Copper-Catalyzed Tandem Sulfuration/Annulation of Propargylamines with Sulfur via C-N Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.9b00685

Copper-catalyzed aerobic oxidative sulfuration and annulation of propargylamines with elemental sulfur is described. The tandem reaction involves C-N bond cleavage and the formation of multiple C-S bonds, affording 1,2-dithiole-3-thiones in good to excellent yields with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.9b00685

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Article
Copper-Catalyzed Tandem Sulfuration/Annulation of
Propargylamines with Sulfur via C-N Bond Cleavage
Hong-Hui Xu, Xiao-Hong Zhang, and Xing-Guo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00685 • Publication Date (Web): 27 May 2019
Downloaded from http://pubs.acs.org on May 27, 2019
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Copper-Catalyzed Tandem Sulfuration/Annulation of
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Propargylamines with Sulfur via C−N Bond Cleavage
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*
*
†, ‡
Hong-Hui Xu,† Xiao-Hong Zhang, and Xing-Guo Zhang
†
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†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China;
‡Guangxi Key Laboratory of Calcium Carbonate Resources Comprehensive Utilization, Hezhou
University, Hezhou 542899, China;
E-Mail: kamenzxh@wzu.edu.cn; zxg@wzu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is
accepted if required according to the journal that you are submitting your paper
to)
Abstract
S
R
CuCl (5 mol%)
N R'
S
S8
+
Ar
K3PO4 (2.0 eq)
DEF, 120 oC, 12h
S
Ar
23 examples, yields up to 90 %
A copper-catalyzed aerobic oxidative sulfuration and annulation of propargylamines
with elemental sulfur is described. The tandem reaction involves C-N bond cleavage
and the formation of multiple C-S bonds, affording 1,2-dithiole-3-thiones in good to
excellent yields with good functional group tolerance.
INTRODUCTION
Transition-metal-catalyzed C-N bonds activation and subsequent transformation
have aroused much attention in synthetic chemistry since the C-N bond is one of the
most abundant chemical bonds in organic compounds and biomacromolecules. 1 As a
class of readily available chemical stocks, some tertiary amines are versatile building
blocks and often used as nitrogen sources to construct new complex
nitrogen-containing molecules through C−N bond cleavage and coupling reaction
with electrophiles (Scheme 1a, path 1).2 In addition, the released alkyl moiety could
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also be used as the carbon source to be incorporated into organic molecules by
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reacting with nucleophiles during the C−N bonds cleavage of tertiary amines
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3
(Scheme 1a, path 2). However, tertiary amines were less reported as alkyl group
9
precursor although they were widely used as nitrogen source. We postulated whether
some complex tertiary amines bearing a special functional group could undergo C−N
bond cleavage and C-S bond formation to retain the major carbon fragment and
release the secondary amines, which would be of great importance for the synthesis of
sulfur-containing compounds.
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Scheme 1. The C-N bond cleavage strategy
a) C-N bond cleavage and subsequent tranformation
R2
1CH2
N
R3
R
M/[O]
C-N bond activation
R2
R3
R2
R2
R3
E+
Nu
1CH2 Nu
1CH N+
E N
N
H
R
+
R
+
1CH
O
R
R3
path 2
path 1
C-N bond cleavage
b) this work
S
R
H N
R
Cu/Base
N R'
S
S
+
S8
+
R'
Ar
Ar
1,2-Dithiole-3-thiones exhibit significant biological activities including antitumor,
4
antioxidant, antithrombotic, chemotherapeutic and radioprotective properties, such
as the commercial drugs oltipraz, 5 anethole dithiolethione (ADT) 6 and its analogues 7.
Furthermore, 1,2-dithiole-3-thiones were often used as versatile building blocks to
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assemble organic electronic conductors,
photoconductive materials
or
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semiconducting polymers. Traditionally, these S-heterocyclics were prepared from
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multi-step reactions of β-ketoesters or terminal alkynes 12 with various sulfurating
reagents, which suffered from harsh reaction conditions or poor atom-economic sulfur
surrogates. Inspired by our recent thioannulations for the synthesis of
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sulfur-heterocycles,
we herein wish to report a novel copper-catalyzed tandem
sulfuration/annulation of propargylamines with elemental sulfur for the practical
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synthesis of 1,2-dithiole-3-thiones through the C−N bond cleavage and the formation
of multiple C-S bonds (Scheme 1b).
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RESULTS AND DISCUSSION
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Table 1. Optimization of the Reaction Conditions a
S
Catalyst (5 mol%)
Base (2.0 eq.)
Solvent, 120 oC
H3C
N Ph
S
S8
+
Ph
S
Ph
H2O (4.0 eq.)
1a
2a
Entry
Catalyst
Base
Solvent
Yield (%)
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3
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5
6
7
8
9
10
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15
CuCl
CuBr
CuI
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaHCO3
KOAc
K3PO4
KF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMSO
DMF
DEF
62
58
55
42
35
63
65
75
66
61
ND
88
58
trace
NR b
CuOAc
Cu2O
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMAc
Toluene
DEF
a
Reaction conditions: 1a (0.2 mmol), S8 (0.3 mmol), catalyst (5 mol%), base (0.4
o
mmol), H2O (4.0 eq.) and anhydrous solvent (2.0 mL), 120 C, air, 12 h; isolated
yield. b under N2.
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In view of the high efficiency of copper(I) catalyst in the C-S bond formation
2a,2d
and the cleavage of C-N bond
,
the model reaction of
with 1.5 equiv of sulfur was
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N-methyl-N-(3-phenylprop-2-yn-1-yl)aniline 1a
conducted in the presence of 5 mol % CuCl, 4.0 equiv H2O, 2.0 equiv of NaOAc in
o
N-methyl pyrrolidone (NMP) at 120 C for 12 h (Table 1). We were pleased to find
that the desired product 2a could be isolated in 62% yield along with PhNHMe in
55% yield (entry 1). Encouraged by these results, various copper catalysts such as
CuBr, CuI, CuOAc, and Cu2O were investigated, but all were less active than CuCl
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(entries 1-5). To further enhance the reaction yield, other bases including NaHCO3,
KOAc, K3PO4 and KF were also examined (entries 6-9), K3PO4 was found to be the
optimal base and 75% yield of 2a was obtained (entry 8). During the testing of
different solvents, N,N-diethylformamide (DEF) was the most suitable by contrast
with DMSO, DMF, N,N-dimethylacetamide (DMAc) and toluene (entries 10-14), and
the product 2a was isolated in 88% yield (entry 12). When DMF was used as solvent,
a messy conversion was observed although all the propargylamines were consumed
(entry 11). When the reaction was performed under N2 atmosphere, no product could
be detected and the substrate 1a was totally recovered, demonstrating that the air play
an essential role in the thioannulation (entry 15).
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With the optimal reaction conditions in hand, we next explored the substrate
scope of the thioannulation by testing a variety of propargylamines (Table 2). Various
secondary and tertiary N-phenylpropargyl amines were compatible with this
transformation. For example, N-phenylpropargyl aniline, N-methyl and N-ethyl
anilines underwent the annulation smoothly to afford product 2a in 63-88% yields.
Aliphatic N,N-dimethyl, N,N-diethyl amines and cyclic piperidine, morpholine were
also compatible with the reaction to give product 2a in 51-71% yields. Moreover, the
thioannulation is feasible to scale-up and a 76% yield was obtained. Subsequently, the
substitution effect of alkyne moiety of N-propargylamines was evaluated. The results
showed that electron-rich and electron-poor aryl group could be tolerated well. For
example, para or meta- methyl, ethyl, tert-butyl, methoxyl substituted phenyl
afforded the products 2b-2h in good to excellent yields. Moreover, the structure of
product 2b was confirmed by X-ray single crystal diffraction analysis. Even steric
ortho-tolyl substituted substrate 1d underwent the thioannulation smoothly to give
product 2d in acceptable yield (34% yield). The commercial prescription drug
anethole dithiolethione (ADT) 2g could be easily prepared in 65% yield through this
tandem sulfuration/annulation strategy. Substrate 1i with a dimethylthiochroman-6-yl
group yielded the corresponding polysulfide 2i in 80% yield. Meta- F, Cl and Br
substituted phenyl delivered the corresponding 1,2-dithiole-3-thiones 2j-2l in 42-65%
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Table 2. Scope with respect to N-propargylamines a
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8
S
S
CuCl (5 mol%)
K3PO4 (2.0 eq.)
DEF, 120 oC
R
N R'
S8
+
Ar
S
Ar
9
H2O (4.0 eq.)
1
2a 2q
-
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R= H, R' = Ph; 63%
R= Me, R' = Ph; 88% (76%b)
S
S
S
R= Et, R' = Ph; 72%
R= Me, R' = Me; 70%
R= Et, R' = Et; 71%
S
S
S
R, R':
N
N
; 70 %
; 51 %
Me
2a
2b
, 90%
R, R':
S
O
S
S
S
Me
S
S
S
Me
S
S
S
S
Et
S
S
S
2c
2d
2e
S
S
, 88%
, 34%
, 65%
, 88%
S
S
MeO
t-Bu
MeO
F
2f
2g
2h
2k
, 86%
, 84%
S
S
S
S
S
Me
Me
S
S
Cl
S
S
S
S
S
S
S
S
S
2i
S
2j
, 65%
, 80%
, 47%
, 42%
S
S
Br
F3C
Ph
2l
S
2m,
S
S
2n,
56%
70%
54%
S
S
S
S
S
S
N
S
2o,
2p,
2q,
65%
55%
a
Reaction conditions: 1 (0.2 mmol), S8 (0.3 mmol), CuCl (5 mol%), K3PO4 (0.4
mmol), H2O (4.0 eq.) and anhydrous DEF (2.0 mL), 120 C, air, 12 h; isolated yield;
R=Me, R’=Ph if not mentioned; b 1a (5 mmol, 1.1 g).
o
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-yields, and the halo group might provide potential handles for further transformation.
The propargylamine 1m bearing strong electron-withdrawing CF3 group afforded
product 2m in 56% yield. Moreover, the reaction of polycyclic aryl and heteroaryl
substituted N-propargylamines also proceeded smoothly. For instance, 1,1'-biphenyl,
naphthalen-1-yl, pyridin-3-yl and thiophen-2-yl provided the products 2n-2q in
54%-70% yields.
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To probe the reaction mechanism, some control experiments were conducted as
shown in Scheme 2. First, the reaction of aniline 1a with S8 was carried out under the
standard conditions by adding 2 equiv. of 2,2,6,6-tetramethylpiperidine oxide
(TEMPO). The product 2a was still isolated in 80% yield (Scheme 2, eq. 1),
suggesting that this transformation might not proceed through a free radical pathway.
Imine 3 was found to be generated by GC-MS analysis when the reaction of
N-(3-phenylprop-2-yn-1-yl)aniline 1a-1 was conducted in the absence of S8 under the
optimal reaction condition (eq. 2). Treatment of imine 3 with S8 gave the desired
product 2a in 45% yield (eq. 3). However, the reaction of 3-phenylpropiolaldehyde 4
with S8 did not work under the standard conditions (eq. 4). These results implied that
imine 3 might be the key intermediate in the thioannulation. Furthermore, when the
reaction of 1a with S8 was carried out in anhydrous DEF and 0.2 mL D2O, the
deuterated product D-2a was observed and the product was obtained in 80% yield
with a 9:1 ratio (D-2a: H-2a, according to NMR), showing that the proton was
derived from water in the solvent (eq. 5).
Based on the obtained experimental results, a possible mechanism is proposed for
this copper-catalyzed tandem reaction (Scheme 3). Firstly, the copper-catalyzed
oxidative dehydrogenation of propargylamines 1 occurs under air atmosphere to give
2a, 3c
the imine A.
The disproportionation reaction of S8 in the presence of K3PO4
releases -S-S- and -SH. 16 Then, the simultaneous nucleophilic additions of -S-S- to the
carbon-carbon triple bond and C=N bond of A and the following protonation afford
the cyclization intermediate B. The further copper-catalyzed dehydrogenative
oxidation of B produces imine C, which undergoes hydrolysis to yield
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1a, 1b
1,2-dithiol-3-one D along with secondary amines.
Finally, the nucleophilic
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–
addition of SH to ketone moiety of D and subsequent elimination deliver the target
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product 2.
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Scheme 2. Control experiments
S
H3C
TEMPO (2.0 eq.)
N Ph
S
S8
+
eq. 1
eq.2
Ph
Ph
standard conditions
S
Ph
1a
2a
, 80 %
N Ph
HN Ph
standard conditions
in the absence of S8
Ph
3,
1a 1
-
detected by GC-MS
S
N Ph
standard conditions
eq.3
eq.4
S
S8
+
+
Ph
Ph
S
Ph
2a
3
4
, 45 %
S
S
standard conditions
standard conditions
S8
CHO
S
Ph
2a
, 0 %
S
S
D
H3C
N Ph
S8
+
eq.5
Ph
D O
dry DEF, 0.2 mL
2
S
Ph
1a
D-2a
D-2a H-2a
, 80 %;
:
= 9:1
Scheme 3. Possible Mechanism
R
R
R'
R'
N
R
R
N
-S-S-
N+ R'
H2O
Ar
N R'
-
[Cu]/O2
Ar
Ar
S
S
S
S
Ar
1
A
B
[Cu]/O2
R'
R
-O
O
-SH
N+
S
S
H2O
SH
S
S
S
S
S
E
Ar
S
Ar
Ar
S
-OH
Ar
2
RNHR'
C
D
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CONCLUSIONS
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In summary, we have developed a copper-catalyzed tandem sulfuration and
annulation of propargylamines with cheap and relatively safe elemental sulfur using
air as oxidant. A variety of tertiary arylpropargylamines were firstly applied to
prepare the 1,2-dithiole-3-thiones in good to excellent yields through this
thioannulation process. This protocol provides a novel method for the synthesis of
polysulfides via the cleavage C-N bonds and the formation of multi C-S bonds, and
also offers a facile and efficient route to construct the key moiety of commercial drug
anethole dithiolethione (ADT).
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EXPERIMENTAL SECTION
General Information
1
Chemicals were either purchased or purified by standard techniques. H NMR
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and C{1H} NMR spectra were measured on a 500 MHz spectrometer (500 MHz
1
13
1
for H and 125 MHz for C) or a 400 MHz spectrometer(400 MHz for H), using
CDCl3 as the solvent with tetramethylsilane (TMS) as an internal standard at room
temperature. Chemical shifts are given in δ relative to TMS, the coupling
constants J are given in Hz. High resolution mass spectra were recorded on an
ESI-Q-TOF mass spectrometry. All reactions under air atmosphere were
conducted using standard Schlenk techniques. Melting points were measured on
X4 melting point apparatus and uncorrected. Column chromatography was
performed using EM Silica gel 60 (300-400 mesh).
General Procedure for the Synthesis of Propargylamines 1a-1q 15
To a mixture of CuBr (35.8 mg, 0.25 mmol), N, N-dimethylaniline (1210 mg,
10.0 mmol) and phenylacetylene (510 mg, 5.0 mmol) was added tert-butyl
hydroperoxide (0.9 mL, 5.5M in decane) under nitrogen over 30 seconds at room
o
temperature. The reaction temperature was raised to 100 C over 15 min. The
resulting mixture was stirred at the same temperature for 3 hour. After the reaction
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mixture was cooled to room temperature, the mixture was poured into ethyl acetate
and evaporated under a vacuum. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 50:1) to afford the desired products
1a-1q.
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General Procedure for the Synthesis of 1,2-Dithiole-3-thiones 2a-2q
To a flame-dried Schlenk tube with a magnetic stirring bar was charged with 1
(44.2 mg, 0.2 mmol), H2O (4.0 eq), S8 (76.8mg, 0.3mmol), CuCl (1.0 mg, 5 mol %),
K3PO4 (84.8 mg, 2 equiv) in anhydrous DEF (2 mL) under air atmosphere. The
reaction mixture was stirred at 120 °C for 12 hours. After the reaction was finished,
the mixture was poured into ethyl acetate, which was washed with brine (2 x 15 mL).
After the aqueous layer was extracted with ethyl acetate, the combined organic layers
were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was
purified by flash column chromatography using petroleum ether/ethyl acetate =50:1
as the eluent to afford the desired products 2a-2q.
General Procedure for the Synthesis of Compound 3 17
To a solution of aniline (0.47 g, 5.0 mmol) in CH2Cl2 (10 mL) in the presence of
molecular sieves 4 A (MS 4 A) (2 g) was added a solution of 3-phenyl-2-propynal
(0.65g, 5.0 mmol) in CH2Cl2 (10 mL) at 0 °C. The reaction mixture was warmed to r.t.
and stirred for 1 h. Then the reaction mixture was filtered and the solvents were
evaporated under vacuum. The residue was purified by flash column chromatography
(petroleum ether/ethyl acetate=50:1) to afford the desired products 3.
N-methyl-N-(3-phenylprop-2-yn-1-yl)aniline (1a): 15 yellow oil (718.3 mg, 65% yield);
1H NMR (400 MHz, CDCl3) δ 7.40 - 7.37 (m, 2H), 7.32 - 7.27 (m, 5H), 6.93 (d, J =
8.4 Hz, 2H), 6.85 - 6.81 (m, 1H), 4.28 (s, 2H), 3.05 (s, 3H).
3d
1
N-(3-phenylprop-2-yn-1-yl)aniline (1a-1):
yellow oil (590.0 mg, 57% yield); H
NMR (400 MHz, CDCl3) δ 7.41 - 7.38 (m, 2H), 7.29 - 7.28 (m, 3H), 7.25 - 7.21 (m,
2H), 6.81 - 6.77 (m, 1H), 6.74(d, J = 8.0 Hz, 2H), 4.15 (s, 2H).
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N-ethyl-N-(3-phenylprop-2-yn-1-yl)aniline (1a-2):
yellow solid (599.3 mg, 51%
5
6
7
8
o
1
yield); m.p. 51-53 C; H NMR (500 MHz, CDCl3) δ 7.40 - 7.38 (m, 2H), 7.29 (m,
5H), 6.93 - 6.91 (m, 2H), 6.80 - 6.79 (m, 1H), 4.25 (s, 2H), 3.53 (q, J = 7.0 Hz, 2H),
1.27 (t, J = 7.0 Hz, 3H).
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N,N-dimethyl-3-phenylprop-2-yn-1-amine (1a-3): 19 yellow oil (302.1 mg, 38% yield);
1H NMR (500 MHz, CDCl3) δ 7.440 - 7.435 (m, 2H), 7.30 (m, 3H), 3.48 (s, 2H), 2.38
(s, 6H).
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N,N-diethyl-3-phenylprop-2-yn-1-amine (1a-4): yellow oil (327.3 mg, 35% yield);
1H NMR (500 MHz, CDCl3) δ 7.43 - 7.42 (m, 2H), 7.30 - 7.29 (m, 3H), 3.65 (s, 2H),
2.64 (q, J = 7.0 Hz, 4H), 1.13 (t, J = 7.0 Hz, 6H).
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1-(3-phenylprop-2-yn-1-yl)piperidine (1a-5): yellow oil (626.9 mg, 63% yield); H
NMR (500 MHz, CDCl3) δ 7.44 - 7.43 (m, 2H), 7.290 - 7.287 (m, 3H), 3.49 (s, 2H),
2.58 (s, 4H), 1.65 - 1.64 (m, 4H), 1.45 (s, 2H).
4-(3-phenylprop-2-yn-1-yl)morpholine (1a-6): 20 yellow oil (532.7 mg, 53% yield); 1H
NMR (500 MHz, CDCl3) δ 7.44 - 7.43 (m, 2H), 7.303 - 7.299 (m, 3H), 3.77 (s, 4H),
3.51 (s, 2H), 2.65 (s, 4H).
15
N-methyl-N-(3-(p-tolyl)prop-2-yn-1-yl)aniline (1b):
yellow oil (787.3 mg, 67%
1
yield); H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H),
6.93 (d, J = 8.4 Hz, 2H), 6.84 - 6.81 (m, 1H), 4.27 (s, 2H), 3.05 (s, 3H), 2.33 (s, 3H).
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N-methyl-N-(3-(m-tolyl)prop-2-yn-1-yl)aniline (1c):
yellow oil (775.5 mg, 66%
yield); 1H NMR (500 MHz, CDCl3) δ 7.29 - 7.26 (m, 2H), 7.19 - 7.14 (m, 3H), 7.08 -
7.06 (m, 1H), 6.92 - 6.90 (m, 2H), 6.82 - 6.79 (m, 1H), 4.24 (s, 2H), 3.02 (s, 3H), 2.28
(s, 3H).
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N-methyl-N-(3-(o-tolyl)prop-2-yn-1-yl)aniline (1d):
yellow oil (693.3 mg, 59%
yield); 1H NMR (500 MHz, CDCl3) δ 7.29 - 7.20 (m, 3H), 7.10 - 7.00 (m, 3H), 6.87 -
6.86 (m, 2H), 6.76 - 6.74 (m, 1H), 4.23 (s, 2H), 2.97 (s, 3H), 2.23 (s, 3H).
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N-(3-(4-ethylphenyl)prop-2-yn-1-yl)-N-methylaniline (1e):
yellow oil (896.4 mg,
1
72% yield); H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 4H), 7.11 - 7.09 (m, 2H),
6.93(d, J = 8.0 Hz, 2H), 6.84 - 6.80 (m, 1H), 4.26 (s, 2H), 3.04 (s, 3H), 2.62 (q, J =
7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H).
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N-(3-(4-(tert-butyl)phenyl)prop-2-yn-1-yl)-N-methylaniline (1f):
yellow solid
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(1024.9 mg, 74% yield); m.p. 54-56 oC; 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.28 (m,
6H), 6.94 (d, J = 8.0 Hz, 2H), 6.84 - 6.81 (m, 1H), 4.26 (s, 2H), 3.04 (s, 3H), 1.29 (s,
9H).
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N-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylaniline (1g):15 yellow solid (853.4
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mg, 68% yield); m.p. 70-72 C; H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 4H),
6.93 (d, J = 8.0 Hz, 2H), 6.84 - 6.79 (m, 3H), 4.26 (s, 2H), 3.79 (s, 3H), 3.05 (s, 3H).
N-(3-(3-methoxyphenyl)prop-2-yn-1-yl)-N-methylaniline (1h): yellow oil (903.6 mg,
1
72% yield); H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 2H), 7.20 - 7.16 (m, 1H),
6.98 - 6.90 (m, 4H); 6.86 - 6.81 (m, 2H), 4.27 (s, 2H), 3.78 (s, 3H), 3.05 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 159.4, 149.4, 129.4, 129.2, 124.5, 124.2, 118.4,
116.8, 114.8, 114.6, 85.0, 84.3, 55.4, 43.5, 38.8; HRMS (ESI) Calcd for C17H18NO+
([M + H]+) 252.1383, found 252.1388.
N-(3-(4,4-dimethylthiochroman-6-yl)prop-2-yn-1-yl)-N-methylaniline (1i): yellow
o
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solid (1219.8 mg, 76% yield); m.p. 71-73 C; H NMR (400 MHz, CDCl3) δ 7.37 -
7.36 (m, 1H), 7.31 - 7.27 (m, 2H), 7.05 - 7.02 (m, 1H), 6.99 - 6.97 (m, 1H), 6.93 (d, J
= 8.0 Hz, 2H), 6.84 - 6.80 (m, 1H), 4.26 (s, 2H), 3.04 (s, 3H), 3.02 (m, 2H), 1.92 (t, J
= 6.4 Hz, 2H), 1.30 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.5, 142.0, 132.8,
129.9, 129.3, 129.2, 126.5, 118.5, 118.3, 114.6, 84.6, 84.2, 43.6, 38.8, 37.5, 33.1, 30.1,
23.3; HRMS (ESI) Calcd for C21H24NS+ ([M + H]+) 322.1624, found 322.1616.
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N-(3-(3-fluorophenyl)prop-2-yn-1-yl)-N-methylaniline (1j): yellow oil (740.9 mg,
1
62% yield); H NMR (500 MHz, CDCl3) δ 7.29 - 7.27 (m, 2H), 7.23 - 7.19 (m, 1H),
7.14 - 7.12 (m, 1H), 7.06 - 7.04 (m, 1H), 6.99 - 6.95 (m, 1H), 6.91 - 6.90 (m, 2H),
6.83 - 6.81 (m, 1H), 4.25 (s, 2H), 3.02 (s, 3H).
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N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-N-methylaniline (1k): yellow oil (765.0 mg,
1
60% yield); H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.30 - 7.22 (m, 4H), 7.18 -
7.14(m, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.83 - 6.80 (m, 1H), 4.24 (s, 2H), 3.01 (s, 3H).
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N-(3-(3-bromophenyl)prop-2-yn-1-yl)-N-methylaniline (1l): yellow oil (930.0 mg,
1
62% yield); H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.43 - 7.42 (m, 1H), 7.33 -
7.30 (m, 3H), 7.16 - 7.13 (m, 1H), 6.94 - 6.92 (m, 2H), 6.87 - 6.84 (m, 1H), 4.28 (s,
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2H), 3.05 (s, 3H).
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N-methyl-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)aniline (1m): yellow oil
(895.9 mg, 62% yield); 1H NMR (400 MHz, CDCl3) δ 7.54 - 7.45 (m, 4H), 7.32 - 7.28
(m, 2H), 6.94 - 6.92 (m, 2H), 6.86 - 6.83 (m, 1H), 4.29 (s, 2H), 3.05 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 149.3, 132.1, 130.0 (q, JC-F = 32.5 Hz), 129.3, 127.0,
125.3, 121.9 (q, JC-F = 270.6 Hz), 118.5, 114.5, 87.9, 83.1, 43.5, 38.9. HRMS (ESI)
Calcd for C17H15F3N+ ([M + H]+) 290.1151, found 290.1145.
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N-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-N-methylaniline (1n):15 yellow solid
(1009.8 mg, 68% yield); m.p. 80-82 oC; 1H NMR (500 MHz, CDCl3) δ 7.59 - 7.58 (m,
2H), 7.54 - 7.52 (m, 2H), 7.47 - 7.44 (m, 4H), 7.38 - 7.30 (m, 3H), 6.97 - 6.95 (m, 2H),
6.86 - 6.84 (m, 1H), 4.31 (s, 2H), 3.08 (s, 3H).
N-methyl-N-(3-(naphthalen-2-yl)prop-2-yn-1-yl)aniline (1o): yellow solid (935.0 mg,
69% yield); m.p. 91-93 oC; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.81 - 7.73 (m,
3H), 7.50 - 7.42 (m, 3H), 7.34 - 7.30 (m, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.87 - 6.83 (m,
1H), 4.33 (s, 2H), 3.09 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.4, 133.1,
132.9, 131.7, 129.3, 128.7, 128.0, 127.84, 127.80, 126.7, 126.6, 120.5, 118.5, 114.6,
85.4, 84.8, 43.6, 38.9. HRMS (ESI) Calcd for C20H18N+ ([M + H]+) 272.1434, found
272.1434.
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N-methyl-N-(3-(pyridin-3-yl)prop-2-yn-1-yl)aniline (1p):
yellow oil (266.4 mg,
1
24% yield); H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 8.50 - 8.49 (m, 1H), 7.65 -
7.63 (m, 1H), 7.31 - 7.28 (m, 2H), 7.20 - 7.18 (m, 1H), 6.92 - 6.91(m, 2H), 6.85 - 6.82
(m, 1H), 4.29 (s, 2H), 3.04 (s, 3H).
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N-methyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)aniline (1q):
black oil (249.7 mg,
1
22% yield); H NMR (500 MHz, CDCl3) δ 7.33 - 7.30 (m, 2H), 7.22 - 7.21 (m, 1H),
7.16 (s, 1H), 6.94 - 6.93 (m, 3H), 6.87 - 6.84 (m, 1H), 4.30 (s, 2H), 3.05 (s, 3H).
5-phenyl-3H-1,2-dithiole-3-thione (2a):13a red solid (37.0 mg, 88% yield); m.p.
124-126 oC; 1H NMR (400 MHz, CDCl3) δ 7.66 - 7.64 (m, 2H), 7.58 - 7.54 (m, 1H),
13
7.50 - 7.47 (m, 2H), 7.44 (s, 1H); C{1H} NMR (125 MHz, CDCl3) δ 215.7, 173.0,
136.1, 132.3, 131.8, 129.7, 127.0; GC-MS (EI, 70 eV) m/z (%): 209.40 (73.22),
144.65 (100), 101.80 (35.32), 76.85 (12.18).
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5-(p-tolyl)-3H-1,2-dithiole-3-thione (2b):13a red solid (40.3 mg, 90% yield); m.p.
117-119 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J= 8.4 Hz, 2H), 7.42 (s, 1H), 7.28
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(d, J= 8.0 Hz, 2H), 2.41 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 215.5, 173.3,
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143.2, 135.5, 130.4, 129.0, 126.9, 21.7; GC-MS (EI 70 ev) m/z (%): 223.40 (100),
209.40 (23.60), 158.60 (88.76), 144.65 (31.59).
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13a
1
5-(m-tolyl)-3H-1,2-dithiole-3-thione (2c):
red oil (37.0 mg, 88% yield); H NMR
(400 MHz, CDCl3) δ 7.46 - 7.44 (m, 2H), 7.42 (s, 1H), 7.37 - 7.35 (m, 2H), 2.42 (s,
13
3H); C{1H} NMR (125 MHz, CDCl3) δ 215.6, 173.3, 139.7, 135.9, 133.1, 131.7,
129.6, 127.6, 124.2, 21.5; GC-MS (EI 70 ev) m/z (%): 223.45 (100), 190.50 (6.79),
158.65 (89.92), 134.70 (7.57).
13a
5-(o-tolyl)-3H-1,2-dithiole-3-thione (2d):
red solid (15.2 mg, 34% yield); m.p.
123-125 oC; 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.39 (m, 2H), 7.33 - 7.27 (m, 2H),
13
7.13 (s, 1H), 2.43 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 216.1, 173.2, 139.5,
136.3, 131.6, 131.2, 130.9, 129.4, 126.6, 20.6; GC-MS (EI 70 ev) m/z (%): 224.35
(100), 190.55 (18.35), 158.65 (37.00), 127.75 (15.18).
13a
5-(4-ethylphenyl)-3H-1,2-dithiole-3-thione (2e):
red solid (41.9 mg, 88% yield);
m.p. 115-116 oC; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H),
13
7.31 (d, J = 8.4 Hz, 2H), 2.71 (q, J = 7.8 Hz, 2H), 1.27 (t, J = 7.8 Hz, 3H); C{1H}
NMR (125 MHz, CDCl3) δ 215.6, 173.3, 149.4, 135.5, 129.2, 127.0, 29.0, 15.2;
GC-MS (EI 70 ev) m/z (%): 237.40 (100), 208.45 (16.85), 172.55 (61.37), 144.65
(15.40).
13a
5-(4-(tert-butyl)phenyl)-3H-1,2-dithiole-3-thione (2f):
red solid (45.8 mg, 86%
yield); m.p. 112-114 oC; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.50
13
(d, J = 8.8Hz, 2H), 7.45 (s, 1H), 1.35 (s, 9H); C{1H} NMR (125 MHz, CDCl3) δ
215.6, 173.3, 156.3, 135.6, 129.0, 126.9, 126.8, 35.3, 31.2; GC-MS (EI 70 ev) m/z
(%): 265.40 (100), 250.40 (53.78), 200.55 (19.86), 170.60 (8.36).
5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (2g): 13a red solid (31.2 mg, 65% yield);
o
1
m.p. 109-111 C; H NMR (400 MHz, CDCl3) δ 7.63 - 7.59 (m, 2H), 7.38 (s, 1H),
13
6.99 - 6.95 (m, 2H), 3.87 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 215.2, 173.1,
163.1, 134.7, 128.7, 124.3, 115.1, 55.7; GC-MS (EI 70 ev) m/z (%): 239.40 (100),
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206.50 (6.13), 174.60 (55.65), 131.75 (27.56).
5-(3-methoxyphenyl)-3H-1,2-dithiole-3-thione (2h): 13a red solid (40.3 mg, 84% yield);
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m.p. 113-115 C; H NMR (400 MHz, CDCl3) δ 7.40 - 7.35 (m, 2H), 7.22-7.20 (m,
1H), 7.11 - 7.10 (m, 1H), 7.08 - 7.06 (m, 1H), 3.84 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 215.5, 172.8, 160.3, 136.1, 132.8, 130.8, 119.3, 117.8, 112.4, 55.6; GC-MS
(EI 70 ev) m/z (%): 239.40 (100), 206.50 (8.15), 174.55 (56.39), 131.70 (19.75).
5-(4,4-dimethylthiochroman-6-yl)-3H-1,2-dithiole-3-thione (2i): red solid (49.6 mg,
80% yield); m.p. 128-130 oC; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 1H),
7.42 (s, 1H), 7.31 - 7.29 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.09 - 3.06 (m, 2H), 1.98 -
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1.95 (m, 2H), 1.35 (s, 6H); C{1H} NMR (125 MHz, CDCl3) δ 215.1, 173.4, 143.3,
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139.2, 134.9, 127.7, 127.4, 124.7, 124.2, 36.8, 33.3, 29.9, 23.4.; GC-MS (EI 70 ev)
m/z (%): 309.20 (100), 294.20 (23.75), 244.40 (46.67), 220.45 (7.44); HRMS (ESI)
Calcd for C14H15S4 ([M + H]+) 311.0051, found 311.0053.
+
13a
5-(3-fluorophenyl)-3H-1,2-dithiole-3-thione (2j):
red solid (29.6 mg, 65% yield);
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m.p. 126-128 C; H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 2H), 7.41 (s, 1H),
7.38 - 7.35 (m, 1H), 7.29 - 7.26 (m, 1H); C{1H} NMR (125 MHz, CDCl3) δ 215.6,
13
170.9 , 163.1 (d, JC-F = 248.8 Hz), 136.6, 133.6, 131.5, 122.8, 119.1 (d, JC-F = 21.3
Hz), 114.1 (d, JC-F = 23.8 Hz); GC-MS (EI 70 ev) m/z (%): 227.40 (100), 162.55
(86.67), 119.75 (39.25), 94.80 (9.53).
13a
5-(3-chlorophenyl)-3H-1,2-dithiole-3-thione (2k):
black solid (20.4 mg, 42%
o
1
yield); m.p. 106-108 C; H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.55 - 7.52 (m,
2H), 7.45 - 7.41 (m, 1H), 7.40 (s, 1H); C{1H} NMR (125 MHz, CDCl3) δ 215.6,
13
170.7, 136.6, 135.9, 133.4, 132.1, 131.0, 127.0, 125.1; GC-MS (EI 70 ev) m/z (%):
243.35 (100), 180.50 (26.50), 135.70 (22.01), 100.80 (13.06).
13a
5-(3-bromophenyl)-3H-1,2-dithiole-3-thione (2l):
red solid (27.2 mg, 47% yield);
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m.p. 123-125 C; H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.69 - 7.67 (m, 1H),
7.60 - 7.58 (m, 1H), 7.39 - 7.35 (m, 2H); C{1H} NMR (125 MHz, CDCl3) δ 215.6,
13
170.6, 136.6, 135.0, 133.7, 131.2, 129.9, 125.6, 123.8; GC-MS (EI 70 ev) m/z (%):
289.20 (100), 243.35 (15.47), 224.20 (68.15), 143.65 (17.62).
13a
5-(4-(trifluoromethyl)phenyl)-3H-1,2-dithiole-3-thione (2m):
red solid (31.1 mg,
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56% yield); m.p. 109-111 oC; 1H NMR (400 MHz, CDCl3) δ 7.80 - 7.75 (m, 4H), 7.44
(s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 215.7, 170.3, 137.1, 135.1, 133.8 (q, JC-F
= 32.5 Hz), 127.5, 126.8, 123.6 (q, JC-F = 271.3 Hz); GC-MS (EI 70 ev) m/z (%):
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277.20 (100), 258.20(4.36), 212.35 (76.20), 169.45 (6.90).
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5-([1,1'-biphenyl]-4-yl)-3H-1,2-dithiole-3-thione (2n):
red solid (40.0 mg, 70%
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1
yield); m.p. 119-122 C; H NMR (400 MHz, CDCl3) δ 7.75 - 7.70 (m, 4H), 7.64 -
7.62 (m, 2H), 7.51 - 7.47 (m, 3H); 7.44 - 7.41 (m, 1H); C{1H} NMR (125 MHz,
13
CDCl3) δ 215.6, 172.6, 145.2, 139.5, 135.8, 130.6, 129.2, 128.6, 128.3, 127.5, 127.2;
GC-MS (EI 70 ev) m/z (%): 285.30 (100), 252.35 (8.70), 220.45 (71.56), 206.50
(10.21).
5-(naphthalen-2-yl)-3H-1,2-dithiole-3-thione (2o): 13a red solid (33.8 mg, 65% yield);
m.p. 68-71 oC; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.2 Hz, 1H), 7.94 - 7.91 (m,
2H), 7.89 - 7.87 (m, 1H), 7.67 - 7.64 (m, 1H), 7.63 - 7.58 (m, 2H), 7.56 (s, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 215.6, 172.9, 136.2, 134.9, 133.1, 129.7, 129.1,
129.0, 128.5, 128.1, 127.7, 127.3, 123.5; GC-MS (EI 70 ev) m/z (%): 259.30 (100),
226.40 (9.72), 194.50 (54.72), 151.65 (22.77).
5-(pyridin-3-yl)-3H-1,2-dithiole-3-thione (2p):12g red solid (23.2 mg, 55% yield); m.p.
o
1
150-152 C; H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.4 Hz, 1H), 8.79 - 8.77 (m,
1H), 7.97 - 7.94 (m, 1H), 7.47 - 7.44 (m, 1H), 7.43 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 215.6, 168.7, 152.9, 147.5, 136.8, 134.1, 128.1, 124.2; GC-MS (EI 70 ev)
m/z (%): 210.30 (79.82), 167.55 (2.43), 145.60 (100), 121.65 (9.91).
5-(thiophen-2-yl)-3H-1,2-dithiole-3-thione (2q):13a red solid (23.3 mg, 54% yield);
m.p. 127-129 oC; 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.58 (m, 1H), 7.55 - 7.54 (m,
1H), 7.33 (s, 1H), 7.16 - 7.14 (m, 1H); C{1H} NMR (125 MHz, CDCl3) δ 214.7,
13
165.2, 134.8, 134.1, 131.1, 129.3, 129.2; GC-MS (EI 70 ev) m/z (%): 215.35 (100),
150.55 (89.46), 126.65 (12.84), 107.75 (69.81).
13a
1
phenyl-3H-1,2-dithiole-3-thione-4-d (D-2a):
red solid (33.7 mg, 80% yield); H
NMR (400 MHz, CDCl3) δ 7.66 - 7.64 (m, 2H), 7.50 – 7.47 (m, 2H), 7.44 (s, 0.10H);
13C{1H} NMR (125 MHz, CDCl3) δ 215.7, 215.6, 172.9, 172.9, 136.04, 135.96, 135.8,
135.5, 132.3, 131.7, 129.7, 127.0; GC-MS (EI 70 ev) m/z (%): 210.35 (71.35), 144.60
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(100), 102.75 (41.07), 76.80 (17.51).
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(Z)-N,3-diphenylprop-2-yn-1-imine (3):17 yellow solid (533.0 mg, 52% yield); m.p.
46-48 oC; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.67 - 7.65 (m, 2H), 7.47 - 7.43
(m, 5H), 7.36 - 7.31 (m, 2H), 7.28 (m, 1H).
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SUPPLEMENTARY INFORMATION
1
13
Copies of H NMR or C{1H} NMR spectra for products 1a-1q, 2a-2q and X-ray
data for compound 2b. This material is available free of charge via the Internet at
http://pubs.acs.org.
Supplementary crystallographic data was deposited at the Cambridge
Crystallographic Data Centre (CCDC) under the number CCDC-1883614 (2b) and
can be obtained free of charge from via www.ccdc.cam.ac.uk/data_request.cif.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No. 21272177) and
Natural Science Foundation of Guangxi Province (No. 2018GXNSFDA281011) for
financial support.
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