Palladium-Catalyzed Regioselective C-H Functionalization/Annulation Reaction of Amides and Allylbenzenes for the Synthesis of Isoquinolinones and Pyridinones

Article abstract of DOI:10.1021/acs.joc.1c00150

A regioselective C-H functionalization/annulation reaction of N-sulfonyl amides and allylbenzenes through a palladium-catalyzed C(sp2)-H allylation/aminopalladation/β-H elimination/isomerization sequence has been reported. Various aryl and alkenyl carboxamides are found to be efficient substrates to construct isoquinolinones and pyridinones in up to 96% yield. Using ambient air as the terminal oxidant is another advantage regarding environmental friendliness and operational simplicity.

Full text of DOI:10.1021/acs.joc.1c00150

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Article
Palladium-Catalyzed Regioselective C−H Functionalization/
Annulation Reaction of Amides and Allylbenzenes for the Synthesis
of Isoquinolinones and Pyridinones
Rong Zhong, Yong Xu, Manman Sun,* and Yurong Wang*
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ABSTRACT: A regioselective C−H functionalization/annulation reaction of N-sulfonyl amides and allylbenzenes through a
palladium-catalyzed C(sp2)−H allylation/aminopalladation/β−H elimination/isomerization sequence has been reported. Various
aryl and alkenyl carboxamides are found to be efficient substrates to construct isoquinolinones and pyridinones in up to 96% yield.
Using ambient air as the terminal oxidant is another advantage regarding environmental friendliness and operational simplicity.
metalacyclic intermediate formed from alkene insertion or
reacted as an internal oxidant (Scheme 1a). A rhodium-
catalyzed oxidative annulation of anilines and allylbenzenes has
also been reported via allylic C−H activation to deliver a
variety of indoles,12 in which the directing group was thought
as an efficient ligand to form the catalytically active complex in
promoting C(sp3)−H activation of allylbenzenes (Scheme 1b).
Herein, we describe an innovative palladium-catalyzed C−H
functionalization/annulation reaction of amides and allylben-
zenes for the synthesis of isoquinolinones and pyridinones
through a C(sp2)−H allylation/aminopalladation/β−H elim-
ination/isomerization sequence, in which the sulfonyl group in
the amides plays an important role2a,3a,13 (Scheme 1c). It
should be mentioned that the reported palladium-catalyzed
annulation reactions of N-sulfonyl amides and aliphatic alkenes
favored the C(sp2)−H alkenylation/aza-Wacker-type cycliza-
tion process to form a five-membered fused aza-heterocycle,2a
due to the formation of a thermodynamically favored alkenylic
intermediate. Hence, the highly regioselective C(sp2)−H
allylation/annulation reaction of amides and allylbenzenes to
form the six-membered fused aza-heterocycle is challenging
and rewarding.
INTRODUCTION
■
The transition-metal-catalyzed C−H functionalization/annula-
tion reaction represents one of the powerful approaches in
organic synthesis,1 as it provides a remarkable atom and step
economic tool to access a variety of valuable cyclic products
from easily accessible starting materials. Among the numerous
unsaturated substrates for the annulation reactions, alkenes
have attracted increasing interest among chemists. Impressive
[n + 1] and [n + 2] annulation reactions have been made with
conjugated alkenes, such as acrylates2 and styrenes,3 and even
aliphatic alkenes.4 However, the transition-metal-catalyzed C−
H functionalization reaction with alkenes, especially with
aliphatic alkenes, still suffers from poor regioselectivities,5 such
as functionalization of Ca or Cb, elimination of the β−H or C−
X bond (X = C, N, O), and cleavage of the carbon−carbon
double bond or the allylic C(sp3)−H bond. Generally, the
developed methods for controlling the regioselectivity of
alkenes include the judicious choice of the transition-metal
catalyst,6 the ligand,7 and the directing group.8 Hence, the
highly regioselective control of the C−H functionalization
reaction with alkenes to undergo an innovative annulation
process is of importance and highly desired.
Allylbenzenes are useful starting materials employed in the
directed C−H functionalization of arenes. However, most of
the directed C−H functionalization of arenes with allylben-
zenes generated the alkenylic6c,9 or allylic adducts.6d−f,8a,10 To
realize the annulation process, the judicious choice of the
directing group proves to be crucial. Several [4 + 2]
annulations of benzamides and allylbenzenes catalyzed by
rhodium or cobalt complexes have been reported for the
formation of 3,4-dihydroisoquinolones,4b,11 in which the
directing group imparted sufficient stabilization to the
Besides the distinctive C−H functionalization/annulation
reaction feature, this approach provides rapid access to
Received: January 19, 2021
Published: March 22, 2021
https://doi.org/10.1021/acs.joc.1c00150
© 2021 American Chemical Society
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Scheme 1. C−H Functionalization/Annulation Reactions with Allylbenzenes
Figure 1. Examples of bioactive compounds containing the isoquinolone and the pyridinone core.
a
isoquinolones and pyridinones, which present as core
structural scaffolds in many natural products and pharmaceut-
icals of biological interest (Figure 1).14 Albeit with several well-
investigated methods for the synthesis of isoquinolinones, such
as the intramolecular aminocarbonylation annulation reac-
tion,15 the 6π-electrocyclization reaction,16 Larock-type
heteroannulation reaction,17 and the C−H functionalization/
annulation reaction of benzamides with alkynes18 or allenes,19
using the easily accessible alkenes as privileged synthons in the
C−H functionalization/annulation reaction is still a valuable
protocol. Additionally, using air as the terminal oxidant is
another advantage regarding environmental friendliness and
operational simplicity.
Table 1. Screening of Reaction Conditions
b
entry
catalyst
co-oxidant
yield (%)
1
2
Pd(TFA)2
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
88%
55%
50%
76%
87%
15%
3
Pd(OAc)2
4
Pd(TFA)2/DMSO
5
6
Pd(TFA)2/Ac-Gly-OH
Pd(TFA)2/1,10-phenanthroline
7
RESULTS AND DISCUSSION
8
9
10
11
12
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
52%
26%
trace
trace
64%
34%
73%
■
BQ
Inspired by the efficient reaction conditions obtained from our
previous efforts in the C−H functionalization/annulation
reactions of benzamides,13b,20 we initially selected N-((4-
nitrophenyl)sulfonyl)benzamide 1a and allylbenzene 2a as the
model substrates to react with 10 mol % Pd(TFA)2 and 20 mol
% Cu(OAc)2 in p-xylene at 110 °C under air (Table 1). To our
delight, the desired product 3a was obtained in 88% yield after
24 h (entry 1). Switching the catalyst to PdCl2 and Pd(OAc)2,
both the yields decreased (entries 2 and 3). Adding the
DMSO, Ac-Gly-OH, or 1,10-phenanthroline ligand to the
reaction also did not improve the yield (entries 4−6). Further,
1,10-phenanthroline proved to not be a suitable ligand for this
C−H functionalization/annulation reaction, which favored
another tandem process of C−H olefination/aza-Wackertype
cyclization to form a five-membered fused aza-heterocycle.2a
No desired product 3a was detected in the absence of a catalyst
(entry 7). Then, other co-oxidants such as Ag2CO3, BQ,
K2S2O8
PhI(OAc)2
Cu(OAc)2
O2
c
d
13
14
e
Cu(OAc)2
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.02
mmol), co-oxidant (0.04 mmol), and p-xylene (2 mL) at 110 °C
under air for 24 h. Isolated yield. Cu(OAc)2 (0.02 mmol) was used.
b
c
d
e
With an O2 balloon. At 100 °C.
K2S2O8, and PhI(OAc)2 were examined. Diminished yields or
the trace product indicated that Cu(OAc)2 was most effective
(entries 8−11). Decreasing the amount of Cu(OAc)2 to 10
mol % decreased the yield to 64% (entry 12). Omitting
Cu(OAc)2 and reacting with an O2 balloon led to a sharp
decrease of the yield to 34% (entry 13). Reducing the
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temperature to 100 °C decreased the yield to 73% (entry 14).
Eventually, the optimal conditions of C−H functionalization
annulation with allylbenzenes were established as using
Pd(TFA)2 (10 mol %) as the catalyst and Cu(OAc)2 (20
mol %) as the co-oxidant in p-xylene at 110 °C under air for 24
h.
To evaluate the influence of the directing groups,
benzamides protected by the Ac, Ph, or OPiv group (A−C)
were conducted in the C−H functionalization/annulation
reaction under the optimal reaction conditions (Scheme 2).
These results suggested that the sulfonyl group in the amides
plays an important role.
With the optimized reaction conditions in hand, the scope of
the C−H functionalization/annulation reaction was inves-
tigated, as depicted in Scheme 3. Both electron-donating and
electron-withdrawing substituents on the phenyl ring of
benzamides were well tolerated, achieving the desired products
3b−3j in moderate to excellent yields. Among them, electron-
rich benzamides performed better than electron-deficient
benzamides (cf. 3b, 3f, 3g vs 3h−3j). The product 3i was
obtained in 75% yield with the help of the 20 mol % Ac-Gly-
OH ligand. The meta-substituted benzamide exhibited
moderate reactivity to take place at the less sterically hindered
position, giving product 3c in 51% yield. Gratifyingly, the
ortho-substituted benzamides functioned excellently, and
products 3d and 3e were formed, respectively, in 96 and
95% yields. Switching the N-protecting group to Ts or Ms did
not retard the annulation reaction, delivering the product 3k
and 3l in yields of 68 and 89%, respectively. Then, other N-
sulfonyl aryl carboxamides were examined. N-((4-
Nitrophenyl)sulfonyl)-1-naphthamide worked well under the
standard reaction conditions to synthesize the desired product
3m in 72% yield, while a small amount of a five-membered
byproduct was formed.2a N-Sulfonyl heteroaryl carboxamides
such as benzofuran-2-carboxamide and furan-2-carboxamide
were not compatible with this annulation reaction (see the
Supporting Information). Subsequently, the variations of
allylbenzenes were explored. Both electron-donating and
electron-withdrawing substituted allylbenzenes reacted
smoothly to afford the desired products 3n−3q in moderate
yields. The internal allylbenzene such as but-2-en-1-ylbenzene
failed to generate any product with N-((4-nitrophenyl)-
sulfonyl)benzamide 1a. When an aliphatic alkene such as 1-
decene was applied as the substrate, the annulation reaction
Scheme 2. Evaluation of Directing Groups
Unfortunately, these benzamides failed to generate the desired
products, and they decomposed (A and C) or remained intact
(B). Benzamides bearing 8-aminoquinoline21 (D) and 2-
pyridinylisopropyl22 (E) directing groups have also been
examined, delivering unreacted starting materials and a small
amount of a five-membered byproduct through the tandem
process of C−H olefination/aza-Wackertype cyclization.2a
Scheme 3. Scope of N-Sulfonyl Benzamides and Allylbenzenes
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Scheme 4. Scope of Alkenyl Carboxamides
Scheme 5. Gram-Scale Synthesis and Synthetic Transformation
Scheme 6. Proposed Plausible Mechanism
became messy, which did not yield the desired product (see
the Supporting Information).
starting materials or undesired products (see the Supporting
Information). These results suggest that the conformation
maintained by α-substitution and β-substitution in starting
materials is essential for this C−H functionalization/
annulation reaction. Substituted allylbenzenes were further
investigated with 2-methylbut-2-enamide, achieving the
corresponding products 5g and 5h in moderate yields.
To further showcase the synthetic feasibility of this
methodology, a gram-scale annulation reaction of substrates
1a and 2a was conducted under optimized reaction conditions.
Gratifyingly, the desired product 3a was isolated in 79% yield
We eventually turned our attention to different alkenyl
carboxamides4c,20b,23 to synthesize pyridinones (Scheme 4).
Cyclohex-1-enecarboxamide and α,β-disubstituted acrylamides
engaged well in this annulation reaction under the standard
reaction conditions to furnish the desired products 5a−5f in
44−53% yields. β-Substituted acrylamides, such as cinnama-
mide, α-substituted acrylamides, such as α-phenylacrylamide
and α-benzylacrylamide, and dihydropyrancarboxamides were
unsuitable substrates for this annulation reaction with intact
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cooled to room temperature, and quenched with HCl (1 N, 20 mL).
The resulting mixture was then extracted with EtOAc (3 × 20 mL).
The combined organic layer was dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel to obtain the pure
product 4.
(Scheme 5a). Furthermore, the N-protecting group could be
smoothly removed by treatment with p-MePhSH and K2CO3
in DMF, giving the product 6 in 85% yield (Scheme 5b).24
Based on all of the abovementioned results and by analogy
with previously reported processes,2a,13b,25 we proposed a
plausible mechanism as depicted in Scheme 6 using 1a and 2a
as the model substrates. Initially, C(sp2)−H activation was
initiated via the deprotonation of the acid N−H bond to form
a N−Pd bond, which was followed by a palladation process to
furnish a five-membered palladacycle I. Then, after coordina-
tion of allylbenzene 2a to palladacycle I, the tandem removal of
an allylic hydrogen (II) and reductive elimination of a C−C
bond process delivered the C(sp2)−H allylation intermediate
III and Pd(0) species.10a,b,13b Subsequently, another N−Pd
bond (VI) was formed by the deprotonation of the acid N−H
bond in intermediate III. Aminopalladation of the carbon−
carbon double bond (V) followed by β−H elimination
(IV)2b,3a,26 and isomerization resulted in formation of the
desired product 3a.27 Finally, the regenerated Pd(0) species
was oxidized to a Pd(II) catalyst by Cu(OAc)2 and O2 in the
air to participate in the next cycle.
(E)-2-Methyl-N-((4-nitrophenyl)sulfonyl)pent-2-enamide (4d).
White solid; 1.1 g; 74% yield; Rf = 0.58 (hexane/EtOAc = 1/1 as
1
the eluent); mp = 88−89 °C; H NMR (400 MHz, CDCl3) δ 8.96
(br, 1H), 8.38 (d, J = 8.9 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H), 6.50 (t, J
= 6.8 Hz, 1H), 2.22−2.14 (m, 2H), 1.77 (s, 3H), 1.02 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.0, 150.7, 144.2, 144.1,
130.1, 128.6, 124.1, 22.3, 12.8, 12.0; HRMS (ESI-TOF) m/z calcd for
[M + Na]+ (C12H14N2O5SNa) 321.0521, found 321.0520.
(E)-2-Methyl-N-((4-nitrophenyl)sulfonyl)hex-2-enamide (4e).
White solid; 1.2 g; 79% yield; Rf = 0.49 (hexane/EtOAc = 1/1 as
1
the eluent); mp = 77−78 °C; H NMR (400 MHz, CDCl3) δ 8.69
(br, 1H), 8.40 (d, J = 9.0 Hz, 2H), 8.32 (d, J = 8.9 Hz, 2H), 6.51 (t, J
= 6.8 Hz, 1H), 2.16 (q, J = 7.3 Hz, 2H), 1.79 (s, 3H), 1.50−1.41 (m,
2H), 0.92 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.7, 150.8, 144.1, 142.8, 130.1, 129.2, 124.1, 30.9, 21.7, 13.9, 12.2;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C13H16N2O5SNa)
335.0678, found 335.0671.
(E)-2,4-Dimethyl-N-((4-nitrophenyl)sulfonyl)pent-2-enamide
(4f). White solid; 1.1 g; 71% yield; Rf = 0.55 (hexane/EtOAc = 1/1 as
the eluent); mp = 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 9.01
(br, 1H), 8.38 (d, J = 8.9 Hz, 2H), 8.31 (d, J = 8.9 Hz, 2H), 6.33 (d, J
= 9.5 Hz, 1H), 2.65−2.56 (m, 1H), 1.78 (s, 3H), 0.97 (d, J = 6.7 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 150.8, 149.3, 144.1,
130.1, 126.9, 124.2, 28.3, 21.7, 12.0; HRMS (ESI-TOF) m/z calcd for
[M + Na]+ (C13H16N2O5SNa) 335.0678, found 335.0674.
CONCLUSIONS
■
In summary, we have developed a highly regioselective C−H
functionalization/annulation reaction of N-sulfonyl amides
with allylbenzenes through a palladium-catalyzed C(sp2)−H
allylation/aminopalladation/β−H elimination/isomerization
sequence. The innovative annulation reaction delivers a
valuable protocol for biologically important isoquinolinones
and pyridinones from the easily accessible alkenes. Using
ambient air as the terminal oxidant is another advantage
regarding environmental friendliness and operational simplic-
ity.
General Procedure for the Synthesis of Compounds 3 and
5. An oven-dried Schlenk tube equipped with a Teflon valve was
charged with a magnetic stir bar, substrate 1 or 4 (0.2 mmol, 1.0
equiv), Pd(TFA)2 (6.6 mg, 0.02 mmol, 10 mol %), Cu(OAc)2 (7.3
mg, 0.04 mmol, 20 mol %), and p-xylene (2 mL). Allylbenzene 2 (0.4
mmol, 2.0 equiv) was added. The reaction mixture was stirred in an
oil bath at 110 °C for 24 h under air. Then, the resulting suspension
was cooled to room temperature, filtered through a pad of filter paper,
and washed with ethyl acetate (50 mL). After evaporating the solvent
under reduced pressure, the residue was purified by column
chromatography on silica gel to give the pure product 3 or 5.
3-Benzyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-one (3a).
Light yellow solid; 73.9 mg; 88% yield; Rf = 0.44 (hexane/EtOAc =
5/1 as the eluent); mp = 193−194 °C; 1H NMR (400 MHz, CDCl3)
δ 8.42−8.36 (m, 4H), 7.97 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.5 Hz,
1H), 7.45−7.40 (m, 2H), 7.37−7.31 (m, 4H), 7.16 (d, J = 7.7 Hz,
1H), 6.82 (s, 1H), 4.00 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
163.1, 150.6, 145.3, 137.9, 134.3, 134.1, 130.4, 130.3, 130.0, 129.0,
128.7, 128.1, 128.0, 127.7, 127.2, 126.8, 124.1, 32.1; HRMS (ESI-
TOF) m/z calcd for [M + Na]+ (C22H16N2O5SNa) 443.0678, found
443.0676.
3-Benzyl-6-methyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3b). Light yellow solid; 71.8 mg; 83% yield; Rf = 0.44 (hexane/
EtOAc = 5/1 as the eluent); mp = 208−209 °C; 1H NMR (400 MHz,
CDCl3) δ 8.41−8.35 (m, 4H), 7.85 (d, J = 8.0 Hz, 1H), 7.42 (t, J =
7.4 Hz, 2H), 7.38−7.31 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.96 (s,
1H), 6.80 (s, 1H), 3.96 (s, 2H), 2.34 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.2, 150.5, 145.6, 145.4, 137.9, 134.1, 130.7, 130.3,
129.4, 129.0, 128.7, 128.6, 128.0, 127.8, 127.7, 124.2, 124.1, 32.0,
21.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa)
457.0834, found 457.0837.
EXPERIMENTAL SECTION
General Information. 1H NMR and 13C NMR spectra were
■
recorded on a Bruker Avance 400 spectrometer, and tetramethylsilane
(TMS) or CDCl3 (7.26 ppm for H NMR, 77.0 ppm for 13C NMR)
1
was used as a reference. Data for 1H were reported as follows:
chemical shift (ppm) and multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets,
m = multiplet, br = broad singlet). Data for 13C NMR were reported
as ppm. A high-resolution mass spectra analysis was performed on a
Waters SYNAPT G2-Si mass spectrometer. Melting points were
determined using a X-4 digital micromelting point apparatus. Thin-
layer chromatography (TLC) was performed, and visualization of the
compounds was accomplished with UV light (254 nm). Flash column
chromatography was performed on silica gel (200−300 mesh).
Amides 1 and 4a−4c were prepared according to the known
literature.13b Allylbenzene 2a was purchased from commercial
sources. Substituted allylbenzenes were prepared according to the
known literature.10a Purchased reagents and solvents were used
without further purification.
General Procedure for the Synthesis of Alkenyl Carbox-
amides 4. To a suspension solution of the corresponding acid (6
mmol, 1.0 equiv) in CH2Cl2 (80 mL) was added DMF (11 mg, 0.15
mmol, 2.5 mol %) at 0 °C. Oxalyl chloride (1.08 mL, 12 mmol, 2.0
equiv) was subsequently added dropwise using a syringe. The reaction
was allowed to warm to room temperature gradually and stirred for
another 3 h. Then, the reaction mixture was evaporated to afford the
acid chloride, which was used without any further purification. To a
round-bottom flask under N2 was added 4-nitrobenzenesulfonamide
(1.01 g, 5 mmol, 1.0 equiv), DMAP (61 mg, 0.5 mmol, 10 mol %),
Et3N (1.7 mL, 12.5 mmol, 2.5 equiv), and EtOAc (10 mL). The
abovementioned acid chloride was then added at 0 °C for over 15
min. The mixture was stirred for 1 h in an oil bath at 55 °C under N2,
3-Benzyl-7-methyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3c). Light yellow solid; 44.3 mg; 51% yield; Rf = 0.46 (hexane/
EtOAc = 5/1 as the eluent); mp = 172−173 °C; 1H NMR (400 MHz,
CDCl3) δ 8.41−8.35 (m, 4H), 7.76 (s, 1H), 7.42 (t, J = 7.4 Hz, 2H),
7.37−7.32 (m, 3H), 7.29 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 7.8 Hz,
1H), 6.81 (s, 1H), 3.96 (s, 2H), 2.32 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.3, 150.5, 145.3, 137.7, 135.2, 135.0, 134.1, 130.6,
130.3, 129.5, 129.0, 128.7, 128.0, 127.8, 127.1, 126.5, 124.1, 31.7,
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21.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa)
457.0834, found 457.0839.
1H), 7.59 (d, J = 8.2 Hz, 1H), 7.47−7.43 (m, 3H), 7.37 (t, J = 7.2 Hz,
1H), 7.33 (d, J = 7.3 Hz, 2H), 6.87 (s, 1H), 4.07 (s, 2H); 19F NMR
(376 MHz, CDCl3) δ −63.34 (s, 3F); 13C{1H} NMR (100 MHz,
3-Benzyl-8-methyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3d). Light yellow solid; 83.3 mg; 96% yield; Rf = 0.48 (hexane/
EtOAc = 5/1 as the eluent); mp = 189−190 °C; 1H NMR (400 MHz,
CDCl3) δ 8.40−8.33 (m, 4H), 7.41 (t, J = 7.3 Hz, 2H), 7.35−7.29
(m, 4H), 7.12 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.83 (s,
1H), 3.92 (s, 2H), 2.58 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
163.5, 150.5, 145.6, 143.0, 138.7, 134.3, 133.1, 131.4, 130.22, 130.20,
129.0, 128.7, 128.0, 127.9, 125.4, 124.9, 124.1, 33.2, 22.1; HRMS
(ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa) 457.0834,
found 457.0832.
2
CDCl3) δ 161.9, 150.7, 144.9, 138.7, 135.5 (C−F, JC−F = 33.0 Hz),
133.7, 130.4, 130.1, 129.9, 129.3, 129.0, 128.9, 128.9, 128.4, 124.6
3
3
(C−F, JC−F = 3.6 Hz), 124.3 (C−F, JC−F = 3.7 Hz), 124.2, 123.1
(C−F, 1JC−F = 271.7 Hz), 31.9; HRMS (ESI-TOF) m/z calcd for [M
+ Na]+ (C23H15F3N2O5SNa) 511.0551, found 511.0548.
3-Benzyl-2-tosylisoquinolin-1(2H)-one (3k). Light yellow solid;
53.0 mg; 68% yield; Rf = 0.56 (hexane/EtOAc = 5/1 as the eluent);
1
mp = 179−180 °C; H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4
Hz, 2H), 7.99 (d, J = 7.0 Hz, 1H), 7.46−7.38 (m, 3H), 7.36−7.29 (m,
6H), 7.12 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 3.96 (s, 2H), 2.43 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.9, 143.8, 136.9, 135.7,
133.5, 132.7, 123.0, 128.5, 128.2, 128.0, 127.9, 127.5, 126.7, 126.4,
126.3, 125.9, 31.0, 20.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C23H19NO3SNa) 412.0983, found 412.0981.
3-Benzyl-6,8-dimethyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-
1(2H)-one (3e). Light yellow solid; 85.1 mg; 95% yield; Rf = 0.49
1
(hexane/EtOAc = 5/1 as the eluent); mp = 175−176 °C; H NMR
(400 MHz, CDCl3) δ 8.39−8.32 (m, 4H), 7.41 (t, J = 7.4 Hz, 2H),
7.36−7.31 (m, 3H), 6.93 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 3.89 (s,
2H), 2.53 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
163.5, 150.4, 145.7, 144.1, 143.0, 138.8, 134.4, 132.2, 130.4, 130.1,
129.0, 128.7, 127.9, 127.7, 125.6, 124.0, 122.6, 33.1, 22.0, 21.4;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa)
471.0991, found 471.0985.
3-Benzyl-2-(methylsulfonyl)isoquinolin-1(2H)-one (3l). White
solid; 55.9 mg; 89% yield; Rf = 0.48 (hexane/EtOAc = 3/1 as the
eluent); mp = 159−160 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J
= 7.8 Hz, 1H), 7.51 (t, J = 8.7 Hz, 1H), 7.43−7.37 (m, 3H), 7.34−
7.27 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 3.98 (s, 2H),
3.63 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 138.2,
134.3, 134.1, 130.5, 129.4, 129.0, 128.6, 127.8, 127.6, 127.2, 126.8,
44.1, 32.1; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C17H15NO3SNa) 336.0670, found 336.0674.
3-Benzyl-2-((4-nitrophenyl)sulfonyl)benzo[h]isoquinolin-1(2H)-
one (3m). Light yellow solid; 67.7 mg; 72% yield; Rf = 0.40 (hexane/
EtOAc = 5/1 as the eluent); mp = 172−173 °C; 1H NMR (400 MHz,
CDCl3) δ 8.99 (d, J = 8.9 Hz, 1H), 8.40−8.36 (m, 4H), 7.93 (d, J =
8.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.63−7.58 (m, 1H), 7.49 (t, J =
7.1 Hz, 1H), 7.45−7.40 (m, 2H), 7.38−7.33 (m, 3H), 7.21 (d, J = 8.4
Hz, 1H), 6.92 (s, 1H), 4.11 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 163.5, 150.5, 145.6, 139.5, 135.3, 134.2, 133.1, 131.5, 130.3,
129.4, 129.1, 129.0, 128.8, 128.6, 128.5, 128.1, 126.6, 125.9, 124.4,
124.1, 121.8, 33.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C26H18N2O5SNa) 493.0834, found 493.0841.
3-(4-Methylbenzyl)-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3n). Light yellow solid; 53.8 mg; 62% yield; Rf = 0.44 (hexane/
EtOAc = 5/1 as the eluent); mp = 201−202 °C; 1H NMR (400 MHz,
CDCl3) δ 8.43−8.34 (m, 4H), 7.96 (dd, J = 7.9, 1.4 Hz, 1H), 7.48
(td, J = 7.5, 1.5 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.25−7.20 (m, 4H),
7.15 (d, J = 7.5 Hz, 1H), 6.78 (s, 1H), 4.01 (s, 2H), 2.39 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 163.2, 150.5, 145.4, 138.1,
134.3, 131.1, 130.3, 129.8, 129.4, 129.4, 129.0, 128.1, 127.7, 127.2,
126.9, 124.1, 32.1, 21.3; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C23H18N2O5SNa) 457.0834, found 457.0829.
3-(4-Chlorobenzyl)-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3o). Light yellow solid; 48.1 mg; 53% yield; Rf = 0.45 (hexane/
EtOAc = 5/1 as the eluent); mp = 205−206 °C; 1H NMR (400 MHz,
CDCl3) δ 8.44−8.34 (m, 4H), 7.96 (d, J = 7.8 Hz, 1H), 7.50 (t, J =
7.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.27
(d, J = 6.9 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.77 (s, 1H), 3.97 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.6, 145.1, 137.6,
134.5, 134.1, 132.5, 130.9, 130.4, 130.3, 129.4, 129.0, 127.9, 127.2,
126.74, 126.71, 124.1, 32.0; HRMS (ESI-TOF) m/z calcd for [M +
Na]+ (C22H15ClN2O5SNa) 477.0288, found 477.0288.
3-([1,1′-Biphenyl]-4-ylmethyl)-2-((4-nitrophenyl)sulfonyl)-
isoquinolin-1(2H)-one (3p). Light yellow solid; 70.4 mg; 71% yield;
Rf = 0.45 (hexane/EtOAc = 5/1 as the eluent); mp = 155−156 °C;
1H NMR (400 MHz, CDCl3) δ 8.42−8.37 (m, 4H), 7.98 (d, J = 7.2
Hz, 1H), 7.68−7.61 (m, 4H), 7.51−7.46 (m, 3H), 7.43−7.39 (m,
3H), 7.34 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H),
4.06 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 150.6,
145.3, 140.9, 140.3, 137.9, 134.3, 133.0, 130.40, 130.35, 129.5, 129.0,
128.9, 127.8, 127.69, 127.65, 127.4, 127.2, 127.0, 126.8, 124.1, 32.2;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C28H20N2O5SNa)
519.0991, found 519.0997.
3-Benzyl-6-ethyl-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3f). Light yellow solid; 83.3 mg; 93% yield; Rf = 0.45 (hexane/
EtOAc = 5/1 as the eluent); mp = 176−177 °C; 1H NMR (400 MHz,
CDCl3) δ 8.41−8.35 (m, 4H), 7.87 (d, J = 8.1 Hz, 1H), 7.43 (t, J =
7.4 Hz, 2H), 7.37−7.32 (m, 3H), 7.15 (d, J = 8.1 Hz, 1H), 6.97 (s,
1H), 6.80 (s, 1H), 3.98 (s, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.19 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 151.7,
150.5, 145.4, 138.0, 134.2, 130.6, 130.3, 129.5, 129.1, 128.7, 128.0,
127.8, 127.5, 126.6, 124.3, 124.1, 32.1, 29.0, 15.0; HRMS (ESI-TOF)
m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found
471.0986.
3-Benzyl-6-methoxy-2-((4-nitrophenyl)sulfonyl)isoquinolin-
1(2H)-one (3g). Light yellow solid; 74.7 mg; 83% yield; Rf = 0.47
1
(hexane/EtOAc = 3/1 as the eluent); mp = 190−191 °C; H NMR
(400 MHz, CDCl3) δ 8.40−8.35 (m, 4H), 7.90 (d, J = 8.8 Hz, 1H),
7.42 (t, J = 7.4 Hz, 2H), 7.36−7.32 (m, 3H), 6.88−6.74 (m, 2H),
6.61 (s, 1H), 3.97 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.3, 162.8, 150.5, 145.6, 140.3, 134.2, 131.7, 130.6, 130.2,
129.0, 128.7, 128.0, 127.7, 124.1, 119.3, 113.8, 111.8, 55.6, 32.4;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O6SNa)
473.0783, found 473.0774.
3-Benzyl-6-chloro-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3h). Light yellow solid; 67.2 mg; 74% yield; Rf = 0.45 (hexane/
EtOAc = 5/1 as the eluent); mp = 216−217 °C; 1H NMR (400 MHz,
CDCl3) δ 8.43−8.35 (m, 4H), 7.90 (d, J = 8.4 Hz, 1H), 7.43 (t, J =
7.4 Hz, 2H), 7.37 (d, J = 7.1 Hz, 1H), 7.34−7.28 (m, 3H), 7.17 (s,
1H), 6.83 (s, 1H), 3.97 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
162.3, 150.6, 145.1, 140.8, 139.6, 133.8, 130.9, 130.4, 129.7, 129.0,
128.8, 128.5, 128.3, 128.2, 127.3, 125.3, 124.1, 31.9; HRMS (ESI-
TOF) m/z calcd for [M + Na]+ (C22H15ClN2O5SNa) 477.0288,
found 477.0281.
3-Benzyl-6-fluoro-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3i). Light yellow solid; 65.7 mg; 75% yield; Rf = 0.42 (hexane/
EtOAc = 5/1 as the eluent); mp = 193−194 °C; 1H NMR (400 MHz,
CDCl3) δ 8.44−8.33 (m, 4H), 7.99 (dd, J = 8.8, 5.6 Hz, 1H), 7.43 (t,
J = 7.3 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.4 Hz, 2H),
7.02 (td, J = 8.5, 2.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.4 Hz, 1H), 6.83 (s,
1H), 3.99 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −102.05−102.11
1
(m, 1F); 13C{1H}NMR (100 MHz, CDCl3) δ 166.0 (C−F, JC−F
=
3
258.0 Hz), 162.2, 150.6, 145.2, 141.0 (C−F, JC−F = 9.2 Hz), 133.8,
3
132.4 (C−F, JC−F = 10.2 Hz), 130.3, 129.8, 129.0, 128.9, 128.4,
128.3, 124.1, 123.2 (C−F, 4JC−F = 2.8 Hz), 115.4 (C−F, 2JC−F = 22.3
2
Hz), 114.2 (C−F, JC−F = 22.6 Hz), 32.1; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C22H15FN2O5SNa) 461.0583, found 461.0582.
3-Benzyl-2-((4-nitrophenyl)sulfonyl)-6-(trifluoromethyl)-
isoquinolin-1(2H)-one (3j). Light yellow solid; 47.8 mg; 49% yield; Rf
1
= 0.48 (hexane/EtOAc = 5/1 as the eluent); mp = 174−175 °C; H
NMR (400 MHz, CDCl3) δ 8.45−8.36 (m, 4H), 8.10 (d, J = 8.2 Hz,
3-(2-Methylbenzyl)-2-((4-nitrophenyl)sulfonyl)isoquinolin-1(2H)-
one (3q). Light yellow solid; 56.4 mg; 65% yield; Rf = 0.48 (hexane/
5260
https://doi.org/10.1021/acs.joc.1c00150
J. Org. Chem. 2021, 86, 5255−5264

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
EtOAc = 5/1 as the eluent); mp = 168−169 °C; 1H NMR (400 MHz,
CDCl3) δ 8.41−8.36 (m, 4H), 7.98 (d, J = 7.1 Hz, 1H), 7.49 (t, J =
7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.28−7.22 (m, 3H), 7.18 (d, J =
7.1 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 3.81 (s, 2H), 2.31
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 150.8, 145.3,
138.1, 137.3, 134.33, 133.27, 130.7, 130.32, 130.31, 129.5, 129.0,
128.4, 127.7, 127.1, 127.0, 125.9, 124.1, 32.3, 20.1; HRMS (ESI-
TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa) 457.0834, found
457.0838.
6-(4-Chlorobenzyl)-3,4-dimethyl-1-((4-nitrophenyl)sulfonyl)-
pyridin-2(1H)-one (5g). Light yellow solid; 37.2 mg; 43% yield; Rf =
1
0.43 (hexane/EtOAc = 5/1 as the eluent); mp = 167−168 °C; H
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.8
Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.63 (s,
1H), 3.36 (s, 2H), 1.87 (s, 3H), 1.75 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.9, 150.5, 148.7, 145.5, 133.8, 132.5, 130.3, 130.2,
130.0, 128.9, 125.1, 124.5, 124.1, 35.1, 20.3, 11.8; HRMS (ESI-TOF)
m/z calcd for [M + Na]+ (C20H17ClN2O5SNa) 455.0444, found
455.0443.
3-Benzyl-2-((4-nitrophenyl)sulfonyl)-5,6,7,8-tetrahydroisoquino-
3,4-Dimethyl-6-(2-methylbenzyl)-1-((4-nitrophenyl)sulfonyl)-
lin-1(2H)-one (5a). Light yellow solid; 44.9 mg; 53% yield; Rf = 0.43
1
pyridin-2(1H)-one (5h). Light yellow solid; 42.0 mg; 51% yield; Rf =
(hexane/EtOAc = 5/1 as the eluent); mp = 177−178 °C; H NMR
1
0.48 (hexane/EtOAc = 5/1 as the eluent); mp = 147−148 °C; H
(400 MHz, CDCl3) δ 8.39 (d, J = 8.3 Hz, 2H), 8.32 (d, J = 8.6 Hz,
2H), 7.40 (t, J = 7.5 Hz, 2H), 7.34−7.28 (m, 3H), 6.66 (s, 1H), 3.34
(s, 2H), 2.23−2.07 (m, 4H), 1.65−1.58 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 163.8, 151.2, 150.4, 145.8, 134.1, 130.1, 129.8,
129.1, 128.6, 127.9, 126.4, 126.0, 124.1, 34.0, 30.4, 22.7, 21.6, 21.5;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C22H20N2O5SNa)
447.0991, found 447.0999.
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.9 Hz, 2H), 8.32 (d, J = 8.9
Hz, 2H), 7.26−7.20 (m, 3H), 7.17 (d, J = 7.1 Hz, 1H), 6.67 (s, 1H),
3.22 (s, 2H), 2.31 (s, 3H), 1.86 (s, 3H), 1.77 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 164.2, 150.4, 149.3, 145.7, 137.2, 133.2, 130.3,
130.1, 129.8, 129.0, 128.2, 125.8, 125.5, 124.5, 124.1, 35.3, 20.3, 20.1,
11.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C21H20N2O5SNa)
435.0991, found 435.0996.
6-Benzyl-3,4-dimethyl-1-((4-nitrophenyl)sulfonyl)pyridin-2(1H)-
one (5b). Light yellow solid; 35.8 mg; 45% yield; Rf = 0.46 (hexane/
EtOAc = 5/1 as the eluent); mp = 190−191 °C; 1H NMR (400 MHz,
CDCl3) δ 8.39 (d, J = 9.0 Hz, 2H), 8.31 (d, J = 8.9 Hz, 2H), 7.41 (t, J
= 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 7.0 Hz, 2H), 6.68
(s, 1H), 3.41 (s, 2H), 1.86 (s, 3H), 1.75 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.0, 150.4, 149.1, 145.7, 134.0, 130.1, 129.5, 129.1,
128.6, 127.9, 126.4, 124.4, 124.0, 35.2, 20.3, 11.8; HRMS (ESI-TOF)
m/z calcd for [M + Na]+ (C20H18N2O5SNa) 421.0834, found
421.0838.
6-Benzyl-3-methyl-1-((4-nitrophenyl)sulfonyl)-4-phenylpyridin-
2(1H)-one (5c). Yellow solid; 40.5 mg; 44% yield; Rf = 0.46 (hexane/
EtOAc = 5/1 as the eluent); mp = 166−167 °C; 1H NMR (400 MHz,
CDCl3) δ 8.44−8.37 (m, 4H), 7.41−7.29 (m, 8H), 7.11−7.06 (m,
2H), 6.76 (s, 1H), 3.72 (s, 2H), 1.77 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.6, 150.5, 150.3, 145.6, 138.0, 133.9, 130.2, 129.6,
129.0, 128.9, 128.7, 128.7, 129.0, 127.4, 126.8, 125.7, 124.1, 35.3,
13.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C25H20N2O5SNa)
483.0991, found 483.0991.
Procedure for the Scale-Up Synthesis of Compound 3a. An
oven-dried Schlenk tube equipped with a Teflon valve was charged
with a magnetic stir bar, substrate 1a (918 mg, 3.0 mmol, 1.0 equiv),
Pd(TFA)2 (99.6 mg, 0.3 mmol, 10 mol %), Cu(OAc)2 (109.2 mg, 0.6
mmol, 20 mol %), p-xylene (30 mL), and 2a (708 mg, 6.0 mmol, 2.0
equiv). The reaction mixture was stirred in an oil bath at 110 °C for
24 h under air. Then, the resulting suspension was cooled to room
temperature, filtered through a pad of filter paper, and washed with
ethyl acetate (200 mL). After evaporating the solvent under reduced
pressure, the residue was purified by column chromatography on silica
gel (PE/EA = 5:1) to give the pure product 3a (995 mg, 79% yield).
Procedure for the Deprotection Reaction. A round-bottom
flask was charged with a stir bar, compound 3a (84 mg, 0.2 mmol, 1.0
equiv), K2CO3 (55.2 mg, 0.4 mmol, 2.0 equiv), p-MePhSH (37.2 mg,
0.3 mmol, 1.5 equiv), and DMF (4 mL). After being stirred at
ambient temperature overnight, the mixture was diluted with water,
and the aqueous layer was extracted with ethyl acetate (3 × 10 mL).
The combined organic layer was washed sequentially with water (1 ×
30 mL) and saturated NaCl solution (1 × 30 mL), dried over
Na2SO4, and concentrated under reduced pressure to obtain the crude
product, which was further purified by silica gel chromatography to
provide the desired product 6.
3-Benzylisoquinolin-1(2H)-one (6). Yellow solid; 40 mg; 85%
yield; Rf = 0.45 (hexane/EtOAc = 2/1 as the eluent); mp = 189−190
°C; 1H NMR (400 MHz, CDCl3) δ 9.92 (br, 1H), 8.35 (d, J = 8.0 Hz,
1H), 7.63 (td, J = 7.6, 7.0, 1.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.42
(t, J = 7.1 Hz, 1H), 7.37−7.26 (m, 5H), 6.32 (s, 1H), 3.94 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.0, 140.0, 138.3, 136.3,
132.7, 129.2, 128.9, 127.4, 127.3, 126.2, 125.9, 124.6, 105.0, 39.6;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C16H13NONa)
258.0895, found 258.0887. The analysis data were identical with the
reported data.28
6-Benzyl-4-ethyl-3-methyl-1-((4-nitrophenyl)sulfonyl)pyridin-
2(1H)-one (5d). Light yellow solid; 39.6 mg; 48% yield; Rf = 0.45
1
(hexane/EtOAc = 5/1 as the eluent); mp = 141−142 °C; H NMR
(400 MHz, CDCl3) δ 8.39 (d, J = 9.0 Hz, 2H), 8.32 (d, J = 8.9 Hz,
2H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 7.4
Hz, 2H), 6.68 (s, 1H), 3.39 (s, 2H), 2.20 (q, J = 7.6 Hz, 2H), 1.76 (s,
3H), 0.97 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.4, 154.2, 150.4, 145.7, 134.1, 130.1, 130.0, 129.0, 128.7, 127.9,
126.3, 124.1, 123.7, 32.8, 27.1, 11.44, 11.38; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C21H20N2O5SNa) 435.0991, found 435.0995.
6-Benzyl-3-methyl-1-((4-nitrophenyl)sulfonyl)-4-propylpyridin-
2(1H)-one (5e). Light yellow solid; 42.6 mg; 50% yield; Rf = 0.54
1
(hexane/EtOAc = 5/1 as the eluent); mp = 172−173 °C; H NMR
(400 MHz, CDCl3) δ 8.39 (d, J = 9.0 Hz, 2H), 8.32 (d, J = 8.9 Hz,
2H), 7.43−7.38 (m, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.1 Hz,
2H), 6.68 (s, 1H), 3.37 (s, 2H), 2.16 (t, J = 7.8 Hz, 2H), 1.76 (s, 3H),
1.42−1.33 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.4, 152.8, 150.4, 145.7, 134.1, 130.1, 129.9, 129.0,
128.7, 127.9, 126.3, 124.4, 124.1, 35.8, 33.3, 20.5, 13.9, 11.7; HRMS
(ESI-TOF) m/z calcd for [M + Na]+ (C22H22N2O5SNa) 449.1147,
found 449.1153.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00150.
NMR (1H, 13C, 19F) spectra (PDF)
6-Benzyl-4-isopropyl-3-methyl-1-((4-nitrophenyl)sulfonyl)-
pyridin-2(1H)-one (5f). Light yellow solid; 38.3 mg; 45% yield; Rf =
1
0.57 (hexane/EtOAc = 5/1 as the eluent); mp = 173−174 °C; H
AUTHOR INFORMATION
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.9 Hz, 2H), 8.32 (d, J = 9.0
Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.29 (d, J =
7.1 Hz, 2H), 6.68 (s, 1H), 3.28 (s, 2H), 2.93−2.86 (m, 1H), 1.78 (s,
3H), 0.92 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.7, 157.4, 150.4, 145.8, 134.2, 130.4, 130.1, 128.8, 128.7, 127.8,
126.2, 124.1, 122.9, 30.7, 27.9, 19.5, 11.3; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C22H22N2O5SNa) 449.1147, found 449.1149.
■
Corresponding Authors
Manman Sun − Advanced Research Institute and Department
of Chemistry, Taizhou University, Taizhou 318000, P. R.
China; orcid.org/0000-0003-1126-8777;
Email: sunmm@tzc.edu.cn
5261
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J. Org. Chem. 2021, 86, 5255−5264

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Direct Regio- and Diastereoselective Synthesis of δ-Lactams from
Acrylamides and Unactivated Alkenes Initiated by RhIII-Catalyzed C−
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Yurong Wang − School of Pharmaceutical Science, Zhejiang
Chinese Medical University, Hangzhou 310053, P. R. China;
Email: yrwang1024@hotmail.com
Authors
Rong Zhong − School of Pharmaceutical Science, Zhejiang
Chinese Medical University, Hangzhou 310053, P. R. China
Yong Xu − School of Pharmaceutical Science, Zhejiang Chinese
Medical University, Hangzhou 310053, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00150
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Natural Science Foundation
of Zhejiang Province (No. LQ20B020007).
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