Regioselective Synthesis of 2,4-Diaryl-6-trifluoromethylated Pyridines through Copper-Catalyzed Cyclization of CF3-Ynones and Vinyl Azides

Article abstract of DOI:10.1021/acs.joc.1c00275

A novel copper-catalyzed cyclization of readily available vinyl azides with CF3-ynones is steadily achieved under mild conditions to furnish the versatile 2,4-diaryl-6-trifluoromethylated pyridine products, which are of great interest in medicinal chemistry. The generation of the vinyl iminophosphorane intermediates from vinyl azides through the Staudinger-Meyer reaction ensures the subsequent 1,4-addition process with CF3-ynones in this transformation.

Full text of DOI:10.1021/acs.joc.1c00275

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Article
Regioselective Synthesis of 2,4-Diaryl-6-trifluoromethylated
Pyridines through Copper-Catalyzed Cyclization of CF3‑Ynones and
Vinyl Azides
Jixin Wang, Da Ba, Mengqi Yang, Guolin Cheng,* and Lianhui Wang*
Cite This: J. Org. Chem. 2021, 86, 6423−6432
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ABSTRACT: A novel copper-catalyzed cyclization of readily
available vinyl azides with CF3-ynones is steadily achieved under
mild conditions to furnish the versatile 2,4-diaryl-6-trifluoromethy-
lated pyridine products, which are of great interest in medicinal
chemistry. The generation of the vinyl iminophosphorane
intermediates from vinyl azides through the Staudinger−Meyer
reaction ensures the subsequent 1,4-addition process with CF3-
ynones in this transformation.
synthetic utility has been limited to some extent because of
the requirement of an excess amount of prefunctionalized
nitrogen substrates, using expensive trifluoromethylating
reagents, low activity, as well as difficulty in controlling
regioselectivity. Meanwhile, a notable alternative is based on
the use of easily available trifluoromethylated building blocks.9
However, the site-selective construction of 2-trifluoromethyl-
pyridines, especially 2,4-diaryl-6-trifluoromethylated pyridines,
through trifluoromethyl building blocks is still challenging and
is therefore rarely reported. To the best of our knowledge, the
direct access to 2,4-diphenyl-6-trifluoromethylpyridine thus far
has only arose from the work of Funabiki and co-workers10 via
the cyclization of α,β-unsaturated trifluoromethyl ketone with
enamine in the presence of NH4OAc in triglyme at reflux
temperature, however, in only 13% yield (Scheme 1b).
Consequently, the exploration of general and concise method-
ologies for constructing more diverse 2,4-diaryl-6-trifluorome-
thylated pyridines with an easily available trifluoromethylated
framework remains highly appealing.11 Within this context,
CF3-ynones have been shown to be prominent building blocks
for the preparation of various fluorinated heterocyclic
compounds.12 More recently, Hu and co-workers reported
the synthesis of polysubstituted trifluoromethylpyridines from
CF3-ynones by the Bohlmann−Rahtz heteroannulation reac-
tion,13 in which enamines bearing β-ester and ketone moieties
served as the suitable coupling partner.12a In recent years, the
divergent modes of reactivity of vinyl azides, which occur due
INTRODUCTION
■
The trifluoromethyl group plays an important role in medicinal
chemistry and materials science.1 When the CF3 moiety is
introduced into molecule compounds, it often enhances
efficacy by promoting electrostatic interactions with targets,
improving cellular membrane permeability as well as increasing
robustness toward oxidative metabolism of the drug.2 On the
other hand, pyridine is not only one of the most important and
high priority nitrogen-containing heterocycles widely distrib-
uted in natural and synthetic biologically active molecules but
also an important intermediate in agrochemical and
pharmaceutical industries.3 Moreover, pyridine derivatives are
versatile precursors of various topoisomerase I inhibitors and
potential anticancer agents.4 Notably, the pyridine skeletons
bearing trifluoromethyl motifs, such as 2-trifluoromethylated
pyridines, have emerged as core units in an increasing number
of valuable drugs and agrochemicals (Figure 1).5
Figure 1. Representative 2-trifluoromethylpyridines of biological
interest.
In recent years, the development of methodologies for the 2-
trifluoromethylpyridine synthesis has aroused great interest
among researchers.6 Among them, the common route was to
incorporate the trifluoromethyl moiety into the 2-position on
the pyridine frameworks through a transition-metal-catalyzed
cross-coupling reaction7 and the more recently direct C−H
trifluoromethylation process (Scheme 1a).8 However, the
Received: February 3, 2021
Published: April 27, 2021
https://doi.org/10.1021/acs.joc.1c00275
© 2021 American Chemical Society
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Scheme 1. Synthetic Protocols of 2-Trifluoromethylpyridines
a
Table 1. Screenings of Various Reaction Parameters
b
c
entry
catalyst
CuI
CuI
AgOTf
AuCl3
Zn(OTf)2
Cu(OTf)2
Cu(OAc)2
CuBr
CuCl2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
additive
base
solvent
3aa (%)
3aa/3′aa
1
2
3
4
5
6
7
8
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PhMe
0
34
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PMe3
PCy3
L1
10:1
10:1
trace
25
trace
trace
38
22
27
42
trace
trace
25
trace
0
32
trace
20
39
31
trace
trace
trace
51
10:1
10:1
10:1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
10:1
10:1
L2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
triisopropylamine
DABCO
DIPEA
10:1
12:1
12:1
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
MeCN
DMF
EtOH
DCM
DMSO/PhMe (2:1)
11:1
10:1
10:1
10:1
10:1
DMSO/PhMe (1:1)
DMSO/PhMe (1:2)
DMSO
60
49
40
55
d
27
28
d
DMSO/PhMe (1:1)
a
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (10 mol %), additive (0.4 mmol), and PMDETA (0.4 mmol) in solvent (1 mL) at room
b
c
d
temperature under air for 12 h. Isolated yields. The ratio was determined by crude 1H NMR. Under N2 atmosphere. PMDETA =
pentamethyldiethylenetriamine; L1 = 3-(2-furyl)phosphine; L2 = trinaphthylphosphate; DIPEA = N,N-diisopropylethylamine.
to their distinct azide-appended olefin motif, have been
explored in various cyclization reactions for the construction
of versatile nitrogen-containing heterocyclic compounds.14 As
a continuation of our ongoing interest in versatile nitrogen-
containing heterocyclic constructions,15 we herein disclose a
novel copper-catalyzed cyclization of readily available vinyl
azides with CF3-ynones under mild reaction conditions.
Notably, the generation of vinyl iminophosphorane inter-
mediates from vinyl azides by making use of the Staudinger−
Meyer reaction16 ensures the steady 1,4-addition with CF3-
ynones and leads to the versatile 2,4-diaryl-6-trifluoromethy-
lated pyridines, which are of great interest in medicinal
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a
chemistry (Scheme 1c). Moreover, a similar strategy, but with
a different regiochemical outcome, was used to produce 2-
hydroxypryidines through the reaction of cyano-enamine with
unsaturated esters (alkynes) by Cushman and co-workers.4
Scheme 2. Scope of CF3-Ynones 1
RESULTS AND DISCUSSION
■
We initiated our investigation on the model reaction of 1,1,1-
trifluoro-4-phenylbut-3-yn-2-one (1a) and (1-azidovinyl)-
benzene (2a) to optimize various parameters, and the
experimental results are summarized in Table 1.17 Initially,
no reaction was observed in the presence of CuI as the catalyst
and PMDETA as the base in DMSO (Table 1, entry 1).
Further investigation showed that the cyclizing 2,4-diaryl-6-
trifluoromethylated pyridine product 3aa was smoothly
achieved in 34% isolated yield by loading PPh3 as the additive
in the reaction system, indicating the vinyl iminophosphorane
intermediate from vinyl azides through the Staudinger−Meyer
process was probably involved in the transformation (Table 1,
entry 2).16 Simultaneously, the 1,2-addition process was
observed in this transformation, delivering 3′aa as the side
product (3aa/3′aa = 10:1). To improve the catalytic efficiency,
various metal salts, such as AgOTf, AuCl3, Zn(OTf)2,
Cu(OTf)2, Cu(OAc)2, CuBr, CuCl2, and CuBr2, were
examined as potential catalysts, and CuBr2 gave the best
performance, leading to 3aa in 42% yield (Table 1, entries 2−
10). In view of the importance of the phosphine additive in
this transformation, we further evaluated various nucleophilic
and sterically hindered phosphines, and PPh3 exhibited the
highest activity, giving 42% yield of the cyclizing product 3aa
(Table 1, entries 10−14). Moreover, the exploration of
different bases revealed that PMDETA provided the best
yield of 42% (Table 1, entry 10 vs entries 15−18). A brief
examination of the organic solvents including DCM, EtOH,
PhMe, THF, MeCN, and DMSO indicated that polar aprotic
solvent DMSO performed better than others, affording 3aa in a
yield of 42% (Table 1, entries 19−23). To our delight, further
investigations showed that the presence of cosolvent could
efficiently promote the conversion, and the target product 3aa
improved to 60% yield in DMSO and PhMe at 1:1 (v/v)
(Table 1, entries 24−27). Finally, the yield of 3aa showed no
further improvement by either increasing or decreasing the
reaction temperature, even when prolonging the reaction time
to 24 h (see Table S7 in the Supporting Information). It
should be noted also that the yields of 3aa did not further
increase under inert reaction conditions compared with that
under air conditions (entry 27 vs 10; entry 28 vs 25). Thus, the
optimized reaction conditions were identified as follows: 1a
(0.3 mmol), 2a (0.2 mmol), CuBr2 (10 mol %), PPh3 (2.0
equiv), and PMDETA (2.0 equiv) in DMSO and PhMe (1:1,
v/v) (1 mL) at room temperature under air for 12 h (entry
25).
a
Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), CuBr2 (0.02
mmol), PPh3 (0.4 mmol), and PMDETA (0.4 mmol) in DMSO/
PhMe (1 mL, 1:1, v/v) at room temperature under air for 12 h. Yields
of isolated products.
was loaded under the standard catalytic reaction conditions;
however, no cyclization product was obtained. Moreover, the
structure of compound 3da was unambiguously confirmed by
X-ray single-crystal diffraction.
Next, we evaluated the scope and limitation of vinyl azides 2
for this transformation (Scheme 3). In general, vinyl azides 2
bearing electron-rich moieties other than electron-deficient
ones could accelerate the conversion more efficiently. More-
over, substrate 2j with an ortho-fluoro substituent led to the
corresponding cyclization product 3aj in 43% yield. Moreover,
the 1,4-addition transformation of CF3-ynone 1a with chloro-
substituted vinyl azides 2e, 2f, and 2i could steadily deliver the
corresponding 2,4-diaryl-6-trifluoromethylpyridine products
3ae, 3af, and 3ai, which might allow for the late-stage
modifications through transition-metal-catalyzed couplings. To
our disappointment, however, α-phenethyl- and butyl-sub-
stituted vinyl azides failed to participate in the cyclization
reaction, and no target products were detected under the
standard reaction conditions. It is noteworthy that a good
chemoselectivity of all the above-mentioned transformations
was observed (1,4-addition products 3/1,2-addition products
3′ > 10:1).
With the optimal conditions in hand, we investigated the
reaction of (1-azidovinyl)benzene (2a) with a variety of CF3-
ynones 1. As shown in Scheme 2, substrates bearing both
electron-donating and -withdrawing moieties on the phenyl
ring proceeded smoothly, delivering the 1,4-addition products
3 in moderate yields. Various functional groups, such as
methyl, methoxyl, trifluoromethyl, and halogen were well-
tolerated in the transformation. Notably, thienyl-substituted
CF3-ynone 1l reacted with (1-azidovinyl)benzene (2a) as well,
steadily generating the pyridine product 3la, which could be
expected to find further applications in organic electronics.18
Moreover, 1,1,1-trifluoro-4-(triisopropylsilyl)but-3-yn-2-one
Moreover, a scale-up experiment was performed to showcase
the synthetic utility of this novel methodology. Thus, a scale of
7.0 mmol (1-azidovinyl)benzene (2a) reacted smoothly with
1,1,1-trifluoro-4-phenylbut-3-yn-2-one (1a) and provided the
target product 3aa in 40% yield under the standard reaction
conditions (Scheme 4).
Moreover, preliminary control studies were conducted to
obtain more insight into the reaction mechanism (Scheme 5).
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a
formation. Moreover, the combination of acetophenone and
NH4OAc (7) instead of (1-azidovinyl)benzene 2a was used as
the coupling partner, whereas the desired product 3aa was not
formed, indicating the uniqueness of the present synthetic
protocol compared with those in previous reports (Scheme
5a).12a,19 Moreover, the reaction of CF3-ynone 1a and vinyl
azide 2a in situ generated the Staudinger−Meyer product A,
which could be further applied in place of 2a and PPh3 under
the standard reaction conditions, generating the target product
3aa in 45% yield, indicating that the aza-Wittig cyclization
process could also be possible in this transformation (Scheme
5b).16g Moreover, intermediates B′ and C′ were, respectively,
isolated in 6 and 4% yields when shortening the reaction time
to 30 min under the standard conditions (Scheme 5c).
On the basis of the above control experiments and previous
reports,14 a plausible mechanism for the copper-catalyzed
trifluoromethylpyridine synthesis is illustrated in Scheme 6.
First, the reaction of vinyl azide 2a with PPh3 generated vinyl
iminophosphorane A via the Staudinger−Meyer reaction,16
and the vinyl iminophosphorane intermediate A (HRMS: [M
+ H]+ = 380.1565) could be detected in the reaction mixture
using HRMS. Subsequently, A was trapped by electrophilic
CF3-ynone 1a through copper-accelerated 1,4-addition to form
intermediate B, which would further generate intermediate C
and the corresponding resonance D in the presence of PPh3
and a trace amount of H2O from the reaction system. The 2,4-
diaryl-6-trifluoromethylpyridine product 3aa was finally
generated through the cascade intramolecular cyclization and
dehydration processes with the assistance of PMEDTA (path
Ia). Moreover, an alternative pathway in which intermediate B
directly underwent the intramolecular aza-Wittig process to
afford the target product 3aa was also possibly included in the
transformation (path Ib).16b,g
Scheme 3. Scope of Vinyl Azides 2
a
Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), CuBr2 (0.02
mmol), PPh3 (0.4 mmol), and PMDETA (0.4 mmol) in DMSO/
PhMe (1 mL, 1:1, v/v) at room temperature under air for 12 h. Yields
of isolated products.
Scheme 4. Scale-up Reaction
Meanwhile, 1,2-addition from intermediate A and 1a could
arise as well to form the iminophosphorane B′, which further
delivered intermediate C′ and the corresponding resonance
D′.14h Subsequently, the intramolecular hydroamination on the
alkyne moiety led to the cyclic intermediate D′ with the
assistance of Cu(II) species, and the successive dehydration
gave the final 2,6-diaryl-4-trifluoromethylpyridine compound
3′aa as a side product (path II).
Thus, the assumptive intermediates 4, 5, and 6 instead of (1-
azidovinyl)benzene 2a were introduced into the standard
reaction conditions. However, the desired trifluoromethylation
product 3aa was completely not observed, proving that
intermediates 4−6 were not involved in the current trans-
Scheme 5. Mechanistic Investigations
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Scheme 6. Proposed Mechanism
resulting residue was purified by preparative thin layer chromatog-
raphy (PTLC) on silica gel with petroleum ether/ethyl acetate (v/v)
afforded the corresponding product 3.
CONCLUSION
■
In conclusion, we have described a copper-catalyzed
regioselective cyclization reaction of CF3-ynones with vinyl
azides in combination with a Staudinger−Meyer process under
mild reaction conditions. This novel catalytic system provides
simple and convenient access to the versatile 2,4-diaryl-6-
trifluoromethylpyridine core, which is hard to achieve through
the previous protocols.
2,4-Diphenyl-6-(trifluoromethyl)pyridine (3aa). The compound
(36.0 mg, 60%) was prepared from the general procedure (ethyl
acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow solid: mp
1
= 89−90 °C; H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 8.0, 1.5
Hz, 2H), 7.89 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.54 (dd,
J = 8.0, 1.5 Hz, 2H), 7.43−7.33 (m, 6H); 13C{1H} NMR (126 MHz,
CDCl3) δ 158.5, 151.0, 148.8 (q, 2JC−F = 34 Hz), 138.0, 137.4, 129.9,
1
129.8, 129.4, 128.9, 127.3, 127.2, 120.8, 121.6 (q, JC−F = 275 Hz),
EXPERIMENTAL SECTION
3
■
116.8 (q, JC−F = 3 Hz); 19F NMR (471 MHz, CDCl3) δ −67.9 (s);
HRMS (ESI) m/z [M + H]+ calcd for C18H13F3N+ 300.0995, found
300.0999. The spectral data were in accordance with those reported in
the literature.10
General Information. All chemicals were obtained from
commercial sources and were used as received unless otherwise
noted. Melting points were determined in open glass capillaries and
were uncorrected. 1H NMR spectra were recorded on a Bruker DRX-
500 instrument (500 MHz). 13C NMR spectra were recorded on a
Bruker DRX-500 instrument (126 MHz) and were fully decoupled by
broad band proton decoupling. 19F NMR spectra were recorded on a
Bruker DRX-500 instrument (471 MHz). NMR spectra were
recorded in CDCl3. 1H NMR spectra were referenced to residual
CHCl3 at 7.26 ppm, and 13C NMR spectra were referenced to the
central peak of CDCl3 at 77.0 ppm. Chemical shifts (δ) are reported
in parts per million (ppm), and coupling constants (J) are reported in
hertz (Hz). Multiplicities are reported using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. High-resolution mass spectra (HRMS) were recorded on an
Agilent 1290 mass spectrometer using ESI-TOF (electrospray
ionization time-of-flight). Column chromatography was performed
on silica gel (70−230 mesh ASTM) using the reported eluents. Thin-
layer chromatography (TLC) was carried out on 4 × 15 cm plates
with a layer thickness of 0.2 mm (silica gel 60 F254). All CF3-ynone
and vinyl azide substrates are known compounds. CF3-ynones (1a−
1l)20 and vinyl azides (2a−2j)21 were synthesized according to the
previously reported procedure.
Representative Procedure for the Synthesis of Products 3.
A flame-dried Schlenk tube was charged with vinyl azide 2 (0.2 mmol,
1.0 equiv), PPh3 (52.4 mg, 0.4 mmol, 2.0 equiv), and PhMe (0.5 mL)
and was stirred at room temperature for 0.5 h. To the mixture were
added CuBr2 (4.5 mg, 0.02 mmol, 10 mol %), PMDETA (69.3 mg,
0.4 mmol, 2.0 equiv), and DMSO (0.5 mL), followed by slow
addition of CF3-ynone 1 (0.3 mmol, 1.5 equiv) under ice bath
conditions. The resulting reaction mixture was stirred at room
temperature for 12 h. When the reaction was completed, the resulting
mixture was diluted with water (15 mL) and extracted with DCM (3
× 15 mL). The organic layer was washed with brine (3 × 15 mL),
dried over MgSO4 and concentrated under reduced pressure. The
2,6-Diphenyl-4-(trifluoromethyl)pyridine (3′aa). The compound
(3.5 mg, 6%) was prepared from the general procedure (ethyl acetate/
petroleum ether = 1:300 → 1:100, v/v) as a yellow solid: mp = 63−
64 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.5 Hz, 4H),
7.88 (s, 2H), 7.53 (dddd, J = 7.8, 7.2, 1.5 Hz, 4H), 7.48 (dd, J = 7.2
Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.2, 140.0 (q, 2JC−F
= 33 Hz), 138.2, 129.8, 128.9, 127.1, 123.2 (q, 1JC−F = 273 Hz), 114.0
(q, 3JC−F = 4 Hz); 19F NMR (471 MHz, CDCl3) δ −64.7 (s); HRMS
(ESI) m/z [M + H]+ calcd for C18H13F3N+ 300.0995, found
300.0998. The spectral data were in accordance with those reported in
the literature.11d
2-Phenyl-4-(p-tolyl)-6-(trifluoromethyl)pyridine (3ba). The com-
pound (33.1 mg, 53%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow
solid: mp = 84−86 °C; 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J =
7.6, 1.5 Hz, 2H), 8.06 (s, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.61 (d, J =
8.2 Hz, 2H), 7.52−7.43 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 2.44 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.4, 150.9, 148.7 (q,
2JC−F = 34 Hz), 140.0, 138.1, 134.5, 130.0, 129.7, 128.9, 127.2, 127.0,
1
3
120.5, 121.6 (q, JC−F = 275 Hz), 116.5 (q, JC−F = 3 Hz), 21.3; 19F
NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI) m/z [M + H]+
calcd for C19H15F3N+ 314.1151, found 314.1156.
4-(4-Methoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3ca).
The compound (33.1 mg, 50%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
1
yellow solid: mp = 93−95 °C; H NMR (500 MHz, CDCl3) δ 8.08
(d, J = 8.8 Hz, 2H), 8.01 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.69 (dd, J
= 7.8, 1.5 Hz, 2H), 7.55−7.43 (m, 3H), 7.02 (dd, J = 8.8, 1.8 Hz, 2H),
3.89 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.1, 158.4,
2
150.4, 148.7 (q, JC−F = 34 Hz), 138.1, 131.4, 129.7, 128.9, 128.4,
1
3
127.2, 121.8 (q, JC−F = 275 Hz), 120.1, 116.2 (q, JC−F = 3 Hz),
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1
3
114.8, 55.4; 19F NMR (471 MHz, CDCl3) δ −68.0 (s); HRMS (ESI)
m/z [M + H]+ calcd for C19H15F3NO+ 330.1100, found 330.1103.
4-(4-Fluorophenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3da).
The compound (29.3 mg, 46%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
127.2, 125.3, 120.7, 121.5 (q, JC−F = 275 Hz), 116.6 (q, JC−F = 3
Hz); 19F NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI) m/z
[M + H]+ calcd for C18H12ClF3N+ 334.0605, found 334.0608.
2-Phenyl-4-(o-tolyl)-6-(trifluoromethyl)pyridine (3ja). The com-
pound (22.3 mg, 35%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow
solid: mp = 70−72 °C; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J =
7.8, 1.6 Hz, 2H), 7.86 (s, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.53−7.42
(m, 3H), 7.39−7.29 (m, 3H), 7.26 (dd, J = 7.6, 1.4 Hz, 1H), 2.32 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 157.8, 152.3, 148.2 (q,
2JC−F = 34 Hz), 138.3, 137.9, 135.0, 130.9, 129.8, 129.2, 129.0, 128.9,
1
yellow solid; mp = 96−98 °C; H NMR (500 MHz, CDCl3) δ 8.10
(dd, J = 7.8, 1.5 Hz, 2H), 8.03 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H),
7.71−7.67 (m, 2H), 7.55−7.44 (m, 3H), 7.23 (dd, J = 8.4, 1.8 Hz,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 163.9 (d, 1JC−F = 246 Hz),
162.8 (d, 5JC−F = 2 Hz), 158.6, 149.9, 149.0 (q, 2JC−F = 34 Hz), 133.6
(d, 4JC−F = 3 Hz), 129.9, 129.0 (d, 3JC−F = 9 Hz), 128.9, 127.2, 121.7
(q, 1JC−F = 275 Hz), 120.6, 117.3 (q, 3JC−F = 3 Hz), 116.4 (d, 2JC−F
=
1
3
127.2, 126.3, 123.3, 124.1 (q, JC−F = 275 Hz), 119.2 (q, JC−F = 3
Hz), 20.2; 19F NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI)
m/z [M + H]+ calcd for C19H15F3N+ 314.1151, found 314.1151.
4-(2-Fluorophenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3ka).
The compound (30.0 mg, 47%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
22 Hz); 19F NMR (471 MHz, CDCl3) δ −68.0 (s), −(111.2−111.3)
(m); HRMS (ESI) m/z [M + Na]+ calcd for C18H11F4Na+ 340.0720,
found 340.0721.
4-(4-Chlorophenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3ea).
The compound (31.0 mg, 46%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
1
yellow solid: mp = 49−50 °C; H NMR (500 MHz, CDCl3) δ 8.09
1
yellow solid: mp = 90−91 °C; H NMR (500 MHz, CDCl3) δ 8.09
(dd, J = 7.8, 1.6 Hz, 2H), 8.07 (s, 1H), 7.78 (s, 1H), 7.55−7.43 (m,
5H), 7.30 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.26−7.20 (m, 1H).
(dd, J = 7.8, 1.6 Hz, 2H), 8.03 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 1.4 Hz,
1H), 7.63 (d, J = 8.4, 1.8 Hz, 2H), 7.53−7.46 (m, 5H); 13C{1H}
13C{1H} NMR (126 MHz, CDCl3) δ 159.8 (d, J = 246 Hz), 158.2,
1
2
148.5 (q, 2JC−F = 34 Hz), 145.9, 137.8, 131.4 (d, 3JC−F = 9 Hz), 130.2
(d, 4JC−F = 3 Hz), 129.8, 128.9, 127.2, 125.5 (d, 2JC−F = 13 Hz), 125.0
(d, 4JC−F = 4 Hz), 122.8 (d, 4JC−F = 4 Hz), 121.7 (q, 1JC−F = 275 Hz),
NMR (126 MHz, CDCl3) δ 158.6, 149.7, 148.9 (q, JC−F = 34 Hz),
1
137.7, 136.1, 135.8, 129.9, 129.6, 128.9, 128.4, 127.2, 121.7 (q, JC−F
3
= 275 Hz), 120.5, 116.5 (d, JC−F = 3 Hz); 19F NMR (471 MHz,
CDCl3) δ −68.0 (s); HRMS (ESI) m/z [M + H]+ calcd for
118.5 (q, JC−F = 3 Hz), 116.6 (d, JC−F = 22 Hz); 19F NMR (471
MHz, CDCl3) δ −67.9 (s), −(116.8−116.9) (m); HRMS (ESI) m/z
[M + H]+ calcd for C18H12F4N+ 318.0900, found 318.0898.
3
2
C18H12ClF3N+ 334.0605, found 334.0601.
2-Phenyl-6-(trifluoromethyl)-4-{4-(trifluoromethyl)phenyl}-
pyridine (3fa). The compound (31.0 mg, 42%) was prepared from
the general procedure (ethyl acetate/petroleum ether = 1:300 →
1:80, v/v) as a yellow solid: mp = 101−102 °C; 1H NMR (500 MHz,
CDCl3) δ 8.11 (dd, J = 6.7, 1.8 Hz, 2H), 8.07 (s, 1H), 7.80−7.79 (m,
5H), 7.54−7.44 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.8,
2-Phenyl-4-(thiophen-2-yl)-6-(trifluoromethyl)pyridine (3la). The
compound (27.2 mg, 45%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a yellow
solid: mp = 102−103 °C; 1H NMR (500 MHz, CDCl3) δ 8.08 (dd, J
= 7.8, 1.5 Hz, 2H), 8.02 (s, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.61 (dd, J
= 3.7, 1.2 Hz, 1H), 7.54−7.44 (m, 4H), 7.18 (dd, J = 5.2, 3.6 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.7, 149.0 (q, 2JC−F = 34
Hz), 143.9, 140.2, 137.8, 129.9, 128.9, 128.7, 128.1, 127.2, 126.3,
2
2
149.6, 149.0 (q, JC−F = 34 Hz), 141.0, 137.6, 131.7 (q, JC−F = 34
3
Hz), 130.1, 129.0, 127.7, 127.2, 126.3 (q, JC−F = 4 Hz), 124.0 (q,
1JC−F = 270 Hz), 121.5 (q, 1JC−F = 275 Hz), 120.9, 116.8 (q, 3JC−F = 3
Hz); 19F NMR (471 MHz, CDCl3) δ −62.7 (s), −68.0 (s); HRMS
(ESI) m/z [M + H]+ calcd for C19H12F6N+ 368.0868, found
368.0864.
121.4 (q, JC−F = 275 Hz), 118.8, 114.9 (q, JC−F = 3 Hz); 19F NMR
(471 MHz, CDCl3) δ −68.1 (s); HRMS (ESI) m/z [M + H]+ calcd
for C16H11F3SN+ 306.0559, found 306.0560.
1
3
2-Phenyl-4-(m-tolyl)-6-(trifluoromethyl)pyridine (3ga). The com-
pound (26.1 mg, 41%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow
solid: mp = 78−80 °C; 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J =
7.8, 1.4 Hz, 2H), 7.86 (s, 1H), 7.58 (s, 1H), 7.52−7.42 (m, 3H),
7.39−7.29 (m, 3H), 7.26 (dd, J = 7.6 Hz, 1H), 2.32 (s, 3H); 13C{1H}
4-Phenyl-2-(p-tolyl)-6-(trifluoromethyl)pyridine (3ab). The com-
pound (41.0 mg, 65%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow
1
solid; mp = 89−90 °C; H NMR (500 MHz, CDCl3) δ 8.04 (d, J =
1.4 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.71−
7.66 (m, 2H), 7.56−7.46 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 2.41 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.1, 158.4, 150.9, 148.6
2
NMR (126 MHz, CDCl3) δ 158.4, 150.8, 148.7 (q, JC−F = 34 Hz),
2
140.0, 138.0, 137.5, 135.1, 134.4, 130.0, 129.7, 128.8, 127.2, 126.9,
(q, JC−F = 34 Hz), 140.0, 137.5, 135.2, 129.6, 129.6, 129.3, 127.1,
1
3
120.5, 121.6 (q, JC−F = 275 Hz), 116.4 (q, JC−F = 3 Hz), 21.2; 19F
NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI) m/z [M + H]+
calcd for C19H15F3N+ 314.1151, found 314.1149.
1
3
127.1, 121.6 (q, JC−F = 275 Hz), 116.4 (q, JC−F = 3 Hz), 21.3; 19F
NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI) m/z [M + H]+
calcd for C19H15F3N+ 314.1151, found 314.1152.
4-(3-Fluorophenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3ha).
The compound (29.2 mg, 46%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
2-(4-Methoxyphenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3ac).
The compound (30.2 mg, 45%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
1
1
yellow solid: mp = 90−91 °C; H NMR (500 MHz, CDCl3) δ 8.10
yellow solid: mp = 92−94 °C; H NMR (500 MHz, CDCl3) δ 8.08
(dd, J = 8.9, 5.4 Hz, 2H), 8.02 (s, 1H), 7.79 (d, J = 1.4 Hz, 1H),
7.72−7.67 (m, 2H), 7.56−7.50 (m, 3H), 7.18 (dd, J = 8.6, 8.6 Hz,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 165.0 (d, 1JC−F = 246 Hz),
157.4, 151.2, 148.8 (q, 2JC−F = 34 Hz), 137.3, 134.1 (d, 4JC−F = 3 Hz),
(dd, J = 8.8, 1.6 Hz, 2H), 8.01 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 1.4 Hz,
1H), 7.69 (dd, J = 7.8, 1.5 Hz, 2H), 7.58−7.46 (m, 3H), 7.02 (dd, J =
8.8, 1.6 Hz, 2H), 3.87 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ
2
161.1, 158.1, 150.8, 148.6 (q, JC−F = 34 Hz), 137.6, 130.5, 129.6,
3
1
129.3, 128.6, 127.1, 120.0, 121.1 (q, 1JC−F = 275 Hz), 116.1 (q, 3JC−F
= 3 Hz), 114.2, 55.4; 19F NMR (471 MHz, CDCl3) δ −68.0 (s);
HRMS (ESI) m/z [M + H]+ calcd for C19H15F3NO+ 330.1100, found
330.1103.
129.8, 129.3, 129.1 (d, JC−F = 9 Hz), 127.1, 121.6 (q, JC−F = 275
Hz), 120.4, 116.6 (q, 3JC−F = 3 Hz), 116.5 (d, 4JC−F = 3 Hz), 116.4 (d,
2JC−F = 22 Hz), 115.9 (d, JC−F = 22 Hz); 19F NMR (471 MHz,
2
CDCl3) δ −68.0 (s), −(109.6−115.0) (m); HRMS (ESI) m/z [M +
H]+ calcd for C18H12F4N+ 318.0900, found 318.0905.
2-(4-Fluorophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3ad).
The compound (25.3 mg, 40%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 98−100 °C; 1H NMR (500 MHz, CDCl3) δ 8.08
(s, 1H), 7.95−7.84 (m, 3H), 7.69 (dd, J = 7.8, 1.4 Hz, 2H), 7.62−
7.45 (m, 4H), 7.14 (dd, J = 8.4, 8.4, 2.3 Hz, 1H); 13C{1H} NMR (126
4-(3-Chlorophenyl)-2-phenyl-6-(trifluoromethyl)pyridine (3ia).
The compound (30.0 mg, 45%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
1
yellow solid: mp = 50−52 °C; H NMR (500 MHz, CDCl3) δ 8.10
(dd, J = 8.2, 1.8 Hz, 2H), 8.03 (s, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.67
(q, J = 1.3 Hz, 1H), 7.56 (qd, J = 4.0, 1.6 Hz, 1H), 7.53−7.45 (m,
5H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.7, 149.6, 148.9 (q,
2JC−F = 34 Hz), 139.2, 137.6, 135.4, 130.6, 130.0, 129.7, 128.9, 127.3,
1
MHz, CDCl3) δ 163.2 (d, JC−F = 246 Hz), 157.0, 161.3, 148.8 (q,
3
3
2JC−F = 34 Hz), 140.2 (d, JC−F = 8 Hz), 137.2, 130.4 (d, JC−F = 8
4
1
Hz), 129.9, 129.4, 127.2, 122.7 (d, JC−F = 3 Hz), 121.7 (q, JC−F
=
6428
https://doi.org/10.1021/acs.joc.1c00275
J. Org. Chem. 2021, 86, 6423−6432

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3
2
275 Hz), 120.8, 117.3 (q, JC−F = 3 Hz), 116.7 (d, JC−F = 22 Hz),
114.3 (d, 2JC−F = 22 Hz); 19F NMR (471 MHz, CDCl3) δ −68.0 (s),
−(109.3−115.0) (m); HRMS (ESI) m/z [M + H]+ calcd for
C18H12F4N+ 318.0900, found 318.0896.
157.4, 151.2, 148.8 (q, 2JC−F = 34 Hz), 137.3, 134.1 (d, 4JC−F = 3 Hz),
129.8, 129.4, 129.1 (d, 3JC−F = 9 Hz), 129.1 (d, 3JC−F = 9 Hz), 127.1,
1
3
121.7 (q, JC−F = 275 Hz), 120.5, 116.7 (q, JC−F = 3 Hz), 115.9 (d,
2
2JC−F = 22 Hz), 115.9 (d, JC−F = 22 Hz); 19F NMR (471 MHz,
2-(4-Chlorophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3ae).
The compound (28.2 mg, 42%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 91−92 °C; H NMR (500 MHz, CDCl3) δ 8.06
(d, J = 8.6 Hz, 2H), 8.05 (s, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.70 (dd, J
CDCl3) δ −68.0 (s), −(111.5−111.6) (m); HRMS (ESI) m/z [M +
Na]+ calcd for C18H11F4NNa+ 340.0720, found 340.0723.
Experiments with Scale-up Reaction (Scheme 4). A 50 mL
round-bottom flask was charged with vinyl azide 2a (1.02 g, 7.0 mmol,
1.0 equiv), PPh3 (3.67 g, 14 mmol, 2.0 equiv), and PhMe (10 mL),
and was stirred at room temperature for 0.5 h. To the mixture were
added CuBr2 (156.3 mg, 0.7 mmol, 10 mol %), PMDETA (2.43 g, 14
mmol, 2.0 equiv), and DMSO (10 mL), followed by slow addition of
CF3-ynone 1a (2.08 g, 10.5 mmol, 1.5 equiv) under ice bath
conditions. The resulting reaction mixture was stirred at room
temperature for 12 h. When the reaction was completed, the resulting
mixture was diluted with water (150 mL) and extracted with DCM (3
× 150 mL). The organic layer was washed with brine (3 × 150 mL),
dried over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by column chromatography on silica gel
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v), affording the
corresponding product 3aa (0.84 g, 40%) as a yellow solid.
Experiments with Mechanistic Studies (Scheme 5a). A flame-
dried Schlenk tube was charged with the assumptive intermediate 4/
5/6/7 (0.2 mmol, 1.0 equiv), PPh3 (52.4 mg, 0.4 mmol, 2.0 equiv),
and PhMe (0.5 mL) and was stirred at room temperature for 0.5 h.
To the mixture were added CuBr2 (4.5 mg, 0.02 mmol, 10 mol %),
PMDETA (69.3 mg, 0.4 mmol, 2.0 equiv), and DMSO (0.5 mL),
followed by slow addition of CF3-ynone 1a (59.4 mg, 0.3 mmol, 1.5
equiv) under ice bath conditions. The resulting reaction mixture was
stirred at room temperature for 12 h. No product was detected by
TLC analysis (ethyl acetate/petroleum ether = 1:100, v/v).
Experiments with Mechanistic Studies (Scheme 5b). A
flame-dried Schlenk tube was charged with the (1-azidovinyl)benzene
2a (29.0 mg, 0.2 mmol, 1.0 equiv), PPh3 (26.2 mg, 0.2 mmol, 1.0
equiv) and DCM (1.0 mL) and was stirred at room temperature for
0.5 h; the solvent was evaporated under reduced pressure.
Subsequently, to the residue were added CuBr2 (4.5 mg, 0.02
mmol, 10 mol %), PMDETA (69.3 mg, 0.4 mmol, 2.0 equiv), and
DMSO/PhMe (1:1) = 1.0 mL, followed by slow addition of CF3-
ynone 1a (59.4 mg, 0.3 mmol, 1.5 equiv) under ice bath conditions.
The resulting reaction mixture was stirred at room temperature for 12
h. When the reaction was completed, the resulting mixture was diluted
with water (15 mL) and extracted with DCM (3 × 15 mL). The
organic layer was washed with brine (3 × 15 mL), dried over MgSO4,
and concentrated under reduced pressure. The resulting residue was
purified by PTLC on silica gel (ethyl acetate/petroleum ether = 1:300
→ 1:100, v/v), affording the corresponding product 3aa (26.9 mg,
45%) as a yellow solid.
1
= 8.4, 1.5 Hz, 2H), 7.59−7.51 (m, 3H), 7.48 (d, J = 8.6 Hz, 2H);
2
13C{1H} NMR (126 MHz, CDCl3) δ 157.2, 151.3, 148.9 (q, JC−F
=
34 Hz), 137.3, 136.3, 136.1, 129.8, 129.4, 129.1, 128.5, 127.1, 123.8
(d, 1JC−F = 275 Hz), 120.5, 117.0 (q, 3JC−F = 3.0 Hz); 19F NMR (471
MHz, CDCl3) δ −68.0 (s); HRMS (ESI) m/z [M + H]+ calcd for
C18H12ClF3N+ 334.0605, found 334.0606.
2-(4-Bromophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3af).
The compound (33.1 mg, 43%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 81−83 °C; 1H NMR (500 MHz, CDCl3) δ 8.02 (s,
1H), 7.98 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 1.4 Hz, 1H), 7.68 (dd, J =
8.4, 1.6 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.57−7.47 (m, 3H);
13C{1H} (126 MHz, CDCl3) δ 157.2, 151.2, 148.8 (q, 2JC−F = 34 Hz),
137.2, 136.7, 132.0, 129.8, 129.4, 128.7, 127.1, 124.4, 120.5, 121.4 (q,
3
1JC−F = 275 Hz), 117.0 (q, JC−F = 3 Hz); 19F NMR (471 MHz,
CDCl3) δ −67.9 (s); HRMS (ESI) m/z [M + H]+ calcd for
C18H12BrF3N+ 378.0100, found 378.0101.
4-Phenyl-2-(m-tolyl)-6-(trifluoromethyl)pyridine (3ag). The com-
pound (25.9 mg, 41%) was prepared from the general procedure
(ethyl acetate/petroleum ether = 1:300 → 1:100, v/v) as a yellow
1
solid: mp = 78−80 °C; H NMR (500 MHz, CDCl3) δ 8.05 (d, J =
1.4 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 1.5
Hz, 1H), 7.70 (dd, J = 7.6, 1.6 Hz, 2H), 7.57−7.46 (m, 3H), 7.38 (dd,
J = 7.6, 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 2.45 (s, 3H); 13C{1H}
2
NMR (126 MHz, CDCl3) δ 158.7, 150.9, 148.7 (q, JC−F = 34 Hz),
138.6, 138.0, 137.5, 130.6, 129.7, 129.3, 128.8, 127.9, 127.1, 124.4,
1
3
120.9, 121.7 (q, JC−F = 275 Hz), 116.7 (q, JC−F = 3 Hz); 19F NMR
(471 MHz, CDCl3) δ −68.0 (s); HRMS (ESI) m/z [M + H]+ calcd
for C19H15F3N+ 314.1151, found 314.1149.
2-(3-Fluorophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3ah).
The compound (23.4 mg, 37%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 74−75 °C; 1H NMR (500 MHz, CDCl3) δ 8.12−
8.07 (m, 2H), 8.01 (s, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.68 (dd, J = 7.8,
1.6 Hz, 2H), 7.57−7.47 (m, 3H), 7.17 (ddd, J = 8.6, 8.6, 1.4 Hz, 2H);
1
13C{1H} NMR (126 MHz, CDCl3) δ 164.2 (d, JC−F = 246 Hz),
2
4
157.4, 151.2, 148.8 (q, JC−F = 34. Hz), 137.3, 134.1 (d, JC−F = 3
3
3
Hz), 129.8, 129.3, 129.1 (d, JC−F = 9 Hz), 129.1 (d, JC−F = 9 Hz),
1
3
127.1, 121.7 (q, JC−F = 275 Hz), 120.4, 116.7 (q, JC−F = 3 Hz),
Experiments with Mechanistic Studies (Scheme 5c). A flame-
dried Schlenk tube was charged with vinyl azide 2a (29.0 mg, 0.2
mmol, 1.0 equiv), PPh3 (52.4 mg, 0.4 mmol, 2.0 equiv), and PhMe
(0.5 mL) and was stirred at room temperature for 0.5 h. To the
mixture were added CuBr2 (4.5 mg, 0.02 mmol, 10 mol %), PMDETA
(69.3 mg, 0.4 mmol, 2.0 equiv), and DMSO (0.5 mL), followed by
slow addition of CF3-ynone 1a (59.4 mg, 0.3 mmol, 1.5 equiv) under
ice bath conditions. The resulting reaction mixture was stirred at
room temperature for 0.5 h. When the reaction was completed, the
resulting mixture was diluted with water (15 mL) and extracted with
DCM (3 × 15 mL). The organic layer was washed with brine (3 × 15
mL), dried over MgSO4, and concentrated under reduced pressure.
The resulting residue was purified by PTLC on silica gel (ethyl
acetate/petroleum ether = 1:300 → 1:100 → 1:30, v/v), affording 3aa
(13.8 mg, 23%) as a yellow solid, B′ (7.0 mg, 6%) as a white solid,
and C′ (2.5 mg, 4%) as a yellow oil.
115.8 (d, JC−F = 22 Hz), 115.8 (d, JC−F = 22 Hz); 19F NMR (471
MHz, CDCl3) δ −68.0 (s), −(111.5−111.6) (m); HRMS (ESI) m/z
[M + H]+ calcd for C18H12F4N+ 318.0900, found 318.0900.
2
2
2-(3-Chlorophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3ai).
The compound (24.2 mg, 36%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 50−51 °C; 1H NMR (500 MHz, CDCl3) δ 8.11 (s,
1H), 8.06 (s, 1H), 7.99 (pd, J = 4.3, 1.7 Hz, 1H), 7.84 (d, J = 1.4 Hz,
1H), 7.71 (dd, J = 7.8, 1.4 Hz, 2H), 7.57−7.51 (m, 3H), 7.46−7.41
(m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 156.9, 151.3, 148.9 (q,
2JC−F = 35 Hz), 139.7, 137.1, 135.0, 130.1, 129.9, 129.8, 129.4, 127.4,
1
3
127.1, 125.3, 120.8, 121.6 (q, JC−F = 275 Hz), 117.3 (q, JC−F = 3
Hz); 19F NMR (471 MHz, CDCl3) δ −67.9 (s); HRMS (ESI) m/z
[M + H]+ calcd for C18H12ClF3N+ 334.0605, found 334.0607.
2-(2-Fluorophenyl)-4-phenyl-6-(trifluoromethyl)pyridine (3aj).
The compound (27.4 mg, 43%) was prepared from the general
procedure (ethyl acetate/petroleum ether = 1:300 → 1:80, v/v) as a
yellow solid: mp = 90−92 °C; 1H NMR (500 MHz, CDCl3) δ 8.14−
8.08 (m, 2H), 8.03 (s, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.71 (dd, J = 7.5,
1.6 Hz, 2H), 7.57−7.50 (m, 3H), 7.20 (ddd, J = 7.6, 7.6, 2.0 Hz, 2H);
(Z)-1,5-Diphenyl-3-(trifluoromethyl)-1-{(triphenyl-λ5-
phosphaneylidene)amino}pent-1-en-4-yn-3-ol (B′): mp = 121−122
°C; 1H NMR (500 MHz, CDCl3) δ 10.96 (br s, 1H), 7.57−7.49 (m,
6H), 7.49−7.40 (m, 5H), 7.36−7.23 (m, 9H), 6.93 (dd, J = 7.4, 7.4
Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 6.77 (dd, J = 7.5, 7.5 Hz, 2H), 4.85
(d, J = 4.4 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 151.7 (d,
1
13C{1H} NMR (126 MHz, CDCl3) δ 164.0 (d, JC−F = 246 Hz),
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J
C−P = 4 Hz), 141.5 (d, JC−P = 6 Hz), 132.5 (d, JC−P = 10 Hz), 131.9,
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2
122.6, 104.0 (d, JC−P = 17 Hz), 87.3, 84.4, 73.4 (q, JC−F = 33 Hz);
19F NMR (471 MHz, CDCl3) δ −81.9 (s); HRMS (ESI) m/z [M +
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5-Imino-1,5-diphenyl-3-(trifluoromethyl)pent-1-yn-3-ol (C′): 1H
NMR (500 MHz, CDCl3) δ 8.00 (d, J = 6.9 Hz, 2H), 7.65 (dd, J =
7.4, 7.4 Hz, 1H), 7.52 (dd, J = 7.8, 7.8 Hz, 2H), 7.39−7.28 (m, 3H),
7.30−7.23 (m, 2H), 5.47 (s, 1H), 3.81 (d, J = 16.7 Hz, 1H), 3.44 (d, J
= 16.7 Hz, 1H), 1.62 (br s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ
1
198.5, 136.3, 134.4, 132.0, 129.2, 128.9, 128.4, 128.2, 123.3 (q, JC−F
= 284 Hz), 121.1, 86.8, 83.3, 70.6 (q, 2JC−F = 33 Hz), 41.7; 19F NMR
(471 MHz, CDCl3) δ −81.5 (s); HRMS (ESI) m/z [M + H]+ calcd
for C18H15F3NO+ 318.1100, found 318.1100.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00275.
Complete tables on optimization of reaction conditions,
1H, 13C{1H}, and 19F NMR spectra of 3aa−3la, 3ab−
3aj, B′, and C′, and the crystallographic data of 3da
(PDF)
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Accession Codes
CCDC 2045672 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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Corresponding Authors
Lianhui Wang − School of Medicine, Huaqiao University,
Quanzhou 362021, P.R. China; orcid.org/0000-0002-
9899-3148; Email: lianhui.wang@hqu.edu.cn
Guolin Cheng − College of Materials Science and Engineering,
Huaqiao University, Xiamen 361021, P.R. China;
orcid.org/0000-0003-1013-2456; Email: glcheng@
hqu.edu.cn
Authors
Jixin Wang − School of Medicine, Huaqiao University,
Quanzhou 362021, P.R. China
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Mengqi Yang − School of Medicine, Huaqiao University,
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00275
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Science and Technology
Project of Quanzhou City (2018C073R), NSF of China (Nos.
22071068 and 21602064), Outstanding Youth Scientific
Research Cultivation Project of Colleges and Universities of
Fujian Province, and the Instrumental Analysis Centre of
Huaqiao University.
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