Synthesis of fluorinated triazole and isoxazole derivatives by electrochemical fluorination

Article abstract of DOI:10.1016/j.tet.2016.07.016

Partially fluorinated triazole derivatives were synthesized through anodic fluorination of alkynes having arylthio group and following Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with benzyl azide. The other route toward the fluorinated triazoles,

Full text of DOI:10.1016/j.tet.2016.07.016

Tetrahedron xxx (2016) 1e7
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Synthesis of fluorinated triazole and isoxazole derivatives by
electrochemical fluorination
*
Shunsuke Kuribayashi, Naoki Shida, Shinsuke Inagi, Toshio Fuchigami
Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Partially fluorinated triazole derivatives were synthesized through anodic fluorination of alkynes having
arylthio group and following Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with benzyl azide. The
other route toward the fluorinated triazoles, namely the anodic fluorination of triazole derivatives once
prepared by advanced CuAAC of the alkyne and azide above was also investigated. It was shown that
these two routes are mutually complementary methodology for the synthesis of new mono- and di-
fluoromethyltriazole derivatives. Furthermore, Cu(I)-catalyzed isoxazole synthesis from fluorinated al-
kynes and imidoyl chloride was demonstrated.
Received 12 March 2016
Received in revised form 5 July 2016
Accepted 5 July 2016
Available online xxx
Keywords:
Electrochemical fluorination
Ó 2016 Elsevier Ltd. All rights reserved.
a
-Fluoroacethylene
Triazole
Isoxazole
Click chemistry
ꢀ
1. Introduction
Medebielle and his co-workers reported the synthesis and antiviral
properties of difluoromethylbenzoxazole pyrimidine thioether de-
Organofluorine compounds are highly useful in various fields
such as pharmaceutical chemistry and material science due to their
unique chemical, physical, and biological properties.1 Since almost
all organofluorine compounds are not naturally occurring, they
must be synthesized according to appropriate molecular design.
Recent development of synthetic technique of organofluorine
compounds is very noticeable. Among them, the anodic partial
fluorination proceeds through electrochemical oxidation of organic
compounds and following fluorination with fluoride ion used as
a supporting electrolyte. This electrochemical method does not
require any hazardous reagents, it is therefore regarded as a green
method.2 We have demonstrated the synthesis of partially fluori-
nated compounds having various functional groups for bioactive
applications and synthetic building blocks so far.3 Previously, we
reported the first electrochemical synthesis of a series of fluori-
nated terminal alkynes,4 which are potentially applicable as syn-
thetic building blocks in organic synthesis. One promising reaction
using terminal alkyne is Cu(I)-catalyzed azide-alkyne cycloaddition
rivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.7
In consideration to these facts, the combination of anodic fluori-
nation and CuAAC is of interest to develop versatile organofluorine
compounds having a triazole moiety. Our goal in this study is to
prepare a variety of fluorinated triazole derivatives from terminal
alkyne having arylthio group and benzyl azide through two path-
ways, i.e., anodic fluorination of alkynes, followed by CuAAC (Route
A) and anodic fluorination of triazoles once prepared by CuAAC
(Route B) as shown in Scheme 1. In addition, another kind of click
chemistry, the Cu(I)-catalyzed isoxazole synthesis8 was also in-
vestigated using fluorinated alkynes (Route C).
2. Results and discussion
According to Scheme 1, Route A, the electrochemical partial
fluorination of alkyne derivative 1 was carried out under optimized
conditions with a passage of constant current between Pt anode
and Pt cathode (Table 1).4 The fluorination of the starting materials
takes place through the anodic oxidation at the arylthio group,
(CuAAC). This so-called click chemistry can produce
a 1,4-
disubstituted triazole derivative in excellent yield without
byproduct under mild conditions.5 For example, Jørgensen and his
co-workers reported the synthesis of fluorinated triazoles by
CuAAC of propargyl fluoride and azide derivative.6 Recently,
followed by deprotonation and subsequent fluorination at its
a-
position. In general, sulfides having an electron-withdrawing group
undergo selective anodic fluorination with good efficiencies due to
the stabilization of once fluorinated products.9 We reported pre-
viously that an acetylene moiety attached to the a-carbon can act as
an electron-withdrawing group such as esters and nitriles evi-
* Corresponding author. Tel./fax: þ81 45 924 5407; e-mail address: fuchi@echem.
titech.ac.jp (T. Fuchigami).
denced by electrochemical measurements.4 In the case of
http://dx.doi.org/10.1016/j.tet.2016.07.016
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S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
Scheme 1. Routes toward triazoles and isoxazoles with fluoromethylsulfenyl group.
fluorination of 1a and 1b, mono-fluorinated products (2a and 2b)
and di-fluorinated products (3a and 3b) were obtained selectively
depending on the supporting HF salt used and electricity. The free
triethylamine contained in Et3N-3HF effectively acted as a base at
the deprotonation step for difluorination even though the sacrificial
oxidation of triethylamine itself also occurred. Other mono-
fluorinated products (2ce2g) were also successfully obtained un-
der optimal conditions including the choice of supporting HF salts.
These fluorinated alkynes were readily available for CuAAC. As in-
dicated in our previous study, mono-fluorinated products 2a and
Table 1
Electrochemical fluorination of alkyne derivative 1
Entry
1
Alkyne 1
Supporting salt
Et3N-5HF
Electricity (F/mol)
4.0
Product
Yield (%)a
77b,c
2
3
Et3N-3HF
Et3N-5HF
8.0
4.0
70c
35
4
Et3N-3HF
8.0
66c
5
6
Et3N-3HF
12.0
10.0
55d
20d
Et4NF-3HF
7
Et3N-3HF
12.0
30d
8
9
Et4NF-4HF
Et4NF-4HF
7.0
8.0
38
42
a
Isolated yield.
b
c
Determined by 19F NMR.
Ref. 4a.
d
Ref. 4b.
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S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
3
Table 3
CuAAC of alkyne 1
2b were relatively unstable to be easily transformed to fluo-
roallenes under basic conditions; therefore, they were used for
further reactions immediately after purification.
The CuAAC of the obtained mono-fluorinated alkynes
(2ae2g) and di-fluorinated alkynes (3a and 3b) was carried out
with benzyl azide in the presence of CuSO4, sodium ascorbate
and benzoic acid in t-BuOH/H2O (1/2) according to the condi-
tions reported (Table 2).10 The CuAAC of di-fluorinated sub-
strates 3a and 3b afforded the corresponding 1,4-disubstituted
triazole products 6a and 6b in high yields (Entries 2 and 4).
Among the mono-fluorinated substrates, the CuAAC of 2ae2c
and benzyl azide did not proceed at all accompanying the for-
mation of unidentified defluorinated products owing to the in-
stability of 2a and 2b. Although 2c seemed to be stable due to
the electron-withdrawing 2-pyrimidyl group, the desired prod-
uct was not formed. On the other hand, substrates 2de2g were
successfully transformed to desired products 5de5g in good to
excellent yields, respectively. In contrast to 2a and 2c, the het-
erocyclic groups of 2de2g are electron-withdrawing to suppress
the defluorination, therefore CuAAC seemed to proceed
smoothly without defluorination. Thus, the two-step reactions
containing electrochemical fluorination and the following
CuAAC (Scheme 1, Route A) gave partially fluorinated triazole
derivatives.
Entry
Alkyne
Product
Yield (%)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
85
82
97
94
53
89
99
1g
4g
a
Isolated yield.
for comparison (Table 4). The anodic fluorination of 4a and 4b did
not yield any fluorinated products after a passage of 4 F/mol of
charge in the presence of Et3N-5HF. Instead, a byproduct, aldehyde
7 was obtained in moderate yield (Entries 1 and 3). Interestingly,
when Et3N-3HF was used as fluorine source and supporting salt,
(Entries 2 and 4), di-fluorinated products 6a and 6b were obtained
as a main product However, aldehyde 7 was also detected even
under these conditions. Other substrates (4ce4g) were treated
under optimized conditions for the case of mono-fluorination of
the corresponding alkynes as shown in Table 1, and resulted in
producing mono-fluorinated products 5ce5g, together with the
formation of aldehyde 7. Although the CuAAC of 2c and benzyl
azide did not give the corresponding 5c at all in Route A (Table 2,
Entry 5), the anodic fluorination of 4c afforded mono-fluorinated
triazole 5c in moderate yield in Route B (Table 4, Entry 5).
Table 2
CuAAC of fluorinated alkyne 2 and 3
Finally, the fluorinated alkynes (2 and 3) were utilized for an-
other click chemistry, namely the Cu(I)-catalyzed cyclization with
a nitrile oxide derived from an imidoyl chloride8 to produce iso-
xazoles 8 and 9 as shown in Route C, Scheme 1. As summarized in
Table 5, each fluorinated alkyne successfully gave the isoxazole
derivatives in moderate yields except for the case of Entry 1, in
which undesired defluorination of substrate 2a mainly occurred
owing to the instability of 2a. In Entry 4, the alkyne having the
pyrimidylthio group (2c) underwent the cyclization in 35% yield
different from the case of CuAAC.
Entry
Fluorinated alkyne
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
2a
3a
2b
3b
2c
2d
2e
2f
5a
6a
5b
6b
5c
5d
5e
5f
0b
80
0b
90
0b
80
98
71
96
2g
5g
a
Isolated yield.
b
Unidentified defluorinated products were mostly formed.
3. Conclusion
We have synthesized various fluorinated compounds by com-
bining the CuAAC and electrochemical fluorination. Through Route
A, the partially fluorinated alkynes underwent the CuAAC with
benzyl azide to give the fluorinated triazole products. In Route B,
anodic fluorination of the triazole substrates was successfully
demonstrated to give the desired products; however the consid-
erable amount of the byproduct was also detected. We found that
the partially fluorinated triazole derivatives could be obtained from
alkynes and benzyl azide by appropriate choice of the Routes. The
partially fluorinated alkynes also reacted with imidoyl chloride in
the presence of Cu(I) as a catalyst to afford the corresponding
partially fluorinated isoxazoles.
The Route B shown in Scheme 1 contains the CuAAC of substrate
1 and benzyl azide to form 1,4-disubsituted triazoles 4, and sub-
sequent anodic fluorination of 4. As expected, the CuAAC of 1ae1g
with benzyl azide successfully afforded the corresponding triazoles
4ae4g in good yields under optimized conditions (Table 3).
The second step of Route B, the anodic fluorination of triazoles 4,
was performed in a similar manner to the fluorination step in Route
A. The triazole moiety seems to work as a weak electron-
withdrawing group similarly to alkyne moiety, which is advanta-
geous for the anodic fluorination of the substrates. In order to es-
timate the oxidation behavior of substrate 4, density functional
theory (DFT) calculation for 4a was carried out.11 The highest oc-
cupied molecular orbital (HOMO) of 4a was located mainly on the
phenylthio moiety, not on the benzyl moiety, indicating the ex-
clusive oxidation at the phenylthio moiety. Consequently the fol-
4. Experimental
4.1. General
lowing deprotonation and fluorination can take place at the
a-
position of the phenylthio group. We then investigated the anodic
fluorination of triazoles 4 under the same conditions with that of 1
1H, 13C, and 19F NMR spectra were recorded on JEOL JNM EX-270
(1H: 270 MHz, 13C: 67.8 MHz, 19F: 254 MHz) spectrometer in CDCl3.
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4
S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
Table 4
Electrochemical fluorination of 1,2,3-triazole derivative 4
Entry
Substrate
Supporting salt
Electricity (F/mol)
Yield of 5 (%)a
Yield of 6 (%)a
Yield of 7 (%)b
Total yield (%)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4d
4e
4f
Et3N-5HF
Et3N-3HF
Et3N-5HF
Et3N-3HF
Et3N-3HF
Et4NF-3HF
Et3N-3HF
Et4NF-4HF
Et4NF-4HF
4.0
8.0
4.0
8.0
12.0
10.0
12.0
7.0
d
d
35
d
53c
d
d
d
d
d
47c
24
48c
17
13
51
18
32
52
47
59
48
70
74
73
82
87
82
d
d
d
61c
22
64c
55c
30
4g
8.0
a
Determined by 19F NMR.
Determined by 1H NMR.
Isolated yield.
b
c
Table 5
Cu(I)-Catalyzed synthesis of 3,5-substituted isoxazole 8 and 9
Entry
1
Substrate
Product
Yield (%)a
0b
2a
2
3
3a
3b
35
40
4
2c
35
5
6
2d
2e
38
56
7
8
2f
35
72
2g
a
Isolated yield.
b
Unidentified defluorinated product was mostly detected.
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S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
5
The chemical shifts for 1H, 13C, and 19F NMR spectra were given in
(ppm) from internal TMS, CDCl3, and monofluorobenzene
HRMS(EI): m/z [Mþ] calcd for C11H7FN2OS: 234.0263; Found:
234.0259.
d
(ꢀ36.5 ppm), respectively. EI mass spectra were recorded on Shi-
madzu GCeMS-QP5050A mass spectrometer. Cyclic voltammetry
measurements were carried out using ALS 600A Electrochemical
Analyzer. The preparative electrolysis was performed using Met-
ronix Corp. constant current power supply model 5944 monitored
with coulomb/ampere hour meter HF-201. High resolution mass
spectra (HRMS) were recorded on JEOL The MStaion JMS-700.
Melting point was determined using Yanako Micro Melting Point
Apparatus MP-500P. Molecular orbital were obtained using
Gaussian 03W calculated by DFT B3LYP/6-31Gþ(2d,p)//B3LYP/6-
31G(d).11
4.4. Typical procedure for CuAAC
To a stirred solution of alkyne 1a (0.5 mmol) and benzyl azide
(1.1 equiv) in t-BuOH/H2O (1/2, 3.0 ml) was added CuSO4$5H2O
(0.01 equiv), sodium ascorbate (0.02 equiv) and benzoic acid
(0.1 equiv), and the reaction mixture was stirred for 20 min at room
temperature. Dichloromethane (10 ml) was added to the mixture
and the organic phase was washed with water and brine. The or-
ganic phase was dried over Na2SO4 and concentrated under re-
duced pressure. The product triazole was further purified by
column chromatography over silica gel using a mixed solution of
EtOAc and hexane as an eluent.
4.2. Materials
4.4.1. 1-Benzyl-4-((phenylthio)methyl)-1H-1,2,3-triazole
All chemicals were obtained commercially and were used
without further purification. Dry solvents were used as received.
Alkynes 1ae1g were synthesized according to the literature.4 The
known compounds 1ae1e were characterized by comparison with
spectral data in the literature.4
(4a). White solid. Mp¼74.8e75.8 ꢁC. 1H NMR (270 MHz, CDCl3):
d
7.36e7.16 (m, 11H), 5.45 (s, 2H), 4.20 (s, 2H). 13C NMR (68 MHz,
CDCl3):
d 144.7, 135.0, 134.4, 129.3, 128.6, 128.5, 128.2, 127.4, 126.1,
121.9, 53.5, 28.5. HRMS(FAB): m/z [MþHþ] calcd for C16H16N3S:
282.1065; Found: 282.1074.
4.2.1. 2-Methyl-5-(prop-2-yn-1-ylthio)-1,3,4-thiadiazole (1f). Dark
4.4.2. 1-Benzyl-4-(((4-chlorophenyl)thio)methyl)-1H-1,2,3-triazole
brown oil. 1H NMR (270 MHz, CDCl3):
d
4.04 (d, J¼2.7 Hz, 2H), 2.75
(4b). White solid. Mp¼93.6e95.0 ꢁC. 1H NMR (270 MHz, CDCl3):
(s, 3H), 2.34 (t, J¼2.7 Hz, 1H). 13C NMR (68 MHz, CDCl3):
d 165.4,
d
7.38e7.33 (m, 3H), 7.22e7.15 (m, 7H), 5.45 (s, 2H), 4.17 (s, 2H). 13
C
162.9, 77.6, 72.5, 21.0. HRMS(EI): m/z [Mþ] calcd for C6H6N2S2:
NMR (68 MHz, CDCl3):
128.6, 128.2, 127.4, 121.8, 53.5, 28.6. HRMS(EI): m/z [Mþ] calcd for
16H14ClN3S: 315.0597; Found: 315.0596.
d 144.3, 134.3, 133.4, 132.0, 130.8, 128.6,
169.9972; Found: 169.9977.
C
4.2.2. 2-Phenyl-5-(prop-2-yn-1-ylthio)-1,3,4-oxadiazole (1g). White
solid. Mp¼45.4e46.4 ꢁC. 1H NMR (270 MHz, CDCl3):
d 8.03e8.00
4.4.3. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)thio)pyrimidine
(4c). Pale yellow oil. 1H NMR (270 MHz, CDCl3):
(m, 2H), 7.57e7.46 (m, 3H), 4.07 (d, J¼2.7 Hz, 2H), 2.35 (t, J¼2.7, 1H).
d
8.50 (d, J¼4.6 Hz,
13C NMR (68 MHz, CDCl3):
d 166.1, 162.4, 131.7, 129.0, 126.6, 123.3,
2H), 7.45 (s, 1H), 7.36e7.34 (m, 3H), 7.24e7.21 (m, 2H), 6.97 (t,
76.5, 72.9. HRMS(EI): m/z [Mþ] calcd for C11H8N2OS: 216.0357;
J¼4.9 Hz, 1H), 5.48 (s, 2H), 4.48 (s, 2H). 13C NMR (68 MHz, CDCl3):
Found: 216.0359.
d
170.6, 156.7, 144.3, 134.2, 128.3, 127.9, 127.3, 122.1, 116.3, 53.3, 25.0.
HRMS(EI): m/z [Mþ] calcd for C14H13N5S: 283.0892; Found:
4.3. Typical procedure for anodic fluorination
283.0890.
Anodic oxidation of 1a (1.0 mmol) was carried out in an un-
divided cell equipped with a platinum plate anode (2ꢂ2 cm2) and
a platinum cathode (2ꢂ2 cm2) in a solution of dimethoxyethane
(DME) (10 ml) containing 1 M HF salt at room temperature. A
constant current (5.0 mA/cm2) was passed until the starting ma-
terial 1a was mostly consumed (monitored by TLC). After the
electrolysis, the electrolytic solution was passed through a short
column filled with silica gel using EtOAc as an eluent to remove the
HF salt. The fluorinated product was further purified by column
chromatography over silica gel using a mixed solution of EtOAc and
hexane as an eluent. Fluorinated products, 2ae2e, 3a, 3b were
identified by comparison with 19F NMR and MS spectral data of
their authentic samples.
4.4.4. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)thio)benzo[d]
thiazole (4d). White solid. Mp¼104.0e105.0 ꢁC. 1H NMR (270 MHz,
CDCl3):
d
7.83 (d, J¼7.6 Hz, 1H), 7.75 (d, J¼7.8 Hz, 1H), 7.53 (s, 1H),
7.42e7.39 (m, 1H), 7.33e7.31 (m, 4H), 7.22e7.18 (m, 2H), 5.47 (s,
2H), 4.66 (s, 2H). 13C NMR (68 MHz, CDCl3):
d
165.4, 152.6, 143.7,
135.1, 134.2, 128.7, 128.3, 127.6, 125.8, 124.1, 122.7, 121.1, 120.8, 53.7,
27.5. HRMS(EI): m/z [Mþ] calcd for C17H14N4S2: 338.0660; Found:
338.0650.
4.4.5. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)thio)-5-
chlorobenzo[d]thiazole (4e). White solid. Mp¼139.8e140.9 ꢁC. 1H
NMR (270 MHz, CDCl3):
d
7.78 (d, J¼1.9 Hz, 1H), 7.64 (d, J¼8.4 Hz,
1H), 7.51 (s, 1H), 7.35e7.20 (m, 6H), 5.48 (s, 2H), 4.65 (s, 2H). 13C
NMR (68 MHz, CDCl3): 167.9, 153.6, 143.8, 134.3, 133.6, 132.0,
d
4.3.1. 2-((1-Fluoroprop-2-yn-1-yl)thio)-5-methyl-1,3,4-thiadiazole
129.0, 128.7, 127.9, 124.6, 123.0, 121.6, 121.2, 54.1, 27.7. HRMS(EI): m/
(2f). Pale yellow oil. 1H NMR (270 MHz, CDCl3):
d
6.79 (dd, J¼52.7,
z [Mþ] calcd for C17H13ClN4S2: 372.0270; Found: 372.0280.
2.2 Hz, 1H), 3.10 (dd, J¼4.9, 2.2 Hz, 1H), 2.81 (s, 3H). 13C NMR
(68 MHz, CDCl3):
d
168.4, 158.8 (d, J¼3.4 Hz), 85.2 (d, J¼222.5 Hz),
4.4.6. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)thio)-5-methyl-
81.3 (d, J¼7.8 Hz), 74.8 (d, J¼29.6 Hz), 15.8. 19F NMR (254 MHz,
1,3,4-thiadiazole (4f). Pale brown solid. Mp¼80.7e81.5 ꢁC. 1H NMR
CDCl3):
d
ꢀ66.0 (dd, J¼53.6, 5.6 Hz). HRMS(EI): m/z [Mþ] calcd for
(270 MHz, CDCl3): d 7.60 (s, 1H), 7.37e7.34 (m, 3H), 7.25e7.23 (m,
C6H5FN2S2: 187.9878; Found: 187.9879.
2H), 5.48 (s, 2H), 4.59 (s, 2H), 2.71 (s, 3H). 13C NMR (68 MHz, CDCl3):
d
164.9, 163.9, 142.9, 134.1, 128.4, 128.0, 127.3, 122.8, 53.4, 27.6, 15.1.
4.3.2. 2-((1-Fluoroprop-2-yn-1-yl)thio)-5-phenyl-1,3,4-oxadiazole
HRMS(EI): m/z [Mþ] calcd for C13H13N5S2: 303.0612; Found:
(2g). Pale yellow oil. 1H NMR (270 MHz, CDCl3):
d
8.05e8.03 (m,
2H), 7.57e7.49 (m, 3H), 6.90 (dd, J¼52.7, 1.9 Hz, 1H), 3.14 (dd, J¼4.6,
1.9 Hz, 1H). 13C NMR (68 MHz, CDCl3):
167.0, 159.0, 132.2, 129.2,
303.0606.
d
4.4.7. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)thio)-5-phenyl-
126.9, 123.1, 84.4 (d, J¼225.2 Hz), 81.75 (d, J¼7.8 Hz), 74.52 (d,
1,3,4-oxadiazole (4g). White solid. Mp¼106.0e108.9 ꢁC. 1H NMR
J¼29.0 Hz). 19F NMR (254 MHz, CDCl3):
d
ꢀ65.6 (dd, J¼51.8, 5.6 Hz).
(270 MHz, CDCl3): d 8.00e7.96 (m, 2H), 7.70 (s, 1H), 7.52e7.47 (m,
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S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
3H), 7.36e7.33 (m, 3H), 7.26e7.23 (m, 2H), 5.49 (s, 2H), 4.58 (s, 2H).
13C NMR (68 MHz, CDCl3):
165.6, 163.4, 142.9, 134.2, 131.4, 128.7,
128.3, 127.6, 126.2, 123.0, 53.8, 26.7. HRMS(EI): m/z [Mþ] calcd for
18H15N5OS: 349.0997; Found: 349.0993.
(270 MHz, CDCl3):
d 7.58 (s, 1H), 7.52e7.48 (m, 2H), 7.40e7.38 (m,
d
3H), 7.30e7.13 (m, 4H), 5.52 (s, 2H). 13C NMR (68 MHz, CDCl3):
d
143.6 (t, J¼31.5 Hz), 137.7, 136.7, 134.3, 133.6, 129.2, 129.0, 128.1,
C
124.7 (t, J¼1.6 Hz), 122.4 (t, J¼2.2 Hz), 54.3. 19F NMR (254 MHz,
CDCl3):
d
8.2 (s). HRMS(EI): m/z [Mþ] calcd for C16H12ClF2N3S:
4.5. Synthesis of fluorinated triazoles
351.0409; Found: 351.0404.
The second step in Route A and Route B was performed by
CuAAC and anodic fluorination, respectively.
4.5.8. 1-Benzyl-1H-1,2,3-triazole-4-carbaldehyde (7). This com-
pound was identified by comparison with 1H NMR spectral data of
its authentic sample.12
4.5.1. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)fluoromethyl)thio)pyrimi-
dine (5c). 1H NMR (270 MHz, CDCl3):
d
8.62 (d, J¼4.9 Hz, 2H), 7.95
4.6. Typical procedure for isoxazole synthesis
(dd, J¼51.6, 0.5 Hz, 1H), 7.68 (s, 1H), 7.42e7.38 (m, 3H), 7.33e7.27
(m, 2H), 7.11 (t, J¼4.9 Hz,1H), 5.57 (s, 2H). 13C NMR (68 MHz, CDCl3):
To a stirred solution of alkyne 2c (0.5 mmol) and imidoyl chlo-
ride8 (1.1 equiv) in t-BuOH/H2O (1/1, 3.0 ml) was added
CuSO4$5H2O (0.02 equiv), sodium ascorbate (0.1 equiv) and KHCO3
(4.3 equiv), and the reaction mixture was stirred for 15 h at room
temperature. Dichloromethane (10 ml) was added to the mixture
and the organic phase was washed with water and brine. The or-
ganic phase was dried over Na2SO4 and concentrated under re-
duced pressure. The product isoxazole was further purified by
column chromatography over silica gel using a mixed solution of
EtOAc and hexane as an eluent.
d
185.1, 157.8, 129.4, 129.3, 129.0, 128.4, 128.3, 122.3 (d, J¼1.6 Hz),
118.0, 90.4 (d, J¼214.7 Hz), 54.5. 19F NMR (254 MHz, CDCl3):
ꢀ70.5
d
(d, J¼51.8 Hz). HRMS(EI): m/z [Mþ] calcd for C14H12FN5S: 301.0797;
Found: 301.0795.
4.5.2. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)fluoromethyl)thio)benzo
[d]thiazole (5d). White solid. Mp¼117.2e120.8 ꢁC. 1H NMR
(270 MHz, CDCl3):
d 8.00e7.97 (m, 1H), 7.83e7.81 (m, 1H), 7.77 (d,
J¼52.9 Hz, 1H), 7.66 (s, 1H), 7.51e7.45 (m, 1H), 7.41e7.26 (m, 6H),
5.56 (s, 2H). 13C NMR (68 MHz, CDCl3):
d
152.8, 143.5, 143.1, 135.9,
133.8, 129.3, 129.1, 128.2, 126.4, 125.1, 122.5, 122.4 (d, J¼2.2 Hz),
4.6.1. 5-(Fluoro(pyrimidin-2-ylthio)methyl)-3-phenylisoxazole
121.2, 91.8 (d, J¼220.8 Hz), 54.5. 19F NMR (254 MHz, CDCl3):
d
ꢀ66.7
(8c). 1H NMR (270 MHz, CDCl3):
d
8.64 (d, J¼4.9 Hz, 2H), 7.98
(d, J¼53.6 Hz). HRMS(EI): m/z [Mþ] calcd for C17H13FN4S2:
(dd, J¼50.0, 0.8 Hz, 1H), 7.84e7.80 (m, 2H), 7.48e7.46 (m, 3H),
356.0566; Found: 356.0569.
7.15 (t, J¼4.9 Hz, 1H), 6.86 (s, 1H). 13C NMR (68 MHz, CDCl3):
d
167.52 (d, J¼2.8 Hz), 165.86 (d, J¼29.6 Hz), 162.5 (d, J¼1.7 Hz),
4.5.3. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)fluoromethyl)thio)-5-
chlorobenzo[d]thiazole (5e). Pale brown solid. Mp¼110.0e111.2 ꢁC.
157.9, 157.4, 130.3, 128.9, 126.8, 118.3, 101.9 (d, J¼1.7 Hz), 88.8 (d,
J¼218.6 Hz). 19F NMR (254 MHz, CDCl3):
d
ꢀ77.5 (d, J¼50.0 Hz).
1H NMR (270 MHz, CDCl3):
d
7.96e7.28 (m, 10H), 5.57 (s, 2H). 13
C
HRMS(EI): m/z [Mþ] calcd for C14H10FN3OS: 287.0529; Found:
NMR (68 MHz, CDCl3):
d
153.6, 134.0, 133.7, 132.5, 129.3, 129.1,
287.0521.
128.6, 128.3, 126.4, 125.6, 122.4, 122.4, 121.8, 91.6 (d, J¼221.4 Hz),
54.6. 19F NMR (254 MHz, CDCl3):
d
ꢀ67.0 (d, J¼51.8 Hz). HRMS(EI):
4.6.2. 5-((Benzo[d]thiazol-2-ylthio)fluoromethyl)-3-phenylisoxazole
(8d). Pale yellow solid. Mp¼88.3e90.2 ꢁC. 1H NMR (270 MHz,
m/z [Mþ] calcd for C17H12ClFN4S2: 390.0176; Found: 390.0186.
CDCl3):
NMR (68 MHz, CDCl3):
d
8.03e7.75 (m, 5H), 7.53e7.37 (m, 5H), 6.86 (s, 1H). 13C
4.5.4. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)fluoromethyl)thio)-5-
methyl-1,3,4-thiadiazole (5f). Pale yellow solid. Mp¼107.8e108.3 ꢁC.
d
165.1 (d, J¼27.3 Hz), 162.6, 159.8, 152.6,
136.0, 131.7, 130.2, 129.3, 128.4, 127.9, 125.8, 122.4, 120.1, 102.2 (d,
1H NMR (270 MHz, CDCl3):
d
7.70 (s, 1H), 7.54e7.27 (m, 6H), 5.56 (s,
J¼175.7 Hz), 91.8 (d, J¼162.3 Hz). 19F NMR (254 MHz, CDCl3):
2H), 2.76 (s, 3H). 13C NMR (68 MHz, CDCl3):
d
167.6, 160.0, 142.8 (d,
d
ꢀ74.0 (d, J¼51.8 Hz). HRMS(EI): m/z [Mþ] calcd for C17H11FN2OS2:
J¼26.2 Hz), 133.8, 129.2, 129.0, 128.2, 122.5 (d, J¼1.6 Hz), 91.9 (d,
342.0297; Found: 342.0298.
J¼222.4 Hz), 54.5, 15.7. 19F NMR (254 MHz, CDCl3):
d
ꢀ66.8 (d,
J¼53.6 Hz). HRMS(EI): m/z [Mþ] calcd for C13H12FN5S2: 321.0518;
4.6.3. 5-(((5-Chlorobenzo[d]thiazol-2-yl)thio)fluoromethyl)-3-
phenylisoxazole (8e). White solid. Mp¼106.5e107.5 ꢁC. 1H NMR
Found: 321.0510.
(270 MHz, CDCl3):
d 8.00e7.73 (m, 4H), 7.50e7.36 (m, 5H), 6.87 (s,
4.5.5. 2-(((1-Benzyl-1H-1,2,3-triazol-4-yl)fluoromethyl)thio)-5-
phenyl-1,3,4-oxadiazole (5g). Pale yellow solid. Mp¼87.9e88.9 ꢁC.
1H). 13C NMR (68 MHz, CDCl3):
d
165.2, 164.7, 162.4 (d, J¼37.4 Hz),
153.4,134.1,132.8,130.6,129.1,127.9,126.9,125.9,122.5,120.8,102.3
1H NMR (270 MHz, CDCl3):
d
8.02e7.99 (m, 2H), 7.79 (s, 1H),
(d, J¼1.1 Hz), 89.9 (d, J¼225.8 Hz). 19F NMR (254 MHz, CDCl3):
7.70e7.46 (m, 4H), 7.38e7.28 (m, 5H), 5.57 (s, 2H). 13C NMR
(68 MHz, CDCl3): 166.5, 163.4, 142.9, 133.7, 132.0, 129.1, 129.0,
128.9, 128.1, 126.7, 123.0, 122.7 (d, J¼1.7 Hz), 90.9 (d, J¼224.7 Hz),
d
ꢀ74.5 (d, J¼49.8 Hz). HRMS(EI): m/z [Mþ] calcd for
d
C
17H10ClFN2OS2: 375.9907; Found: 375.9917.
54.4. 19F NMR (254 MHz, CDCl3):
d
ꢀ66.4 (d, J¼51.8 Hz).
4.6.4. 5-(Fluoro((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-3-
HRMS(EI): m/z [Mþ] calcd for C18H15FN5OS: 368.0981; Found:
phenylisoxazole (8f). Yellow solid. Mp¼45.0e45.6 ꢁC. 1H NMR
368.0989.
(270 MHz, CDCl3): d C
7.82e7.41 (m, 6H), 6.82 (s, 1H), 2.80 (s, 3H). 13
NMR (68 MHz, CDCl3):
d
168.2, 164.7 (d, J¼29.0 Hz), 162.6, 158.5,
4.5.6. 1-Benzyl-4-(difluoro(phenylthio)methyl)-1H-1,2,3-triazole
(6a). White solid. Mp¼96.7e97.2 ꢁC. 1H NMR (270 MHz, CDCl3):
130.6, 129.0, 127.9, 126.9, 102.4, 90.2 (d, J¼226.9 Hz), 15.8. 19F NMR
(254 MHz, CDCl3):
d
ꢀ74.7 (d, J¼49.8 Hz). HRMS(EI): m/z [Mþ] calcd
d
7.61e7.59 (m, 2H), 7.51 (s, 1H), 7.41e7.38 (m, 3H), 7.35e7.21 (m,
for C13H10FN3OS2: 307.0249; Found: 307.0243.
5H), 5.53 (s, 2H). 13C NMR (68 MHz, CDCl3):
d
143.9 (t, J¼31.3 Hz),
136.5, 133.7, 130.0, 129.2, 129.0, 128.1, 126.3 (t, J¼1.7 Hz), 122.4 (t,
4.6.5. 2-((Fluoro(3-phenylisoxazol-5-yl)methyl)thio)-5-phenyl-1,3,4-
J¼2.2 Hz), 54.3. 19F NMR (254 MHz, CDCl3):
d
8.2 (s). HRMS(EI): m/z
oxadiazole (8g). Brown paste. 1H NMR (270 MHz, CDCl3):
[Mþ] calcd for C16H13F2N3S: 317.0798; Found: 317.0798.
d
8.02e8.00 (m, 2H), 7.80e7.77 (m, 2H), 7.70e7.45 (m, 7H), 6.88 (s,
1H). 13C NMR (68 MHz, CDCl3):
d
167.0, 164.4 (d, J¼7.8 Hz), 162.6 (d,
4.5.7. 1-Benzyl-4-(((4-chlorophenyl)thio)difluoromethyl)-1H-1,2,3-
triazole (6b). Pale yellow solid. Mp¼95.1e97.7 ꢁC. 1H NMR
J¼1.2 Hz), 158.9, 131.7, 130.2, 128.3, 127.9, 127.6, 126.1, 125.6, 122.8,
102.5 (d, J¼174.5 Hz), 90.7 (d, J¼230.3 Hz). 19F NMR (254 MHz,
Please cite this article in press as: Kuribayashi, S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.016

S. Kuribayashi et al. / Tetrahedron xxx (2016) 1e7
7
20; (g) Fuchigami, T.; Inagi, S. In Fundamentals and Applications of Organic
Electrochemistry; Fuchigami, T., Ed.; Wiley: West Sussex, 2015, Chapter 5.
3. (a) Fuchigami, T.; Narizuka, S.; Konno, A. J. Org. Chem. 1992, 57, 3755e3757; (b)
Tajima, T.; Nakajima, A.; Fuchigami, T. J. Org. Chem. 2004, 69, 1276e1282; (c)
Suzuki, K.; Fuchigami, T. J. Org. Chem. 2005, 70, 9614e9617; (d) Yin, B.; Inagi, S.;
Fuchigami, T. Synlett 2011, 1313e1317.
CDCl3):
d
ꢀ74.6 (d, J¼49.8 Hz). HRMS(EI): m/z [Mþ] calcd for
C
18H12FN3O2S: 353.0634; Found: 353.0642.
4.6.6. 5-(Difluoro(phenylthio)methyl)-3-phenylisoxazole
(9a). White solid. Mp¼65.7e67.1 ꢁC. 1H NMR (270 MHz, CDCl3):
4. (a) Riyadh, S. M.; Ishii, H.; Fuchigami, T. Tetrahedron 2002, 58, 5877e5883; (b)
Riyadh, S. M.; Ishii, H.; Fuchigami, T. Tetrahedron 2001, 57, 8817e8821.
5. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596e2599.
d
7.77e7.73 (m, 2H), 7.62e7.59 (m, 2H), 7.47e7.34 (m, 6H), 6.69 (s,
1H). 13C NMR (68 MHz, CDCl3):
d
164.1 (t, J¼35.1 Hz), 162.3, 136.8,
130.7,130.6,129.3,129.0,127.8,126.8,125.1 (t, J¼2.2 Hz),121.5,102.5
~
6. Jiang, H.; Falcicchio, A.; Jensen, K. J.; Paixao, M. W.; Bertelsen, S.; Jørgensen, K. A.
(t, J¼1.7 Hz). 19F NMR (254 MHz, CDCl3):
d 3.8 (s). HRMS(EI): m/z
J. Am. Chem. Soc. 2009, 131, 7153e7157.
[Mþ] calcd for C16H11F2N4OS: 303.0529; Found: 303.0531.
ꢀ
7. Boyer, J.; Arnoult, E.; Medebielle, M.; Guillemont, J.; Unge, J.; Jochmans, D. J.
Med. Chem. 2011, 54, 7974e7985.
8. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210e216.
4.6.7. 5-(((4-Chlorophenyl)thio)difluoromethyl)-3-phenylisoxazole
(9b). Pale yellow solid. Mp¼73.5e75.7 ꢁC. 1H NMR (270 MHz,
9. (a) Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J. Org. Chem. 1990, 55,
6074e6075; (b) Fuchigami, T.; Shimojo, M.; Konno, A. J. Org. Chem. 1995, 60,
3459e3464.
10. Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. J. Org. Chem. 2010, 75,
7002e7005.
CDCl3):
NMR (68 MHz, CDCl3):
138.0, 137.5, 130.7, 129.6, 128.6, 127.7, 126.9, 123.4 (t, J¼2.2 Hz),
d
7.78e7.75 (m, 2H), 7.56e7.34 (m, 7H), 6.73 (s, 1H). 13C
d
163.9 (t, J¼35.1 Hz), 162.4 (t, J¼1.1 Hz),
121.2, 102.6. 19F NMR (254 MHz, CDCl3):
d 3.9 (s). HRMS(EI): m/z
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Re-
vision E.01; Gaussian: Wallingford, CT, 2004.
[Mþ] calcd for C16H10ClF2N4OS: 337.0140; Found: 337.0144.
References and notes
1. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouvermeur, V. Chem. Soc. Rev. 2008, 37,
320e330; (b) Boschet, F.; Ameduri, B. Chem. Rev. 2014, 114, 927e980.
2. (a) Childs, W. V.; Christensen, L.; Klink, F. W.; Kolpin, C. F. In Organic Electro-
chemistry, 3rd ed.; Lund, H., Baizer, M. M., Eds.; Marcel Dekker: New York, 1991,
Chapter 24; (b) Fuchigami, T. In Organic Electrochemistry, 4th ed.; Lund, H.,
Hammerich, O., Eds.; Marcel Dekker: New York, 2001, Chapter 25; (c) Noel, M.;
Suryanarayanan, V. J. Appl. Electrochem. 2004, 34, 357e369; (d) Dawood, K. M.
Tetrahedron 2004, 60, 1435e1451; (e) Fuchigami, T.; Inagi, S. Chem. Commun.
2011, 10211e10223; (f) Fuchigami, T.; Inagi, S. In Organic Electrochemistry, 5th
ed.; Hammerich, O., Speiser, B., Eds.; CRC Press: Boca Raton, FL, 2015, Chapter
12. Chan, T. R.; Fokin, V. V. QSAR Comb. Sci. 2007, 26, 1274e1279.
Please cite this article in press as: Kuribayashi, S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.016