Synthesis of thiocarbamoyl fluorides and isothiocyanates using amines with CF3SO2Cl

Article abstract of DOI:10.1021/acs.joc.0c01634

A practical and efficient method to synthesize thiocarbamyl fluorides and isothiocyanates from amines with trifluoromethanesulfonyl chloride was developed. In the presence of the reducing agent triphenylphosphine and sodium iodide, thiocarbamyl fluorides and isothiocyanates were synthesized from secondary/primary amine in moderate to excellent yields, respectively. A broad scope of substrates and good functional group compatibility were observed.

Full text of DOI:10.1021/acs.joc.0c01634

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Article
Synthesis of Thiocarbamoyl Fluorides and
Isothiocyanates using Amines with CF3SO2Cl
Jingjing Wei, Shuaishuai Liang, Lvqi Jiang, and Wenbin Yi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01634 • Publication Date (Web): 31 Aug 2020
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Synthesis of Thiocarbamoyl Fluorides and
Isothiocyanates using Amines with CF3SO2Cl
Jingjing Wei,†, §Shuaishuai Liang,†, § Lvqi Jiang,*,† Wenbin Yi*,†
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† School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P.
R. China
ABSTRACT: A practical and efficient produce to synthesize thiocarbamyl fluorides and isothiocyanates from
amines with trifluoromethanesulfonyl chloride was developed. In the presence of reducing agent
triphenylphosphine and sodium iodide, secondary amines/primary amines method thiocarbamyl fluorides and
isothiocyanates in moderate to excellent yields, respectively. A broad scope of substrates and good functional
group compatibility were observed.
S
R
F
H
N
N
21 examples
18 examples
R
R
R'
R'
PPh3, NaI
DMF, rt
CF3SO2Cl
+
NH2
R
NCS
INTRODUCTION
Organofluorine compounds are important in pharmaceutical chemistry and agrochemistry because of their
special chemical and biological properties.1 In recent years, the synthesis of thiocarbamoyl fluoride has
received much attention owing to the special structure, which contains nitrogen, sulfur and fluorine elements,
makes it have enormous potential applications in the pharmaceuticals field.2 Isothiocyanates are important
organic compounds that are widely present in drugs, natural products, and material molecules.3 As one of the
most important classes of organic compounds, they are widely used in biological fields and synthetic
chemistry.4 Considering the wide applications of isothiocyanates, the use of simple and efficient methods to
construct the –NCS group in molecules is of great significance for the pharmaceutical and agrochemical
industries. Thus, the development of synthetic methods for the synthesis of those compounds under mild
conditions is highly desired.
In the last years, several strategies have been reported for the synthesis of thiocarbamoyl fluoride and/or
isothiocyanates from secondary amines and/or primary amines. Until now, there are about five reagents has
been development for the simultaneous synthesis of thiocarbamoyl fluorides and isothiocyanates. In 2017, the
group of Schoenebeck demonstrated that amines react with Me4NSCF3 furnishing thiocarbamoyl fluorides
and/or isothiocyanates at room temperature, respectively (Scheme 1).5 Afterwards the group of Xiao reported
-
reaction of thiocarbonyl fluoride generated from Ph3P+CF2CO2 , S8 with amines (Scheme 1).6 Recently, Jiang’s
group7 described two pathways to access thiocarbamoyl fluorides and isothiocyanation by using CF3SiMe3,
S8, KF or AgSCF3, KBr (Scheme 1). Although Zheng’s group8 has reported that Langlois reagent (CF3SO2Na)
can also participate in isothiocyanation of primary amines in the presence of CuI/HPO(OEt)2 in 2017, a mild
method for the synthesize of thiocarbamoyl fluoride using CF3SO2Na and triphenylphosphine has recently
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been reported by our group (Scheme 1)9. With our continuous interest in exploring construction of N-C bounds,
we thought the development of efficient methods by cheap material would constitute an attractive option for
the access of thiocarbamoyl fluorides and isothiocyanates.
6
7
Scheme 1. Synthetic strategies for Thiocarbamoyl Fluorides/Isothiocyanates.
8
Schoenebeck's work
Xiao's work
9
S
R
F
Ph3P+CF2CO2-, S8
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Me4NSCF3
N
DCM or CH3CN
DME, 50°C
R'
RT
our
PPh
rece
H
N
n
t
R
R'
3
,
MeCN,
work
CH3CN or
THF, RT
RT
CF3SiMe3, S8, KF
or AgSCF3, KBr
CuI, HPO(OEt)2
toluene, 110°C
CF3SO2Na
R
NCS
Jiang's work
Tang and Zheng's work
this work
S
F
R'H
H
N
PPh3, NaI
DMF, rt
R'
N
R
R
R
R'
CF3SO2Cl
+
R'=H
NCS
R =aryl or alkyl
Trifluoromethanesulfonyl chloride (CF3SO2Cl), as a easy-to-handle and commercially available cheap
material, has been widely used in the formation of sulfonamides and sulfonic esters,10 and also in electrophilic
chlorination,11 trifluoromethylation or trifluoromethyl-chlorosulfonylation etc.12 Our group has reported its
application in the electrophilic trifluoromethylthiolation of indoles, pyrroles, enamines and chloro-
trifluoromethylthiolation of alkenes and alkynes.13 In this context, we envisioned that straightforward synthesis
of thiocarbamoyl fluoride and isothiocyanates by CF3SO2Cl can be achieved under suitable reductive
conditions, we herein disclose a novel use of trifluoromethanesulfonyl chloride to prepare thiocarbamoyl
fluoride and isothiocyanates.
RESULTS AND DISCUSSION
We initially investiagated the treatment of N-methylaniline 1a with CF3SO2Cl 2a (1.5 equiv) in the presence
of PPh3(3.0 equiv) in DMF at r.t. to yield the thiocarbamyl fluorides product 3a in 18% yield (Table 1, entry
1). Encouraged by this result, optimisation of the reaction conditions was then carried out. Considering that
iodide anion can promote the reduction of sulfonyl chloride,14 a series of iodide sources including KI, NH4I,
NaI, and I2 were tested (Table 1, entries 2−6). and among them NaI giving the highest yield (47%, Table 1,
entry 4). When KI and NH4I was used as the catalyst, the product 3a was obtained in 40% and 35% yield,
respectively (Table 1, entries 2, 3), I2 did not increase the yield obviously (Table 1, entry 5). Increasing the
loadings of NaI to 1.5 equiv increase the product yield to 88% (Table 1, entries 6, 7). We next examined the
effect of solvents on yield. After several solvents were screened, DMF proved to be the best option in the
transformation. Other solvents such as MeCN, THF, and 1,2-dichloroethane were less effective for this kind
of reation (Table 1, entries 8-12). When the amount of CF3SO2Cl 2a is reduced to 1.2 equiv, the yield will be
reduced to 61% (Table 1, entries 13). Thus, 1:1.5:3:1.5 amine/CF3SO2Cl/PPh3/NaI in DMF at r.t. for 4 h was
selected as the optimized reaction conditions. Notably, the present reaction is scalable, and 1.25 g (74%) of 3a
was isolated when the reaction was performed on a 10 mmol scale (Table 1, entry 14).
Table 1. Optimization of reaction conditionsa
S
F
H
PPh3, additive
solvent, r.t.
N
CF3SO2Cl
N
+
Ph
Ph
2a
1a
3a
entry
additive (equiv)
solvent
DMF
yield(%)[b]
1
2
-
18
40
KI (0.5)
DMF
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NH4I (0.5)
NaI (0.5)
I2 (0.5)
DMF
35
4
DMF
47
5
DMF
13
7
8
9
6
NaI (1.0)
NaI (1.5)
NaI (1.5)
NaI (1.5)
NaI (1.5)
NaI (1.5)
NaI (1.5)
NaI (1.5)
NaI (1.5)
DMF
68
7
DMF
88
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MeCN
THF
22
9
41
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14
1,4-dioxane
DCE
trace
40
AcOH
DMF
18
61[c]
74[d]
DMF
aReaction conditions: N-methylaniline (0.5 mmol), CF3SO2Cl (0.75 mmol), PPh3 (1.5 mmol), DMF (2.5 mL), r.t. for 4h. Yield
determined by 19F NMR using p-fluorotoluene as an internal standard on crude products. cCF3SO2Cl (0.6 mmol), PPh3 (1.2 mmol)
was used. dYield was obtained at 10 mmol scale.
b
With the optimized reaction conditions in hand, we next investigated the substrate scope. Various secondary
amines, including N-phenyl (3a–3k), N-benzyl (3l–3m) and N-alkyl (3n–3r) amines, were converted into the
corresponding thiocarbamoyl fluorides with good yields (Scheme 2). Substrates bearing electron-donating and
electron-withdrawing substituents on aryl rings also proceeded well. A good range of functional groups,
including ester (3e), nitro (3f), ether (3g), and bromide (3j), were well tolerated under the mild reaction
conditions. The conversion is not particularly sensitive to steric effects, as evidenced by the good yields of 3b,
3c, and 3d. Notably, heterocyclic and heterocycle-containing amines and amino acid derivative were also
successfully employed to provide the corresponding products in 71–83% yields (3m-3p). Alkyl amines (3q,
3r) were also suitable for this reaction. It was worth mentioning that products 3s-3u, which are the
thiocarbamyl fluorides of the drug-like molecules, was obtained without affecting the core structure of these
molecules. Indeed antidepressants such as sertraline and fluoxetine proceeded smoothly to provide the
corresponding product 3s and 3t with yields 69% and 70%, respectively. Maprotiline, bearing an alkyl chain
amine group, was also successfully transformed (3u).
Scheme 2. Scope of secondary aminesa
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F
S
PPh3, NaI
H
N
+
CF3SO2Cl
N
R
R'
R
R'
DMF, r.t., 4 h
3
2a
1
6
F
S
F
S
F
S
F
S
7
N
N
N
N
8
9
3b
3c
3d
, 80%
, 81%
, 77%
3a
, 86%
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F
S
F
S
F
S
F
S
N
N
N
N
nBu
O
O2N
O
O
3h
. 79%
S
3g
, 80%
3f
, 76%
F
3e
, 82%
S
F
F
S
F
S
N
N
O
N
N
Br
3j
3k
, 78%
N
, 73%
F
3l
, 75%
F
3i
, 73%
F
N
S
S
S
F
N
S
S
N
N
N
N
Boc
N
3p
, 75%
3m
3n
, 69%
, 82%
3o
, 74%
S
F
F
S
N
3r
N
, 76%
3q
, 69%
N
S
F
F
F
S
N
F
F
Cl
N
O
Cl
S
F
3s
, 65%
3u
, 70%
3t
, 70%
aReaction conditions: secondary amine (0.5 mmol), CF3SO2Cl (0.75 mmol), PPh3 (1.5 mmol), NaI (0.75 mmol) in DMF (2.5 mL)
at r.t. for 4h; isolated yields.
The successful reaction of CF3SO2Cl with secondary amines prompted us to investigate its reaction with
primary amines, to our delight, the protocol was also efficient for the primary amines to form isothiocyanates
(Scheme 3). A variety of primary amines with electron-donating or electron-withdrawing groups conducted
under the optimized condition and proceeded in good yields. Para-substituted amines with functional groups
such as fluoride (5d), chloride (5e), bromine (5f), phenyl (5g), methoxy (5h), alkynyl (5i), cyano (5j), and
nitro (5k) groups reacted to generate the corresponding products with yields ranging from 77% to 86%.
Pyridin-3-amine was also applied in the reaction successfully to afford 5l with satisfactory results. Then alkyl
amines were also investigated, affording the corresponding isothiocyanate products 5m-5o in moderate yields.
In particular, antiviral and antiparkinsonian drug amantadine was also tolerated (5o). Moreover, intramolecular
thiocarbamides (5p-5r) could also be obtained from the corresponding amines.
Scheme 3. Scope of primary aminesa
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PPh3, NaI
R
NCS
+
CF3SO2Cl
R
NH2
DMF, r.t., 4 h
5
4
2a
6
7
NCS
NCS
NCS
NCS
F
8
9
b
5a
5b
5c
5d
, 84% (71%)
, 85%
NCS
, 82%
NCS
, 79%
NCS
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NCS
Ph
O
Br
Cl
5e
5f
5g
5h
, 80%
, 82%
, 86%
, 83%
NCS
NCS
NCS
NCS
O2N
N
N
5i
5j
5k
5l
, 82%
, 85%
, 79%
, 77%
H
N
NCS
NCS
S
N
H
N
H
, 75%
N
C S
5m
5q
5n
5o
5p
, 69%
, 74%
, 77%
S
O
S
S
N
H
N
H
, 70%
5r
, 67%
a Reaction conditions: primary amine (0.5 mmol), CF3SO2Cl (0.75 mmol), PPh3 (1.5 mmol), NaI (0.75 mmol) in DMF (2.5 mL) at
r.t. for 4h; isolated yields. bYield was obtained at 10 mmol scale.
To gain some insight into the mechanism, some preliminary studies were conducted (Scheme 4). When N-
methylaniline reacted with CF3SO2Cl in the absence of PPh3 and NaI, 11% yield of acylamide product was
detected. Moreover, only trace of acylamide product was observed under standard conditions. The results
indicated that reaction between CF3SO2Cl and amines do not occur rapidly without any additives, and the
presence of PPh3 and NaI also inhibited the amidation (Scheme 4, a). Based on the previous reports involving
the formation of thiocarbamoyl fluoride from secondary amines[5-9], it seems that thiocarbonyl fluoride may
be the key intermediate in this reaction. Accordingly, we performed a reaction in which amines was replaced
by pentamethylcyclopentadiene 6 and observed the the corresponding bridged product 7 (Scheme 4, b). At the
same time, 31P NMR analysis of the reaction mixture revealed tjhat iodophosphonium salt (δ: +42 ppm)15 was
present in the reaction. A proposed mechanism was illustrated on the basis of these results and previous reports
(Scheme 4).12e, 16 At first, sulfenyl chloride react with PPh3 to form chlorophosphonium salt (Ph3P+Cl) via a
halogen bonding process, the in situ generated chlorophosphonium sulfinate was converted into the O-
sulfinatophosphonium chloride, which then undergo Arbuzov collapse to yield CF3SOCl and
trimethylphosphine oxide. CF3SOCl was then reduced by Ph3P to form CF3SCl (trifluoromethanesulfenyl
chloride) via a similar process. Next, sulfenyl chloride react with PPh3 to form CF3S- and chlorophosphonium
salt (Ph3P+Cl), which was attacked by NaI to produce CF3SNa and (Ph3P+I Cl-), while CF3SNa decomposed to
thiocarbonyl fluoride and NaF due to its instability.17 Finally, thiocarbonyl fluoride react with amines to
affords the product thiocarbamoyl fluorides or isothiocyanates. Because of the reversible equilibrium between
Ph3P+I Cl- and Ph3P, iodophosphonium salt can still participate in the reduction of the reaction.
Scheme 4. Control Experiment and Proposed Reaction Mechanism
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S
F
SO2CF3
N
N
+
DMF, r.t., 4h
H
none
11%
N
+
CF3SO2Cl
S
F
a)
SO2CF3
N
PPh3, NaI
2a
1a
N
DMF, r.t., 4h
+
trace
88%
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PPh3, NaI
DMF, rt, 4 h
S
+
CF3SO2Cl
2a
b)
F
F
6
7,
16%
O
S
O
S
O
PPh3
P+Ph3
F3C
Cl
F3C
O
Ph3P Cl
CF3SOCl
CF3SCl
F3C
S
O
O
Cl
Ph3P
O
O
S
O
PPh3
PPh3
S
Ph3P Cl
F3C S O
P+Ph3
F3C
F3C
Cl
F3C
Cl
Ph3P
F2C
O
NaI
S
CF3SNa
Ph3P Cl
S
Cl
F3C S
Ph3P+I Cl-
NaF
detected by 31P NMR
: +42 ppm
H
N
S
R
F
R
R'
S
Ph3P+I Cl-
R
NCS
or
N
Ph3P
ICl
R'
F
F
R'=H
HF
R'H
CONCLUSIONS
In summary, we have developed a convenient method for the synthesis of thiocarbamoyl fluorides and
isothiocyanates with amines using trifluoromethanesulfonyl chloride. The reaction system consists of a
reducing agent, PPh3 and NaI, all reagents used in this process were widely available, and the reactions
occurred smoothly under mild conditions. The highly efficient and concise nature of the reaction process along
with the mild conditions employed, are the major advantages of this new method.
EXPERIMENTAL SECTION
General information
All chemical reagents are obtained from commercial suppliers and used without further purification. All
known compounds are identified by appropriate technique such as H NMR, 13C{1H} NMR, 19F NMR and
compared with previously reported data. All unknown compounds are characterized by H NMR, 13C{1H}
NMR, 19F NMR and HRMS. Analytical thin-layer chromatography is performed on glass plates precoated
1
1
with silica gel impregnated with a fluorescent indicator (254 nm), and the plates are visualized by exposure to
ultraviolet light. H, 13C{1H} and 19F NMR spectra were recorded on a 500 MHz Bruker DRX 500 and
1
tetramethylsilane (TMS) was used as a reference. Chemical shifts were reported in parts per million (ppm),
and the residual solvent peak was used as an internal reference: proton (chloroform δ 7.26), carbon (chloroform
δ 77.0). and chemical shifts are reported in ppm. GC-MS data was recorded on a ISQ LT Single Quadrupole
Mass Spectrometer, coupled with a Trace 1300 Gas Chromatograph (Thermo Fisher Scientific). Melting points
were measured on a melting point apparatus and were uncorrected. High resolution mass spectral data were
acquired on Waters Micromass GCT Premier spectrometer (electro ionization: EI) and Waters Q-Tof microTM
(electrospray ionization: ESI).
A typical procedure for preparation of thiocarbamoyl fluorides or isothiocyanates
A 10 mL oven-dried reaction vessel was charged with PPh3 (1.5 mmol, 393 mg, 3 equiv.) and NaI (0.75
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mmol, 112.5 mg, 1.5 equiv.) under N2, N-Methylaniline (0.5 mmol, 54 mg, 1.0 equiv.) was dissolved in DMF
(1.25 mL) and the solution was added to the vessel by syringe, CF3SO2Cl (0.75 mmol, 126 mg, 1.5 equiv.)
was dissolved in DMF (1.25 mL) and the solution was added to the vessel by syringe. The resulting solution
was stirred at room temperature for 4h. After that, the reaction mixture was diluted with water and extracted
with CH2Cl2, the organic layers were washed with brine and concentrated under reduced pressure. Then the
residue was purified by column chromatography to give the corresponding products.
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A typical procedure of gram-scale synthesis for thiocarbamoyl fluorides
In a 150 mL oven-dried reaction vessel was consecutively placed PPh3 (30 mmol, 7.86 g, 3 equiv), NaI (15
mmol, 2.25 g, 1.5 equiv) under N2, N-Methylaniline 1a (1.07 g, 10 mmol, 1 equiv) dissolved in DMF (40 mL)
was added to the sealed reaction vessel by syringe, then the mixture was cooled to 0 ℃ under stirring.
CF3SO2Cl (15 mmol, 2.52 g, 1.5 equiv.) dissolved in DMF (10 mL) was then slowly added via syringe. The
resulting mixture was then allowed to warm to room temperature and stirred for 5h. Upon completion, the
reaction mixture was diluted with water (300ml) and extracted with CH2Cl2 (300ml), the organic layers were
washed with brine (300ml) three times and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel to obtain 3a in 74% yield (1.25 g).
A typical procedure of gram-scale synthesis for isothiocyanates
In a 150 mL oven-dried reaction vessel was consecutively placed PPh3 (30 mmol, 7.86 g, 3 equiv), NaI (15
mmol, 2.25 g, 1.5 equiv) under N2, aniline 1a (0.93 g, 10 mmol, 1 equiv) dissolved in DMF (40 mL) was added
to the sealed reaction vessel by syringe, then the mixture was cooled to 0 ℃ under stirring. CF3SO2Cl (15
mmol, 2.52 g, 1.5 equiv.) dissolved in DMF (10 mL) was then slowly added via syringe. The resulting mixture
was then allowed to warm to room temperature and stirred for 5h. Upon completion, the reaction mixture was
diluted with water (300ml) and extracted with CH2Cl2 (300ml), the organic layers were washed with brine
(300ml) three times and concentrated under reduced pressure.. The crude product was purified by column
chromatography on silica gel to obtain 3a in 71% yield (0.96 g).
Unsymmetrical thiocarbamoyl fluoride compounds can form two conformers 3’ and 3’’ which can be
observed as distinct species in the NMR:
R2
R2
N+
N+ S-
F
and
R1
R1
S-
F
3''
3'
methyl(phenyl)carbamothioic fluoride 3a’ and 3a’’.7 3a’:3a’’=5:1, yellow oil, yield 86% (72.7 mg). Eluent:
ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.50 – 7.32 (m, 5H+3H, 3a’’+3a’),
7.20 (dt, J = 8.2, 1.3 Hz, 2H, 3a’), 3.65 (s, 3H, 3a’), 3.49 (d, J = 2.5 Hz, 3H, 3a’’). 19F NMR (470 MHz,
Chloroform-d) δ 21.57 (3a’), 20.05 (3a’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 181.6 (d, J = 319.6 Hz,
3a’), 145.1 (3a’’), 142.1 (3a’), 131.0 (3a’’), 130.7 (3a’), 129.7 (3a’’), 129.6 (3a’), 127.0 (d, J = 1.8 Hz, 3a’’),
125.9 (3a’), 45.9 (d, J = 7.3 Hz, 3a’), 41.9 (3a’’).
methyl(o-tolyl)carbamothioic fluoride 3b’ and 3b’’. 7 3b’:3b’’=4:1, yellow solid, yield 81% (74.1 mg).
Eluent: ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.37 – 7.22 (m, 3H+3H,
3b’+3b’’), 7.19 (d, J = 6.7 Hz, 1H, 3b’’), 7.15 – 7.08 (m, 1H, 3b’), 3.56 (d, J = 1.6 Hz, 3H, 3b’), 3.41 (d, J =
2.2 Hz, 3H, 3b’’), 2.29 (s, 3H, 3b’’), 2.24 (s, 3H, 3b’). 19F NMR (470 MHz, Chloroform-d) δ 21.32 (3b’),
17.25 (3b’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.5 (d, J = 325.4 Hz, 3b’’), 182.0 (d, J = 318.0 Hz,
3b’), 143.6 (3b’’), 141.2 (3b’), 135.2 (3b’’), 134.9 (3b’), 132.8 (3b’’), 132.5 (3b’), 130.2 (3b’’+3b’), 128.9
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(3b’’), 128.4 (3b’), 126.9 (d, J = 2.1 Hz, 3b’’), 126.3 (3b’), 45.0 (d, J = 7.3 Hz, 3b’), 40.9 (d, J = 4.2 Hz,
3b’’), 18.2 (3b’+3b’’).
methyl(m-tolyl)carbamothioic fluoride 3c’ and 3c’’.7 3c’:3c’’=6:1, yellow oil, yield 77% (70.5 mg). Eluent:
ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.36 – 7.25 (m, 1H+1H, 3c’’+3c’),
7.20 – 7.12 (m, 1H+3H, 3c’+3c’’), 7.04 – 6.96 (m, 2H, 3c’), 3.62 (s, 3H, 3c’), 3.45 (d, J = 2.5 Hz, 3H, 3c’’),
2.37 (d, J = 5.4 Hz, 3H+3H, 3c’’+3c’).19F NMR (470 MHz, Chloroform-d) δ 21.32 (3c’), 19.76 (3c’’).13C{1H}
NMR (126 MHz, Chloroform-d) δ 183.2 (d, J = 323.9 Hz, 3c’’), 181.6 (d, J = 319.2 Hz, 3c’), 145.1 (3c’’),
142.1 (3c’), 141.1 (3c’’), 140.8 (3c’), 130.7 (3c’’), 130.4 (3c’), 130.3 (3c’), 128.3 (3c’’), 127.4 (3c’’), 126.4
(3c’), 123.9 (d, J = 1.9 Hz, 3c’’), 122.9 (3c’), 45.9 (d, J = 7.2 Hz, 3c’), 42.0 (d, J = 4.4 Hz, 3c’’), 22.4 (3c’’),
22.3 (3c’).
methyl(p-tolyl)carbamothioic fluoride 3d’ and 3d’’.7 3d’:3d’’=5:1, yellow oil, yield 80% (73.2 mg). Eluent:
ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.26 (d, J = 7.3 Hz, 2H, 3d’’), 7.22
(d, J = 8.4 Hz, 2H+2H, 3d’+3d’’), 7.08 (d, J = 8.0 Hz, 2H, 3d’), 3.62 (s, 3H, 3d’), 3.46 (d, J = 2.5 Hz, 3H,
3d’’), 2.37 (d, J = 5.6 Hz, 3H+3H, 3d’’+3d’). 19F NMR (470 MHz, Chloroform-d) δ 21.14 (3d’), 19.76 (3d’’).
13C{1H} NMR (126 MHz, Chloroform-d) δ 183.4 (d, J = 324.0 Hz, 3d’’), 181.7 (d, J = 319.1 Hz, 3d’), 142.7
(3d’’), 139.7 (3d’’), 139.6 (3d’), 139.6 (3d’), 131.5 (3d’’), 131.2 (3d’), 126.6 (d, J = 2.0 Hz, 3d’’), 125.6
(3d’), 46.0 (d, J = 7.1 Hz, 3d’), 42.0 (d, J = 4.7 Hz, 3d’’), 22.3 (3d’’), 22.1 (3d’).
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methyl 4-((fluorocarbonothioyl)(methyl)amino)benzoate 3e’ and 3e’’. 3e’:3e’’=6:1, White solid, M.p.
1
66.8-68.2 ºC, yield 82% (93.1 mg). Eluent: ethyl acetate/petroleum ether (10:90). H NMR (500 MHz,
Chloroform-d) δ 8.07 (d, J = 8.3 Hz, 2H+2H, 3e’’+3e’), 7.43 (d, J = 8.2 Hz, 2H, 3e’’), 7.33 – 7.25 (m, 2H,
3e’), 3.90 (s, 3H+3H, 3e’’+3e’), 3.64 (s, 3H, 3e’), 3.49 (d, J = 4.3 Hz, 3H, 3e’’). 19F NMR (470 MHz,
Chloroform-d) δ 22.07 (3e’), 21.21 (3e’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 181.1 (d, J = 320.6 Hz,
3e’), 166.8 (3e’), 145.7 (3e’), 132.0 (3e’), 131.0 (3e’), 127.2 (3e’), 126.0 (3e’), 53.5 (3e’), 45.6 (d, J = 7.1 Hz,
3e’), 41.7 (3e’). HR-MS (EI) m/z: M+ Calcd. For C10H10FNO2S 227.0416; f ound 227.0415.
methyl(4-nitrophenyl)carbamothioic fluoride 3f’ and 3f’’. 7 3f’:3f’’=4:1 , yellow solid, yield 76% (81.3
mg). Eluent: ethyl acetate/petroleum ether (10:90). 1H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 8.5 Hz,
2H, 3f’), 7.47 (d, J = 8.6 Hz, 2H, 3f’), 3.71 (s, 3H, 3f’). 19F NMR (470 MHz, Chloroform-d) δ 23.03 (3f’),
22.46 (3f’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 180.7 (d, J = 317.0 Hz, 3f’), 147.9 (3f’), 147.2 (3f’),
127.0 (3f’), 126.1 (3f’), 45.6 (3f’).
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(4-methoxyphenyl)(methyl)carbamothioic fluoride 3g’ and 3g’’. 3g’:3g’’=5:1, yellow oil, yield 80%
(79.6 mg). Eluent: ethyl acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.9
Hz, 2H, 3g’’), 7.14 – 7.09 (m, 2H, 3g’), 6.97 – 6.89 (m, 2H+2H, 3g’’+3g’), 3.80 (d, J = 2.8 Hz, 3H+3H,
3g’’+3g’), 3.61 (s, 3H, 3g’), 3.45 (d, J = 2.5 Hz, 3H, 3g’’). 19F NMR (470 MHz, Chloroform-d) δ 21.11 (3g’),
19.76 (3g’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.6 (d, J = 324.3 Hz, 3g’’), 181.8 (d, J = 318.7 Hz,
3g’), 160.3 (3g’’+3g’), 138.0 (3g’’), 134.9 (3g’), 128.0 (d, J = 2.0 Hz, 3g’’), 127.0 (3g’), 116.0 (3g’’), 115.8
(3g’), 56.6 (3g’), 56.6 (3g’’), 46.1 (d, J = 7.3 Hz, 3g’), 42.1 (d, J = 4.6 Hz, 3g’’).
butyl(phenyl)carbamothioic fluoride 3h’ and 3h’’. 3h’:3h’’=4:1, yellow oil, yield 79% (83.3 mg). Eluent:
ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.49 – 7.39 (m, 3H+2H, 3h’’+3h’),
7.39 – 7.34 (m, 1H, 3h’), 7.30 (dd, J = 7.6, 1.9 Hz, 2H, 3h’’), 7.17 (dd, J = 7.7, 2.0 Hz, 2H, 3h’), 4.09 – 4.01
(m, 2H, 3h’), 3.80 (td, J = 7.5, 1.6 Hz, 2H, 3h’’), 1.71 – 1.57 (m, 2H+2H, 3h’+3h’’), 1.34 (hd, J = 7.4, 2.5 Hz,
2H+2H, 3h’+3h’’), 0.91 (td, J = 7.4, 2.5 Hz, 3H+3H, 3h’’+3h’). 19F NMR (470 MHz, Chloroform-d) δ 24.40
(3h’), 16.74 (3h’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.4 (d, J = 324.3 Hz, 3h’’), 181.5 (d, J =
319.5 Hz, 3h’), 143.8 (3h’’), 140.6 (3h’), 130.9 (3h’’), 130.7 (3h’), 129.7 (3h’’+3h’), 127.9 (3h’’), 126.9
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(3h’), 57.9 (d, J = 7.3 Hz, 3h’), 54.9 (d, J = 3.3 Hz, 3h’’), 31.1 (3h’’), 29.1 (3h’), 20.9 (3h’), 20.8 (3h’’), 14.7
(3h’), 14.6 (3h’’). HR-MS (EI) m/z: M+ Calcd. For C11H14FNS 211.0831; found 211.0825.
benzyl(phenyl)carbamothioic fluoride 3i’ and 3i’’. 3i’:3i’’=4:1, yellow oil, yield 73% (89.4 mg). Eluent:
ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.38 – 7.23 (m, 6H+8H, 3i’’+3i’),
7.17 – 7.11 (m, 4H, 3i’’), 6.98 (dd, J = 7.5, 2.3 Hz, 2H, 3i’), 5.28 (s, 2H, 3i’), 4.94 (s, 2H, 3i’’). 19F NMR (470
MHz, Chloroform-d) δ 24.43 (3i’), 18.31 (3i’’).13C{1H} NMR (126 MHz, Chloroform-d) δ 183.0 (d, J = 324.3
Hz, 3i’’), 182.6 (d, J = 319.8 Hz, 3i’), 143.8 (3i’’), 140.4 (3i’), 135.4 (3i’’), 135.3 (3i’), 130.8 (3i’), 130.6 (3i’),
130.0 (3i’), 129.8 (3i’’), 129.7 (3i’), 129.5 (3i’’), 129.5 (3i’), 128.0 (3i’’), 127.1 (3i’), 61.7 (d, J = 6.9 Hz, 3i’),
58.7 (d, J = 3.4 Hz, 3i’’). HR-MS (EI) m/z: M+ Calcd. For C14H12FNS 245.0674; found 245.0669.
5-bromoindoline-1-carbothioyl fluoride 3j’ and 3j’’. 3j’:3j’’=1:4, yellow solid, M.p. 117.7-121.5 ºC, yield
78% (101.0 mg). Eluent: ethyl acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 8.66 (dd,
J = 8.7, 2.2 Hz, 1H, 3j’), 7.40 (td, J = 7.9, 7.2, 2.0 Hz, 3H+1H, 3j’’+3j’), 7.27 (s, 1H, 3j’), 4.41 – 4.30 (m,
2H+2H, 3j’+3j’’), 3.21 (dt, J = 16.7, 8.3 Hz, 2H+2H, 3j’’+3j’). 19F NMR (470 MHz, Chloroform-d) δ 39.56
(3j’), 16.86 (3j’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 177.2 (d, J = 326.5 Hz,), 140.1 , 140.1 , 137.0 ,
136.2 , 132.3 (d, J = 3.6 Hz), 131.4 , 130.0 , 129.2 , 120.3 , 119.9 (d, J = 2.1 Hz), 119.7 , 119.5 , 55.2 (d, J =
6.8 Hz), 52.3 , 27.7 , 27.3 . Due to difficulty to assign peaks in 13C NMR to 3j’ and 3j’’ only chemical shifts
are indicated. HR-MS (EI) m/z: M+ Calcd. For C9H7BrFNS 258.9467; found 258.9471.
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2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carbothioyl fluoride 3k’ and 3k’’. 3k’:3k’’=1:25, yellow oil,
yield 73% (71.9 mg). Eluent: ethyl acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 7.41
(t, J = 7.5 Hz, 1H, 3k’’), 7.16 (t, J = 7.9 Hz, 1H, 3k’’), 6.93 (t, J = 7.7 Hz, 2H, 3k’’), 4.38 (dp, J = 9.7, 4.7 Hz,
4H, 3k’’). 19F NMR (470 MHz, Chloroform-d) δ 25.58 (3k’), 18.11 (3k’’). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 180.5 (d, J = 324.6 Hz), 147.0 , 129.2 , 125.3 , 125.2 , 124.7 , 121.8 , 118.9 , 66.2 , 49.7 (d,
J = 6.4 Hz). Due to difficulty to assign peaks in 13C NMR to 3k’ and 3k’’ only chemical shifts are indicated.
HR-MS (EI) m/z: M+ Calcd. For C9H8FNOS 197.0311; found 197.0317.
methyl(naphthalen-1-ylmethyl)carbamothioic fluoride 3l’ and 3l’’. 3l’:3l’’=10:7, yellow solid, M.p. 69.6-
71.3 ºC, yield 75% (87.1 mg). Eluent: ethyl acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-
d) δ 8.05(d, J = 8.3 Hz, 1H, 3l’), 7.95 – 7.91 (m, 1H+1H, 3l’’+3l’), 7.91 – 7.84 (m, 1H+2H, 3l’+3l’’), 7.63 –
7.54 (m, 2H+2H, 3l’+3l’’), 7.49 (td, J = 7.6, 2.8 Hz, 1H+1H, 3l’+3l’’), 7.42 (d, J = 6.9 Hz, 1H, 3l’), 7.30 (d,
J = 7.1 Hz, 1H, 3l’’), 5.43 (s, 2H, 3l’), 5.17 (s, 2H, 3l’’), 3.28 (s, 3H, 3l’’), 2.96 (d, J = 2.3 Hz, 3H, 3l’). 19F
NMR (470 MHz, Chloroform-d) δ 17.58 , 13.79 . 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.1 (d, J =
321.1 Hz), 182.5 (d, J = 320.6 Hz), 135.0 , 134.9 , 133.3 (d, J = 10.9 Hz), 132.6 , 131.9 , 130.6 , 130.5 , 130.4
, 130.3 , 130.2 , 130.0 , 129.6 (d, J = 12.7 Hz), 128.3 , 128.2 (d, J = 2.5 Hz), 127.4 (d, J = 4.1 Hz), 126.6 ,
126.5 , 126.4 , 124.5 , 123.2 , 58.0 (d, J = 6.4 Hz), 53.7 (d, J = 6.1 Hz), 42.0 (d, J = 6.2 Hz), 36.1 (d, J = 6.5
Hz). Due to difficulty to assign peaks in 13C NMR to 3l’ and 3l’’ only chemical shifts are indicated. HR-MS
(EI) m/z: M+ Calcd. For C13H12FNS 233.0674; found 233.0680.
methyl(thiophen-3-ylmethyl)carbamothioic fluoride 3m’ and 3m’’. 3m’:3m’’=10:7, yellow oil, yield 69%
(65.1 mg). Eluent: ethyl acetate/petroleum ether (1:99). 1H NMR (500 MHz, Chloroform-d) δ 7.33 – 7.26 (m,
1H+1H, 3m’+3m’’), 7.16 – 7.12 (m, 1H, 3m’), 7.05 – 6.97 (m, 1H+2H, 3m’+3m’’), 5.09 (s, 2H, 3m’), 4.81
(s, 2H, 3m’’), 3.31 (d, J = 1.7 Hz, 3H, 3m’’), 3.12 (d, J = 2.2 Hz, 3H, 3m’).19F NMR (470 MHz, Chloroform-d)
δ 16.52 (3m’), 14.02 (3m’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.9 (d, J = 321.4 Hz, 3m’), 182.0
(d, J = 320.6 Hz, 3m’’), 136.9 (3m’’), 136.4 (3m’), 129.4 (3m’), 128.9 (3m’’), 128.3 (3m’’), 127.9 (3m’),
127.7 (3m’), 127.7 (3m’’), 54.6 (d, J = 5.6 Hz, 3m’), 50.5 (d, J = 6.4 Hz, 3m’’), 41.9 (d, J = 6.2 Hz, 3m’’),
36.7 (d, J = 6.4 Hz, 3m’). HR-MS (EI) m/z: M+ Calcd. For C7H8FNS2 189.0082; found 189.0079.
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4-phenylpiperazine-1-carbothioyl fluoride 3n.
Off-white solid, yield 82% (91.8 mg). Eluent: ethyl
acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 7.29 (t, J = 7.7 Hz, 2H), 6.92 (t, J = 7.0
Hz, 3H), 4.11 (t, J = 5.2 Hz, 2H), 3.91 – 3.79 (m, 2H), 3.24 (dt, J = 40.8, 5.2 Hz, 4H). 19F NMR (470 MHz,
Chloroform-d) δ 13.34 . 13C{1H} NMR (126 MHz, Chloroform-d) δ 181.1 (d, J = 320.3 Hz), 151.2 , 130.5 ,
122.2 , 118.0 , 51.4 (d, J = 6.2 Hz), 50.1 , 49.6 , 47.6 (d, J = 5.3 Hz).
4-(pyridin-2-yl)piperazine-1-carbothioyl fluoride 3o. Yellow solid, M.p. 80.0-83.1 ºC, yield 74% (83.3 mg).
Eluent: ethyl acetate/petroleum ether (10:90). 1H NMR (500 MHz, Chloroform-d) δ 8.22 (dd, J = 5.0, 1.9 Hz,
1H), 7.56 (ddd, J = 8.9, 7.2, 2.0 Hz, 1H), 6.81 – 6.64 (m, 2H), 4.19 – 4.07 (m, 2H), 3.93 – 3.83 (m, 2H), 3.71
(ddd, J = 19.2, 6.8, 4.8 Hz, 4H). 19F NMR (470 MHz, Chloroform-d) δ 13.91 . 13C{1H} NMR (126 MHz,
Chloroform-d) δ 181.2 (d, J = 320.8 Hz), 159.2 , 148.8 , 139.2 , 115.5 , 108.5 , 51.0 (d, J = 6.2 Hz), 47.2 (d, J
= 5.1 Hz), 45.6 , 45.2 . HR-MS (EI) m/z: M+ Calcd. For C10H12FN3S 225.0736; found 225.0745.
tert-butyl 4-(fluorocarbonothioyl)piperazine-1-carboxylate 3p. 18 Off-white solid, yield 75% (93.0 mg).
Eluent: ethyl acetate/petroleum ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 3.97 (dd, J = 6.4, 4.4 Hz,
2H), 3.72 (t, J = 5.3 Hz, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.56 – 3.49 (m, 2H), 1.48 (s, 9H). 19F NMR (470 MHz,
Chloroform-d) δ 14.43 . 13C{1H} NMR (126 MHz, Chloroform-d) δ 181.1 (d, J = 320.3 Hz), 155.2 , 81.9 ,
51.3 (d, J = 6.0 Hz), 47.5 , 29.3 .
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diallylcarbamothioic fluoride 3q. Yellow oil, yield 69% (54.7 mg). Eluent: ethyl acetate/petroleum ether
(1:99).1H NMR (500 MHz, Chloroform-d) δ 5.81 (dddt, J = 47.8, 16.3, 10.2, 5.9 Hz, 2H), 5.36 – 5.16 (m, 4H),
4.33 (dd, J = 6.2, 1.5 Hz, 2H), 4.04 (dd, J = 5.8, 1.7 Hz, 2H). 19F NMR (470 MHz, Chloroform-d) δ 15.21 .
13C{1H} NMR (126 MHz, Chloroform-d) δ 182.8 (d, J = 321.6 Hz), 131.4 , 130.6 , 120.9 , 120.2 , 56.6 (d, J
= 5.6 Hz), 52.1 (d, J = 5.5 Hz). HR-MS (EI) m/z: M+ Calcd. For C7H10FNS 159.0518; found 159.0522.
bis(2-ethylhexyl)carbamothioic fluoride 3r. Yellow oil, yield 76% (115.1 mg). Eluent: ethyl
acetate/petroleum ether (1:99). 1H NMR (500 MHz, Chloroform-d) δ 3.60 (d, J = 7.5 Hz, 2H), 3.44 – 3.30 (m,
2H), 2.01 (p, J = 6.8 Hz, 1H), 1.70 (p, J = 6.5 Hz, 1H), 1.38 – 1.21 (m, 16H), 0.95 – 0.85 (m, 12H). 19F NMR
(470 MHz, Chloroform-d) δ 17.53 . 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.0 (d, J = 319.8 Hz), 58.1 ,
54.8 , 39.1 , 37.4 , 31.4 , 31.3 , 29.5 , 29.5 , 24.8 , 24.7 , 24.0 , 24.0 , 15.1 , 15.0 , 11.6 , 11.5 . HR-MS (EI)
m/z: M+ Calcd. For C17H34FNS 303.2396; found 303.2406.
((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamothioic fluoride 3s’
and 3s’’. 3s’:3s’’=5:3, white solid, M.p. 92.2-95.7 ºC, yield 65% (119.3 mg). Eluent: ethyl acetate/petroleum
ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 7.38 – 7.30 (m, 3H+1H, 3s’+3s’’), 7.28 (d, J = 2.0 Hz, 2H,
3s’’), 7.21 (d, J = 7.7 Hz, 1H, 3s’), 7.14 (d, J = 7.7 Hz, 1H, 3s’’), 7.09 (dd, J = 8.9, 2.1 Hz, 1H+1H, 3s’’+3s’),
7.02 (ddd, J = 6.2, 5.0, 1.3 Hz, 1H+1H, 3s’+3s’’), 6.82 (ddd, J = 11.0, 8.3, 2.1 Hz, 1H+1H, 3s’+3s’’), 6.17 (dt,
J = 11.1, 5.7 Hz, 1H, 3s’), 5.63 (t, J = 8.4 Hz, 1H, 3s’’), 4.24 (td, J = 6.0, 2.9 Hz, 1H+1H, 3s’+3s’’), 3.10 (s,
3H, 3s’’), 2.91 (d, J = 2.7 Hz, 3H, 3s’), 2.31 (ddddt, J = 17.9, 12.4, 8.6, 5.6, 2.9 Hz, 1H+1H, 3s’’+3s’), 2.08
(dtt, J = 13.4, 5.0, 3.0 Hz, 1H+1H, 3s’+3s’’), 2.00 (dtd, J = 11.8, 5.8, 2.6 Hz, 1H, 3s’), 1.94 – 1.82 (m, 2H,
3s’’), 1.74 (tdd, J = 13.1, 10.6, 2.8 Hz, 1H, 3s’). 19F NMR (470 MHz, Chloroform-d) δ 20.30 (3s’), 11.65
(3s’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ 184.1 (d, J = 320.5 Hz, 3s’), 183.0 (d, J = 320.8 Hz, 3s’’),
147.4 (3s’), 147.2 (3s’’), 139.1 (3s’), 139.0 (3s’’), 134.5 (3s’’), 134.1 (3s’), 133.6 (3s’’), 133.6 (3s’), 132.3
(3s’), 131.6 (3s’’), 131.6 (3s’’), 131.5 (3s’), 131.4 (3s’’), 131.3 (3s’), 129.6 (3s’), 129.6 (3s’’), 129.5 (3s’’),
129.4 (3s’), 129.1 (3s’’), 129.0 (3s’), 128.9 (3s’), 128.9 (3s’’), 128.2 (3s’’+3s’), 63.4 (d, J = 6.5 Hz, 3s’), 59.9
(3s’’), 43.8 (3s’), 43.8 (3s’’), 38.7 (3s’’), 33.1 (3s’), 30.8 (3s’’), 30.7 (3s’), 23.9 (3s’’), 21.6 (3s’). HR-MS
(EI) m/z: M+ Calcd. For C18H16Cl2FNS 367.0365; found 367.0371.
methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)carbamothioic fluoride 3t. 3t’:3t’’=5:6, yellow
oil, yield 70% (129.9 mg). Eluent: ethyl acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ
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7.43 (d, J = 8.4 Hz, 2H, 3t’+3t’’), 7.38 – 7.26 (m, 5H, 3t’+3t’’), 6.89 (dd, J = 8.6, 6.1 Hz, 2H, 3t’+3t’’), 5.23
(ddd, J = 38.3, 8.6, 4.1 Hz, 1H, 3t’+3t’’), 4.00 – 3.86 (m, 1H, 3t’+3t’’), 3.81 – 3.65 (m, 1H, 3t’+3t’’), 3.36 –
3.09 (m, 3H, 3t’+3t’’), 2.42 – 2.13 (m, 2H, 3t’+3t’’). 19F NMR (470 MHz, Chloroform-d) δ 17.69 , 13.64 , -
61.47 .13C{1H} NMR (126 MHz, Chloroform-d) δ 183.8 (d, J = 6.5 Hz), 181.2 (d, J = 4.7 Hz), 161.0 (d, J =
21.1 Hz), 140.8 (d, J = 40.4 Hz), 133.3 (d, J = 10.6 Hz), 130.1 (d, J = 11.2 Hz), 129.4 (d, J = 13.5 Hz), 127.9
(p, J = 3.6 Hz), 126.6 (d, J = 7.3 Hz), 124.6 – 123.7 (m), 116.8 (d, J = 3.6 Hz), 78.9 , 53.7 (d, J = 5.5 Hz), 49.7
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(d, J = 4.9 Hz), 42.8 (d, J = 5.9 Hz), 38.1 (d, J = 6.5 Hz), 37.8 , 35.5 . Due to difficulty to assign peaks in 13
NMR to 3t’ and 3t’’ only chemical shifts are indicated. HR-MS (EI) m/z: M+ Calcd. For C18H17F4NOS
C
371.0967; found 371.0972.
(3-(9,10-ethanoanthracen-9(10H)-yl)propyl)(methyl)carbamothioic fluoride 3u’ and 3u’’. 3u’:3u’’=1:1,
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yellow oil, yield 70% (118.5 mg). Eluent: ethyl acetate/petroleum ether (3:97). H NMR (500 MHz,
Chloroform-d) δ 7.37 – 7.27 (m, 3H+3H, 3u’+3u’’), 7.24 – 7.10 (m, 5H+5H, 3u’+3u’’), 4.34 (d, J = 2.8 Hz,
1H+1H, 3u’+3u’’), 4.02 (t, J = 7.9 Hz, 1H+1H, 3u’+3u’’), 3.79 (t, J = 7.5 Hz, 1H+1H, 3u’+3u’’), 3.49 – 3.21
(m, 3H+3H, 3u’+3u’’), 2.60 – 2.44 (m, 2H+2H, 3u’+3u’’), 2.31 – 2.20 (m, 1H+1H, 3u’+3u’’), 2.20 – 2.09
(m, 1H+1H, 3u’+3u’’), 1.93 – 1.83 (m, 2H+2H, 3u’+3u’’), 1.62 (ddd, J = 16.5, 7.1, 3.5 Hz, 2H+2H, 3u’+3u’’).
19F NMR (470 MHz, Chloroform-d) δ 17.52 (3u’), 13.16 (3u’’). 13C{1H} NMR (126 MHz, Chloroform-d) δ
182.7 (d, J = 321.1 Hz), 182.5 (d, J = 319.7 Hz), 146.0 , 145.8 , 126.6 , 126.5 , 124.7 , 124.6 , 122.2 , 121.9 ,
57.5 (d, J = 5.9 Hz), 53.7 (d, J = 4.7 Hz), 45.8 , 45.6 , 45.5 (d, J = 6.3 Hz), 42.7 (d, J = 6.0 Hz), 37.8 (d, J =
6.4 Hz), 30.7 , 28.9 (d, J = 13.0 Hz), 28.7 (d, J = 8.0 Hz), 24.7 , 22.5 . Due to difficulty to assign peaks in 13C
NMR to 3u’ and 3u’’ only chemical shifts are indicated. HR-MS (EI) m/z: M+ Calcd. For C21H22FNS 339.1457;
found 339.1460.
Isothiocyanatobenzene 5a. 7 Yellow oil, yield 84% (56.7 mg). Eluent: ethyl acetate/petroleum ether (3:97).
1H NMR (500 MHz, Chloroform-d) δ 7.36 (tt, J = 9.7, 4.7 Hz, 2H), 7.30 (td, J = 7.2, 3.5 Hz, 1H), 7.21 (dt, J
= 12.6, 6.3 Hz, 2H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 136.5 , 132.3 , 130.6 , 128.4 , 126.8 .
1-isothiocyanato-4-methylbenzene 5b. 7 Yellow oil, yield 85% (63.3 mg). Eluent: ethyl acetate/petroleum
ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.16 (d, J = 8.3 Hz, 2H), 7.13 – 7.09 (m, 2H), 2.36 (s, 3H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 138.6 , 135.6 , 131.2 , 129.4 , 126.6 , 22.3 .
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2-isothiocyanato-1,3,5-trimethylbenzene 5c.
White solid, yield 82% (72.6 mg). Eluent: ethyl
acetate/petroleum ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 6.87 (s, 2H), 2.34 (s, 6H), 2.30 (s, 3H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 159.6 , 136.0 , 131.6 , 131.0 , 130.2 , 130.0 , 127.8 , 114.8 , 62.5 ,
56.2 , 42.7 , 42.1 .
1-fluoro-4-isothiocyanatobenzene 5d. 7 Yellow oil, yield 79% (60.4 mg). Eluent: ethyl acetate/petroleum
ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.25 – 7.18 (m, 2H), 7.11 – 7.00 (m, 2H). 19F NMR (470
MHz, Chloroform-d) δ -112.00 . 13C{1H} NMR (126 MHz, Chloroform-d) δ 162.2 (d, J = 249.1 Hz), 128.4 ,
128.4 , 117.8 , 117.6 .
1-chloro-4-isothiocyanatobenzene 5e. 7 Yellow oil, yield 80% (67.6 mg). Eluent: ethyl acetate/petroleum
ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.32 (dq, J = 9.1, 2.5, 2.0 Hz, 2H), 7.24 – 7.10 (m, 2H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 137.8 , 134.0 , 130.8 , 130.2 , 128.0 .
1-bromo-4-isothiocyanatobenzene 5f. 7 Yellow oil, yield 82% (87.3 mg). Eluent: ethyl acetate/petroleum
ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.70 – 7.62 (m, 2H), 7.00 – 6.90 (m, 2H). 13C{1H} NMR
(126 MHz, Chloroform-d) δ 139.7 , 138.1 , 132.2 , 128.5 , 93.1 .
4-isothiocyanato-1,1'-biphenyl 5g. 6 White solid, yield 86% (90.7 mg). Eluent: ethyl acetate/petroleum ether
(3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.63 – 7.56 (m, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 – 7.37 (m,
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1H), 7.34 – 7.29 (m, 2H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 141.3 , 140.7 , 136.6 , 131.3 , 130.0 ,
129.2 , 128.9 , 128.0 , 127.2 .
1-isothiocyanato-4-methoxybenzene 5h. 7 Yellow oil, yield 83% (68.5 mg). Eluent: ethyl acetate/petroleum
ether (5:95). 1H NMR (500 MHz, Chloroform-d) δ 7.18 – 7.13 (m, 2H), 6.85 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 159.6 , 134.9 , 128.0 , 124.6 , 115.9 , 56.6 .
1-ethynyl-4-isothiocyanatobenzene 5i. 6 Yellow solid, yield 85% (67.6 mg). Eluent: ethyl acetate/petroleum
ether (3:97). 1H NMR (500 MHz, Chloroform-d) δ 7.48 – 7.44 (m, 2H), 7.20 – 7.14 (m, 2H), 3.18 (s, 1H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 138.0 , 134.4 , 132.6 , 126.8 , 122.2 , 83.5 , 80.3 .
4-isothiocyanatobenzonitrile 5j. 7 Yellow oil, yield 79% (63.2 mg). Eluent: ethyl acetate/petroleum ether
(10:90). 1H NMR (500 MHz, Chloroform-d) δ 7.68 – 7.63 (m, 2H), 7.33 – 7.28 (m, 2H). 13C{1H} NMR (126
MHz, Chloroform-d) δ 140.6 , 137.1 , 134.7 , 127.5 , 118.9 , 111.7 .
1-isothiocyanato-4-nitrobenzene 5k. 5b Yellow solid, yield 77% (69.3 mg). Eluent: ethyl acetate/petroleum
ether (10:90). 1H NMR (500 MHz, Chloroform-d) δ 8.31 – 8.22 (m, 2H), 7.42 – 7.33 (m, 2H). 13C{1H} NMR
(126 MHz, Chloroform-d) δ 146.8 , 141.3 , 139.0 , 127.4 , 126.3 .
3-isothiocyanatopyridine 5l.7 Yellow oil, yield 82% (55.8 mg). Eluent: ethyl acetate/petroleum ether (10:90).
1H NMR (500 MHz, Chloroform-d) δ 8.55 – 8.35 (m, 2H), 7.53 – 7.39 (m, 1H), 7.28 (dd, J = 9.0, 3.5 Hz, 1H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 148.6 , 148.1 , 140.2 , 133.3 , 130.5 , 125.0 .
(2-isothiocyanatoethyl)benzene 5m. 20 Colorless oil, yield 74% (60.3 mg). Eluent: ethyl acetate/petroleum
ether (1:99). 1H NMR (500 MHz, Chloroform-d) δ 7.34 (dd, J = 8.1, 6.7 Hz, 2H), 7.30 – 7.26 (m, 1H), 7.24 –
7.18 (m, 2H), 3.72 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H).
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3-(2-isothiocyanatoethyl)-1H-indole 5n.19 White solid, yield 75% (75.8 mg). Eluent: ethyl acetate/petroleum
ether (10:90). 1H NMR (500 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz,
1H), 7.24 – 7.20 (m, 1H), 7.17 – 7.13 (m, 1H), 7.10 (d, J = 2.3 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.16 (t, J =
6.8 Hz, 2H).
1-isothiocyanatoadamantane 5o. 7 White solid, yield 77% (74.3 mg). Eluent: ethyl acetate/petroleum ether
(1:99). 1H NMR (500 MHz, Chloroform-d) δ 2.10 (q, J = 3.2 Hz, 3H), 1.97 (d, J = 2.9 Hz, 6H), 1.70 – 1.60
(m, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 59.5 , 44.8 , 36.6 , 30.3 .
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1,3-dihydro-2H-benzo[d]imidazole-2-thione 5p.
White solid, yield 69% (51.8 mg). Eluent: ethyl
acetate/petroleum ether (10:90). 1H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 2H), 7.07 (ddt, J = 19.4, 5.8, 3.4
Hz, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 169.6 , 133.7 , 123.8 , 110.9 .
benzo[d]oxazole-2(3H)-thione 5q. 21 White solid, yield 70% (52.9 mg). Eluent: ethyl acetate/petroleum ether
(10:90). 1H NMR (500 MHz, DMSO-d6) δ 13.81 (s, 1H), 7.48 – 7.41 (m, 1H), 7.28 – 7.15 (m, 3H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 181.6 , 149.6 , 132.6 , 126.6 , 125.2 , 111.9 , 111.4 .
benzo[d]thiazole-2(3H)-thione 5r. 22 White solid, yield 67% (55.9 mg). Eluent: ethyl acetate/petroleum ether
(10:90). 1H NMR (500 MHz, DMSO-d6) δ 13.70 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.38 – 7.30 (m, 1H), 7.30 –
7.20 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 191.3 , 142.7 , 130.8 , 128.6 , 125.6 , 123.2 , 113.9 .
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at DOI:
1H NMR, 13C NMR, and 19F NMR for products (PDF).
AUTHOR INFORMATION
Corresponding Authors
* E-mail: lvqi.jiang@njust.edu.cn, yiwb@njust.edu.cn
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Author Contributions
§ These authors contributed equally to this paper.
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ORCID
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Lvqi Jiang: 0000-0002-1921-985X
Wen-bin Yi: 0000-0003-4606-7668
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science Foundation of China (21776138, 21476116),
Fundamental Research Funds for the Central Universities (30920021124， 30918011314), Natural Science
Foundation of Jiangsu (BK20180476), the China Postdoctoral Science Foundation Funded Project (No.
2019M661848), Qing Lan and Six Talent Peaks in Jiangsu Province and Priority Academic Program
Development of Jiangsu Higher Education Institutions, Bruker DRX 500 at Analysis and Test Center Nanjing
University of Science and Technology for the help in obtaining NMR data.
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