Syntheses of trifluoroethylated unsymmetrical 1,3-diynes by using 1,1-dichloro-2,2,2-trifluoroethane

Article abstract of DOI:10.1016/j.tetlet.2016.11.015

Copper-mediated reaction of terminal 1,3-diynes with 1,1-dichloro-2,2,2-trifluoroethane (CF₃CHCl₂) using ethanolamine as ligand gave trifluoroethylated unsymmetrical 1,3-diynes in moderate to good yields. The reaction were carried out under mild conditions, and were easy to operate. Aryl groups with weak electron-withdrawing group or electron-donating group, and alkyl substitutents at terminal 1,3-diynes were tolerated. Synthesis of a trifluoroethylated conjugated triyne by using this method was demonstrated. Further transformation of the trifluoroethylated unsymmetrical 1,3-diyne to provide trifluoroethyl-substituted 1,2,3-triazole and isoxazole as application examples were successfully realized.

Full text of DOI:10.1016/j.tetlet.2016.11.015

Accepted Manuscript
Syntheses of Trifluoroethylated Unsymmetrical 1,3-Diynes by Using 1,1-Di-
chloro-2,2,2-trifluoroethane
Jian Zheng, Qing-Yun Chen, Ke Sun, Yangen Huang, Yong Guo
PII:
S0040-4039(16)31471-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.015
TETL 48301
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2016
1 November 2016
4 November 2016
Please cite this article as: Zheng, J., Chen, Q-Y., Sun, K., Huang, Y., Guo, Y., Syntheses of Trifluoroethylated
Unsymmetrical 1,3-Diynes by Using 1,1-Dichloro-2,2,2-trifluoroethane, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.11.015
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Syntheses of Trifluoroethylated Unsymmetrical 1,3-Diynes by
Using 1,1-Dichloro-2,2,2-trifluoroethane
Jian Zhenga, Qing-Yun Chen b,*, Ke Sunc, Yangen Huang a,*, Yong Guo b,*
a
College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, 2999 North Renmin Road, Shanghai 201620, P. R. of China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
of China
c
State Key Laboratory of the Discovery and Development of Novel Pesticide,
Shenyang Sinochem Agrochemicals R&D Ltd., Shenyang 110021, P. R. of China
Email address: hyg@dhu.edu.cn, chenqy@sioc.ac.cn and yguo@sioc.ac.cn
Abstract:
Copper-mediated
reaction
of
terminal
1,3-diynes
with
1,1-dichloro-2,2,2-trifluoroethane (CF3CHCl2) using ethanolamine as ligand gave
trifluoroethylated unsymmetrical 1,3-diynes in moderate to good yields. The reaction
were carried out under mild conditions, and were easy to operate. Aryl groups with
weak electron-withdrawing group or electron-donating group, and alkyl substitutents
at terminal 1,3-diynes were tolerated. Synthesis of a trifluoroethylated conjugated
triyne by using this method was demonstrated. Further transformation of the
trifluoroethylated unsymmetrical 1,3-diyne to provide trifluoroethyl-substituted
1,2,3-triazole and isoxazole as application examples were successfully realized.
Keywords: Trifluoroethylation, Unsymmetrical 1,3-diynes, Copper, Heterocycle,
Cross-coupling

Introduction
The incorporation of trifluoroethyl moieties into organic molecules has captured the
attention of synthetic chemists recently.1-16 The presence of fluorinated functional
groups profoundly modify the physicochemical and biological properties of an
organic compounds, and the steric, electronic, lipophilic, and metabolic characteristics
of the compounds often changes significantly and commonly positive.17-22 In recent
years, trifluoroethyl-containing aromatic compounds have found an increasing
number of applications in the fields of medicinal chemistry and biochemistry.23 Many
trifluoroethyl-containing compounds with biological activities, such as antimalarial
activity, hypolipidemic activity, anesthetic property, anti-inflammatory activity and
enzyme inhibition ability have been developed (Fig 1).24-27 Although fluorinated
organic molecules have a great prospect, few natural organic fluorides have been
found so far. The development of efficient synthetic methods for fluorinated organic
compounds becomes essentially important for building a fluorinated realm as an
abundant screening resource of medicinal and biological research.
Fig 1. Some trifluoroethylated compounds with biological activities
Unsymmetrical 1,3-diynes have various potential applications in non-linear
optical materials, liquid crystal materials and molecular devices.28 In recent years,
they were also found in natural products and some of them have antibacterial,

anti-HIV or anticancer ability.29-32 Simultaneously, unsymmetrical 1,3-diynes are
important building blocks for polyynes in organic synthesis,33 and were more often
applied as the synthetic precursor for various heterocyclic compounds.34 Methods for
the syntheses of unsymmetrical diynes, are thus of great importance.
Typical ways of making conjugate diynes include Glaser-Hay coupling and
Cadiot−Chodkiewicz coupling.35 Cu-salt mediated Glaser coupling and related
modified methods are still widely applied in the syntheses of conjugated diynes. In
addition to the Cu-salt the scientists found that Pd, Ni or Au-catalysis is also effective
for syntheses of the unsymmetrical 1,3-diynes.32,36,37 In 2015, Rao’s group38 realized
CuI-catalyzed reaction of 1,1-dibromoalkene and terminal alkynes to provide
unsymmetrically substituted 1,3-diynes in a one-pot process. Methods to syntheses of
unsymmetrical diynes by using terminal 1,3-diynes are few, because the terminal
1,3-diynes are unstable and easily undergo polymerization.39 In 2012, Ma’s group
synthesized unsymmetrical diynes by using trifluoroethyl diazo compound prepared
in situ as the trifluoroethylating reagent. 40 But preparation and utilization of explosive
trifluoroethyl diazo compound required high caution in operation. In 2015, we
developed a copper promoted method to synthesize trifluoroethylated alkynes by
using 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).41 HCFC-123 is used as
refrigerant, centrifugal chiller, blowing agent, fire-extinguishing agent or detergent in
industry. However, HCFC-123 is an ozone-depleting toxic substance, and will cause
hepatitis. The research on the conversion of HCFC-123 to valuable materials will
definitely important for developing an environmentally benign process for industrial
utilization of bulk hydrochlorofluorocarbon. We herein provide this kind of
convenient approach for the syntheses of versatile trifluoroethylated unsymmetrical
1,3-diynes by taking the advantage of HCFC-123.

Results and discussion
We began our investigation with biphenyl-1,3-diacetylene (1a) as the model
substrate. Initially, according to our previous result,41 a general solvent
1,2-dichloroethane (DCE) was selected as the solvent, and activated copper and
19
diethylamine were used (Table 1, entry 1). To our delight, a new F NMR signal at
-65.9 ppm (t, J = 9.4 Hz) was found in 7% yield. Considering the effect of amines in
solvent, different amines were screened in order to improve the yield. A 10% 19F
NMR yield of expected product was observed when the secondary amines
dipropylamine was added, but no product was found when diisopropylamine was used
(Table 1, entries 2 and 3). The desired product was not detected in the presence of
tertiary amines, such as triethylamine, and pyridine (Table 1, entries 4 and 5). Then
primary amines were examined in order to improve the yield of 3a. Fortunately, the
desired product was obtained in 24% yield when ethylenediamine was added (Table 1,
entry 8) although aniline and β-alanine were noneffective (Table 1, entries 6 and 7).
The yield was further increased to 45% and 58%, respectively, when benzylamine and
N-ethylenediamine was used (Table 1, entries 9 and 10). Propylamine and butylamine
afforded the desired product in the same yield of 65% (Table 1, entries 11 and 12).
The highest yield of the desired product (83%) was achieved when ethanolamine was
used as the additive (Table 1, entry 13). Then a series of solvents including CH3CN,
CCl4, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetone and
tetrahydrofuran (THF) were screened and proved to be noneffective. Benzene, toluene
and CH3NO2 were found to be less effective than DCE (Table 1, entries 14-16).

Table 1 Screening of the Optimal Reaction Conditionsa
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Cu (0.4 mmol), amine (0.6 mmol) and solvent
(2 mL) at 75 oC in a Schlenk tube under a nitrogen atmosphere for 8 h.
b The yields was determined by 19F NMR with benzotrifluoride as an internal standard.
With the optimized reaction conditions in hand, we next investigated the substrate
scope of this reaction (Table 2). We found that various terminal 1,3-diynes (Table 2,
entries 1-10) could be transformed to the corresponding products in moderate to good
yields. 1,3-Diyne 1 with a methoxy substituent in the para position reacted smoothly
to give product 3b in 71% yield (Table 2, entry 2). When the methoxyl group was in
the ortho and meta position, the yield of 3c and 3d was slightly decreased to 58% and
50%, respectively (Table 2, entries 3 and 4). Halogen atoms on the aromatic ring of
1,3-diyne including fluoro, chloro and bromo were all well tolerated in the
copper-mediated reaction, which provided the possibility for further functionalization
(Table 2, entries 8-10). Naphthyl substituted 1,3-diyne was also a good substrate and
gave product 3k in 73% yield (Table 2, entry 11 ). 1,3-Diynes with aliphatic

substituent such as alkyl group and alkenyl group were also suitable substrates for the
reaction condition to afford the corresponding trifluoroethylated products 3l-3n in
moderated yields (40%-58%)(Table 2, entries 12-14).
Table 2 Syntheses of Unsymmetrical Conjugated 1,3-Diynesa
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cu (0.4 mmol), ethanolamine (0.6 mmol) and
DCE (2 mL) at 75 oC in a Schlenk tube under a nitrogen atmosphere for 8 h.
b Isolated yields.

In order to test the generality of the developed approach for synthesizing
trifluoroethylated unsymmetrical conjugated alkynes, a 1,3,5-triyne 4 was synthesized
and subjected to the trifluoroethylation reaction (Scheme 1). Under the standard
reaction conditions, the desired product 5 was obtained in yields of 50%.
Scheme 1. Synthesis of trifluoroethylated conjugated 1,3,5-triyne 5
To further demonstrated the synthetic potential of the prepared trifluoroethylated
1,3-diynes, two cycloaddition reactions to provide trifluoroethyl-substituted isoxazole
and 1,2,3-triazole were conducted (Scheme 2). Isoxazole derivatives represent an
interesting structural motif found in natural compounds and their analogs, including
prostanoids, antibiotics, antitumor substances, vitamins, nucleosides, and alkaloids.42
The reaction of 1,3-diyne 3a with hydroxyamine readily gave isoxazole 7 in 51%
yield (Scheme 2, eq. a). In 2015, we reported a methodology for the syntheses of
fluorinated 1,4,5-substituted 1,2,3-triazoles.43 Heterocycles which containing a
1,2,3-triazole ring possess anti-HIV, anticancer, antifungal, antituberculosis, or
antibacterial activity and are also used in material science.43,44 Introducing the
trifluoroethyl group to 1,2,3-triazole would generate good candidates for drug,
agrochemical, material discovery. The Ruthenium(II)-catalyzed cycloaddition
reaction of 1,3-diyne 3a with azide 6 underwent smoothly to furnish 1,4,5-substituted
1,2,3-triazole 8 in 61% yield (Scheme 2, eq. b ). The structure of 8 is unambiguously
determined by single crystal X-ray analysis (Fig 2).

Scheme 2. Synthetic transformation of trifluoroethylated 1,3-diyne 3a
Fig 2 Single-crystal X-ray structure of triazole 8
Conclusion
In summary, we have successfully developed a Cu-mediated syntheses of a series
of the unsymmetrical trifluoroethylated 1,3-diynes by using
hydrochlorofluorocarbon (1,1-dichloro-2,2,2-trifluoroethane, HCFC-123) as
a
a
trifluoroethylating reagent. The reactions were carried out under mild reaction
conditions. All the reagents used in the reactions, such as Cu and ethanolamine, were
inexpensive. These trifluoroethylated unsymmetrical 1,3-diynes can be used as
versatile building blocks for the syntheses of trifluoroethyl-substituted 1,2,3-triazoles
and isoxazoles.
Acknowledgment
Support of our work by National Basic Research Program of China (973 Program)
(No. 2012CB821600), National Natural Science Foundation of China (Nos. 21421002,
21032006, 21172241), the Innovation Program of Shanghai Municipal Education
Commission (No. 13ZZ047) is gratefully acknowledged.

Supplementary data
Supplementary data associated with this article can be found, in the online version,
at
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Highlights
(1) A hydrochlorofluorocarbon (HCFC) is used to synthesize 2,2,2-trifluoroethyl
diynes.
(2) The C-C bond formation is promoted by copper and ethanolamine.
(3) Two examples of converting the diynes to heterocycles are demonstrated.

Graphic Abstract

Entry
1
Amine
Diethylamine
Dipropylamine
Diisopropylamine
Triethylamine
Pyridine
Solvent
DCE
DCE
DCE
DCE
Yield(%)b
7
2
3
4
5
10
<5
<5
<5
<5
<5
24
45
58
65
65
DCE
6
7
8
9
10
11
12
13
14
15
16
Aniline
β-Alanine
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Ethylenediamine
Benzylamine
N-Ethylethylenediamine
Propylamine
Butylamine
Ethanolamine
Ethanolamine
Ethanolamine
Ethanolamine
DCE
83
35
64
50
Benzene
Toluene
CH3NO2

Entry
1
Products
Yield(%)b
75
3a
3b
2
71
3
4
58
50
3c
3d
5
6
53
60
3e
3f
7
8
64
50
70
62
73
3g
3h
3i
9
10
11
3j
3k

12
13
14
58
45
40
3l
3m
3n