Copper-Catalyzed Regioselective Coupling of Tosylhydrazones and 2-Pyridones: A Strategy for the Production of N-Alkylated Compounds

Article abstract of DOI:10.1021/acs.joc.1c00009

The highly regioselective N-alkylation reaction of 2-pyridones was achieved through hydrazone chemistry, especially for substrates with bulky secondary alkyl groups. Described herein is a copper-catalyzed coupling reaction of pyridone derivatives with tosylhydrazones.

Full text of DOI:10.1021/acs.joc.1c00009

pubs.acs.org/joc
Note
Copper-Catalyzed Regioselective Coupling of Tosylhydrazones and
2‑Pyridones: A Strategy for the Production of N‑Alkylated
Compounds
Ye-bin Wu,⊥ You-zhi Wu,⊥ Jian Wu, Dan Xu, Hui Jiang, Wen-wu Chang, and Chang-you Ma*
Cite This: J. Org. Chem. 2021, 86, 6918−6926
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The highly regioselective N-alkylation reaction of 2-
pyridones was achieved through hydrazone chemistry, especially
for substrates with bulky secondary alkyl groups. Described herein
is a copper-catalyzed coupling reaction of pyridone derivatives with
tosylhydrazones.
-Substituted 2-pyridones and analogues are key motifs in
limited. Despite the considerable progress, selective N-
alkylation of 2-pyridones is still a problem, especially with
bulky secondary alkyl groups.
N
natural products and many active drugs (Figure 1),1−3
In 2018, a rhodium-catalyzed dearomatization of O-
substituted pyridines to produce N-substituted 2-pyridones
was developed by Sun et al.,10 inspiring us to achieve
regioselective synthesis of N-substituted 2-pyridones and
analogues via the hydrazone chemistry.11 As we all know,
copper can catalyze C−N coupling between amines and
tosylhydrazones, but it is hard for C−O coupling. Hence, we
propose that high regioselectivity could be achieved through
the hydrazone chemistry (Figure 2).
Initially, 1a and 2a were used as model substrates to
establish the optimal reaction conditions. To our delight, the
reaction proceeded smoothly under the “standard conditions”,
affording the desired product 3a without O-alkylated product
3a′ (Table 1, entry 2). Upon switching the catalyst to other Cu
salts, it was found that Cu(acac)2 shows better performance
than CuI (entries 2−7). Addition of different bases such as
KOtBu, LiOH, and DIPEA led to diminished yields (entries
8−15). After screening the catalysts, bases, and solvents, the
combination of Cu(acac)2, Cs2CO3, and 1,4-dioxane gave the
highest yield without O-alkylation byproducts.
Figure 1. Drugs with pyridone-like structures.
but their synthesis is plagued by the regioselectivity control of
N- and O-alkylation of 2-pyridones over the past decades.4−6
Various modified methods have been established to enhance
the regioselectivity of the N-alkylation process, and a variety of
reaction parameters including solvents, bases, and temperature
have been identified to be vital for its regioselectivity.7 In 2015,
Ren and co-workers reported that Tween 20 (2% w/w) was
used as an effective additive to improve the N-selectivity,8 but
the regioselectivity decreases a lot in the case of bulky alkyl
halides. More recently, a very impressive work reported by Xu
et al. demonstrated that N-alkylation of hydroxypyridines
could proceed in the absence of catalysts and bases.9 On the
other hand, it means that this type of reaction depends on the
intrinsic activity of organohalides. The substrate scope is
With the optimized conditions in hand, the substrate scope
was explored (Scheme 1). According to LCMS analysis, only
Received: February 6, 2021
Published: April 14, 2021
https://doi.org/10.1021/acs.joc.1c00009
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6918−6926
6918

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
with complex structures is relatively low, the regioselectivity is
still well maintained.
EXPERIMENTAL SECTION
■
General Information. All chemicals were used as received
without further purification unless stated otherwise. 1H and 13C NMR
spectra were collected on a Bruker AVANCE NEO (400 MHz)
spectrometer using DMSO-d6 as solvent. Chemical shifts of 1H NMR
were recorded in parts per million (ppm, δ) relative to
tetramethylsilane (δ = 0.00 ppm) with the solvent resonance as the
internal standard (DMSO-d6: δ = 2.50 ppm). Data are reported as
follows: chemical shift in ppm (δ), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constant
(Hz), and integration. Chemical shifts of 13C NMR were reported in
ppm with the solvent as the internal standard (DMSO-d6: δ = 39.52
ppm). Mass measurement was performed on a Shimadzu-2020EV
mass spectrometer with electron spray ionization (ESI) as the ion
source. Reverse flash chromatography was carried out to purify the
products.
General Procedure for the Preparation of Starting
Materials. All the compound pyridin-2(1H)-one derivations and
tosylhydrazones are known or commercially available, and data are
consistent with the literature.13 Tosylhydrazones are obtained by
condensation of 4-toluenesulfonyl hydrazide with the corresponding
ketone.14 A solution of 4-toluenesulfonyl hydrazide (0.8 equiv) in
MeOH (5.0 mL) was heated in an oil bath to 60 °C and stirred for 5
min under a nitrogen atmosphere. The reaction mixture was cooled to
room temperature. Ketone (1.0 equiv) was added to the mixture at
room temperature. After stirring for 2 h at 60 °C, the reaction mixture
was cooled to room temperature. The precipitated solids were
collected by filtration and washed with a PE/EA mixture to afford the
corresponding hydrazone.
Ethyl 2-diazopropanoate was obtained by condensation of ethyl 2-
methyl-3-oxobutanoate with tosyl azide.15 DBU (22.5 mmol, 1.5
equiv) was added slowly to a stirred solution of ethyl 2-methyl-3-
oxobutanoate (15.0 mmol, 1.0 equiv) and tosyl azide (22.5 mmol, 1.5
equiv) in MeCN (50 mL) at 0 °C. The reaction mixture was allowed
to warm to room temperature, and the reaction was quenched with
H2O and extracted with MTBE (3 × 50 mL). We combined the
organic layers and washed with a saturated solution of brine (50 mL).
The solvent was removed under reduced pressure and purified by
flash column chromatography on silica gel (100:0−10:1 petrol ether/
ethyl acetate) to afford ethyl 2-diazopropanoate.
Methyl α-diazobenzeneacetate was obtained by condensation of
ethyl 2-phenylacetate with tosyl azide.16 We charged a round-
bottomed flask with methyl 2-phenylacetate (13.3 mmol, 1.0 equiv),
MeCN (30 mL), and tosyl azide (20 mmol, 1.5 equiv) under nitrogen
at room temperature. The reaction temperature was cooled to 0 °C,
and DBU (20 mmol, 1.5 equiv) was added slowly to the reaction
mixture. The reaction mixture was allowed to warm to room
temperature and stirred at room temperature overnight. The reaction
was quenched with an aqueous saturated solution of NH4Cl. The
reaction mixture was extracted with MTBE (3 × 50 mL). The solvent
was removed under reduced pressure and purified by flash column
chromatography (100:0−10:1 petrol ether/ethyl acetate) to afford
methyl α-diazobenzeneacetate.
Experimental Procedures. To a stirred mixture of 2-pyridones 1
(0.25 mmol, 1.0 equiv), tosylhydrazones ordiazoacetates 2 (0.5 mmol,
2.0 equiv), and Cs2CO3 (0.5 mmol, 2.0 equiv) in dioxane (2.0 mL)
was added Cu salt (0.05 mmol, 0.2 equiv) at room temperature under
a nitrogen atmosphere. After raising the temperature to 110 °C on a
heating plate and stirring for 2 h, the reaction mixture was cooled to
room temperature. The resulting mixture was diluted with DCM (20
mL). The resulting mixture was filtered, and the filter cake was
washed with DCM:EA (1:1) (3 × 20 mL). The filtrate was
concentrated under reduced pressure. The residue was purified by
reverse flash chromatography with the following conditions: column,
C18 silica gel; mobile phase, MeCN in water (0.05% NH4HCO3);
Figure 2. Previous reports and our new strategy.
N-alkylated products were detected on most substrates.
Initially, a range of aryl tosylhydrazones bearing various
substituents, such as methoxy, chloro, and nitro groups, at the
para, meta, or ortho position of the phenyl ring, were tested,
and the products were obtained in moderate yields with
excellent regioselectivity. Note that the yield of tosylhydra-
zones with nitro groups (3b, 3c) is somewhat reduced. The
reaction is also amenable to other types of heteroaromatic
tosylhydrazones. For instance, the use of furanyl and pyridinyl
tosylhydrazones produced 3i, 3j, and 3n in moderate yields.
Notably, the alkyl tosylhydrazones (3q, 3s) were also tolerated.
Expectedly, the reaction was not limited to tosylhydrazones but
also amenable to the diazoacetates (3t, 3u). We think it will
greatly expand the scope of application of this reaction.
Considering that this reaction can be applied to the
synthesis of drug molecules, many 2-pyridone derivatives
with complex structures have been examined (Scheme 2).
When we started exploring the compatibility of our established
methods with different 2-pyridones, we found that CuI is
better than Cu(acac)2 (SI). For polysubstituted 2-pyridones,
most of them delivered products (4b−4d, 4f) with moderate
yields. Pyridones with parallel ring structure (4g−4p) were
also tested. Based on the results, high regioselectivity of this
reaction is well maintained for most of these substrates with
only a slight decrease in product yield. Finally, the scalability of
the method was evaluated using 2-pyridinol 4q on a gram scale
to afford the corresponding product with 72.2% yield.
Since the copper-catalyzed C−N coupling reaction has been
widely reported,12 we propose that the reaction proceeded via
copper carbene, followed by the chemoselectively inserted
copper carbene into the N−H bond over the O−H bond.
In conclusion, we have discovered a copper-catalyzed N-
alkylation of 2-pyridones with tosylhydrazones. The key
advantage of the process is its excellent regioselectivity,
especially for substrates with bulky secondary alkyl groups.
Typically, the reaction is amenable to various pyridone
derivatives. Although the yield of some 2-pyridone derivatives
6919
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a
Table 1. Optimization of Reaction Conditions
b
b
entry
[Cu]
none
CuI
Cu(OAc)2
Cu(SO3CF3)2
Cu(acac)2
Cu2O
solvent
base
ratio of 3a/M
ratio of 3a/3a′
1
2
3
4
5
6
7
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
DCE
MeCN
toluene
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Li2CO3
NaOH
NaOtBu
KOtBu
K3PO4
DBU
LiOH
DIPEA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
no
/
1.33
0.98
1.28
1.97
0.76
0.30
0.21
no
single peak
single peak
single peak
single peak
single peak
single peak
single peak
/
Cu
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
9
10
11
12
13
14
15
16
17
no
/
0.82
1.42
1.57
0.17
trace
1.81
trace
no
trace
0.30
0.79
0.80
no
single peak
single peak
single peak
single peak
/
single peak
/
/
c
18
19
20
d
/
e
single peak
single peak
single peak
/
21
22
23
24
25
f
g
no
1.69
1.74
/
h
single peak
single peak
i
26
a
Reaction conditions: 1a (0.25 mmol), 2a (2 equiv), Cu salt (0.2 equiv), base (2.0 equiv), solvent (2.0 mL), and vigorous stirring under a N2
b
atmosphere at 110 °C, 2 h. Ratio of isomers based on LCMS and HPLC using 5-bromo-2-methyl-2H-indazole (M, 1.0 equiv) as an internal
standard. 65 °C for 2 h. 85 °C for 2 h. 80 °C for 2 h. Room temperature for 2 h. 50 °C for 2 h. 80 °C for 2 h. 80 °C for 10 h.
c
d
e
f
g
h
i
30% to 100% gradient in 15 min; detector, UV 254 nm to afford the
corresponding products.
126.8, 105.6, 52.9, 19.2; HRMS (ESI) m/z [M + H]+ calcd for
C17H15ClNO 284.0842; found 284.0834.
Gram-Scale Experiment of 4q. To a stirred mixture of 2-
pyridones 1 (10.0 mmol, 1.0 equiv), tosylhydrazones 2a (20.0 mmol,
2.0 equiv), and Cs2CO3 (20.0 mmol, 2.0 equiv) in dioxane (80 mL)
was added CuI (2.0 mmol, 0.2 equiv) at room temperature under a
nitrogen atmosphere. After stirring for 2 h at 110 °C, the reaction
mixture was cooled to room temperature. The resulting mixture was
diluted with DCM (20 mL). The resulting mixture was filtered, and
the filter cake was washed with DCM:EA (1:1) (3 × 50 mL). The
filtrate was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (100:0−10:3 petrol
ether/ethyl acetate) to afford the corresponding product 5a (1.66 g,
72.2%).
7-Chloro-2-(1-(3-nitrophenyl)ethyl)isoquinolin-1(2H)-one (3b).
32.5 mg, 39.6% yield; a light yellow semisolid. The title compound
was purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
1
254 nm; H NMR (400 MHz, DMSO-d6) δ 8.21−8.13 (m, 3H),
7.82−7.73 (m, 3H), 7.70−7.65 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H),
6.75 (d, J = 7.5 Hz, 1H), 6.33 (q, J = 7.2 Hz, 1H), 1.83 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.3, 148.4, 143.8,
135.7, 134.2, 133.2, 131.9, 130.7, 130.2, 129.0, 126.9, 126.8, 123.0,
122.0, 105.9, 53.1, 19.0; HRMS (ESI) m/z [M + H]+ calcd for
C17H14ClN2O3 329.0693; found 329.0682.
7-Chloro-2-(1-phenylethyl)isoquinolin-1(2H)-one (3a). 39.1 mg,
55.3% yield; a light yellow semisolid. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.23−8.17 (m, 1H), 7.80−7.69
(m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.41−7.33 (m, 4H), 7.33−7.25 (m,
1H), 6.70 (dd, J = 7.6, 0.7 Hz, 1H), 6.30 (q, J = 7.2 Hz, 1H), 1.75 (d,
J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.3,
141.4, 135.6, 133.0, 131.8, 130.2, 129.11, 128.9, 128.1, 127.4, 126.9,
7-Chloro-2-(1-(4-nitrophenyl)ethyl)isoquinolin-1(2H)-one (3c).
15.3 mg, 18.6% yield; a light yellow semisolid. The title compound
was purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
1
254 nm; H NMR (400 MHz, DMSO-d6) δ 8.24−8.13 (m, 3H),
7.80−7.71 (m, 2H), 7.63−7.49 (m, 3H), 6.75 (d, J = 7.5 Hz, 1H),
6.30 (q, J = 7.2 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 160.3, 149.2, 147.2, 135.7, 133.2, 131.9,
130.3, 129.3, 129.0, 128.6, 126.9, 126.8, 124.2, 105.9, 53.3, 19.1;
6920
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a
a
Scheme 1. Scope of Tosylhydrazones
Scheme 2. Scope of Pyridones
a
Reaction conditions: 1a (0.25 mmol), 2 (2 equiv), CuI2 (0.2 equiv),
Cs2CO3 (2.0 equiv), 1,4-dioxane (2.0 mL), vigorous stirring under N2
atmosphere at 110 °C, 2 h. If not noted, only N-alkylated products are
detected in LCMS.
a
Reaction conditions: 1a (0.25 mmol), 2 (2.0 equiv), Cu(acac)2 (0.2
equiv), Cs2CO3 (2.0 equiv), 1,4-dioxane (2.0 mL), vigorous stirring
under N2 atmosphere at 110 °C, 2 h. If not noted, only N-alkylated
b
products are detected in LCMS. CuI as catalyst.
131.8, 130.1, 129.3, 129.0, 128.95, 126.9, 126.8, 105.8, 52.6, 19.1;
HRMS (ESI) m/z [M + H]+ calcd for C17H14Cl2NO 318.0452; found
318.0441.
HRMS (ESI) m/z [M + H]+ calcd for C17H14ClN2O3 329.0693;
found 329.0682.
7-Chloro-2-(1-(3-chlorophenyl)ethyl)isoquinolin-1(2H)-one (3e).
42.5 mg, 53.6% yield; a light yellow oil. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 2.1 Hz, 1H),
7.81−7.70 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.44−7.33 (m, 3H),
7.34−7.26 (m, 1H), 6.76−6.69 (m, 1H), 6.25 (q, J = 7.2 Hz, 1H),
1.76 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
160.3, 144.1, 135.6, 133.8, 133.1, 131.8, 131.0, 130.1, 129.0, 128.1,
7-Chloro-2-(1-(4-chlorophenyl)ethyl)isoquinolin-1(2H)-one (3d).
44.9 mg, 56.7% yield; a light yellow semisolid. The title compound
was purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
1
254 nm; H NMR (400 MHz, DMSO-d6) δ 8.21−8.16 (m, 1H),
7.81−7.69 (m, 2H), 7.49−7.33 (m, 5H), 6.71 (dd, J = 7.6, 0.7 Hz,
1H), 6.25 (q, J = 7.2 Hz, 1H), 1.74 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 160.3, 140.5, 135.6, 133.1, 132.7,
6921
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
127.2, 126.9, 126.8, 126.2, 105.8, 52.8, 19.0; HRMS (ESI) m/z [M +
H]+ calcd for C17H14Cl2NO 318.0452; found 318.0442.
MeCN in water (0.05% NH4HCO3), 30% to 100% gradient in 15
min; detector, UV 254 nm; H NMR (400 MHz, DMSO-d6) δ 8.24
1
7-Chloro-2-(1-(2-chlorophenyl)ethyl)isoquinolin-1(2H)-one (3f).
28.6 mg, 36.1% yield; a light yellow oil. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.3 Hz, 1H),
7.7 (d, J = 2.2 Hz, 1H), 7.73 (s, 1H), 7.60−7.56 (m, 1H), 7.50−7.47
(m, 1H), 7.43−7.38 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 6.67 (d, J =
7.6 Hz, 1H), 6.32 (q, J = 6.8 Hz, 1H), 1.71 (d, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 159.9, 138.2, 135.6, 133.6,
(d, J = 2.3 Hz, 1H), 7.79−7.68 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H),
6.78 (s, 1H), 6.70 (d, J = 1.5 Hz, 2H), 6.62 (d, J = 7.5 Hz, 1H), 6.14
(dd, J = 8.5, 5.9 Hz, 1H), 3.73 (s, 3H), 2.98−2.88 (m, 1H), 2.82−
2.72 (m, 1H), 2.15−2.05 (m, 1H), 2.04−1.68 (m, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 160.7, 158.8, 140.5, 135.7, 133.0,
131.7, 131.1, 129.4, 129.0, 127.0, 126.8, 126.8, 114.0, 113.5, 105.3,
55.5, 53.4, 29.9, 29.5, 20.9; HRMS (ESI) m/z [M + H]+ calcd for
C20H19ClNO2 340.1104; found 340.1101.
7-Chloro-2-(2,3-dihydro-1H-inden-1-yl)isoquinolin-1(2H)-one
(3l). 35.5 mg, 48.1% yield; a light yellow oil. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 2.3 Hz, 1H),
7.80−7.70 (m, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H),
7.22 (td, J = 7.5, 1.2 Hz, 1H), 7.03 (dd, J = 17.8, 7.5 Hz, 2H), 6.65 (d,
J = 7.5 Hz, 1H), 6.53 (t, J = 7.7 Hz, 1H), 3.20−3.10 (m, 1H), 3.04−
2.94 (m, 1H), 2.75−2.56 (m, 2H), 2.14−2.03 (m, 1H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 160.7, 144.5, 141.7, 135.7, 133.0,
131.8, 130.1, 129.0, 128.8, 127.5, 126.8, 125.5, 124.6, 105.9, 60.1,
32.5, 30.5; HRMS (ESI) m/z [M + H]+ calcd for C18H15ClNO
296.0842; found 296.0835.
7-Chloro-2-(1-(pyridin-3-yl)ethyl)isoquinolin-1(2H)-one (3n).
32.0 mg, 45.0% yield; a brown oil. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.76 (br, 2H), 8.18 (d, J = 2.2 Hz,
1H), 7.77 (dd, J = 8.4, 2.3 Hz, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.64−
7.33 (m, 2H), 6.73 (d, J = 7.5 Hz, 1H), 6.30 (q, J = 7.2 Hz, 1H), 1.80
(d, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.3,
135.6, 133.1, 131.8, 130.1, 129.0, 126.9, 126.8, 105.9, 19.0; HRMS
(ESI) m/z [M + H]+ calcd for C16H14ClN2O 285.0795; found
285.0789.
133.1, 131.8, 130.3, 130.2, 129.8, 129.2, 129.0, 128.1, 126.8, 126.7,
105.5, 51.8, 18.8; HRMS (ESI) m/z [M + H]+ calcd for
C17H14Cl2NO 318.0452; found 318.0437.
7-Chloro-2-(1-(3-methoxyphenyl)ethyl)isoquinolin-1(2H)-one
(3g). 35.9 mg, 45.9% yield; a light yellow oil. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.2 Hz, 1H),
7.80−7.69 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H),
6.93−6.84 (m, 3H), 6.69 (dd, J = 7.6, 0.7 Hz, 1H), 6.26 (q, J = 7.2
Hz, 1H), 3.74 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 160.2, 159.9, 143.0, 135.6, 133.1, 131.7, 130.2,
130.2, 129.0, 126.9, 126.8, 119.6, 113.5, 113.2, 105.6, 55.5, 52.8, 19.2;
HRMS (ESI) m/z [M + H]+ calcd for C18H17ClNO2 314.0948; found
314.0941.
7-Chloro-2-(1-(2-methoxyphenyl)ethyl)isoquinolin-1(2H)-one
(3h). 42.7 mg, 54.5% yield; a light yellow oil. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.6 Hz, 1H),
7.80−7.65 (m, 2H), 7.40−7.29 (m, 2H), 7.24 (dd, J = 7.5, 2.8 Hz,
1H), 7.05−6.96 (m, 2H), 6.61 (dd, J = 7.6, 2.6 Hz, 1H), 6.37−6.26
(m, 1H), 3.67 (d, J = 2.7 Hz, 3H), 1.72−1.75 (m, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 159.9, 157.4, 135.7, 132.8, 131.5,
130.2, 129.8, 128.8, 128.7, 127.9, 127.0, 126.7, 120.8, 111.8, 104.8,
56.0, 49.3, 18.6; HRMS (ESI) m/z [M + H]+ calcd for C18H17ClNO2
314.0948; found 314.0938.
7-Chloro-2-(1-(furan-2-yl)ethyl)isoquinolin-1(2H)-one (3i). 31.7
mg, 46.5% yield; a light yellow oil. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.23−8.18 (m, 1H), 7.81−7.74
(m, 1H), 7.74−7.65 (m, 1H), 7.63 (dd, J = 1.9, 0.8 Hz, 1H), 7.23 (d,
J = 7.5 Hz, 1H), 6.69 (dd, J = 7.6, 0.7 Hz, 1H), 6.61 (dt, J = 3.3, 1.0
Hz, 1H), 6.49 (dd, J = 3.3, 1.8 Hz, 1H), 6.34−6.24 (m, 1H), 1.66 (d, J
= 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 159.9, 153.5,
143.8, 135.7, 133.2, 131.9, 129.4, 129.0, 126.9, 126.8, 111.0, 109.2,
105.8, 47.6, 18.1; HRMS (ESI) m/z [M + H]+ calcd for
C15H13ClNO2 274.0635; found 274.0630.
7-Chloro-2-(1-(pyridin-4-yl)ethyl)isoquinolin-1(2H)-one (3o).
12.4 mg, 17.4% yield; a brown oil. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.68−8.54 (m, 2H), 8.32 (d, J =
2.2 Hz, 1H), 8.00−7.92 (m, 2H), 7.80 (dd, J = 8.8, 2.2 Hz, 1H),
7.55−7.49 (m, 2H), 7.41 (d, J = 5.8 Hz, 1H), 6.45 (q, J = 6.6 Hz,
1H), 1.72 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6)
δ 158.2, 140.5, 136.6, 132.1, 132.1, 129.3, 122.9, 119.9, 115.5, 72.5,
22.6; HRMS (ESI) m/z [M + H]+ calcd for C16H14ClN2O 285.0795;
found 285.0788.
7-Chloro-2-(1-cyclohexylethyl)isoquinolin-1(2H)-one (3q). 31.1
mg, 43% yield; a brown oil. The title compound was purified by
reverse flash chromatography with the following conditions: column,
C18 silica gel; mobile phase, MeCN in water (0.05% NH4HCO3),
1
30% to 100% gradient in 15 min; detector, UV 254 nm; H NMR
(400 MHz, DMSO-d6) δ 8.22−8.09 (m, 1H), 7.78−7.67 (m, 2H),
7.49 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 4.79 (s, 1H), 1.87
(d, J = 12.8 Hz, 1H), 1.71 (d, J = 17.9 Hz, 2H), 1.58 (d, J = 9.2 Hz,
2H), 1.33 (d, J = 6.9 Hz, 3H), 1.27−0.96 (m, 5H), 0.87−0.76 (m,
1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.4, 135.5, 132.8,
131.5, 130.2, 128.8, 126.9, 126.8, 105.3, 41.8, 30.0, 29.5, 26.2, 26.1,
25.9, 25.7, 17.8; HRMS (ESI) m/z [M + H]+ calcd for C17H21ClNO
290.1312; found 290.1303.
2-Benzyl-7-chloroisoquinolin-1(2H)-one (3r). 18.3 mg, 27.2%
yield; an off-white solid. The title compound was purified by reverse
flash chromatography with the following conditions: column, C18
silica gel; mobile phase, MeCN in water (0.05% NH4HCO3), 30% to
100% gradient in 15 min; detector, UV 254 nm; 1H NMR (400 MHz,
DMSO-d6) δ 8.17 (d, J = 2.2 Hz, 1H), 7.79−7.70 (m, 2H), 7.62 (d, J
= 7.4 Hz, 1H), 7.44−7.21 (m, 6H), 6.70 (d, J = 7.4 Hz, 1H), 5.20 (s,
2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.5, 137.9, 136.2,
134.1, 133.0, 131.8, 129.1, 129.1, 128.1, 128.0, 127.1, 126.6, 105.3,
7-Chloro-2-(1-(furan-3-yl)ethyl)isoquinolin-1(2H)-one (3j). 28.8
mg, 42.2% yield; a light yellow oil. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.2 Hz, 1H), 7.79−
7.68 (m, 3H), 7.66 (t, J = 1.7 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 6.69
(d, J = 7.5 Hz, 1H), 6.43 (dd, J = 1.8, 0.9 Hz, 1H), 6.23−6.13 (m,
1H), 1.64 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6)
δ 160.0, 144.6, 141.4, 135.7, 133.0, 131.7, 129.7, 128.9, 126.9, 126.8,
126.3, 110.3, 105.6, 46.2, 19.5; HRMS (ESI) m/z [M + H]+ calcd for
C15H13ClNO2 274.0635; found 274.0629.
7-Chloro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
isoquinolin-1(2H)-one (3k). 31.5 mg, 37.2% yield; a light yellow oil.
The title compound was purified by reverse flash chromatography
with the following conditions: column, C18 silica gel; mobile phase,
6922
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
51.6; HRMS (ESI) m/z [M + H]+ calcd for C16H13ClNO 270.0686;
found 270.0680.
3.74 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 159.3, 158.7, 144.3 (d, J = 228.3 Hz), 132.6, 128.8,
126.0 (d, J = 23.2 Hz), 122.6, 122.0 (d, J = 38.4 Hz), 114.5, 55.6,
53.2, 19.1; 19F NMR (377 MHz, DMSO-d6) δ −145.20; HRMS (ESI)
m/z [M + H]+ calcd for C14H14BrFNO2 326.0192; found 326.0186.
5-Bromo-1-(1-(4-methoxyphenyl)ethyl)-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (4d). 25.4 mg, 30.6% yield; a light yellow solid.
The title compound was purified by reverse flash chromatography
with the following conditions: column, C18 silica gel; mobile phase,
MeCN in water (0.05% NH4HCO3), 30% to 100% gradient in 15
7-Chloro-2-(cyclohexylmethyl)isoquinolin-1(2H)-one (3s). 19.8
mg, 28.8% yield; an off-white solid. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.15 (dd, J = 2.0, 0.9 Hz, 1H),
7.78−7.68 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H), 6.65 (dd, J = 7.4, 0.7
Hz, 1H), 3.82 (d, J = 7.3 Hz, 2H), 1.79 (ddt, J = 11.1, 7.2, 3.6 Hz,
1H), 1.72−1.64 (m, 2H), 1.64−1.52 (m, 3H), 1.21−1.09 (m, 3H),
1.07−0.95 (m, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.5,
136.1, 134.7, 132.8, 131.5, 128.9, 127.0, 126.5, 104.4, 54.6, 37.2, 30.4,
26.4, 25.7; HRMS (ESI) m/z [M + H]+ calcd for C16H19ClNO
276.1155; found 276.1148.
Ethyl 2-(7-Chloro-1-oxoisoquinolin-2(1H)-yl)propanoate (3t).
55.0 mg, 78.9% yield; a white solid. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 2.2 Hz, 1H), 8.02−
7.95 (m, 2H), 7.83 (dd, J = 8.7, 2.2 Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H),
5.43 (q, J = 7.0 Hz, 1H), 4.17−4.07 (m, 2H), 1.66 (d, J = 7.0 Hz,
3H), 1.15 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6)
δ 171.7, 158.2, 140.3, 136.6, 132.1, 132.1, 129.4, 122.7, 119.4, 115.7,
70.6, 61.0, 17.8, 14.4; HRMS (ESI) m/z [M + H]+ calcd for
C14H15ClNO3 280.0740; found 280.0730.
Methyl 2-(7-Chloro-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetate
(3u). 60 mg, 73.3% yield; a light yellow solid. The title compound
was purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.2 Hz, 1H),
8.08−8.01 (m, 2H), 7.86 (dd, J = 8.7, 2.2 Hz, 1H), 7.74−7.69 (m,
2H), 7.56−7.47 (m, 4H), 6.44 (s, 1H), 3.65 (s, 3H); 13C NMR (101
MHz, DMSO-d6) δ 170.3, 158.1, 140.3, 136.7, 135.1, 132.3, 132.3,
129.7, 129.4, 129.4, 128.2, 122.6, 119.4, 116.1, 76.0, 52.8; HRMS
(ESI) m/z [M + H]+ calcd for C18H15ClNO3 328.0740, found
328.0731.
1
min; detector, UV 254 nm; H NMR (400 MHz, DMSO-d6) δ 8.38
(d, J = 2.7 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.40−7.30 (m, 2H),
6.98−6.90 (m, 2H), 6.04 (q, J = 7.2 Hz, 1H), 3.75 (s, 3H), 1.73 (d, J
= 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 159.5, 158.3,
150.1, 142.2, 131.8, 129.1, 115.7, 114.6, 105.1, 96.6, 55.6, 55.3, 19.0;
HRMS (ESI) m/z [M + K]+ calcd for C15H13BrN2O2K 372.9777;
found 372.9762.
Methyl 1-(1-(4-Methoxyphenyl)ethyl)-2-oxo-1,2-dihydropyri-
dine-4-carboxylate (4e). 8.5 mg, 11.9% yield; a colorless oil. The
title compound was purified by reverse flash chromatography with the
following conditions: column, C18 silica gel; mobile phase, MeCN in
water (0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector,
UV 254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 7.1, 2.2
Hz, 1H), 7.88 (dd, J = 6.8, 2.2 Hz, 1H), 7.32−7.24 (m, 2H), 6.97−
6.89 (m, 2H), 6.32 (t, J = 6.9 Hz, 1H), 6.17 (q, J = 7.2 Hz, 1H), 3.74
(s, 6H), 1.67 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-
d6) δ 165.8, 159.3, 158.4, 143.7, 140.9, 132.9, 128.9, 120.3, 114.5,
105.1, 55.6, 53.0, 52.2, 19.6; HRMS (ESI) m/z [M + H]+ calcd for
C16H18NO4 288.1236; found 288.1225.
Methyl 1-(1-(4-Methoxyphenyl)ethyl)-2-oxo-1,2-dihydropyri-
dine-3-carboxylate (4f). 22.0 mg, 30.7% yield; a colorless oil. The
title compound was purified by reverse flash chromatography with the
following conditions: column, C18 silica gel; mobile phase, MeCN in
water (0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector,
UV 254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J = 7.1, 0.6
Hz, 1H), 7.31−7.23 (m, 2H), 6.97−6.92 (m, 1H), 6.92−6.86 (m,
2H), 6.55 (dd, J = 7.2, 2.0 Hz, 1H), 6.13 (q, J = 7.2 Hz, 1H), 3.84 (s,
3H), 3.74 (s, 3H), 2.47 (s, 1H), 1.67 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 165.1, 161.3, 159.3, 140.0, 136.9,
132.7, 128.9, 121.1, 114.5, 104.1, 55.6, 53.3, 52.8, 19.4; HRMS (ESI)
m/z [M + H]+ calcd for C16H18NO4 288.1236; found 288.1229.
2-Bromo-5-(1-(4-methoxyphenyl)ethyl)thieno[3,2-c]pyridin-
4(5H)-one (4g). 20.6 mg, 22.7% yield; a pink semisolid. The title
compound was purified by reverse flash chromatography with the
following conditions: column, C18 silica gel; mobile phase, MeCN in
water (0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector,
4-Methoxy-1-(1-(4-methoxyphenyl)ethyl)-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (4a). 10.5 mg, 14.8% yield; a white solid. The title
compound was purified by reverse flash chromatography with the
following conditions: column, C18 silica gel; mobile phase, MeCN in
water (0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector,
1
UV 254 nm; H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.0 Hz,
1H), 7.30−7.23 (m, 2H), 6.96−6.89 (m, 2H), 6.41 (d, J = 7.9 Hz,
1H), 6.05 (q, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.75 (s, 3H), 1.67 (d, J =
7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.6, 160.9,
159.4, 142.7, 128.8, 115.1, 114.5, 95.2, 86.4, 58.1, 55.6, 53.2, 19.3;
HRMS (ESI) m/z [M + Na]+ calcd for C16H16N2O3Na 307.1059;
found 307.1051.
5-Bromo-1-(1-(4-methoxyphenyl)ethyl)pyridin-2(1H)-one (4b).
51.9 mg, 67.6% yield; a white solid. The title compound was purified
by reverse flash chromatography with the following conditions:
column, C18 silica gel; mobile phase, MeCN in water (0.05%
NH4HCO3), 30% to 100% gradient in 15 min; detector, UV 254 nm;
1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 2.8 Hz, 1H), 7.47 (dd,
J = 9.7, 2.8 Hz, 1H), 7.33−7.27 (m, 2H), 6.96−6.90 (m, 2H), 6.41 (d,
J = 9.6 Hz, 1H), 6.09 (q, J = 7.2 Hz, 1H), 3.74 (s, 3H), 1.67 (d, J =
7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.2, 159.3,
142.4, 135.7, 132.8, 128.9, 121.7, 114.5, 97.5, 55.6, 53.0, 19.2; HRMS
(ESI) m/z [M + H]+ calcd for C14H15BrNO2 310.0266; found
310.0257.
4-Bromo-5-fluoro-1-(1-(4-methoxyphenyl)ethyl)pyridin-2(1H)-
one (4c). 36.2 mg, 44.5% yield; a white solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 5.4 Hz, 1H),
7.32−7.27 (m, 2H), 6.95−6.89 (m, 3H), 6.02 (q, J = 7.2 Hz, 1H),
1
UV 254 nm; H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 0.6 Hz,
1H), 7.45 (d, J = 7.5 Hz, 1H), 7.32−7.24 (m, 2H), 6.95−6.86 (m,
3H), 6.23 (q, J = 7.2 Hz, 1H), 3.73 (s, 3H), 1.69 (d, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 159.2, 156.9, 148.5, 133.3,
130.9, 130.4, 128.8, 127.7, 114.5, 112.5, 101.8, 55.6, 52.0, 19.5;
HRMS (ESI) m/z [M + H]+ calcd for C16H15BrNO2S 364.0007;
found 364.0000.
4-Bromo-2-(1-(4-methoxyphenyl)ethyl)-2,7-naphthyridin-1(2H)-
one (4h). 31.5 mg, 35.2% yield; a light yellow solid. The title
compound was purified by reverse flash chromatography with the
following conditions: column, C18 silica gel; mobile phase, MeCN in
water (0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector,
1
UV 254 nm; H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 0.8 Hz,
1H), 8.88 (d, J = 5.5 Hz, 1H), 7.96 (s, 1H), 7.61 (dd, J = 5.6, 0.8 Hz,
1H), 7.42−7.33 (m, 2H), 6.97−6.89 (m, 2H), 6.21 (q, J = 7.1 Hz,
1H), 3.75 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 159.9, 159.4, 152.6, 151.2, 140.8, 135.4, 132.5,
129.0, 121.0, 118.5, 114.5, 97.0, 55.6, 53.0, 18.9; HRMS (ESI) m/z
[M + H]+ calcd for C17H16BrN2O2 359.0395; found 359.0389.
5-Bromo-2-(1-(4-methoxyphenyl)ethyl)isoquinolin-1(2H)-one
(4i). 43.7 mg, 49% yield; an off-white solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
6923
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dt, J = 8.1, 1.0 Hz,
1H), 8.03 (dd, J = 7.7, 1.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.44 (t, J
= 7.9 Hz, 1H), 7.33−7.27 (m, 2H), 6.95−6.90 (m, 2H), 6.73 (dd, J =
7.8, 0.7 Hz, 1H), 6.24 (q, J = 7.1 Hz, 1H), 3.74 (s, 3H), 1.71 (d, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.5, 159.2,
136.5, 135.8, 133.1, 131.4, 128.8, 128.2, 127.9, 127.4, 120.3, 114.5,
104.0, 55.6, 52.5, 19.2; HRMS (ESI) m/z [M + H]+ calcd for
C18H17BrNO2 358.0443; found 358.0437.
7-Chloro-2-(1-(4-methoxyphenyl)ethyl)isoquinolin-1(2H)-one
(4j). 46.8 mg, 59.8% yield; an off-white solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.2 Hz, 1H),
7.75 (dd, J = 8.5, 2.2 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.38 (d, J =
7.5 Hz, 1H), 7.34−7.26 (m, 2H), 6.96−6.88 (m, 2H), 6.67 (d, J = 7.5
Hz, 1H), 6.26 (q, J = 7.2 Hz, 1H), 3.74 (s, 3H), 1.71 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.2, 159.2, 135.6,
133.2, 133.0, 131.7, 130.0, 128.9, 128.8, 126.9, 126.8, 114.5, 105.5,
55.6, 52.3, 19.2; HRMS (ESI) m/z [M + H]+ calcd for C18H17ClNO2
314.0948; found 314.0941.
6-(1-(4-Methoxyphenyl)ethyl)-1,6-naphthyridin-5(6H)-one (4k).
9.2 mg, 13.1% yield; a light yellow semisolid. The title compound
was purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 4.5, 1.8 Hz,
1H), 8.58 (ddd, J = 8.1, 1.9, 0.7 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H),
7.53 (dd, J = 8.1, 4.5 Hz, 1H), 7.36−7.24 (m, 2H), 6.97−6.89 (m,
2H), 6.70 (dd, J = 7.8, 0.7 Hz, 1H), 6.25 (q, J = 7.2 Hz, 1H), 3.74 (s,
3H), 1.73 (d, J = 7.2 Hz, 3H), 1.33−1.22 (m, 1H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 161.5, 159.2, 155.2, 153.2, 136.2, 133.5,
133.1, 128.9, 122.5, 121.4, 114.5, 107.6, 55.6, 52.4, 19.2; HRMS (ESI)
m/z [M + H]+ calcd for C17H17N2O2 281.1290; found 281.1282.
4-Chloro-1-(1-(4-methoxyphenyl)ethyl)quinolin-2(1H)-one (4l).
27.0 mg, 34.5% yield; an off-white solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 8.1, 1.6 Hz,
1H), 7.47 (t, J = 7.9 Hz, 1H), 7.35−7.22 (m, 2H), 7.20−7.13 (m,
2H), 7.05 (s, 1H), 6.93−6.86 (m, 2H), 6.84−6.70 (s, 1H), 3.72 (s,
3H), 1.86 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6)
δ 160.8, 158.5, 143.8, 138.2, 132.4, 131.7, 127.3, 127.3, 126.2, 126.2,
122.9, 121.1, 119.6, 117.5, 114.6, 114.6, 55.5, 16.7; HRMS (ESI) m/z
[M + H]+ calcd for C18H17ClNO2 314.0948; found 314.0939.
8-(4-(Difluoromethoxy)phenyl)-6-(1-(4-methoxyphenyl)ethyl)-2-
(methylthio)pyrido[4,3-d]pyrimidin-7(6H)-one (4m). 22.1 mg, 18.8%
yield; a yellow solid. The title compound was purified by reverse flash
chromatography with the following conditions: column, C18 silica
gel; mobile phase, MeCN in water (0.05% NH4HCO3), 30% to 100%
gradient in 15 min; detector, UV 254 nm; 1H NMR (400 MHz,
DMSO-d6) δ 9.10 (s, 1H), 8.99 (s, 1H), 7.74−7.61 (m, 2H), 7.41−
7.31 (m, 2H), 7.29 (t, J = 74 Hz, 1H), 7.23−7.13 (m, 2H), 7.01−6.89
(m, 2H), 6.36 (q, J = 7.1 Hz, 1H), 3.75 (s, 3H), 2.37 (s, 3H), 1.83 (d,
J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 173.5,
163.3, 161.0, 159.4, 150.0, 148.2, 144.7, 133.4, 132.6, 130.8, 129.0,
127.9, 117.5, 116.9 (t, J = 258.6 Hz), 114.6, 108.5, 55.6, 55.1, 20.4,
14.1; 19F NMR (377 MHz, DMSO-d6) δ −81.72; HRMS (ESI) m/z
[M + H]+ calcd for C24H22F2N3O3S 470.1350; found 470.1346.
1-(1-(4-Methoxyphenyl)ethyl)-6-methylquinolin-2(1H)-one (4n).
19.1 mg, 26% yield; a light yellow semisolid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 9.4 Hz, 1H),
7.50−7.45 (m, 1H), 7.19−6.99 (m, 4H), 6.93−6.76 (m, 3H), 6.66 (d,
J = 9.4 Hz, 1H), 3.72 (s, 3H), 2.28 (s, 3H), 1.83 (d, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 162.1, 158.4, 140.0, 136.2,
20.3, 16.7; HRMS (ESI) m/z [M + H]+ calcd for C19H20NO2
294.1494; found 294.1487.
7-Bromo-1-(1-(4-methoxyphenyl)ethyl)quinolin-2(1H)-one (4o).
25.7 mg, 28.8% yield; a light yellow solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 9.5 Hz, 1H),
7.67 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.7 Hz, 2H), 7.18−7.11
(m, 2H), 6.97−6.89 (m, 2H), 6.72 (d, J = 9.5 Hz, 2H), 3.73 (s, 3H),
1.83 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
162.0, 158.6, 139.8, 132.4, 131.5, 127.3, 125.1, 123.5, 122.0, 120.8,
119.1, 114.7, 55.5, 16.5; HRMS (ESI) m/z [M + H]+ calcd for
C18H17BrNO2 358.0443; found 358.0435.
1-(1-(4-Methoxyphenyl)ethyl)-4-methylquinolin-2(1H)-one (4p).
23.1 mg, 31.5% yield; a light yellow solid. The title compound was
purified by reverse flash chromatography with the following
conditions: column, C18 silica gel; mobile phase, MeCN in water
(0.05% NH4HCO3), 30% to 100% gradient in 15 min; detector, UV
254 nm; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (dd, J = 8.1, 1.6 Hz,
1H), 7.33 (t, J = 8.1 Hz, 1H), 7.22−7.08 (m, 4H), 6.93−6.78 (m,
3H), 6.62 (s, 1H), 3.72 (s, 3H), 2.46 (d, J = 1.2 Hz, 3H), 1.84 (d, J =
7.2 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.9, 158.4,
147.4, 137.9, 133.0, 130.0, 127.2, 126.2, 122.2, 122.0, 120.7, 117.2,
114.5, 55.5, 18.9, 16.8; HRMS (ESI) m/z [M + H]+ calcd for
C19H20NO2 294.1494; found 294.1486.
1-(1-(4-Methoxyphenyl)ethyl)pyridin-2(1H)-one (4q). 1.66 g,
72.2% yield. The title compound was isolated as a light yellow solid
after flash chromatography on silica gel (100:0−10:3 petrol ether/
ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 7.52 (ddd, J = 7.0,
2.1, 0.7 Hz, 1H), 7.35 (ddd, J = 8.9, 6.5, 2.1 Hz, 1H), 7.28−7.22 (m,
2H), 6.95−6.88 (m, 2H), 6.39 (ddd, J = 9.2, 1.4, 0.7 Hz, 1H), 6.24−
6.12 (m, 2H), 3.73 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H); 13C NMR (101
MHz, DMSO-d6) δ 161.6, 159.1, 139.7, 135.7, 133.3, 128.8, 119.9,
114.4, 106.2, 55.6, 51.9, 19.5; HRMS (ESI) m/z [M + H]+ calcd for
C14H16NO2 230.1181; found 230.1174.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00009.
■
sı
Experimental procedures and spectral data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−3l, 3n−3o, 3q−3u, and 4a−4q (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Chang-you Ma − Nanjing Chia Tai-Tianqing Pharmaceutical
Co., Ltd., Qixia Nanjing, Jiangsu 210046, People’s Rupublic
of China; Email: machangyou5816@dingtalk.com
Authors
Ye-bin Wu − Nanjing Chia Tai-Tianqing Pharmaceutical Co.,
Ltd., Qixia Nanjing, Jiangsu 210046, People’s Rupublic of
China
You-zhi Wu − Nanjing Chia Tai-Tianqing Pharmaceutical
Co., Ltd., Qixia Nanjing, Jiangsu 210046, People’s Rupublic
of China
Jian Wu − Nanjing Chia Tai-Tianqing Pharmaceutical Co.,
Ltd., Qixia Nanjing, Jiangsu 210046, People’s Rupublic of
China
Dan Xu − Nanjing Chia Tai-Tianqing Pharmaceutical Co.,
Ltd., Qixia Nanjing, Jiangsu 210046, People’s Rupublic of
China
Hui Jiang − Pharmaron (Shang Hai), Shang Hai 201203,
People’s Rupublic of China
132.9, 131.3, 131.2, 129.3, 127.3, 121.7, 121.4, 116.9, 114.5, 55.5,
6924
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(10) Xu, G. Y.; Chen, P.; Liu, P.; Tang, S. B.; Zhang, X. H.; Sun, J. T.
Access to N-Substituted 2-Pyridones by Catalytic Intermolecular
Dearomatization and 1,4-Acyl Transfer. Angew. Chem., Int. Ed. 2019,
58, 1980−1984.
Wen-wu Chang − Pharmaron (Shang Hai), Shang Hai
201203, People’s Rupublic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00009
(11) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. N-
Tosylhydrazones as Reagents for Cross-Coupling Reactions: A Route
to Polysubstituted Olefins. Angew. Chem., Int. Ed. 2007, 46, 5587−
5590. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.; Aznar, F.;
Valdes, C. Pd-Catalyzed Cross-Coupling Reactions with Carbonyls:
Application in a Very Efficient Synthesis of 4-Aryltetrahydropyridines.
Chem. - Eur. J. 2008, 14, 4792−4795. (c) Yu, W. Y.; Tsoi, Y. T.; Zhou,
Z.; Chan, A. S. C. Palladium-Catalyzed Cross Coupling Reaction of
Benzyl Bromides with Diazoesters for Stereoselective Synthesis of
(E)-α,β-Diarylacrylates. Org. Lett. 2009, 11, 469−472. (d) Barluenga,
J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdes, C. Synthesis of Enol
Ethers and Enamines by Pd-Catalyzed Tosylhydrazide-Promoted
Cross-Coupling Reactions. Chem. - Eur. J. 2009, 15, 13291−13294.
(12) (a) Ramakrishna, K.; Murali, M.; Sivasankar, C. Chemo-
selective Carbene Insertion into the N−H Bond over O−H Bond
Using a Well-Defined Single Site (P-P)Cu(I) Catalyst. Org. Lett.
2015, 17, 3814−3817. (b) Lee, E. C.; Fu, G. C. Copper-Catalyzed
Asymmetric N-H Insertion Reactions: Couplings of Diazo Com-
pounds with Carbamates to Generate α-Amino Acids. J. Am. Chem.
Soc. 2007, 129, 12066−12067. (c) Li, M. L.; Yu, J. H.; Li, Y. H.; Zhu,
S. F.; Zhou, Q. L. Highly Enantioselective Carbene Insertion into N−
H bonds of Aliphatic Amines. Science 2019, 366, 990−994.
Author Contributions
⊥Ye-bin Wu and You-zhi Wu contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Nanjing Chia Tai-Tianqing is gratefully
acknowledged. At the same time, we thank the cooperation of
Pharmaron (Shang Hai).
REFERENCES
■
́
̃
(1) Good, J. A. D.; Silver, J.; Nunez-Otero, C.; Bahnan, W.;
Krishnan, K. S.; Salin, O.; Engström, P.; Svensson, R.; Artursson, P.;
Gylfe, Å.; Bergström, S.; Almqvist, F. Thiazolino 2-Pyridone Amide
Inhibitors of Chlamydia Trachomatis Infectivity. J. Med. Chem. 2016,
59, 2094−2108.
(2) (a) Neckles, C.; Pschibul, A.; Lai, C. T.; Hirschbeck, M.; Kuper,
J.; Davoodi, S.; Zou, J.; Liu, N.; Pan, P.; Shah, S.; Daryaee, F.;
Bommineni, G. R.; Lai, C.; Simmerling, C.; Kisker, C.; Tonge, P. J.
Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the
Yersinia Pestis FabV Enoyl-ACP Reductase. Biochemistry 2016, 55,
2992−3006. (b) Reich, S. H.; Sprengeler, P. A.; Chiang, G. G.;
Appleman, J. R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J. T.; Han, Q.;
Goel, V. K.; Han, E. Z. R.; Huang, V.; Hung, I. N. J.; Jemison, A.;
Jessen, K. A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G. S.; Shaghafi,
M.; Sperry, S.; Staunton, J.; Stumpf, C. R.; Thompson, P. A.; Tran, C.;
Webber, S. E.; Wegerski, C. J.; Zheng, H. K.; Webster, R. Structure-
Based Design of Pyridone−Aminal eFT508 Targeting Dysregulated
Translation by Selective Mitogen-Activated Protein Kinase Interacting
Kinases 1 and 2 (MNK1/2) Inhibition. J. Med. Chem. 2018, 61,
3516−3540.
́
(13) (a) Sinai, A.; SimkóDániel, Cs; Szabó, F.; Paczal, A.; Gáti, T.;
Bényei, A.; Novák, Z.; Kotschy, A. Synthesis, Structural Analysis and
Application of Aryl-Diadamantyl Phosphine ligands in Palladium
Catalyzed Cross-Coupling Reactions. Eur. J. Org. Chem. 2020, 34,
5634−5634. (b) Ghiya, S.; Joshi, Y. C. Synthesis and Antimicrobial
Evaluation of Hydrazones Derived from 4-Methylbenzenesulfonohy-
drazide in Aqueous Medium. Med. Chem. Res. 2016, 25, 970−976.
(c) Ojha, D. P.; Prabhu, K. R. Regioselective Synthesis of Vinyl
Halides, Vinyl Sulfones, and Alkynes: A Tandem Intermolecular
Nucleophilic and Electrophilic Vinylation of Tosylhydrazones. Org.
Lett. 2015, 17, 18−21. (d) Zhang, K.; El Bouakher, A.; Levaique, H.;
Bignon, J.; Retailleau, P.; Alami, M.; Hamze, A. Pyrrolo-imidazo[1,2-
a]pyridine Scaffolds through a Sequential Coupling of N-Tosylhy-
drazones with Imidazopyridines and Reductive Cadogan Annulation,
Synthetic Scope, and Application. J. Org. Chem. 2019, 84, 13807−
13823. (e) Wang, C.-Y.; Han, J.-B.; Wang, L.; Tang, X.-Y. Lewis Acid
Catalyzed [4 + 2] Cycloaddition of N-Tosylhydrazones with Ortho-
Quinone Methides. J. Org. Chem. 2019, 84, 14258−14269. (f) Huang,
Y. b.; Yu, Y.; Zhu, Z. Z.; Zhu, C. L.; Cen, J. H.; Li, X. W.; Wu, W. Q.;
Jiang, H. F. Copper-Catalyzed Cyanation of N-Tosylhydrazones with
Thiocyanate Salt as the “CN” Source. J. Org. Chem. 2017, 82, 7621−
7627. (g) Jha, A. K.; Jain, N. The Microwave-Assisted Ortho-
Alkylation of Azine N-oxides with N-Tosylhydrazones Catalyzed by
Copper(I) Iodide. Chem. Commun. 2016, 52, 1831−1834. (h) Yin, B.
L.; Zhang, X. Y.; Zhang, X. T.; Peng, H.; Zhou, W.; Liu, B.; Jiang, H.
F. Access to Polysubstituted Indoles or Benzothiophenes via
Palladium-catalyzed Cross-coupling of Furfural Tosylhydrazones
with 2-iodoanilines or 2-iodothiophenols. Chem. Commun. 2015, 51,
6126−6129. (i) Huang, Y. B.; Zhou, P. Q.; Wu, W. Q.; Jiang, H. F.
Selective Construction of 2-Substituted Benzothiazoles from o-
Iodoaniline Derivatives S8 and N-Tosylhydrazones. J. Org. Chem.
2018, 83, 2460−2466. (j) Katsina, T.; Papoulidou, K. E.; Zografos, A.
L. Umpolung-like Cross-coupling of Tosylhydrazones with 4-
Hydroxy-2-pyridones under Palladium Catalysis. Org. Lett. 2019, 21,
8110−8115.
(3) (a) Njarđarson group’s Top Pharmaceuticals Poster. (b) Drug
Approval Package: Pifeltro (doravirine); U.S. Food and Drug
Administration (FDA), 9 October 2018.
(4) (a) LaPlante, S. R.; Bilodeau, F.; Aubry, N.; Gillard, J. R.;
O’Meara, J.; Coulombe, R. N- versus O-alkylation: Utilizing NMR
Methods to Establish Reliable Primary Structure Determinations for
Drug Discovery. Bioorg. Med. Chem. Lett. 2013, 23, 4663−4668.
(b) Sun, C.; Qi, X. T.; Min, X. L.; Bai, X. D.; Liu, P.; He, Y.
Asymmetric Allylic Substitution-Isomerization to Axially Chiral
Enamides via Hydrogen-Bonding Assisted Central-to-Axial Chirality
Transfer. Chem. Sci. 2020, 11, 10119−10126.
(5) Fang, Y. Q.; Bio, M. M.; Hansen, K. B.; Potter, M. S.; Clausen, A.
Magnesium Coordination-Directed N-Selective Stereospecific Alkyla-
tion of 2-Pyridones, Carbamates, and Amides Using Alpha-
Halocarboxylic Acids. J. Am. Chem. Soc. 2010, 132, 15525−15527.
(6) (a) Mayr, H.; Breugst, M.; Ofial, A. R. Farewell to the HSAB
Treatment of Ambident Reactivity. Angew. Chem., Int. Ed. 2011, 50,
6470−6505. (b) Breugst, M.; Mayr, H. Ambident Reactivities of
Pyridone Anions. J. Am. Chem. Soc. 2010, 132, 15380−389.
(7) (a) Sato, T.; Yoshimatsu, K.; Otera, J. CsF in Organic Synthesis.
Tuning of N- or O-Alkylation of 2-Pyridone. Synlett 1995, 8, 845−
846. (b) Liu, H.; Ko, S. B.; Josien, H.; Curran, D. P. Selective N-
Functionalization of 6-Substituted-2-Pyridones. Tetrahedron Lett.
1995, 36, 8917−8920.
(14) Chen, Z.; Yan, Q.; Yi, H.; Liu, Z.; Lei, A.; Zhang, Y. Efficient
Synthesis of 1,2,3-Triazoles by Copper-Mediated C-N and N-N Bond
Formation Starting from N-Tosylhydrazones and Amines. Chem. -
Eur. J. 2014, 20, 13692−13697.
(8) Hao, X.; Xu, Z. M.; Lu, H. F.; Dai, X. D.; Yang, T.; Lin, X. C.;
Ren, F. Mild and Regioselective N-Alkylation of 2-Pyridones in Water.
Org. Lett. 2015, 17, 3382−3385.
(15) Nakagawa, Y.; Chanthamath, S.; Fujisawa, I.; et al. Ru (II)-
Pheox-catalyzed Si−H Insertion Reaction: Construction of Enan-
tioenriched Carbon and Silicon Centers. Chem. Commun. 2017, 53,
3753−3756.
(9) Feng, B.; Li, Y.; Li, H.; Zhang, X.; Xie, H. M.; Cao, H. G.; Yu, L.;
Xu, Q. Specific N-Alkylation of Hydroxypyridines Achieved by a
Catalyst- and Base-Free Reaction with Organohalides. J. Org. Chem.
2018, 83, 6769−6775.
6925
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(16) Stivanin, M. L.; Fernandes, A. A. G.; Silva, A. F.; Okada, C. Y.;
Jurberg, I. D.; et al. Blue Light-Promoted N-H Insertion of
Carbazoles, Pyrazoles and 1, 2, 3-Triazoles into Aryldiazoacetates.
Adv. Synth. Catal. 2020, 362, 1106−1111.
6926
https://doi.org/10.1021/acs.joc.1c00009
J. Org. Chem. 2021, 86, 6918−6926