Copper-Catalyzed Reductive Ring-Cleavage of Isoxazoles: Synthesis of Fluoroalkylated Enaminones and Application for the Preparation of Celecoxib, Deracoxib, and Mavacoxib

Article abstract of DOI:10.1021/acs.joc.0c02980

We have identified a new reactivity of copper/diamine catalysis for the reductive ring-cleavage of isoxazoles to yield fluoroalkylated enaminones. This protocol has the advantage of using commercially available reagents, ease of setting up, broad tolerance of functionality, and is regiospecific and free of defluorination and reduction of reducible functional groups. The utility was demonstrated by a one-step, regioselective synthesis of fluoroalkylated pyrazole-based drugs such as celecoxib, deracoxib, and mavacoxib.

Full text of DOI:10.1021/acs.joc.0c02980

pubs.acs.org/joc
Article
Copper-Catalyzed Reductive Ring-Cleavage of Isoxazoles: Synthesis
of Fluoroalkylated Enaminones and Application for the Preparation
of Celecoxib, Deracoxib, and Mavacoxib
Chao Wan,∥ Jian-Yu Pang,∥ Wei Jiang, Xiao-Wei Zhang,* and Xiang-Guo Hu*
Cite This: J. Org. Chem. 2021, 86, 4557−4566
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We have identified a new reactivity of copper/
diamine catalysis for the reductive ring-cleavage of isoxazoles to
yield fluoroalkylated enaminones. This protocol has the advantage
of using commercially available reagents, ease of setting up, broad
tolerance of functionality, and is regiospecific and free of
defluorination and reduction of reducible functional groups. The
utility was demonstrated by a one-step, regioselective synthesis of
fluoroalkylated pyrazole-based drugs such as celecoxib, deracoxib, and mavacoxib.
Enaminone compounds are highly versatile intermediates in
organic synthesis.4 However, literature surveys show that the
application of their fluoroalkylated counterparts remains
largely underdeveloped (Scheme 1b), which could be
attributed to the synthesis difficulties.5,6 For instance,
trifluoromethylated enaminones can be synthesized from
CF3CN. However, CF3CN is a toxic gas, and the reaction
needs to use highly acidic and basic reagents.5 Alternatively,
they can be prepared from corresponding diketones. However,
regioselectivity could be a problem.6
INTRODUCTION
■
The modification of molecules with fluorinated units is an
important means in drug development to optimize the
properties of lead compounds.1 Whereas more efforts have
been devoted to introducing these units by direct fluorination
or fluoroalkylation, the importance of approaches utilizing
fluorinated building blocks can never be underestimated.2 For
example, fluorinated intermediates such as diazoalkanes, azides,
and enol ethers have been successfully applied for the synthesis
of various high-value compounds,3 some of which are not easy
or even impossible to synthesize with direct fluoroalkylation
approaches (Scheme 1a).
On the basis of our previous work,7a,b we envisioned that the
reductive ring-cleavage of fluoroalkylated isoxazoles could
provide a convenient access to fluoromethylated enaminones.
The reductive cleavage of N−O bond of isoxazoles could be
achieved by hydrogenolysis in the presence of Raney-nickel,8a,b
Pd/C,8c or aged NMP/FeCl3;8d alternatively, it could be
realized by the reductive ring opening promoted by metal
reagents or catalysts including Na,9a SmI2,9b EtMgBr/Ti(Oi-
Pr)4,9c Mo(CO)6,9d,e Fe/Cu/HCl,9f or Fe(II)Cl2.9g Though
methods are well documented, our optimization showed that it
was not a trivial job to achieve the ring-opening of fluoroalkyl
isoxazoles (vide infra).
Scheme 1. Previous Research and This Work
Herein, we report an unexpected reactivity of copper/
diamine system (Scheme 1c),10 that is, the cleavage of N−O
bond of isoxazole, which allows an easy and general access to
the fluoroalkyl enaminones (Scheme 1d). This method avoids
the reduction of functional groups and the unexpected
Received: December 19, 2020
Published: February 15, 2021
https://dx.doi.org/10.1021/acs.joc.0c02980
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 4557−4566
4557

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Reaction Optimization
yields (%)
of 2a
entry
reagents/solvent/temp (°C)
19
20
21
22
23
24
CuI (30 mol %)/L3 (200 mol %)/dioxane/140
CuI (30 mol %)/L4 (200 mol %)/dioxane/140
CuI (30 mol %)/L5 (200 mol %)/dioxane/140
CuI (30 mol %)/L6 (200 mol %)/dioxane/140
CuI (30 mol %)/L7 (200 mol %)/dioxane/140
CuI (30 mol %)/L8 (200 mol %)/dioxane/140
67
17
31
52
12
21
Variation of the solvent
25
26
27
28
CuI (30 mol %)/L2 (200 mol %)/THF/140
53
41
66
74
CuI (30 mol %)/L2 (200 mol %)/MeOH/140
CuI (30 mol %)/L2 (200 mol %)/toluene/140
CuI (30 mol %)/L2 (200 mol %)/DMF/140
yields (%)
entry
reagents/solvent/temp (°C)
Pd/C (20 wt %)/MeOH/35
Pd/C (20 wt %)/MeOH/80
Raney-Ni (20 wt %)/MeCN/35
Raney-Ni (20 wt %)/EtOH/35
Raney-Ni (20 wt %)/MeOH/35
Raney-Ni (20 wt %)/MeOH/0
of 2a
1
2
3
4
n.d.
n.d.
38
42
62
8
Variation of other parameters
29
30
31
32
33
CuI (30 mol %)/L1 (50 mol %)/dioxane/140
CuI (30 mol %)/L1 (100 mol %)/dioxane/140
CuI (30 mol %)/L1 (150 mol %)/dioxane/140
CuI (30 mol %)/L1 (200 mol %)/dioxane/120
CuI (30 mol %)/L1 (200 mol %)/dioxane/100
52
67
80
70
52
c
5
6
7
8
9
10
11
FeCl2 (400 mol %)/MeCN/90
n.d.
21
77
12
92
Control experiments
Mo(CO)6 (50 mol %)/MeCN/85
Mo(CO)6 (50 mol %)/MeCN/140
CuI (30 mol %)/L1 (20 mol %)/dioxane/140
CuI (30 mol %)/L1 (200 mol %)/dioxane/140
34
35
36
37
CuI (30 mol %)/L1 (200 mol %) + H2O (100 mol %)
90
55
56
65
/dioxane/140
CuI (30 mol %)/L1 (100 mol %) + H2O (100 mol %)
/dioxane/140
CuI (30 mol %)/L1 (200 mol %) + HCO2H (100
mol %)/dioxane/140
CuI (30 mol %)/L1 (200 mol %) + AcOH (100
mol %)/dioxane/140
Variation of the copper catalyst
12
13
14
CuCl (30 mol %)/L1 (200 mol %)/dioxane/140
CuBr (30 mol %)/L1 (200 mol %)/dioxane/140
CuTC (30 mol %)/L1 (200 mol %)/dioxane/140
80
71
27
90
58
74
38
39
CuI (30 mol %)/dioxane/140
L1 (200 mol %)/dioxane/140
n.d.
n.d.
15 Cu(OAc)2(30 mol %)/L1 (200 mol %)/dioxane/140
16
17
Variation of the ligand
18 CuI (30 mol %)/L2 (200 mol %)/dioxane/140
a
b
CuCl2 (30 mol %)/L1 (200 mol %)/dioxane/140
Cu(acac)2 (30 mol %)/L1 (200 mol %)/dioxane/140
Conditions: 1a (0.1 mmol), solvent (3 mL) for 36 h. Yields were
determined by 19F NMR analysis using 3,5-bis(trifluoromethyl)-
c
bromobenzene as an internal standard. 2a and 2aa were isolated in
62% and 18% yield, respectively.
80
defluorination side reaction, which would be encountered by
conventional methods for the reductive ring-cleavage of
isoxazoles (vide infra).8,9 The usefulness of fluoroalkyl
enaminones was demonstrated by a one-step, regioselective
synthesis of nonsteroidal drugs such as celecoxib, deracoxib,
mavacoxib, and related lead compounds.
because Mo(CO)6 is a dangerous source of volatile metal as
well as CO.11 Fortuitously, we found that the copper/diamine
could yield the desired product in 12% yield at 140 °C, and no
trace of 2aa was observed (Table 1, Entry 10).12 Interestingly,
when increasing the loading of L1 (1R,2R)-N1,N2-dimethylcy-
clohexane-1,2-diamine (t-DMACH) to a two molar ratio, the
desired product 3a was isolated in 92% yield (Entry 11).
Further screening showed that the reaction could occur under
various copper(I)/copper(II) catalysts (Entries 12−17), with
Cu(OAc)2 (Entry 15) being equally efficient to that with CuI
(Entry 11). Different diamine- and bis-pyridine-ligands were
then tested, which showed that t-DMACH was the most
suitable one for this reaction (Entries 18−24). The reaction
could occur in solvents other than dioxane, but with lower
efficiencies (Entries 25−28 vs Entry 11). Variation of the
ligand loading showed that the reaction requires at least two
equivalents of t-DMACH (Entries 29−31). Lower yields were
obtained when the temperature was dropped to 120 or 100 °C
(Entries 32−33). Though water does not affect the reaction
efficiency, it could not replace L1,9d,e indicating that t-DMACH
may act as both the hydrogen source and the ligand (Entries
34−35).13 The addition of organic acids lowered the yield
significantly (Entries 36−37), indicating that the high loading
of t-DMACH is not due to the competitive coordination of
enaminone 2a to the copper catalyst. Finally, control
experiments proved that both the copper catalyst and the
RESULTS AND DISCUSSION
■
As shown in Table 1, The Pd/C catalyzed hydrogenolysis of 1a
could hardly afford the desired product even at elevated
temperature (Entries 1−2), reflecting that 1a has a lower
reactivity compared to reported nonfluorinated isoxazoles.8c
With freshly activated Raney-Ni, expected β-enaminone 2a was
obtained in 38−62% yields in different solvents (Entries 3−5),
but the reaction was plagued by the defluorination byproduct
2aa in various amounts (e.g., 18% for Entry 5), which was not
easy to separate from 2a. Lowering the temperature could
avoid the above side reaction, but the yield was only 8% (Entry
9g
6). Whereas the reductive method using Fe(II)Cl2 afforded
no desired product (Entry 7), the reaction of Mo(CO)6 under
the reported conditions (in CH3CN at 85 °C),9d,e one of the
most used protocols, gave 2a in a low yield of 21%, again
indicating the sluggish reactivity of fluorinated isoxazoles.
Although increasing the temperature to 140 °C could push the
reaction to completion, the yield was not ideal (77%) and
some unidentified polar byproducts were observed. Further-
more, it is not desirable to use this reagent at this temperature,
4558
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
b
ligand t-DMACH are essential for this reaction (Entries 38−
39).
Table 3. Substrate Scope of CF3-Isoxazoles
Having identified the optimal reaction conditions (Table 1,
entry 11), the generality of the reaction with respect to the
substituent on the aromatic ring of difluoromethylated
isoxazoles was explored (Table 2). Alkyl, hydrogen, and
a
Table 2. Substrate Scope of CF2-Isoxazoles
a
b
On gram-scale. Conditions B: 3 (0.1 mmol), Cu(OAc)2 (0.05
mmol)/t-DMACH (0.2 mmol), dioxane (3 mL), 140 °C, 36 h.
As shown in Table 4, fluoroalkylated isoxazoles with other
substituents instead of aryls are viable compounds. For
Table 4. Reductive Ring-Cleavage of Other Representative
Isoxazoles Including Non-Fluorinated Ones
a
a
Conditions A: 1 (0.1 mmol), CuI (0.03 mmol)/t-DMACH (0.2
mmol), dioxane (3 mL), 140 °C, 36 h.
phenyl substituted compounds (2b−2d) are viable substrates,
affording the desired products in good yields. Isoxazoles
bearing electron-donating groups exhibited excellent reactivity,
affording the corresponding product in >90% yields (2a, 2e).
Halogens (2f−2g) were tolerated under the reaction
conditions, which leaves a reactive handle for further
derivatization. Isoxazoles bearing electron-withdrawing groups
(2h−2j) underwent the reaction successfully, yielding the
products in good yields. In contrast to previous methods, easily
reducible groups (e.g., CN, NO2) were intact in this work (2i−
2j). Finally, meta-substitution and disubstitution were compat-
ible under the reaction conditions, and 2k and 2l were
obtained in 97% and 93% yield, respectively. The structures of
2i and 2j were confirmed unambiguously by means of X-ray
crystallographic analysis (CCDC 1577900, 2038891, and
Supporting Information).
Next, we proceed to test the limit of this transformation with
respect to the CF3-isoxazoles (Table 3). Interestingly, the
introduction of another fluorine makes the reaction more
sluggish under previous conditions (with CuI, Table 1, entry
11). Fortunately, after slight adjustment, the reaction could
occur smoothly with a higher loading (50 mol %) of copper
acetate (Table 1, entry 11). Generally, the reaction shows
equally excellent tolerance of functionalities to that with CF2-
counterparts and the yields (80−95%) are a little higher than
those listed in Table 2. Note that the reaction could be run on
gram scale, and 4a was obtained in 77% yield. The structures of
4a and 4h were confirmed unambiguously by means of X-ray
crystallographic analysis (CCDC 2038890, 2041334, and
Supporting Information).
a
Conditions: 5 (0.1 mmol), Cu(OAc)2 (0.05 mmol)/t-DMACH (0.2
mmol), dioxane (3 mL), 140 °C, 36 h.
example, 6a and 6b with a styrene group could be obtained
in 89% and 87% yield, respectively. As observed before, the
reducible double bond was not affected under the reaction
conditions. Alkyl-substituted compounds also underwent the
reaction successfully, and 6c−6f were all obtained in high
yields. Note that 6c and 6d are very volatile and need to be
handled with care. Isoxazoles were viable substrates (6g, 6h),
thus demonstrating the utility of this method for the
preparation of polyfluorinated enaminones. Finally, the
reaction is also suitable for the ring-opening of nonfluorinated
compounds, yielding the products (6i, 6j) in 97% and 72%
yield, respectively. These two experiments, along with our
earlier observation in the reaction optimization section,
indicate the utility of this method in a broader perspective.
In a preliminary demonstration of the utility of the
fluoroalkylated enaminones, we attempted to transform them
into fluoroalkylated 1,5-diarylpyrazoles, which are privileged
cores in medicinal chemistry.14 For example, celecoxib is a
4559
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
cyclooxygenase-2 (COX-2) inhibitor and nonsteroidal anti-
inflammatory drug and among the most prescribed medi-
cations in the United States. After some optimization
(Supporting Information, Table S1), celecoxib (7), mavacoxib
(8), SC-560 (9), deracoxib (10), and 11 were obtained
regioselectively in high yields by the reaction of the above-
obtained enaminones with corresponding aryl hydrazines in
ethanol with 3 equiv of acetic acid. Although these compounds
can be prepared from fluoroalkylated pyrazoles,15 β-dike-
tones,14,16 and ynones,17 our method provides a high-yielding,
regioselective alternative to obtain them. Importantly, whereas
demonstrating comparable efficiency, all the enaminones listed
in Tables 2, 3, and 5 are solid and stable, and thus more
synthesis of fluoroalkylated pyrazole-based drugs and lead
compounds such as celecoxib, deracoxib, and mavacoxib. We
anticipate that the easy access of fluoroalkylated enaminones,
coupled with their favorable physical properties (e.g., solid and
stable) and potentially versatile reactivity, should promote
more research using them for the synthesis of high-value
compounds in future.
EXPERIMENTAL SECTION
■
General Information. All solvents were dried over activated 4 Å
molecular sieves. Difluoroethylamine and trifluoroethylamine were
purified by distillation. Chromatographic purification of products was
carried out by flash column chromatography on silica gel (300−400
1
mesh). NMR spectra were measured in CDCl3 (TMS, H δ = 0;
a
1
1
CDCl3, H δ = 7.26, 13C δ = 77.16) or DMSO-d6 (TMS, H δ = 0;
Table 5. Synthesis of Celecoxib-Related Pyrazoles
1
DMSO-d6, H δ = 2.50, 13C δ = 39.52) on a Bruker AV 400 (1H at
400 MHz, 13C at 100 MHz, 19F at 376 MHz) magnetic resonance
spectrometer. HRESI mass spectra were recorded on an AB Sciex
Triple-TOF 5600+ mass instrument.
General Procedure for the Synthesis of Isoxazoles. 1a−1l,
3a−3l, 5a−5n were synthesized according to our previous method.7a
General Procedure for the Raney-Ni Catalyzed Ring-
Opening of Fluoroalkylated Isoxazoles. A reaction vessel charged
with isoxazole 1a (0.2 mmol, 45 mg, 1 equiv), Raney-Ni catalyst (20
wt %), and MeOH (3 mL) were evacuated and backfilled with
hydrogen (1 atm) three times. The reaction mixture was stirred under
a hydrogen balloon at 35 °C on a heating mantle. Upon completion,
the mixture was filtered over a plug of Celite (AcOEt as the eluent)
and concentrated under reduced pressure. The resulting mixture was
purified by flash column chromatography on silica gel to afford the
compound 2a and 2aa.
General Procedures for the Synthesis of 2a−2l, 4a−4l, and
6a−6j. A solution of 1,4-dioxane (3 mL) and (1R,2R)-N1,N2-
dimethylcyclohexane-1,2-diamine (t-DMACH) (0.2 mmol, 32 μL, 2
equiv) was added to a 15 mL Schlenk tube charged with CuI (30
mmol %, 5.7 mg for 2a−2l; Cu(OAc)2, 50 mmol %, 10 mg for 4a−4l
and 6a−6j), isoxazole 1 (0.1 mmol, 1 equiv), and a magnetic stirring
bar under nitrogen atmosphere. The mixture was stirred at 140 °C for
36 h on a heating mantle, then cooled to room temperature and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography to afford the desired
products.
Procedure for the Gram-Scale Synthesis of Trifluoromethy-
lated β-Enaminones 4a. In a round-bottom flask (250 mL)
equipped with a condenser was charged with 3a (6.6 mmol, 1.5 g, 1
equiv), Cu(OAc)2 (50 mmol %, 660 mg), and purged with nitrogen
three times. Then 1,4-dioxane (100 mL) and t-DMACH (13.2 mmol,
2.1 mL, 2 equiv) were added and the resulting solution was allowed to
stir at 140 °C for 36 h in an oil bath under nitrogen atmosphere. After
completion of the reaction (monitored by TLC), the reaction mixture
was cooled to room temperature and concentrated under reduced
pressure. The resulting residue was filtered over a plug of Celite
(AcOEt as eluent) and the filtrate was washed with saturated aqueous
NaCl (30 mL). The two layers were separated and the aqueous layer
was extracted with AcOEt and dried over anhydrous Na2SO4. After
filtration and evaporation of the solvents under reduced pressure, the
crude product was purified by column chromatography on silica gel
(petroleum ether/AcOEt) to give the desired product 4a (1.16 g, 77%
yield, 93% yield based on the recovery of the starting material).
General Procedure for the Synthesis of Fluorinated
Pyrazoles 7−12. A reaction vessel charged with 4-hydrazinobenzene
hydrochloride (0.15 mmol, 1.5 equiv), acetic acid (0.3 mmol, 17 μL, 3
equiv), and enaminone (0.1 mmol, 1.0 equiv) in ethanol (2 mL) was
stirred at 80 °C on a heating mantle. Upon completion, the solvent
was removed under reduced pressure and the resulting residue was
purified by silica gel column chromatography.
a
Conditions: 2 or 3 (0.1 mmol), ArNH2NH2·HCl (0.15 mmol),
AcOH (0.3 mmol), EtOH (2 mL), 80 °C, 10 h. The isomer ratios in
the parentheses were determined by 19F NMR analysis using 2,2,2-
trifluoroacetophenone as an internal standard.
convenient to handle than corresponding fluoroalkylated
diketones; furthermore, this reaction is complementary in
synthesizing certain compounds of interest and could provide
pyrazoles (e.g., 12) that are not accessible from fluoroalkyl β-
diketones.18 Finally, it is worth noting that using fluoroalky-
lated enaminones as key intermediates enables a high yielding,
3-steps access to these fluoroalkylated pyrazoles from
commercially available reagents based on our previous work.7a
CONCLUSIONS
■
In summary, we have identified a new reactivity of copper/
diamine catalysis for the reductive ring-cleavage of isoxazoles,
and provided a general and efficient method for the synthesis
of CF2- and CF3-substituted enaminones. This protocol has
the advantage of using commercially available reagents, ease of
setting up, broad tolerance of functionality, and is regiospecific
and free of defluorination and reduction of reducible functional
groups. Furthermore, the method is also suitable for the
reductive ring-cleavage of polyfluorinated as well as non-
fluorinated isoxazoles. The utility of fluoroalkylated enami-
nones was demonstrated by the one-step, regioselective
5-(4-Methoxyphenyl)-3-(perfluoroethyl)isoxazole (5g). Purified
by flash column chromatography (petroleum ether/AcOEt =
1
200:1), yellow solid, mp 90−92 °C; 726 mg, 62%; H NMR (400
4560
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H),
6.63 (s, 1H), 3.88 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −84.30 (t,
J = 1.85 Hz, 3F), −114.6 (q, J = 1.85 Hz, 2F); 19F{1H} NMR (376
MHz, CDCl3) δ −84.30 (t, J = 1.85 Hz, 3F), −114.6 (q, J = 1.85 Hz,
2F); 13C{1H} NMR (100 MHz, CDCl3) δ 172.5, 162.1, 155.1 (C−F,
2JC−F = 28.0 Hz), 127.9, 119.9 (C−F, 1JC−F = 285.9, 36.1 Hz), 118.9,
114.8, 109.9 (C−F, 1JC−F = 253.8, 40.3 Hz), 96.4, 55.6; HRMS (ESI-
AcOEt = 10:1), white solid, mp 127−129 °C, 22.4 mg, 82% yield; 1H
NMR (400 MHz, CDCl3) δ 9.54 (bs, 1H), 7.98 (d, J = 8.3 Hz, 2H),
7.68 (d, J = 8.3 Hz 2H), 7.66−7.60 (m, 2H), 7.47 (t, J = 7.3 Hz, 2H),
7.43−7.36 (m, 1H), 6.16 (t, J = 55.3 Hz, 1H), 6.06 (s, 1H), 5.40 (bs,
1H); 19F NMR (376 MHz, CDCl3) δ −122.43 (d, J = 55.3 Hz, 2F);
19F{1H} NMR (376 MHz, CDCl3) δ −122.43 (s, 2F); 13C{1H} NMR
2
(100 MHz, CDCl3) δ 191.1, 153.3 (C−F, JC−F = 22.0 Hz), 144.8,
−
TOF) m/z calcd for C12H9F5NO2 [M + H]+ 294.0548, found
1
140.2, 137.8, 129.0, 128.1 (2C), 127.4, 127.3, 111.7 (C−F, JC−F
=
243.7 Hz), 91.2 (C−F, 3JC−F = 6.0 Hz); HRMS (ESI-TOF) m/z calcd
294.0545.
for C16H12F2NO− [M−H]− 272.0892, found 272.0896.
3-(Difluoromethyl)-5-phenethylisoxazole (5e). Purified by flash
column chromatography (petroleum ether/AcOEt = 200:1), colorless
oil, 432 mg, 48%; 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 2H),
7.25−7.21 (m, 1H), 7.19−7.14 (m, 2H), 6.70 (t, J = 53.9 Hz, 1H),
6.15 (s, 1H), 3.13−3.07 (m, 2H), 3.05−2.99 (m, 2H); 19F NMR (376
MHz, CDCl3) δ −115.19 (d, J = 53.9 Hz, 2F); 19F{1H} NMR (376
MHz, CDCl3) δ −115.19 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3)
(Z)-3-Amino-4,4-difluoro-1-(4-(methylthio)phenyl)but-2-en-1-
one (2e). Purified by flash column chromatography (petroleum ether/
AcOEt = 8:1), pale brown solid, mp 107−108 °C, 23.2 mg, 95% yield;
1H NMR (400 MHz, CDCl3)δ 9.46 (bs, 1H), 7.81 (d, J = 8.5 Hz,
2H), 7.24 (d, J = 8.5 Hz, 2H), 6.12 (t, J = 55.0 Hz, 1H), 5.96 (s, 1H),
5.52 (bs, 1H), 2.49 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −122.27
(d, J = 55.0 Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −122.27
2
δ 174.4, 158.8 (C−F, JC−F = 30.0 Hz), 139.7, 128.8, 128.3, 126.7,
1
(s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 153.2 (C−F,
109.3 (C−F, JC−F = 237.6 Hz), 98.2, 33.5, 28.6; HRMS (ESI-TOF)
m/z calcd for C12H12F2NO− [M + H]+ 224.0881, found 224.0884.
5-Phenethyl-3-(trifluoromethyl)isoxazole (5f). Purified by flash
column chromatography (petroleum ether/AcOEt = 200:1), colorless
oil, 503 mg, 52%; 1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 2H),
7.27−7.20 (m, 1H), 7.19−7.14 (m, 2H), 6.16 (s, 1H), 3.16−3.10 (m,
2H), 3.07−3.00 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −63.30 (s,
3F); 19F{1H} NMR (376 MHz, CDCl3) δ −63.30 (s, 3F); 13C{1H}
1
2JC−F = 21.9 Hz), 144.3, 135.3, 127.9, 125.2, 111.7 (C−F, JC−F
=
244.6 Hz), 90.8 (C−F, 3JC−F = 6.0 Hz), 15.0; HRMS (ESI-TOF) m/z
calcd for C11H12ONF2S+ [M + H]+ 244.0602, found 244.0609.
(Z)-3-Amino-4,4-difluoro-1-(4-fluorophenyl)but-2-en-1-one (2f).
Purified by flash column chromatography (petroleum ether/AcOEt =
10:1), pale yellow solid, mp 70−72 °C, 19.4 mg, 90% yield; 1H NMR
(400 MHz, CDCl3) δ 9.47 (bs, 1H), 7.95−7.87 (m, 2H), 7.06−7.05
(m, 2H), 6.13 (t, J = 54.8 Hz, 1H), 5.95 (s, 1H), 5.47 (bs, 1H); 19F
NMR (376 MHz, CDCl3) δ −107.46 to −107.54 (m, 1F), −122.57
(d, J = 54.8 Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −107.49
(s, 1F), −122.57 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.1,
165.2 (C−F, 1JC−F = 253.2 Hz), 153.5 (C−F, 2JC−F = 22.0 Hz), 135.3
2
NMR (100 MHz, CDCl3) δ 175.3, 155.5 (C−F, JC−F = 38.0 Hz),
139.4, 128.8, 128.3, 126.9, 119.9 (C−F, 1JC−F = 271.0 Hz), 99.1, 33.5,
28.6; HRMS (ESI-TOF) m/z calcd for C12H11F3NO− [M + H]+
242.0787, found 242.0791.
(Z)-3-Amino-4,4-difluoro-1-(4-methoxyphenyl)but-2-en-1-one
(2a). Purified by flash column chromatography (petroleum ether/
AcOEt = 10:1), off white solid, mp 87−88 °C, 21.6 mg, 95% yield; 1H
NMR (400 MHz, CDCl3) δ 9.35 (bs, 1H), 7.88 (d, J = 8.7 Hz, 2H),
6.91 (d, J = 8.7 Hz, 2H), 6.11 (t, J = 55.8 Hz, 1H), 5.96 (s, 1H), 5.56
(bs, 1H), 3.83 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −122.29 (d, J
= 55.8 Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −122.29 (s,
2F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 162.8, 152.7 (C−F,
2JC−F = 22.0 Hz), 131.8, 129.6, 113.8, 111.8 (C−F, 1JC−F = 244.0 Hz),
4
3
(C−F, JC−F = 2.9 Hz), 129.9 (C−F, JC−F = 9.7 Hz), 115.6 (C−F,
2JC−F = 21.2 Hz), 111.5 (C−F, 1JC−F = 244.1 Hz), 90.7 (C−F, 3JC−F
=
6.0 Hz); HRMS (ESI-TOF) m/z calcd for C10H7F3NO− [M−H]−
214.0485, found 214.0490.
(Z)-3-Amino-1-(4-chlorophenyl)-4,4-difluorobut-2-en-1-one
(2g). Purified by flash column chromatography (petroleum ether/
1
AcOEt = 10:1), yellow solid, mp 85−86 °C, 18.5 mg, 80% yield; H
NMR (400 MHz, CDCl3) δ 9.51 (bs, 1H), 7.82 (d, J = 8.6 Hz, 2H),
7.40 (d, J = 8.6 Hz, 2H), 6.13 (t, J = 55.0 Hz, 1H), 5.94 (s, 1H), 5.53
(bs, 1H); 19F NMR (376 MHz, CDCl3) δ −122.65 (d, J = 55.0 Hz,
2F); 19F{1H} NMR (376 MHz, CDCl3) δ −122.65 (s, 2F); 13C{1H}
3
90.9 (C−F, JC−F = 6.1 Hz), 55.5; HRMS (ESI-TOF) m/z calcd for
−
C11H10F2NO2 [M−H]− 226.0685, found 226.0687.
(Z)-3-Amino-1-(4-methoxyphenyl)but-2-en-1-one (2aa).19a Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
3:1), yellow solid, 6.8 mg, 18% yield; 1H NMR (400 MHz, CDCl3) δ
10.13 (bs, 1H), 7.89−7.84 (m, 2H), 6.94−6.88 (m, 2H), 5.71 (s, 1H),
5.09 (bs, 1H), 3.85 (s, 3H), 2.05 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 188.6, 162.2, 161.8, 132.8, 129.0, 113.4, 91.9, 55.3, 22.9.
(Z)-3-Amino-4,4-difluoro-1-(p-tolyl)but-2-en-1-one (2b). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
2
NMR (100 MHz, CDCl3) δ 190.2, 153.8 (C−F, JC−F = 22.3 Hz),
138.3, 137.4, 128.9, 128.8, 111.5 (C−F, 1JC−F = 243.9 Hz), 90.6 (C−
F, 3JC−F = 6.0 Hz); HRMS (ESI-TOF) m/z calcd for C10H7ClF2NO−
[M−H]− 230.0189, found 230.0198.
(Z)-3-Amino-4,4-difluoro-1-(4-(trifluoromethyl)phenyl)but-2-en-
1-one (2h). Purified by flash column chromatography (petroleum
ether/AcOEt = 8:1), white solid, mp 86−87 °C, 23.1 mg, 87% yield;
1H NMR (400 MHz, CDCl3) δ 9.60 (bs, 1H), 7.98 (d, J = 7.9 Hz,
1
off white solid, mp 82−84 °C, 19.4 mg, 92% yield; H NMR (400
MHz, CDCl3) δ 9.45 (bs, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.24 (d, J =
7.9 Hz, 2H), 6.12 (t, J = 55.2 Hz, 1H), 5.99 (s, 1H), 5.44 (bs, 1H),
2.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −122.34 (d, J = 55.2
Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −122.34 (s, 2F);
13C{1H} NMR (100 MHz, CDCl3) δ 191.4, 153.1 (C−F, 2JC−F = 21.5
Hz), 142.7, 136.4, 129.3, 127.5, 111.7 (C−F, 1JC−F = 242.0 Hz), 91.1
2H), 7.69 (d, J = 7.9 Hz, 2H), 6.16 (t, J = 55.0 Hz, 1H), 5.98 (s, 1H),
5.52 (bs, 1H); 19F NMR (376 MHz, CDCl3) δ −62.96 (s, 3F),
−122.81 (d, J = 55.0 Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ
−62.96 (s, 3F), −122.81 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3)
2
2
δ 190.2, 154.4 (C−F, JC−F = 21.9 Hz), 142.0, 133.4 (C−F, JC−F
=
=
3
1
3
32.5 Hz), 127.8, 125.6 (C−F, JC−F = 3.8 Hz), 123.9 (C−F, JC−F
1 3
(C−F, JC−F = 6.0 Hz), 21.6; HRMS (ESI-TOF) m/z calcd for
C11H10F2NO− [M−H]− 210.0736, found 210.0735.
272.4 Hz), 111.3 (C−F, JC−F = 244.1 Hz), 90.7 (C−F, JC−F = 5.9
Hz); HRMS (ESI-TOF) m/z calcd for C11H7NF5O− [M−H]−
264.0453, found 264.0457.
(Z)-3-Amino-4,4-difluoro-1-phenylbut-2-en-1-one (2c). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
1
(Z)-4-(3-Amino-4,4-difluorobut-2-enoyl)benzonitrile (2i). Purified
pale yellow solid, mp 65−68 °C, 17.9 mg, 91% yield; H NMR (400
by flash column chromatography (petroleum ether/AcOEt = 5:1),
MHz, CDCl3) δ 9.49 (bs, 1H), 7.90 (d, J = 7.4 Hz, 2H), 7.54−7.40
(m, 3H), 6.14 (t, J = 55.0 Hz, 1H), 6.01 (s, 1H), 5.50 (bs, 1H); 19F
NMR (376 MHz, CDCl3) δ −122.43 (d, J = 55.0 Hz, 2F); 19F{1H}
NMR (376 MHz, CDCl3) δ −122.43 (s, 2F); 13C{1H} NMR (100
1
pale brown solid, mp 138−140 °C, 17.8 mg, 80% yield; H NMR
(400 MHz, CDCl3) δ 9.64 (bs, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.74 (d,
J = 8.3 Hz, 2H), 6.17 (t, J = 55.0 Hz, 1H), 5.96 (s, 1H), 5.65 (bs,
1H); 19F NMR (376 MHz, CDCl3) δ −122.95 (d, J = 55.0 Hz, 2F);
19F{1H} NMR (376 MHz, CDCl3) δ −122.95 (s, 2F); 13C{1H} NMR
2
MHz, CDCl3) δ 191.6, 153.4 (C−F, JC−F = 22.0 Hz), 139.1, 132.1,
128.6, 127.5, 111.6 (C−F, 1JC−F = 224.0 Hz), 91.1 (C−F, 3JC−F = 6.0
Hz); HRMS (ESI-TOF) m/z calcd for C10H8F2NO− [M−H]−
196.0579, found 196.0577.
2
(100 MHz, CDCl3) δ 189.4, 154.8 (C−F, JC−F = 22.4 Hz), 142.5,
132.5, 127.9, 118.4, 115.2, 111.1 (C−F, 1JC−F = 245.0 Hz), 90.6 (C−
3
F, JC−F = 5.6 Hz); HRMS (ESI-TOF) m/z calcd for C11H7N2F2O−
(Z)-1-([1,1′-Biphenyl]-4-yl)-3-amino-4,4-difluorobut-2-en-1-one
(2d). Purified by flash column chromatography (petroleum ether/
[M−H]− 221.0532, found 221.0532.
4561
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
(Z)-3-Amino-4,4-difluoro-1-(4-nitrophenyl)but-2-en-1-one (2j).
Purified by flash column chromatography (petroleum ether/AcOEt
= 5:1), yellow solid, mp 123−125 °C, 17.9 mg, 74% yield; H NMR
140.1, 137.5, 129.1, 128.2 (2C), 127.4 (2C), 120.6 (C−F, JC−F
=
277.7 Hz), 90.5 (C−F, 3JC−F = 3.5 Hz); HRMS (ESI-TOF) m/z calcd
for C16H11F3NO− [M−H]− 290.0798, found 290.0798.
1
(Z)-3-Amino-4,4,4-trifluoro-1-(4-methoxyphenyl)but-2-en-1-one
(4d). Purified by flash column chromatography (petroleum ether/
AcOEt = 30:1), yellow solid, mp 80−81 °C, 22.5 mg, 92% yield; H
(400 MHz, CDCl3) δ 9.68 (bs, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.04 (d,
J = 8.5 Hz, 2H), 6.19 (t, J = 55.0 Hz, 1H), 5.99 (s, 1H), 5.65 (bs,
1H); 19F NMR (376 MHz, CDCl3) δ −123.01 (d, J = 55.0 Hz, 2F);
19F{1H} NMR (376 MHz, CDCl3) δ −123.01 (s, 2F); 13C{1H} NMR
1
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8
Hz, 2H), 6.20 (s, 1H), 3.86 (s, 3H); 19F NMR (376 MHz, CDCl3) δ
−71.52 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ −71.52 (s, 3F);
13C{1H} NMR (100 MHz, CDCl3) δ 190.6, 163.1, 148.2 (C−F, 2JC−F
= 33.0 Hz), 131.6, 129.7, 120.7 (C−F, 1JC−F = 277.5 Hz), 113.9, 90.3
2
(100 MHz, CDCl3) δ 189.1, 154.9 (C−F, JC−F = 22.4 Hz), 144.1,
128.4, 123.9, 111.1 (C−F, 1JC−F = 246.0 Hz), 90.8 (C−F, 3JC−F = 6.0
−
Hz); HRMS (ESI-TOF) m/z calcd for C10H7N2F2O3 [M−H]−
241.0430, found 241.0431.
3
(C−F, JC−F = 3.5 Hz), 55.5; HRMS (ESI-TOF) m/z calcd for
(Z)-3-Amino-4,4-difluoro-1-(3-fluorophenyl)but-2-en-1-one (2k).
Purified by flash column chromatography (petroleum ether/AcOEt =
10:1), yellow solid, mp 76−78 °C, 20.9 mg, 97% yield; 1H NMR (400
MHz, CDCl3) δ 9.52 (bs, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.61−7.55
(m, 1H), 7.44−7.37 (m, 1H), 7.20 (tdd, J = 8.3, 2.7, 1.0 Hz, 1H),
6.14 (t, J = 54.8 Hz, 1H), 5.94 (s, 1H), 5.55 (bs, 1H); 19F NMR (376
MHz, CDCl3) δ −112.33 to −112.41 (m, 1F), −122.65 (d, J = 54.8
Hz, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −112.37 (s, 1F),
−122.65 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.0 (C−F,
−
C11H9F3NO2 [M−H]− 244.0591, found 244.0587.
(Z)-3-Amino-4,4,4-trifluoro-1-(4-(methylthio)phenyl)but-2-en-1-
one (4e). Purified by flash column chromatography (petroleum ether/
AcOEt = 1:1), pale yellow solid, mp 109−110 °C, 20.9 mg, 80% yield;
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.26 (d, J =
8.1 Hz, 2H), 6.20 (s, 1H), 2.51 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ −71.52 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.52 (s, 3F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.8, 148.6
2
4JC−F = 2.2 Hz), 163.0 (C−F, 1JC−F = 247.4 Hz), 154.0 (C−F, 2JC−F
=
(C−F, JC−F = 33.6 Hz), 145.0, 135.0, 128.0, 125.3, 120.2 (C−F,
1JC−F = 276.4 Hz), 90.3, 15.0; HRMS (ESI-TOF) m/z calcd for
22.0 Hz), 141.3 (C−F, 3JC−F = 6.3 Hz), 130.2 (C−F, 3JC−F = 7.7 Hz),
C11H9F3NOS− [M−H]− 260.0362, found 260.0361.
4
2
123.1 (C−F, JC−F = 3.0 Hz), 119.0 (C−F, JC−F = 21.5 Hz), 114.4
(C−F, 2JC−F = 22.5 Hz), 111.4 (C−F, 1JC−F = 244.1 Hz), 90.8 (C−F,
3JC−F = 6.0 Hz); HRMS (ESI-TOF) m/z calcd for C10H7F3NO− [M−
(Z)-3-Amino-4,4,4-trifluoro-1-(4-fluorophenyl)but-2-en-1-one
(4f). Purified by flash column chromatography (petroleum ether/
AcOEt = 50:1), white solid, mp 65−67 °C, 22.1 mg, 95% yield; H
1
H]− 214.0485, found 214.0488.
NMR (400 MHz, CDCl3) δ 7.99−7.88 (m, 2H), 7.12 (t, J = 8.6 Hz,
2H), 6.18 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −71.56 (s, 3F),
−106.65 to −106.85 (m, 1F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.56 (s, 3F), −106.79 (s, 1F); 13C{1H} NMR (100 MHz, CDCl3)
(Z)-3-Amino-4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)but-2-
en-1-one (2l). Purified by flash column chromatography (petroleum
ether/AcOEt = 6:1), pale yellow solid, mp 75−76 °C, 22.8 mg, 93%
1
yield; H NMR (400 MHz, CDCl3)δ 9.41 (bs, 1H), 7.63−7.60 (m,
1
2
δ 190.3, 165.5 (C−F, JC−F = 253.3 Hz), 149.0 (C−F, JC−F = 33.3
2H), 6.93 (t, J = 8.5 Hz, 1H), 6.12 (t, J = 55.0 Hz, 1H), 5.88 (s, 1H),
5.62 (bs, 1H), 3.89 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −122.35
(d, J = 55.0 Hz, 2F), −134.72 to −134.78 (m, 1F); 19F{1H} NMR
(376 MHz, CDCl3) δ −122.35 (s, 2F), −134.75 (s, 1F); 13C{1H}
NMR (100 MHz, CDCl3) δ 189.2 (C−F, 4JC−F = 1.7 Hz), 153.4 (C−
4
3
Hz), 135.0 (C−F, JC−F = 3.0 Hz), 130.0 (C−F, JC−F = 9.2 Hz),
1
2
120.5 (C−F, JC−F = 277.5 Hz), 115.7 (C−F, JC−F = 21.9 Hz), 90.1
3
(C−F, JC−F = 3.5 Hz); HRMS (ESI-TOF) m/z calcd for
C10H6F4NO− [M−H]− 232.0391, found 232.0391.
(Z)-3-Amino-1-(4-chlorophenyl)-4,4,4-trifluorobut-2-en-1-one
(4g). Purified by flash column chromatography (petroleum ether/
2
1
F, JC−F = 22.0 Hz), 152.1 (C−F, JC−F = 236.8 Hz), 150.8 (C−F,
2JC−F = 10.8 Hz), 132.1 (C−F, 3JC−F = 5.2 Hz), 124.3 (C−F, 3JC−F
=
1
AcOEt = 50:1), yellow solid, mp 81−83 °C, 22.9 mg, 92% yield; H
3.3 Hz), 115.1 (C−F, 2JC−F = 19.2 Hz), 112.4 (C−F, 4JC−F = 1.7 Hz),
NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2
Hz, 2H), 6.18 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −71.54 (s,
3F); 19F{1H} NMR (376 MHz, CDCl3) δ −71.54 (s, 3F); 13C{1H}
1
3
111.6 (C−F, JC−F = 244.0 Hz), 90.3 (C−F, JC−F = 6.0 Hz),
+
56.2;HRMS (ESI-TOF) m/z calcd for C11H11O2NF3 [M + H]+
2
246.0736, found 246.0726.
(Z)-3-Amino-4,4,4-trifluoro-1-(p-tolyl)but-2-en-1-one (4a). Puri-
NMR (100 MHz, CDCl3) δ 190.5, 149.2 (C−F, JC−F = 33.2 Hz),
138.8, 137.1, 129.0 (2C), 120.5 (C−F, 1JC−F = 276.0 Hz), 90.1 (C−F,
3JC−F = 3.5 Hz); HRMS (ESI-TOF) m/z calcd for C10H6ClF3NO−
[M−H]− 248.0095, found 248.0093.
fied by flash column chromatography (petroleum ether/AcOEt =
1
50:1), pale blue solid, mp 85−87 °C, 21.8 mg, 95% yield; H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 7.9 Hz,
2H), 6.23 (s, 1H), 2.41 (s, 3H); 19F NMR (376 MHz, CDCl3) δ
−71.54 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ −71.54 (s, 3F);
13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 148.5 (C−F, 2JC−F = 33.1
Hz), 143.2, 136.2, 129.4, 127.7, 120.7 (C−F, 1JC−F = 276.3 Hz), 90.5
(Z)-4-(3-Amino-4,4,4-trifluorobut-2-enoyl)benzonitrile (4h). Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
5:1), white solid, mp 164−166 °C, 20.6 mg, 86% yield; H NMR
1
(400 MHz, CDCl3) δ 9.64 (bs, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.76 (d,
J = 8.5 Hz, 2H), 6.18 (s, 1H), 5.54 (bs, 1H); 19F NMR (376 MHz,
CDCl3) δ −71.51 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.51 (s, 3F); 13C{1H} NMR (100 MHz, CDCl3) δ 188.8, 149.1
3
(C−F, JC−F = 3.3 Hz), 21.7; HRMS (ESI-TOF) m/z calcd for
C11H9F3NO- [M−H]− 228.0641, found 228.0639.
2
1
(Z)-3-Amino-4,4,4-trifluoro-1-phenylbut-2-en-1-one (4b). Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
50:1), pale green solid, mp 64−66 °C, 19.6 mg, 91% yield; 1H NMR
(400 MHz, CDCl3) δ 7.90 (d, J = 7.7 Hz, 2H), 7.62−7.37 (m, 3H),
6.25 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −71.54 (s, 3F);
19F{1H} NMR (376 MHz, CDCl3) δ −71.54 (s, 3F); 13C{1H} NMR
(C−F, JC−F = 33.4 Hz), 141.1, 131.6, 127.1, 119.3 (C−F, JC−F
=
3
277.0 Hz), 117.3, 114.5, 89.0 (C−F, JC−F = 3.4 Hz); HRMS (ESI-
TOF) m/z calcd for C11H6F3N2O− [M−H]− 239.0437, found
239.0436.
(Z)-3-Amino-4,4,4-trifluoro-1-(4-nitrophenyl)but-2-en-1-one (4i).
Purified by flash column chromatography (petroleum ether/AcOEt =
5:1), yellow solid, mp 140−142 °C, 20.8 mg, 80% yield; H NMR
2
1
(100 MHz, CDCl3) δ 191.9, 148.8 (C−F, JC−F = 33.0 Hz), 138.7,
132.4, 128.7, 127.6, 120.6 (C−F, 1JC−F = 274.6 Hz), 90.5 (C−F, 3JC−F
= 3.3 Hz); HRMS (ESI-TOF) m/z calcd for C10H7F3NO− [M−H]−
214.0485, found 214.0486.
(400 MHz, CDCl3) δ 8.69 (bs, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.04 (d,
J = 8.7 Hz, 2H), 6.20 (s, 1H), 5.66 (bs, 1H); 19F NMR (376 MHz,
CDCl3) δ −71.51 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.51 (s, 3F); 13C{1H} NMR (100 MHz, CDCl3) δ 189.6, 150.2
(Z)-1-([1,1′-Biphenyl]-4-yl)-3-amino-4,4,4-trifluorobut-2-en-1-
one (4c). Purified by flash column chromatography (petroleum ether/
AcOEt = 50:1), yellow solid, mp 138−140 °C, 26.5 mg, 91% yield; 1H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5
Hz, 2H), 7.68−7.61 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.44−7.38 (m,
1H), 6.31 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −71.47 (s, 3F);
19F{1H} NMR (376 MHz, CDCl3) δ −71.47 (s, 3F); 13C{1H} NMR
2
(C−F, JC−F = 33.5 Hz), 150.0, 143.6, 128.6, 124.4, 120.2 (C−F,
1JC−F = 276.0 Hz), 90.1 (C−F, JC−F = 3.3 Hz); HRMS (ESI-TOF)
3
−
m/z calcd for C10H6F3N2O3 [M−H]− 259.0336, found 259.0335.
(Z)-3-Amino-4,4,4-trifluoro-1-(3-fluorophenyl)but-2-en-1-one
(4j). Purified by flash column chromatography (petroleum ether/
1
AcOEt = 50:1), yellow solid, mp 63−65 °C, 21.9 mg, 94% yield; H
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.7 Hz, 1H), 7.62−7.56 (m,
2
(100 MHz, CDCl3) δ 191.4, 148.7 (C−F, JC−F = 33.0 Hz), 145.2,
4562
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 7.46−7.38 (m, 1H), 7.25−7.19 (m, 1H), 6.18 (s, 1H); 19F NMR
(376 MHz, CDCl3) δ −71.55 (s, 3F), −112.11 to −112.18 (m, 1F);
19F{1H} NMR (376 MHz, CDCl3) δ −71.55 (s, 3F), −112.15 (s, 1F);
oil, 18.1 mg, 81% yield; 1H NMR (400 MHz, CDCl3) δ 5.51 (s, 1H),
2.41 (t, J = 7.5 Hz, 1H), 1.53−1.67 (m, 2H), 1.25−1.35 (m, 6H),
0.81−0.91 (m, 3H); 19F NMR (376 MHz, CDCl3) δ −71.75 (s, 3F);
19F{1H} NMR (376 MHz, CDCl3) δ −71.75 (s, 3F); 13C{1H} NMR
4
13C{1H} NMR (100 MHz, CDCl3) δ 190.3 (C−F, JC−F = 2.3 Hz),
2
163.1 (C−F, 1JC−F = 247.4 Hz), 149.4 (C−F, 2JC−F = 33.6 Hz), 140.9
(100 MHz, CDCl3) δ 202.7, 147.0 (C−F, JC−F = 33.0 Hz), 120.5
1
3
3
(C−F, JC−F = 276.0 Hz), 93.7, 43.5, 31.8, 29.1, 25.1, 22.6, 14.2;
(C−F, JC−F = 6.2 Hz), 130.3 (C−F, JC−F = 7.6 Hz), 123.2 (C−F,
HRMS (ESI-TOF) m/z calcd for C10H15F3NO− [M−H]− 222.1111,
found 222.1105.
4JC−F = 3.0 Hz), 120.5 (C−F, 1JC−F = 276.7 Hz), 119.3 (C−F, 2JC−F
=
21.5 Hz), 114.5 (C−F, 2JC−F = 22.4 Hz), 90.2 (C−F, 3JC−F = 3.4 Hz);
HRMS (ESI-TOF) m/z calcd for C10H6F4NO− [M−H]− 232.0391,
found 232.0392.
(Z)-5-Amino-6,6-difluoro-1-phenylhex-4-en-3-one (6e). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
1
colorless oil, 18.5 mg, 82% yield; H NMR (400 MHz, CDCl3) δ
(Z)-N-(3-(3-Amino-4,4,4-trifluorobut-2-enoyl)phenyl)acetamide
7.31−7.24 (m, 2H), 7.22−7.15 (m, 3H), 5.96 (t, J = 55.0 Hz, 1H),
5.27 (s, 1H), 2.93 (t, J = 8.2 Hz, 2H), 2.71 (t, J = 8.2 Hz, 2H); 19F
NMR (376 MHz, CDCl3) δ −122.51 (d, J = 55.0 Hz, 2F); 19F{1H}
NMR (376 MHz, CDCl3) δ −122.51 (s, 2F); 13C{1H} NMR (100
(4k). Purified by flash column chromatography (petroleum ether/
1
AcOEt = 2:1), white solid, mp 142−144 °C, 24.8 mg, 91% yield; H
NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.11 (s, 1H), 7.82 (d, J
= 8.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.12
(s, 1H), 2.06 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −69.60 (s,
3F); 19F{1H} NMR (376 MHz, DMSO-d6) δ −69.60 (s, 3F);
13C{1H} NMR (100 MHz, DMSO-d6) δ 189.7, 168.6, 149.0 (C−F,
2JC−F = 32.6 Hz), 139.7, 139.0, 129.1, 122.5, 121.8, 120.5 (C−F, 1JC−F
2
MHz, CDCl3) δ 200.7, 151.6 (C−F, JC−F = 22.2 Hz), 141.3, 128.6,
128.4, 126.1, 111.5 (C−F, 1JC−F = 245.0 Hz), 94.3 (C−F, 3JC−F = 5.9
Hz), 44.5, 31.0; HRMS (ESI-TOF) m/z calcd for C12H12F2NO− [M−
H]− 224.0892, found 224.0886.
(Z)-5-Amino-6,6,6-trifluoro-1-phenylhex-4-en-3-one (6f). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
3
= 276.5 Hz), 117.5, 87.5 (C−F, JC−F = 3.5 Hz), 24.0; HRMS (ESI-
−
TOF) m/z calcd for C12H10F3N2O2 [M−H]− 271.0700, found
1
blue solid, mp 56−58 °C, 19.4 mg, 80% yield; H NMR (400 MHz,
271.0698.
CDCl3) δ 7.26 (q, J = 7.6 Hz, 2H), 7.21−7.14 (m, 3H), 5.50 (s, 1H),
2.93 (t, J = 7.8 Hz, 2H), 2.74 (t, J = 7.8 Hz, 2H); 19F NMR (376
MHz, CDCl3) δ −71.70 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.70 (s, 3F); 13C{1H} NMR (100 MHz, CDCl3) δ 201.1, 147.2
(Z)-3-Amino-4,4,4-trifluoro-1-(3-fluoro-4-methoxyphenyl)but-2-
en-1-one (4l). Purified by flash column chromatography (petroleum
ether/AcOEt = 10:1), yellow solid, mp 84−86 °C, 24.4 mg, 93%
yield; 1H NMR (400 MHz, CDCl3) δ 7.70−7.63 (m, 2H), 6.98 (t, J =
8.3 Hz, 1H), 6.14 (s, 1H), 3.93 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ −71.56 (s, 3F), −134.35 to −134.45 (m, 1F); 19F{1H}
NMR (376 MHz, CDCl3) δ −71.56 (s, 3F), −134.4 (s, 1F); 13C{1H}
2
(C−F, JC−F = 33.0 Hz), 141.2, 128.6, 128.4, 126.2, 120.4 (C−F,
1JC−F = 279.0 Hz), 93.6, 44.7, 30.8; HRMS (ESI-TOF) m/z calcd for
C12H11F3NO− [M−H]− 242.0798, found 242.0794.
(Z)-3-Amino-4,4,5,5,5-pentafluoro-1-(4-methoxyphenyl)pent-2-
en-1-one (6g). Purified by flash column chromatography (petroleum
ether/AcOEt = 10:1), yellow solid, mp 90−92 °C, 22.7 mg, 77%
1
NMR (100 MHz, CDCl3) δ 189.5, 152.2 (C−F, JC−F = 247.0 Hz),
2
2
151.3 (C−F, JC−F = 10.9 Hz), 148.7 (C−F, JC−F = 33.1 Hz), 131.9
3
3
(C−F, JC−F = 5.1 Hz), 124.5 (C−F, JC−F = 3.2 Hz), 120.6 (C−F,
1JC−F = 275.7 Hz), 115.4 (C−F, 2JC−F = 19.2 Hz), 112.5 (C−F, 4JC−F
= 1.9 Hz), 89.9 (C−F, 3JC−F = 3.5 Hz), 56.4; HRMS (ESI-TOF) m/z
1
yield; H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.6 Hz, 2H), 6.94
(d, J = 8.6 Hz, 2H), 6.16 (s, 1H), 3.86 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ −84.15 (t, J = 1.8 Hz, 3F), −122.84 (q, J = 1.8 Hz, 2F);
19F{1H} NMR (376 MHz, CDCl3) δ −84.15 (t, J = 1.8 Hz, 3F),
−122.84 (q, J = 1.8 Hz, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ
190.3, 163.2, 147.5 (C−F, 2JC−F = 23.9 Hz), 131.6, 129.8, 118.5 (C−
F, 2JC−F = 37.1 Hz, 284.5 Hz), 113.9, 110.4 (C−F, 1JC−F = 258.0 Hz,
38.9 Hz), 92.0 (C−F, 3JC−F = 6.1 Hz), 55.6; HRMS (ESI-TOF) m/z
−
calcd for C11H8F4NO2 [M−H]− 262.0496, found 262.0497.
5-Amino-6,6-difluoro-1-phenylhexa-1,4-dien-3-one (6a). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
1
pale yellow solid, mp 73−75 °C, 19.9 mg, 89% yield; H NMR (400
MHz, CDCl3) δ 7.60−7.51 (m, 3H), 7.42−7.33 (m, 3H), 6.74 (d, J =
16.0 Hz, 1H), 6.08 (t, J = 55.0 Hz, 1H), 5.53 (s, 1H); 19F NMR (376
MHz, CDCl3) δ −122.51 (d, J = 55.0 Hz, 2F); 19F{1H} NMR (376
MHz, CDCl3) δ −122.51 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3)
−
calcd for C12H9F5NO2 [M−H]− 294.0559, found 294.0556.
(Z)-3-Amino-4,4,5,5,6,6,6-heptafluoro-1-(4-methoxyphenyl)hex-
2-en-1-one (6h). Purified by flash column chromatography
(petroleum ether/AcOEt = 10:1), yellow oil, 24.8 mg, 72% yield;
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 9.0 Hz, 2H), 6.94 (d, J =
2
δ 190.0, 152.8 (C−F, JC−F = 22.5 Hz), 140.6, 135.2, 130.1, 129.0,
1
3
128.2, 127.6, 111.5 (C−F, JC−F = 245.3 Hz), 94.9 C−F, JC−F = 6.0
Hz); HRMS (ESI-TOF) m/z calcd for C12H10F2NO− [M−H]−
222.0736, found 222.0733.
9.0 Hz, 2H), 6.15 (s, 1H), 3.86 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ −80.3 (t, J = 9.9 Hz, 3F), −120.0 to −120.1 (m, 2F),
−126.9 (s, 2F); 19F{1H} NMR (376 MHz, CDCl3) δ −80.3 (t, J = 9.9
Hz, 3F), −120.0 to −120.1 (m, 2F), −126.9 (s, 2F); 13C{1H} NMR
(1E,4Z)-5-Amino-6,6,6-trifluoro-1-phenylhexa-1,4-dien-3-one
(6b). Purified by flash column chromatography (petroleum ether/
AcOEt = 20:1), pale green solid, mp 79−81 °C, 20.9 mg, 87% yield;
1H NMR (400 MHz, CDCl3) δ 7.62−7.52 (m, 3H), 7.42−7.34 (m,
2
(100 MHz, CDCl3) δ 190.2, 163.2, 147.5 (C−F, JC−F = 24.3 Hz),
131.6, 129.8, 122.1, 119.2 (C−F, 1JC−F = 288.2, 33.5 Hz), 113.5 (m),
109.2 (m), 92.3 (C−F, 3JC−F = 5.8 Hz), 55.5; HRMS (ESI-TOF) m/z
3H), 6.76 (d, J = 15.9 Hz, 1H), 5.77 (s, 1H); 19F NMR (376 MHz,
CDCl3) δ −71.58 (s, 3F); 19F{1H} NMR (376 MHz, CDCl3) δ
−71.58 (s, 3F); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 148.3
−
calcd for C13H9F7NO2 [M−H]− 344.0527, found 344.0525.
(Z)-3-Amino-1,3-diphenylprop-2-en-1-one (6i). Purified by flash
2
(C−F, JC−F = 33.0 Hz), 141.3, 135.0, 130.3, 129.0, 128.3, 127.4,
column chromatography (petroleum ether/AcOEt = 10:1), yellow oil,
1
1
120.5 (C−F, JC−F = 276.4 Hz), 94.1; HRMS (ESI-TOF) m/z calcd
21.6 mg, 97% yield; H NMR (400 MHz, CDCl3) δ 10.42 (bs, 1H),
for C12H11F3NO− [M + H]+ 242.0787, found 242.0790.
7.99−7.91 (m, 2H), 7.69−7.60 (m, 2H), 7.53−7.38 (m, 6H), 6.15 (s,
1H), 5.59 (bs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2,
163.1, 140.4, 137.7, 131.1, 130.8, 129.1, 128.4, 127.3, 126.5, 91.9;
HRMS (ESI-TOF) m/z calcd for C15H12NO− [M−H]− 222.0924,
found 222.0918.
(Z)-1-([1,1′-Biphenyl]-4-yl)-3-aminohex-2-ene-1,4-dione (6j). Pu-
rified by flash column chromatography (petroleum ether/AcOEt =
10:1), yellow oil, 21.2 mg, 72% yield; 1H NMR (400 MHz, CDCl3) δ
9.50 (bs, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.71−7.61 (m, 4H), 7.50−
7.35 (m, 3H), 6.71 (s, 1H), 6.05 (bs, 1H), 4.40 (q, J = 7.1 Hz, 2H),
1.42 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.4,
164.0, 147.6, 144.7, 140.3, 138.1, 129.0, 128.1 (2C), 127.4, 127.3,
93.4, 62.8, 14.3; HRMS (ESI-TOF) m/z calcd for C18H16NO3− [M−
H]− 294.1135, found 294.1128.
(Z)-2-Amino-1,1-difluorodec-2-en-4-one (6c). Purified by flash
column chromatography (petroleum ether/AcOEt = 10:1), colorless
1
oil, 17.8 mg, 87% yield; H NMR (400 MHz, CDCl3) δ 5.97 (t, J =
55.0 Hz, 1H), 5.26 (s, 1H), 2.35 (t, J = 7.4 Hz, 2H), 1.62−1.51 (m,
2H), 1.32−1.22 (m, 6H), 0.90−0.79 (m, 3H); 19F NMR (376 MHz,
CDCl3) δ −122.47 (d, J = 55.0 Hz, 2F); 19F{1H} NMR (376 MHz,
CDCl3) δ −122.47 (s, 2F); 13C{1H} NMR (100 MHz, CDC13) δ
202.4, 151.4 (C−F, 2JC−F = 22.0 Hz), 111.6 (C−F, 1JC−F = 243.5 Hz),
94.3 (C−F, 3JC−F = 6.0 Hz), 43.2, 31.7, 29.1, 25.3, 22.6, 14.1; HRMS
(ESI-TOF) m/z calcd for C10H16F2NO− [M−H]− 204.1205, found
204.1205.
(Z)-2-Amino-1,1,1-trifluorodec-2-en-4-one (6d). Purified by flash
column chromatography (petroleum ether/AcOEt = 20:1), colorless
4563
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Celecoxib (7).19b Purified by flash column chromatography
(petroleum ether/AcOEt = 2:1), white solid, mp 157−159 °C, 34.7
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02980.
■
sı
1
mg, 91% yield (isomer ratio = 40:1); H NMR (400 MHz, DMSO-
d6)δ 7.89 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 4H), 7.24−7.20 (m,
4H), 7.18 (s, 1 H), 2.31 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ
−60.89 (s, 3F); 19F{1H} NMR (376 MHz, DMSO-d6) δ −60.89 (s,
3F); 13C{1H} NMR (100 MHz, DMSO-d6) δ 145.3, 144.0, 142.2
Experimental procedures, spectroscopic data, and NMR
spectra of new compounds (PDF)
2
(C−F, JC−F = 38.0 Hz), 141.2, 139.2, 129.5, 128.8, 126.9, 126.0,
Accession Codes
1
125.4, 121.3 (C−F, JC−F = 269.0 Hz), 106.2, 20.8.
Mavacoxib (8).19b Purified by flash column chromatography
(CH2Cl2/MeOH = 50:1), white solid, mp 160−162 °C, 36.6 mg,
95% yield (isomer ratio = 70:1); 1H NMR (400 MHz, CDCl3) δ 7.92
(d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.27−7.20 (m, 2H),
7.09 (t, J = 8.6 Hz, 2H), 6.76 (s, 1H), 4.99 (s, 2H); 19F NMR (376
MHz, DMSO-d6) δ −62.51 (s, 3F), −110.12 to −110.20 (m, 1F);
19F{1H} NMR (376 MHz, CDCl3) δ −62.51 (s, 3F), −110.16 (s, 1F);
13C{1H} NMR (100 MHz, CDCl3) δ 163.4 (C−F, 1JC−F = 251.6 Hz),
144.4 (C−F, 2JC−F = 38.8 Hz), 142.4, 141.7, 131.0 (C−F, 3JC−F = 8.8
CCDC 1577900, 2038890−2038891, and 2041334 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Hz), 127.8, 125.7, 124.9 (C−F, 4JC−F = 3.5 Hz), 121.1 (C−F, 1JC−F
=
2
3
269.4 Hz), 116.5 (C−F, JC−F = 22.0 Hz), 106.7 (C−F, JC−F = 1.8
Xiao-Wei Zhang − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, PR China; School of Chemistry
and Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China; orcid.org/0000-0002-2262-
4143; Email: xwzhang@jxnu.edu.cn
Xiang-Guo Hu − National Engineering Research Center for
Carbohydrate Synthesis and Key Laboratory of Small
Functional Organic Molecule, Ministry of Education, Jiangxi
Normal University, Nanchang, Jiangxi 330022, PR China;
orcid.org/0000-0002-5909-2582; Email: xiangguo.hu@
jxnu.edu.cn
Hz).
SC-560 (9).19c Purified by flash column chromatography (petro-
leum ether/AcOEt = 60:1), colorless oil, 32.4 mg, 92% yield (isomer
1
ratio = 22:1); H NMR (400 MHz, CDCl3)δ 7.35−7.30 (m, 2H),
7.29−7.23 (m, 2H), 7.17−7.10 (m, 2H), 6.89−6.84 (m, 2H), 6.69 (s,
1H), 3.82 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −62.3 (s, 3F);
19F{1H} NMR (376 MHz, CDCl3) δ −62.3 (s, 3F); 13C{1H} NMR
2
(100 MHz, CDCl3) δ 160.4, 144.8, 143.5 (C−F, JC−F = 38.1 Hz),
1
138.0, 134.3, 130.3, 129.4, 126.7, 121.4 (C−F, JC−F = 168.7 Hz),
121.3, 114.4, 105.5, 55.4 (d, J = 2.8 Hz).
Deracoxib (10).19d Purified by flash column chromatography
(petroleum ether/AcOEt = 3:2), white crystalline solid,; mp 160−161
1
°C, 37.7 mg, 95% yield (isomer ratio >185:1); H NMR (400 MHz,
Authors
DMSO-d6)δ 7.89 (d, J = 8.6 Hz, 2H), 7.54−7.52 (m, 4H), 7.26−7.17
(m, 2H), 7.14 (t, J = 54.0 Hz, 1H), 7.06−7.04 (m, 1H), 6.98 (s, 1H),
3.85 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −111.88 (d, J = 54.0
Hz, 2F), −134.48 (m, 1F); 19F{1H} NMR (376 MHz, DMSO-d6) δ
−111.88 (s, 2F), −134.48 (s, 1F); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 151.1 (C−F, 1JC−F = 245.0 Hz), 147.8 (C−F, 2JC−F = 10.2 Hz),
Chao Wan − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, PR China
Jian-Yu Pang − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, PR China
Wei Jiang − Research Center for Traditional Chinese Medicine
Resources and Ethnic Minority Medicine, Jiangxi University
of Traditional Chinese Medicine, Nanchang, Jiangxi 330006,
PR China; orcid.org/0000-0002-3206-4856
2
147.2 (C−F, JC−F = 29.0 Hz), 143.6, 143.4, 141.3, 126.8, 125.7,
3
3
125.6 (C−F, JC−F = 3.4 Hz), 121.4 (C−F, JC−F = 7.3 Hz), 116.5
2
4
(C−F, JC−F = 22.3 Hz), 114.0 (C−F, JC−F = 2.0 Hz), 111.3 (C−F,
1JC−F = 232.4 Hz), 105.8, 56.1.
3-(Difluoromethyl)-1-(4-methoxyphenyl)-5-(4-(methylthio)-
phenyl)-1H-pyrazole (11).19e Purified by flash column chromatog-
raphy (petroleum ether/AcOEt = 10:1), colorless crystals, mp 100−
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02980
1
101 °C, 31.5 mg, 91% yield (isomer ratio = 76:1); H NMR (400
MHz, CDCl3)δ 7.22−7.20 (m, 2H), 7.17−7.11 (m, 4H), 6.89−6.86
(m, 2H), 6.76 (t, J = 55.0 Hz, 1H), 6.69 (s, 1H), 3.82 (s, 3H), 2.47 (s,
3H); 19F NMR (376 MHz, CDCl3) δ −111.51 (d, J = 55.0 Hz, 2F);
19F{1H} NMR (376 MHz, CDCl3) δ −111.51 (s, 2F); 13C{1H} NMR
Author Contributions
∥C.W. and J.Y.P. contributed equally.
Notes
2
The authors declare no competing financial interest.
(100 MHz, CDCl3) δ 159.6, 147.3 (C−F, JC−F = 30.0 Hz), 144.5,
1
140.0, 132.9, 129.3, 127.1, 126.3, 126.2, 114.6, 111.7 (C−F, JC−F
=
ACKNOWLEDGMENTS
237.0 Hz), 104.3, 55.9, 15.5.
■
N-(3-(1-(4-Sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-
yl)phenyl)acetamide (12). Purified by flash column chromatography
(CH2Cl2/MeOH = 50:1), colorless oil, 38.6 mg, 91% yield (isomer
ratio = 36:1); 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.87
(d, J = 8.6 Hz, 2H), 7.67 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50−7.57
(m, 4H), 7.31 (t, J = 7.9 Hz, 1H), 7.18 (s, 1H), 6.90 (d, J = 8.0 Hz,
1H), 2.02 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −60.89 (s, 3F);
19F{1H} NMR (376 MHz, CDCl3) δ −60.89 (s, 3F); 13C{1H} NMR
We thank the Natural Science Foundation of Jiangxi province
for funding (20202BABL203006). We also thank Ms. Judy Li
at JXNU for the proofreading.
REFERENCES
■
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
(b) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.
2015, 58, 8315−8359.
(2) (a) Tomashenko, O. A.; Grushin, V. V. Aromatic Trifluor-
omethylation with Metal Complexes. Chem. Rev. 2011, 111, 4475−
2
(100 MHz, DMSO) δ 168.6, 145.2, 144.0, 142.3 (C−F, JC−F = 37.7
Hz), 141.0, 139.8, 129.3, 128.7, 126.8, 125.8, 123.5, 121.2 (C−F,
1JC−F = 268.1 Hz), 119.7, 119.1, 106.5, 24.0; HRMS (ESI-TOF) m/z
calcd for C18H16F3N4O3S+ [M + H]+ 425.0890, found 425.0897.
4564
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4521. (b) Charpentier, J.; Frueh, N.; Togni, A. Electrophilic
Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem.
Rev. 2015, 115, 650−682. (c) Furuya, T.; Kamlet, A. S.; Ritter, T.
Catalysis for fluorination and trifluoromethylation. Nature 2011, 473,
470−477.
Construct Isoxazoles and Isoxazolines. J. Org. Chem. 2020, 85 (23),
15726−15735. For selected examples and reviews from other groups:
(c) Khutorianskyi, A.; Chalyk, B.; Borysko, P.; Kondratiuk, A.;
Mykhailiuk, P. K. Difluoromethyl Nitrile Oxide (CF2HCNO): A
Neglected Chemical Reagent. Eur. J. Org. Chem. 2017, 2017, 3935−
(3) CF3CHN2: (a) Mertens, L.; Koenigs, R. M. Fluorinated
diazoalkanes - a versatile class of reagents for the synthesis of
fluorinated compounds. Org. Biomol. Chem. 2016, 14, 10547−10556.
(b) Mykhailiuk, P. K. 2,2,2-Trifluorodiazoethane (CF3CHN2): A
Long Journey since 1943. Chem. Rev. 2020, 120, 12718−12755.
CF2HCHN2: (c) Mykhailiuk, P. K. In Situ Generation of
Difluoromethyl Diazomethane for [3 + 2]Cycloadditions with
Alkynes. Angew. Chem., Int. Ed. 2015, 54, 6558−6561. CF3N3:
(d) Blastik, Z. E.; Voltrova, S.; Matousek, V.; Jurasek, B.; Manley, D.
W.; Klepetarova, B.; Beier, P. Azidoperfluoroalkanes: Synthesis and
Application in Copper(I)-Catalyzed Azide-Alkyne Cycloaddition.
Angew. Chem., Int. Ed. 2017, 56, 346−349. Fluorinated enol ethers:
(e) Decostanzi, M.; Campagne, J. M.; Leclerc, E. Fluorinated enol
ethers: their synthesis and reactivity. Org. Biomol. Chem. 2015, 13,
7351−7380.
3940. (d) Gonca̧ lves, R. S. B.; Dos Santos, M.; Bernadat, G.; Bonnet-
Delpon, D.; Crousse, B. A one-pot synthesis of 3-trifluoromethyl-2-
isoxazolines from trifluoromethyl aldoxime. Beilstein J. Org. Chem.
́
̃
2013, 9, 2387−2394. (e) Poh, J.-S.; García-Ruiz, C.; Zuniga, A.;
Meroni, F.; Blakemore, D. C.; Browne, D. L.; Ley, S. V. Synthesis of
trifluoromethylated isoxazoles and their elaboration through inter-
and intra-molecular C-H arylation. Org. Biomol. Chem. 2016, 14 (25),
5983−5991. (f) Kumar, V.; Kaur, K. Fluorinated isoxazolines and
isoxazoles: A synthetic perspective. J. Fluorine Chem. 2015, 180, 55−
97. (g) Chalyk, B. A.; Khutorianskyi, A.; Lysenko, A.; Fil, Y.;
Kuchkovska, Y. O.; Gavrilenko, K. S.; Bakanovych, I.; Moroz, Y. S.;
Gorlova, A. O.; Grygorenko, O. O. Regioselective Synthesis of
Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from
Fluoroalkyl Ynones and Binucleophiles. J. Org. Chem. 2019, 84 (23),
15212−15225.
(4) For the versatile reactivities of enaminones: (a) Elassar, A.-Z. A.;
El-Khair, A. A. Recent developments in the chemistry of enaminones.
Tetrahedron 2003, 59, 8463−8480. For selected synthetic methods to
enaminones: (b) Singh, S.; Nerella, S.; Pabbaraja, S.; Mehta, G.
Access to 2-Alkyl/Aryl-4-(1H)-Quinolones via Orthogonal “NH3”
Insertion into o-Haloaryl Ynones: Total Synthesis of Bioactive
Pseudanes, Graveoline, Graveolinine, and Waltherione F. Org. Lett.
2020, 22, 1575−1579. (c) Chandran, R.; Pise, A.; Shah, S. K.; Rahul,
D.; Suman, V.; Tiwari, K. N. Copper-Catalyzed Thiolation of
Terminal Alkynes Employing Thiocyanate as the Sulfur Source
Leading to Enaminone-Based Alkynyl Sulfides under Ambient
Conditions. Org. Lett. 2020, 22, 6557−6561. (d) Liang, X.; Huang,
X.; Xiong, M.; Shen, K.; Pan, Y. Copper(I)-catalyzed N-H olefination
of sulfonamides for N-sulfonyl enaminone synthesis. Chem. Commun.
2018, 54, 8403−8406. (e) Li, Y.; Zhang, R.; Bi, X.; Fu, J.
Multifunctionalization of Unactivated Cyclic Ketones via Synergistic
Catalysis of Copper and Diarylamine: Access to Cyclic alpha-
Enaminone. Org. Lett. 2018, 20, 1207−1211. (f) Lee, D.; Kim, S. M.;
Hirao, H.; Hong, S. H. Gold(I)/Gold(III)-Catalyzed Selective
Synthesis of N-Sulfonyl Enaminone Isomers from Sulfonamides and
Ynones via Two Distinct Reaction Pathways. Org. Lett. 2017, 19,
4734−4737. (g) Kim, J.; Hong, S. H. Organocatalytic activation of
isocyanides: N-heterocyclic carbene-catalyzed enaminone synthesis
from ketones. Chem. Sci. 2017, 8, 2401−2406. (h) Yu, D.; Sum, Y. N.;
Ean, A. C. C.; Chin, M. P.; Zhang, Y. Acetylide Ion (C22) as a
Synthon to Link Electrophiles and Nucleophiles: A Simple Method
for Enaminone Synthesis. Angew. Chem., Int. Ed. 2013, 52, 5125−
5128.
(5) (a) Lee, L. F.; Sing, Y. L. Syntheses of trifluoromethylated
pyridinones and pyrimidinones. J. Org. Chem. 1990, 55, 380−384.
(b) Gellerman, G.; Pariente, N.; Paz, Z.; Shnaiderman, A.; Yarden, O.
Synthesis and antifungal activity of β-trifluoroalkyl aminovinyl ketone
derivatives. J. Agric. Food Chem. 2009, 57, 8303−8307. (c) Baldwin, A.
G.; Tapia, V. S.; Swanton, T.; White, C. S.; Beswick, J. A.; Brough, D.;
Freeman, S. Design, Synthesis and Evaluation of Oxazaborine
Inhibitors of the NLRP3 Inflammasome. ChemMedChem 2018, 13,
312−320.
(6) (a) Luo, B. H.; Guan, H. P.; Hu, C. M. One-pot synthesis of
(fluoroalkyl)pyrimidines from α-fluoroalkyl carbonyl compounds,
orthoesters, and ammonium carbonate. Synlett 1997, 1997, 1261−
1262. (b) Vasil’ev, L. S.; Prezent, M. A.; Ignatenko, A. V.; Dorokhov,
V. A. 2-(N-Alkylamino)-1-(trifluoroacetimidoyl)vinyl ketone deriva-
tives as potential reagents in heterocyclic synthesis. Russ. Chem. Bull.
2008, 57, 2359−2363.
(8) (a) Sviridov, S. I.; Vasil’ev, A. A.; Shorshnev, S. V.
Straightforward transformation of isoxazoles into pyrazoles: renewed
and improved. Tetrahedron 2007, 63, 12195−12201. (b) D’Alcontres,
G. S. Hydrogenation of isoxazoles with Raney nickel. Gazz. Chim. Ital.
1950, 80, 441−455. (c) Stork, G.; Ohashi, M.; Kamachi, H.;
Kakisawa, H. Pyridine synthesis via 4-(3-oxoalkyl)isoxazoles. J. Org.
Chem. 1971, 36, 2784−2786. (d) Liu, X.; Hong, D.; Sapir, N. G.;
Yang, W.; Hersh, W. H.; Leung, P. H.; Yang, D.; Chen, Y. Iron-
Catalyzed Transfer Hydrogenation in Aged N-Methyl-2-pyrrolidone:
Reductive Ring-Opening of 3,5-Disubstituted Isoxazoles and Isoxazo-
lines. J. Org. Chem. 2019, 84, 16204−16213.
(9) (a) Buechi, G.; Vederas, J. C. Interchange of functionality in
conjugated carbonyl compounds through isoxazoles. J. Am. Chem. Soc.
1972, 94, 9128−9132. (b) Natale, N. R. Selective reduction of
isoxazoles with samarium diiodide. Tetrahedron Lett. 1982, 23, 5009−
5012. (c) Kulinkovich, O.; Churykau, D.; Zinovich, V. A Convenient
and Chemoselective Method for the Reductive Ring Cleavage of
Isoxazoles and Isoxazolines with EtMgBr/Ti(Oi-Pr)4 Reagent. Synlett
2004, 2004, 1949−1952. (d) Nitta, M.; Kobayashi, T. Reductive ring
opening of isoxazoles with Mo(CO)6 and water. J. Chem. Soc., Chem.
Commun. 1982, 877−878. (e) Nitta, M.; Kobayashi, T. Metal-
carbonyl-induced reaction of isoxazoles. Ring cleavage and reduction
by hexacarbonylmolybdenum, pentacarbonyliron, or nonacarbonyldi-
́
iron. J. Chem. Soc., Perkin Trans. 1 1985, 1401−1406. (f) Kovacs, S.;
́
Novak, Z. Copper on iron promoted one-pot synthesis of β-
aminoenones and 3,5-disubstituted pyrazoles. Tetrahedron 2013, 69,
8987−8993. (g) Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A.
M. Iron dichloride induced isomerization or reductive cleavage of
isoxazoles: A facile synthesis of 2-carboxy-azirines. Tetrahedron 1997,
53, 10911−10920.
(10) Copper/diamine is a well-established catalytic system for the
C−N, C−O, C−halogen bond formation. For a review: (a) Surry, D.
S.; Buchwald, S. L. Diamine Ligands in Copper-Catalyzed Reactions.
Chem. Sci. 2010, 1, 13−31. For selected early examples: (b) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. A General and Efficient
Copper Catalyst for the Amidation of Aryl Halides and the N-
Arylation of Nitrogen Heterocycles. J. Am. Chem. Soc. 2001, 123,
7727−7729. (c) Nakajima, M.; Miyoshi, I.; Kanayama, K.;
Hashimoto, S.-i.; Noji, M.; Koga, K. Enantioselective Synthesis of
Binaphthol Derivatives by Oxidative Coupling of Naphthol
Derivatives Catalyzed by Chiral Diamine·Copper Complexes. J. Org.
Chem. 1999, 64, 2264−2271.
(11) Faller, J. W.; Brummond, K. M.; Mitasev, B. Hexacarbonylmo-
lybdenum. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L., Ed.; John Wiley & Sons: New York, 2006. DOI: 10.1002/
047084289X.rh004.pub2.
(12) One of the authors attempted to do an experiment of N-
arylation of pyrazole, and wrongly took an isoxazole substrate as a
pyrazole compound.
(7) (a) Zhang, X.-W.; Hu, W.-L.; Chen, S.; Hu, X.-G. Cu-Catalyzed
Synthesis of Fluoroalkylated Isoxazoles from Commercially Available
Amines and Alkynes. Org. Lett. 2018, 20, 860−863. (b) Zhang, X. W.;
He, X. L.; Yan, N.; Zheng, H. X.; Hu, X. G. Oxidize Amines to Nitrile
Oxides: One Type of Amine Oxidation and Its Application to Directly
4565
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(13) D2O and deuterated t-DMACH were also used in this reaction
to detect where the hydrogens on the nitrogen atom come from.
However, no conclusive results could be obtained, mainly because
they are not so reliable for integration, and they are also
interchangeable with protons from D2O and the ligand.
yl) phenyl] pyrazole and Related Compounds. Chem. Pharm. Bull.
1997, 45, 1475−1481.
(14) (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. Synthesis and biological evaluation of the 1,5-diarylpyrazole
class of cyclooxygenase-2 inhibitors: Identification of 4−5-(4-methyl
-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl benzene-sulfonami-de
(SC-58635, Celecoxib). J. Med. Chem. 1997, 40, 1347−1365.
(b) Smith, C. J.; Zhang, Y.; Koboldt, C. M.; Muhammad, J.;
Zweifel, B. S.; Shaffer, A.; Talley, J. J.; Masferrer, J. L.; Seibert, K.;
Isakson, P. C. Pharmacological analysis of cyclooxygenase-1 in
inflammation. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 13313−
13318. (c) Mykhailiuk, P. K. Fluorinated Pyrazoles: From Synthesis
to Applications. Chem. Rev. 2020, DOI: 10.1021/acs.chem-
rev.0c01015.
(15) (a) Gaulier, S. M.; McKay, R.; Swain, N. A. A novel three-step
synthesis of celecoxib via palladium-catalyzed direct arylation.
Tetrahedron Lett. 2011, 52, 6000−6002. (b) Li, F.; Nie, J.; Sun, L.;
Zheng, Y.; Ma, J. A. Silver-Mediated Cycloaddition of Alkynes with
CF3CHN2: Highly Regioselective Synthesis of 3-Trifluoromethyl-
pyrazoles. Angew. Chem., Int. Ed. 2013, 52, 6255−6258. (c) Zhu, C.;
Zeng, H.; Liu, C.; Cai, Y.; Fang, X.; Jiang, H. Regioselective Synthesis
of 3-Trifluoromethylpyrazole by Coupling of Aldehydes, Sulfonyl
Hydrazides, and 2-Bromo-3,3,3-trifluoropropene. Org. Lett. 2020, 22,
809−813.
(16) Sthalam, V. K.; Singh, A. K.; Pabbaraja, S. An Integrated
Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS)
for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors.
Org. Process Res. Dev. 2019, 23, 1892−1899.
(17) (a) Hsieh, M.-T.; Kuo, S.-C.; Lin, H.-C. Solvent- and
Transition Metal Catalyst-Dependent Regioselectivity in the [3 + 2]
Cyclocondensation of Trifluoromethyl-α,β-ynones with Hydrazines:
Switchable Access to 3- and 5-Trifluoromethyl-pyrazoles. Adv. Synth.
Catal. 2015, 357, 683−689. (b) Muzalevskiy, V. M.; Rulev, A. Y.;
Romanov, A. R.; Kondrashov, E. V.; Ushakov, I. A.; Chertkov, V. A.;
Nenajdenko, V. G. Selective, Metal-Free Approach to 3- or 5-CF3-
Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with
Hydrazines. J. Org. Chem. 2017, 82, 7200−7214.
(18) Fluorinated β-diketones are generally prepared via a based
mediated process as shown below, which is not compatible with
compounds with an activated hydrogen (e.g., NH in 12 in Table 5).
(19) (a) Li, J.-H.; Xu, S.-L.; Li, C.-P. Solid-State Synthesis of β-
Enamino Ketones from Solid 1,3-Dicarbonyl Compounds and
Ammonium Salts or Amines. Synlett 2009, 2009, 818−822.
(b) Britton, J.; Jamison, T. F. Synthesis of Celecoxib, Mavacoxib,
SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow
Reaction Modules. Eur. J. Org. Chem. 2017, 2017, 6566−6574.
(c) Utecht, G.; Fruzinski, A.; Jasinski, M. Polysubstituted 3-
trifluoromethylpyrazoles: regioselective (3 + 2)-cycloaddition of
trifluoroacetonitrile imines with enol ethers and functional group
transformations. Org. Biomol. Chem. 2018, 16, 1252−1257. (d) Talley,
J. J.; Penning, T. D.; Collins, P. W.; Rogier, D. J., Jr.; Malecha, J. W.;
Miyashiro, J. M.; Bertenshaw, S. R.; Khanna, I. K.; Graneto, M. J.;
Rogers, R. S.; Carter, J. S.; Docter, S. H.; Yu, S. S. US 6492411 B1,
2002. (e) Tsuji, K. K. N.; Spears, G. W.; Ogino, T.; Nakamura, K.;
Tojo, T.; Ochi, T.; Shimojo, F.; Senoh, H.; Matsuo, M. Studies on
Anti-inflammatory Agents. V. Synthesis and Pharmacological Proper-
ties of 3-(Difluoromethyl)-1-(4-methoxy-phenyl)-5-[4-(methylsulfin-
4566
https://dx.doi.org/10.1021/acs.joc.0c02980
J. Org. Chem. 2021, 86, 4557−4566