Direct Synthesis of N-Difluoromethyl-2-pyridones from Pyridines

Article abstract of DOI:10.1021/acs.joc.1c00228

A novel method for the synthesis of N-difluoromethyl-2-pyridones was described. This protocol enables the synthesis of N-difluoromethyl-2-pyridones from readily available pyridines using mild reaction conditions that are compatible with a wide range of functional groups. The preliminary mechanistic study revealed that N-difluoromethylpyridinium salts were the key intermediates to complete this conversion.

Full text of DOI:10.1021/acs.joc.1c00228

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Direct Synthesis of N‑Difluoromethyl-2-pyridones from Pyridines
Sen Zhou, Xiaoya Hou, Kai Yang, Minjie Guo,* Wentao Zhao, Xiangyang Tang, and Guangwei Wang*
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ABSTRACT: A novel method for the synthesis of N-difluoromethyl-2-pyridones was described. This protocol enables the synthesis
of N-difluoromethyl-2-pyridones from readily available pyridines using mild reaction conditions that are compatible with a wide
range of functional groups. The preliminary mechanistic study revealed that N-difluoromethylpyridinium salts were the key
intermediates to complete this conversion.
elective introduction of fluorine into organic molecules is a
well-established strategy for the design and optimization of
Scheme 1. Recent Advances in the Synthesis of N-CF2H-2-
Pyridones
S
bioactive molecules, since the fluorinated compounds have
enhanced lipophilicity, metabolic stability, and receptor
binding affinity,1 among which the incorporation of difluor-
omethyl group (CF2H)2 into organic molecules receives
special attention because the CF2H moiety, known to be
isosteric and isopolar to a carbinol (CH2OH) unit and also, as
a lipophilic group, can act as a hydrogen donor through weak
hydrogen bonding interactions.3 N-Methyl-2-pyridones are
frequently encountered motifs in many pharmaceuticals and
biologically active molecules.4 Therefore, N-difluoromethyl-2-
pyridone may be a potential surrogate for bioactive molecules
bearing N-methyl-2-pyridone. Moreover, previous studies have
shown that N-difluoromethyl-2-pyridone units provide the
novel pharmacophore with anti-inflammatory activities.5
However, only limited methods have been developed for the
construction of N-difluoromethyl-2-pyridone. For example, in
2006, Ando et al. reported a one-pot synthesis of N-
difluoromethyl-2-pyridone derivatives, where there must be
an acetamido group at the ortho-position of pyridine rings
(Scheme 1a).6 In 2010, Knaus et al. developed a method for
the synthesis of N-difluoromethyl-2-pyridone derivatives,
where FSO2CF2CO2H served as a CF2H source and the
ortho-position of pyridine rings must contain halogens
(Scheme 1b).7 Therefore, more practical protocols are still
needed for the synthesis of N-difluoromethyl-2-pyridone.
In the currently available methods, it is required to
prefunctionalize the ortho-position to facilitate further
conversion to the ketone group. However, the ortho-position
of pyridine ring is the activation site. If the oxidative
dearomatization of the ortho-site can be realized, 2-pyridone
can be directly generated from pyridine without any
prefunctionalization. In recent years, difluoromethylation of
various substrates has been widely studied in our group.8
Recently, a copper-catalyzed dearomatization−difunctionaliza-
tion of pyridines has been disclosed.9 N-Difluoromethylacet-
lyation of pyridines possibly leads to corresponding N-
difluoromethylpyridinium salts, which serve as activated
pyridines for the subsequent transformation. Therefore, we
Received: January 29, 2021
Published: April 27, 2021
https://doi.org/10.1021/acs.joc.1c00228
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6879−6887
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envisioned that it is possible to construct N-difluoromethyl-2-
pyridones through oxidation of N-difluoromethylpyridinium
salts. However, different from N-alkyl/acylpyridinium salts
which are easy to access through the reaction of pyridines with
alkyl/acyl halides,10 N-difluoromethylpyridinium salts are
difficult to synthesize, especially for pyridines involving
electron-withdrawing groups. Due to the difficulty in
preparation, the subsequent conversion of N-difluoromethyl-
pyridinium salts is greatly limited. Until now, only a few
examples about the synthesis of N-difluoromethylpyridinium
peroxide (30% in water) as an oxidant led to a low yield (29%)
of 3a. Next, we screened other solvents for this transformation,
but these solvents could not afford better yields than MeCN
(Table 1, entries 11−15). Notably, 1,2-dichloroethane (DCE)
was also effective, affording product 3a in 82% yield. In the
absence of TBHP or DBU, no reaction occurred. On the basis
of the above screening results, we chose the following reaction
parameters as the optimized conditions: TBHP as an oxidant,
DBU as a base, and MeCN as a solvent under 80 °C.
With the optimized conditions in hand, we evaluated the
substrate scope of the reaction (Scheme 2). Pyridines with
various substitutions at the meta-position could proceed well,
affording the corresponding N-difluoromethyl-2-pyridones in
good to excellent yields. For example, when 3-acetylpyridine
salts were reported.11 In 2020, Marchan et al. reported the
́
synthesis of the N-difluoromethylpyridinium salts by using
ethyl bromodifluoroacetate.11c Recently, we reported a
nucleophilic addition of in situ generated N-difluoromethylpyr-
idinium salts with nitroalkanes to synthesize N-CF2H-
dihydropyridines in a highly efficient way.11d Herein, we
describe a facile one-pot synthesis of N-difluoromethyl-2-
pyridones from pyridines, which might involve in situ
generation of N-difluoromethylpyridinium salts followed by
oxidization by tert-butyl hydroperoxide (TBHP) (Scheme 1c).
We began our study by investigating the reaction between 3-
acetylpyridine (1a) and ethyl bromodifluoroacetate (2) using
TBHP (70% in water) as an oxidant in MeCN. It was
gratifying that product 3a was isolated with a 30% yield in the
presence of K2CO3 (Table 1, entry 1). Further screening of
a b
,
Scheme 2. Scope of N-CF2H-2-Pyridones
a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
base
solvent
yield /%
1
2
3
4
5
6
7
8
TBHP (aq)
TBHP (aq)
TBHP (aq)
TBHP (aq)
TBHP (aq)
TBHP (aq)
H2O2 (aq)
DTBP
K2CO3
Cs2CO3
Na2CO3
NaOH
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
−
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
DMF
Tol
THF
dioxane
MeCN
MeCN
30
12
41
43
77
86(81)
29
nr
9
K2S2O8
m-CPBA
nr
nr
10
11
12
13
14
15
16
17
TBHP (aq)
TBHP (aq)
TBHP (aq)
TBHP (aq)
TBHP (aq)
−
82
73
67
23
49
nr
TBHP (aq)
nr
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv), 2 (2.0 mmol, 2.0
equiv), oxidant (2.0 mmol, 2.0 equiv), base (1.5 mmol, 1.5 equiv),
b
solvent (0.3 M), 80 °C, 12 h. Yields determined by GC. The value in
parentheses is the isolated yield. nr: no reaction.
other bases revealed that organic bases could effectively
promote the conversion processes (Table 1, entries 2−6).
When 1,8-diazabicyclo[5.4.0]undecane-7-ene (DBU) was used
as a base, product 3a was afforded with the isolation yield
being 81% (Table 1, entry 6). Subsequently, other oxidants
were screened for this transformation (Table 1, entries 7−10).
No desired product 3a was formed except that using hydrogen
a
Reaction conditions: 1 (1.0 mmol, 1.0 equiv), 2 (2.0 mmol, 2.0
t
equiv), BuO2H (2.0 mmol, 2.0 equiv, 70% in water), DBU (1.5
b
mmol, 1.5 equiv), MeCN (0.3 M), 80 °C, 12 h. Isolated yields.
c
DCE as a solvent.
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a b
,
was subjected to the reactions, product 3a could be isolated
with 81% yield. Similarly, 5-benzoyl (3b) and 5-formyl-N-
difluoromethyl-2-pyridones (3c) were obtained with 70% and
66% yields. When 3-chloropyridine and 3-bromopyridine were
applied to the reactions, the products 3d and 3e were obtained
with 42% and 54% yields, where the oxidation mainly occurred
at the position that is between 3-halogen and pyridine N atom.
3-Cyanopyridine was also suitable for the transformation,
affording product 3f with a 63% yield. Besides, pyridines
containing ester groups at the meta-position of the pyridine
ring could deliver corresponding N-difluoromethyl-2-pyridones
in good yields from 61% to 84% (3g−3j). Next, under the
same conditions, pyridines containing acylamino groups
provided the desired products with 47% to 82% yields (3k−
3n). Besides, 3-tosylpyridine also underwent smoothly to
afford product 3o with 59% yields. It was noteworthy that
when we introduced amino acid esters to the pyridine rings,
they could proceed well and provide the corresponding N-
difluoromethyl-2-pyridones in good yields (3p−3q). It was
important to develop methods that could be used to modify
biologically active molecular architectures in late-stage. As
shown in Scheme 2, biologically active molecules, such as
geraniol, estrone, and cholesterol derivatives, could also be
applied to the conversions, delivering the target products with
41% to 72% yields (3r−3t). However, pyridines with electron-
withdrawing groups at the ortho- or para-position of the
pyridine ring did not participate in this reaction.
Scheme 3. Scope of N-CF2H-2-Quinolinones
a
Reaction conditions: 1 (1.0 mmol, 1.0 equiv), 2 (2.0 mmol, 2.0
t
equiv), BuO2H (2.0 mmol, 2.0 equiv, 70% in water), DBU (1.5
b
mmol, 1.5 equiv), solvent (0.3 M), 80 °C, 12 h. Isolated yields.
c
DBU (1.5 equiv), K2CO3 (1.5 equiv).
In addition to pyridines bearing electron-withdrawing
groups, other pyridines were also tested. However, for
pyridines possessing a methyl or N,N-dimethylamino group,
the corresponding N-difluoromethyl-2-pyridone was not
detected under the same reaction conditions. Instead, only
N-difluoromethylpyridinium salts were isolated. When pyridine
was subjected to the reaction conditions, N-difluoromethylpyr-
idinium salt was isolated in 22% yield together with N-
difluoromethyl-4-pyridone (19%). When 4-methoxypyridine or
4-hydroxypyridine was subjected to the standard reaction
conditions, only N-difluoromethyl-4-pyridone was obtained in
a high yield for both cases. When 2-hydroxypyridine was used,
2-(difluoromethoxy)pyridine was afforded in 81% yield, and no
N-difluoromethyl-2-pyridone was detected (see Supporting
Information for the details and discussions of these reactions).
Subsequently, the substrate scope of quinolines was also
explored (Scheme 3). Various substitutions at the quinoline
rings were also compatible for the above reaction conditions,
affording N-difluoromethyl-2-quinolinones with moderate to
good yields. When quinoline was conducted to the reaction
conditions, product 4a could be isolated with 85% yield.
Various substitution groups, such as 6-bromo (4b), 6-chloro
(4c), 4-chloro (4e), 4-acetamido (4f) could be well tolerated,
resulting in the desired products with moderate yields from
43% to 56%. Isoquinoline was also suitable for the conditions,
delivering product 4d with 82% yield. Besides, when 4-
chloroquinoline was applied to this transformation process, 4-
chloro-N-difluoromethyl-2-quinolinone (4ga) was obtained in
17% yield together with N-difluoromethyl-4-quinolinone
(4gb) in 51% yield. However, 8-bromoquinoline could not
afford the expected product 4h.
Scheme 4. Control Experiments
To gain mechanistic insight into the reactions, several
control experiments were conducted (Scheme 4). First, when
the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine
1-oxide) was added to the reaction mixture, no inhibition
occurred, and product 3a was formed with 73% yield, which
indicated that this transformation might not involve a radical
pathway (Scheme 4a). Since DBU might be oxidized by TBHP
to form N-oxide, TEMPO was used instead of DBU and
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analyses were performed on an Agilent 7890 gas chromatography
TBHP, but no 3a was formed, so N-oxide was not a true
oxidant in this transformation (Scheme 4b). In addition, when
2-thiopyridine was added to the reaction mixture in order to
capture difluorocarbene, 29% of 3a was isolated with 46% of
disulfide 5, which was attributed to the oxidation of 2-
thiopyridine by TBHP (Scheme 4c). Subsequently, deuterium-
labeling experiments were performed to explore the source of
hydrogen in the CF2H group. When 10.0 equiv of deuterium
oxide was added to the reaction conditions, 57% of 3a-D was
obtained with 65% D in the CF2D group (Scheme 4d). Next,
when CD3CN was used as the solvent instead of CH3CN, no
deuterated product 3a-D was detected. Instead, only the
nondeuterated product 3a was isolated in 71% yield (Scheme
4e). These results showed that the hydrogen in the CF2H
group came from water in the TBHP aqueous solution.
On the basis of the experimental results described above and
previous work,11c,12 the postulated mechanism was depicted in
Scheme 5. First, difluorocarbene (:CF2) could be formed from
instrument using an HP-5 capillary column (30 m × 0.32 mm, 0.5 μm
1
film). H, 13C, and 19F NMR spectra were recorded in CDCl3 or
DMSO-d6 on a Bruker AVANCE III, JEOL JNM−ECZ400S/L1
spectrometer or JEOL JNM−ECZ600R spectrometer. Chemical shifts
(δ) are reported in ppm, and coupling constants (J) are in hertz (Hz).
The following abbreviations were used to explain the multiplicities: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-
resolution mass spectra (HRMS) were recorded on a QTOF mass
analyzer with electrospray ionization (ESI) through Waters G2−XS
QTOF. Melting points were measured in an X-6 Micro melting point
apparatus purchased from Beijing TECH Instrumental Company.
Pyridines (1h−1t) were synthesized according to the reported
procedures.13,14
5-Acetyl-1-(difluoromethyl)pyridin-2(1H)-one (3a): representa-
tive procedure I. The oven-dried 25 mL Schlenk tube equipped
with a magnetic stirring bar was backfilled with argon. Next, MeCN
(3.0 mL) was added. Subsequently, 3-acetylpyridine (110 μL, 1.0
mmol, 1.0 equiv), BrCF2CO2Et (256 μL, 2.0 mmol, 2.0 equiv), DBU
(224 μL, 1.5 mmol, 1.5 equiv), and TBHP (290 μL, 2.0 mmol, 2.0
equiv, 70% in water) were added successively. The reaction mixture
was stirred for 12 h under 80 °C (oil bath). The reaction mixture was
diluted with EtOAc and filtered with a pad of Celite. The filtrate was
concentrated, and the residue was purified with silica gel
chromatography (petroleum ether/EtOAc = 2:1) to give the target
Scheme 5. Proposed Mechanism
1
product 3a (148.8 mg, 81% yield) as a yellow oil. H NMR (400
MHz, CDCl3): δ 8.17 (d, J = 2.5 Hz, 1H), 7.90 (ddd, J = 9.8 Hz, 2.6
Hz, 1.3 Hz, 1H), 7.63 (t, 2JH−F = 60.0 Hz, 1H), 6.53 (d, J = 10.1 Hz,
1H), 2.45 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 192.5,
160.4, 138.8, 134.5 (t, 3JC−F = 3.3 Hz), 121.3, 119.1, 107.5 (t, 1JC−F
=
=
254.0 Hz), 25.6. 19F NMR (376 MHz, CDCl3): δ −103.66 (d, 2JF−H
59.9 Hz, 2F). IR (KBr): νmax 3079, 1702, 1672, 1622, 1554, 1150,
+
1070. HRMS (ESI) m/z: [M + H]+ calcd for C8H8F2NO2 , 188.0518;
found, 188.0521.
5-Benzoyl-1-(difluoromethyl)pyridin-2(1H)-one (3b). The title
compound was prepared according to representative procedure I.
The title compound was purified with silica gel chromatography
(petroleum ether/EtOAc = 2:1) as a yellow gum (173.5 mg, 70%
yield). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 2.5 Hz, 1H), 7.94
(dd, J = 9.7 Hz, 2.5 Hz, 1H), 7.73−7.67 (m, 2H), 7.66 (t, 2JH−F = 59.9
Hz, 1H), 7.64−7.56 (m, 1H), 7.55−7.43 (m, 2H), 6.62 (d, J = 9.7 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 191.1, 160.4, 140.4, 136.5,
3
136.3 (t, JC−F = 3.5 Hz), 133.0, 129.2, 128.9, 121.4, 118.6, 107.5 (t,
1JC−F = 254.0 Hz). 19F NMR (376 MHz, CDCl3): δ −103.58 (d, 2JF−H
= 60.0 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd for
C13H10F2NO2 , 250.0674; found, 250.0680.
the ethyl bromodifluoroacetate under basic conditions.
Second, 3-acetylpyridine reacted with difluorocarbene to
form N-difluoromethyl-substituted pyridinium ylide I. Then
intermediate I underwent rapid protonation, affording the
intermediate II, which was oxidized by TBHP under basic
conditions to give intermediate III. Finally, the target product
3a was obtained by deprotonation.
In summary, we have developed an efficient one-pot strategy
for the synthesis of N-difluoromethyl-2-pyridones and N-
difluoromethyl-2-quinolinones. This protocol exhibits simple-
operation, excellent functional group tolerance, and high yields.
Besides, some bioactive molecules have also been successfully
applied to the conversions, which increase its potential
application. Further studies to elucidate the detailed reaction
mechanism and apply this strategy to more complicated
molecules are underway in our laboratory.
+
1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde
(3c). The title compound was prepared according to representative
procedure I. The title compound was purified with silica gel
chromatography (petroleum ether/EtOAc = 2:1) as a yellow oil
(113.7 mg, 66% yield). 1H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H),
8.08 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 9.8 Hz, 2.4 Hz, 1H), 7.66 (t,
2JH−F = 59.9 Hz, 1H), 6.62 (d, J = 9.7 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3): δ 185.8, 160.6, 139.2 (t, 3JC−F = 3.8 Hz), 136.8, 122.3,
1
119.4, 107.4 (t, JC−F = 254.6 Hz). 19F NMR (376 MHz, CDCl3): δ
−103.71 (d, 2JF−H = 59.9 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd
+
for C7H6F2NO2 , 174.0361; found, 174.0368.
3-Chloro-1-(difluoromethyl)pyridin-2(1H)-one (3d). The title
compound was prepared according to representative procedure I.
The title compound was purified with silica gel chromatography
(petroleum ether/EtOAc = 5:1) as a yellow oil (74.7 mg, 42% yield).
2
1H NMR (400 MHz, CDCl3): δ 7.63 (t, JH−F = 60.1 Hz, 1H), 7.53
(dd, J = 7.2 Hz, 1.8 Hz, 1H), 7.39 (dd, J = 7.2 Hz, 1.9 Hz, 1H), 6.25
(t, J = 7.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.5,
EXPERIMENTAL SECTION
■
3
1
138.9, 128.0 (t, JC−F = 3.8 Hz), 127.0, 107.8 (t, JC−F = 253.3 Hz),
106.6. 19F NMR (376 MHz, CDCl3): δ −102.88 (d, 2JF−H = 60.7 Hz,
2F). HRMS (ESI) m/z: [M + H]+ calcd for C6H5ClF2NO+, 180.0022;
found, 180.0020.
General Information. All experiments were conducted in flame-
dried glassware under an argon atmosphere. All reagents were
purchased from commercial sources and used without further
purification, unless otherwise stated. Flash chromatographic separa-
tions were carried out on 200−300 mesh silica gel. Reactions were
monitored by TLC and GC analysis of the reaction aliquots. GC
3-Bromo-1-(difluoromethyl)pyridin-2(1H)-one (3e). The title
compound was prepared according to representative procedure I.
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The title compound was purified with silica gel chromatography
(petroleum ether/EtOAc = 5:1) as a yellow oil (120.4 mg, 54% yield,
C2 isomer/C6 isomer = 1:0.07). HRMS (ESI) m/z: [M + H]+ calcd
Hz, 1H), 7.44−7.38 (m, 1H), 6.51 (d, J = 9.8 Hz, 1H), 6.46 (d, J =
3.2 Hz, 1H), 6.36 (dd, J = 3.2 Hz, 1.9 Hz, 1H), 5.25 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 163.1, 160.5, 148.9, 143.6, 139.9, 135.4
(t, 3JC−F = 3.6 Hz), 120.9, 111.4, 111.2, 110.7, 107.4 (t, 1JC−F = 254.2
Hz), 58.9. 19F NMR (376 MHz, CDCl3): δ −103.72 (d, 2JF−H = 59.9
Hz, 2F). HRMS (ESI) m/z: [M + Na]+ calcd for C12H9F2NO4Na+,
292.0392; found, 292.0399.
1
for C6H5BrF2NO+ 223.9517; found, 223.9519. C2 isomer: H NMR
(400 MHz, CDCl3): δ 7.72 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 7.58 (t,
2JH−F = 60.1 Hz, 1H), 7.41 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 6.17 (t, J =
7.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.3, 142.8,
3
1
N,N-Diallyl-1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-car-
boxamide (3k). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a yellow
oil (125.3 mg, 47% yield). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J
= 2.5 Hz, 1H), 7.55 (t, 2JH−F = 60.1 Hz, 1H), 7.46 (dd, J = 9.7 Hz, 2.5
Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.75 (ddt, J = 17.3 Hz, 10.5 Hz, 5.3
Hz, 2H), 5.20 (d, J = 10.2 Hz, 2H), 5.13 (d, J = 17.1 Hz, 2H), 4.08−
3.73 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.8, 160.1,
128.8 (t, JC−F = 3.7 Hz), 116.8, 107.8 (t, JC−F = 253.5 Hz), 107.2.
19F NMR (376 MHz, CDCl3): δ −102.95 (d, JF−H = 60.0 Hz, 2F).
2
C6 isomer: 1H NMR (400 MHz, CDCl3): δ 7.49 (t, 2JH−F = 60.0 Hz,
1H), 7.47 (d, J = 2.6 Hz, 1H), 7.31 (dd, J = 9.9 Hz, 2.7 Hz, 1H), 6.37
(d, J = 9.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.2,
3
1
144.2, 129.2 (t, JC−F = 3.8 Hz), 122.8, 107.1 (t, JC−F = 253.9 Hz),
99.5. 19F NMR (376 MHz, CDCl3): δ −103.51 (d, JF−H = 60.0 Hz,
2
2F).
1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3f).6 The title compound was prepared according to representative
procedure I. The title compound was purified with silica gel
chromatography (petroleum ether/EtOAc = 2:1) as a yellow solid
(106.6 mg, 63% yield). Mp: 145−148 °C. 1H NMR (400 MHz,
3
140.1, 132.4, 130.1 (t, JC−F = 3.6 Hz), 121.1, 118.0, 115.7, 107.3 (t,
1JC−F = 253.1 Hz). 19F NMR (376 MHz, CDCl3): δ −103.77 (d, 2JF−H
= 60.0 Hz, 2F). HRMS (ESI) m/z: [M + Na]+ calcd for
C13H14F2N2O2Na+, 291.0916; found, 291.0925.
2
1-(Difluoromethyl)-5-(morpholine-4- carbonyl)pyridin-2(1H)-
one (3l). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (EtOAc) as a yellow oil (156.5 mg, 61%
yield). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 2.4 Hz, 1H), 7.58
(t, 2JH−F = 60.0 Hz, 1H), 7.38 (dd, J = 9.7 Hz, 2.5 Hz, 1H), 6.49 (d, J
= 9.6 Hz, 1H), 3.68−3.60 (m, 4H), 3.59−3.45 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3): δ 165.6, 160.0, 140.0, 131.3 (t, 3JC−F = 3.6
CDCl3): δ 7.98 (d, J = 2.4 Hz, 1H), 7.60 (t, JH−F = 59.7 Hz, 1H),
7.44 (dd, J = 9.8 Hz, 2.4 Hz 1H), 6.63 (d, J = 9.8 Hz, 1H). 13C{1H}
3
NMR (101 MHz, CDCl3): δ 158.9, 139.8, 137.9 (t, JC−F = 3.8 Hz),
123.1, 115.1, 107.1 (t, 1JC−F = 255.9 Hz), 93.9. 19F NMR (376 MHz,
2
CDCl3): δ − 103.63 (d, JF−H = 59.6 Hz, 2F).
Methyl 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carbox-
ylate (3g).6 The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a
1
Hz), 121.2, 115.1, 107.3 (t, JC2−F = 253.4 Hz), 66.6. 19F NMR (376
1
MHz, CDCl3): δ −103.64 (d, JF−H = 60.1 Hz, 2F). IR (KBr): νmax
3070, 2859, 1688, 1634, 1542, 1136, 1114, 1069. HRMS (ESI) m/z:
colorless solid (123.1 mg, 61% yield). Mp: 108−110 °C. H NMR
(400 MHz, CDCl3): δ 8.20 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 9.8 Hz,
2.5 Hz, 1H), 7.56 (t, 2JH−F = 59.9 Hz, 1H), 6.43 (d, J = 9.8 Hz, 1H),
3.77 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.6, 160.3,
139.7, 135.0 (t, 3JC−F = 3.7 Hz), 120.8, 111.2, 107.3 (t, 1JC−F = 253.9
Hz), 52.2. 19F NMR (376 MHz, CDCl3): δ −104.02 (d, 2JF−H = 59.9
Hz, 2F).
+
[M + H]+ calcd for C11H13F2N2O3 , 259.0889; found, 259.0894.
1-(Difluoromethyl)-5-(piperidine-1-carbonyl)pyridin-2(1H)-one
(3m). The title compound was prepared according to representative
procedure I. The title compound was purified with silica gel
chromatography (petroleum ether/EtOAc = 1:1) as a yellow oil
1
(199.3 mg, 78% yield). H NMR (400 MHz, CDCl3): δ 7.66 (d, J =
Naphthalen-2-yl 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-
3-carboxylate (3h). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a yellow
oil (204.1 mg, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J
= 2.5 Hz, 1H), 7.99 (dd, J = 9.8 Hz, 2.5 Hz, 2H), 7.93−7.78 (m, 3H),
7.71 (t, 2JH−F = 59.9 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.54−7.43 (m,
2H), 7.31 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 6.60 (d, J = 9.8 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 162.1, 160.4, 147.8, 139.8,
2
2.6 Hz, 1H), 7.63 (t, JH−F = 59.8 Hz, 1H), 7.42 (dd, J = 9.8 Hz, 2.5
Hz, 1H), 6.52 (d, J = 9.6 Hz, 1H), 3.63−3.37 (m, 4H), 1.76−1.63 (m,
2H), 1.62−1.45 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3): δ
3
165.6, 160.3, 140.3, 130.7 (t, JC−F = 3.6 Hz), 121.2, 116.3, 107.4 (t,
1JC−F = 253.1 Hz), 26.1, 24.4. 19F NMR (376 MHz, CDCl3): δ
−103.62 (d, 2JF−H = 60.2 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd
+
for C12H15F2N2O2 , 257.1096; found, 257.1106.
N-Benzyl-1-(difluoromethyl)-6-oxo-1,6-dihydropyrid-ine-3-car-
boxamide (3n). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a yellow
3
136.1 (t, JC−F = 3.7 Hz), 133.6, 131.6, 129.7, 127.8, 127.7, 126.8,
1
126.0, 121.1, 120.8, 118.6, 110.8, 107.4 (t, JC−F = 254.6 Hz). 19F
2
NMR (376 MHz, CDCl3): δ −103.51 (d, JF−H = 59.9 Hz, 2F). IR
1
oil (227.2 mg, 82% yield, C6/C2 = 1:1). C6 isomer H NMR (400
(KBr): νmax 3137, 3073, 1744, 1686, 1621, 1596, 1509, 1464, 1300,
MHz, CDCl3): δ 8.10 (d, J = 2.5 Hz, 1H), 7.67 (dd, J = 9.8 Hz, 2.6
+
1157, 1136. HRMS (ESI) m/z: [M + H]+ calcd for C17H12F2NO3 ,
2
Hz, 1H), 7.52 (t, JH−F = 60.0 Hz, 1H), 7.30−7.16 (m, 5H), 6.83−
316.0780; found, 316.0793.
6.70 (m, 1H), 6.41 (d, J = 9.7 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H).
Cyclohexyl 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-car-
boxylate (3i). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a yellow
oil (224.3 mg, 83% yield). 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J
= 2.4 Hz, 1H), 7.87 (dd, J = 9.8 Hz, 2.5 Hz, 1H), 7.63 (t, 2JH−F = 60.0
Hz, 1H), 6.52 (d, J = 9.8 Hz, 1H), 5.03−4.85 (m, 1H), 1.98−1.81 (m,
2H), 1.79−1.64 (m, 2H), 1.61−1.45 (m, 4H), 1.43−1.33 (m, 2H),
1.32−1.06 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.8,
13C{1H} NMR (101 MHz, CDCl3): δ 163.4, 160.7, 139.4, 137.8,
3
132.0 (t, JC−F = 3.4 Hz), 128.7, 127.7, 127.6, 120.7, 115.1, 107.4 (t,
1JC−F = 253.9 Hz), 44.0. 19F NMR (376 MHz, CDCl3): δ −103.55 (d,
2JF−H = 60.0 Hz, 2F). IR (KBr): νmax 3320, 3065, 1691, 1642, 1539,
1496, 1454, 1132, 1078. HRMS (ESI) m/z: [M + H]+ calcd for
+
C14H13F2N2O2 , 279.0940; found, 279.0952. C2 isomer 1H NMR
(400 MHz, CDCl3): δ 9.59 (s, 1H), 8.61 (dd, J = 7.1 Hz, 2.2 Hz, 1H),
2
7.71 (t, JH−F = 60.1 Hz, 1H), 7.66 (dd, J = 7.0, 2.2 Hz, 1H), 7.38−
160.6, 140.1, 134.8 (t, 3JC−F = 3.7 Hz), 120.8, 112.2, 107.4 (t, 1JC−F
=
7.30 (m, 4H), 7.29−7.18 (m, 1H), 6.52 (t, J = 7.1 Hz, 1H), 4.63 (d, J
= 5.8 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.4, 161.0,
253.9 Hz), 74.2, 31.6, 25.3, 23.8. 19F NMR (376 MHz, CDCl3): δ
3
−103.74 (d, 2JFH = 60.0 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd
145.8, 138.2, 132.8 (t, JC−F = 3.9 Hz), 128.6, 127.6, 127.3, 122.7,
1
107.7, 107.3 (t, JC−F = 254.3 Hz), 43.6. 19F NMR (376 MHz,
+
for C13H16F2NO3 , 272.1093; found, 272.1093.
2
CDCl3): δ −103.46 (d, JF−H = 60.1 Hz, 2F). IR (KBr): νmax 3304,
Furan-2-ylmethyl 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-
3-carboxylate (3j). The title compound was prepared according to
representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 2:1) as a yellow
oil (225.6 mg, 84% yield). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J
= 2.4 Hz, 1H), 7.86 (dd, J = 9.8 Hz, 2.5 Hz, 1H), 7.62 (t, 2JH−F = 60.0
3065, 1683, 1642, 1598, 1554, 1497, 1165, 1076. HRMS (ESI) m/z:
+
[M + H]+ calcd for C14H13F2N2O2 , 279.0940; found, 279.0936.
1-(Difluoromethyl)-5-tosylpyridin-2(1H)-one (3o). The title com-
pound was prepared according to representative procedure I. The title
compound was purified with silica gel chromatography (petroleum
6883
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The Journal of Organic Chemistry
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Note
1
ether/EtOAc = 2:1) as a yellow oil (175.5 mg, 59% yield). H NMR
(400 MHz, CDCl3): δ 8.29 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 8.4 Hz,
2H), 7.59 (t, 2JH−F = 59.8 Hz, 1H), 7.57 (dd, J = 9.9 Hz, 2.6 Hz, 1H),
7.35 (d, J = 8.1 Hz, 2H), 6.55 (d, J = 9.9 Hz, 1H), 2.42 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 159.6, 145.4, 137.3, 137.2,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 162.3, 160.5, 148.1, 140.1,
3
138.4, 138.1, 136.1 (t, JC−F = 3.4 Hz), 126.7, 121.5, 121.2, 118.7,
1
111.1, 107.4 (t, JC−F = 254.6 Hz), 50.5, 48.0, 44.2, 38.0, 35.9, 31.6,
29.5, 26.4, 25.8, 21.7, 13.9. 19F NMR (376 MHz, CDCl3): δ −103.57
2
(d, JF−H = 59.9 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd for
+
133.8 (t, 3JC−F = 3.9 Hz), 130.5, 127.8, 123.3, 122.5, 107.4 (t, 1JC−F
255.5 Hz), 21.7. 19F NMR (376 MHz, CDCl3): δ −103.61 (d, 2JF−H
=
=
C25H26F2NO4 , 442.1824; found, 442.1825.
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6- methyl-
heptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-yl 1-(difluoromethyl)-6-oxo-1,6-
dihydropyridine-3-carboxylate (3t). The title compound was
prepared according to representative procedure I. The title compound
was purified with silica gel chromatography (petroleum ether/EtOAc
= 4:1) as a yellow solid (226.3 mg, 41% yield). Mp: 110−113 °C. 1H
NMR (400 MHz, CDCl3): δ 8.27 (d, J = 2.4 Hz, 1H), 7.88 (dd, J =
59.9 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd for C13H12F2NO3S+,
300.0500; found, 300.0507.
Ethyl (1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-
carbonyl)glycinate (3p). The title compound was prepared according
to representative procedure I. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 1:1) as a yellow
oil (174.7 mg, 64% yield). 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J
= 2.5 Hz, 1H), 7.80 (dd, J = 9.7 Hz, 2.5 Hz, 1H), 7.59 (t, 2JH−F = 60.0
Hz, 1H), 7.55−7.47 (m, 1H), 6.59−6.42 (m, 1H), 4.24−4.13 (m,
2H), 4.12−4.02 (m, 2H), 1.35−1.11 (m, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 170.1, 163.6, 160.6, 139.2, 132.4 (t, 3JC−F = 3.3 Hz),
2
9.8 Hz, 2.4 Hz, 1H), 7.65 (t, JH−F = 60.0 Hz, 1H), 6.53 (d, J = 9.8
Hz, 1H), 5.39 (d, J = 5.0 Hz, 1H), 4.88−4.71 (m, 1H), 2.47−2.36 (m,
2H), 2.07−1.97 (m, 2H), 1.95−1.74 (m, 4H), 1.59−1.42 (m, 6H),
1.39−1.28 (m, 4H), 1.22−1.07 (m, 6H), 1.04 (s, 3H), 0.90 (d, J = 6.4
Hz, 3H), 0.84 (dd, J = 6.7 Hz, 1.8 Hz, 6H), 0.67 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 162.7, 160.6, 140.1, 139.3, 134.9 (t,
3JC−F = 3.4 Hz), 123.2, 120.9, 112.1, 107.4 (t, 1JC−F = 253.8 Hz), 75.5,
56.8, 56.2, 50.1, 42.4, 39.8, 39.6, 38.2, 37.0, 36.7, 36.3, 35.9, 32.0,
31.9, 28.3, 28.1, 27.9, 24.4, 23.9, 22.9, 22.7, 21.1, 19.4, 18.8, 11.9. 19F
120.9, 114.6, 107.5 (t, JC−F = 253.8 Hz), 61.8, 41.7, 14.1. 19F NMR
1
2
(376 MHz, CDCl3): δ −103.74 (d, JF−H = 60.0 Hz, 2F). IR (KBr):
νmax 3337, 3077, 2984, 1748, 1692, 1655, 1540, 1207, 1139, 1076.
+
HRMS (ESI) m/z: [M + H]+ calcd for C11H13F2N2O4 , 275.0838;
found, 275.0847.
2
NMR (376 MHz, CDCl3): δ −103.58 (d, JF−H = 59.9 Hz, 2F). IR
Methyl (1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-car-
bonyl)-L-phenylalaninate (3q). The title compound was prepared
according to representative procedure I. The title compound was
purified with silica gel chromatography (petroleum ether/EtOAc =
1:1) as a yellow oil (184.5 mg, 53% yield, C6/C2 = 1:0.17). HRMS
(KBr): νmax 2936, 2867, 1701, 1619, 1548, 1219, 1184, 1106. HRMS
+
(ESI) m/z: [M + H]+ calcd for C34H50F2NO3 , 558.3753; found,
558.3752.
1-(Difluoromethyl)quinolin-2(1H)-one (4a):6 representative pro-
cedure II. The oven-dried 25 mL Schlenk tube equipped with a
magnetic stirring bar was charged with K2CO3 (207 mg, 1.5 mmol, 1.5
equiv). Next, the reaction mixture was backfilled with argon, and then
MeCN (3.0 mL) was added. Subsequently, quinoline (118 μL, 1.0
mmol, 1.0 equiv), BrCF2CO2Et (256 μL, 2.0 mmol, 2.0 equiv), DBU
(224 μL, 1.5 mmol, 1.5 equiv), and TBHP (290 μL, 2.0 mmol, 2.0
equiv, 70% in water) were added successively. The reaction mixture
was stirred for 12 h under 80 °C (oil bath). The reaction mixture was
diluted with EtOAc and filtered with a pad of Celite. The filtrate was
concentrated, and the residue was purified with silica gel
chromatography (petroleum ether/EtOAc = 2:1) as a yellow oil
(165.2 mg, 85% yield) to give the target product 4a. Mp: 108−110
+
(ESI) m/z: [M + H]+ calcd for C17H17F2N2O4 , 351.1151; found,
351.1163. C6 isomer 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 2.5
Hz, 1H), 7.68 (dd, J = 9.8 Hz, 2.5 Hz, 1H), 7.59 (t, 2JH−F = 60.0 Hz,
1H), 7.33−7.08 (m, 6H), 6.47 (d, J = 9.7 Hz, 1H), 5.09−4.90 (m,
1H), 3.74 (s, 3H), 3.23 (dd, J = 5.7 Hz, 13.9 Hz, 1H), 3.11 (dd, J =
7.1 Hz, 13.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 172.3,
3
163.0, 160.5, 138.9, 135.9, 132.3 (t, JC−F = 3.3 Hz), 129.1, 128.6,
127.2, 120.9, 114.6, 107.4 (t, JC−F = 253.9 Hz), 53.8, 52.5, 37.6. 19F
1
2
NMR (376 MHz, CDCl3): δ −103.71 (d, JF−H = 60.2 Hz, 2F). C2
isomer 1H NMR (400 MHz, CDCl3): δ 9.73 (d, J = 7.4 Hz, 1H), 8.49
(dd, J = 7.1 Hz, 2.2 Hz, 1H), 7.72 (t, 2JH−F = 60.0 Hz, 1H). 7.33−7.08
(m, 6H), 6.51 (d, J = 7.1 Hz, 1H), 5.11−4.82 (m, 1H), 3.69 (s, 1H),
3.17−3.03 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.8,
1
2
°C. H NMR (400 MHz, CDCl3): δ 8.14 (t, JH−F = 58.7 Hz, 1H),
7.87−7.73 (m, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.57−7.43 (m, 2H),
7.27 (t, J = 7.5 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 161.6, 141.9, 135.0, 130.9, 129.1, 124.0, 120.7,
3
162.3, 160.8, 145.9, 136.1, 133.2 (t, JC−F = 3.7 Hz), 129.2, 128.5,
127.0, 122.1, 107.6, 107.4 (t, JC−F = 253.9 Hz), 54.2, 52.3, 38.0. 19F
1
2
NMR (376 MHz, CDCl3): δ −103.43 (d, JF−H = 60.0 Hz, 2F).
120.6, 116.4 (t, JC−F = 6.5 Hz), 109.9 (t, JC−F = 249.8 Hz). 19F
NMR (376 MHz, CDCl3): δ −106.46 (d, JF−H = 58.7 Hz, 2F).
3
1
(E)-3,7-Dimethylocta-2,6-dien-1-yl 1-(difluoromethyl)-6-oxo-1,6-
dihydropyridine-3-carboxylate (3r). The title compound was
prepared according to representative procedure I. The title compound
was purified with silica gel chromatography (petroleum ether/EtOAc
2
6-Bromo-1-(difluoromethyl)quinolin-2(1H)-one (4b). The title
compound was prepared according to representative procedure I
except that K2CO3 was not involved. The title compound was purified
with silica gel chromatography (petroleum ether/EtOAc = 5:1) as a
yellow solid (144.3 mg, 53% yield). Mp: 124−127 °C. 1H NMR (600
1
= 2:1) as a yellow oil (194.1 mg, 60% yield). H NMR (400 MHz,
CDCl3): δ 8.29 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 9.8 Hz, 2.4 Hz, 1H),
7.64 (t, 2JH−F = 59.9 Hz, 1H), 6.53 (d, J = 9.8 Hz, 1H), 5.45−5.31 (m,
1H), 5.12−4.98 (m, 1H), 4.78 (d, J = 7.2 Hz, 2H), 2.15−1.99 (m,
4H), 1.73 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 163.4, 160.6, 143.3, 140.1, 135.1 (t, 3JC−F = 3.6 Hz),
2
MHz, CDCl3): δ 8.08 (t, JH−F = 58.5 Hz, 1H), 7.67 (dt, J = 9.1 Hz,
2.9 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 9.1 Hz, 2.3 Hz,
1H), 7.58 (d, J = 9.7 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H). 13C{1H}
NMR (151 MHz, CDCl3): δ 161.2, 140.7, 134.0, 133.7, 131.4, 122.3,
1
132.0, 123.6, 120.9, 117.7, 111.8, 107.4 (t, JC−F = 254.0 Hz), 62.5,
3
1
39.6, 26.3, 25.7, 17.8, 16.6. 19F NMR (376 MHz, CDCl3): δ −103.65
122.1, 118.1 (t, JC−F = 6.6 Hz), 117.0, 109.8 (t, JC−F = 250.5 Hz).
19F NMR (565 MHz, CDCl3): δ −106.13 (d, 2JF−H = 58.5 Hz, 2F). IR
(KBr): νmax 3061, 1681, 1588, 1556, 1484, 1430, 1143, 1111, 1040.
HRMS (ESI) m/z: [M + H]+ calcd for C10H7BrF2NO+, 273.9674;
found, 273.9677.
(d, JF−H = 60.1 Hz, 2F). HRMS (ESI) m/z: [M + Na]+ calcd for
2
+
C17H21F2NNaO3 , 348.1382; found, 348.1384.
(8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-
decahydro-6H-cyclopenta[a]phenanthren-3-yl 1-(difluoromethyl)-
6-oxo-1,6-dihydropyridine-3-carbox-ylate (3s). The title compound
was prepared according to representative procedure I. The title
compound was purified with silica gel chromatography (petroleum
6-Chloro-1-(difluoromethyl)quinolin-2(1H)-one (4c). The title
compound was prepared according to representative procedure I
except that K2CO3 was not involved. The title compound was purified
with silica gel chromatography (petroleum ether/EtOAc = 5:1) as a
yellow solid (109.5 mg, 48% yield). Mp: 133−135 °C. 1H NMR (600
1
ether/EtOAc = 2:1) as a yellow oil (316.8 mg, 72% yield). H NMR
(400 MHz, CDCl3): δ 8.49 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 9.8 Hz,
2.4 Hz, 1H), 7.69 (t, 2JH−F = 59.9 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H),
6.94 (dd, J = 8.4 Hz, 2.7 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.62 (d, J
= 9.8 Hz, 1H), 2.99−2.81 (m, 2H), 2.51 (dd, J = 18.9 Hz, 8.6 Hz,
1H), 2.45−2.37 (m, 1H), 2.34−2.25 (m, 1H), 2.21−2.07 (m, 2H),
2.05−1.92 (m, 2H), 1.72−1.57 (m, 2H), 1.56−1.43 (m, 4H), 0.91 (s,
2
MHz, CDCl3): δ 8.09 (t, JH−F = 58.5 Hz, 1H), 7.73 (dt, J = 9.1 Hz,
2.9 Hz, 1H), 7.59 (d, J = 9.7 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.47
(dd, J = 9.1 Hz, 2.5 Hz, 1H), 6.60 (d, J = 9.6 Hz, 1H). 13C{1H} NMR
(151 MHz, CDCl3): δ 161.2, 140.8, 133.6, 131.0, 129.7, 128.3, 122.1,
3
1
122.0, 117.9 (t, JC−F = 6.5 Hz), 109.8 (t, JC−F = 250.4 Hz). 19F
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J. Org. Chem. 2021, 86, 6879−6887

The Journal of Organic Chemistry
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Note
2
1
NMR (565 MHz, CDCl3): δ −106.12 (d, JF−H = 58.5 Hz, 2F).
HRMS (ESI) m/z: [M + H]+ calcd for C10H7ClF2NO+, 230.0179;
found, 230.0188.
oil (100.7 mg, 46% yield). Mp: 53−56 °C. H NMR (400 MHz,
CDCl3): δ 8.56−8.42 (m, 2H), 7.71−7.55 (m, 4H), 7.21−7.04 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.0, 149.6, 137.5, 121.2,
119.7.
2-(Difluoromethyl)isoquinolin-1(2H)-one (4d). The title com-
pound was prepared according to representative procedure II. The
title compound was purified with silica gel chromatography
(petroleum ether/EtOAc = 5:1) as a yellow solid (159.4 mg, 82%
yield). Mp: 66−69 °C. H NMR (600 MHz, CDCl3): δ 8.32 (d, J =
8.1 Hz, 1H), 7.80 (t, JH−F = 60.4 Hz, 1H), 7.62 (td, J = 7.5 Hz, 1.4
ASSOCIATED CONTENT
■
1
sı
* Supporting Information
2
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00228.
Hz, 1H), 7.48−7.35 (m, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.50 (d, J =
7.7 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ 161.2, 136.5,
133.7, 128.2, 127.7, 126.4, 125.4, 122.7 (t, 3JC−F = 3.5 Hz), 107.91 (t,
1JC−F = 249.0 Hz), 107.87. 19F NMR (565 MHz, CDCl3): δ −102.68
Experimental procedures, compound characterization
data, copies of H, 19F, and 13C NMR spectra for new
1
2
(d, JF−H = 60.3 Hz, 2F). IR (KBr): νmax 3054, 1678, 1634, 1603,
compounds, and X-ray crystal structures of 3a (PDF)
1562, 1488, 1149, 1110. HRMS (ESI) m/z: [M + H]+ calcd for
C10H8F2NO+, 196.0568; found, 196.0573.
Accession Codes
5-Chloro-1-(difluoromethyl)quinolin-2(1H)-one (4e). The title
compound was prepared according to representative procedure I
except that K2CO3 was not involved. The title compound was purified
with silica gel chromatography (petroleum ether/EtOAc = 5:1) as a
CCDC 2014936 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.
1
white solid (98.2 mg, 43% yield). Mp: 126−128 °C. H NMR (600
MHz, CDCl3): δ 8.17 (d, J = 10.0 Hz, 1H), 8.11 (t, 2JH−F = 58.5 Hz,
1H), 7.73 (dt, J = 9.0 Hz, 3.1 Hz, 1H), 7.44 (t, J = 8.3 Hz, 1H), 7.34
(d, J = 7.9 Hz, 1H), 6.65 (d, J = 10.0 Hz, 1H). 13C{1H} NMR (151
MHz, CDCl3): δ 161.2, 137.8, 136.5, 133.5, 131.1, 124.9, 121.7,
AUTHOR INFORMATION
3
1
118.7, 115.3 (t, JC−F = 6.8 Hz), 109.9 (t, JC−F = 251.0 Hz). 19F
■
2
Corresponding Authors
NMR (565 MHz, CDCl3): δ −106.01 (d, JF−H = 58.5 Hz, 2F).
HRMS (ESI) m/z: [M + H]+ calcd for C10H7ClF2NO+, 230.0179;
found, 230.0189.
Guangwei Wang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China;
orcid.org/0000-0003-4466-9809; Email: wanggw@
tju.edu.cn.
Minjie Guo − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, P. R. China; Email: gmj2016@
tju.edu.cn
N-(1-(Difluoromethyl)-2-oxo-1,2-dihydroquinolin-5-yl)-
acetamide (4f). The title compound was prepared according to
representative procedure I except that K2CO3 was not involved. The
title compound was purified with silica gel chromatography
(petroleum ether/EtOAc = 1:1) as a yellow solid (140.5 mg, 56%
yield). Mp: 226−229 °C. H NMR (400 MHz, DMSO-d6): δ 10.04
(s, 1H), 8.24 (t, JH−F = 57.9 Hz, 1H), 8.06 (d, J = 10.0 Hz, 1H),
1
2
7.68−7.49 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 10.0 Hz,
1H), 2.14 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6): δ 169.2,
160.6, 138.1, 136.2, 135.2, 131.1, 120.7, 119.4, 115.1, 112.7, 110.2 (t,
1JC−F = 248.7 Hz), 23.3. 19F NMR (376 MHz, DMSO-d6): δ −105.62
Authors
Sen Zhou − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Xiaoya Hou − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Kai Yang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Wentao Zhao − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Xiangyang Tang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
(d, JF−H = 58.0 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd for
2
+
C12H11F2N2O2 , 253.0783; found, 253.0789.
4-Chloro-1-(difluoromethyl)quinolin-2(1H)-one (4ga). The title
compound was prepared according to representative procedure I
except that K2CO3 was not involved. The title compound was purified
with silica gel chromatography (petroleum ether/EtOAc = 3:1) as a
yellow solid (38.4 mg, 17% yield. Mp: 63−66 °C. H NMR (400
MHz, CDCl3) δ 8.08 (t, JH−F = 58.5 Hz, 1H), 7.99 (dd, J = 8.2 Hz,
1.5 Hz, 1H), 7.83 (dt, J = 8.6 Hz, 3.0 Hz, 1H), 7.60 (ddd, J = 8.7 Hz,
7.2 Hz, 1.6 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.76 (s, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ 160.1, 147.6, 134.8, 132.2, 126.5, 124.5,
1
2
3
1
120.0, 119.4, 116.6 (t, JC−F = 6.8 Hz), 109.7 (t, JC−F = 251.0 Hz).
19F NMR (376 MHz, CDCl3): δ −106.12 (d, JF−H = 58.5 Hz, 2F).
2
HRMS (ESI) m/z: [M + H]+ calcd for C10H7ClF2NO+, 230.0179;
found, 230.0180.
1-(Difluoromethyl)quinolin-4(1H)-one (4gb).15 The title com-
pound was prepared according to representative procedure I. The title
compound was purified with silica gel chromatography (petroleum
ether/EtOAc = 1:1) as a yellow solid (99.1 mg, 51% yield). Mp: 118−
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00228
1
120 °C. H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.1 Hz, 1H),
Notes
7.78 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 4.3, 1.5 Hz, 2H), 7.42−7.35
2
The authors declare no competing financial interest.
(m, 1H), 7.33 (t, JH−F = 59.5 Hz, 1H), 6.25 (d, J = 8.2 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 178.6, 137.0, 136.5, 133.0,
127.1, 126.3, 125.1, 115.4 (t, 3JC−F = 3.4 Hz), 112.5 (t, 1JC−F = 253.6
Hz), 111.4. 19F NMR (376 MHz, CDCl3): δ − 95.47 (d, 2JF−H = 59.4
Hz, 2F).
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support from Major
National Science and Technology Projects of water pollution
control and treatment (2017ZX07402003). We also thank the
Natural Science Foundation of Tianjin (19JCYBJC20200) and
Tianjin University for their support of this research.
1,2-Di(pyridin-2-yl)disulfane (5).16 The title compound was
prepared according to representative procedure II except that
K2CO3 was not involved. The title compound was purified with
silica gel chromatography (petroleum ether/EtOAc = 3:1) as a yellow
6885
https://doi.org/10.1021/acs.joc.1c00228
J. Org. Chem. 2021, 86, 6879−6887

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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NOTE ADDED AFTER ASAP PUBLICATION
In Scheme 4, compound 5 was corrected on April 28, 2021.
■
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J. Org. Chem. 2021, 86, 6879−6887