Thiocyanation of α-amino carbonyl compounds for the synthesis of aromatic thiocyanates

Article abstract of DOI:10.1177/1747519820923553

A procedure for K₂S₂O₈-mediated thiocyanation of α-amino carbonyl compounds has been developed for the synthesis of aromatic thiocyanates. A series of α-amino carbonyl compounds have been investigated, and the desired products are obtained in 74%–93% yields. This strategy has the advantages of simple reaction conditions without use of a transition-metal catalyst, high regioselectivity, and high efficiency. Moreover, we found that arylamine thiocyanates can also be obtained from α-amino carbonyl compounds and potassium thiocyanate in the presence of CoCl₂·6H₂O, I₂, and dimethyl sulfoxide through the cleavage of the C–N bond. To explore the reaction mechanism, we designed several control experiments and proposed a possible mechanism using the experimental results and related literature reports.

Full text of DOI:10.1177/1747519820923553

923553CHL0010.1177/1747519820923553Journal of Chemical ResearchYi et al.
research-article2020
Research Paper
Journal of Chemical Research
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Thiocyanation of α-amino carbonyl compounds
for the synthesis of aromatic thiocyanates
https://doi.org/10.1177/1747519820923553
DOI: 10.1177/1747519820923553
journals.sagepub.com/home/chl
Niannian Yi , Mingjing Ouyang, Huimin Liu, Miao Yan,
Xiaoyong Wen, Yi Xiong and Bing Yi
Abstract
A procedure for K2S2O8-mediated thiocyanation of α-amino carbonyl compounds has been developed for the synthesis
of aromatic thiocyanates. A series of α-amino carbonyl compounds have been investigated, and the desired products are
obtained in 74%–93% yields. This strategy has the advantages of simple reaction conditions without use of a transition-
metal catalyst, high regioselectivity, and high efficiency. Moreover, we found that arylamine thiocyanates can also be
obtained from α-amino carbonyl compounds and potassium thiocyanate in the presence of CoCl2·6H2O, I2, and dimethyl
sulfoxide through the cleavage of the C–N bond. To explore the reaction mechanism, we designed several control
experiments and proposed a possible mechanism using the experimental results and related literature reports.
Keywords
α-amino carbonyl compounds, aromatic thiocyanates, thiocyanation reaction
Date received: 12 January 2020; accepted: 13 April 2020
R'
N
H
N
O
R'
N
O
K2S2O8
R'
CoCl2g6H2O
R
+
K
SCN
R
I2 DMSO, 80oC
CH CN rt
,
,
3
NCS
12 examples,
SCN
21 examples,
up to 93% yield
up to 75% yield
simple and efficient method to achieve the thiocyanation of
α-amino carbonyl compounds for the synthesis of organic
thiocyanates.
As a continuation of our research on α-functionalized
carbonyl compounds,17,20,42–48 herein, we describe a straight-
forward synthesis of aromatic thiocyanates through K2S2O8-
mediated thiocyanation of α-amino carbonyl compounds
using KSCN as the thiocyanation reagent (Scheme 1A).
Moreover, we can prepare arylamine thiocyanates from α-
amino carbonyl compounds and KSCN in the presence of
Introduction
As an important structural unit, the α-amino carbonyl frag-
ment exists in numerous natural products and pharmaceuti-
cal compounds,1–7 and it is a versatile precursor for the
synthesis of various heterocyclic compounds.8–14 Glycine,
the simplest α-amino carbonyl compound, is one of the
essential amino acids in the human body. Besides, amoxi-
cillin and clopidogrel demonstrate the application of α-
amino carbonyl compounds in medicine and provide
resistance to some diseases. α-Amino carbonyl compounds
are involved in many reactions, the most important among
which are the reactions with nucleophiles, which include
alcohols,15 thiols,15 amines,16,17 phosphites,18,19 nitrometh-
ane,20 ketones,21 1,3-dicarbonyl compounds,22–24 (hetero)
arenes,25–31 and others.
To the best of our knowledge, there are no reports on the
thiocyanation of α-amino carbonyl compounds. Organic
thiocyanates are well known in the area of organosulfur
chemistry and have become a hot research field in organic
synthetic chemistry, since they are not only the substructures
or building blocks of bioactive natural products32–35 but also
versatile synthetic precursors for the synthesis of sulfur-con-
taining compounds such as thiols,36,37 thioethers,38,39 and
Hunan Provincial Key Laboratory of Environmental Catalysis and Waste
Recycling, College of Chemistry and Chemical Engineering, Hunan
Institute of Engineering, Xiangtan, P.R. China
Corresponding authors:
Niannian Yi, Hunan Provincial Key Laboratory of Environmental
Catalysis and Waste Recycling, College of Chemistry and Chemical
Engineering, Hunan Institute of Engineering, Xiangtan 411104, Hunan,
P.R. China.
Email: yiniannian@hnu.edu.cn
Bing Yi, Hunan Provincial Key Laboratory of Environmental Catalysis
and Waste Recycling, College of Chemistry and Chemical Engineering,
Hunan Institute of Engineering, Xiangtan 411104, Hunan, P.R. China.
disulfides.40,41 Therefore, it is worthwhile to develop a Email: bingyi2004@126.com

2
Journal of Chemical Research 00(0)
including DTBP (di-tert-butylperoxide), TBHP (tert-butyl
hydroperoxide, 70% in water), DDQ (2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone), K2S2O8, and O2. The oxidant
K2S2O8 was the best, giving the product in 87% yield
(entries 2–6). Solvents often have a large effect on reactions,
so we screened the effect of different solvents on the
reaction. Common solvents such as DMF (N,N-
dimethylformamide), DMSO, CHCl3, EtOH, 1,4-dioxane,
and toluene were selected for this reaction. Among them,
the reaction using CHCl3 or toluene was better, but it was
still inferior to the use of acetonitrile (entries 7–12). Next,
we explored the effect of the amount of K2S2O8 on the reac-
tion. As the amount of K2S2O8 increased, the corresponding
yield also increased, and the yield reached a maximum
when K2S2O8 (3 equiv.) was used (entries 13–15). Besides,
when the amount of KSCN was increased from 1equiv. to
4equiv., the corresponding yield was also increased, up to
93% (entries 16–18). When NH4SCN was selected as the
SCN reagent, the yield of 3a was reduced to 76% (entry 19).
The temperature had a great effect on the reaction, and as
the temperature increased, the yield decreased, mainly due
to the formation of by-products (entries 20 and 21).
Therefore, the optimal conditions for the reaction are 1a
(1equiv.), 2 (4equiv.), K2S2O8 (3equiv.), and CH3CN (2mL)
in a sealed tube at room temperature for 16h (entry 18).
With the optimal conditions in hand, we then investigated
the substrate scope of the transformation (Table 2). First, we
screened the substituents on the aromatic ring of the 1-aryle-
thanone moiety. For the substrates bearing electron-with-
drawing substituents on the aromatic ring, including F–, Cl–,
I–, CF3–, CN–, and NO2– at the p-position, the protocol was
applicable, and the corresponding products were obtained in
moderate to good yields (3b–3g). In the cases of substrates
having electron-withdrawing substituents at the m- or o-posi-
tion, the desired products were also obtained in good yields
(3h–3j). By comparing the yields of 3c, 3h, and 3j, it was
deduced that steric effects have little effect on the reaction.
For the substrates bearing electron-donating substituents
such as methyl (1k and 1m) and methoxy (1l), these substitu-
ents were also tolerated under the reaction conditions.
O
R'
N
rt
K2S2O8 CH CN,
,
3
R
(A)
(B)
SCN
O
R'
N
+
KSCN
R
H
N
CoCl2 6H O
g
I2 DMSO, 80oC
2
R'
,
NCS
Scheme 1. Thiocyanation of α-amino carbonyl compounds.
Table 1. Optimization of reaction conditions.a
O
O
N
N
Oxidant
+
KSCN
Solvent, rt
SCN
1a
3a
2
Entry [SCN] (equiv.) Oxidant (equiv.) Solvent
Yield (%)b
28
1
2
3
4
5
6
7
8
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (3)
KSCN (1)
KSCN (2)
KSCN (4)
NH4SCN (4)
KSCN (4)
KSCN (4)
PhI(OAc)2 (3)
DTBP (3)
TBHP (3)
CH3CN
CH3CN Trace
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
CHCl3
EtOH
12
73
87
0
54
31
80
9
DDQ (3)
K2S2O8 (3)
O2 (balloon)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (1)
K2S2O8 (2)
K2S2O8 (4)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
9
10
11
12
13
14
15
16
17
18
19
20c
21d
Dioxane 45
Toluene 82
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
54
81
87
51
70
CH3CN 93
CH3CN
CH3CN
CH3CN
76
85
71
aReaction conditions: 1a (0.2mmol), KSCN, oxidant, and solvent (2mL)
in a sealed tube at room temperature for 16h.
bIsolated yields based on 1a.
cAt 50°C.
Moreover, we explored the reactivity of α-amino car-
bonyl compounds having substituents on the nitrogen atom.
The reaction can proceed smoothly when other alkyl groups
are attached to the nitrogen atom, such as ethyl, n-butyl,
allyl, and benzyl (3o–3r). It is worth noting that the car-
bon–carbon double bond of allyl is not affected during the
reaction (3q). For the substrate having an aromatic group at
the nitrogen atom (3s), the method was successful and the
corresponding product was obtained in moderate yield.
Unfortunately, 1-phenyl-2-(phenylamino)ethan-1-one was
not applicable to the reaction. When ethyl N-methyl-N-
phenylglycinate (1t) and 2-(methyl(phenyl)amino) acetoni-
trile (1u) were chosen as the substrates, the corresponding
products 3t and 3u were obtained in good yields, which
further increased the scope of the reaction.
dAt 80°C.
Bold figure represents the best conditions.
CoCl2·6H2O, I2, and dimethyl sulfoxide (DMSO) through
the cleavage of the C–N bond (Scheme 1B). The α-amino
carbonyl compounds can be easily fabricated from ketones
and amines49,50 and are used as raw materials for the synthe-
sis of a wide range of compounds.51
Results and discussion
We began the investigation using 2-(methyl(phenyl)amino)-
1-phenylethan-1-one (1a) and KSCN (2) as model sub-
strates (Table 1). The desired product 3a was obtained in
28% yield using PhI(OAc)2 (3 equiv.) and CH3CN (2mL) in
a sealed tube at room temperature for 16h (entry 1). This
result greatly encouraged us to further explore the reaction.
First, we investigated different oxidants for the reaction,
Furthermore, we found that arylamine thiocyanates can
also be obtained from α-amino carbonyl compounds and
KSCN. After screening, the catalyst system CoCl2·6H2O
(10mol%)/I2 (2equiv.)/DMSO was shown to be the best

Yi et al.
3
Table 2. Substrate scope for the reaction.a,b.
R'
N
O
R'
N
O
K
2S2O8
+
KSCN
R
R
CH3CN, rt
SCN
1
2
3
O
O
O
N
N
N
F
SCN
SCN
Cl
SCN
SCN
3c
83%
,
3a
93%
3b
85%
,
,
O
O
O
N
N
N
F
3C
SCN
NC
I
SCN
3f
3d
3e
, 78%
89%
86%
,
,
O
O
O
N
Br
N
N
89%
N
Cl
O2N
SCN
SCN
SCN
3i
90%
,
3g 74%
,
3h
,
O
O
O
N
N
Cl
SCN
Me
SCN
MeO
SCN
3k
3j
,
88%
82%
3l 75%
,
,
O
Et
N
O
O
O
N
Me
N
SCN
SCN
SCN
3m
86%
3n
3q
,
76%
3o
80%
,
,
n-
N
O
Bn
N
O
Bu
N
SCN
SCN
SCN
85%
,
3p
3s
84%
3r 75%
,
,
O
O
NC
N
N
N
EtO
SCN
SCN
SCN
3t
78%
83%
3u
86%
,
,
,
aReaction conditions: 1 (0.2mmol), 2 (0.8mmol), K2S2O8 (0.6mmol), and CH3CN (2mL) in a sealed tube at room temperature for 16h.
bIsolated yields based on 1.
combination. Then, we investigated the substrate scope of pathway. Moreover, when compound 5 was chosen as the
this transformation (Table 3). For the carbonyl moiety, substrate instead of 1a, none of the products 3a or 6 were
regardless of whether an electron-donating or electron- detected (Scheme 2C). When 3a was chosen as the sub-
withdrawing group was attached to the benzene ring, the strate in the presence of CoCl2·6H2O, I2, and DMSO, prod-
product 4a was obtained in moderate yields. For the amino uct 4a was obtained in 67% yield and benzoylformic acid
moiety, when a substituent is attached to the ortho or meta was detected by gas chromatography–mass spectrometry
position of the benzene ring, the target product can also be (GC-MS; Scheme 2D).
obtained in a moderate yield (4b–e). Unfortunately, as the
Based on these experimental results and previous repo
alkyl chain on the nitrogen atom increases, the reaction rts,52–60 a possible mechanism for the thiocyanation of α-
efficiency decreases. When 2-(n-butyl(phenyl)amino)- amino carbonyl compounds is proposed (Scheme 3).
1-phenylethan-1-one was used as the substrate, the target Initially, +SCN is formed from the KSCN by the oxidant
product 4g was only obtained in a low yield.
and adds to the substrate 1a to afford intermediate I. The
To explore the reaction mechanism, several control intermediate I is unstable and converts into the product 3a
experiments were carried out (Scheme 2). When the radical by losing a hydrogen ion. The product 4a was obtained from
inhibitor TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) 3a under the conditions of cobalt catalyst, I2, and DMSO.
was added to the reaction under the optimal conditions, the
product 3a was obtained in 84% yield (Scheme 2A). When
the radical inhibitor BHT (2,6-di-tert-butyl-4-methylphe-
Conclusion
nol) was added, the yield of 3a was almost unaffected In conclusion, we have demonstrated a novel procedure for
(Scheme 2B). These two results indicate that the reaction the synthesis of aromatic thiocyanates through K2S2O8-
might not be a radical process and may involve an ionic mediated thiocyanation of α-amino carbonyl compounds.

4
Journal of Chemical Research 00(0)
Table 3. Substrate scope for the synthesis of arylamine thiocyanates.a,b.
H
N
R'
R'
N
O
g
CoCl2 6H2O (10 mol%)
+
K
SCN
R
I
equiv.), DMSO, 80oC
2 (2
NCS
2
1
4
H
H
N
H
N
N
Cl
NCS
NCS
NCS
4b
4c
4a
4a
4a
4a
4a
4a
4a
,70%
, 67%
: R = Ph, 76%
: R = 4-MeC6H4 75%
,
H
N
H
N
: R = 4-ClC6H4 72%
,
: R = 4-CF3C6H4 65%
,
: R = 3-BrC6H4 68%
,
NCS
Cl
: R = 2-MeC6H4 72%
,
NCS
: R = OEt, 67%
4e
, 53%
4d
, 68%
H
H
N
N
n
-Bu
Et
NCS
NCS
4f
4g
, 36%
, trace
aReaction conditions: 1 (0.3mmol), 2 (0.3mmol), CoCl2·6H2O (10mol%), I2 (0.6mmol), and DMSO (2mL) in a sealed tube at 80°C for 16h.
bIsolated yields based on 1.
O
O
K2S2O8
N
N
N
+
KSCN
KSCN
(A)
(B)
CH3CN, rt
SCN
1a
3a,
84%
TEMPO (2 equiv.)
O
O
K2S2O8
N
+
CH3CN, rt
SCN
N
1a
3a,
89%
BHT (2 equiv.)
O
O
SCN
K2S2O8
N
+
+
3a
KSCN
KSCN
(C)
(D)
CH3CN, rt
0%
5
6
, not detected
O
H
N
O
CoCl2g6H2O
N
+
+
o
Ph
H
CO2
2
I , DMSO, 80 C
NCS
SCN
4a
, 67%
detected by GC-MS
3a
Scheme 2. Control experiments.
This strategy has the advantages of simple reaction condi- of the protocol for the synthesis of bioactive molecules are
tions without the use of a transition-metal catalyst, high currently underway.
regioselectivity, and high efficiency. Moreover, arylamine
thiocyanates can also be obtained from α-amino carbonyl
compounds and potassium thiocyanate in the presence of Experimental section
cobalt catalyst, I2, and DMSO through the cleavage of the
C–N bond. These reactions expand further the use of α-
General information
amino carbonyl compounds in organic synthesis. Studies to Commercially available reagents were purchased from
gain insights into the reaction mechanism and application commercial suppliers and used without further purification.

Yi et al.
5
1-(4-Iodophenyl)-2-(methyl(4-thiocyanatophenyl)
amino)ethan-1-one (3d): White solid, 89% yield (72mg),
m.p.=163–164°C; 1H NMR (400MHz, CDCl3) δ 7.88 (d,
J= 6.8Hz, 2H), 7.67 (d, J=6.4Hz, 2H), 7.38 (d, J=7.2Hz,
O
N
-
[O]
KSCN
SCN
SCN
I
H
O
2H), 6.61 (d, J=6.8Hz, 2H), 4.76 (s, 2H), 3.11 (s, 3H); 13
C
N
+
H
Ph
Ph
NMR (100MHz, CDCl3) δ 194.5, 150.6, 138.2, 134.4,
134.1, 129.0, 113.2, 112.3, 107.9, 102.0, 58.3, 39.6; HRMS
(EI): m/z [M]+ calcd for C16H13IN2OS:407.9788, found:
407.9789.
1a
O
NCS
[Co], I2, DMSO
N
N
H
SCN
4a
2-(Methyl(4-thiocyanatophenyl)amino)-1-(4-
(trifluoromethyl)phenyl)ethan-1-one (3e): Light yellow
solid, 86% yield (60mg), m.p.=143–144°C; 1H NMR
(400MHz, CDCl3) δ 8.08 (d, J=6.0Hz, 2H), 7.79 (d,
J=6.4Hz, 2H), 7.40 (d, J=7.2Hz, 2H), 6.63 (d, J=7.2Hz,
2H), 4.84 (s, 2H), 3.13 (s, 3H); 13C NMR (100MHz, CDCl3)
δ 194.4, 150.5, 137.5, 135.1 (q, J = 26.0Hz), 134.4, 128.1,
126.0 (q, J=2.9Hz), 123.4 (q, J=216.6Hz), 113.3, 112.2,
108.2, 58.7, 39.7; HRMS (EI): m/z [M]+ calcd for
C17H13F3N2OS: 350.0696, found: 350.0691.
3a
Scheme 3. Possible mechanism.
Reactions were monitored by thin-layer chromatography
(TLC). Flash column chromatography was performed over
silica gel (200–300 mesh). H and 13C NMR spectra were
1
recorded on a 400MHz NMR plus spectrometer using resi-
due solvent peaks as internal standards. High-resolution
mass spectra were obtained using a GCT time of flight
(TOF) instrument with the electron ionization (EI) source.
Melting points are uncorrected.
4-(N-Methyl-N-(4-thiocyanatophenyl)glycyl)benzoni-
trile (3f): Yellow solid, 78% yield (48mg), m.p.=151–
1
152°C; H NMR (400MHz, CDCl3) δ 8.05 (d, J=6.8Hz,
2H), 7.82 (d, J=6.4Hz, 2H), 7.40 (d, J=7.2Hz, 2H), 6.62
(d, J=7.6Hz, 2H), 4.82 (s, 2H), 3.12 (s, 3H); 13C NMR
(100MHz, CDCl3) δ 194.2, 150.4, 137.7, 134.4, 132.8,
128.2, 117.6, 117.1, 113.3, 112.2, 108.4, 58.8, 39.7; HRMS
General procedure for the synthesis of
product 3
To a sealed tube were added α-amino carbonyl compound (EI): m/z [M]+ calcd for C17H13N3OS: 307.0772, found:
1 (0.2mmol), KSCN (0.8mmol), K2S2O8 (0.6mmol), and 307.0766.
CH3CN (2mL). Then, the tube was stirred at room tempera-
2-(Methyl(4-thiocyanatophenyl)amino)-1-(4-nitrophe-
ture for 16h. After completion of the reaction, the resulting nyl)ethan-1-one (3g): Yellow solid, 74% yield (48mg),
mixture was concentrated in vacuo and purified by column m.p.=162–163°C; 1H NMR (400MHz, CDCl3) δ 8.35 (d,
chromatography on silica gel (petroleum ether/ethyl ace- J=6.8Hz, 2H), 8.12 (d, J=7.2Hz, 2H), 7.40 (d, J=7.2Hz,
tate) to afford the desired product 3.
2H), 6.63 (d, J=7.2Hz, 2H), 4.85 (s, 2H), 3.13 (s, 3H); 13
C
2-(Methyl(4-thiocyanatophenyl)amino)-1-phenylethan- NMR (100MHz, CDCl3) δ 194.1, 150.6, 150.4, 139.2,
1-one (3a): White solid, 93% yield (52mg), m.p.= 145– 134.4, 128.9, 124.1, 113.3, 112.2, 108.4, 58.9, 39.7; HRMS
146°C; H NMR (400MHz, CDCl3) δ 7.98 (d, J=5.6Hz, (EI): m/z [M]+ calcd for C16H13N3O3S: 327.0673, found:
1
2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.39 (d, J= 327.0670.
7.2Hz, 2H), 6.63 (d, J=7.2Hz, 2H), 4.83 (s, 2H), 3.13 (s,
1-(3-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl)
3H); 13C NMR (100MHz, CDCl3) δ 195.0, 150.7, 134.9, amino)ethan-1-one (3h): White solid, 89% yield (56mg),
1
134.4, 133.9, 128.9, 127.7, 113.2, 112.3, 107.7, 58.4, 39.7; m.p.=127–128°C; H NMR (400MHz, CDCl3) δ 7.93 (t,
high resolution mass spectrometry (HRMS) (EI): m/z [M]+ J=1.2Hz, 1H), 7.85–7.83 (m, 1H), 7.61–7.59 (m, 1H), 7.46
calcd for C16H14N2OS: 282.0822, found: 282.0824.
(t, J=6.4Hz, 1H), 7.38 (d, J=7.2Hz, 2H), 6.61 (d,
1-(4-Fluorophenyl)-2-(methyl(4-thiocyanatophenyl) J=7.6Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H); 13C NMR
amino)ethan-1-one (3b): White solid, 85% yield (51mg), (100MHz, CDCl3) δ 193.9, 150.5, 136.3, 135.2, 134.3,
m.p.=160–162°C; 1H NMR (400MHz, CDCl3) δ 7.99–8.02 133.8, 130.2, 127.8, 125.7, 113.2, 112.3, 107.9, 58.5, 39.6;
(m, 2H), 7.38 (d, J=7.6Hz, 2H), 7.16–7.20 (m, 2H), 6.62 (d, HRMS (EI): m/z [M]+ calcd for C16H13ClN2OS: 316.0432,
J=6.8Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H); 13C NMR found: 316.0433.
(100MHz, CDCl3) δ 193.4, 166.0 (d, J=203.7Hz), 150.7,
1-(3-Bromophenyl)-2-(methyl(4-thiocyanatophenyl)
134.3, 131.3 (d, J=2.9Hz), 130.4 (d, J=7.2Hz), 116.1 (d, amino)ethan-1-one (3i): White solid, 90% yield (65mg),
1
J=17.3Hz), 113.2, 112.3, 107.7, 58.3, 39.6; HRMS (EI): m/z m.p.=138–139°C; H NMR (400MHz, CDCl3) δ 8.08 (t,
[M]+ calcd for C16H13FN2OS: 300.0728, found: 300.0723.
J=1.2Hz, 1H), 7.88–7.89 (m, 1H), 7.74–7.76 (m, 1H),
1-(4-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl) 7.37–7.41 (m, 3H), 6.61 (d, J=7.6Hz, 2H), 4.78 (s, 2H),
amino)ethan-1-one (3c): White solid, 83% yield (52mg), 3.11 (s, 3H); 13C NMR (100MHz, CDCl3) δ 193.9, 150.5,
m.p.=156–157°C; 1H NMR (400MHz, CDCl3) δ 7.91 (d, 136.7, 136.5, 134.3, 130.8, 130.5, 126.2, 123.2, 113.2,
J=7.2Hz, 2H), 7.49 (d, J=7.2Hz, 2H), 7.39 (d, J=6.8Hz, 112.3, 107.9, 58.5, 39.6; HRMS (EI): m/z [M]+ calcd for
2H), 6.62 (d, J=7.2Hz, 2H), 4.78 (s, 2H), 3.11 (s, 3H); 13
NMR (100MHz, CDCl3) δ 193.9, 150.6, 140.4, 134.4,
C
C16H13BrN2OS: 359.9927, found: 359.9921.
1-(2-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl)
133.2, 129.3, 129.1, 113.2, 112.3, 107.9, 58.4, 39.7; HRMS amino)ethan-1-one (3j): White solid, 82% yield (52mg),
1
(EI): m/z [M]+ calcd for C16H13ClN2OS: 316.0432, found: m.p.=108–109°C; H NMR (400MHz, CDCl3) δ 7.44–
316.0436.
7.47 (m, 3H), 7.40 (d, J=7.2Hz, 2H), 7.33–7.37 (m, 1H),

6
Journal of Chemical Research 00(0)
6.65 (d, J=7.6Hz, 2H), 4.72 (s, 2H), 3.10 (s, 3H); 13C NMR 112.4, 106.7, 56.8, 52.0, 29.3, 20.1, 13.8; HRMS (EI): m/z
(100MHz, CDCl3) δ 199.2, 150.4, 137.2, 134.3, 132.5, [M]+ calcd for C19H20N2OS: 324.1296, found: 324.1291.
130.9, 130.5, 129.1, 127.2, 113.2, 112.3, 107.9, 61.9, 39.6;
2-(Allyl(4-thiocyanatophenyl)amino)-1-phenylethan-
HRMS (EI): m/z [M]+ calcd for C16H13ClN2OS: 316.0432, 1-one (3q): Light yellow solid, 85% yield (52mg),
1
found: 316.0430.
m.p.=73–75°C; H NMR (400MHz, CDCl3) δ 7.99–8.01
2-(Methyl(4-thiocyanatophenyl)amino)-1-(p-tolyl) (m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.36 (d,
ethan-1-one (3k): White solid, 88% yield (52mg), J=6.8Hz, 2H), 6.59 (d, J=7.2Hz, 2H), 5.85–5.92 (m, 1H),
m.p.=131–133°C; 1H NMR (400MHz, CDCl3) δ 7.87 (d, 5.21–5.26 (m, 2H), 4.80 (s, 2H), 4.04–4.06 (m, 2H); 13C
J=6.4Hz, 2H), 7.37 (d, J=7.2Hz, 2H), 7.31 (d, J=6.4Hz, NMR (100MHz, CDCl3) δ 194.9, 150.1, 134.8, 134.3,
2H), 6.62 (d, J=7.2Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H), 2.44 133.9, 132.7, 128.9, 127.7, 116.7, 113.4, 112.3, 107.6, 56.3,
(s, 3H); 13C NMR (100MHz, CDCl3) δ 194.5, 150.8, 144.8, 54.3; HRMS (EI): m/z [M]+ calcd for C18H16N2OS:
134.3, 132.4, 129.5, 127.8, 113.1, 112.3, 107.3, 58.2, 39.6, 308.0978, found: 308.0982.
21.6; HRMS (EI): m/z [M]+ calcd for C17H16N2OS:
2-(Benzyl(4-thiocyanatophenyl)amino)-1-phenylethan-
296.0978, found: 296.0975.
1-one (3r): Light yellow solid, 75% yield (54mg),
1
1-(4-Methoxyphenyl)-2-(methyl(4-thiocyanatophenyl) m.p.=80–81°C; H NMR (400MHz, CDCl3) δ 7.97–7.99
amino)ethan-1-one (3l): White solid, 75% yield (47mg), (m 2H), 7.63–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.34–7.38
m.p.=125–126°C; 1H NMR (400MHz, CDCl3) δ 7.95 (d, (m, 4H), 7.27–7.31 (m, 3H), 6.63 (d, J=7.2Hz, 2H), 4.87
J=8.8Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8Hz, (s, 2H), 4.69 (s, 2H); 13C NMR (100MHz, CDCl3) δ 195.0,
2H), 6.62 (d, J=8.8Hz, 2H), 4.77 (s, 2H), 3.89 (s, 3H), 3.11 150.8, 135.8, 134.4, 132.4, 132.2, 129.5, 129.4, 128.9,
(s, 3H); 13C NMR (100MHz, CDCl3) δ 193.4, 164.0, 150.8, 127.9, 127.1, 123.3, 113.2, 112.4, 107.7, 58.5, 39.7; HRMS
134.3, 130.0, 127.9, 114.0, 113.1, 112.4, 107.3, 58.0, 55.5, (EI): m/z [M]+ calcd for C22H18N2OS: 358.1135, found:
39.7; HRMS (EI): m/z [M]+ calcd for C17H16N2O2S: 358.1132.
312.0927, found: 312.0926.
2-(Methyl(3-methyl-4-thiocyanatophenyl)amino)-
2-(Methyl(4-thiocyanatophenyl)amino)-1-(m-tolyl) 1-phenylethan-1-one (3s): White solid, 78% yield (46mg),
1
ethan-1-one (3m): White solid, 86% yield (51mg), m.p.=146–147°C; H NMR (400MHz, CDCl3) δ 7.97–
m.p.=107–109°C; 1H NMR (400MHz, CDCl3) δ 7.77 (d, 7.99 (m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.39
J=7.2Hz, 2H), 7.45 (d, J=6.0Hz, 1H), 7.37–7.41 (m, 3H), (d, J=6.8Hz, 1H), 6.56 (d, J=2.0Hz, 1H), 6.47 (dd, J=2.4,
6.62 (d, J=6.8Hz, 2H), 4.81 (s, 2H), 3.12 (s, 3H), 2.43 (s, 6.8Hz, 1H), 4.82 (s, 2H), 3.11 (s, 3H), 2.47 (s, 3H); 13C
3H); 13C NMR (100MHz, CDCl3) δ 195.1, 150.8, 138.8, NMR (100MHz, CDCl3) δ 195.1, 151.3, 142.7, 136.0,
134.9, 134.6, 134.4, 128.7, 128.2, 124.8, 113.1, 112.4, 134.9, 133.8, 128.9, 127.7, 114.3, 111.9, 110.9, 107.4, 58.4,
107.4, 58.4, 39.6, 21.3; HRMS (EI): m/z [M]+ calcd for 39.6, 21.4; HRMS (EI): m/z [M]+ calcd for C17H16N2OS:
C17H16N2OS: 296.0978, found: 296.0976.
296.0978, found: 296.0975.
2-(Methyl(4-thiocyanatophenyl)amino)-1-(naphthalen-
Ethyl N-methyl-N-(4-thiocyanatophenyl)glycinate (3t):
2-yl)ethan-1-one (3n): White solid, 76% yield (50mg), White solid, 83% yield (42mg), m.p.=78–79°C; 1H NMR
1
m.p.=128–129°C; H NMR (400MHz, CDCl3) δ 8.51 (s, (400MHz, CDCl3) δ 7.42 (d, J=7.6Hz, 2H), 6.66 (d,
1H), 7.90–8.02 (m 4H), 7.63–7.67 (m, 1H), 7.58–7.61 (m, J=7.6Hz, 2H), 4.18 (q, J=6.0Hz, 2H), 4.06 (s, 2H), 3.08
1H), 7.40 (d, J = 6.8Hz, 2H), 6.67 (d, J = 7.6Hz, 2H), (s, 3H), 1.25 (t, J=6.0Hz, 3H); 13C NMR (100MHz,
4.97 (s, 2H), 3.17 (s, 3H); 13C NMR (100MHz, CDCl3) δ CDCl3) δ 169.9, 150.4, 134.3, 113.2, 112.2, 108.1, 61.1,
195.0, 150.8, 135.8, 134.4, 132.4, 132.2, 129.5, 129.4, 54.0, 39.5, 14.1; HRMS (EI): m/z [M]+ calcd for
128.9, 127.9, 127.1, 123.3, 113.2, 112.4, 107.7, 58.5, 39.7; C12H14N2O2S: 250.0771, found: 250.0776.
HRMS (EI): m/z [M]+ calcd for C20H16N2OS: 332.0978,
2-(Methyl(4-thiocyanatophenyl)amino)acetonitrile
found: 332.0974.
(3u): White solid, 86% yield (35mg), m.p.=120–122°C;
2-(Ethyl(4-thiocyanatophenyl)amino)-1-phenylethan- 1H NMR (400MHz, CDCl3) δ 7.51 (d, J=8.8Hz, 2H), 6.85
1-one (3o): White solid, 80% yield (47mg), m.p.=134– (d, J=8.8Hz, 2H), 4.22 (s, 2H), 3.07 (s, 3H); 13C NMR
1
135°C; H NMR (400MHz, CDCl3) δ 7.99–8.01 (m 2H), (100MHz, CDCl3) δ 149.0, 133.8, 115.2, 114.9, 112.1,
7.62–7.66 (m, 1H), 7.51–7.54 (m, 2H), 7.37 (d, J=7.2Hz, 111.6, 41.4, 39.1; HRMS (EI): m/z [M]+ calcd for C10H9N3S:
2H), 6.57 (d, J=7.6Hz, 2H), 4.79 (s, 2H), 3.50 (q, J=5.6Hz, 203.0512, found: 203.0511.
2H), 1.24 (t, J=5.6Hz, 3H); 13C NMR (100MHz, CDCl3) δ
194.9, 149.6, 134.9, 134.6, 133.8, 128.9, 127.7, 113.0,
General procedure for the synthesis of
product 4
112.4, 107.0, 56.4, 46.4, 12.2; HRMS (EI): m/z [M]+ calcd
for C17H16N2OS: 296.0978, found: 296.0973.
2-(Butyl(4-thiocyanatophenyl)amino)-1-phenylethan- To a sealed tube were added α-amino carbonyl compound
1-one (3p): Light yellow solid, 84% yield (54mg), 1 (0.3mmol), KSCN (0.3mmol), CoCl2·6H2O (10mol%),
1
m.p.=87–88°C; H NMR (400MHz, CDCl3) δ 7.99–8.01 I2 (0.6mmol), and DMSO (2mL). Then, the tube was
(m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.35 (d, stirred at 80°C for 16h. After completion of the reaction, a
J=7.2Hz, 2H), 6.56 (d, J=7.2Hz, 2H), 4.80 (s, 2H), 3.41 Na2S2O3 solution was added, and the resulting mixture was
(t, J=6.4Hz, 2H), 1.61–1.68 (m, 2H), 1.34–1.42 (m, 2H), extracted with EtOAc. The organic layer was washed with
0.97 (t, J=6.0Hz, 3H); 13C NMR (100MHz, CDCl3) δ water and brine, dried over Na2SO4, and concentrated in
194.8, 149.9, 134.8, 134.5, 133.8, 128.8, 127.7, 112.9, vacuo. The resulting mixture was purified by column

Yi et al.
7
chromatography on silica gel (petroleum ether/ethyl ace- References
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N-Methyl-4-thiocyanatoaniline (4a):52,54 Light yellow
oil, 76% yield (37mg); 1H NMR (400MHz, CDCl3) δ 7.38
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solid, 67% yield (40mg), m.p.=57–59°C; 1H NMR 10. Zhu ZQ, Xie ZB and Le ZG. J Org Chem 2016; 81: 9449.
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solid, 68% yield (36mg), m.p.=51–52°C; 1H NMR
(400MHz, CDCl3) δ 7.36–7.34 (m, 1H),7.26–7.25 (m, 1H),
6.56 (d, J = 6.8Hz, 1H), 3.91 (s, 1H), 2.90 (s, 3H), 2.11 (s,
3H); 13C NMR (100MHz, CDCl3) δ 149.1, 134.5, 132.8,
123.5, 112.7, 109.8, 106.9, 30.3, 17.1; HRMS (EI): m/z
[M]+ calcd for C9H10N2S: 178.0560, found: 178.0556.
2-Chloro-N-methyl-4-thiocyanatoaniline (4e): White
solid, 53% yield (31mg), m.p.=52–53°C; 1H NMR
(400MHz, CDCl3) δ 7.48 (d, J=2.0Hz, 1H), 7.39–7.37 (m,
1H), 6.62 (d, J=7.2Hz, 1H), 4.70 (s, 1H), 2.92 (d, J=3.2
Hz, 3H); 13C NMR (100MHz, CDCl3) δ 146.8, 133.4,
133.3, 119.5, 111.8, 111.1, 107.4, 30.0; HRMS (EI): m/z
[M]+ calcd for C8H7ClN2S: 198.0013, found: 198.0011.
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yield (19mg), m.p.=55–56°C; 1H NMR (400MHz, CDCl3)
δ 7.36 (d, J=6.8Hz, 2H), 6.57 (d, J=6.8Hz, 2H), 3.97 (s,
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
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The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this paper: This
work was supported by the National Natural Science Foundation
of China (No. 21772035) and the Provincial Natural Science
Foundation of Hunan (No. 2019JJ50104).
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ORCID iD
Niannian Yi
https://orcid.org/0000-0001-6008-5649
Supplemental material
Supplemental material for this article is available online.

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