Synthesis of 3-Hydroxyisoindolin-1-ones through 1,4-Dioxane-Mediated Hydroxylhydrative aza-Cyclization of 2-Alkynylbenzamide in Water

Article abstract of DOI:10.1021/acs.joc.9b03466

In this work, 1,4-dioxane-mediated hydroxylhydrative aza-cyclization of 2-alkynylbenzamide is developed for the synthesis of 3-hydroxylisoindolin-1-ones. The transformation proceeds smoothly in water with good yields and a broad reaction scope. Mechanistic studies show that regioselective brimonative 5-exo-dig aza-cyclization, bromohydration of the resulting alkene groups, and hydrolysis of dibromo compounds are involved. Compared to the traditional methodologies, the synthetic procedure reported herein represents a cleaner route toward 3-hydroxylisoindolin-1-ones.

Full text of DOI:10.1021/acs.joc.9b03466

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Article
Synthesis of 3‑Hydroxyisoindolin-1-ones through 1,4-Dioxane-
Mediated Hydroxylhydrative aza-Cyclization of 2‑Alkynylbenzamide
in Water
Renzhi Liu, Min Yang, Wenlin Xie,* Wenbi Dong, Hongwei Zhou, Sarita Yadav,
Vladimir Ivanovich Potkin, and Guanyinsheng Qiu*
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ABSTRACT: In this work, 1,4-dioxane-mediated hydroxylhydrative aza-cycliza-
tion of 2-alkynylbenzamide is developed for the synthesis of 3-hydroxylisoindolin-
1-ones. The transformation proceeds smoothly in water with good yields and a
broad reaction scope. Mechanistic studies show that regioselective brimonative 5-
exo-dig aza-cyclization, bromohydration of the resulting alkene groups, and
hydrolysis of dibromo compounds are involved. Compared to the traditional
methodologies, the synthetic procedure reported herein represents a cleaner route toward 3-hydroxylisoindolin-1-ones.
Scheme 1. Proposed Route for the Synthesis of 3-
Hydroxyisoindolin-1-one from 2-Alkynylbenzamide
INTRODUCTION
■
As a powerful building block, alkynes have attracted the
attention of scientific community, and alkyne-based chemistry
has proved to be highly efficient for synthesizing diverse
synthons and biologically interesting architectures.1 One of the
demanding challenges associated with alkynes is the
regioselectivity control. Electronic, steric, and directing-group
cumulatively determine the regioselectivity in alkyne-based
chemistry. Keeping the directing-group-assisted transformation
strategy in mind, a series of dual-functionalized substrates with
alkynyl and reactive groups at the ortho position have been
developed in the past few years.2
2-Alkynylbenzamide, one of the versatile dual-functionalized
substrates, dominantly underwent O-attacked 5-exo-dig/6-
endo-dig cyclizations to produce diverse heterocyclic com-
pounds.3−5 To the best of our knowledge, the reactions under
the Lewis acid-promoted conditions4 and electrophilic
conditions5 were prior to offer O-attacked cyclization products,
and yet N-attacked cyclization remains rare.6 Recently, several
research groups found that the use of indium salt,7a,b platinum
salt,7c copper salt,7d and silver salt7e could enable the N-
attacked 6-endo-cyclization to produce isoquinolin-1-ones.7
Subsequently, a metal-free synthesis was realized by Zhao and
Du toward 3-hydroxylisoquinolin-1,4-diones through a hyper-
valent iodine reagent-mediated oxidative 6-endo aza-cycliza-
tion of 2-alkynylbenzamide (Scheme 1, eq a).8 Inspired by
what has been mentioned above, it is of high desire to further
develop N-attacked cyclization of 2-alkynylbenzammide under
mild conditions.
eq b).10 As expected, 2 mol % CuCl2 under an O2 atmosphere
enabled the above N-attacked 6-endo cyclization toward 3-
hydroxylisoquinolin-1,4-diones. Different from Zhao and Du’s
work,8 our work was ascribed to the N-center radical pathway.
In light of the above findings, it is of high significance to realize
regioselective N-attacked 5-exo-dig aza-cyclization of 2-
alkynylbenzamide. We envisioned that an amide N-center
Received: December 23, 2019
Published: March 31, 2020
Over the past few years, our group has been focusing on
developing a cleaner, safer, and more economic system to
realize regioselective transformations of alkynes.9 The initial
emphasis in our group was put on copper-catalyzed oxidative
6-endo-dig aza-cyclization of 2-alkynylbenzamide (Scheme 1,
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radical11 cyclization pathway under metal-free condition could
enable the synthesis of 3-hydroxylisoindolin-1-ones (Scheme 1,
eq c), a ubiquitous structural core in many natural products.12
Very recently, we disclosed a n-tetrabutyl ammonium
bromide (TBAB)/oxone system-promoted 2,4-dibromohydra-
tion of 2-enynylbenzoate. In the process, assistance of the
ortho-ester group contributed to the regioselectivity control of
this reaction.13a Considering our continuous interest in oxone
chemistry,13 the reaction of 2-alkynylbenzamide was then
explored using the TBAB/oxone system. However, under this
reaction condition, an O-attacked regioselective 5-exo-dig
cyclization took place to solely produce isofunran-1-imines
with high efficiency.13b Interestingly, by adding 10 equiv of 1,4-
dioxane, it is surprising to find that the use of TBAB/oxone
made the N-attacked 5-exo-dig cyclization of N-methoxyl-2-
alkynylbenzamide 1a to proceed in tap water, with the
formation of 3-hydroxylisoindolin-1-one 3a in a 88% yield
(Scheme 1, eq d).
1). A blank reaction without 1,4-dioxane did not produce the
desired 3a, but a O-attacked benzoisofuran-1-imine (entry 2,
Table 1). A similar result was obtained when the loading of
1,4-dioxane was increased from 10.0 to 20.0 equiv (entry 5,
Table 1). However, the use of 5.0 equiv of 1,4-dioxane was
unfavorable for the reaction, leading to the desired product 3a
in a 40% yield (entry 6, Table 1). Other bromide sources
including KBr, ZnBr2, and NBS were also explored, and
inferior yields were detected (entries 7−9, Table 1). The use of
n-tetrabutyl ammonium chloride (TBAC) and n-tetrabutyl
ammonium iodide (TBAI) as replacements of TBAB did not
give rise to better yields (entries 10−11, Table 1). Decrease of
TBAB loading was not favorable for the outcomes (entries 12−
13, Table 1). For instance, the reaction was greatly retarded
when 0.5 equiv of TBAB was used (entry 13, Table 1).
Lowering of temperature was not helpful for the reaction
(entry 14, Table 1). Therefore, the optimized conditions are
2.0 equiv of TBAB, 2.0 equiv of oxone, 10 equiv of 1,4-dioxane,
and water, 80 °C
Imaginably, this paper provides another protocol to realize
N-attacked cyclization of 2-alkynylbenzamide, thus serving as
an important supplementary in the field of 2-alkynylbenza-
mide-based chemistry. Together with high importance of 3-
hydroxylisoquinolin-1-one core and a few synthetic method-
ologies,12 we started to optimize the reaction. The results are
illustrated in Table 1.
After optimizing the conditions, we then explored the
reaction generality. The results are outlined in Scheme 2. As
shown in Scheme 2, a series of substituted 3-hydroxylisoindo-
lin-1-ones were achieved in good yields.
Scheme 2. Generation of 3-Hydroxyisoindolin-1-one 3
through Regioselective 5-exo-trig Hydroxylcarbonylative
Cyclization of 2-Alkynylbenzamide
a
Table 1. Optimization of the Reaction Conditions
a b
,
ab
,
entry [Br] (equiv)
additives (equiv)
1,4-dioxane (10)
temp. (°C) yield of 3a
1
2
3
4
TBAB (2)
TBAB (2)
TBAB (2)
TBAB(2)
TBAB(2)
TBAB(2)
KBr(2)
80
80
80
80
80
80
80
80
80
80
80
80
80
50
88
nd
43
67
THF (10)
tBuOMe (10)
5
6
7
1,4-dioxane (20)
1,4-dioxane (5)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
1,4-dioxane (10)
87
40
45
51
57
83
8
9
ZnBr2 (1)
NBS (2)
10
11
12
13
14
TBAC (2)
TBAI (2)
TBAB (1)
TBAB(0.5)
TBAB (2)
complex
41
20
53
a
b
Isolated yield based on 2-alkynylbenzamide 1a. Standard
conditions: 2-alknylbenzamide 1a (0.2 mmol), TBAB (2.0 equiv),
oxone (2.0 equiv), 1,4-dioxane (10.0 equiv), H2O (2.0 mL), 80 °C,
overnight. TBAB = n-tetrabutyl ammonium bromide; TBAC = n-
tetrabutyl ammonium chloride; TBAI = n-tetrabutyl ammonium
iodide; NBS = N-Bromosuccinimide; oxone = 2KHSO5·KHSO4·
K2SO4; nd = no desired product.
RESULTS AND DISCUSSION
■
Based on the preliminary result, the desired product 3a
afforded when 2.0 equiv of TBAB, 2.0 equiv of oxone, and 10.0
equiv of 1,4-dioxane in tap water were used (entry 1, Table 1).
No better yields were observed when 1, 4-dioxane was replaced
with tetrahydrofuran (THF) and tBuOMe (entries 3−4, Table
a
b
Isolated yield based on 1; 1 mmol scaled-reaction was conducted.
B
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The substituent effects of R1 were investigated. The results
revealed that electron-donating groups and electron-rich
groups were compatible for the reactions. For example, the
reaction with the substrate containing a 4-methyl group on R1
afforded the desired 3-hydroxylisoindolin-1-one 3c in a 65%
yield, whereas the substrate having 5-fluoro substitution gave
the corresponding product 3d in a 77% yield. Other
substituents including methoxyl, chloro, and bromo groups
were suitable for the reaction, leading to the corresponding
products 3b−3f in 63−76% yields. The reactions of the
napthalenyl-connected substrate and the thiophenyl-linked
substrate also worked well, producing the desired compounds
3g and 3h in good yields. In particular, the reaction of N-
methoxy-5-phenylpent-4-ynamide under standard conditions
provided the desired product 3aa in 41% yield as expected. A 1
mmol scaled-reaction of 1a was conducted accordingly, and a
similar yield (82%) was observed with the formation of the
desired 3a.
mo-3-hydroxylisoindolin-1-ones 4a and 4b in 69 and 47%
yields, respectively. The formation of the products 4a and 4b
indicated a plausible truth that product 3 was derived from the
hydrolysis of product 4. The exact structures for compounds
4a and 4b were all identified by X-ray diffraction.
Interestingly, under standard conditions, we also tried the
reactions when the substrates with tert-butylethynyl, iso-
propylethynyl, and cyclohexyl were used. To our surprise,
the desired products were not observed. Distinctive dibromo
benzoates 5a−5c were afforded in moderate yields. According
to previous findings,14 conversion of N-methoxyl benzamide
radical into benzoates seemed reliable through the oxidative
ring-opening and removal of N2.14 The exact structure for 5a
was identified by X-ray diffraction.
To gain insights into the reaction mechanism, some control
experiments were carried out. The results are presented in
Scheme 4. As shown in Scheme 4, a plausible intermediate 5
Subsequently, we explored the tolerance of R2 substituents.
From the results, it seemed that R2 substituents could be equal
to aryl, vinyl, and alkyl. The corresponding products 3i−3n
were achieved in 48−87% yields. For example, the reaction
using the substrate with 2-chlorophenyl as the substituent
produced the desired 3-hydroxylisoindolin-1-one 3l in a 48%
yield, whereas employing the substrate with 2-thiophenyl as
the substituent gave rise to 3m in a 87% yield. In particular, an
estrone-connected 3-hydroxylisoinodin-1-one 3o could be
facilely obtained. It is noteworthy that the reaction of the
cyclopropylalkynyl-linked substrate also proceeded smoothly
with the formation of the desired product 3n in a 67% yield.
This cyclopropyl-linked substrate was not an efficient reaction
partner in the previous works from Zhao and Du’s group.8
Substrates with other N-protecting groups including
benzoxyl, aryl, and alkyl also proved to be efficient reaction
partners, leading to the corresponding products 3p-3z in 49−
89% yields (Scheme 2). It is worthy to note that by using
Zhao’s conditions or our previous conditions, the reactions of
N-aryl/alkyl-2-alkynylbenzamides did not give the correspond-
ing products. The exact structures for compounds 3g, 3n, and
3x were identified by X-ray diffraction.
Scheme 4. Control Experiments
was isolated when the reaction was quenched after 4 h, and the
reaction of intermediate 5 under standard conditions offered
the desired product 3a in a quantitative yield as expected.
Moreover, the oxygen atoms in hydroxyl and carbonyl in
products probably came from water on the basis of the O18-
labeling experiment.
Other alkylalkynyl-connected substrates were also explored.
The results are presented in Scheme 3. From the results, it can
be seen that the expected 3-hydroxylisoindolin-1-ones were not
produced. Under standard conditions, the reactions of N-
methoxy-2-(3-methoxyprop-1-yn-1-yl)benzamide and 2-(3-hy-
droxyprop-1-yn-1-yl)-N-methoxybenzamide gave rise to dibro-
In light of the aforementioned results, a plausible mechanism
is proposed in Scheme 5. In the process, oxone oxidized 1,4-
dioxane and bromide into 1,4-dioxane radical and bromo
radical, respectively. The sequential H-abstraction of 1,4-
dioxane radical with 2-alkynylbenzamide provided the key
intermediate 2-alkynylbenzamide N-center radical A. We
thought the in situ generated bromo radical could stablize 2-
alkynylbenzamide N-center radical A to form another
intermediate B. The N-center 5-exo-cyclization of intermediate
A gave bromo-containing isoindolin-1-one species C. Sub-
sequently, addition of another bromo-radical to intermediate C
took place to yield D. Followed by oxidation, intermediate D
converted into intermediate E. Finally, the reaction of
intermediate E and water offered intermediate 4. Compound
4 was described as an important synthon to deliver 3-
hydroxylisoindolin-1-ones 3 through hydrolysis. Interestingly,
in the presence of an oxidant, intermediate 4 probably
underwent an oxidative ring-opening and removal of N2 to
offer another product 5.
Scheme 3. Reaction Scope: the Reaction of 2-
a
alkylalkynylbenzamide
a
Isolated yield based on 1.
C
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mixture was stirred at room temperature overnight and then extracted
with AcOEt (3 × 40 mL), washed with water (50 mL) and brine (50
mL), and dried over MgSO4. Evaporation gave a crude solid that was
recrystallized from AcOEt and collected by filtration. Then, 2-iodo-N-
methoxybenzamide was obtained (white solid, 4.46 g, 84% yield).
Sodium hydride (640 mg, 16 mmol) was added into a solution of
2-iodo-N-methoxybenzamide (4.05 g, 14.6 mmol) in dry THF (100
mL) at 0 °C. After that, Boc2O (3.83 g, 17.5 mmol) was added slowly
at 0 °C. The mixture was stirred at room temperature overnight and
then quenched with saturated aqueous NH4Cl solution (30 mL). The
mixture was extracted with AcOEt (3 × 30 mL), washed with
saturated aqueous bicarbonate solution (30 mL) and brine (30 mL),
and dried over MgSO4. Using flash column chromatography, a white
solid tert-butyl methoxy(2-(phenylethynyl)benzoyl)carbamate was
obtained (4.80 g, 87% yield).
Scheme 5. Plausible Mechanism
To a solution of the above solid, tert-butyl methoxy(2-
(phenylethynyl)benzoyl)carbamate (1.56 g, 4.4 mmol), in toluene
(20 mL) were successively added PdCl2(PPh3)2 (308.8 mg, 0.44
mmol), CuI (41.9 mg, 0.22 mmol), phenylacetylene (1.4 mL, 13.2
mmol), and tert-butylamine (0.93 mL, 8.8 mmol). The mixture was
stirred at 50 °C in an oil bath for 3 h. After completion of the
reaction, the crude was filtrated by chromatography on silica gel
(pentane/Et2O 9:1 to 8:2) to afford the crude product. Then, the
solvent was removed, and trifluoroacetic acid (3 mL) in CH2Cl2 (5
mL) was added at 0 °C. The crude mixture was purified by flash
chromatography on silica gel to afford the pure product 1a (0.905 g,
82%) as a white solid. Other substrates 1 were prepared according to
the above procedure.
In the whole process, the bromo atom was not found to be
incorporated into the final product 3, although stoichiometric
TBAB was employed, which probably resulted because the
hydrolysis reaction of the dibromo group in 4 proceeded
slowly than that of brominative cyclization. In our previous
work, the N-center radical A was transformed into oxygen-
center radical A′ by resonance.13b In this paper, we reasoned
the use of 1,4-dioxane to facilitate the formation of 2-
alkynylbenzamide N-center radical B. However, the substantial
evidence for the exact roles of 1,4-dioxane and TBAB is still
under exploration. According to the previous findings,15 we
reasoned that 1,4-dioxane served as a radical trigger to facilitate
the formation of 2-alkynylbenzamide N-center radical A.
General Procedure for the Synthesis of Compounds 3 and
4. 2-Alkynylbenzamide 1 (0.2 mmol), TBAB (2.0 equiv), and oxone
(2.0 equiv) were added to a test tube, and then solvent H2O (2.0 mL)
and 1,4-dioxane (10.0 equiv) were added. The mixture was stirred at
80 °C in a heating mantle overnight. After the disappearance of the
substrate as indicated by TLC, the last mixture was filtrated, and the
resulting filtrate was extracted by ethyl acetate (EA) (3 × 2 mL). The
organic layers were combined and dried by Na2SO4. After another
filtration, evaporation of the solvent, and purification by flash column
chromatography, the desired products 3 and 4 were obtained.
N-Methoxy-2-(phenylethynyl)benzamide (1a).10 Following the
general procedure, 1a was purified by silica gel chromatography (EA/
CONCLUSIONS
■
1
We have developed a 1,4-dioxane-mediated reaction of 2-
alkynylbenzamides for the synthesis of 3-hydroxylisoindolin-1-
ones. The transformation proceeds smoothly in water. Based
on mechanistic studies, it is believed that regioselective
brimonative 5-exo azacyclization, bromohydration of the
resulting alkene group, and hydrolysis of dibromo compound
were involved. Compared to the traditional methodologies, the
synthetic procedure reported herein represents a cleaner route
toward 3-hydroxylisoindolin-1-ones with a high reaction
efficiency and a broad reaction scope.
PE = 1/5). Yield: 82%, 906 mg, white solid, mp 107−109 °C; H
NMR (400 MHz, CDCl3): δ 9.88 (s, 1H), 7.83 (d, J = 5.8 Hz, 1H),
7.56−7.47 (m, 3H), 7.42−7.29 (m, 5H), 3.86 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 165.1, 133.6, 133.0, 131.5, 130.8, 129.5, 129.1,
128.8, 128.5, 122.0, 119.9, 95.1, 87.1, 64.6.
N,5-Dimethoxy-2-(phenylethynyl)benzamide (1b).10 Following
the general procedure, 1b was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 80%, 990 mg, white solid, mp 155−158 °C;
1H NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 7.52−7.45 (m, 4H),
7.40−7.33 (m, 3H), 6.99−6.96 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 164.7, 159.9, 134.9, 134.6,
131.3, 128.9, 128.6, 122.2, 118.1, 114.0, 111.7, 94.0, 87.3, 64.6, 55.6.
5-Fluoro-N-methoxy-2-(phenylethynyl)benzamide (1d).10 Fol-
lowing the general procedure, 1d was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 81%, 923 mg, white solid,
mp 133−135 °C; 1H NMR (400 MHz, CDCl3): δ 9.99 (s, 1H), 7.64
(d, J = 8.6 Hz, 1H), 7.57−7.50 (m, 3H), 7.37−7.34 (m, 3H), 7.17−
7.11 (m, 1H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
162.3 (d, J = 252.2 Hz), 135.7, 135.2 (d, J = 8.0 Hz), 131.4, 129.3,
128.6, 121.7, 118.5 (d, J = 22.3 Hz), 117.0 (d, J = 24.4 Hz), 116.0,
113.5, 95.1, 86.2, 64.6.
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise stated, all
commercial reagents and solvents were used without additional
purification. All solvents were dried and distilled according to
standard procedures. Flash column chromatography was performed
using silica gel (60 Å pore size, 32−63 μm, standard grade). Analytical
thin-layer chromatography (TLC) was performed using glass plates
precoated with 0.25 mm 230−400 mesh silica gel impregnated with a
fluorescent indicator (254 nm). TLC plates were visualized by
exposure to ultraviolet light. Organic solutions were concentrated on
rotary evaporators at ∼20 Torr (house vacuum) at 25−35 °C.
Commercial reagents and solvents were used as received. Nuclear
magnetic resonance (NMR) spectra were recorded in parts per
million from internal tetramethylsilane on the δ scale.
5-Bromo-N-methoxy-2-(phenylethynyl)benzamide (1e).10 Fol-
lowing the general procedure, 1e was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 80%, 1158 mg, white solid,
mp 112−114 °C; 1H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 8.05
(s, 1H), 7.58−7.49 (m, 3H), 7.42−7.37 (m, 4H), 3.88 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 163.6, 134.9, 134.3, 134.0,
132.7, 131.5, 129.4, 128.6, 123.2, 121.6, 118.7, 96.4, 86.3, 64.7.
5-Chloro-N-methoxy-2-(phenylethynyl)benzamide (1f).10 Fol-
lowing the general procedure, 1f was purified by silica gel
General Procedure for the Synthesis of Compound 1a. To a
solution of 2-iodobenzoyl chloride (4 g, 15.0 mmol) in AcOEt/H2O
(v/v = 2:1, 180 mL) were added potassium carbonate (4.14 g, 30
mmol) and methoxyamine hydrochloride (1.5 g, 18.0 mmol). The
D
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chromatography (EA/PE = 1/5). Yield: 78%, 978 mg, white solid, mp
165.7, 161.1, 137.0, 133.4, 129.9, 129.2, 128.8, 126.2, 122.0, 120.5,
111.8, 93.5, 65.2, 56.1; IR (KBr): 3259, 1686, 1640, 1594, 1448, 1371,
1131, 1281, 1131, 998, 873, 757; HRMS (ESI-TOF) m/z: (M + H)+
1
110−112 °C; H NMR (400 MHz, CDCl3): δ 9.89 (s, 1H), 7.90 (s,
1H), 7.54−7.47 (m, 3H), 7.43−7.35 (m, 4H), 3.89 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.7, 135.1, 134.8, 134.2, 131.5, 131.1,
129.9, 129.4, 128.6, 121.5, 118.3, 96.3, 86.2, 64.7.
+
calcd for C17H16NO5 , 314.1023; found, 314.1027.
3-Benzoyl-3-hydroxy-2-methoxy-5-methylisoindolin-1-one (3c).
3c was purified by silica gel chromatography (EA/PE = 1/5). Yield:
65%, 39 mg, white solid, mp 148−150 °C 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.59−7.57 (m, 1H),
7.41−7.37 (m, 2H), 7.31−7.23 (m, 3H), 5.02 (s, 1H), 4.02 (s, 3H),
2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 191.0, 161.7,
144.4, 136.6, 136.5, 129.3, 129.1, 128.9, 128.7, 128.2, 127.6, 126.4,
93.9, 65.3, 21.4; IR (KBr): 3266, 1706, 1658, 1644, 1373, 1287, 1125,
1008, 870, 752; HRMS (ESI-TOF) m/z: (M + H)+ calcd for
N-Methoxy-3-(phenylethynyl)-2-naphthamide (1p).10 Following
the general procedure, 1p was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 62%, 821 mg, white solid, mp 130−132 °C;
1H NMR (400 MHz, CDCl3): δ 9.84 (s, 1H), 8.46 (d, J = 8.1 Hz,
1H), 7.89−7.83 (m, 3H), 7.66−7.57 (m, 4H), 7.47−7.39 (m, 3H),
3.94 (s, 3H)·13C{1H} NMR (100 MHz, CDCl3): δ 165.9, 134.0,
132.7, 132.3, 131.6, 129.4, 129.2, 128.7, 128.3, 127.9, 127.7, 127.0,
125.3, 122.0, 118.1, 100.9, 85.1, 64.7.
N-Methoxy-2-(p-tolylethynyl)benzamide (1i).10 Following the
general procedure, 1i was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 72%, 840 mg, white solid, mp 109−112 °C;
1H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.92 (d, J = 6.2 Hz,
1H), 7.58−7.52 (m, 1H), 7.45−7.38 (m, 4H), 7.17 (d, J = 7.9 Hz,
2H), 3.88 (s, 3H), 2.37 (s, 3H).
+
C17H16NO4 , 298.1074; found, 298.1074.
3-Benzoyl-6-fluoro-3-hydroxy-2-methoxyisoindolin-1-one (3d).
3d was purified by silica gel chromatography (EA/PE = 1/5).
Yield: 77%, 47 mg, white solid, mp 149−151 °C 1H NMR (400 MHz,
CDCl3): δ 8.03−7.88 (m, 2H), 7.42−7.36 (m, 2H), 7.34−7.27 (m,
4H), 5.09 (s, 1H), 4.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 189.2, 167.2 (d, J = 260.4 Hz), 160.2, 136.3, 133.9 (d, J = 9.3 Hz),
130.8 (d, J = 9.5 Hz), 129.5, 129.0, 126.3, 125.6 (d, J = 3.1 Hz), 121.0
(d, J = 22.7 Hz), 115.7 (d, J = 24.6 Hz), 93.9, 65.3. IR (KBr): 3296,
1699, 1646, 1602, 1441, 1362, 1277, 1156, 1008, 816, 763; HRMS
2-((4-Fluorophenyl)ethynyl)-N-methoxybenzamide (1k).10 Fol-
lowing the general procedure, 1k was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 75%, 888 mg, white solid,
mp 148−150 °C; 1H NMR (400 MHz, CDCl3): δ 9.62 (s, 1H), 7.89
(d, J = 6.3 Hz, 1H), 7.57−7.49 (m, 3H), 7.48−7.40 (m, 2H), 7.07 (t,
J = 8.5 Hz, 2H), 3.89 (s, 3H).
+
(ESI-TOF) m/z: (M + H)+ calcd for C16H13FNO4 , 302.0823; found,
302.0813.
2-((2-Chlorophenyl)ethynyl)-N-methoxybenzamide (1l).10 Fol-
lowing the general procedure, 1l was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 76%, 953 mg, white solid,
3-Benzoyl-6-bromo-3-hydroxy-2-methoxyisoindolin-1-one (3e).
3e was purified by silica gel chromatography (EA/PE = 1/5). Yield:
69%, 50 mg, white solid, mp 188−189 °C 1H NMR (400 MHz,
CDCl3): δ 8.56−8.42 (m, 1H), 7.82−7.76 (m, 2H), 7.41−7.36 (m,
2H), 7.33−7.28 (m, 3H), 4.81 (s, 1H), 4.04 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 189.8, 160.2, 136.6, 136.2, 132.0, 131.8, 131.5,
129.6, 129.0, 128.9, 127.7, 126.3, 93.9, 65.4; IR (KBr): 3291, 1700,
1642, 1581, 1424, 1352, 1276, 1136, 875, 717; HRMS (ESI-TOF) m/
1
mp 107−109 °C; H NMR (400 MHz, CDCl3): δ 10.19 (s, 1H),
8.11−8.05 (m, 1H), 7.61 (m, 2H), 7.50−7.42 (m, 3H), 7.35−7.27
(m, 2H), 3.90 (s, 3H).
2-(Cyclopropylethynyl)-N-methoxybenzamide (1n).10 Following
the general procedure, 1n was purified by silica gel chromatography
1
+
(EA/PE = 1/5). Yield: 67%, 634 mg, white solid, mp 80−82 °C; H
z: (M + H)+ calcd for C16H13BrNO4 , 362.0022; found, 362.0040.
NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H),
7.43−7.31 (m, 3H), 3.89 (s, 3H), 1.53−1.46 (m, 1H), 0.97−0.91 (m,
2H), 0.88−0.82 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
165.1, 133.2, 133.1, 130.9, 129.7, 128.1, 120.2, 100.4, 74.1, 64.5, 8.8,
0.2.
3-Benzoyl-6-chloro-3-hydroxy-2-methoxyisoindolin-1-one (3f).
3f was purified by silica gel chromatography (EA/PE = 1/5). Yield:
76%, 48 mg, white solid, mp 169−171 °C 1H NMR (400 MHz,
CDCl3): δ 8.29 (s, 1H), 7.88−7.86 (m, 1H), 7.62−7.59 (m, 1H),
7.40−7.38 (m, 2H), 7.32−7.28 (m, 3H), 4.95 (s, 1H), 4.03 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 189.6, 160.3, 142.8, 136.2,
133.6, 132.2, 129.6, 129.0, 128.7, 128.4, 127.4, 126.3, 93.9, 65.4; IR
(KBr): 3288, 1701, 1646, 1586, 1449, 1354, 1276, 1136, 1021, 875;
N-(Benzyloxy)-2-(phenylethynyl)benzamide (1p).10 Following the
general procedure, 1p was purified by silica gel chromatography (EA/
1
PE = 1/5). Yield: 80%, 1151 mg, white solid, mp 129−131 °C; H
+
HRMS (ESI-TOF) m/z: (M + H)+calcd for C16H13ClNO4 ,
NMR (400 MHz, CDCl3): δ 9.86 (s, 1H), 7.97 (s, 1H), 7.58−7.52
(m, 1H), 7.46−7.32 (m, 9H), 7.28−7.25 (m, 3H), 5.06 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 164.9, 135.3, 133.2, 131.6,
131.0, 129.8, 129.1, 128.8, 128.6, 128.5, 128.5, 121.7, 119.9, 95.5,
87.2, 78.4.
318.0528; found, 318.0528.
3-Benzoyl-3-hydroxy-2-methoxy-2,3-dihydro-1H-benzo[f ]-
isoindol-1-one (3g). 3g was purified by silica gel chromatography
(EA/PE = 1/8). Yield: 69%, 46 mg, white solid, mp 144−146 °C 1H
NMR (400 MHz, CDCl3): δ 8.06−8.03 (m, 1H), 7.98−7.88 (m, 2H),
7.79−7.76 (m, 1H), 7.60−7.51 (m, 2H), 7.46−7.35 (m, 3H), 7.19−
7.15 (m, 2H), 6.22 (s, 1H), 4.03 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 196.4, 165.2, 138.2, 136.2, 134.0, 132.6, 131.9, 129.3,
128.7, 128.6, 128.4, 128.3, 127.8, 127.1, 123.1, 119.5, 90.5, 66.3; IR
(KBr): 3349, 1718, 1693, 1444, 1290, 1256, 1170, 1123, 1036, 984,
2-(3-Hydroxyprop-1-yn-1-yl)-N-methoxybenzamide (1q).10 Fol-
lowing the general procedure, 1q was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 44%, 397 mg, white solid,
mp 110−112 °C; 1H NMR (400 MHz, CDCl3): δ 10.13 (s, 1H), 7.68
(d, J = 6.0 Hz, 1H), 7.42−7.29 (m, 3H), 4.47 (s, 2H), 3.95 (s, 1H),
3.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.3, 133.7,
133.0, 130.8, 129.1, 128.7, 119.8, 93.7, 82.9, 64.4, 51.1.
+
760; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H16NO4 ,
3-Benzoyl-3-hydroxy-2-methoxyisoindolin-1-one (3a). 3a was
purified by silica gel chromatography (EA/PE = 1/5). Yield: 88%,
50 mg, white solid, mp 135−137 °C 1H NMR (400 MHz, CDCl3): δ
8.31 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 7.5 Hz,
1H), 7.63 (t, J = 7.5 Hz, 1H), 7.43−7.39 (m, 2H), 7.30−7.24 (m,
3H), 5.16 (s, 1H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 190.7, 161.4, 136.5, 135.7, 133.4, 130.7, 129.4, 129.2, 128.9, 128.7,
127.4, 126.4, 93.9, 65.3; IR (KBr): 3265, 1702, 1645, 1579, 1384,
1283, 1132, 1024, 991, 869, 757; HRMS (ESI-TOF) m/z: (M + H)+
334.1074; found, 334.1070.
4-Benzoyl-4-hydroxy-5-methoxy-4H-cyclopenta[b]thiophen-
6(5H)-one (3h). 3h was purified by silica gel chromatography (EA/PE
= 1/5). Yield: 87%, 50 mg, white solid, mp 180−182 °C H NMR
(400 MHz, CDCl3): δ 7.61 (d, J = 5.1 Hz, 1H), 7.47−7.39 (m, 3H),
7.36−7.31 (m, 3H), 4.64 (s, 1H), 4.01 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 185.4, 157.6, 144.8, 137.0, 136.4, 133.3, 129.5,
128.9, 126.3, 125.7, 95.2, 65.5; IR (KBr): 3407, 1702, 1648, 1529,
1354, 1255, 1186, 1011, 956, 849, 756; HRMS (ESI-TOF) m/z: (M
+ H)+ calcd for C14H12NO4S+, 290.0482; found, 290.0488.
1
+
calcd for C16H14NO4 , 284.0917; found, 284.0915.
3-Hydroxy-2-methoxy-3-(4-methylbenzoyl)isoindolin-1-one (3i).
3i was purified by silica gel chromatography (EA/PE = 1/5). Yield:
77%, 46 mg, white solid, mp 127−129 °C 1H NMR (400 MHz,
CDCl3): δ 8.39−8.32 (m, 1H), 7.94−7.92 (m, 1H), 7.83−7.77 (m,
1H), 7.68−7.62 (m, 1H), 7.29−7.27 (m, 2H), 7.09 (d, J = 8.1 Hz,
2H), 4.79 (s, 1H), 4.05 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (100
3-Benzoyl-3-hydroxy-2,6-dimethoxyisoindolin-1-one (3b). 3b
was purified by silica gel chromatography (EA/PE = 1/5). Yield:
63%, 40 mg, white solid, mp 162−164 °C 1H NMR (400 MHz,
CDCl3): δ 7.93−7.84 (m, 1H), 7.80−7.79 (m, 1H), 7.40−7.38 (m,
2H), 7.31−7.24 (m, 3H), 7.12−7.09 (m, 1H), 4.98 (s, 1H), 4.02 (s,
3H), 3.95 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 189.5,
E
https://dx.doi.org/10.1021/acs.joc.9b03466
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
MHz, CDCl3): δ 190.7, 161.5 139.5, 135.6, 133.5, 133.3, 130.8, 129.6,
129.2, 128.7, 127.4, 126.3, 93.9, 65.3, 21.0; IR (KBr): 3296, 1706,
1667, 1596, 1581, 1380, 1285, 1117, 1038, 995, 819; HRMS (ESI-
1661, 1463, 1375, 1280, 992; HRMS (ESI-TOF) m/z: (M + H)+
calcd for C28H30NO5 , 460.2118; found, 460.2110.
+
3-Benzoyl-2-(benzyloxy)-3-hydroxyisoindolin-1-one (3p). 3p was
purified by silica gel chromatography (EA/PE = 1/5). Yield: 83%, 60
+
TOF) m/z: (M + H)+ calcd for C17H16NO4 , 298.1074; found,
1
mg, white solid, mp 159−161 °C H NMR (400 MHz, CDCl3): δ
298.1070.
8.38 (d, J = 7.3 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.83−7.79 (m,
1H), 7.68−7.64 (m, 1H), 7.49−7.40 (m, 4H), 7.29−7.23 (m, 6H),
5.25−5.18 (m, 2H), 4.77 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3):
δ 190.8, 161.7, 136.7, 135.7, 134.9, 133.3, 130.8, 129.6, 129.3, 129.3,
128.9, 128.6, 128.3, 127.4, 126.4, 123.5, 93.8, 79.6; IR (KBr): 3303,
2893, 1698, 1645, 1580, 1361, 1284, 1179, 1133, 977, 757; HRMS
3-([1,1′-Biphenyl]-4-carbonyl)-3-hydroxy-2-methoxyisoindolin-
1-one (3j). 3j was purified by silica gel chromatography (EA/PE = 1/
1
5). Yield: 81%, 58 mg, white solid, mp 174−176 °C H NMR (400
MHz, CDCl3): δ 8.38−8.36 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 7.7 Hz,
1H), 7.85−7.78 (m, 1H), 7.70−7.63 (m, 1H), 7.53−7.47 (m, 6H),
7.43−7.27 (m, 3H), 5.06 (s, 1H), 4.08 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 190.7, 161.5, 142.3, 139.9, 135.7, 135.4, 133.4,
131.9, 130.8, 129.2, 128.8, 128.7, 127.7, 127.6, 127.0, 126.9, 93.9,
65.4. IR (KBr): 3304, 1706, 1659, 1638, 1582, 1387, 1282, 994, 763,
+
(ESI-TOF) m/z: (M + H)+ calcd for C22H18NO4 , 360.1230; found,
360.1224.
3-Benzoyl-3-hydroxy-2-phenylisoindolin-1-one (3q). 3q was
purified by silica gel chromatography (EA/PE = 1/10). Yield: 61%,
+
694; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H18NO4 ,
1
40 mg, yellow oil. H NMR (400 MHz, CDCl3): δ 8.05−8.01 (m,
360.1230; found, 360.1233 360.1230.
1H), 7.65−7.62 (m, 2H), 7.50−7.47 (m, 1H), 7.43−7.36 (m, 5H),
7.33−7.19 (m, 3H), 7.10−7.06 (m, 2H), 6.01 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 195.5, 167.7, 144.0, 134.4, 133.9, 133.8, 132.2,
131.0, 130.9, 129.3, 128.9, 128.1, 124.9, 122.7, 121.3, 91.8; IR (KBr):
3372, 1716, 1682, 1490, 1343, 1180, 1070, 818, 758; HRMS (ESI-
3-(4-Fluorobenzoyl)-3-hydroxy-2-methoxyisoindolin-1-one (3k).
3k was purified by silica gel chromatography (EA/PE = 1/5). Yield:
51%, 31 mg, white solid, mp 147−149 °C 1H NMR (400 MHz,
CDCl3): δ 8.32 (d, J = 7.3 Hz, 1H), 7.94−7.92 (m, 1H), 7.83−7.79
(m, 1H), 7.69−7.65 (m, 1H), 7.40−7.37 (m, 2H), 6.99−6.95 (m,
2H), 5.02 (s, 1H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 190.6, 163.2 (d, J = 249.8 Hz), 161.4, 135.8, 133.5, 132.4 (d, J = 3.1
Hz), 130.6, 129.0, 128.7, 128.5 (d, J = 8.7 Hz), 127.5, 115.9 (d, J =
22.0 Hz), 93.4, 65.3. IR (KBr): 3270, 1701, 1648, 1597, 1508, 1382,
1284, 1135, 1028, 995, 873, 733; HRMS (ESI-TOF) m/z: (M + H)+
+
TOF) m/z: (M + H)+ calcd for C21H16NO3 , 330.1125; found,
330.1121.
3-Benzoyl-2-(tert-butyl)-3-hydroxyisoindolin-1-one (3r). 3r was
purified by silica gel chromatography (EA/PE = 1/10). Yield: 49%, 30
1
mg, yellow solid, mp 115−117 °C H NMR (400 MHz, CDCl3): δ
+
7.90−7.84 (m, 1H), 7.66−7.61 (m, 2H), 7.54−7.44 (m, 3H), 7.31−
7.25 (m, 2H), 7.16−7.13 (m, 1H), 5.72 (s, 1H), 1.40 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ 197.9, 169.7, 144.8, 134.2,
132.9, 132.3, 131.8, 130.3, 129.8, 128.7, 123.9, 121.2, 92.8, 56.9, 28.1;
IR (KBr): 3367, 2967, 2928, 1688, 1674, 1599, 1528, 1488, 1394,
calcd for C16H13FNO4 , 302.0823; found, 302.0805.
3-(2-Chlorobenzoyl)-3-hydroxy-2-methoxyisoindolin-1-one (3l).
3l was purified by silica gel chromatography (EA/PE = 1/5). Yield:
48%, 31 mg, white solid, mp 182−184 °C 1H NMR (400 MHz,
CDCl3): δ 8.24−8.20 (m, 1H), 8.15−8.13 (m, 1H), 8.10−8.06 (m,
1H), 7.81−7.71 (m, 2H), 7.48−7.44 (m, 1H), 7.41−7.33 (m, 2H),
5.27 (s, 1H), 3.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
188.5, 161.2, 148.1, 135.1, 133.3, 131.8, 130.6, 130.2, 130.0, 129.9,
129.9, 128.6, 127.2, 127.0, 90.4, 63.6; IR (KBr): 3222, 1720, 1667,
1596, 1348, 1272, 1131, 1023, 859, 754; HRMS (ESI-TOF) m/z: (M
+
1221, 813; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H20NO3 ,
310.1438; found, 310.1430.
3-Benzoyl-2-benzyl-3-hydroxyisoindolin-1-one (3s). 3s was puri-
fied by silica gel chromatography (EA/PE = 1/10). Yield: 60%, 41
1
mg, white solid, mp 120−122 °C H NMR (400 MHz, CDCl3): δ
+
+ H)+ calcd for C16H13ClNO4 , 318.0528; found, 318.0541.
8.00 (d, J = 7.3 Hz, 1H), 7.62−7.52 (m, 2H), 7.33−7.26 (m, 2H),
7.09−6.92 (m, 9H), 6.00 (s, 1H), 4.90 (d, J = 15.0 Hz, 1H), 4.31 (d, J
= 15.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.1, 168.5,
144.7, 135.4, 133.7, 133.2, 131.8, 131.5, 130.6, 129.2, 129.2, 128.2,
128.0, 127.3, 124.4, 122.5, 89.9, 42.7; IR (KBr): 3223, 2925, 1692,
1648, 1450, 1288, 1173, 1122, 1069, 710, 698; HRMS (ESI-TOF) m/
3-Hydroxy-2-methoxy-3-(thiophene-2-carbonyl)isoindolin-1-one
(3m). 3m was purified by silica gel chromatography (EA/PE = 1/5).
1
Yield: 87%, 50 mg, yellow solid, mp 112−114 °C H NMR (400
MHz, CDCl3): δ 7.92−7.90 (m, 1H), 7.61−7.58 (m, 2H), 7.34−7.32
(m, 1H), 7.11 (d, J = 4.1 Hz, 1H), 6.93 (d, J = 4.2 Hz, 1H), 5.83 (s,
1H), 4.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 185.4,
164.1, 140.8, 137.3, 135.9, 133.8, 131.8, 131.2, 129.4, 125.9, 124.3,
122.8, 89.9, 66.2; IR (KBr): 3351, 1709, 1655, 1399, 1304, 1075,
1003, 756, 679; HRMS (ESI-TOF) m/z: (M + H)+ calcd for
C14H12NO4S+, 290.0482; found, 290.0486.
+
z: (M + H)+ calcd for C22H18NO3 , 344.1281; found, 344.1289.
3-Benzoyl-3-hydroxy-6-methoxy-2-phenylisoindolin-1-one (3t).
3t was purified by silica gel chromatography (EA/PE = 1/10).
1
Yield: 89%, 64 mg, white solid, mp 80−82 °C H NMR (400 MHz,
CDCl3): δ 7.53−7.47 (m, 2H), 7.44−7.37 (m, 4H), 7.29−7.25 (m,
4H), 7.19−7.14 (m, 1H), 7.08−7.04 (m, 2H), 3.93 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 195.9, 167.6, 162.0, 135.9, 134.3, 133.9,
132.8, 132.4, 132.2, 129.3, 128.8, 128.0, 123.7, 121.4, 121.3, 108.1,
91.6, 55.9; IR (KBr): 3381, 2925, 1713, 1693, 1596, 1490, 1351,
1285, 1134, 1011, 826; HRMS (ESI-TOF) m/z: (M + H)+ calcd for
3-(Cyclopropanecarbonyl)-3-hydroxy-2-methoxyisoindolin-1-
one (3n). 3n was purified by silica gel chromatography (EA/PE = 1/
1
5). Yield: 67%, 33 mg, white solid, mp 114−116 °C H NMR (400
MHz, CDCl3): δ 7.89−7.87 (m, 1H), 7.65−7.55 (m, 2H), 7.33−7.31
(m, 1H), 5.55 (s, 1H), 4.02 (s, 3H), 1.54−1.47 (m, 1H), 1.21−1.13
(m, 1H), 1.05−0.99 (m, 2H), 0.82−0.74 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 204.4, 165.0, 140.0, 133.6, 130.7, 129.9, 124.0,
122.5, 91.3, 66.3, 15.1, 13.5, 13.3; IR (KBr): 3249, 2937, 1720, 1693,
1372, 1225, 1108, 1082, 892, 764; HRMS (ESI-TOF) m/z: (M + H)+
+
C22H18NO4 , 360.1230; found, 360.1212.
3-Benzoyl-3-hydroxy-4-methyl-2-phenylisoindolin-1-one (3u).
3u was purified by silica gel chromatography (EA/PE = 1/10).
Yield: 87%, 60 mg, white solid, mp 131−133 °C 1H NMR (400 MHz,
CDCl3): δ 7.88 (d, J = 7.5 Hz, 1H), 7.56−7.38 (m, 8H), 7.29−7.25
(m, 2H), 7.03−7.00 (m, 2H), 5.92 (s, 1H), 2.19 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 195.8, 167.9, 141.6, 135.5, 134.6, 134.3,
133.4, 132.3, 132.2, 131.3, 130.9, 129.2, 129.0, 128.9, 122.4, 121.8,
91.5, 17.1; IR (KBr): 3387, 1725, 1709, 1668, 1488, 1332, 1113,
+
calcd for C13H14NO4 , 248.0917; found, 248.0917.
3-Hydroxy-2-methoxy-3-((8R,9S,13S,14S)-13-methyl-17-oxo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-
phenanthrene-2-carbonyl)isoindolin-1-one (3o). 3o was purified by
silica gel chromatography (EA/PE = 1/4). Yield: 54%, 50 mg, white
solid, mp 99−101 °C 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 7.8
Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.84−7.80 (m, 1H), 7.67 (t, J = 7.6
Hz, 1H), 7.21−7.10 (m, 3H), 4.71 (s, 1H), 4.06 (s, 3H), 2.93−2.78
(m, 2H), 2.50−2.43 (m, 1H), 2.35−2.27 (m, 1H), 2.15−2.02 (m,
2H), 2.00−1.89 (m, 2H), 1.67−1.53 (m, 2H), 1.52−1.34 (m, 5H),
0.84 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 220.6, 190.7,
161.3, 141.3, 137.5, 135.6, 133.9, 133.3, 130.9, 129.2, 128.7, 127.5,
126.9, 126.0, 123.6, 93.8, 65.3, 50.4, 47.8, 44.2, 37.7, 35.7, 31.4, 29.4,
26.2, 25.4, 21.5, 13.7. IR (KBr): 3387, 2955, 2925, 2853, 1735, 1709,
+
1003, 681; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H18NO3 ,
344.1281; found, 344.1281.
3-Benzoyl-6-fluoro-3-hydroxy-2-phenylisoindolin-1-one (3v). 3v
was purified by silica gel chromatography (EA/PE = 1/10). Yield:
63%, 43 mg, white oil. 1H NMR (400 MHz, CDCl3): δ 7.74−7.68 (m,
1H), 7.55−7.50 (m, 1H), 7.46−7.26 (m, 9H), 7.08−7.02 (m, 2H),
5.96 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.1, 166.4,
164.3 (d, J = 252.3 Hz), 139.5 (d, J = 2.7 Hz), 134.6, 133.5, 132.3,
132.0, 129.3, 129.0, 128.1, 124.6 (d, J = 8.7 Hz), 121.5 (d, J = 37.2
F
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Hz), 121.1, 112.1, 111.9, 91.3. IR (KBr): 3401, 1719, 1700, 1490,
129.8, 124.5, 123.1, 94.6, 74.0, 73.7, 65.9; IR (KBr): 3250, 1706,
1441, 1352, 1271, 1123, 825, 804; HRMS (ESI-TOF) m/z: (M + H)+
1467, 1359, 1068, 1012, 744, 690; HRMS (ESI-TOF) m/z: (M + H)+
+
+
calcd for C21H15FNO3 , 348.1030; found, 348.1071.
calcd for C11H12Br2NO4 , 379.9128; found, 379.9132.
3-(Bromo(phenyl)methylene)-2-methoxyisoindolin-1-one (5). 5
was purified by silica gel chromatography (EA/PE = 1/50). Yield: 9%,
6 mg, white solid 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 7.9 Hz,
1H), 7.83−7.75 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.7 Hz,
1H), 7.49−7.39 (m, 3H), 7.36 (t, J = 7.6 Hz, 1H), 3.96 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 149.2, 147.4, 133.1, 131.3,
130.7, 129.9, 129.6, 128.9, 128.1, 126.2, 123.7, 121.4, 100.6, 62.9;
3-Benzoyl-6-chloro-3-hydroxy-2-phenylisoindolin-1-one (3w).
3w was purified by silica gel chromatography (EA/PE = 1/10).
1
Yield: 58%, 42 mg, yellow solid, mp 157−159 °C H NMR (400
MHz, CDCl3): δ 8.00 (d, J = 1.9 Hz, 1H), 7.61−7.59 (m, 1H), 7.53
(t, J = 7.4 Hz, 1H), 7.45−7.43 (m, 2H), 7.40−7.37 (m, 2H), 7.35−
7.26 (m, 4H), 7.06−7.02 (m, 2H), 5.98 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 194.9, 166.3, 142.2, 137.3, 134.7, 133.9, 133.4,
132.8, 132.3, 131.9, 129.3, 129.0, 128.1, 125.1, 124.0, 121.7, 91.4; IR
(KBr): 3440, 1679, 1631, 1384, 1177, 1102, 748, 618; HRMS (ESI-
+
HRMS (ESI-TOF) m/z: (M + H)+ calcd for C16H13BrNO2 ,
330.0124; found, 330.0124.
+
TOF) m/z: (M + H)+ calcd for C21H15ClNO3 , 364.0735; found,
2-(2,2-Dibromo-3,3-dimethylbutanoyl)-N-methoxybenzoate
(5a). 5a was purified by silica gel chromatography (EA/PE = 1/100).
Yield: 55%, white oil 1H NMR (400 MHz, CDCl3): δ 7.98−7.95 (m,
2H), 7.58−7.47 (m, 2H), 3.85 (s, 3H), 1.52 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 194.1, 166.6, 139.7, 131.3, 130.2, 130.1, 129.6,
129.3, 83.4, 52.5, 44.8, 28.3; IR (KBr): 3401, 2977, 2952, 2931, 1729,
1706, 1434, 1281, 1139, 1091, 710; HRMS (ESI) calcd for
364.0735.
2-(4-Bromophenyl)-3-hydroxy-3-(3-methylbenzoyl)isoindolin-1-
one (3x). 3x was purified by silica gel chromatography (EA/PE = 1/
1
10). Yield: 81%, 68 mg, white solid, mp 140−142 °C H NMR (400
MHz, CDCl3): δ 8.09−7.99 (m, 1H), 7.67−7.60 (m, 2H), 7.45−7.34
(m, 3H), 7.33−7.26 (m, 2H), 7.15−7.04 (m, 4H), 5.99 (s, 1H), 2.22
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 195.6, 167.6, 144.1,
138.8, 135.3, 133.9, 133.8, 132.2, 132.1, 131.1, 130.8, 130.0, 128.7,
128.2, 126.3, 124.8, 122.7, 121.3, 91.7, 21.2; IR (KBr): 3253, 1698,
1678, 1491, 1371, 1115, 1063, 799, 776; HRMS (ESI-TOF) m/z: (M
+
C14H17Br2O3 , 390.9539 (M+ + H): found, 390.9539.
2-(2,2-Dibromo-3-methylbutanoyl)-N-methoxybenzoate (5b).
5b was purified by silica gel chromatography (EA/PE = 1/100).
Yield: 51%, white oil 1H NMR (400 MHz, CDCl3): δ 7.99−7.92 (m,
2H), 7.60−7.50 (m, 2H), 3.86 (s, 3H), 2.93−2.83 (m, 1H), 1.31 (s,
3H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.2, 166.5,
138.6, 131.5, 130.2, 129.9, 129.8, 129.6, 78.9, 52.6, 40.0, 20.2; IR
(KBr): 3413, 2973, 2943, 1728, 1432, 1284, 1215, 1093, 932, 709;
+
+ H)+ calcd for C22H17BrNO3 , 422.0386; found, 422.0381.
3-(4-Chlorobenzoyl)-3-hydroxy-2-phenylisoindolin-1-one (3y).
3y was purified by silica gel chromatography (EA/PE = 1/10).
Yield: 55%, 40 mg, white solid, mp 145−147 °C 1H NMR (400 MHz,
CDCl3): δ 8.06−8.01 (m, 1H), 7.67−7.63 (m, 2H), 7.43−7.37 (m,
5H), 7.30−7.23 (m, 3H), 7.14−7.00 (m, 2H), 5.93 (s, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 194.4, 167.5, 143.8, 141.2, 133.9, 133.7,
132.3, 131.1, 130.7, 130.4, 129.3, 129.1, 127.9, 126.7, 125.0, 122.7,
91.7; IR (KBr): 3381, 1717, 1694, 1586, 1490,1347, 1092, 1011, 815,
+
HRMS (ESI) calcd for C13H15Br2O3 , 376.9382 (M+ + H): found,
376.9384.
2-(2,2-Dibromo-2-cyclohexylacetyl)-N-methoxybenzoate (5c).
5c was purified by silica gel chromatography (EA/PE = 1/100).
Yield: 64%, white oil 1H NMR (400 MHz, CDCl3): δ 7.98−7.96 (m,
1H),7.91−7.90 (m, 1H), 7.62−7.54 (m, 1H), 7.54−7.48 (m, 1H),
3.86 (s, 3H), 2.50−2.40 (m, 1H), 2.34−2.28 (m, 2H), 1.89−1.83 (m,
2H), 1.72−1.69 (m, 1H), 1.46−1.31 (m, 4H), 1.28−1.18 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 194.0, 166.4, 138.6, 131.6, 130.2,
130.0, 129.7, 129.6, 78.3, 52.6, 49.1, 30.0, 26.0, 25.9; IR (KBr): 3428,
2931, 2854, 1727, 1283, 1217, 1138, 1097, 709, 618; HRMS (ESI)
+
765; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H15ClNO3 ,
364.0735; found, 364.0731.
3-(3-Fluorobenzoyl)-3-hydroxy-2-phenylisoindolin-1-one (3z). 3z
was purified by silica gel chromatography (EA/PE = 1/10). Yield:
50%, 35 mg, white solid, mp 136−138 °C 1H NMR (400 MHz,
CDCl3): δ 8.08−8.03 (m, 1H), 7.69−7.66 (m, 2H), 7.43−7.38 (m,
3H), 7.23−7.07 (m, 7H), 5.84 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 194.7, 167.5, 162.3 (d, J = 249.6 Hz), 143.6, 133.9, 133.7,
132.3, 131.2, 130.9, 130.7 (d, J = 7.7 Hz), 128.0, 125.0, 124.9 (d, J =
3.3 Hz), 122.7, 121.7, 121.5 (d, J = 6.6 Hz), 116.3 (d, J = 23.5 Hz),
104.9, 91.7. IR (KBr): 3416, 1717, 1685, 1585, 1490, 1177, 1117,
+
calcd for C16H19Br2O3 , 416.9695 (M+ + H): found, 416.9691.
ASSOCIATED CONTENT
■
sı
* Supporting Information
+
618; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H15FNO3 ,
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03466.
348.1030; found, 348.1053.
3-(Dibromo(methoxy)methyl)-3-hydroxy-2-methoxyisoindolin-
1-one (4a). 4a was purified by silica gel chromatography (EA/PE =
1/5). Yield: 69%, 54 mg, white solid, mp 177−179 °C 1H NMR (400
MHz, CDCl3): δ 8.02 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H),
7.64−7.60 (m, 1H), 7.56−7.53 (m, 1H), 6.07 (s, 1H), 4.83 (d, J =
10.8 Hz, 1H), 4.15 (d, J = 10.8 Hz, 1H), 4.09 (s, 3H), 3.63 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 162.9, 141.3, 132.2, 130.6,
X-ray crystal structure for compounds (CCDC-1958230,
1958232, 1958234, 1958235, 1958236, and 1958231)
(PDF)
Crystallographic data for compounds combined (CIF)
Crystallographic data for compound 5a (CIF)
129.9, 124.5, 122.9, 94.5, 83.4, 68.8, 65.7, 59.7. IR (KBr): 3369, 2941,
1716, 1466, 1390, 1203, 1115, 1092, 976, 758; HRMS (ESI-TOF) m/
+
z: (M + H)+ calcd for C12H14Br2NO4 , 393.9284; found, 393.9282.
AUTHOR INFORMATION
■
5-Benzoyl-5-hydroxy-1-methoxypyrrolidin-2-one (3aa). 3aa was
purified by silica gel chromatography (EA/PE = 1/3). Yield: 41%, 19
mg, white oil H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 7.4 Hz,
Corresponding Authors
1
Wenlin Xie − School of Chemistry and Chemical Engineering,
Hunan University of Science and Technology, Xiangtan 411201,
China; Email: xwl2000zsu@163.com
Guanyinsheng Qiu − College of Biological, Chemical Sciences
and Engineering, Jiaxing University, Jiaxing, Zhejiang 314001,
China; orcid.org/0000-0002-6587-8522;
2H), 7.62 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 5.44 (s, 1H),
3.90 (s, 3H), 2.76−2.70 (m, 1H), 2.51−2.40 (m, 2H), 2.22−2.14 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.7, 170.2, 134.1, 132.2,
129.4, 129.0, 91.0, 65.0, 29.6, 25.6; HRMS (ESI-TOF) m/z: (M +
+
H)+ calcd for C12H14NO4 , 236.0917; found, 236.0917.
3-(1,1-Dibromo-2-hydroxyethyl)-3-hydroxy-2-methoxyisoindo-
lin-1-one (4b). 4b was purified by silica gel chromatography (EA/PE
= 1/4). Yield: 47%, 36 mg, white solid, mp 174−176 °C H NMR
(400 MHz, CDCl3): δ 8.02 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.4 Hz,
1H), 7.68−7.62 (m, 1H), 7.61−7.54 (m, 1H), 6.02 (s, 1H), 4.96 (d, J
= 12.7 Hz, 1H), 4.38 (d, J = 12.7 Hz, 1H), 4.13 (s, 3H). 3.94 (s, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 163.4, 141.1, 132.4, 130.7,
Email: qiuguanyinsheng@mail.zjxu.edu.cn
1
Authors
Renzhi Liu − School of Chemistry and Chemical Engineering,
Hunan University of Science and Technology, Xiangtan 411201,
China
G
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Min Yang − Department of Forensic Science, Gannan Medical
University, Ganzhou, Jiangxi 341000, China; orcid.org/
0000-0001-8338-9725
Wenbi Dong − College of Biological, Chemical Sciences and
Engineering, Jiaxing University, Jiaxing, Zhejiang 314001,
China
Hongwei Zhou − College of Biological, Chemical Sciences and
Engineering, Jiaxing University, Jiaxing, Zhejiang 314001,
China; orcid.org/0000-0001-8308-960X
Sarita Yadav − College of Biological, Chemical Sciences and
Engineering, Jiaxing University, Jiaxing, Zhejiang 314001,
China
Vladimir Ivanovich Potkin − College of Biological, Chemical
Sciences and Engineering, Jiaxing University, Jiaxing, Zhejiang
314001, China
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial supports from the Natural Science Foundation of
China (nos: 21502069, 21571058, and 21772067) and the
Zhejiang Provincial Natural Science Foundation (grant no.
LY19B020004) are gratefully acknowledged.
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