U.S. patent application number 16/968149 was filed with the patent office on 2021-02-11 for method for synthesizing 2-benzylidene tetrahydrothiophene derivative.
The applicant listed for this patent is SOOCHOW UNIVERSITY. Invention is credited to Shunjun JI, Jinghao LI, Shunyi WANG.
Application Number | 20210040060 16/968149 |
Document ID | / |
Family ID | 1000005179665 |
Filed Date | 2021-02-11 |
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United States Patent
Application |
20210040060 |
Kind Code |
A1 |
WANG; Shunyi ; et
al. |
February 11, 2021 |
METHOD FOR SYNTHESIZING 2-BENZYLIDENE TETRAHYDROTHIOPHENE
DERIVATIVE
Abstract
The present invention relates to a method for synthesizing a
2-benzylidene tetrahydrothiophene derivative, which comprises the
step of reacting a (cyclopropylethynyl) aromatic cyclic compound of
Formula (I) with a sulfur source in an organic solvent as a
reaction medium in air atmosphere at 100-200.degree. C. to obtain a
2-benzylidene tetrahydrothiophene derivative of Formula (III). The
reaction route is as follows: ##STR00001## where Ar is selected
from phenyl ring, a substituted phenyl ring, biphenylyl, thiophenyl
ring or naphthyl ring, in which the substituent on the substituted
phenyl ring is selected from the group consisting of halo,
trifluoromethyl, cyano, a C.sub.1-C.sub.20 alkyl group and any
combination thereof; and R.sup.1 is selected from hydrogen or a
C.sub.1-C.sub.20 alkyl group. The method of the present invention
has the advantages of simple reaction conditions, convenient
post-treatment, environmental friendliness, and requiring no
transition metal catalysis.
Inventors: |
WANG; Shunyi; (Suzhou,
CN) ; JI; Shunjun; (Suzhou, CN) ; LI;
Jinghao; (Suzhou, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SOOCHOW UNIVERSITY |
Suzhou |
|
CN |
|
|
Family ID: |
1000005179665 |
Appl. No.: |
16/968149 |
Filed: |
February 26, 2018 |
PCT Filed: |
February 26, 2018 |
PCT NO: |
PCT/CN2018/077178 |
371 Date: |
August 6, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 333/08
20130101 |
International
Class: |
C07D 333/08 20060101
C07D333/08 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 9, 2018 |
CN |
201810134894.1 |
Claims
1. A method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative, comprising the step of: reacting a (cyclopropylethynyl)
aromatic cyclic compound of Formula (I) with a sulfur source in an
organic solvent as a reaction medium in air atmosphere at
100-200.degree. C. to obtain a 2-benzylidene tetrahydrothiophene
derivative of Formula (III), wherein the reaction route is as
follows: ##STR00008## where Ar is selected from phenyl ring, a
substituted phenyl ring, biphenylyl, thiophenyl ring or naphthyl
ring, in which the substituent on the substituted phenyl ring is
selected from the group consisting of halo, trifluoromethyl, cyano,
a C.sub.1-C.sub.20 alkyl group and any combination thereof; and
R.sup.1 is selected from hydrogen or a C.sub.1-C.sub.20 alkyl
group.
2. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein Ar is phenyl ring, and
R.sup.1 is hydrogen or methyl.
3. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein Ar is selected from a
substituted phenyl ring, biphenylyl, thiophenyl ring or naphthyl
ring, in which the substituent on the substituted phenyl ring is
selected from the group consisting of halo, trifluoromethyl, cyano
a C.sub.1-C.sub.20 alkyl and any combination thereof, and R.sup.1
is hydrogen.
4. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the (cyclopropylethynyl)
aromatic cyclic compound of Formula (I) is
(cyclopropylethynyl)benzene,
1-chloro-4-(cyclopropylethynyl)-benzene,
1-bromo-4-(cyclopropylethynyl)benzene,
1-(cyclopropylethynyl)-4-(tri-fluoromethyl)benzene,
1-(cyclopropylethynyl)-4-methylbenzene,
4-(cyclopropyl-ethynyl)benzonitrile,
1-chloro-2-(cyclopropylethynyl)benzene,
1-(cyclopropyl-ethynyl)-2-methylbenzene,
1-(cyclopropylethynyl)-3-methylbenzene),
1-chloro-3-(cyclopropylethynyl)benzene,
4-(cyclopropylethynyl)-1,1'-biphenyl,
1-(cyclopropyl-ethynyl)naphthalene,
4-bromo-1-(cyclopropylethynyl)-2-methylbenzene,
2-chloro-4-(cyclopropylethynyl)-1-methylbenzene,
3-(cyclopropylethynyl)thiophene, or
((1-methylcyclopropyl)ethynyl)benzene.
5. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the sulfur source is
sodium sulfide and/or potassium sulfide.
6. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 5, wherein the sulfur source is
sodium sulfide nonahydrate.
7. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the molar ratio of the
(cyclopropylethynyl) aromatic cyclic compound to the sulfur source
is 1:1-6.
8. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the organic solvent is
selected from the group consisting of N,N'-dimethyl formide,
dimethyl sulfoxide, N,N'-dimethyl acetamide and any combination
thereof.
9. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein in units of mole and
milliliter respectively, the ratio of the (cyclopropylethynyl)
aromatic cyclic compound and the organic solvent is 0.3-1
mol:0.1-10 mL.
10. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the reaction time is 8-20
hrs.
11. The method for synthesizing a 2-benzylidene tetrahydrothiophene
derivative according to claim 1, wherein the reaction temperature
is 130-150.degree. C.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the technical field of
organic synthesis, and particularly to a method for synthesizing a
2-benzylidene tetrahydrothiophene derivative.
DESCRIPTION OF THE RELATED ART
[0002] Natural or artificial organic sulfur-containing compounds
play an important role in medicinal chemistry and biochemistry, and
tetrahydrothiophene is particularly notable among many organic
sulfur-containing compounds. In the past few decades, it has
attracted the attention of many chemists, pharmacologists and
biologists. The compound based on tetrahydrothiophene includes
Biotin, a water-soluble vitamin that is involved in many biological
functions and has been chemically synthesized on a large scale
(Org. Lett., 1999, 1:99-102). Representative biologically active
tetrahydrothiophene derivatives include a 4'-thioadenine derivative
that is a highly potent and highly selective A3 adenosine receptor
antagonist (Chem. Pharm. Bull., 1998, 46: 1339-1440), and
4'-thiocytidine that is an anti-HIV and HBV inhibitor (J. Med.
Chem, 2007, 50: 3159-3162). Due to the excellent nucleophilic
performance and coordination ability of sulfur atoms, the
substituted tetrahydrothiophene compounds are often used as a
ligand for transition metal catalysis, a nucleophilic organic small
molecule catalyst, and a sulfur ylide precursor in organic
synthesis. The 2-benzylidene tetrahydrothiophene derivative
reported herein also has potential biological activity and
catalytic ability, but the synthesis method therefor is rarely
reported.
[0003] At present, the synthesis of 2-benzylidene
tetrahydrothiophene is mainly achieved by generating sulfur
radicals by a thiol having an unsaturated bond in the presence of a
nickel catalyst or others to attack unsaturated bonds (Tetrahedron
Lett., 1998, 39, 8121-8124.) or by preparing a special phosphorus
ylide to undergo wittig reaction with a carbonyl group (J. Org.
Chem., 1979, 44 (16), 2911-2915). The reaction has the
disadvantages of complex raw material preparation, expensive metal
catalyst and others. Therefore, it is particularly important to
explore the synthesis of a 2-benzylidene tetrahydrothiophene
derivative with cheap and readily available raw materials in the
absence of metal.
SUMMARY OF THE INVENTION
[0004] To solve the above technical problems, an object of the
present invention is to provide a method for synthesizing a
2-benzylidene tetrahydrothiophene derivative. The method of the
present invention has the advantages of simple reaction conditions,
convenient post-treatment, environmental friendliness, and
requiring no transition metal catalysis.
[0005] The present invention provides a method for synthesizing a
2-benzylidene tetrahydrothiophene derivative, which includes the
step of reacting a (cyclopropylethynyl) aromatic cyclic compound of
Formula (I) with a sulfur source in an organic solvent as a
reaction medium in air atmosphere at 100-200.degree. C. to obtain a
2-benzylidene tetrahydrothiophene derivative represented of Formula
(III). The reaction route is as follows:
##STR00002##
[0006] where Ar is selected from phenyl ring, a substituted phenyl
ring, biphenylyl, thiophenyl ring or naphthyl ring, in which the
substituent on the substituted phenyl ring is selected from the
group consisting of halo, trifluoromethyl, cyano, a
C.sub.1-C.sub.20 alkyl group and any combination thereof; and
[0007] R.sup.1 is selected from hydrogen or a C.sub.1-C.sub.20
alkyl group.
[0008] The wavy line in Formula (III) indicates that the product
has different configurations and can be a mixture of cis-trans
isomers, which contains both Z-configuration products and
E-configuration products, or contains only Z-configuration products
or E-configuration products.
[0009] Preferably, the alkyl group is a C.sub.1-05 group. More
preferably, the alkyl group is methyl.
[0010] More preferably, halo is chloro or bromo.
[0011] More preferably, Ar is a phenyl ring, and R.sup.1 is
hydrogen or methyl.
[0012] More preferably, Ar is selected from a substituted phenyl
ring, biphenylyl, thiophenyl ring or naphthyl ring, in which the
substituent on the substituted phenyl ring is selected from the
group consisting of halo, trifluoromethyl, cyano, a
C.sub.1-C.sub.20 alkyl group and any combination thereof; and
R.sup.1 is hydrogen. Preferably, the alkyl group is a
C.sub.1-C.sub.5 group. More preferably, the alkyl group is
methyl.
[0013] Preferably, the (cyclopropylethynyl) aromatic cyclic
compound of Formula (I) is (cyclopropylethynyl)benzene (1),
1-chloro-4-(cyclopropylethynyl)benzene (2),
1-bromo-4-(cyclopropylethynyl)benzene (3),
1-(cyclopropylethynyl)-4-(trifluoro-methyl)benzene (4),
1-(cyclopropylethynyl)-4-methylbenzene (5),
4-(cyclopropyl-ethynyl)benzonitrile (6),
1-chloro-2-(cyclopropylethynyl)benzene (7),
1-(cyclopropyl-ethynyl)-2-methylbenzene (8),
1-(cyclopropylethynyl)-3-methylbenzene (9),
1-chloro-3-(cyclopropylethynyl)benzene (10),
4-(cyclopropylethynyl)-1,1'-biphenyl (11),
1-(cyclopropylethynyl)naphthalene (12),
4-bromo-1-(cyclopropyl-ethynyl)-2-methylbenzene (13),
2-chloro-4-(cyclopropylethynyl)-1-methylbenzene (14),
3-(cyclopropylethynyl)thiophene (15), or
((1-methylcyclopropyl)ethynyl)-benzene (16). The specific
structural formulas of the compounds of Formula (I) corresponding
to the above numbers are as follows:
##STR00003## ##STR00004##
[0014] Preferably, the sulfur source is sodium sulfide and/or
potassium sulfide. Sodium sulfide is sodium sulfide nonahydrate or
anhydrous sodium sulfide, and potassium sulfide is anhydrous
potassium sulfide or hydrated potassium sulfide. Preferably, the
sulfur source is sodium sulfide nonahydrate (Na2S.9H.sub.2O).
[0015] Preferably, the molar ratio of the (cyclopropylethynyl)
aromatic cyclic compound to the sulfur source is 1:1-6.
[0016] Preferably, the organic solvent is selected from the group
consisting of N,N'-dimethyl formide (DMF), dimethyl sulfoxide
(DMSO) N,N'-dimethyl acetamide (DMA) and any combination thereof.
Preferably, the organic solvent is DMA.
[0017] Preferably, the ratio of the (cyclopropylethynyl) aromatic
cyclic compound and the organic solvent in units of mole and
milliliter, respectively is 0.3-1 mol:0.1-10 mL. Preferably, the
ratio of the (cyclopropylethynyl) aromatic cyclic compound to the
organic solvent is 0.3-1 mol:0.5-3 mL. More preferably, the ratio
of the (cyclopropylethynyl) aromatic cyclic compound to the organic
solvent is 0.5 mol:2.5 mL.
[0018] Preferably, the reaction time is 8-20 h. Preferably, the
reaction time is 9-11 hrs.
[0019] Preferably, the reaction temperature is 130-150.degree. C.
More preferably, the reaction temperature is 150.degree. C.
[0020] More preferably, the above synthesis method further
comprises column chromatography after the reaction is completed to
obtain the compound of Formula (III).
[0021] For example, if DMA is used as a solvent, the reaction
principle underlying the reaction involving
(cyclopropylethynyl)benzene (1a in the scheme shown below) and
sodium sulfide nonahydrate (2 in the scheme shown below) is as
follows:
##STR00005##
[0022] In the scheme, sodium sulfide nonahydrate 2 produces
negatively charged trisulfur radicals (S.sub.3.sup.-.) in situ in
the solvent DMA. Then the negatively charged trisulfur radicals
attack and open the three-membered ring in (cyclopropylethynyl)
benzene 1a, to produce an intermediate A having a carbon free
radical at the propargylic position and a negatively charged
trisulfur group. The carbon radical abstracts hydrogen in water to
produce an intermediate B. Then the negatively charged trisulfur
group undergoes homolysis of sulfur-sulfur bond, and the generated
new sulfur radical is added to the carbon-carbon triple bond in the
alkyne to produce an intermediate C. Then, the alkenyl radical
abstracts hydrogen in water to produce the product 3a that is
2-benzylidene tetrahydrothiophene. The water mentioned above comes
from the crystal water in the sulfur source or the trace water
contained in the organic solvent. The other (cyclopropylethynyl)
aromatic cyclic compounds involved in the present invention
participate in the reaction through a similar mechanism.
[0023] By virtue of the above solution, the present invention has
at least the following advantages.
[0024] In the present invention, a (cyclopropylethynyl) aromatic
cylic compound is used as a reaction raw material, cheap, readily
available, easy-to-operate, and low-toxic sodium sulfide or
potassium sulfate is directly used as a sulfur source, and DMA is
used as a solvent to prepare a 2-benzylidene tetrahydrothiophene
compound without metal catalysis.
[0025] Compared with the prior art, the present invention provides
a green, simple and efficient method for synthesizing a
2-benzylidene tetrahydrothiophene compound. The method has the
advantages of cheap and readily available raw materials, simple
reaction conditions, convenient post-treatment, requiring no metal
catalysis, high atom economy, and high yield, thus meeting the
requirements of green chemistry. The experimental results show that
the method provided in the present invention can be used to
synthesize 2-benzylidene tetrahydrothiophene compounds with a yield
of 36%-76%.
[0026] The above description is only an overview of the technical
solutions of the present invention. In order to illustrate the
technical means of the present invention more clearly and implement
the technical solutions in accordance with the specification, the
preferred embodiments of the invention are described hereinafter in
more detail.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The invention will be described in further detail with
reference to embodiments. The following examples are intended to
illustrate the present invention, instead of limit the scope of the
present invention.
[0028] In the following examples of the present invention, the
specific structural formula of the (cyclopropylethynyl) aromatic
cyclic compound corresponding to each number above is as
follows:
##STR00006## ##STR00007##
Example 1
Synthesis of 2-benzylidene tetrahydrothiophene
[0029] (Cyclopropylethynyl)benzene (compound corresponding to No.
(1), 0.0711 g, 0.5 mmol) and sodium sulfide nonahydrate (0.2402 g,
1.0 mmol) were weighed and fed to a 25 mL reaction tube. DMA (2.5
mL) was added as a solvent, and the reaction was performed under
stirring for 9 hrs at 150.degree. C. After the reaction, the
reaction solution was extracted with ethyl acetate and saturated
brine, dried over anhydrous sodium sulfate and filtered with
suction. The resulting filtrate was rotary evaporated to dryness,
the sample was loaded, and separated by column chromatography
(conditions: stationary phase 300-400-mesh silica gel powder, and
mobile phase petroleum ether) to afford a reaction product (0.0608
g).
[0030] The reaction product was characterized. The results are
shown below:
[0031] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.42 (d, J=7.3 Hz,
1H), 7.35-7.24 (m, 2H), 7.24-7.10 (m, 1H), 6.46 (s, 0.76.times.1H),
6.42 (t, J=1.9 Hz, 0.24.times.1H), 3.14 (t, J=6.4 Hz,
0.76.times.2H), 3.03 (t, J=6.4 Hz, 0.24.times.2H), 2.84-2.74 (m,
2H), 2.12-2.05 (m, 0.24.times.2H), 1.98 (p, J=6.6 Hz,
0.76.times.2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=145.6,
143.2, 138.4, 137.8, 128.3, 127.7, 127.7, 125.7, 125.7, 117.3,
117.1, 40.3, 35.7, 34.4, 33.0, 31.1, 28.4 ppm.
[0032] According to the characterization data, the prepared product
is 2-benzylidene tetrahydrothiophene (E/Z=24:76) (purity >95%);
and the yield of the product is calculated to be 69%.
Example 2
Synthesis of 2-(4-chlorobenzylidene)tetrahydrothiophene
[0033] 1-chloro-4-(cyclopropylethynyl)benzene (compound
corresponding to No. (2), 0.0883 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0759 g).
[0034] The reaction product was characterized. The results are
shown below:
[0035] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.40-7.31 (m, 2H),
7.31-7.25 (m, 2H), 6.41 (s, 0.95.times.1H), 6.36 (s,
0.05.times.1H), 3.19 (t, J=6.4 Hz, 0.95.times.2H), 3.07 (t, J=6.4
Hz, 0.05.times.2H), 2.80 (td, J=6.8, 1.5 Hz, 2H), 2.13 (p, J=6.6
Hz, 0.05.times.2H), 2.02 (p, J=6.6 Hz, 0.95.times.2H); .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta.=144.3, 136.4, 131.1, 128.9, 128.5,
115.9, 40.4, 35.8, 28.5 ppm.
[0036] According to the characterization data, the prepared product
is pure 2-(4-chlorobenzylidene) tetrahydrothiophene (E/Z=5:95)
(purity >95%); and the yield of the product is calculated to be
72%.
Example 3
Synthesis of 2-(4-bromobenzylidene)tetrahydrothiophene
[0037] 1-bromo-4-(cyclopropylethynyl)benzene (compound
corresponding to No. (3), 0.1105 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0842 g).
[0038] The reaction product was characterized. The results are
shown below:
[0039] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.48-7.38 (m),
7.32-7.27 (m), 7.12-7.04 (m), 6.41 (s, 0.77.times.1H), 6.36 (t,
J=2.0 Hz, 0.23.times.1H), 3.20 (t, J=6.4 Hz, 0.77.times.2H), 3.09
(t, J=6.4 Hz, 0.23.times.2H), 2.87-2.76 (m, 2H), 2.15 (p, J=6.6 Hz,
0.23.times.2H), 2.05 (p, J=6.6 Hz, 0.77.times.2H); .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta.=146.8, 144.5, 137.3, 136.8, 131.4,
131.4, 129.3, 129.2, 119.3, 119.2, 116.1, 116.0, 40.4, 35.9, 34.5,
33.1, 31.1, 28.5 ppm.
[0040] According to the characterization data, the prepared product
is pure 2-(4-bromobenzylidene) tetrahydrothiophene (E/Z=23:77)
(purity >95%); and the yield of the product is calculated to be
66%.
Example 4
Synthesis of
2-(4-(trifluoromethyl)benzylidene)tetrahydrothiophene
[0041] 1-(cyclopropylethynyl)-4-(trifluoromethyl)benzene (compound
corresponding to No. (4), 0.1051 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0831 g).
[0042] The reaction product was characterized. The results are
shown below:
[0043] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.62-7.46 (m),
7.28 (d, J=8.2 Hz), 6.49 (s, 0.7.times.1H), 6.44 (s, 0.3.times.1H),
3.21 (t, J=6.4 Hz, 0.7.times.2H), 3.08 (t, J=6.4 Hz, 0.3.times.2H),
2.91-2.76 (m, 2H), 2.15 (p, J=6.6 Hz, 0.3.times.2H), 2.04 (p, J=6.6
Hz, 0.7.times.2H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta.=149.2, 147.0, 141.8 (d, J=1.3 Hz), 141.4, 129.5, 129.2,
128.6, 127.7, 127.7, 127.5, 127.2 (d, J=32.1 Hz), 127.1, 126.8,
125.3 (q, J=7.5 Hz), 124.5 (d, J=270 Hz), 120.5, 115.9, 115.8,
40.6, 36.0, 34.7, 33.1, 31.2, 28.4 ppm.
[0044] According to the characterization data, the prepared product
is pure 2-(4-(trifluoromethyl)benzylidene) tetrahydrothiophene
(E/Z=30:70) (purity >95%); and the yield of the product is
calculated to be 68%.
Example 5
Synthesis of 2-(4-methylbenzylidene)tetrahydrothiophene
[0045] 1-(cyclopropylethynyl)-4-methylbenzene (compound
corresponding to No. (5), 0.0781 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0495 g).
[0046] The reaction product was characterized. The results are
shown below:
[0047] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.35 (d, J=8.1
Hz), 7.20-7.12 (m), 6.48 (s, 0.87.times.1H), 6.43 (t, J=2.0 Hz,
0.13.times.1H), 3.20 (t, J=6.4 Hz, 0.87.times.2H), 3.09 (t, J=6.4
Hz, 0.13.times.2H), 2.83 (td, J=6.8, 1.5 Hz, 2H), 2.35 (s, 2H),
2.15 (p, J=6.6 Hz, 0.13.times.2H), 2.05 (p, J=6.6 Hz,
0.87.times.2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=144.4,
142.0, 135.7, 135.4, 135.3, 135.1, 129.1, 127.66, 127.6, 117.2,
117.0, 40.2, 35.6, 34.3, 32.9, 31.1, 28.5, 21.3, 21.2 ppm.
[0048] According to the characterization data, the prepared product
is pure 2-(4-methylbenzylidene) tetrahydrothiophene (E/Z=13:87)
(purity >95%); and the yield of the product is calculated to be
52%.
Example 6
Synthesis of
(Z)-4-((dihydrothiophen-2(3H)-ylidene)methyl)benzamide
[0049] 4-(cyclopropylethynyl)benzonitrile (compound corresponding
to No. (6), 0.0836 g, 0.5 mmol) and sodium sulfide nonahydrate
(0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL reaction tube.
DMA (2.5 mL) was added as a solvent, and the reaction was performed
under stirring for 12 hrs at 150.degree. C. After the reaction, the
reaction solution was extracted with ethyl acetate and saturated
brine, dried over anhydrous sodium sulfate and filtered with
suction. The resulting filtrate was rotary evaporated to dryness,
the sample was loaded, and separated by column chromatography
(conditions: stationary phase 300-400-mesh silica gel powder, and
mobile phase petroleum ether) to afford a reaction product (0.0526
g).
[0050] The reaction product was characterized. The results are
shown below:
[0051] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=8.07-7.68 (m,
3H), 7.52-7.14 (m, 3H), 6.55 (s, 1H), 3.19 (s, 2H), 2.80 (s, 2H),
1.94 (s, 2H); .sup.13C NMR (100 MHz, DMSO) .delta.=167.6, 146.3,
140.3, 131.0, 127.7, 126.7, 115.7, 40.0, 35.4, 28.0 ppm.
[0052] According to the characterization data, the prepared product
is pure (Z)-4-((dihydrothiophen-2(3H)-ylidene)methyl)benzamide
(purity >95%); and the yield of the product is calculated to be
48%.
Example 7
Synthesis of (Z)-2-(2-chlorobenzylidene)tetrahydrothiophene
[0053] 1-chloro-2-(cyclopropylethynyl)benzene (compound
corresponding to No. (7), 0.0883 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0579 g).
[0054] The reaction product was characterized. The results are
shown below:
[0055] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.73 (dd, J=7.8,
1.4 Hz, 1H), 7.35 (dd, J=8.0, 1.2 Hz, 1H), 7.29-7.23 (m, 1H), 7.09
(td, J=7.7, 1.5 Hz, 1H), 6.76 (s, 1H), 3.18 (t, J=6.4 Hz, 2H), 2.87
(td, J=6.9, 1.6 Hz, 2H), 2.06 (p, J=6.6 Hz, 2H); .sup.13C NMR (100
MHz, CDCl.sub.3) .delta.=146.3, 135.8, 132.8, 129.5, 128.4, 127.0,
126.6, 113.3, 40.3, 35.4, 28.5 ppm.
[0056] According to the characterization data, the prepared product
is pure (Z)-2-(2-chlorobenzylidene) tetrahydrothiophene (purity
>95%); and the yield of the product is calculated to be 55%.
Example 8
Synthesis of 2-(2-methylbenzylidene)tetrahydrothiophene
[0057] 1-(cyclopropylethynyl)-2-methylbenzene (compound
corresponding to No. (8), 0.0781 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0647 g).
[0058] The reaction product was characterized. The results are
shown below:
[0059] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.59 (d, J=7.7
Hz), 7.26-7.01 (m), 6.52 (s, 0.82.times.1H), 6.44 (s,
0.18.times.1H), 3.09 (t, J=6.4 Hz, 0.82.times.2H), 3.05 (t, J=6.4
Hz, 0.18.times.2H), 2.79 (td, J=6.8, 1.6 Hz, 0.82.times.2H), 2.69
(td, J=6.8, 2.1 Hz, 0.18.times.2H), 2.28 (s, 0.82.times.3H), 2.25
(s, 0.18.times.3H), 2.02 (dp, J=19.9, 6.6 Hz, 2H); .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta.=145.2, 144.0, 137.5, 136.8, 135.7,
135.5, 123.0, 129.9, 128.1, 127.1, 126.2, 125.7, 125.6, 115.7,
114.6, 39.8, 34.9, 34.3, 33.1, 30.7, 28.6, 20.1 ppm.
[0060] According to the characterization data, the prepared product
is pure 2-(2-methylbenzylidene) tetrahydrothiophene (E/Z=18:82)
(purity >95%); and the yield of the product is calculated to be
68%.
Example 9
Synthesis of 2-(3-methylbenzylidene)tetrahydrothiophene
[0061] 1-(cyclopropylethynyl)-3-methylbenzene (compound
corresponding to No. (9), 0.0781 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0647 g).
[0062] The reaction product was characterized. The results are
shown below:
[0063] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.30-7.11 (m),
6.98 (dd, J=23.7, 7.3 Hz), 6.42 (s, 0.83.times.1H), 6.38 (s,
0.17.times.1H), 3.13 (t, J=6.4 Hz, 0.83.times.2H), 3.01 (t, J=6.4
Hz, 0.17.times.2H), 2.78 (dtd, J=8.4, 6.9, 1.8 Hz, 2H), 2.32 (d,
J=9.5 Hz, 3H), 2.11-2.03 (m, 0.17.times.2H), 1.97 (p, J=6.6 Hz,
0.83.times.2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=145.3,
142.9, 137.7, 137.7, 123.0, 128.5, 128.4, 128.3, 128.2, 127.4,
126.5, 126.4, 126.2, 124.7, 117.2, 117.1, 40.2, 35.6, 34.3, 32.8,
31.1, 28.4, 21.6, 21.4 ppm.
[0064] According to the characterization data, the prepared product
is pure 2-(3-methylbenzylidene) tetrahydrothiophene (E/Z=17:83)
(purity >95%); and the yield of the product is calculated to be
68%.
Example 10
Synthesis of 2-(3-chlorobenzylidene)tetrahydrothiophene
[0065] 1-chloro-3-(cyclopropylethynyl)benzene (compound
corresponding to No. (10), 0.0883 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0769 g).
[0066] The reaction product was characterized. The results are
shown below:
[0067] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.40 (d, J=1.6 Hz,
1H), 7.25 (dq, J=13.8, 7.9 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 6.41
(s, 0.92.times.1H), 6.36 (s, 0.08.times.1H), 3.20 (t, J=6.4 Hz,
0.92.times.2H), 3.08 (t, J=6.4 Hz, 0.08.times.2H), 2.83 (td, J=6.8,
1.4 Hz, 2H), 2.09 (dp, J=19.9, 6.6 Hz, 2H); .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta.=145.4, 139.7, 134.3, 129.6, 127.6, 125.7,
125.7, 115.8, 40.5, 35.9, 28.5 ppm.
[0068] According to the characterization data, the prepared product
is pure 2-(3-chlorobenzylidene) tetrahydrothiophene (E/Z=8:92)
(purity >95%); and the yield of the product is calculated to be
73%.
Example 11
2-([1,1'-biphenyl]-4-ylmethylidene)tetrahydrothiophene
[0069] 4-(cyclopropylethynyl)-1,1'-biphenyl (compound corresponding
to No. (11), 0.1091 g, 0.5 mmol) and sodium sulfide nonahydrate
(0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL reaction tube.
DMA (2.5 mL) was added as a solvent, and the reaction was performed
under stirring for 12 hrs at 150.degree. C. After the reaction, the
reaction solution was extracted with ethyl acetate and saturated
brine, dried over anhydrous sodium sulfate and filtered with
suction. The resulting filtrate was rotary evaporated to dryness,
the sample was loaded, and separated by column chromatography
(conditions: stationary phase 300-400-mesh silica gel powder, and
mobile phase petroleum ether) to afford a reaction product (0.0959
g).
[0070] The reaction product was characterized. The results are
shown below:
[0071] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.56 (ddd, J=25.3,
12.8, 4.8 Hz, 6H), 7.42 (t, J=7.7 Hz, 2H), 7.36-7.27 (m, 1H), 6.52
(s, 0.85.times.1H), 6.47 (s, 0.15.times.1H), 3.22 (t, J=6.4 Hz,
0.85.times.2H), 3.10 (t, J=6.4 Hz, 0.15.times.2H), 2.87 (dtd,
J=8.2, 6.9, 1.8 Hz, 2H), 2.17 (p, J=6.6 Hz, 0.15.times.2H), 2.06
(p, J=6.6 Hz, 0.85.times.2H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta.=145.9, 143.6, 141.0, 140.8, 138.3, 137.5, 137.0, 128.8,
128.1, 127.2, 127.1, 127.0, 127.0, 116.9, 116.7, 40.4, 35.8, 34.5,
33.0, 31.2, 28.5 ppm.
[0072] According to the characterization data, the prepared product
is pure 2-([1,1'-biphenyl]-4-ylmethylidene)tetrahydrothiophene
(E/Z=15:85) (purity >95%); and the yield of the product is
calculated to be 76%.
Example 12
Synthesis of 2-(naphthalen-1-ylmethylidene)tetrahydrothiophene
[0073] 1-(cyclopropylethynyl)naphthalene (compound corresponding to
No. (12), 0.0961 g, 0.5 mmol) and sodium sulfide nonahydrate
(0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL reaction tube.
DMA (2.5 mL) was added as a solvent, and the reaction was performed
under stirring for 12 hrs at 150.degree. C. After the reaction, the
reaction solution was extracted with ethyl acetate and saturated
brine, dried over anhydrous sodium sulfate and filtered with
suction. The resulting filtrate was rotary evaporated to dryness,
the sample was loaded, and separated by column chromatography
(conditions: stationary phase 300-400-mesh silica gel powder, and
mobile phase petroleum ether) to afford a reaction product (0.0679
g).
[0074] The reaction product was characterized. The results are
shown below:
[0075] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.98-7.87 (m, 1H),
7.71-7.60 (m, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.31 (dddd, J=14.0,
12.3, 7.2, 5.4 Hz, 3H), 6.91 (s, 0.76.times.1H), 6.81 (s,
0.24.times.1H), 2.92 (t, J=6.4 Hz, 2H), 2.70 (td, J=6.9, 1.6 Hz,
0.76.times.2H), 2.51 (td, J=6.8, 2.1 Hz, 0.24.times.2H), 1.91-1.77
(m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=146.9, 145.9,
135.6, 135.0, 133.7, 133.6, 131.6, 131.3, 128.5, 128.4, 126.7,
126.6, 125.8, 125.8, 125.7, 125.6, 125.6, 125.5, 125.3, 125.2,
124.7, 124.0, 114.4, 113.4, 39.6, 34.7, 34.6, 33.3, 30.5, 28.6
ppm.
[0076] According to the characterization data, the prepared product
is pure 2-(naphthalen-1-ylmethylidene) tetrahydrothiophene
(E/Z=24:76) (purity >95%); and the yield of the product is
calculated to be 60%.
Example 13
Synthesis of 2-(4-bromo-2-methylbenzylidene)tetrahydrothiophene
[0077] 4-bromo-1-(cyclopropylethynyl)-2-methylbenzene (compound
corresponding to No. (13), 0.1176 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0875 g).
[0078] The reaction product was characterized. The results are
shown below:
[0079] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.45 (d, J=8.3
Hz), 7.37-7.15 (m, 2H), 7.01 (d, J=8.1 Hz), 6.41 (s,
0.79.times.1H), 6.32 (s, 0.21.times.1H), 3.11 (t, J=6.4 Hz,
0.79.times.2H), 3.06 (t, J=6.4 Hz, 0.21.times.2H), 2.78 (td, J=6.8,
1.6 Hz, 0.79.times.2H), 2.64 (td, J=6.8, 2.1 Hz, 0.21.times.2H),
2.22 (d, J=9.9 Hz, 3H), 2.12-1.93 (m, 2H); .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta.=146.4, 145.1, 137.9, 137.7, 136.4, 135.8,
132.6, 132.6, 129.5, 128.7, 128.6, 128.5, 119.5, 119.4, 114.4,
113.5, 39.9, 35.1 34.3, 33.2, 30.7, 28.6, 19.9, 19.9 ppm.
[0080] According to the characterization data, the prepared product
is pure 2-(4-bromo-methylbenzylidene) tetrahydrothiophene
(E/Z=21:79) (purity >95%); and the yield of the product is
calculated to be 65%.
Example 14
Synthesis of
2-(3-chloro-4-methylbenzylidene)tetrahydrothiophene
[0081] 2-chloro-4-(cyclopropylethynyl)-1-methylbenzene (compound
corresponding to No. (14), 0.0953 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0641 g).
[0082] The reaction product was characterized. The results are
shown below:
[0083] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.39 (d, J=1.6
Hz), 7.24-7.08 (m, 2H), 6.96 (dd, J=7.9, 1.6 Hz), 6.35 (s,
0.86.times.1H), 6.31 (s, 0.14.times.1H), 3.15 (t, J=6.4 Hz,
0.86.times.2H), 3.04 (t, J=6.4 Hz, 0.14.times.2H), 2.77 (ddd,
J=8.3, 5.9, 2.5 Hz, 2H), 2.37-2.31 (m, 3H), 2.05 (dp, J=44.2, 6.7
Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=146.4, 144.1,
137.6, 137.2, 134.3, 134.2, 133.1, 133.0, 130.7, 128.0, 127.8,
126.0, 125.8, 115.7, 115.6, 40.2, 35.7, 34.4, 33.0, 31.1, 28.4,
19.8, 19.7 ppm.
[0084] According to the characterization data, the prepared product
is pure 2-(3-chloro-4-methylbenzylidene) tetrahydrothiophene
(E/Z=14:86) (purity >95%); and the yield of the product is
calculated to be 57%.
Example 15
Synthesis of 3-((dihydrothienyl-2(3H)-ylidene)methyl)thiophene
[0085] 3-(cyclopropylethynyl)thiophene (compound corresponding to
No. (15), 0.0741 g, 0.5 mmol) and sodium sulfide nonahydrate
(0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL reaction tube.
DMA (2.5 mL) was added as a solvent, and the reaction was performed
under stirring for 12 hrs at 150.degree. C. After the reaction, the
reaction solution was extracted with ethyl acetate and saturated
brine, dried over anhydrous sodium sulfate and filtered with
suction. The resulting filtrate was rotary evaporated to dryness,
the sample was loaded, and separated by column chromatography
(conditions: stationary phase 300-400-mesh silica gel powder, and
mobile phase petroleum ether) to afford a reaction product (0.0620
g).
[0086] The reaction product was characterized. The results are
shown below:
[0087] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.23 (ddd, J=7.5,
6.9, 4.3 Hz), 7.15 (dd, J=4.9, 1.3 Hz), 7.01 (dd, J=5.0, 1.2 Hz),
6.96 (d, J=2.7 Hz), 6.50 (s, 0.88.times.1H), 6.42 (t, J=1.9 Hz,
0.12.times.1H), 3.16 (t, J=6.4 Hz, 0.88.times.2H), 3.04 (t, J=6.4
Hz, 0.12.times.2H), 2.83-2.68 (m, 2H), 2.07 (dp, J=42.7, 6.7 Hz,
2H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=144.4, 142.6,
139.6, 139.3, 128.1, 127.8, 124.9, 124.8, 120.5, 120.0, 111.7,
111.4, 39.4, 35.5, 34.5, 33.3, 31.0, 28.9 ppm.
[0088] According to the characterization data, the prepared product
is pure 3-((dihydrothienyl-2(3H)-ylidene)methyl)thiophene
(E/Z=12:88) (purity >95%); and the yield of the product is
calculated to be 68%.
Example 16
Synthesis of (Z)-2-benzyl-3-methyltetrahydrothiophene
[0089] ((1-methylcyclopropyl)ethynyl)benzene (compound
corresponding to No. (16), 0.0781 g, 0.5 mmol) and sodium sulfide
nonahydrate (0.2402 g, 1.0 mmol) were weighed and fed to a 25 mL
reaction tube. DMA (2.5 mL) was added as a solvent, and the
reaction was performed under stirring for 12 hrs at 150.degree. C.
After the reaction, the reaction solution was extracted with ethyl
acetate and saturated brine, dried over anhydrous sodium sulfate
and filtered with suction. The resulting filtrate was rotary
evaporated to dryness, the sample was loaded, and separated by
column chromatography (conditions: stationary phase 300-400-mesh
silica gel powder, and mobile phase petroleum ether) to afford a
reaction product (0.0343 g).
[0090] The reaction product was characterized. The results are
shown below:
[0091] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.51 (d, J=7.5 Hz,
2H), 7.39 (t, J=7.7 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 6.42 (s, 1H),
3.24-3.09 (m, 2H), 2.98 (dd, J=13.3, 6.6 Hz, 1H), 2.22 (dq, J=11.9,
5.9 Hz, 1H), 1.75 (ddd, J=14.3, 12.4, 7.8 Hz, 1H), 1.32 (d, J=6.7
Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.=147.0, 137.4,
127.8, 127.4, 125.3, 115.9, 44.5, 35.9, 31.9, 18.4 ppm.
[0092] According to the characterization data, the prepared product
is pure (Z)-2-benzyl-3-methyltetrahydrothiophene (purity >95%);
and the yield of the product is calculated to be 36%.
[0093] While preferred embodiments of the present invention have
been described above, the present invention is not limited thereto.
It should be appreciated that some improvements and variations can
be made by those skilled in the art without departing from the
technical principles of the present invention, which are also
contemplated to be within the scope of the present invention.
* * * * *