In-Water Synthesis of 5-Thiolated 1,2,3-Triazoles from β-Thioenaminones by Diazo Transfer Reaction

Article abstract of DOI:10.1021/acs.joc.9b01817

The synthesis of 1,2,3-triazoles with a sulfur-based side chain has been accessed with the metal-free annulation reactions of readily available β-thiolated enaminones and tosyl hydrazine. By these reactions with water as the only medium, a broad array of

Full text of DOI:10.1021/acs.joc.9b01817

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Note
In-Water Synthesis of 5-Thiolated 1,2,3-Triazoles
From #-Thioenaminones by Diazo Transfer Reaction
Leiling Deng, Xiaoji Cao, Yunyun Liu, and Jie-Ping Wan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01817 • Publication Date (Web): 14 Oct 2019
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Page 1 of 11
The Journal of Organic Chemistry
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In-Water Synthesis of 5-Thiolated 1,2,3-Triazoles From β-
Thioenaminones by Diazo Transfer Reaction
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Leiling Deng,a Xiaoji Cao,b Yunyun Liu*a and Jie-Ping Wan*a
†College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China.
‡Research Centre of Analysis and Measurement, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou,
Zhejiang 310014, China
ABSTRACT: The synthesis of 1,2,3-triazoles with sulfur-based side chain has been accessed with the metal-free annulation
reactions of readily available β-thiolated enaminones and tosyl hydrazine. By these reactions with water as the only
medium, a broad array of 5-thiolated 1,2,3-triazoles have been synthesized with generally good to excellent yields. Except
using TMEDA (N,N,N',N'-tetramethylethylenediamine) as the only base promoter, not any other catalyst or additive is
required, thus providing an efficient and environmentally benign methods for useful 1,2,3-triazole synthesis.
Over the last few decades, 1,2,3-triazole heterocycle
synthesis has become a prominent area of chemical
research owing to their application in almost every
research discipline and industry associated with organic
molecules.1 After the disclosure of Huisgen 1,3-dipolar
azide–alkyne cycloaddition (AAC) to 1,2,3-triazoles,2 the
revolutionary method of copper-catalyzed AAC (CuAAC)
reported respectively by Sharpless and Meldal group has
intrigued the splendid progress of 1,2,3-triazole
chemistry.3 For the sake of extending the understanding
and application of 1,2,3-triazoles, the availability of the
1,2,3-triazole library is inarguably a precondition.4 On the
other hand, among the 1,2,3-triazole scaffolds with
attractive applications, 1,2,3-triazoles elaborated with
sulfur side chain have displayed particular merits for their
versatile utilities in discovering bioactive compounds, and
assisting important synthetic procedures.5 In this regard,
extensive attention has been paid over the past decade to
the synthesis of thiolated 1,2,3-triazoles. Representatively,
besides those early employed multiple step routes
involving the post elaboration on synthesized 1,2,3-
triazoles,6 the thioalkyne-azide cycloaddition catalyzed by
noble metal such as Ir- and Rh- and Ru-catalyst (Scheme
1A) have been realized as efficient one-step approach to
the synthesis of C5-thiolated 1,2,3-triazoles.7 On the other
hand, the copper-catalyzed reactions of alkynes, azides
and sulfur-heteroatom-based electrophiles involving the
interrupted AAC has been devised as another robust
tactic for the synthesis of such functionalized 1,2,3-
triazoles (Scheme 1B).8 The organocatalytic azide–ketone
[3+2] cycloaddition of α-thioketones and organo azides
has been realized for C4-thiolated 1,2,3-triazole
synthesis.9a Despite these notable advances, it should
pointed out that restrictions remain in the chemistry of
thiolated 1,2,3-triazole synthesis. Typical ones are the
employment of transition metal-catalyst, the N-
substitution dependent on explosive and limitedly
available organo azides and/or the interference of region-
isomer by-product resulting from undesired cycloaddition
pathway. Therefore, considering the currently leading
trends in designing organocatalytic,9 transition metal-
free10 and/or green solvent mediated synthesis11 in the
1,2,3-triazole synthesis, it is thus highly desirable to search
and establish alternative methods for the synthesis of
thiolated 1,2,3-triazoles benefiting these sustainable
advantages.
During the past couple of years, enaminones has been
identified as robust building block in the synthesis of
diversified organic products.12 By means of different
transformation pathways, the enaminone derivatives have
been used for successful synthesis of acyclic molecules,13
heteroaryls,14 non-aromatic heterocycles15 as well as full
carbon cyclic compounds16 with highly enriched
structural divergence. In light of the previous results
Scheme 1 One-step synthesis of 5-thiolated 1,2,3-
triazoles
A) Previous:
MAAC (M = Ir, Ru, Rh)
R3
N
N
N
noble metal
R3N3
R1
S
R2
+
R1
S
R2
B) Previous:
copper-catalyzed interrupted click reaction
N
R1
N
N
Cu-cat.
R1N3
E
+
LG
E = N, S, Se
+
R2
R2
E
C) This work:
metal-free annulation in water
R3
N
R3
N
N
O
HN
TMEDA
water
+
TsN3
R1
SR2
R2S
COR1
> No metal reagent, no organic solvent
> Easily accessible and enriched N-substitution
> Practical scale-up synthesis
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depicting the featured application of enaminones in the was used as alternative azide substrate, but no better
construction of 1,2,3-triazoles,17 we have assumed that it is
possible to develop alternative synthetic route to sulfur
side chain functionalized with proper enaminone
derivatives without metal catalysis,18 which would provide
compliment the presently known methods of transition
metal catalysis. Herein, we present our results in the first
metal-free synthesis of 5-thiolated 1,2,3-triazoles via the [3
+ 2] annulation of thiolated enaminones and tosyl azide
(Scheme 1C). Beside the totally metal-free procedure,
using pure water as medium,19 the easy and abundant
sources of N-substitution from the stable enaminone
substrates (See ESI for the substrate preparation) as well
as the scalable synthesis constitute the major novelty and
feature of greenness manifested in the present work.
Notably, Ila et al have reported in 1988 the cycloaddition
reactions of the same substrates providing 5-amino
substituted 1,2,3-triazoles via Dimroth rearrangement by
losing MeSH at 0 oC-rt by strong base (NaOH) induced α-
H elimination in the triazoline intermediate.20 In contrast,
the present work is of particular interest in succesfully
tuning the reaction pathway to the diazo transfer via
azide N-N bond cleavage by employing weak base
(TMEDA) and water as medium.
result was observed for this reaction (entry 21, Table 1).
Table 1 Optimization on reaction conditionsa
1
2
3
4
5
6
7
8
N
Ph
N
N
Base
O
HN
Solvent/T
+
TsN3
SMe
SMe
O
1a
2
3a
Entry
1
Base
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
toluene
DMSO
Temp(oC)
120
120
120
120
120
120
120
120
120
120
120
130
Yield (%)b
45
9
Cs2CO3
NaHCO3
t-BuONa
TMEDA
DBU
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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53
54
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56
57
58
59
60
2
trace
trace
58
3
4
5
29
6
Et3N
24
7
8c
9d
10e
11f
12e
13e
14e
15e
16e,g
17e,h
18e,h
19e,h
20e,h,i
21e,h,j
DMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
30
47
62
68
50
60
As initial attempt, the reaction of β-thioenaminone 1a and
tosyl azide 2 was employed in water in the presence of a
110
63
o
base promoter. By heating at 120 C, a variety inorganic
100
90
50
and organic bases, such as Cs2CO3, NaHCO3, t-BuONa,
41
DBU,
Et3N,
TMEDA
(N,N,N’,N’-
120
120
120
120
62
tetramethylethylenediamine) and the DMEDA (N,N’-
dimethylethylenediamine) were capable of promoting the
formation of target product 3a. However, TMEDA
exhibited the best activity by providing 3a with evidently
higher yield than any other entry (entries 1-7, Table 1),
probably because of the water miscible property of
TMEDA, which also explained why 2 equiv. TMEDA was
needed for satisfactory yield. With this encouraging result,
the impact of the TMEDA loading was further examined,
which disclosed that 2 equiv TMEDA was most favoured
(entries 8-11, Table 1). Later on, the reaction was
performed at different temperature. It was found that
higher temperature did not improve the yield, and lower
temperature displayed negative effect to the reaction by
providing 3a with clearly lower yields (entries 12-15, Table
1). Higher temperature was needed for the reaction
indicated the higher activation energy of this
unprecedented reaction pathway between the two
substrates. Interestingly, shortening the reaction time to
6 h was able to afford 3a with even higher yield (entries
16-17, Table 1), indicating that 3a was possibly
decomposed by long time heating. Notably, parallel
experiments in organic solvents such as toluene and
DMSO didn’t show advantage over the water-mediated
reaction (entries 18-19, Table 1). An entry using mixed
water and DMSO gave also low yield (entry 20, Table 1),
supporting that water was a specifically proper medium
for this reaction. Finally, a reported effective diazo group
transferring azide, the 3-carboxybenzolsulfonyl azide21
87
22
61
H2O/DMSO 120
H2O 120
42
15
aGeneral conditions: 1a (0.2 mmol), 2 (0.3 mmol), base (1.0
equiv), in 2 mL solvent, stirred in sealed tube for 12 h.
c
d
bIsolated yield based on 1a. With 0.5 equiv TMEDA. With
e
f
1.5 equiv TMEDA. With 2.0 equiv TMEDA. With 3.0 equiv
TMEDA. The reaction time was 4 h. The reaction time was
6 h. H2O/DMSO (1/1 mL). 3-Carboxybenzolsulfonyl azide
was used as alternative azide substrate.
g
h
i
j
In the section of application scope investigation, a variety
of β-thiolated enaminones 1 were employed to react with
azide 2 under the optimized conditions. Notably, flexible
variation in the phenyl, N-substitution as well as the S-
substitution was allowed for the practical synthesis of
correspondingly diverse thiolated 1,2,3-triazoles
3
(Scheme 2). For the reaction using substrates with
different group in the phenyl ring (R1), alkyl, alkoxyl,
naphthyl, CF3, halogen, nitro were all tolerated to give
products with good to excellent yields (3a-3l, Scheme 2).
Importantly, alternating this fragment with furyl gave the
product 3m with high yield (Scheme 2). On the other
hand, for the substituent in the amino group, N-aryl and
N-alkyl substitution both exhibited applicability in the
synthesis, and N-alkylated products were provided with
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aGeneral conditions: enaminone 1 (0.2 mmol), tosyl azide 2
(0.3 mmol), TMEDA (0.4 mmol) in H2O (2 mL), stirred in
sealed tube for 6 h at 120 C. Isolated yield based on 1. The
slightly lower yields than the N-aryl ones (3n-3q vs 3r-3s,
1
2
3
4
5
6
7
8
Scheme 2). Moreover, it was noteworthy that various
alkylthio substructures, including ethyl-, propyl- and i-
butylthiolated enaminones participated the reaction to
give products with different sulfur side chain with good
yields (3t-3v, Scheme 2).
o
b
c
yield resulting from 2 mmol scale reaction.
featured Regitz diazo transfer22 on 6 then affords diazo
functionalized intermediate 7. The intramolecular
annulation of intermediate 7 then yields the final
thiolated 1,2,3-triazoles 3 (Scheme 3).
To further examine application potential, the scale-up
synthesis of 3a was executed. In the reaction of 2 mmol
scale, product 3a was acquired with 70% yield (Scheme 2),
suggested the usefulness of the present method in the
preparation of such 1,2,3-triazole scaffolds with large
amount.
Scheme 3 The proposed reaction mechanism
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B
R1
O
N
(TMEDA)
R1
R1
O
N
O
HN
Ph
SR2
According to the reaction results involving the
decomposition of the tosyl fragment, the reaction
mechanism is proposed wherein a key Regitz diazo
transfer is involved. Initially, the β-thioenaminone 1
undergoes deprotonation to provide anionic intermediate
5 via the tautomer 4 in the presence of base. Subsequently,
the nucleophilic addition of 5 to the azide 2 gives rise to
intermediate 6. The
5
SR2
Ph
SR2
Ph
4
N
N
N
Ts
1
BH
2
B = base
O
R1
O
SR2
O
N
H
BH
B
N
R1
SR2
N
Ph
R2S
Ph
N
Ph
N
N
N
N
N
7
R1
N
Ts
TsNH2
6
3
Scheme 2 Scope of the thio-1,2,3-triazole synthesis a,b
N
R2
N
R2
N
O
TMEDA, 2 equiv
In conclusion, by employing readily available β-
thioenaminones and tosyl azide as starting materials, the
synthesis of 5-thiolated 1,2,3-triazoles have been
synthesized for the first time via triazole annulation
without using any metal catalyst or reagent. In addition,
the broad and practical synthesis of the these 1,2,3-
triazoles employing water as the only reaction medium
makes the present method with unprecedented
advantages in terms of greenness, thus offers the only
hitherto option in synthesizing such useful heterocyclic
scaffolds without suffering from the interference of any
trace metal contamination.
O
HN
water, 120 o
C
+
TsN3
SR3
SR3
R1
R1
sealed
1
2
3
N
N
N
N
O
N
N
N
N
N
SMe
SMe
SMe
O
O
3c
c
3b
3a
, 80%
, 87% (70% )
, 83%
N
N
N
N
N
O
N
MeO
MeO
N
N
N
O
MeO
SMe
, 72%
SMe
SMe
O
3d
3e
, 75%
3f
, 89%
N
N
N
Experimental section
General experimental information
N
N
N
O
N
N
O
N
Cl
F
SMe
SMe
, 69%
SMe
O
, 85%
All experiments were carried out under air atmosphere.
The β-thioenaminones 1 were synthesized following
literature processes at 10 mmol scale.21 Other chemicals
and solvents used in the experiments were obtained from
commercial sources and used directly without further
3g
3i
3h
, 73%
N
N
N
N
N
O
N
N
N
N
O2N
Br
F3C
SMe
SMe
SMe
O
1
13
O
3l
, 56%
treatment. The H and C NMR spectra were recorded in
400 MHz apparatus in CDCl3 or DMSO-d6, and the
frequencies for 1H and 13C NMR test are 400 MHz and 100
MHz, respectively. The chemical shifts were reported in
ppm with TMS as internal standard. Melting points were
tested in X-4A instrument without correcting
temperature. The HRMS were obtained under ESI model
in a mass spectrometer equipped with TOF analyzer.
3j
, 70%
3k
, 76%
N
N
N
N
O
N
N
O
N
N
N
SMe
SMe
3n
SMe
O
O
3o
3m
, 78%
, 74%
, 75%
OMe
Cl
N
Bn
N
N
N
N
O
N
N
N
O
N
Synthesis of β-thioenaminones 1. Procedure A:23a to an
ice-cooled solution of appropriately substituted
acetophenone (10 mmol, 1 equiv) in 15 mL of DMF was
added sodium hydride(12 mmol, 288 mg). Subsequently, a
SMe
SMe
SMe
, 72%
O
3q
3r
, 65%
3p
, 76%
N
Me
N
N
O
N
solution
of
appropriately
substituted
phenyl
3t
3u
3v
, R = Et, 62%
, R= Pr, 65%
, R = i-Bu, 70%
N
O
N
SMe
isothiocyanate (10 mmol, 1 equiv) in 6 mL DMF was added
dropwise. The reaction mixture was stirred at room
SR
3s
, 63%
o
temperature for 45 min. The solution was cooled to 0 C.
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Iodomethane (10 mmol, 1.42g) was added, and the
56.0, 56.0, 14.8; HRMS (ESI-TOF) m/z Calcd for
C18H20NO3S [M+H]+: 330.1158, found: 330.1154.
1
2
3
4
5
6
7
8
reaction mixture was stirred at room temperature for 45
min. The solution was then poured into 30 mL of water
and extracted with (2 × 25 mL) of Et2O. The organic
layers were washed with 30 mL of brine and dried over
NaSO4. After filtration and evaporation, the residue was
subjected to silica gel column chromatography to give
pure products by using mixed petroleum ether and ethyl
acetate (v/v = 30:1).
(E)-3-(Methylthio)-1-(naphthalen-2-yl)-3-
(phenylamino)prop-2-en-1-one (1g). General procedure
A. Yield 1.69 g (53%); yellow solid; m.p. 119-120 oC; 1H NMR
(400 MHz, CDCl3): δ 13.54 (s, 1 H), 8.33 (s, 1H), 7.91 (dd, J =
8.4, 1.2 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.82–7.74 (m, 2
H), 7.47–7.39 (m, 2 H), 7.28 (d, J = 8.4 Hz, 4 H), 7.19–7.13
(m, 1 H), 5.95 (s, 1 H), 2.38 (s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3): 185.9, 167.6, 138.3, 137.6, 134.7, 132.9, 129.2, 129.1,
128.1, 127.7, 127.5, 127.3, 126.5, 126.4, 125.3, 124.1, 89.1, 14.9;
HRMS (ESI-TOF) m/z Calcd for C20H18NOS [M+H]+:
320.1104, found: 320.1100.
Procedure B:23b A mixture of ketene S,S-acetal (2 mmol, 1
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17
18
19
20
21
22
23
24
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59
60
equiv) and amine (4 mmol, 2 equiv) in EtOH (5 mL) was
o
stirred at 80 C overnight with oil bath heating. After the
acetal was completely consumed by TLC monitoring on
silica gel, the resultant mixture was allowed to cool down
to ambient temperature and then evaporated to remove
the solvent under reduced pressure. The resulting residue
was employed to silica gel column chromatography to
give pure product (eluent: petroleum ether /AcOEt = 30:1,
v/v).
(E)-1-(4-Fluorophenyl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one
(1h).26
General
1
procedure A. Yield 1.95 g (68%); H NMR (400 MHz,
CDCl3): δ 13.48 (s, 1 H), 7.94 (t, J = 8.8, 5.6 Hz, 2 H), 7.44–
7.38 (m, 2 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 1
H), 7.14 (t, J = 8.6 Hz, 2 H), 5.86 (s, 1 H), 2.47 (s, 3 H).
(E)-3-(Methylthio)-3-(phenylamino)-1-(p-tolyl)prop-2-
en-1-one (1a).24 General procedure A. Yield: 2.09 g (74%);
1H NMR (400 MHz, CDCl3): δ 13.50 (s, 1 H), 7.81 (d, J = 8.0
Hz, 2 H), 7.38–7.27 (m, 5 H), 7.21 (d, J = 7.2 Hz, 2 H), 5.86
(s, 1 H), 2.37 (s, 6 H).
(E)-1-(4-Chlorophenyl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one
(1i).24
General
o
1
procedure A. Yield 2.06 g (68%), m.p. 66-67 C; H NMR
(400 MHz, CDCl3): δ 13.52 (s, 1 H), 7.87 (d, J = 8.4 Hz, 2
H), 7.43 (d, J = 8.4 Hz, 4 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.30
(d, J = 7.4 Hz, 1 H), 5.86 (s, 1 H), 2.47 (s, 3 H).
(E)-3-(Methylthio)-1-phenyl-3-(phenylamino)prop-2-
en-1-one (1b).22 General procedure A. Yield: 1.83 g (68%),
m.p. 54-55 oC; 1H NMR (400 MHz, CDCl3): δ 13.56 (s, 1 H),
7.94 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 7.2 Hz, 3 H), 7.38 (d, J
= 7.6 Hz, 4 H), 7.29 (d, J = 6.8 Hz, 1 H), 5.92 (s, 1 H), 2.46
(s, 3 H).
(E)-1-(4-Bromophenyl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one
(1j).26
General
1
procedure A. Yield 2.08 g (60%); H NMR (400 MHz,
CDCl3): δ 13.51 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.59 (d, J =
8.4 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 7.34 (d, J = 7.6 Hz, 2
H), 7.30 (d, J = 7.2 Hz, 1 H), 5.85 (s, 1 H), 2.46 (s, 3 H).
(E)-3-(Methylthio)-3-(phenylamino)-1-(m-tolyl)prop-
2-en-1-one (1c).24 General procedure A. Yield 1.98 g (70%);
1H NMR (400 MHz, CDCl3): δ 13.57 (s, 1 H), 7.79–7.70 (m, 2
H), 7.44–7.35 (m, 5 H), 7.30 (dd, J = 11.3, 7.5 Hz, 2 H), 5.91
(s, 1 H), 2.46 (s, 3 H), 2.45 (s, 3 H).
(E)-3-(Methylthio)-3-(phenylamino)-1-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one
(1k).27
1
General procedure A. Yield 2.63 g (78%); H NMR (400
MHz, CDCl3): δ 13.56 (s, 1 H), 8.02 (d, J = 7.6 Hz, 2 H), 7.72
(d, J = 8.0 Hz, 2 H), 7.42 (d, J = 7.4 Hz, 2 H), 7.36 (d, J = 7.2
Hz, 2 H), 7.32 (d, J = 7.2 Hz, 1 H), 5.89 (s, 1 H), 2.48 (s, 3
H).
(E)-3-(Methylthio)-3-(phenylamino)-1-(o-tolyl)prop-2-
en-1-one (1d). General procedure A. Yield 2.04 g (72%);
o
1
yellow solid; m.p. 54-55 C; H NMR (400 MHz, CDCl3): δ
13.37 (s, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.46–7.34 (m, 5 H),
7.33–7.26 (m, 3 H), 5.52 (s, 1 H), 2.55 (s, 3 H), 2.38 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3): 190.9, 167.2, 142.0, 138.1,
135.8, 131.0, 129.2, 129.1, 127.3, 126.5, 125.5, 125.4, 92.5, 20.3,
14.8; HRMS (ESI-TOF) Calcd for C17H18NOS [M+H]+:
284.1104, found: 284.1099.
(E)-3-(Methylthio)-1-(4-nitrophenyl)-3-
(phenylamino)prop-2-en-1-one (1l). General procedure
o
1
A. Yield 1.54 g (49%); yellow solid; m.p. 102-103 C; H
NMR (400 MHz, CDCl3): δ 13.60 (s, 1 H), 8.31 (d, J = 8.8
Hz, 2 H), 8.05 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 7.6 Hz, 2 H),
7.39–7.31 (m, 3 H), 5.88 (s, 1 H), 2.50 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3): 183.1, 169.7, 145.9, 137.6, 130.0, 129.2,
128.0, 127.1, 125.5, 123.6, 88.8, 14.8; HRMS (ESI-TOF) m/z
Calcd for C16H15N2O3S [M+H]+: 315.0798, found: 315.0794.
(E)-1-(4-Methoxyphenyl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one
(1e).25
General
o
1
procedure A. Yield 2.12 g (71%); m.p. 45-46 C; H NMR
(400 MHz, CDCl3): δ 13.47 (s, 1 H), 7.92 (d, J = 8.8 Hz, 2
H), 7.45–7.33 (m, 4 H), 7.27 (d, J = 8.0 Hz, 1 H), 6.97 (d, J =
8.8 Hz, 2 H), 5.89 (s, 1 H), 3.89 (s, 3 H), 2.46 (s, 3 H).
(E)-1-(Furan-2-yl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one
(1m).23a
General
1
procedure A. Yield 1.81 g (70%); H NMR (400 MHz,
CDCl3): δ 13.22 (s, 1 H), 7.53 (s, 1 H), 7.38 (d, J = 7.2 Hz, 2
H), 7.33 (d, J = 7.2 Hz, 2 H), 7.27 (d, J = 6.0 Hz, 1 H), 7.11 (d,
J = 3.2 Hz, 1 H), 6.54 (s, 1 H), 5.89 (s, 1 H), 2.47 (s, 3 H).
(E)-1-(3,4-Dimethoxyphenyl)-3-(methylthio)-3-
(phenylamino)prop-2-en-1-one (1f). General procedure
1
A. Yield 2.17 g (66%); yellow liquid; H NMR (400 MHz,
CDCl3): δ 13.45 (s, 3 H), 7.57 (s, 1 H), 7.50 (dd, J = 8.4, 1.6
Hz, 1 H), 7.43–7.30 (m, 5 H), 6.89 (d, J = 8.4 Hz, 1 H), 5.89
(E)-3-(Methylthio)-1-(p-tolyl)-3-(p-tolylamino)prop-2-
en-1-one (1n). General procedure A. Yield 1.99 g (67%);
13
(s, 1 H), 3.96 (s, 1 H), 3.93 (s, 3 H), 2.43 (s, 3 H); C{1H}
1
yellow liquid; H NMR (400 MHz, CDCl3): δ 13.37 (s, 1 H),
NMR (100 MHz, CDCl3): 185.2, 166.8, 151.6, 148.9, 138.2,
133.0, 129.5, 129.1, 126.3, 125.2, 125.1, 120.4, 110.1, 110.1, 88.4,
7.81 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.20–7.14
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The Journal of Organic Chemistry
(m, 4 H), 5.85 (s, 1 H), 2.41 (s, 3 H), 2.39 (s, 3 H), 2.35 (s, 3
(E)-3-(Phenylamino)-3-(propylthio)-1-(p-tolyl)prop-2-
en-1-one (1u). General procedure A. Yield 1.77 g (57%);
H); 13C{1H} NMR (100 MHz, CDCl3): 185.9, 167.6, 141.3,
137.6, 136.4, 135.6, 129.6, 129.1, 127.1, 125.4, 88.2, 21.5, 21.1,
14.8; HRMS (ESI-TOF) m/z Calcd for C18H20NOS [M+H]+:
298.1260, found: 298.1256.
1
2
3
4
5
6
7
8
o
1
yellow solid; m.p. 65-66 C; H NMR (400 MHz, CDCl3): δ
13.54 (s, 1 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.39–7.29 (m, 4 H),
7.23 (d, J = 7.6 Hz, 3 H), 5.93 (s, 1 H), 2.89 (d, J = 7.2 Hz, 2
H), 2.40 (s, 3 H), 1.80–1.69 (m, 2 H), 1.03 (t, J = 7.2 Hz, 3
H); 13C{1H} NMR (100 MHz, CDCl3): 186.0, 166.3, 141.3,
138.4, 137.5, 129.1, 129.0, 127.1, 126.2, 125.2, 89.6, 33.8, 21.8,
21.5, 13.6; HRMS (ESI-TOF) m/z Calcd for C19H22NOS
[M+H]+: 312.1417, found: 312.1412.
(E)-3-(Methylthio)-1-(p-tolyl)-3-(m-tolylamino)prop-
2-en-1-one (1o). General procedure A. Yield 1.78 g (60%);
yellow liquid ; 1H NMR (400 MHz, CDCl3): δ 13.48 (s, 1 H),
7.81 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 7.6 Hz, 3 H), 7.13 (d, J =
8.0 Hz, 2 H), 7.04 (d, J = 6.8 Hz, 1 H), 5.86 (s, 1 H), 2.41 (s,
3 H), 2.39 (s, 3 H), 2.35 (s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3): 185.9, 167.2, 141.3, 139.1, 138.2, 137.6, 129.1, 128.8,
127.1, 125.8, 122.2, 88.5, 21.5, 21.4, 14.8; HRMS (ESI-TOF)
m/z Calcd for C18H20NOS [M+H]+: 298.1260, found:
298.1256.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-(isobutylthio)-3-(phenylamino)-1-(p-tolyl)prop-
2-en-1-one (1v). General procedure A. Yield 1.66 g (51%);
o
1
yellow solid; m.p. 53-54 C; H NMR (400 MHz, CDCl3): δ
13.56 (s, 1 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.42–7.30 (m, 5 H),
7.23 (d, J = 7.6 Hz, 2 H), 5.92 (s, 1 H), 2.78 (d, J = 6.4 Hz, 2
H), 2.39 (s, 3 H), 2.02–1.91 (m, 1 H), 1.03 (d, J = 6.8 Hz, 6
H). 13C{1H} NMR (100 MHz, CDCl3): 185.9, 166.5, 141.3,
138.5, 137.6, 129.1, 129.0, 129.0, 127.2, 127.1, 126.2, 125.2, 89.9,
40.6, 28.0, 22.2, 21.5; HRMS (ESI-TOF) m/z Calcd for
C20H24NOS [M+H]+: 326.1573, found: 326.1569.
(E)-3-((4-Methoxyphenyl)amino)-3-(methylthio)-1-(p-
tolyl)prop-2-en-1-one (1p). General procedure A. Yield
o
1
1.91 g (61%); yellow solid; m.p. 93-94 C; H NMR (400
MHz, CDCl3): δ 13.23 (s, 1 H), 7.80 (d, J = 8.0 Hz, 2 H),
7.30–7.10 (m, 4 H), 6.89 (d, J = 8.8 Hz, 2 H), 5.83 (s, 1 H),
3.81 (s, 3 H), 2.41 (s, 3 H), 2.40 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3): 185.9, 168.3, 158.3, 141.2, 137.6, 131.0, 129.0,
127.3, 127.1, 114.2, 87.8, 55.5, 21.5, 14.7; HRMS (ESI-TOF)
m/z Calcd for C18H20NO2S [M+H]+: 314.1209, found:
314.1205.
General procedure for the synthesis of triazoles 3
To a 10 mL sealed tube equipped with stirring bar were
charged with β-thioenaminone 1 (0.2 mmol, 1 equiv), tosyl
azide 2 (0.3 mmol, 59.1 mg), TMEDA (0.4 mmol, 46.4 mg)
and H2O (2 mL). The tube was sealed and the resulting
o
(E)-3-((4-Chlorophenyl)amino)-3-(methylthio)-1-(p-
mixture was stirred at 120 C with oil bath heating under
tolyl)prop-2-en-1-one (1q). General procedure A. Yield
air atmosphere for 6 h. Upon completion (TLC), the
reaction mixture was allowed to cool down to room
temperature, and water (5 mL) was added to the vessel.
The resulting suspension was extracted with ethyl acetate
(3 × 10 mL). The organic phases were combined and dried
over Na2SO4. After filtration, the solvent was removed
from the solution under reduced pressure. The residue
was subjected to silica gel column chromatography to
give pure products by using mixed petroleum ether and
ethyl acetate (v/v = 10:1). Caution: sulfonyl azide is
potentially explosive, especially at high temperature.
Therefore, appropriate safety precautions should be
taken when performing the 1,2,3-triazole synthesis in
the paper.
o
1
2.28 g (72%); yellow solid; m.p. 107-108 C; H NMR (400
MHz, CDCl3): δ 13.49 (s, 1 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.32
(d, J = 8.4 Hz, 2 H), 7.29–7.21 (m, 4 H), 5.89 (s, 1 H), 2.43
(s, 3 H), 2.40 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3):
186.2, 166.8, 141.6, 137.2, 137.0, 131.7, 129.2, 129.1, 127.2, 126.4,
89.1, 21.5, 14.8; HRMS (ESI-TOF) m/z Calcd for
C17H17ClNOS [M+H]+: 318.0714, found: 318.0711.
(E)-3-(Benzylamino)-3-(methylthio)-1-(p-tolyl)prop-2-
en-1-one (1r).23b General procedure B. Yield 0.48 g (81%);
m.p. 79-80 oC; 1H NMR (400 MHz, CDCl3): δ 12.18 (s, 1 H),
7.79 (d, J = 8.0 Hz, 2H), 7.41–7.35 (m, 4 H), 7.35–7.29 (m, 1
H), 7.23 (d, J = 8.0 Hz, 2 H), 5.73 (s, 1 H), 4.63 (d, J = 5.6
Hz, 2 H), 2.49 (s, 3 H), 2.41 (s, 3 H).
Procedure for the scale-up synthesis of 3a. To a 50 mL
sealed tube equipped with stirring bar were charged with
β-thioenaminone 1a (2 mmol, 566 mg), tosyl azide 2 (3
mmol, 591 mg), TMEDA (4 mmol, 464 mg) and H2O (10
mL). The tube was sealed and the resulting mixture was
stirred at 120 oC with oil bath heating under air
atmosphere for 6 h. After stopping stirring, the reaction
mixture was allowed to cool down to room temperature,
and water (20 mL) was added to the vessel. The resulting
suspension was extracted with ethyl acetate (3 × 30 mL).
The organic phases were combined and dried over
Na2SO4. After filtration, the solvent was removed from the
solution under reduced pressure. The residue was
subjected to silica gel column chromatography to give 3a
(431 mg, 70% yield) by using mixed petroleum ether and
ethyl acetate (v/v = 10:1).
(E)-3-(Methylamino)-3-(methylthio)-1-(p-tolyl)prop-
2-en-1-one (1s). General procedure B. Yield 0.28 g (64%);
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1
yellow solid; m.p. 103-104 C; H NMR (400 MHz, CDCl3):
δ 11.72 (s, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.0 Hz,
2 H), 5.63 (s, 1 H), 3.05 (s, 3 H), 2.45 (s, 3 H), 2.37 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3): 185.1, 170.3, 140.7, 138.0,
128.9, 126.9, 86.1, 30.2, 21.4, 14.2; HRMS (ESI-TOF) m/z
Calcd for C12H16NOS [M+H]+: 222.0947, found: 222.0945.
(E)-3-(Ethylthio)-3-(phenylamino)-1-(p-tolyl)prop-2-
en-1-one (1t). General procedure A. Yield 1.84 g (62%);
1
yellow liquid; H NMR (400 MHz, CDCl3): δ 13.52 (s, 1 H),
7.80 (d, J = 8.0 Hz, 2 H), 7.40–7.30 (m, 4 H), 7.23 (d, J = 7.2
Hz, 3 H), 5.93 (s, 1 H), 2.95 (q, J = 7.0 Hz, 2 H), 2.39 (s, 3
H), 1.36 (d, J = 7.4 Hz, 3 H); 13C{1H} NMR (100 MHz,
CDCl3): 186.0, 166.1, 141.4, 138.4, 137.5, 129.1, 129.0, 127.1,
126.3, 125.2, 89.5, 26.2, 21.5, 13.4; HRMS (ESI-TOF) m/z
Calcd for C18H20NOS [M+H]+: 298.1260, found: 298.1256.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3a). Yield: 54.0 mg (87%); yellow solid;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
o
1
m.p. 110-112 C; H NMR (400 MHz, CDCl3): δ 8.24 (d, J =
8.0 Hz, 2 H), 7.80–7.51 (m, 5 H), 7.33 (d, J = 8.0 Hz, 2 H),
2.45 (s, 3 H), 2.38 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3):
185.9, 146.6, 144.1, 138.4, 135.8, 134.6, 130.9, 130.2, 129.4,
129.1, 125.7, 21.7, 18.0; HRMS (ESI-TOF) m/z Calcd for
C17H16N3OS (M+H)+ 310.1009, found 310.1010.
(4-Fluorophenyl)(5-(methylthio)-1-phenyl-1H-1,2,3-
triazol-4-yl)methanone (3h). Yield: 45.8 mg (73%);
1
2
3
4
5
6
7
8
o
1
yellow solid; m.p. 83-85 C; H NMR (400 MHz, CDCl3): δ
8.42 (dd, J = 8.8, 3.2 Hz, 2 H), 7.64–7.57 (m, 5 H), 7.20 (t, J
= 8.8 Hz, 2 H), 2.38 (s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3): 184.4, 165.9(d, J = 253.5 Hz), 146.2, 138.9, 135.7,
133.5(d, J = 9.2 Hz), 133.4, 130.3, 129.5, 125.7, 115.5(d, J = 21.8
Hz), 18.0; HRMS (ESI-TOF) m/z Calcd for C16H13FN3OS
(M+H)+ 314.0758, found 314.0754.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-
yl)(phenyl)methanone (3b). Yield: 47.5 mg (80%);
yellow liquid; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.2
Hz, 2 H), 7.63–7.57 (m, 6 H), 7.53 (t, J = 7.6 Hz, 2 H), 2.39
(s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 186.3, 146.3, 138.7,
137.2, 135.7, 133.2, 130.7, 130.2, 129.5, 128.3, 127.8, 125.7, 18.0;
9
(4-Chlorophenyl)(5-(methylthio)-1-phenyl-1H-1,2,3-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
triazol-4-yl)methanone (3i). Yield: 45.3 mg (69%);
o
1
yellow solid; m.p. 91-93 C; H NMR (400 MHz, CDCl3): δ
8.33 (d, J = 8.4 Hz, 2 H), 7.61 (s, 5 H), 7.51 (d, J = 8.6 Hz, 2
HRMS
(ESI-TOF)
m/z
Calcd
for
C16H14N3OS
13
(M+H)+296.0852, found 296.0855.
H), 2.39 (s, 3 H); C{1H} NMR (100 MHz, CDCl3): 184.7,
146.1, 139.7, 139.1, 135.7, 135.5, 132.2, 130.3, 129.5, 128.7, 125.7,
17.9; HRMS (ESI-TOF) m/z Calcd for C16H13ClN3OS
(M+H)+ 330.0462, found 330.0457.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(m-
tolyl)methanone (3c). Yield: 51.2 mg (83%); yellow
1
liquid; H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.8 Hz, 2
H), 7.64–7.56 (m, 5 H), 7.42 (d, J = 6.4 Hz, 2 H), 2.46 (s, 3
(4-Bromophenyl)(5-(methylthio)-1-phenyl-1H-1,2,3-
triazol-4-yl)methanone (3j). Yield: 52.0 mg (70%);
yellow solid; m.p. 96-98 oC; 1H NMR (400 MHz, CDCl3): δ
8.24 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.60 (s, 5
13
H), 2.38 (s, 3 H); C{1H} NMR (100 MHz, CDCl3): 186.5,
146.4, 138.6, 138.1, 137.2, 135.7, 134.0, 131.1, 130.2, 129.4, 128.2,
128.0, 125.7, 21.4, 18.0; HRMS (ESI-TOF) m/z Calcd for
C17H16N3OS (M+H)+ 310.1009, found 310.1008.
13
H), 2.38 (s, 3 H); C{1H} NMR (100 MHz, CDCl3): 184.9,
146.0, 139.1, 135.9, 135.6, 132.3, 131.6, 130.3, 129.5, 128.5, 125.7,
17.9; HRMS (ESI-TOF) m/z Calcd for C16H13BrN3OS
(M+H)+ 373.9957, found 373.9950.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(o-
tolyl)methanone (3d). Yield: 46.4 mg (75%); yellow solid;
o
1
m.p. 103-105 C; H NMR (400 MHz, CDCl3): δ 7.71 (d, J =
7.6 Hz, 1 H), 7.61–7.57 (m, 5 H), 7.43 (d, J = 8.0 Hz, 1 H),
7.32 (d, J = 7.6 Hz, 2 H), 2.51 (s, 3 H), 2.43 (s, 2 H); 13C{1H}
NMR (100 MHz, CDCl3): 189.9, 146.8, 138.5, 138.1, 137.8,
135.6, 131.4, 131.3, 130.5, 130.2, 129.4, 125.7, 125.3, 20.5, 17.9;
HRMS (ESI-TOF) m/z Calcd for C17H16N3OS (M+H)+
310.1009, found 310.1010.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(4-
(trifluoromethyl)phenyl)methanone (3k). Yield: 55.1
1
mg (76%); yellow solid; m.p. 128-130 oC; H NMR (400
MHz, CDCl3): δ 8.45 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.4
Hz, 2 H), 7.60 (s, 5 H), 2.41 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3): 185.0, 145.8, 140.0, 139.6, 135.6, 134.2(d, J =
32.4 Hz), 131.0, 130.4, 129.5, 125.7, 125.3(q, J = 3.8 Hz), 122.4,
17.9; HRMS (ESI-TOF) m/z Calcd for C17H13F3N3OS
(M+H)+ 364.0726, found 364.0720.
(4-Methoxyphenyl)(5-(methylthio)-1-phenyl-1H-1,2,3-
triazol-4-yl)methanone (3e). Yield: 46.6 mg (72%);
o
1
yellow solid; m.p. 77-79 C; H NMR (400 MHz, CDCl3): δ
8.38 (d, J = 8.8 Hz, 2 H), 7.68–7.53 (m, 5 H), 7.02 (d, J = 8.8
Hz, 2 H), 3.90 (s, 3 H), 2.37 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3): 184.6, 163.8, 146.7, 138.1, 135.8, 133.2, 130.2,
130.1, 129.4, 125.7, 113.7, 55.5, 18.1; HRMS (ESI-TOF) m/z
Calcd for C17H16N3O2S (M+H)+ 326.0958, found 326.0954.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(4-
nitrophenyl)methanone(3l). Yield: 37.8 mg (56%);
yellow solid; m.p. 157-159 oC; 1H NMR (400 MHz, CDCl3): δ
8.44 (d, J = 8.8 Hz, 2 H), 8.30 (d, J = 8.8 Hz, 2 H), 7.54 (s, 5
H), 2.35 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 183.2,
149.2, 144.6, 141.0, 139.0, 134.5, 130.7, 129.5, 128.6, 124.7,
122.4, 16.8; HRMS (ESI-TOF) m/z Calcd for C16H13N4O3S
(M+H)+ 341.0703, found 341.0699.
(3,4-Dimethoxyphenyl)(5-(methylthio)-1-phenyl-1H-
1,2,3-triazol-4-yl)methanone (3f). Yield: 63.2 mg (89%);
yellow solid; m.p. 137-139 oC;1H NMR (400 MHz, CDCl3): δ
8.18 (d, J = 8.4 Hz, 1 H), 7.92 (s, 1 H), 7.66–7.56 (m, 5 H),
6.99 (d, J = 8.8 Hz, 1 H), 3.99 (s, 6 H), 2.37 (s, 3 H); 13C{1H}
NMR (100 MHz, CDCl3): 184.4, 153.7, 148.9, 146.8, 138.2,
135.8, 130.2, 130.0, 129.4, 126.4, 125.7, 112.4, 110.1, 56.1, 56.0,
18.1; HRMS (ESI-TOF) m/z Calcd for C18H18N3O3S (M+H)+
356.1063, found 356.1057.
Furan-2-yl(5-(methylthio)-1-phenyl-1H-1,2,3-triazol-4-
yl)methanone (3m). Yield: 42.4 mg (74%); yellow liquid;
1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 3.6 Hz, 1 H), 7.77
(d, J = 0.8 Hz, 1 H), 7.67–7.48 (m, 5 H), 6.65 (dd, J = 3.6, 1.8
13
Hz, 2 H), 2.45 (s, 3 H); C{1H} NMR (100 MHz, CDCl3):
172.5, 151.6, 147.7, 145.3, 138.6, 135.6, 130.2, 129.4, 125.8,
122.8, 112.5, 18.1; HRMS (ESI-TOF) m/z Calcd for
C14H12N3O2S (M+H)+ 286.0645, found 286.0644.
(5-(Methylthio)-1-phenyl-1H-1,2,3-triazol-4-
yl)(naphthalen-2-yl)methanone (3g). Yield: 58.8 mg
o
1
(85%); yellow solid; m.p. 102-104 C; H NMR (400 MHz,
CDCl3): δ 9.03 (s, 1 H), 8.32 (d, J = 8.8 Hz, 1 H), 8.03 (d, J =
8.0 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1
H), 7.64 (d, J = 7.6 Hz, 2 H), 7.61–7.52 (m, 5 H), 2.40 (s, 3
H); 13C{1H} NMR (100 MHz, CDCl3): 185.9, 146.6, 138.7,
135.8, 135.7, 134.4, 133.5, 132.5, 130.2, 130.1, 129.5, 128.6, 128.2,
127.7, 126.6, 125.7, 125.6, 18.1; HRMS (ESI-TOF) m/z Calcd
for C20H16N3OS (M+H)+ 346.1009, found 346.1006.
(5-(Methylthio)-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3n). Yield: 48.6 mg (75%); yellow solid;
o
1
m.p. 97-99 C; H NMR (400 MHz, CDCl3): δ 8.24 (d, J =
8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2
H), 7.33 (d, J = 7.6 Hz, 2 H), 2.47 (s, 3 H), 2.45 (s, 3 H), 2.37
(s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 185.9, 146.5, 144.0,
140.5, 138.3, 134.7, 133.3, 130.9, 130.0, 129.1, 125.5, 21.7, 21.3,
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18.0; HRMS (ESI-TOF) m/z Calcd for C18H18N3OS (M+H)+ 0.79 (t, J = 7.2 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3):
1
2
3
4
5
6
7
8
324.1165, found 324.1162.
186.0, 147.2, 144.1, 136.9, 135.8, 134.7, 130.9, 130.1, 129.3, 129.1,
125.9, 37.2, 22.6, 21.8, 12.8; HRMS (ESI-TOF) m/z Calcd for
C19H20N3OS (M+H)+ 338.1322, found 338.1316.
(5-(Methylthio)-1-(m-tolyl)-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3o). Yield: 50.3 mg (78%); yellow solid;
o
1
m.p. 123-125 C; H NMR (400 MHz, CDCl3): δ 8.24 (d, J =
8.4 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.43–7.36 (m, 3 H),
7.33 (d, J = 8.0 Hz, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.38 (s,
(5-(Isobutylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3v). Yield: 49.4 mg (70%); yellow
liquid; 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.4 Hz, 2
H), 7.74–7.49 (m, 5 H), 7.33 (d, J = 8.4 Hz, 2 H), 112.74 (d, J
= 6.8 Hz, 2 H), 2.45 (s, 3 H), 1.61–1.46 (m, 1 H), 0.80 (s, 3
13
3 H); C{1H} NMR (100 MHz, CDCl3): 185.9, 146.4, 144.1,
139.8, 138.4, 135.7, 134.7, 131.0, 130.9, 129.2, 129.1, 126.3, 122.8,
21.7, 21.3, 18.0; HRMS (ESI-TOF) m/z Calcd for C18H18N3OS
(M+H)+ 324.1165, found 324.1160.
13
H), 0.79 (s, 3 H); C{1H} NMR (100 MHz, CDCl3): 186.0,
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13
14
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17
18
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26
27
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32
33
34
35
36
37
38
39
40
41
42
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45
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59
60
147.1, 144.0, 137.2, 135.8, 134.7, 130.8, 130.1, 129.3, 129.1, 125.9,
44.0, 28.6, 21.7, 21.5; HRMS (ESI-TOF) m/z Calcd for
C20H22N3OS (M+H)+ 352.1478, found 352.1476.
(1-(4-Methoxyphenyl)-5-(methylthio)-1H-1,2,3-triazol-
4-yl)(p-tolyl)methanone (3p). Yield: 51.5 mg (76%);
yellow solid; m.p. 119-121 oC; 1H NMR (400 MHz, CDCl3): δ
8.16 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.25 (d, J
= 8.0 Hz, 2 H), 7.00 (d, J = 8.8 Hz, 2 H), 3.82 (s, 3 H), 2.37
(s, 3 H), 2.29 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3):
184.9, 159.8, 145.4, 143.0, 137.4, 133.7, 129.8, 128.0, 127.6,
126.0, 113.5, 54.6, 20.7, 16.9; HRMS (ESI-TOF) m/z Calcd
for C18H18N3O2S (M+H)+ 340.1114, found 340.1108.
ASSOCIATED CONTENT
Supporting Information. The 1H and 13C NMR spectra of all
products (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
(1-(4-Chlorophenyl)-5-(methylthio)-1H-1,2,3-triazol-4-
yl)(p-tolyl)methanone (3q). Yield: 49.6mg (72%); yellow
* Email: chemliuyunyun@jxnu.edu.cn
* Email: wanjieping@jxnu.edu.cn
Notes
o
1
solid; m.p. 115-117 C; H NMR (400 MHz, CDCl3): δ 8.22
(d, J = 8.0 Hz, 2 H), 7.58 (s, 4 H), 7.33 (d, J = 8.0 Hz, 2 H),
2.45 (s, 3 H), 2.42 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3):
185.7, 146.7, 144.2, 138.4, 136.4, 134.5, 134.2, 130.8, 129.7,
129.1, 126.9, 21.8, 18.2; HRMS (ESI-TOF) m/z Calcd for
C17H15ClN3OS (M+H)+ 344.0619, found 344.0615.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is financially supported by the National Natural
Science Foundation of China (21562024, 21861019) and the
Natural Science Foundation of Jiangxi Province
(20161ACB21010).
(1-Benzyl-5-(methylthio)-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3r). Yield: 42.2 mg (65%); yellow
liquid; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.6 Hz, 2
H), 7.34 (s, 5 H), 7.30 (d, J = 7.6 Hz, 2 H), 5.71 (s, 2 H), 2.43
(s, 3 H), 2.40 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3):
185.9, 147.5, 144.0, 134.6, 130.8, 129.6, 129.0, 129.0, 128.6,
128.0, 127.8, 52.2, 21.7, 18.5; HRMS (ESI-TOF) m/z Calcd
for C18H18N3OS (M+H)+ 324.1165, found 324.1163.
REFERENCES
1 (a) Meldal, M.; Tomøe, C. W. Cu-Catalyzed Azide-Alkyne
Cycloaddition. Chem. Rev. 2008, 108, 2952-3015. (b) Muller, T.;
Braese, S. Click Chemistry Finds Its Way into Covalent Porous
Organic Materials. Angew. Chem. Int. Ed. 2011, 50, 11844-11845. (c)
Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click Chemistry for
Drug Development and Diverse Chemical–Biology Applications.
Chem. Rev. 2013, 113, 4905-4979.
2 (a) Huisgen, R. Kinetics and Mechanism of 1,3-Dipolar
Cycloadditions. Angew. Chem. Int. Ed. Engl. 1963, 2, 633-645. (b)
Huisgen, R.; Knorr, R.; Möbius, L.; Szeimies, G. 1.3-Dipolare
Cycloadditionen, XXIII. Einige Beobachtungen zur Addition
organischer Azide an CC-Dreifachbindungen. Chem. Ber. 1965,
98, 4014-4021.
(1-Methyl-5-(methylthio)-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3s). Yield: 31.0 mg (63%); yellow solid;
o
1
m.p. 78-80 C; H NMR (400 MHz, CDCl3): δ 8.18 (d, J =
6.4 Hz, 2 H), 7.30 (d, J = 6.4 Hz, 2 H), 4.15 (s, 3 H), 2.58 (s,
3 H), 2.43 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 185.9,
147.0, 144.0, 137.2, 134.6, 130.8, 129.0, 35.2, 21.7, 18.3; HRMS
(ESI-TOF) m/z Calcd for C12H14N3OS (M+H)+ 248.0852,
found 248.0850.
(5-(Ethylthio)-1-phenyl-1H-1,2,3-triazol-4-yl)(p-
3 (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
tolyl)methanone (3t). Yield: 40.0 mg (62%); yellow solid;
B.
A Stepwise Huisgen Cycloaddition Process: Copper(I)-
o
1
m.p. 60-62 C; H NMR (400 MHz, CDCl3): δ 8.23 (d, J =
8.0 Hz, 2 H), 7.63–7.55 (m, 5 H), 7.33 (d, J = 8.0 Hz, 2 H),
2.90 (q, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 1.08 (t, J = 7.4 Hz, 3
H); 13C{1H} NMR (100 MHz, CDCl3): 186.0, 147.2, 144.1,
136.6, 135.8, 134.6, 130.9, 130.1, 129.4, 129.1, 125.9, 29.4, 21.8,
14.4; HRMS (ESI-TOF) m/z Calcd for C18H18N3OS (M+H)+
324.1165, found 324.1165.
Catalyzed Regioselective “Ligation” of Azides and Terminal
Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. (b) Tornøe,
C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid
Phase:ꢀ[1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-
Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org.
Chem. 2002, 67, 3057-3064.
4 For selected reviews, see (a) Hassan, S.; Müller, T. J. J.
Multicomponent Syntheses based upon Copper-Catalyzed
Alkyne-Azide Cycloaddition. Adv. Synth. Catal. 2015, 357, 617-
666. (b) Chen, Z.; Liu, Z.; Cao, G.; Li, H.; Ren, H. Recent
Advances in Multicomponent Synthesis of 1,4,5-Trisubstituted
1,2,3-Triazoles. Adv. Synth. Catal. 2017, 359, 202-224. (c) Chen, Z.;
Cao, G.; Song, J.; Ren, H. Recent Developments in Azide-Free
(1-Phenyl-5-(propylthio)-1H-1,2,3-triazol-4-yl)(p-
tolyl)methanone (3u). Yield: 44.0 mg (65%); yellow solid;
o
1
m.p. 44-46 C; H NMR (400 MHz, CDCl3): δ 8.23 (d, J =
8.0 Hz, 2 H), 7.63–7.54 (m, 5 H), 7.33 (d, J = 8.4 Hz, 2 H),
2.84 (t, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 1.53–1.33 (m, 2 H),
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Synthesis of 1,2,3-Triazoles. Chin. J. Chem. 2017, 35, 1797-1807. (d)
Toward Sulfonyl-1,2,3-triazoles. Org. Lett. 2015, 17, 6206-6209. (f)
Jiang, Y.; Kuang, C. Recent Advances in the Synthesis of 1-
Monosubstituted 1,2,3-Triazoles. Mini-Rev. Med. Chem. 2013, 13,
713-719. (e) Zhu, L.; Zhang, H.; Wang, C.; Chen, Z. Recent
Progress in the Synthesis of N2-Substituted 1, 2, 3-Triazoles. Chin.
J. Org. Chem. 2018, 38, 1052-1064. (f) Anbarasan, P.; Yadagiri, D.;
Rajasekar, S. Recent Advances in Transition-Metal-Catalyzed
Denitrogenative Transformations of 1,2,3-Triazoles and Related
Compounds. Synthesis 2014, 46, 3004-3023.
5 (a) Mady, M. F.; Awad, G. E. A.; Jørgensen, K. B. Ultrasound-
Assisted Synthesis of Novel 1,2,3-Triazoles Coupled Diaryl
Sulfone Moieties by the CuAAC Reaction, and Biological
Evaluation of Them as Antioxidant and Antimicrobial Agents.
Eur. J. Med. Chem. 2014, 84, 433-443. (b) González-Calderon, D.;
Mejía-Dionicio, M. G.; Morales-Reza, M. A.; Ramírez-Villalva, A.;
Morales-Rodríguez, M.; Jauregui-Rodríguez, B.; Díaz-Torres, E.;
González-Romero, C.; Fuentes-Benítes, A. Azide-Enolate 1,3-
Dipolar Cycloaddition in the Synthesis of Novel Triazole-Based
Miconazole Analogues as Promising Antifungal Agents. Eur. J.
Med. Chem. 2016, 112, 60-65. (c) Morzherin, Y.; Prokhorova, P. E.;
Musikhin, D. A.; Glukhareva, T. V.; Fan, Z. 2-Hydroxypropyl
Derivatives of 1,2,3-Thiadiazole and 1,2,3-Triazole: Synthesis and
Antifungal Activity. Pure Appl. Chem. 2011, 83, 715-722.
6 (a) Worrell, B. T.; Hein, J. E.; Fokin, V. V. Halogen Exchange
(Halex) Reaction of 5-Iodo-1,2,3-triazoles: Synthesis and
Applications of 5-Fluorotriazoles. Angew. Chem. Int. Ed. 2012, 51,
11791. (b) Volkova, N. N.; Tarasov, E. V.; Meervelt, L. V.; Toppet,
S.; Dehaen, W.; Bakulev, V. A. Reaction of 5-Halo-1,2,3-
Thiadiazoles with Arylenediamines as A New Approach to
Tricyclic 1,3,6-Thiadiazepines. J. Chem. Soc. Perkin Trans. 1, 2002,
1574-1580.
7 (a) Ding, S.; Jia, G.; Sun, J. Iridium-Catalyzed Intermolecular
Azide-Alkyne Cycloaddition of Internal Thioalkynes under Mild
Conditions. Angew. Chem. Int. Ed. 2014, 53, 1877-1880. (b) Destito,
P.; Couceiro, J. R.; Faustino, H.; López, F.; Mascareñas, J. L.
Ruthenium-Catalyzed Azide-Thioalkyne Cycloadditions in
Kwok, S. W.; Fosing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V.
V. Transition-Metal-Free Catalytic Synthesis of 1,5-Diaryl-1,2,3-
triazoles. Org. Lett. 2010, 12, 4217-4219.
1
2
3
4
5
6
7
8
10 (a) Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X. A Metal-
Free Multicomponent Cascade Reaction for the Regiospecific
Synthesis of 1,5-Disubstituted 1,2,3-Triazoles. Angew. Chem. Int.
Ed. 2013, 52, 13265-13268. (b) Cai, Z. J.; Lu, X. M.; Zi, Y.; Yang, C.;
Shen, L. J.; Li, J.; Wang, S. Y.; Ji, S.-J. I2/TBPB Mediated Oxidative
Reaction of N-Tosylhydrazones with Anilines: Practical
Construction of 1,4-Disubstituted 1,2,3-Triazoles under Metal-
Free and Azide-Free Conditions. Org. Lett. 2014, 16, 5108-5111. (c)
van Berkel, S. S.; Brauch, S.; Gabriel, L.; Henze, M.; Stark, S.;
Vasilev, D.; Wessjohann, L. A.; Abbas, M.; Westermann, B.
Traceless Tosylhydrazone-Based Triazole Formation: A Metal-
Free Alternative to Strain-Promoted Azide-Alkyne Cycloaddition.
Angew. Chem. Int. Ed. 2012, 51, 5343-5346. (d) Wan, J.-P. Cao, S.;
Liu, Y. A Metal- and Azide-Free Multicomponent Assembly
toward Regioselective Construction of 1,5-Disubstituted 1,2,3-
Triazoles. J. Org. Chem. 2015, 80, 9028-9033. (e) Chen, Z.; Yan, Q.;
Liu, Z.; Zhang, Y. Metal-Free C-N- and N-N-Bond Formation:
Synthesis of 1,2,3-Triazoles from Ketones, N-Tosylhydrazines,
and Amines in One Pot. Chem. Eur. J. 2014, 20, 17635-17639. (f)
Hu, Q.; Liu, Y.; Deng, X.; Li, Y.; Chen, Y. Aluminium(III)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chloride-Catalyzed
Three-Component
Condensation
of
Aromatic Aldehydes, Nitroalkanes and Sodium Azide for the
Synthesis of 4-Aryl-NH-1,2,3-triazoles. Adv. Synth. Catal. 2016,
358, 1689-1693. (g) Xie, Y.Y.; Wang, Y. C.; Qu, H. E. Tan, X. C.;
Wang, H. S.; Pan, Y. M. Regioselective Synthesis of β-Aryl
Enaminones and 1,4,5-Trisubstituted 1,2,3-Triazoles from
Chalcones and Benzyl Azides. Adv. Synth. Catal. 2014, 356, 3347-
3355.
11 (a) Wang, Z. X.; Qin, H. L. Regioselective synthesis of 1,2,3-
triazole derivatives via 1,3-dipolar cycloaddition reactions in
water. Chem. Commun. 2003, 2450-2451. (b) Roy, S.; Chatterjee,
T.; Islam, S. M. Polymer anchored Cu(II) complex: an efficient
and recyclable catalytic system for the one-pot synthesis of 1,4-
disubstituted 1,2,3-triazoles starting from anilines in water. Green
Chem. 2013, 15, 2532-2539. (c) Payra, S.; Saha, A.; Banerjee, S. On
Water Cu@g-C3N4 Catalyzed Synthesis of NH-1,2,3-Triazoles via
[2+3] Cycloadditions of Nitroolefins/Alkynes and Sodium Azide.
ChemCatChem 2018, 10, 5468-5474. (d) Yang, L.; Wu, Y.; Yang, Y.;
Wen, C.; Wan, J.-P. Catalyst-free synthesis of 4-acyl-NH-1,2,3-
triazoles by water-mediated cycloaddition reactions of
enaminones and tosyl azide. Beilstein J. Org. Chem. 2018, 14,
2348-2353. (e) Zhang, Z.; Rakesh, K. P.; Qin, H. L. Transition-
metal-free regioselective construction of 1,5-diaryl-1,2,3-triazoles
through dehydrative cycloaddition of alcohols with aryl azides
mediated by SO2F2. Chem. Commun. 2019, 55, 2845-2848.
12 For reviews, see (a) Elassar, A.-Z. A.; El-Khair, A. A. Recent
developments in the chemistry of enaminones. Tetrahedron 2003,
59, 8463-8480. (b) Chattopadhyay, A. K.; Hanessian, S. Cyclic
enaminones. Part II: applications as versatile intermediates in
alkaloid synthesis. Chem. Commun. 2015, 51, 16450-16467. (c)
Wan, J.-P.; Gao, Y. Domino Reactions Based on Combinatorial
Bond Transformations in Electron-Deficient Tertiary Enamines.
Chem. Rec. 2016, 16, 1164-1177. (d) Zhang, L.; Dong, J.; Xu, X.; Liu,
Q. Chemistry of Ketene N,S-Acetals: An Overview. Chem. Rev.
2016, 116, 287-322.
Aqueous Media:
A Mild, Orthogonal, and Biocompatible
Chemical Ligation. Angew. Chem. Int. Ed. 2017, 56, 10766-10770.
(c) Song, W.; Zheng, N.; Li, M.; He, J.; Li, J.; Dong, K.; Ullah, K.;
Zheng, Y. Rhodium(I)-Catalyzed Regioselective Azide-internal
Alkynyl Trifluoromethyl Sulfide Cycloaddition and Azide-
internal Thioalkyne Cycloaddition under Mild Conditions. Adv.
Synth. Catal. 2019, 361, 469-475. (d) Song, W.; Zheng, N.; Li, M.;
Dong, K.; Li, J.; Ullah, K.; Zheng, Y. Regiodivergent Rhodium(I)-
Catalyzed Azide-Alkyne Cycloaddition (RhAAC) To Access
Either Fully Substituted Sulfonyl-1,2,3-triazoles under Mild
Conditions. Org. Lett. 2018, 20, 6705-6709.
8 Wang, W.; Peng, X.; Wei, F.; Tung, C.-H.; Xu, Z. Copper(I)-
Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-
Hetero-Functionalized Triazoles. Angew. Chem. Int. Ed. 2016, 55,
649-653.
9 (a) Ramachary, D. B.; Drishna, P. M.; Gujral, J.; Reddy, G. S.
An Organocatalytic Regiospecific Synthesis of 1,5-Disubstituted
4-Thio-1,2,3-triazoles and 1,5-Disubstituted 1,2,3-Triazoles. Chem.
Eur. J. 2015, 21, 16775-16780. (b) Ramasastry, S. S. V.
Enamine/Enolate-Mediated Organocatalytic Azide-Carbonyl
[3+2]ꢁCycloaddition Reactions for the Synthesis of Densely
Functionalized 1,2,3-Triazoles. Angew. Chem. Int. Ed. 2014, 53,
14310-14312. (c) John, J.; Thomas, J.; Dehaen, W. Organocatalytic
Routes Toward Substituted 1,2,3-Triazoles. Chem Commun. 2015,
51, 10797-10806. (d) Li, W.; Du, Z.; Huang, J.; Jia, Q.; Zhang, K.;
Wang, J. Direct Access to 1,2,3-Triazoles Through
Organocatalytic 1,3-Dipolar Cycloaddition Reaction of Allyl
Ketones with Azides. Green Chem. 2014, 16, 3003-3006. (e)
Saraiva, M. T.; Costa, G. P.; Seus, N.; Schumacher, R. F.; Perin, G.;
Paixão, M. W.; Luque R.; Alves, D. Room-Temperature
Organocatalytic Cycloaddition of Azides with β-Keto Sulfones:
13 (a) Liu, Z.; Huang, F.; Wu, P.; Wang, Q.; Yu, Z. Amide Bond
Formation Assisted by Vicinal Alkylthio Migration in
Enaminones: Metal- and CO-Free Synthesis of α,β-Unsaturated
Amides. J. Org. Chem. 2018, 83, 5731-5750. (b) Bhattacherjee, D.;
Thakur, V.; Shil, A. K.; Da, P. Hypervalent Iodine ‐ Promoted
Aromatization of Exocyclic β-Enaminones for the Synthesis of
meta-N,N-Diarylaminophenols. Adv. Synth. Catal. 2017, 359,
2202-2208. (c) Zhou, P.; Hu, B.; Li, L.; Rao, K.; Yang, J.; Yu, F.
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Mn(OAc)3-Promoted Oxidative Csp –P Bond Formation through
Csp2–Csp2 and P–H Bond Cleavage: Access to β-Ketophosphonates.
J. Org. Chem. 2017, 82, 13268-13276. (d) Gan, L.; Gao, Y.; Wei, L.;
Wan, J.-P. Synthesis of α-Keto Thioamides by Metal-Free C=C
Bond Cleavage in Enaminones Using Elemental Sulfur. J. Org.
Chem. 2019, 84, 1064-1069. (e) Wan, J.-P.; Zhong, S.; Xie, L.; Cao,
X.; Liu Y.; Wei, L. KIO3-Catalyzed Aerobic Cross-Coupling
Reactions of Enaminones and Thiophenols: Synthesis of
Polyfunctionalized Alkenes by Metal-Free C–H Sulfenylation.
Org. Lett. 2016, 18, 584-587. (f) Sun, J.; Zhang-Negrerie, D.; Du, Y.
Oxidative Coupling of Enamines and Disulfides via
Annulation of Enaminones with Vinyl Esters through C-H Bond
Functionalization. Org. Lett. 2018, 20, 7326-7331. (b) Yang, L.;
Wei, L.; Wan, J.-P. Redox neutral [4+2] benzannulation of
dienals and tertiary enaminones for benzaldehyde synthesis.
Chem. Commun. 2018, 54, 7475-7478. (c) Zhang, F.; Qin, Z.; Kong,
L.; Zhao, Y.; Liu; Y.; Li, Y. Metal/Benzoyl Peroxide (BPO)-
1
2
3
4
5
6
7
8
Controlled
Chemoselective
Cycloisomerization
of
(o-
Alkynyl)phenyl Enaminones: Synthesis of α-Naphthylamines and
Indeno[1,2-c]pyrrolones. Org. Lett. 2016, 18, 5150-5153.
17 (a) Thomas, J.; Goyvaerts, V.; Liekens, S.; Dehaen, W.
Metal-Free Route for the Synthesis of 4-Acyl-1,2,3-Triazoles from
Readily Available Building Blocks. Chem. Eur. J. 2016, 22, 9966-
9970. (b) Wan, J.-P.; Cao, S.; Liu, Y. Base-Promoted Synthesis of
9
Tetrabutylammonium
Iodide/tert-Butyl
10
11
12
13
14
15
16
17
18
19
20
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28
29
30
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32
33
34
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37
38
39
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51
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Hydroperoxide-Mediated Intermolecular Oxidative C(sp2)-S
Bond Formation Under Transition Metal-Free Conditions. Adv.
Synth. Catal. 2016, 358, 2035-2040.
N-Substituted
1,2,3-Triazoles
via
Enaminone-Azide
Cycloaddition Involving Regitz Diazo Transfer. Org. Lett. 2016,
18, 6034-6037. (c) Cao, S.; Liu, Y.; Hu, C.; Wen, C.; Wan, J.-P.
Alkyl Propiolates Participated [3+2] Annulation for the
Switchable Synthesis of 1,5- and 1,4-Disubstituted 1,2,3-Triazoles
Containing Ester Side Chain. ChemCatChem 2018, 10, 5007-5011.
(d) Bakulev, V. A.; Beryozkina, T.; Thomas, J.; Dehaen, W. The
Rich Chemistry Resulting from the 1,3-Dipolar Cycloaddition
Reactions of Enamines and Azides. Eur. J. Org. Chem. 2018, 262-
294.
18 For selected reviews in transition metal-free synthesis, see
(a) Sun, C.-L.; Shi, Z.-J. Transition-Metal-Free Coupling
Reactions. Chem. Rev. 2014, 114, 9219-9280. (b) Bhunia, A.; Yetra,
S. R.; Biju, A. T. Recent advances in transition-metal-free carbon-
carbon and carbon-heteroatom bond-forming reactions using
arynes. Chem. Soc. Rev. 2012, 41, 3140-3152. (c) D Liu, Y.; Xiong, J.
Wei, L. Recent Advances in the C(sp2)-S Bond Formation
Reactions by Transition Metal-Free C(sp2)-H Functionalization.
Chin. J. Org. Chem. 2017, 37, 1667-1680.
19 For selected references, see (a) Yang, J.; Mei, F.; Fu, S.; Gu, Y.
Facile Synthesis of 1,4-Diketones via Three-component Reactions
of α-Ketoaldehyde, 1,3-Dicarbonyl Compound, and a Nucleophile
in Water. Green Chem. 2018, 20, 1367-1374. (b) Wu, C.; Lu, L.-H.;
Peng, A.-Z.; Jia, G.-K.; Peng, C.; Cao, Z.; Tang, Z.; He, W.-M. Xu,
X. Ultrasound-Promoted Brønsted Acid Ionic Liquid-Catalyzed
Hydrothiocyanation of Activated Alkynes under Minimal Solvent
Conditions. Green Chem. 2018, 20, 3683-3688. (c) Köhling, S.;
Exner, M. P.; Nojoumi, S.; Schiller, J.; Budisa, N.; Rademann, J.
One-Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in
Water for Glycan Ligation Reactions with Highly Functionalized
Sugars. Angew. Chem. Int. Ed. 2016, 55, 15510-15514. (d) Liu, L.;
Wang, Z. Metal-Free Intramolecular Amino-Acyloxylation of 2-
Aminostyrene with Carboxylic Acid for the Synthesis of 3-
Acyloxyl Indolines in Water. Green Chem. 2017, 19, 2076-2079. (e)
Guo, Y.; Wang, G.; Wei, L.; Wan, J.-P. Domino C-H Sulfonylation
and Pyrazole Annulation for Fully Substituted Pyrazole Synthesis
in Water Using Hydrophilic Enaminones. J. Org. Chem. 2019, 84,
2984-2990.
14 (a) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Copper-
Catalyzed C-C Bond Formation through C-H Functionalization:
Synthesis of Multisubstituted Indoles from N-Aryl Enaminones.
Angew. Chem. Int. Ed. 2009, 48, 8078-8081. (b) Kong, L.; Shao, Y.;
Li, Y.; Liu Y.; Li, Y. LDA-Promoted Synthesis of 3-Amino Furans
by Selective Lithiation of Enaminones. J. Org. Chem. 2015, 80,
12641-12645. (c) Gu, Z. Y.; Zhu, T. H.; Cao, J. J.; Xu, X. P.; Wang, S.
Y.; Ji, S. J. Palladium-Catalyzed Cascade Reactions of Isocyanides
with Enaminones: Synthesis of 4-Aminoquinoline Derivatives.
ACS Catal. 2014, 4, 49-52. (d) Palmieri, A.; Gabrielli, S.; Cimarelli,
C.; Ballini, R. Fast, mild, eco-friendly synthesis of
polyfunctionalized pyrroles from β-nitroacrylates and β-
enaminones. Green Chem. 2011, 13, 3333-3336. (e) Chen, G.; Wang,
Z.; Zhang, X.; Fan, X. Synthesis of Functionalized Pyridines via
Cu(II)-Catalyzed One-Pot Cascade Reactions of Inactivated
Saturated Ketones with Electron-Deficient Enamines. J. Org.
Chem. 2017, 82, 11230-11237. (f) Zhao, X.; Zhang, Y.; Deng, J.;
Zhang-Negrerie, D.; Du, Y. TBHP/TBAI-Mediated Oxidative
Cascade Reaction Consisting of Dimerization, Cyclization, and
1,2-Aryl Migration: Metal-Free Synthesis of Pyrrolin-4-ones and
Highly Substituted Pyrroles. J. Org. Chem. 2017, 82, 12682-12690.
(g) Xu, X.; Zhou, B.; Zhou, P.; Zhou, J.; Shen, Y.; Yu, F.; Lu, L. L.
Insights Into the Unexpected Chemoselectivity in Brønsted Acid
Catalyzed Cyclization of Isatins with Enaminones: Convenient
Synthesis of Pyrrolo[3,4-c]quinolin-1-ones and Spirooxindoles.
Chem. Commun. 2016, 52, 8002-8005. (h) Jiang, B.; Yi, M.-S.; Tu,
M.-S.; Wang, S.-L.; Tu, S.-J. Brønsted Acid-Promoted Divergent
Reactions of Enaminones: Efficient Synthesis of Fused Pyrroles
with Different Substitution Patterns. Adv. Synth. Catal. 2012, 354,
2504-2510.
15 (a) Sun, J.; Cheng, X.; Mansaray, J. K.; Fei, W.; Wan, J.; Yao,
W. A Copper-Catalyzed Three Component Reaction of Aryl
Acetylene, Sulfonyl Azide and Enaminone to Form Iminolactone
via 6π Electrocyclization. Chem. Commun. 2018, 54, 13953-13956.
(b) Guo, Y.; Xiang, Y.; Wei, L.; Wan, J.-P. Thermoinduced Free-
Radical C-H Acyloxylation of Tertiary Enaminones: Catalyst-Free
Synthesis of Acyloxyl Chromones and Enaminones. Org. Lett.
2018, 20, 3971-3974. (c) Ge, H.; Niphakis, M. J.; Georg, G. I.
Palladium(II)-Catalyzed Direct Arylation of Enaminones Using
Organotrifluoroborates. J. Am. Chem. Soc. 2008, 130, 3708-3709.
(d) Goutham, K.; Kumar, D. A.; Suresh, S.; Sridhar, B.; Narender,
R.; Karunakar, G. V. Gold-Catalyzed Intramolecular Cyclization
of N-Propargylic β-Enaminones for the Synthesis of 1,4-
Oxazepine Derivatives. J. Org. Chem. 2015, 80, 11162-11168. (e)
Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D.
Vilsmeier Reaction of Enaminones: Efficient Synthesis of
Halogenated Pyridin-2(1H)-ones. J. Org. Chem. 2008, 73, 9504-
9507. (f) Wen, L.-R.; Man, N.-N.; Yuan, W.-K.; Li, M. Direct
Construction of 2-Aryliminochromenes from Arynes, N,S-
Keteneacetals, and DMF. J. Org. Chem. 2016, 81, 5942-5948.
16 (a) Liang, G.; Rong, J.; Sun, W.; Chen, G.; Jiang, Y.; Loh, T.-P.
Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5+1]
20 Chakarasali, R. T.; Ila, H.; Junjappa, H. Cycloaddition of
Aroyl/Acylketene S,N-Acetals with Tosyl Azide: Synthesis of
Novel 4-Aroyl/Acyl-5-amino-1H-1,2,3-triazoles and 3,4-Annulated
1,2,3-Triazoles. Synthesis 1988, 851-854.
21 Dar’in, D.; Kantin, G.; Krasavin, M. A ‘sulfonyl-azide-free’
(SAFE) aqueous-phase diazo transfer reaction for parallel and
diversity-oriented synthesis. Chem. Commun. 2019, 55, 5239-5242.
22 (a) Regitz, M.; Eine Neue Synthese für α-Diazo-Carbonyl-
Verbindungen. Tetrahedron Lett. 1964, 5, 1403-1407. (b) Regitz,
M.; New Methods of Preparative Organic Chemistry. Transfer of
Diazo Groups. Angew. Chem. Int. Ed. Engl. 1967, 6, 733-749.
23 (a) Surmont, R.; Verniest, G.; De Schrijver, M.; Thuring, J.
W.; ten Holte, P.; Deroose, F.; De Kimpe. N. J. Org. Chem. 2011,
76, 4105-4111. (b) Huang, F.; Liu, Z.; Wang, Q.; Lou, J.; Yu, Z.
Copper-Catalyzed Formal Carbene Migratory Insertion into Internal
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Olefinic C=C Bonds with N-Tosylhydrazones To Access Iminofuran
and 2(3H)-Furanone Derivatives. Org. Lett. 2017, 19, 3660-3663.
24 Huang, F.; Wu, P.; Wang, L.; Chen, J.; Sun, C.; Yu, Z.
Copper-Mediated Intramolecular Oxidative C-H/C-H Cross-
Coupling of α-Oxo Ketene N,S-Acetals for Indole Synthesis. J.
Org. Chem. 2014, 79, 10553-10560.
25 Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H. A Novel and
Convenient Synthesis of 2-Amino-4-(N-alkyl-N-arylamino)-
pyrimidines using Polarized Ketene S,S- and S,N- Acetals.
Synthesis 1980, 748-751.
26 Sharmaa, N.; Chundawatb, T. S.; Mohapatraa, S. C.; Bhagat,
Sunita. Synthesis of Novel Fluorinated Multisubstituted
Pyrimidines and1,5-Benzodiazepines via Fluorinated N,S-Acetals.
Synthesis 2016, 48, 4495-4508.
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27 Vinayaka, A. C.; Swaroop, T. R.; Chikkade, P. K.; Rangappa,
K. S.; Sadashiva, M. P. Transition-Metal-Free Solid Phase
Synthesis of 1,2-Disubstituted 4-Quinolones via the Regiospecific
Synthesis of Enaminones. RSC Adv. 2016, 6, 11528-11535.
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The Journal of Organic Chemistry
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R3
N
R3
Metal-free 1,2,3,-triazole ring formation
O
HN
N
N
TMEDA
+
TsN3
Water as the sole medium
Easy diversity in N-substitution
Fixed C5-sulfur side chain
Practical scale-up synthesis
H2O, 100 oC
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R1
S
R2
R2
S
COR1
22 examples; up to 89% yield
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