CH2), 60.3 (CH), 126.1 (CH), 126.8 (CH), 128.3 (CH),
132.6 (CH), 135.1 (C), 144.7 (C), 171.2 (C) ppm; EI-MS
(70 eV): m/z (%)=249 (M+, 1), 166 (26), 151 (47), 126 (67),
121 (78), 83 (100).
Experimental
All reagents, catalysts, and solvents were obtained from
commercial sources (Aldrich, Acros, Merck, Fluka). Sol-
vents were stored over activated molecular sieves 3 Å or 4 Å
before the use. All reactions were carried out in Schlenk tube
(25 cm3). M.p.: Electrothermal-9100 apparatus. IR Spectra:
Shimadzu IR-460 spectrometer. 1H and 13C NMR spectra:
Bruker DRX-500 AVANCE instrument; in CDCl3 at 500.1
and 125.7 MHz, resp; δ in ppm, J in Hz. EI-MS (70 eV):
Finnigan-MAT-8430 mass spectrometer. Elemental analyses
(C, H, N) were performed with a Heraeus Rapid analyzer.
Column chromatography was performed using Silica gel 60
(particle size 63–200 µm). The reactions were monitored
by thin layer chromatography (silica gel 60, Merck, item
number 116835) using UV light (254 nm) to visualize the
progress of the reactions.
S‑(p‑Tolyl) cyclohexylcarbamothioate (4c, C14H19NOS) The
crude product was purified by column chromatography
(SiO2, hexane/EtOAc 4/1, Rf: 0.19) afording 0.20 g (81%)
4c. IR (KBr): ̄ꢀ = 3316, 3030, 2973, 1647, 1472, 1311,
1
1158 cm−1; H NMR (500.1 MHz, CDCl3): δ = 1.30–2.06
(10H, m, 5 CH2), 2.41 (3H, s, Me), 3.75–3.80 (1H, m, CH),
3
3
6.72 (1H, d, J = 5.7 Hz, NH), 6.85 (2H, d, J = 7.5 Hz,
2 CH), 6.97 (2H, d, J = 7.5 Hz, 2 CH) ppm; 13C NMR
3
(125.7 MHz, CDCl3): δ = 23.5 (Me), 26.3 (2 CH2), 29.2
(CH2), 36.4 (2 CH2), 59.7 (CH), 128.7 (2 CH), 130.6 (2
CH), 133.5 (C), 139.2 (C), 171.5 (C) ppm; EI-MS (70 eV):
m/z (%)=249 (M+, 1), 166 (19), 151 (43), 121 (55), 98 (63),
83 (100).
General procedure for compounds 4
A Schlenk tube (25 cm3) was charged with Cu salt
(0.1 mmol), NMP (1.5 mmol), isocyanide (1.2 mmol),
Phen (0.1 mmol), elemental sulfur (0.2 equiv.), aryl iodide
(1.0 mmol), and 3.0 cm3 DMF. The mixture was stirred for
30 min at ambient conditions and then warmed up to 80 °C.
The reaction mixture was then stirred for 22 h at 80 °C.
After consuming the starting material (TLC monitoring), the
resulting slurry was quenched with 5 cm3 sat.aq NH4Cl and
extracted with CH2Cl2 (3×10 cm3). The organic layers were
dried over MgSO4, fltered, and concentrated under vacuum.
The residue was subjected to fash chromatography (silica
gel, hexane:EtOAc) to give the pure targeted product 4.
S‑(m‑Tolyl) cyclohexylcarbamothioate (4d, C14H19NOS) The
crude product was purified by column chromatography
(SiO2, hexane/EtOAc 3/1, Rf: 0.29) afording 0.21 g (83%)
4d. IR (KBr): ̄ꢀ = 3322, 3019, 2958, 1643, 1462, 1266,
1
1097 cm−1; H NMR (500.1 MHz, CDCl3): δ = 1.26–1.92
(10H, m, 5 CH2), 2.45 (3H, s, Me), 3.71–3.77 (1H, m, CH),
6.72 (1H, d, 3J=5.5 Hz, NH), 6.91 (1H, d, 3J=7.9 Hz, CH),
7.13 (1H, s, CH), 7.19 (1H, t, 3J=7.9 Hz, CH), 7.33 (1H,
d, 3J=7.8 Hz, CH) ppm; 13C NMR (125.7 MHz, CDCl3):
δ=23.7 (Me), 26.1 (2 CH2), 27.9 (CH2), 35.1 (2 CH2), 58.1
(CH), 127.1 (CH), 127.9 (CH), 129.8 (CH), 134.3 (CH),
1 3

M. Khalaj
137.1 (C), 141.4 (C), 172.3 (C) ppm; EI-MS (70 eV): m/z
(%)=249 (M+, 1), 166 (19), 151 (54), 126 (39), 123 (69),
83 (100).
CDCl3): δ=1.33–1.96 (10H, m, 5 CH2), 3.86–3.91 (1H, m,
CH), 7.08 (1H, d, 3J=5.8 Hz, NH), 7.71 (2H, d, 3J=7.4 Hz,
3
2 CH), 8.11 (2H, d, J = 7.4 Hz, 2 CH) ppm; 13C NMR
(125.7 MHz, CDCl3): δ = 24.7 (2 CH2), 30.1 (CH2), 35.7
(2 CH2), 60.7 (CH), 126.4 (2 CH), 134.1 (2 CH), 139.7 (C),
148.3 (C), 172.4 (C) ppm; EI-MS (70 eV): m/z (%) = 280
(M+, 1), 197 (11), 182 (34), 154 (26), 126 (89), 83 (100).
S‑(Naphthalen‑1‑yl) cyclohexylcarbamothioate (4e,
C17H19NOS) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 4/1, Rf: 0.16) aford-
ing 0.20 g (71%) 4e. IR (KBr): ̄ꢀ = 3317, 3031, 2971,
1647, 1456, 1311, 1201, 1068 cm−1; 1H NMR (500.1 MHz,
CDCl3): δ = 1.19–1.87 (10H, m, 5 CH2), 3.76–3.82 (1H,
Methyl 4‑[(cyclohexylcarbamoyl)thio]benzoate (4i,
C15H19NO3S) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 3/1, Rf: 0.34) aford-
ing 0.26 g (89%) 4i. IR (KBr): ̄ꢀ = 3327, 3032, 2961, 1737,
3
m, CH), 6.88 (1H, d, J = 5.7 Hz, NH), 7.39–7.55 (4H,
3
m, 4 CH), 7.84 (1H, d, J = 7.6 Hz, CH), 8.03 (1H, d,
3
1
3J = 7.8 Hz, CH), 8.26 (1H, d, J = 7.4 Hz, CH) ppm; 13C
1644, 1272, 1068 cm−1; H NMR (500.1 MHz, CDCl3):
NMR (125.7 MHz, CDCl3): δ=25.8 (2 CH2), 28.3 (CH2),
36.2 (2 CH2), 59.3 (CH), 124.3 (CH), 125.2 (CH), 127.3
(CH), 127.8 (CH), 129.5 (CH), 129.8 (CH), 130.3 (C), 131.7
(CH), 134.5 (C), 136.1 (C), 170.8 (C) ppm; EI-MS (70 eV):
m/z (%) = 285 (M+, 1), 202 (13), 187 (32), 159 (41), 127
(72), 83 (100).
δ = 1.29–1.95 (10H, m, 5 CH2), 3.81 (3H, s, OMe), 3.90–
3.95 (1H, m, CH), 6.72 (1H, d, 3J=5.4 Hz, NH), 7.37 (2H,
d, 3J=7.6 Hz, 2 CH), 7.90 (2H, d, 3J=7.6 Hz, 2 CH) ppm;
13C NMR (125.7 MHz, CDCl3): δ = 24.8 (2 CH2), 29.6
(CH2), 35.3 (2 CH2), 54.12 (OMe), 59.5 (CH), 128.2 (C),
130.5 (2 CH), 132.7 (2 CH), 141.4 (C), 167.4 (C), 170.8 (C)
ppm; EI-MS (70 eV): m/z (%)=293 (M+, 1), 262 (11), 210
(31), 195 (48), 126 (78), 83 (100).
S‑(4‑Methoxyphenyl) cyclohexylcarbamothioate (4f,
C14H19NO2S) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 3/1, Rf: 0.14) aford-
ing 0.15 g (57%) 4f. IR (KBr): ̄ꢀ = 3314, 3042, 2981, 1640,
S‑[3‑(Trifuoromethyl)phenyl] cyclohexylcarbamothioate (4j,
C14H16F3NOS) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 2/1, Rf: 0.29) aford-
ing 0.28 g (93%) 4j. IR (KBr): ̄ꢀ = 3332, 3044, 2985, 1652,
1
1311, 1232, 1066 cm−1; H NMR (500.1 MHz, CDCl3):
δ = 1.24–1.84 (10H, m, 5 CH2), 3.76 (3H, s, OMe), 3.87–
3.92 (1H, m, CH), 6.89 (1H, d, 3J=5.6 Hz, NH), 7.12 (2H,
d, 3J=7.8 Hz, 2 CH), 7.55 (2H, d, 3J=7.8 Hz, 2 CH) ppm;
13C NMR (125.7 MHz, CDCl3): δ = 24.1 (2 CH2), 28.4
(CH2), 36.2 (2 CH2), 56.1 (OMe), 60.3 (CH), 114.3 (2 CH),
129.9 (C), 131.2 (2 CH), 159.1 (C), 171.2 (C) ppm; EI-MS
(70 eV): m/z (%)=265 (M+, 1), 182 (13), 167 (25), 139 (78),
126 (52), 107 (100), 83 (89).
1
1467, 1248, 1076 cm−1; H NMR (500.1 MHz, CDCl3):
δ=1.18–1.92 (10H, m, 5 CH2), 3.96–4.03 (1H, m, CH), 7.02
(1H, d, 3J=5.4 Hz, NH), 7.18 (1H, d, 3J=7.5 Hz, CH), 7.31
(1H, t, 3J=7.6 Hz, CH), 7.40 (1H, d, 3J=7.6 Hz, CH), 7.53
(1H, s, CH) ppm; 13C NMR (125.7 MHz, CDCl3): δ=23.8
(2 CH2), 27.8 (CH2), 36.7 (2 CH2), 60.7 (CH), 124.2 (CH,
3
3
q, J = 4.1 Hz), 125.3 (CH, q, J = 4.1 Hz), 128.2 (CF3,
1
q, J = 268.5 Hz), 129.7 (CH), 129.5 (CH), 132.6 (C, q,
S‑(4‑Bromophenyl) cyclohexylcarbamothioate (4g,
C13H16BrNOS) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 4/1, Rf: 0.29) aford-
ing 0.25 g (81%) 4g. IR (KBr): ̄ꢀ = 3328, 3017, 2981, 1651,
2J=34.8 Hz), 134.2 (CH), 137.6 (C), 173.8 (C) ppm; EI-MS
(70 eV): m/z (%)=303 (M+, 4), 220 (9), 205 (31), 177 (74),
98 (66), 83 (100).
1
1478, 1244, 1063 cm−1; H NMR (500.1 MHz, CDCl3):
S‑(4‑Cyanophenyl) cyclohexylcarbamothioate (4k,
C14H16N2OS) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 2/1, Rf: 0.31) aford-
ing 0.16 g (61%) 4k. IR (KBr): ̄ꢀ = 3322, 3045, 2976,
2241, 1649, 1463, 1266, 1061 cm−1; 1H NMR (500.1 MHz,
CDCl3): δ=1.21–1.88 (10H, m, 5 CH2), 3.84–3.91 (1H, m,
CH), 6.92 (1H, d, 3J=5.7 Hz, NH), 7.41 (2H, d, 3J=7.8 Hz,
δ=1.34–1.95 (10H, m, 5 CH2), 3.93–3.97 (1H, m, CH), 6.77
3
(1H, d, 3J=5.5 Hz, NH), 7.32 (2H, d, J=7.3 Hz, 2 CH),
7.82 (2H, d, 3J=7.3 Hz, 2 CH) ppm; 13C NMR (125.7 MHz,
CDCl3): δ = 25.7 (2 CH2), 29.6 (CH2), 35.4 (2 CH2), 58.7
(CH), 122.1 (C), 130.5 (2 CH), 132.8 (2 CH), 136.2 (C),
170.2 (C) ppm; EI-MS (70 eV): m/z (%)=313 (M+ +2, 3),
313 (M+, 3), 217 (26), 215 (26), 189 (43),187 (43), 126 (62),
98 (81), 83 (100).
3
2 CH), 7.67 (2H, d, J = 7.8 Hz, 2 CH) ppm; 13C NMR
(125.7 MHz, CDCl3): δ = 24.3 (2 CH2), 30.1 (CH2), 36.1
(2 CH2), 60.1 (CH), 116.3 (C), 128.9 (2 CH), 134.1 (2 CH),
139.2 (C), 142.7 (C), 170.5 (C) ppm; EI-MS (70 eV): m/z
(%)=260 (M+, 1), 177 (34), 162 (16), 134 (31), 128 (89),
83 (100).
S‑(4‑Nitrophenyl) cyclohexylcarbamothioate (4h,
C
13H16N2O3S) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 1/1, Rf: 0.18) aford-
ing 0.26 g (93%) 4h. IR (KBr): ̄ꢀ = 3341, 3018, 2953, 1654,
1518, 1473, 1344, 1219, 1054 cm−1; 1H NMR (500.1 MHz,
1 3

Synthesis of carbamothioate derivatives via a copper catalyzed thiocarboxamidation of aryl…
S‑(Thiophen‑2‑yl) cyclohexylcarbamothioate (4l,
C11H15NOS2) The crude product was purifed by column
chromatography (SiO2, hexane/EtOAc 4/1, Rf: 0.16) aford-
ing 0.18 g (75%) 4l. IR (KBr): ̄ꢀ = 3316, 3044, 2980, 1647,
S‑Phenyl phenylcarbamothioate (4p, C13H11NOS) The crude
product was purifed by column chromatography (SiO2,
hexane/EtOAc 3/1, Rf: 0.18) afording 0.16 g (72%) 4p.
IR (KBr): ̄ꢀ = 3341, 3045, 2971, 1655, 1411, 1314, 1182,
1
1
1454, 1311, 1198, 1046 cm−1; H NMR (500.1 MHz,
1061 cm−1; H NMR (500.1 MHz, CDCl3): δ = 7.11 (1H,
3
CDCl3): δ=1.29–1.93 (10H, m, 5 CH2), 3.88–3.93 (1H, m,
CH), 6.71 (1H, d, 3J=5.5 Hz, NH), 6.93 (1H, t, 3J=7.0 Hz,
CH), 7.19 (1H, d, 3J=7.0 Hz, CH), 7.54 (1H, d, 3J=7.0 Hz,
CH) ppm; 13C NMR (125.7 MHz, CDCl3): δ=25.3 (2 CH2),
28.2 (CH2), 35.1 (2 CH2), 57.9 (CH), 124.6 (C), 125.1 (CH),
128.3 (CH), 129.7 (CH), 169.6 (C) ppm; EI-MS (70 eV):
m/z (%) = 241 (M+, 1), 158 (43), 143 (24), 126 (67), 115
(86), 83 (100).
t, J = 7.8 Hz, CH), 7.23–7.34 (5H, m, 5 CH), 7.43 (2H,
3
3
d, J = 7.4 Hz, 2 CH), 7.66 (2H, d, J = 7.8 Hz, 2 CH),
8.19 (1H, br s, NH) ppm; 13C NMR (125.7 MHz, CDCl3):
δ = 119.8 (2 CH), 126.2 (CH), 127.1 (CH), 128.1 (2 CH),
129.7 (2 CH), 130.7 (2 CH), 136.1 (C), 138.2 (C), 168.3 (C)
ppm; EI-MS (70 eV): m/z (%)=229 (M+, 1), 152 (54), 120
(76), 109 (43), 77 (100), 54 (42).
S‑Phenyl (2,6‑dimethylphenyl)carbamothioate (4q,
C15H15NOS) The crude product was purified by column
chromatography (SiO2, hexane/EtOAc 5/1, Rf: 0.21) aford-
ing 0.13 g (51%) 4q. IR (KBr): ̄ꢀ = 3341, 3046, 2966,
1652, 1478, 1317, 1178, 1072 cm−1; 1H NMR (500.1 MHz,
S‑Phenyl (2,4,4‑trimethyl‑2‑pentyl)carbamothioate (4m,
C15H23NOS) The crude product was purifed by column chro-
matography (SiO2, hexane/EtOAc 4/1, Rf: 0.35) afording
0.21 g (81%) 4m. IR (KBr): ꢀ̄ = 3331, 3035, 2973, 1651,
1471, 1411, 1265, 1143, 1062 cm−1; 1H NMR (500.1 MHz,
CDCl3): δ = 1.09 (9H, s, 3 Me), 1.45 (2H, s, CH2), 1.54
3
CDCl3): δ = 2.29 (6H, s, 2 Me), 6.98 (1H, t, J = 7.3 Hz,
CH), 7.13 (2H, d, 3J=7.3 Hz, 2 CH), 7.25–7.34 (3H, m, 3
CH), 7.44 (2H, d, 3J=7.6 Hz, 2 CH), 8.02 (1H, br s, NH)
ppm; 13C NMR (125.7 MHz, CDCl3): δ=20.1 (2 Me), 125.2
(CH), 126.7 (CH), 127.6 (2 CH), 128.7 (2 CH), 129.4 (2
CH), 132.5 (2 C), 136.3 (C), 137.1 (C), 167.1 (C) ppm;
EI-MS (70 eV): m/z (%)=257 (M+, 1), 152 (19), 148 (67),
109 (43), 105 (100), 77 (76).
3
(6H, s, 2 Me), 6.80 (1H, d, J = 5.4 Hz, NH), 7.29 (1H, t,
3J=7.7 Hz, CH), 7.33 (2H, t, 3J=7.7 Hz, 2 CH), 7.46 (2H,
t, 3J=7.7 Hz, 2 CH) ppm; 13C NMR (125.7 MHz, CDCl3):
δ=28.9 (2 Me), 32.6 (3 Me), 34.1 (C), 48.2 (C), 55.7 (CH2),
126.4 (CH), 128.9 (2 CH), 130.4 (2 CH), 136.4 (C), 169.2
(C) ppm; EI-MS (70 eV): m/z (%)=265 (M+, 2), 208 (16),
156 (55), 152 (34), 113 (78), 109 (19), 57 (100).
S‑Phenyl naphthalen‑2‑ylc arbamothioate (4r,
C17H13NOS) The crude product was purified by column
chromatography (SiO2, hexane/EtOAc 3/1, Rf: 0.30) aford-
ing 0.21 g (74%) 4r. IR (KBr): ̄ꢀ = 3340, 3051, 2963,
1651, 1478, 1287, 1167, 1076 cm−1; 1H NMR (500.1 MHz,
CDCl3): δ=6.98 (1H, t, 3J=7.3 Hz, CH), 7.08 (1H, s, CH),
S‑Phenyl tert‑butylcarbamothioate (4n, C11H15NOS) The
crude product was purified by column chromatography
(SiO2, hexane/EtOAc 3/1, Rf: 0.32) afording 0.17 g (80%)
4n. IR (KBr): ̄ꢀ = 3327, 3043, 2952, 1651, 1473, 1311,
1199, 1075 cm−1; 1H NMR (500.1 MHz, CDCl3): δ=1.49
3
3
(9H, s, 3 Me), 6.72 (1H, d, J = 5.6 Hz, NH), 7.26 (1H, t,
7.27–7.44 (8H, m, 8 CH), 7.59 (1H, d, J = 7.4 Hz, CH),
3J=7.4 Hz, CH), 7.32 (2H, t, 3J=7.4 Hz, 2 CH), 7.43 (2H,
t, 3J=7.4 Hz, 2 CH) ppm; 13C NMR (125.7 MHz, CDCl3):
δ=32.9 (3 Me), 60.3 (C), 126.9 (CH), 129.3 (2 CH), 129.8
(2 CH), 136.7 (C), 169.8 (C) ppm; EI-MS (70 eV): m/z
(%) = 209 (M+, 2), 152 (27), 109 (16), 100 (57), 77 (83),
57 (100).
7.73 (1H, d, 3J=7.2 Hz, CH), 7.82 (1H, d, 3J=7.4 Hz, CH),
8.11 (1H, br s, NH) ppm; 13C NMR (125.7 MHz, CDCl3):
δ=118.2 (CH), 120.2 (CH), 122.5 (CH), 125.1 (CH), 125.5
(C), 125.7 (CH), 126.2 (CH), 126.7 (CH), 128.9 (CH), 129.2
(2 CH), 130.5 (2 CH), 134.1 (C), 136.2 (C), 137.8 (C), 167.5
(C) ppm; EI-MS (70 eV): m/z (%)=279 (M+, 2), 170 (74),
142 (51), 137 (40), 127 (83), 77 (100).
S‑Phenyl benzylcarbamothioate (4o, C14H13NOS) The crude
product was purifed by column chromatography (SiO2, hex-
ane/EtOAc 5/1, Rf: 0.19) afording 0.20 g (83%) 4o. (KBr):
O‑Ethyl S‑phenyl cyclohexylcarbonimidothioate (6,
C15H21NOS) The crude product was purifed by column chro-
matography (SiO2, hexane/EtOAc 6/1, Rf: 0.32) afording
0.20 g (71%) of 6. IR (KBr): ꢀ̄ = 3052, 2981, 1606, 1452,
1311, 1182 cm−1; 1H NMR (500.1 MHz, CDCl3): δ=1.20
(3H, t, 3J=5.8 Hz, CH3), 1.32–1.87 (10H, m, 5 CH2), 3.76
1
̄ꢀ = 3322, 3017, 2971, 1653, 1455, 1276, 1083 cm−1; H
3
NMR (500.1 MHz, CDCl3): δ = 4.44 (2H, d, J = 5.7 Hz,
CH2), 6.83 (1H, t, 3J=5.7 Hz, NH), 7.24–7.41 (10H, m, 10
CH) ppm; 13C NMR (125.7 MHz, CDCl3): δ=49.2 (CH2),
124.7 (CH), 126.3 (CH), 127.3 (2 CH), 128.8 (2 CH), 130.1
(2 CH), 131.3 (2 CH), 136.2 (C), 139.4 (C), 171.1 (C) ppm;
EI-MS (70 eV): m/z (%)=243 (M+, 1), 152 (16), 134 (61),
106 (33), 91 (100), 77 (68).
3
(2H, q, J = 5.8 Hz, CH2), 4.03–4.09 (1H, m, CH), 7.26
3
3
(2H, d, J = 7.8 Hz, 2 CH), 7.31 (1H, t, J = 7.8 Hz, CH),
7.43 (2H, t, 3J=7.8 Hz, 2 CH) ppm; 13C NMR (125.7 MHz,
CDCl3): δ=17.9 (CH3), 27.3 (2 CH2), 29.1 (CH2), 35.2 (2
CH2), 60.8 (CH), 64.2 (CH2), 126.7 (CH), 130.2 (2 CH),
1 3

M. Khalaj
18. Baskin JM, Wang Z (2002) Org Lett 4:4423
131.6 (2 CH), 134.9 (C), 155.2 (C) ppm; EI-MS (70 eV):
m/z (%)=235 (M+, 2), 152 (13), 126 (34), 83 (81), 77 (100).
19. Xu R, Wan JP, Mao H, Pan Y (2010) J Am Chem Soc 132:15531
20. Ma D, Xie S, Xue P, Zhang X, Dong J, Jiang Y (2009) Angew
Chem Int Ed 48:4222
21. Zheng N, McWilliams JC, Fleitz FJ, Armstrong JD, Volante RP
(1998) J Org Chem 63:9606
Acknowledgements The laboratory support by the Islamic Azad Uni-
versity, Buinzahra Branch is highly acknowledged.
22. You W, Yan X, Liao Q, Xi C (2015) Org Lett 12:3930
23. Firouzabadi H, Iranpoor N, Gholinejada M (2010) Adv Synth
Catal 352:119
24. Boyer JH, Ramakrishnan VT (1972) J Org Chem 37:1360
25. Samzadeh-Kermani A, Zamenraz S (2017) Monatsh Chem
148:1753
References
1. Liu C, Zhang H, Shi W, Lei A (2011) Chem Rev 111:1780
2. Xu J, Liu RY, Yeung CS, Buchwald SL (2019) ACS Catal 97:6461
3. Chen TG, Zhang H, Mykhailiuk PK, Merchant RR, Smith CA,
Qin T, Baran PS (2019) Angew Chem Int Ed 58:2454
4. Sindhu KS, Abi TG, Mathai G, Anilkumar G (2019) Polyhedron
158:270
26. Beji M, Sbihi H, Baklouti A, Cambon A (1999) J Fluor Chem
99:17
27. Heyns AJ, Carter GA, Rothwell K, Wain RL (1966) Ann Appl
Biol 57:33
28. Padiya KJ, Gavade S, Kardile B, Tiwari M, Bajare S, Mane M,
Gaware V, Varghese S, Harel D, Kurhade S (2012) Org Lett
14:2814
5. Han J, Wang K, You G, Wang G, Sun J, Duan G, Xia C (2019)
Catal Commun 128:105708
29. Wei W, Bao P, Yue H, Liu S, Wang L, Li Y, Yang D (2018) Org
Lett 20:5291
6. Sikari R, Sinha S, Das S, Saha A, Chakraborty G, Mondal R, Paul
ND (2019) J Org Chem 84:4072
30. Wu S, Lei X, Fan E, Sun Z (2018) Org Lett 20:522
31. Mampuys P, Zhu Y, Sergeyev S, Ruijter E, Orru RVA, Van
Doorslaer S, Maes BUW (2016) Org Lett 18:2808
32. Grzyb JA, Shen M, Yoshina-Ishii C, Chi W, Brown RS, Batey RA
(2005) Tetrahedron 61:7153
7. Migita T, Shimizu T, Asami Y, Shiobara JI, Kato Y, Kosugi M
(1980) Bull Chem Soc Jpn 53:1385
8. Kosugi M, Ogata T, Terada M, Sano H, Migita T (1985) Chem
Soc Jpn 58:3657
9. Hartwig JF (1998) Acc Chem Res 31:852
33. Nasrollahzadeh M, Sajadi SM, Rostami-Vartoonia A, Khalaj M
(2014) RSC Adv 4:43477
10. Mann G, Baranano D, Hartwig JF, Rheingold AL, Guzei IA
(1998) J Am Chem Soc 120:9205
34. Nasrollahzadeh M, Sajadi SM (2016) J Colloid Interface Sci
469:191
11. Louie J, Hartwig JF (1995) J Am Chem Soc 117:11598
12. Bates CG, Gujadhur RK, Venkataraman D (2002) Org Lett 4:2803
13. Klapars A, Antilla JC, Huang XH, Buchwald SL (2001) J Am
Chem Soc 123:7727
35. Nasrollahzadeh M, Motahharifar N, Ghorbannezhad F, Soheili
Bidgoli NS, Baran T, Varma RS (2020) Mol Catal 480:110645
14. Li GY (2001) Angew Chem Int Ed 40:1513
15. Li GY (2002) J Org Chem 67:3643
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
16. Schopfer U, Schlapbach A (2001) Tetrahedron 57:3069
17. Kwong FY, Buchwald SL (2002) Org Lett 4:3517
1 3