PhI(OCOCF3)2-Mediated Cyclization of o -(1-Alkynyl)benzamides: Metal-Free Synthesis of 3-Hydroxy-2,3-dihydroisoquinoline-1,4-dione

Article abstract of DOI:10.1021/acs.joc.5b00576

The synthesis of an undocumented skeleton of 3-hydroxy-2,3-dihydroisoquinoline-1,4-diones has been discovered and reported. The reaction consists of an intramolecular cyclization of o-(1-alkynyl)benzamides in MeCN/H₂O, mediated by metal-free, h

Full text of DOI:10.1021/acs.joc.5b00576

Note
pubs.acs.org/joc
PhI(OCOCF3)2‑Mediated Cyclization of o‑(1-Alkynyl)benzamides:
Metal-Free Synthesis of 3‑Hydroxy-2,3-dihydroisoquinoline-1,4-
dione
Chao Yang,† Xiang Zhang,† Daisy Zhang-Negrerie,† Yunfei Du,*,†,‡ and Kang Zhao*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: The synthesis of an undocumented skeleton of 3-
hydroxy-2,3-dihydroisoquinoline-1,4-diones has been discovered and
reported. The reaction consists of an intramolecular cyclization of o-
(1-alkynyl)benzamides in MeCN/H2O, mediated by metal-free,
hypervalent reagent of PhI(OCOCF3)2, followed by an oxidative
hydroxylation reaction. The mechanism consisting of two pathways
has been proposed and discussed.
he intramolecular cyclization of alkynes possessing a
nucleophilic moiety in the proximity of the carbon−carbon
T
triple bond1 has been reported to be a convenient and effective
process for the construction of a variety of heterocycles.2 Among
these transformations is the construction of N-containing
heterocycles through intramolecular cyclization reactions
between an amide moiety and the carbon−carbon triple bond.
For this reason, during the past decades o-(1-alkynyl)benzamide
derivatives have been widely studied as a basic enyne-amide
system for exploring novel and useful cyclization trans-
formations.3 The existing strategies mainly involve the N-
nucleophilic or O-nucleophilic attack of the amide group onto
the nearby carbon−carbon triple bond, giving rise to the five- or
six-membered heterocyclic compounds through 5-exo-dig or 6-
endo-dig cyclization, respectively.4 For examples, upon treatment
with electrophilic oxidants such as I2, ICl, NBS and PhSeCl, o-(1-
alkynyl)benzamides could be converted into isobenzofuranimine
and isochromenimine compounds, with the electrophilic E+
being incorporated into the products (Figure 1, route a).5
Interestingly, in the presence of AgSbF6 or AgOTf as catalyst, the
reaction provided isochomenimines with excellent regioselectiv-
ity with no formation of the five-membered isobenzofuranimine
compounds (route b).4c,d On the other hand, in the presence of a
base4a or mediated by AlCl3 and acyl chlorides,4b o-(1-
alkynyl)benzamides were converted into isoindolinone com-
pounds I, obviously resulting from the nucleophilicity of the
amide group instead while going through the similar reactions as
in routes a and b (route c). Moreover, by the combining Cs2CO3
and catalytic amount of Cu(OAc)2,4e or InBr34f,g as Lewis acids, o-
(1-alkynyl)benzamides could be transformed into isoquinoli-
nones II (route d). It was also reported that with ZnCl2 as
catalyst and DMF as solvent, and the reaction temperature at 100
°C, both I and II were formed.6 It is worth noting that for o-(1-
alkynyl)benzamide derivatives bearing certain types of R2
Figure 1. Existing intramolecular cyclization of o-(1-alkynyl)-
benzamides.
substituents, cascade heteroannulation could occur leading to
the formation of various fused heterocylic compounds such as
indole[3, 2-c]isoquinoliones,7 3,4-dihydro-1H-benzo[c]-
chromen-6(2H)-imine8 derivatives, and indeno[1,2-c]azepin-
3(2H)-ones9 (not shown).
These reported transformations showed that o-(1-alkynyl)-
benzamides could be converted into various interesting hetero-
cycles, the particular type of which depended on the reaction
conditions and substitution pattern of the starting substrates. In
this communication, we report a novel transformation, which
yielded products carrying the skeleton of 3-hydroxy-2,3-
dihydroisoquinoline-1,4-dione, a structure that has never been
Received: March 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00576
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The Journal of Organic Chemistry
Note
reported before to the best of our knowledge, by treating o-(1-
alkynyl)benzamide derivatives with hypervalent iodine reagent,10
i.e., phenyl iodide bistrifluoroacetate (PIFA) in a mixture of
MeCN and H2O as solvent.
solvent containing a mixture of acetonitrile and water was
applied, the reaction yield was greatly improved. A satisfactory
85% yield of the desired product was achieved when the volume
ratio of acetonitrile to water was 1:1 (Table 1, entry 7). Further
solvents screening showed that the solvent system of 1,4-
dioxane/water (1:1 v/v) gave only 10% yield of the product and
reactions in methanol/water (1:1 v/v) or trifluoroethanol
(TFE)/water (1:1 v/v) only provided a complex mixture with
no desired product formed. Screens of other hypervalent iodine
reagents were also carried out, but results showed that none of
the ones tested (PIDA, PhIO and IBX) gave better yield than
with PIFA.
As part of our ongoing effort in searching for new methods to
construct heterocyclic compounds utilizing hypervalent iodine
reagents,11 we launched the study of potential cyclization
reactions of o-(1-alkynyl)benzamides mediated by suitable
hypervalent iodine reagents.12 During those first trials, we used
the readily available N-methoxy-2-(phenylethynyl)benzamide 1a
(1.0 equiv) as the model substrate, PIFA (1.2 equiv) as the
hypervalent iodine reagent, and DCE as the solvent, one of the
most frequently chosen solvents for the types of reactions
involving hypervalent iodine(III) reagents. However, the
reaction provided a complex mixture of products. By switching
the solvent to the more polar acetonitrile, the reaction furnished
3-hydroxy-2,3-dihydroisoquinoline-1,4-dione (the structure of
which was unambiguously confirmed through X-ray crystallo-
graphic analysis) as the major product in 10% yield, with 80% of
the starting material recovered. This initial result indicated that
the reaction sequence involved not only a cyclization reaction,
but also a sequential oxidative hydroxylation reaction. This
finding gave rise to the synthesis of a brand new class of
heterocyclic compounds, namely, the 3-hydroxy-2,3-dihydroiso-
quinoline-1,4-dione derivatives.
Under the optimal conditions (Table 1, entry 7), a series of
substituted o-(1-alkynyl)benzamides were prepared (see Sup-
porting Information for details) to investigate the scope of this
novel method (Table 2). Reaction-yield data show that the
Table 2. Synthesis of 3-Hydroxy-2,3-dihydroisoquinoline-1,4-
dione via PIFA-Mediated Cyclization and Oxidative
a
Hydroxylation
As the yield from the initial reactions were far from satisfactory,
we set out the study of reaction conditions in order to maximize
the yields. The results are summarized in Table 1. When 2.1
b
entry
R1
R2
R3
product 2
yield (%)
1
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
n-Pr
H
H
H
H
H
2a
2b
2c
2d
2e
2f
85
78
85
87
88
85
90
77
89
83
78
70
78
67
87
92
2
5-Me
5-OMe
5-F
4-Cl
H
a
3
Table 1. Optimization of the Reaction Conditions
4
5
6
4-Cl
7
H
3-Cl
2g
2h
2i
8
H
4-F
9
H
3-NO2
3-CF3
3,4-diCl
4-Cl
b
10
11
12
13
H
2j
entry oxidant (equiv)
solvent (v/v)
DCE
time (h) yield (%)
H
2k
2l
c
1
PIFA (1.2)
PIFA (1.2)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIFA (2.1)
PIDA (2.1)
PhIO (2.1)
IBX (2.1)
1
−
5-Me
4-Cl
H
2
CH3CN
1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
2
10
42
−
62
78
85
10
−
4-Cl
2m
2n
2o
2p
3
CH3CN
c
14
3-Cl
4
CH3CN (dried)
CH3CN/H2O (10:1)
CH3CN/H2O (5:1)
CH3CN/H2O (1:1)
1,4-dioxane/H2O (1:1)
MeOH/H2O (1:1)
TFE/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
c
15
c
H
i-Pr
3-CF3
4-Cl
5
16
H
cyclo-Pr
6
a
Conditions: 1 (0.5 mmol), PIFA (2.1 mmol) in CH3CN/H2O (1:1
v/v) at rt for 0.5 h. Isolated yield. Reaction carried out in TFE/H2O
7
b
c
8
(1:1) at 50 °C.
9
10
11
12
13
−
electronic effects of R1 was insignificant, and that the method was
applicable for substrates bearing electron-withdrawing R3 groups,
including strong electron-withdrawing groups such as nitro or
trifluoromethyl groups. For the R2 groups, when the methoxy
group was replaced by an alkyl group such as n-Pr, i-Pr or
cyclopropyl, the starting material could not be fully consumed,
much to our surprise, even at high temperature of 70 °C. Further
attempts to improve the reaction yield were successful: when the
solvent was switched to TFE the reaction went to completion
with the corresponding products being obtained in good to high
yields (Table 2, entries 14−16).
68
58
<5
5
0.5
a
All reactions were carried out with 1a (0.5 mmol) and oxidant in
b
c
solvent (c = 0.05 M) at rt. Isolated yields. Not detected.
equiv of PIFA was used, the starting material 1a was completely
consumed with the product 2a being obtained in 42% yield. To
our surprise, when the pure, dried acetonitrile was used as the
solvent, the reaction afforded a complex mixture with only trace
of the desired product formed. This result suggested that the
water in the original untreated acetonitrile had to be involved in
the reactions and likely the source for the oxygen and hydroxyl
groups in the products. This hypothesis was proven true based on
the results from the following control experiments: when a
While the electron-withdrawing R3 groups exerted no
significant influence on the substrates for the reaction, it was
not the case for the electron-donating ones. Reactions involving
substrates with R3 being methyl, methoxyl, or 1-naphthyl, an
inseparable mixture of the desired 3-hydroxy-2,3-dihydroisoqui-
B
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Note
noline-1,4-diones 2 along with its 5-membered isomer 3-
benzoyl-3-hydroxy-2-methoxyisoindolin-1-ones 3 were afforded
in good to excellent total yields (Table 3). In addition, the ratios
Further studies were carried out in order to elucidate the
reaction mechanism (Scheme 1). Since both the amide and
Scheme 1. Control Experiments
Table 3. Formation of Inseparable Isomeric 3-Hydroxy-2,3-
dihydroisoquinoline-1,4-diones and 3-Benzoyl-3-hydroxy-2-
methoxyisoindolin-1-ones
a
b
c
entry
substrate
R1
R3
4-Me
2:3
yield (%)
1
2
3
4
5
1q
1r
1s
1t
H
H
H
H
5:1
1:1
2:3
1:2
3:1
81
90
92
88
78
4-OMe
3,4-diOMe
1-naphthyl
H
1u
4-NO2
a
Conditions: 1 (0.5 mmol), PIFA (2.1 mmol) in CH3CN/H2O (1:1
b
c
v/v) at rt for 0.5 h. The ratio was based on crude 1H NMR. Isolated
yields.
of two products varied in different deuterium solvents as well as
temperatures during the 1H NMR experiments, which suggested
that an isomeric equilibrium should exist between compounds 2
and 3.13 It is logical to suspect that the isomerization was
probably due to the presence of the electron-donating R3 group
which would increase the nucleophilicity of the carbon−carbon
triple bond as well as provide stability for the carbocation
intermediate necessary for the formation of the 5-membered
product 3. Quantitative relationships between the relative yields
of the two isomers and the electron-donating ability of R3
provided support for the hypothesis, as results in Table 3 show
that the amount of 3 relative to 2 consistently increased as R3
became more and more electron-donating, namely, from methyl
to methoxyl (singly substituted), to methoxyl (doubly
substituted). We rationalized that if the “push” effect from R3
had caused the formation of the 5-membered isomer, then the
“pull” effect from R1 should yield similar results. As expected, the
reaction of 1u yielded a mixture of compounds 2 and 3 in a ratio
of 3:1.
alkyne moieties can interact with the electrophilic hypervalent
iodine reagent, our control reactions involved treating N-
methoxybenzamide A and diphenylacetylene D separately with
oxidants. A complex mixture was obtained from reactions
between A and PIFA. By switching the oxidant to the less potent
PIDA, A was converted to N′-benzoyl-N,N′-dimethoxybenzohy-
drazide B14 and N-acetoxy-N-methoxybenzamide C, in 70% and
20% of the total yield, respectively15 (Scheme 1a). Reaction
between D and PIFA under our standard conditions yielded an
oxazole derivative E,16 instead of a diketone F as we had expected
based on the report that 1,2-diphenylethyne derivatives could be
converted into diketones under Vasil’eva’s conditions (Scheme
1b).17 Further studies showed that no reaction occurred between
G and acetonitrile under acidic condition in TFA (Scheme 1c), a
negative evidence that excluded the diketone pathway in the
generation of E. All the control experiments unambiguously
indicated that both the N-methoxyamide moiety and the alkyne
moiety in 1a were strong enough nucleophiles to react with the
hypervalent iodine reagents applied.18
To our disappointment, the method cannot be applied to the
substrates in which R represents an alkyl group, or to the
substrates in which R2 is an H or aryl group. When substrates 1v−
z was subjected to the optimal conditions, the reaction provided
no desired cyclized/hydroxylated product and an inseparable
complex mixture was always obtained in each case (Figure 2).
It is worthy to note that when substrate 1a was subjected to
PIFA (1.2 equiv) in trifluoroethanol (TFE), trifluoroethoxyl
moiety was incorporated into the product and the reaction
furnished 4-trifluoroethanolated isoquinolin-1(2H)-one product
4a in 50% yield. Furthermore, one can envisage that by replacing
water with the nucleophilic methanol, the reaction might provide
the corresponding 3-methoxyl-2,3-dihydroisoquinoline-1,4-
dione 6a. However, when substrate 1a was treated with PIFA
in CH3CN/MeOH (1:1 v/v), the reaction provided the N-
methoxylated product 5a as the major product, with no desired
6a being detected.19
On the basis of the experimental evidence, both from
literature16,17 as well as this study, we propose a mechanism
which consists of two plausible pathways in the initial stage of the
reaction sequence (Scheme 2). In path a, the N-methoxyamide
moiety, as the nucleophile, reacts with PIFA and gave
intermediate H, accompanied by the loss of one molecule of
trifluoroacetic acid.20 Then an intramolecular cyclization occurs
Figure 2. Other models that failed to cyclize.
C
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Note
values were given in ppm and referred to the internal standard TMS set
as 0.00 ppm. The peak patterns were indicated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; qui, quintet; m, multiplet; td, triplet of
doublets and dd, doublet of doublets. The coupling constants, J, are
reported in Hertz (Hz). High resolution mass spectrometry (HRMS)
was obtained on a Q-TOF microspectrometer. Melting points were
determined with a micromelting point apparatus without corrections.
TLC plates were visualized by exposure to ultraviolet light. Reagents and
solvents were purchased as reagent grade and were used without further
purification. All reactions were performed in standard glassware, heated
at 70 °C for 3 h before use. Flash column chromatography was
performed over silica gel 200−300 mesh and the eluent was a mixture of
ethyl acetate (EA) and petroleum ether (PE).
Scheme 2. Plausible Mechanistic Pathway
2. General Procedure for the Synthesis of Amides 1. Procedure
A.23 To a mixture of PdCl2(PPh3)2 (562 mg, 0.8 mmol) and CuI (76 mg,
0.4 mmol) in trimethylamine (100 mL) was added substitute 2-bromo
methoxybenzoate (20 mmol). The flask was purged with N2. After
stirring for 5 min, ethynyltrimethylsilane (22 mmol) was added slowly
and the reaction mixture was stirred at 40 °C for 2 h then at 70 °C for 5 h.
After the completion of the reaction (monitored by TLC), the reaction
mixture was cooled down to room temperature, filtered over Celite,
washed with ethyl acetate, and evaporated. To the crude material,
MeOH (40 mL), K2CO3 (3.5 g) and water (10 mL) were added and the
mixture was stirred for 80 min at room temperature. After completion of
the desilylation, water (200 mL) was added and the mixture was
extracted with ethyl acetate (3 × 100 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product o-(1-
alkynyl)benzoates can be used for the next step without any purification.
Procedure B.24 To a mixture of the corresponding o-(1-alkynyl)-
benzoates (20 mmol) and iodobenzene (30 mmol, 1.5 equiv) in Et3N
(80 mL) were added PdCl2(PPh3)2 (28 mg, 2 mol %) and CuI (40 mg, 1
mol %). The resulting mixture was then heated under an N2 atm at 55
°C. The reaction was monitored by TLC to establish completion. When
the reaction was complete, the mixture was allowed to cool to room
temperature, and the ammonium salt was removed by filtration. The
solvent was removed under reduced pressure.24a The residue was
dissolved in MeOH (40 mL) and KOH (aq.) (40 mL, 1.0 mol/L) was
added to the solution slowly. The resulting mixture was then heated to
70 °C until TLC indicated the total consumption of the ester. After
cooling, the reaction mixture was poured into crushed ice, acidified with
3 M HCl (15 mL) to pH 2−3 carefully and extracted with EtOAc (3 ×
100 mL). The combined organic layer was dried over Na2SO4 and
evaporated under reduced pressure.24b
To a solution of the corresponding o-(1-alkynyl)benzoic acid in
DCM (0.3 M) was added a catalytic amount of DMF. At ambient
temperature, oxalyl chloride (1.2 equiv) was added dropwise over a
period of 0.5 h, forming a homogeneous solution. The resulting solution
was kept at room temperature until TLC indicated the total
consumption of the acid. Then, the solvent was removed under reduced
pressure. The residue was dissolved in dry EA and slowly added
dropwise to a solution of the NH2OMe·HCl (1.2 equiv) and K2CO3 (3
equiv) in EA/H2O = 2:1 (40 mL).24c The reaction mixture was
maintained at ambient temperature and monitored by TLC. Upon
completion, the mixture was extracted with EA (3 × 50 mL) and the
combined organic phase was washed with NH4Cl (1 × 80 mL) and brine
(1 × 80 mL). Dried over Na2SO4 and evaporation of the solvent under
reduced pressure and purification of the crude residue by flash column
chromatography on silica gel (EA/PE) afforded the desired amides.
For 1n, 1o, 1p,24d the acyl chloride residue was dissolved in dry DCM
and slowly added dropwise to a solution of the appropriate aniline
derivative (1.2 equiv) and Et3N (2.5 equiv) in DCM (0.25 M). The
reaction mixture was maintained at ambient temperature and monitored
by TLC. Upon completion, the mixture was extracted with CH2Cl2 (3 ×
50 mL) and the combined organic phase was washed with NH4Cl (1 ×
80 mL) and brine (1 × 80 mL). Dried over Na2SO4 and evaporation of
the solvent under reduced pressure and purification of the crude residue
by flash column chromatography on silica gel (EA/PE) afforded the
desired amides.
in H, giving rise to the cationic intermediate I, along with the
release of one molecule of iodobenzene and a trifluoroacetate
anion. In path b, it was the triple bond instead that serves as a
nucleophile and initially activated by PIFA and forms the
electrophilic intermediate J,21 which reacts with the nucleophilic
N-methoxyamide moiety to produce intermediate K. The
elimination of the iodobenzene and trifluoroacetate anion from
K leads to the same cationic intermediate I. Next, intermediate L
was yielded from trapping a H2O molecule, and is further
oxidized by PIFA to furnish intermediate M.22 Conversion to the
iminium salt intermediate N after releasing an iodobenzene
molecule and a trifluoroacetate anion, followed by the
nucleophilic attack of water and the removal of one proton
furnishes the title product 2a. The proposed mechanism not only
explains the indispensible involvement of water, but also the
reasons why an electron-donating R3 or an electron-withdrawing
R1 will facilitate the formation of the 5-membered isomer 3. As
the mechanism depicts, there is the possibility of forming an
alternative five-membered isomeric cationic intermediate I′
during the formation of intermediate I, via path a or path b. In
comparison to intermediate I, this carbocation intermediate I′
would particularly benefit from the stabilization received from
the electron-donating R1 or less destabilization caused by the
electron-withdrawing R3 group. The formation of 4a and 5a can
also be well explained by the above reaction mechanism: when
MeOH was present, it will competitively attack the electron-
positive N center in H to give the N-methoxylated product 5a,
while when the less nucleophilic TFE was as the solvent, it
captured the reactive intermediate I species to give the stable 4-
trifluoroethanolated isoquinolin-1(2H)-one product 4a.
In summary, we have reported an efficient method for the
construction of some unprecedented new compounds contain-
ing the 3-hydroxy-2,3-dihydroisoquinoline-1,4-dione skeleton
through hypervalent iodine-mediated intramolecular amidation
of o-(1-alkynyl)benzamide compounds. A sound mechanism
consisting of two pathways in the beginning of the reaction
sequence has been proposed and is shown to agree with all
experimental observations mentioned. Further studies on
reaction mechanism are still in progress in our lab.
EXPERIMENTAL SECTION
■
1. General Information. All reactions were carried out at room
temperature and stirred magnetically. H and 13C NMR spectra were
1
recorded on a 600 MHz spectrometer (150 MHz for 13C NMR) or 400
MHz spectrometer (100 MHz for 13C NMR) at 25 °C. Chemical shifts
D
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Note
3. General Procedures for the Synthesis of 2. To a stirred
solution of 1 (1.0 mmol) in MeCN/H2O = 1:1 (50 mL) was added PIFA
(2.1 mmol) slowly at 0 °C. The resulting mixture was kept at the same
temperature until the TLC indicated that the total consumption of 1.
The reaction was quenched by sat. NaHCO3 (50 mL) and extracted with
ethyl acetate (3 × 20 mL). The combined organic layer was washed with
brine and dried over anhydrous Na2SO4 and then evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel to afford the desired product 2.
4. Procedures for the Synthesis of B and C. A mixture of A (1.0
mmol) and PIDA (1.0 mmol) in acetonitrile (20 mL) was stirred at the
designated temperature. The reaction was monitored by TLC. After the
reaction was completed, the reaction mixture was allowed to cool to
room temperature, and EA (20 mL) was added. The resulting mixture
was washed with saturated aqueous Na2S2O3 (10 mL). The organic layer
was dried over anhydrous Na2SO4, filtered, and removed under reduced
pressure. The residue was purified by flash column chromatography on
silica gel.
5. Procedures for the Synthesis of E. A solution of D (1.0 mmol)
and PIFA (2.0 mmol) in acetonitrile (20 mL) was stirred at the
designated temperature. The reaction was monitored by TLC. After the
reaction was completed, the reaction mixture was allowed to cool to
room temperature, and EA (20 mL) was added. The resulting mixture
was washed with saturated aqueous NaHCO3 (20 mL). The organic
layer was dried over anhydrous Na2SO4, filtered, and removed under
reduced pressure. The residue was purified by flash column
chromatography on silica gel.
129.7, 129.3, 128.8, 128.7, 122.4, 121.7, 93.9, 85.9, 63.4; HRMS (ESI)
m/z calcd for C16H13ClNO2+ [M + H+] 286.0629, found 286.0626.
2-((4-Chlorophenyl)ethynyl)-N-methoxybenzamide (1f). Follow-
ing the general procedure, 1f was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 55%, 1.5 g, white solid, mp 118−120 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.64 (br s, 1H), 7.64 (d, J = 7.6 Hz,
1H), 7.53−7.51 (m, 5H), 7.50 (d, J = 6.5 Hz, 2H), 3.73 (s, 3H); 13C
NMR (150 MHz, DMSO-d6) δ 164.2, 136.7, 133.7, 132.9, 132.3, 130.2,
129.0, 128.9, 127.9, 121.0, 120.0, 91.4, 88.3, 63.3; HRMS (ESI) m/z
calcd for C16H13ClNO2+ [M + H+] 286.0629, found 286.0629.
2-((3-Chlorophenyl)ethynyl)-N-methoxybenzamide (1g). Follow-
ing the general procedure, 1g was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 60%, 1.7 g, white solid, mp 122−124 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.62 (br s, 1H), 7.65 (d, J = 7.6 Hz,
1H), 7.56 (s, 1H), 7.54 (dd, J = 7.7, 2.8 Hz, 1H), 7.52−7.50 (m, 3H),
7.48 (d, J = 5.0 Hz, 2H), 3.74 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
δ 164.1, 136.8, 133.3, 132.4, 130.7, 130.6, 130.2, 129.9, 129.1, 129.0,
127.9, 124.2, 119.9, 91.0, 88.6, 63.2; HRMS (ESI) m/z calcd for
C16H13ClNO2+ [M + H+] 286.0629, found 286.0629.
2-((4-Fluorophenyl)ethynyl)-N-methoxybenzamide (1h). Follow-
ing the general procedure, 1h was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 60%, 1.6 g, white solid, mp 148−150 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.57 (dd, J = 8.7, 5.5 Hz, 2H), 7.55−7.51 (m, 1H), 7.51−7.46 (m,
2H), 7.30 (t, J = 8.9 Hz, 2H), 3.74 (s, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 164.2, 162.1 (d, J = 248.1 Hz), 136.7, 133.6 (d, J = 8.7 Hz),
132.3, 130.1, 128.7, 127.8, 120.2, 118.7 (d, J = 3.4 Hz), 116.1 (d, J = 22.4
Hz), 91.6, 87.0, 63.2; HRMS (ESI) m/z calcd for C16H13FNO2+ [M +
H+] 270.0925, found 270.0925.
6. Spectroscopic Data of 1a−u. N-Methoxy-2-(phenylethynyl)-
benzamide (1a). Following the general procedure, 1a was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 64%, 3.2 g, white
solid, mp 107−109 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.64 (br s,
1H), 7.66−7.62 (m, 1H), 7.54−7.51 (m, 3H), 7.50−7.48 (m, 2H),
7.46−7.44 (m, 3H), 3.75 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
164.3, 136.7, 132.3, 131.2, 130.1, 129.0, 128.8, 128.7, 127.8, 122.2, 120.4,
N-Methoxy-2-((3-nitrophenyl)ethynyl)benzamide (1i). Following
the general procedure, 1i was purified by silica gel chromatography (EA/
PE = 40/60). Yield: 20%, 0.6 g, white solid, mp 153−155 °C; 1H NMR
(600 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.29 (s, 1H), 7.94 (d, J = 7.6
Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.61−7.55 (m,
2H), 7.54 (s, 2H), 3.76 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
164.1, 147.9, 137.3, 136.8, 132.6, 130.6, 130.3, 129.3, 128.0, 125.6, 123.7,
+
92.6, 87.2, 63.2; HRMS (ESI) m/z calcd for C16H14NO2 [M + H+]
252.1019, found 252.1016.
+
N-Methoxy-5-methyl-2-(phenylethynyl)benzamide (1b). Follow-
ing the general procedure, 1b was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 70%, 3.7 g, white solid, mp 123−125 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.61 (br s, 1H), 7.54−7.47 (m, 3H),
7.43 (d, J = 6.6 Hz, 3H), 7.37−7.28 (m, 2H), 3.73 (s, 3H), 2.36 (s, 3H);
13C NMR (150 MHz, DMSO-d6) δ 164.3, 138.6, 136.6, 132.2, 131.1,
130.7, 128.8, 128.7, 128.3, 122.4, 117.4, 91.9, 87.4, 68.1, 63.2, 20.8;
119.5, 105.8, 90.3, 89.4, 63.2; HRMS (ESI) m/z calcd for C16H13N2O4
[M + H+] 297.0870, found 297.0873.
N-Methoxy-2-((3-(trifluoromethyl)phenyl)ethynyl)benzamide (1j).
Following the general procedure, 1j was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 75%, 2.23 g, white solid,
mp 130−132 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.64 (br s, 1H),
7.84 (s, 1H), 7.83−7.79 (m, 2H), 7.72−7.68 (m, 2H), 7.58−7.54 (m,
1H), 7.52 (d, J = 7.0 Hz, 2H), 3.75 (s, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 164.1, 136.8, 135.0, 132.5, 130.2, 130.1, 129.7 (q, J = 32.1
Hz), 129.1, 127.9, 127.6 (q, J = 3.6 Hz), 125.5 (q, J = 3.8 Hz), 123.7 (q, J
= 272.7 Hz), 123.3, 119.8, 90.9, 88.9, 63.2; HRMS (ESI) m/z calcd for
C17H13F3NO2+ [M + H+] 320.0893, found 320.0893.
2-((3,4-Dichlorophenyl)ethynyl)-N-methoxybenzamide (1k). Fol-
lowing the general procedure, 1k was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 45%, 1.4 g, white solid, mp
154−156 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.62 (br s, 1H), 7.76
(d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H),
7.55 (td, J = 7.6, 6.5, 3.2 Hz, 1H), 7.52 (d, J = 5.1 Hz, 2H), 7.49 (dd, J =
8.3, 1.9 Hz, 1H), 3.74 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 164.1,
136.7, 132.6, 132.5, 131.9, 131.6, 131.3, 131.1, 130.2, 129.2, 127.9, 122.8,
119.7, 90.2, 89.4, 63.3; HRMS (ESI) m/z calcd for C16H12Cl2NO2+ [M
+ H+] 320.0240, found 320.0245.
2-((4-Chlorophenyl)ethynyl)-N-methoxy-5-methylbenzamide (1l).
Following the general procedure, 1l was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 64%, 1.9 g, white solid, mp
105−108 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.66 (br s, 1H), 7.58−
7.56 (m, 5H), 7.42−7.35 (m, 2H), 3.77 (s, 3H), 2.41 (s, 3H); 13C NMR
(150 MHz, DMSO-d6) δ 164.2, 138.9, 136.6, 133.5, 132.8, 132.3, 130.8,
129.0, 128.4, 121.2, 117.1, 90.7, 88.5, 63.3, 20.8; HRMS (ESI) m/z calcd
for C17H15ClNO2+ [M + H+] 300.0786, found 300.0786.
4-Chloro-2-((4-chlorophenyl)ethynyl)-N-methoxybenzamide
(1m). Following the general procedure, 1m was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 30%, 0.9 g, white solid, mp
146−148 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.72 (br s, 1H), 7.76
+
HRMS (ESI) m/z calcd for C17H16NO2 [M + H+] 266.1176, found
266.1176.
N,5-Dimethoxy-2-(phenylethynyl)benzamide (1c). Following the
general procedure, 1c was purified by silica gel chromatography (EA/PE
= 30/70). Yield: 57%, 0.9 g, white solid, mp 155−158 °C; 1H NMR (600
MHz, DMSO-d6) δ 11.61 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (d, J =
6.1 Hz, 2H), 7.42 (d, J = 7.3 Hz, 3H), 7.09 (d, J = 8.2 Hz, 1H), 7.04 (s,
1H), 3.83 (s, 3H), 3.73 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
163.9, 159.1, 138.2, 133.9, 131.0, 128.7, 128.6, 122.6, 116.0, 113.2, 112.3,
91.1, 87.3, 63.2, 55.6; HRMS (ESI) m/z calcd for C17H16NO3+ [M + H+]
282.1125, found 282.1127.
5-Fluoro-N-methoxy-2-(phenylethynyl)benzamide (1d). Following
the general procedure, 1d was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 49%, 1.3 g, white solid, mp 133−135 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.70 (dd, J = 7.9, 5.6
Hz, 1H), 7.55−7.48 (m, 2H), 7.44 (d, J = 4.9 Hz, 3H), 7.41 (d, J = 8.5
Hz, 2H), 3.74 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 162.9, 161.3
(d, J = 249.6 Hz), 138.9 (d, J = 7.4 Hz), 134.7 (d, J = 1.2 Hz), 131.2 (the
two peaks overlapped), 129.0, 128.8, 122.0, 117.4 (d, J = 22.0 Hz), 116.9,
115.2 (d, J = 23.8 Hz), 92.3, 86.2, 63.4; HRMS (ESI) m/z calcd for
C16H13FNO2+ [M + H+] 270.0925, found 270.0925.
4-Chloro-N-methoxy-2-(phenylethynyl)benzamide (1e). Follow-
ing the general procedure, 1e was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 65%, 1.8 g, white solid, mp 148−150 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.69 (br s, 1H), 7.74 (s, 1H), 7.58−7.55
(m, 1H), 7.52 (d, J = 8.2 Hz, 3H), 7.46 (d, J = 3.2 Hz, 3H), 3.74 (s, 3H);
13C NMR (150 MHz, DMSO-d6) δ 163.3, 135.3, 134.6, 131.6, 131.4,
E
DOI: 10.1021/acs.joc.5b00576
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(s, 1H), 7.58 (dd, J = 8.3, 2.0 Hz, 1H), 7.55−7.53 (m, 5H), 3.74 (s, 3H);
13C NMR (150 MHz, DMSO-d6) δ 163.3, 135.3, 134.7, 134.1, 133.0,
N-Methoxy-4-nitro-2-(phenylethynyl)benzamide (1u). Following
the general procedure, 1u was purified by silica gel chromatography
(EA/PE = 40/60). Yield: 65%, 3.8 g, yellow solid, mp 127−130 °C; 1H
NMR (600 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.42 (s, 1H), 8.29 (dd, J
= 8.4, 2.3 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 6.7, 3.0 Hz,
2H), 7.48 (dd, J = 4.9, 2.1 Hz, 3H), 3.77 (s, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 162.7, 148.1, 141.9, 131.5, 129.6, 129.5, 128.9, 126.8,
123.4, 122.1, 121.3, 94.7, 85.2, 63.5; HRMS (ESI) m/z calcd for
C16H13N2O4+ [M + H+] 297.0870, found 297.0870.
131.7, 129.7, 129.1, 129.0, 122.1, 120.6, 92.7, 86.9, 63.3; HRMS (ESI)
m/z calcd for C16H12Cl2NO2+ [M + H+] 320.0240, found 320.0240.
2-((3-Chlorophenyl)ethynyl)-N-propylbenzamide (1n). Following
the general procedure, 1n was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 57%, 1.7 g, white solid, mp 130−133 °C; 1H
NMR (600 MHz, DMSO-d6) δ 8.41 (br s, 1H), 7.63 (d, J = 5.6 Hz, 1H),
7.54−7.47 (m, 7H), 7.47 (s, 1H), 3.23 (q, J = 6.6 Hz, 2H), 1.53 (q, J = 7.2
Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ
167.2, 140.1, 133.2, 132.5, 132.4, 130.7, 130.6, 129.8, 129.5, 128.9, 127.6,
124.3, 119.2, 90.8, 89.2, 40.8, 22.4, 11.5; HRMS (ESI) m/z calcd for
C18H17ClNO+ [M + H+] 298.0993, found 298.0990.
N-Isopropyl-2-((3-(trifluoromethyl)phenyl)ethynyl)benzamide
(1o). Following the general procedure, 1o was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 63%, 2 g, white solid, mp
118−120 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.32 (br s, 1H), 7.84 (s,
1H), 7.81 (t, J = 7.4 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.67−7.64 (m,
1H), 7.54−7.47 (m, 3H), 4.10 (d, J = 6.9 Hz, 1H), 1.15 (d, J = 6.6 Hz,
6H); 13C NMR (150 MHz, DMSO-d6) δ 166.3, 140.2, 134.9, 132.4,
130.1, 129.6 (q, J = 32.3 Hz), 129.4, 127.6 (q, J = 3.4 Hz), 125.3 (q, J =
3.0 Hz), 124.6, 123.6 (q, J = 272.3 Hz) 123.5, 122.8, 119.0, 90.6, 89.5,
41.0, 22.2; HRMS (ESI) m/z calcd for C19H17F3NO+ [M + H+]
332.1257, found 332.1255.
2-(Hex-1-yn-1-yl)-N-methoxybenzamide (1v). Following the gen-
eral procedure, it was purified by silica gel chromatography (EA/PE =
1
30/70). Yield: 56%, 2.5 g, white solid, mp 79−81 °C; H NMR (600
MHz, DMSO-d6) δ 11.45 (s, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 3.71 (s,
3H), 2.41 (t, J = 6.9 Hz, 2H), 1.53−1.47 (m, 2H), 1.43 (m, 2H), 0.89 (t, J
= 7.2 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 164.4, 136.7, 132.3,
129.8, 127.7, 127.5, 121.3, 94.2, 78.2, 63.1, 30.1, 21.3, 18.4, 13.5; HRMS
(ESI) m/z calcd for C14H18NO2+ [M + H+] 232.1332, found 232.1330.
2-(3,3-Dimethylbut-1-yn-1-yl)-N-methoxybenzamide (1w). Fol-
lowing the general procedure, it was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 46%, 1.9 g, white solid, mp
85−87 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.41 (m,
2H), 7.37 (m, 2H), 3.73 (s, 3H), 1.26 (s, 9H); 13C NMR (150 MHz,
DMSO-d6) δ 164.4, 136.7, 132.1, 129.7, 127.7, 127.5, 121.1, 101.9, 76.7,
+
63.1, 30.5, 27.7; HRMS (ESI) m/z calcd for C14H18NO2 [M + H+]
2-((4-Chlorophenyl)ethynyl)-N-cyclopropylbenzamide (1p). Fol-
lowing the general procedure, 1p was purified by silica gel
chromatography (EA/PE = 20/80). Yield: 60%, 1.7 g, white solid, mp
152−154 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.46 (br s, 1H), 7.60
(dd, J = 7.6, 1.9 Hz, 1H), 7.51−7.54 (m, 4H), 7.51−7.44 (m, 3H), 2.86
(s, 1H), 0.69 (td, J = 7.0, 4.7 Hz, 2H), 0.59−0.46 (m, 2H); 13C NMR
(150 MHz, DMSO-d6) δ 168.4, 139.7, 133.6, 132.8, 132.2, 129.5, 129.0,
128.8, 127.6, 121.2, 119.5, 91.2, 88.8, 22.7, 5.8; HRMS (ESI) m/z calcd
for C18H15ClNO+ [M + H+] 296.0837, found 296.0835.
232.1332, found 232.1330.
2-(Cyclopropylethynyl)-N-methoxybenzamide (1x). Following the
general procedure, it was purified by silica gel chromatography (EA/PE
= 30/70). Yield: 33%, 1.7 g, white solid, mp 80−82 °C; 1H NMR (600
MHz, DMSO-d6) δ 11.39 (s, 1H), 7.41 (m, 2H), 7.36 (m, 2H), 3.71 (s,
3H), 1.52 (m, 1H), 0.95−0.84 (m, 2H), 0.76−0.65 (m, 2H); 13C NMR
(150 MHz, DMSO-d6) δ 164.5, 136.8, 132.2, 129.8, 127.6, 127.6, 121.3,
97.6, 73.2, 63.1, 8.4 (one signal was missing due to the overlap of peaks);
+
HRMS (ESI) m/z calcd for C13H14NO2 [M + H+] 216.1019, found
N-Methoxy-2-(p-tolylethynyl)benzamide (1q). Following the gen-
eral procedure, 1q was purified by silica gel chromatography (EA/PE =
30/70). Yield: 50%, 2.5 g, white solid, mp 109−122 °C; 1H NMR (400
MHz, DMSO-d6) δ 11.57 (br s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.54−7.43
(m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.73 (s, 3H),
2.34 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.8, 139.3, 137.2,
132.7, 131.6, 130.5, 129.9, 129.0, 128.3, 121.0, 119.7, 93.3, 87.1, 63.7,
216.1015.
2-(Phenylethynyl)benzamide (1y). Following the general procedure,
1y was purified by silica gel gel chromatography (EA/PE = 30/70).
Yield: 30%, 226 mg, white solid, mp 145−147 °C; 1H NMR (600 MHz,
CDCl3) δ 8.10 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.57−7.51
(m, 2H), 7.45 (m, 3H), 7.40−7.33 (m, 3H), 6.71 (s, 1H). The 1H NMR
spectral data are in good agreement with the literature.4d
N-Phenyl-2-(phenylethynyl)benzamide (1z). Following the general
procedure, 1z was purified by silica gel gel chromatography (EA/PE =
+
21.5; HRMS (ESI) m/z calcd for C17H16NO2 [M + H+] 266.1176,
found 266.1174.
1
N-Methoxy-2-((4-methoxyphenyl)ethynyl)benzamide (1r). Fol-
lowing the general procedure, 1r was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 44%, 2.5 g, white solid, mp
119−121 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.56 (br s, 1H), 7.59
(d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.48−7.41 (m, 4H), 7.00 (d,
J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 164.4, 159.7, 136.5, 132.8, 132.0, 130.0, 128.2, 127.8,
120.8, 114.4, 114.1, 92.9, 85.9, 63.2, 55.3; HRMS (ESI) m/z calcd for
C17H16NO3+ [M + H+] 282.1125, found 282.1127.
10/90). Yield: 40%, 226 mg, white solid, mp 156−157 °C; H NMR
(600 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.26−8.05 (m, 1H), 7.67 (d, J
= 7.7 Hz, 3H), 7.49−7.52 (m, 4H), 7.33−7.40 (m, 5H), 7.15 (t, J = 7.4
1
Hz, 1H). The H NMR spectral data are in good agreement with the
literature.4d
7. Spectroscopic Data of 2a−u. 3-Hydroxy-2-methoxy-3-
phenyl-2,3-dihydroisoquinoline-1,4-dione (2a). Following the general
procedure, 2a was purified by silica gel chromatography (EA/PE = 30/
70). Yield: 80%, 226 mg, white solid, mp 138−140 °C; 1H NMR (600
MHz, CDCl3) δ 8.40 (dd, J = 8.0, 1.3 Hz, 1H), 7.96 (dd, J = 7.7, 1.4 Hz,
1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.69 (td, J = 7.5, 1.3 Hz, 1H), 7.46−
7.38 (m, 2H), 7.31 (dd, J = 5.1, 2.2 Hz, 3H), 4.72 (s, 1H), 4.07 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 190.8, 161.5, 136.6, 135.8, 133.4, 130.9,
2-((3,4-Dimethoxyphenyl)ethynyl)-N-methoxybenzamide (1s).
Following the general procedure, 1s was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 57%, 3.5 g, white solid, mp
137−140 °C; 1H NMR (600 MHz, CDCl3) δ 9.86 (br s, 1H), 7.95 (s,
1H), 7.68−7.51 (m, 1H), 7.52−7.34 (m, 2H), 7.16 (ddd, J = 8.2, 4.5, 1.9
Hz, 1H), 7.04 (dd, J = 4.3, 1.9 Hz, 1H), 6.87 (dd, J = 8.3, 4.7 Hz, 1H),
3.91 (t, J = 5.3 Hz, 9H); 13C NMR (150 MHz, DMSO-d6) δ 165.3,
150.2, 148.8, 133.4, 132.9, 131.0, 129.9, 128.7, 125.1, 120.1, 114.0, 111.1,
129.5, 129.2, 129.0, 128.8, 127.5, 126.4, 93.9, 65.4; HRMS (ESI) m/z
calcd for C16H14NO4+ [M + H+] 284.0917, found 284.0913.
3-Hydroxy-2-methoxy-7-methyl-3-phenyl-2,3-dihydroisoquino-
line-1,4-dione (2b). Following the general procedure, 2b was purified by
silica gel chromatography (EA/PE = 20/80). Yield: 78%, 232 mg, white
+
100.0, 95.8, 86.0, 64.7, 56.0; HRMS (ESI) m/z calcd for C18H18NO4
1
[M + H+] 312.1230, found 312.1230.
solid, mp 123−125 °C; H NMR (600 MHz, CDCl3) δ 8.19 (s, 1H),
N-Methoxy-2-(naphthalen-2-ylethynyl)benzamide (1t). Following
the general procedure, 1t was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 54%, 2.4 g, white solid, mp 156−158 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 8.48 (d, J = 8.1 Hz,
1H), 8.02 (dd, J = 7.8, 2.6 Hz, 2H), 7.79 (t, J = 6.4 Hz, 2H), 7.70−7.49
(m, 6H), 3.75 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.0, 137.1,
133.3, 133.2, 133.0, 131.0, 130.7, 129.8, 129.2, 128.9, 128.3, 127.7, 127.3,
126.4, 126.1, 121.1, 120.2, 92.5, 91.2, 63.8; HRMS (ESI) m/z calcd for
C20H16NO2+ [M + H+] 302.1176, found 302.1175.
7.85 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.9 Hz,
2H), 7.31 (d, J = 5.5 Hz, 3H), 4.87 (s, 1H), 4.06 (s, 3H), 2.52 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 190.6, 161.7, 147.6, 136.8, 134.3, 130.8,
129.4, 129.2, 129.0, 127.8, 126.7, 126.4, 93.8, 65.4, 22.2; HRMS (ESI)
m/z calcd for C17H16NO4+ [M + H+] 298.1074, found 298.1074.
3-Hydroxy-2,7-dimethoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-
dione (2c). Following the general procedure, 2c was purified by silica gel
chromatography (EA/PE = 20/80). Yield: 85%, 243 mg, white solid, mp
148−151 °C; 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 8.5 Hz, 1H),
F
DOI: 10.1021/acs.joc.5b00576
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.84 (s, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.31 (d, J = 4.8 Hz, 3H), 7.14 (d, J
= 8.5 Hz, 1H), 4.82 (s, 1H), 4.06 (s, 3H), 3.98 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 189.6, 165.9, 161.2, 137.1, 133.6, 130.0, 129.3, 128.9,
126.3, 122.0, 120.7, 111.9, 93.6, 65.3, 56.2; HRMS (ESI) m/z calcd for
C17H16NO5+ [M + H+] 314.1023, found 314.1020.
7-Fluoro-3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquino-
line-1,4-dione (2d). Following the general procedure, 2d was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 85%, 256 mg, white
solid, mp 133−135 °C; 1H NMR (600 MHz, CDCl3) δ 8.04 (dt, J = 8.8,
2.9 Hz, 1H), 8.00 (td, J = 6.2, 5.4, 1.7 Hz, 1H), 7.40 (td, J = 5.8, 5.1, 3.4
Hz, 2H), 7.38−7.30 (m, 4H), 4.94−4.54 (m, 1H), 4.06 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 189.3, 167.3 (d, J = 260.7 Hz), 160.3, 136.4,
134.1 (d, J = 9.0 Hz), 130.9 (d, J = 9.4 Hz), 129.7, 129.1, 126.3, 125.7 (d,
J = 1.2 Hz), 121.1 (d, J = 22.8 Hz), 115.8 (d, J = 26.4 Hz), 93.9, 65.4;
HRMS (ESI) m/z calcd for C16H13FNO4+ [M + H+] 302.0823, found
302.0823.
(s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.9
Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 4.93 (s, 1H), 4.04 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 190.5, 161.3, 138.0, 136.2, 133.7, 131.7 (q, J = 33.0
Hz), 130.8, 129.9 (q, J = 276.2 Hz), 129.5, 129.4, 129.0, 127.7, 126.4 (q, J
= 3.0 Hz), 123.9 (q, J = 3.6 Hz), 93.2, 65.4; HRMS (ESI) m/z calcd for
C17H13F3NO4+ [M + H+] 352.0791, found 352.0791.
3-(3,4-Dichlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoqui-
noline-1,4-dione (2k). Following the general procedure, 2k was purified
by silica gel chromatography (EA/PE = 30/70). Yield: 88%, 308 mg,
white solid, mp 165−168 °C; 1H NMR (600 MHz, CDCl3) δ 8.38 (dd, J
= 7.9, 1.2 Hz, 1H), 7.98 (dd, J = 7.7, 1.3 Hz, 1H), 7.87 (td, J = 7.7, 1.3 Hz,
1H), 7.73 (td, J = 7.6, 1.2 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.36 (d, J =
8.5 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 4.87 (s, 1H), 4.05 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 190.2, 161.2, 136.9, 136.2, 134.0, 133.7,
133.4, 130.8, 130.7, 129.0, 128.9, 128.9, 127.7, 125.6, 92.8, 65.5; HRMS
+
(ESI) m/z calcd for C16H12Cl2NO4 [M + H+] 352.0138, found
6-Chloro-3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquino-
line-1,4-dione (2e). Following the general procedure, 2e was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 87%, 276 mg, white
solid, mp 151−153 °C; 1H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 8.4
Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 7.42−
7.38 (m, 2H), 7.33 (dd, J = 5.1, 2.0 Hz, 3H), 4.63 (s, 1H), 4.06 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 189.6, 160.9, 140.3, 136.1, 135.8, 130.5,
352.0138.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-7-methyl-2,3-dihydroi-
soquinoline-1,4-dione (2l). Following the general procedure, 2l was
purified by silica gel chromatography (EA/PE = 20/80). Yield: 70%, 231
mg, white solid, mp 158−160 °C; 1H NMR (600 MHz, CDCl3) δ 8.18
(s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 8.6
Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 4.84 (s, 1H), 4.06 (s, 3H), 2.53 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 190.3, 161.64 147.9, 135.6, 135.4,
134.5, 130.7, 129.3, 129.2, 127.9, 127.8, 126.5, 93.3, 65.5, 22.2; HRMS
129.8, 129.2, 129.1, 127.3, 126.4, 119.8, 94.1, 65.5; HRMS (ESI) m/z
calcd for C16H13ClNO4+ [M + H+] 318.0528, found 318.0528.
+
(ESI) m/z calcd for C17H15ClNO4 [M + H+] 332.0684, found
332.0682.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquino-
line-1,4-dione (2f). Following the general procedure, 2f was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 85%, 269 mg, white
solid, mp 175−178 °C; 1H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 7.8
Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.70 (t, J = 7.5
Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 4.99 (s, 1H),
4.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 190.6, 161.5, 136.0, 135.7,
135.2, 133.6, 130.7, 129.2, 129.0, 128.9, 128.0, 127.6, 93.5, 65.5; HRMS
6-Chloro-3-(4-chlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroi-
soquinoline-1,4-dione (2m). Following the general procedure, 2m was
purified by silica gel chromatography (EA/PE = 30/70). Yield: 77%, 273
mg, white solid, mp 166−168 °C; 1H NMR (600 MHz, CDCl3) δ 8.31
(d, J = 8.4 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.1 Hz,
1H), 7.36−7.28 (m, 4H), 4.74 (s, 1H), 4.04 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 189.4, 160.8, 140.5, 136.0, 135.9, 134.8, 130.5, 130.3,
129.3, 128.9, 128.0, 127.3, 93.6, 65.5; HRMS (ESI) m/z calcd for
C16H12Cl2NO4+ [M + H+] 352.0138, found 352.0135.
+
(ESI) m/z calcd for C16H13ClNO4 [M + H+] 318.0528, found
318.0525.
3-(3-Chlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquino-
line-1,4-dione (2g). Following the general procedure, 2g was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 90%, 285 mg, white
solid, mp 152−155 °C; 1H NMR (600 MHz, CDCl3) δ 8.39 (dd, J = 7.9,
1.2 Hz, 1H), 7.98 (dd, J = 7.7, 1.3 Hz, 1H), 7.86 (td, J = 7.6, 1.3 Hz, 1H),
7.71 (td, J = 7.6, 1.3 Hz, 1H), 7.48 (q, J = 1.4 Hz, 1H), 7.29−7.27 (m,
1H), 7.24−7.23 (m, 2H), 4.79 (s, 1H), 4.06 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 190.5, 161.3, 138.7, 136.1, 135.1, 133.6, 130.8, 130.1,
129.6, 129.0, 128.9, 127.6, 127.0, 124.5, 93.2, 65.5; HRMS (ESI) m/z
calcd for C16H13ClNO4+ [M + H+] 318.0528, found 318.0526.
3-(4-Fluorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquino-
line-1,4-dione (2h). Following the general procedure, 2h was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 77%, 231 mg, white
solid, mp 160−162 °C; 1H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 7.8
Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6
Hz, 1H), 7.45−7.34 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 4.82 (s, 1H), 4.06
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 190.7, 163.3 (d, J = 249.7 Hz),
161.4, 135.9, 133.6, 132.5 (d, J = 3.2 Hz), 130.8, 129.1, 128.8, 128.6 (d, J
= 8.7 Hz), 127.6, 116.0 (d, J = 21.9 Hz), 93.4, 65.4; HRMS (ESI) m/z
calcd for C16H13FNO4+ [M + H+] 302.0823, found 302.0820.
3-Hydroxy-2-methoxy-3-(3-nitrophenyl)-2,3-dihydroisoquino-
line-1,4-dione (2i). Following the general procedure, 2i was purified by
silica gel chromatography (EA/PE = 30/70). Yield: 89%, 292 mg, yellow
solid, mp 170−172 °C; 1H NMR (600 MHz, CDCl3) δ 8.45 (d, J = 7.8
Hz, 1H), 8.39 (s, 1H), 8.19 (d, J = 9.3 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H),
7.91 (t, J = 8.1 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H),
7.50 (t, J = 8.0 Hz, 1H), 4.82 (s, 1H), 4.06 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 190.3, 161.2, 148.7, 139.2, 136.5, 133.9, 132.1, 130.8, 129.9,
129.2, 128.8, 127.8, 124.4, 122.2, 92.8, 65.6; HRMS (ESI) m/z calcd for
C16H13N2O6+ [M + H+] 329.0768, found 329.0768.
3-(3-Chlorophenyl)-3-hydroxy-2-propyl-2,3-dihydroisoquinoline-
1,4-dione (2n). Following the general procedure, 2n was purified by
silica gel chromatography (EA/PE = 20/80). Yield: 67%, 220 mg,
colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.95 (dd, J = 7.1, 1.2 Hz,
1H), 7.66−7.54 (m, 3H), 7.48−7.43 (m, 1H), 7.33−7.28 (m, 1H),
7.21−7.12 (m, 2H), 5.74 (s, 1H), 3.38 (ddd, J = 14.2, 9.8, 5.8 Hz, 1H),
3.16 (ddd, J = 14.2, 9.8, 6.1 Hz, 1H), 1.57−1.44 (m, 2H), 0.83 (t, J = 7.4
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 196.1, 168.5, 144.0, 135.2,
134.3, 133.6, 133.2, 131.9, 130.9, 130.1, 129.6, 127.2, 124.4, 122.5, 90.7,
41.7, 22.2, 11.5; HRMS (ESI) m/z calcd for C18H17ClNO3+ [M + H+]
330.0891, found 330.0888.
3-Hydroxy-2-isopropyl-3-(3-(trifluoromethyl)phenyl)-2,3-dihy-
droisoquinoline-1,4-dione (2o). Following the general procedure, 2o
was purified by silica gel chromatography (EA/PE = 20/80). Yield: 87%,
1
315 mg, colorless oil; H NMR (600 MHz, CDCl3) δ 7.99−7.91 (m,
2H), 7.76−7.72 (m, 1H), 7.60 (td, J = 7.5, 1.1 Hz, 1H), 7.58−7.51 (m,
2H), 7.38 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 1.1 Hz, 1H), 5.73 (s, 1H),
3.89−3.52 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 196.3, 168.2, 143.8, 133.1, 132.8, 132.5,
132.4, 131.6 (q, J = 33.4 Hz), 130.6 (q, J = 3.5 Hz), 130.6, 129.5, 126.6
(q, J = 4.1 Hz), 123.2 (q, J = 261.2 Hz), 122.2, 91.4, 45.9, 20.6, 20.4;
HRMS (ESI) m/z calcd for C19H17F3NO3+ [M + H+] 364.1155, found
364.1152.
3-(4-Chlorophenyl)-2-cyclopropyl-3-hydroxy-2,3-dihydroisoqui-
noline-1,4-dione (2p). Following the general procedure, 2p was purified
by silica gel chromatography (EA/PE = 20/80). Yield: 92%, 300 mg,
colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.4 Hz, 1H),
7.61−7.53 (m, 2H), 7.50−7.45 (m, 2H), 7.28−7.23 (m, 3H), 5.86 (s,
1H), 1.13 (dddd, J = 10.3, 6.6, 5.2, 4.0 Hz, 1H), 0.79−0.65 (m, 2H), 0.48
(dddd, J = 10.6, 6.8, 5.2, 3.9 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
195.3, 169.7, 144.2, 141.1, 133.4, 131.6, 130.8, 130.8, 130.4, 129.4, 124.5,
3-Hydroxy-2-methoxy-3-(3-(trifluoromethyl)phenyl)-2,3-dihydroi-
soquinoline-1,4-dione (2j). Following the general procedure, 2j was
purified by silica gel chromatography (EA/PE = 30/70). Yield: 83%, 291
mg, white solid, mp 155−158 °C; 1H NMR (600 MHz, CDCl3) δ 8.39
(d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.80
+
122.4, 91.5, 22.5, 4.8, 4.2; HRMS (ESI) m/z calcd for C18H15ClNO3
[M + H+] 328.0735, found 328.0733.
G
DOI: 10.1021/acs.joc.5b00576
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3-Hydroxy-2-methoxy-3-(p-tolyl)-2,3-dihydroisoquinoline-1,4-
dione (2q) and 3-(3,4-Dimethoxybenzoyl)-3-hydroxy-2-methoxyi-
soindolin-1-one (3q). Following the general procedure, 2q and 3q were
purified by silica gel chromatography (EA/PE = 30/70): yield 81%, 240
Hz, 2H), 6.20 (s, 1H), 4.06 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
188.5, 159.7, 150.7, 135.5, 135.0, 134.7, 130.7, 130.5, 130.1, 129.5, 129.3,
129.2, 128.9, 126.4, 125.6, 122.8, 118.4, 94.3, 89.9, 66.5, 65.6; HRMS
(ESI) m/z calcd for C16H13N2O6+ [M + H+] 329.0768, found 329.0766.
N′-Benzoyl-N,N′-dimethoxybenzohydrazide (B).3 Following the
general procedure, B was purified by silica gel chromatography (EA/
PE = 10/90). Yield: 70%, 210 mg, colorless oil; H NMR (600 MHz,
CDCl3) δ 7.66 (d, J = 7.6 Hz, 4H), 7.53−7.49 (m, 2H), 7.39 (t, J = 7.4
Hz, 4H), 3.86 (s, 6H).
1
mg, isomers (2q/3q ratio 5:1) are reported together, white solid; H
NMR (600 MHz, CDCl3) major isomer 2q δ 8.38 (d, J = 7.8 Hz, 1H),
7.95 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H),
7.30 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.81 (s, 1H), 4.07 (s,
3H), 2.27 (s, 3H); minor isomer 3q δ 7.92−7.91 (m, 1H), 7.62−7.56
(m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 2.5 Hz, 1H, peaks of two
isomers overlapped), 7.07 (d, J = 8.2 Hz, 2H), 6.12 (s, 1H), 3.98 (s, 3H),
2.30 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 194.5, 190.8, 161.5, 139.6,
135.7, 133.7, 133.5, 133.4, 130.8, 130.8, 129.7, 129.6, 129.3, 129.2, 128.7,
127.5, 126.3, 124.3, 122.7, 93.9, 90.0, 66.1, 65.4, 21.7, 21.1; HRMS (ESI)
m/z calcd for C17H16NO4+ [M + H+] 298.1074, found 298.1074.
3-Hydroxy-2-methoxy-3-(4-methoxyphenyl)-2,3-dihydroisoqui-
noline-1,4-dione (2r) and 3-Hydroxy-2-methoxy-3-(4-
methylbenzoyl)isoindolin-1-one (3r). Following the general proce-
dure, 2r and 3r were purified by silica gel chromatography (EA/PE =
30/70): yield 90%, 282 mg, isomers (2r/3r ratio 1:1) are reported
together, white solid; 1H NMR (600 MHz, CDCl3) isomer 2r δ 8.38 (d,
J = 7.8 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (t,
J = 7.5 Hz, 1H), 7.33 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 4.73 (s,
1H), 4.07 (s, 3H), 3.73 (s, 3H), isomer 3r δ 7.94−7.90 (m, 1H), 7.61−
7.56 (m, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.31−7.28 (m, 1H), 6.75 (d, J =
9.0 Hz, 2H), 6.19 (s, 1H), 3.98 (s, 3H), 3.77 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 192.6, 190.7, 164.4, 161.5, 160.5, 142.0, 135.6, 133.7,
133.4, 132.0, 130.8, 130.7, 129.4, 129.3, 128.7, 128.4, 127.9, 127.5, 124.6,
124.4, 122.7, 114.4, 114.2, 93.8, 89.8, 66.0, 65.1, 55.5, 55.3; HRMS (ESI)
m/z calcd for C17H16NO5+ [M + H+] 314.1023, found 314.1020.
3-(3,4-Dimethoxyphenyl)-3-hydroxy-2-methoxy-2,3-dihydroiso-
quinoline-1,4-dione (2s) and 3-(3,4-Dimethoxybenzoyl)-3-hydroxy-
2-methoxyisoindolin-1-one (3s). Following the general procedure, 2s
and 3s were purified by silica gel chromatography (EA/PE = 20/80):
yield 92%, 316 mg, isomers (2s/3s ratio 2:3) are reported together,
white solid; 1H NMR (600 MHz, CDCl3) major isomer 3s δ 7.93 (d, J =
7.7 Hz, 1H), 7.60 (p, J = 7.3 Hz, 2H), 7.33−7.32 (d, J = 8.3 Hz, 1H)7.16
(d, J = 8.3 Hz, 2H), 6.70 (d, J = 8.3 Hz, 1H), 6.24 (s, 1H), 4.00 (s, 3H),
3.85 (s, 3H), 3.73 (s, 3H), minor isomer 2s δ 8.37 (d, J = 7.7 Hz, 1H),
7.96 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H),
7.01 (s, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.99 (s,
1H), 4.07 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 192.4, 190.5, 164.3, 161.6, 154.3, 149.9, 149.3, 148.7, 142.1,
137.4, 135.6, 133.8, 133.4, 130.8, 130.7, 129.4, 129.2, 128.7, 128.6, 127.5,
124.6, 124.5, 124.2, 122.8, 119.0, 111.6, 110.9, 110.5, 109.5, 93.8, 89.9,
66.2, 65.4, 56.1, 55.9, 55.9, 55.8; HRMS (ESI) m/z calcd for
C18H18NO6+ [M + H+] 344.1129, found 344.1130.
1
N-Acetoxy-N-methoxybenzamide (C). Following the general
procedure, C was purified by silica gel chromatography (EA/PE = 5/
1
95). Yield: 20%, 42 mg, colorless oil; H NMR (600 MHz, CDCl3) δ
7.88−7.72 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 3.96
(s, 3H), 2.14 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 174.1, 168.2,
132.9, 131.5, 129.0, 128.4, 62.6, 18.8; HRMS (ESI) m/z calcd for
C10H12NO4+ [M + H+] 210.0761, found 210.0760.
Methyl 2-(2-methyl-5-phenyloxazol-4-yl)benzoate (E). Following
the general procedure, E was purified by silica gel chromatography (EA/
1
PE = 10/90). Yield: 85%, 248 mg, colorless oil; H NMR (400 MHz,
CDCl3) δ 8.00−7.88 (m, 1H), 7.59−7.42 (m, 3H), 7.41−7.34 (m, 2H),
7.31−7.18 (m, 3H), 3.61 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.6, 159.6, 145.5, 134.3, 133.4, 131.9, 131.3, 131.1, 130.5,
128.6, 128.6, 128.5, 127.9, 125.2, 52.0, 14.0; HRMS (ESI) m/z calcd for
C18H16NO3+ [M + H+] 294.1125, found 294.1125.
2-Methoxy-3-phenyl-4-(2,2,2-trifluoroethoxy)isoquinolin-1(2H)-
one (4a). Following the general procedure, 4a was purified by silica gel
chromatography (EA/PE = 5/95). Yield: 50%, 98 mg, white solid, mp
105−108 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 1H),
7.69−7.50 (m, 5H), 7.34 (t, J = 7.5 Hz, 1H), 7.24−7.16 (m, 1H), 6.45
(d, J = 8.0 Hz, 1H), 4.17 (s, 3H), 4.02 (q, J = 8.4 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 163.6, 138.5, 132.8, 131.9, 131.3, 131.0, 130.7,
129.6, 128.4, 126.3, 123.5, 123.1 (q, J = 278.2 Hz), 121.7, 121.2, 66.4 (q,
J = 35.1 Hz), 65.2; 19F NMR (566 MHz, CDCl3) δ −73.76 (s, 3F);
HRMS (ESI) m/z calcd for C18H15F3NO3+ [M + H+] 350.0999, found
350.1004.
N,N-Dimethoxy-2-(phenylethynyl)benzamide (5a). Following the
general procedure, 5a was purified by silica gel chromatography (EA/PE
= 5/95). Yield: 70%, 126 mg, white solid, mp 156−158 °C; 1H NMR
(600 MHz, CDCl3) δ 7.61 (d, J = 7.0 Hz, 1H), 7.53 (m, 2H), 7.50−7.41
(m, 2H), 7.39 (d, J = 6.7 Hz, 1H), 7.38−7.35 (m, 3H) 3.83 (s, 6H); 13C
NMR (150 MHz, CDCl3) δ 173.00, 136.6, 132.7, 131.7, 130.2, 128.7,
128.4, 127.9, 127.5, 122.8, 121.3, 93.6, 86.8, 61.2; HRMS (ESI) m/z
calcd for C17H16NO3+ [M + H+] 282.1125, found 282.1125.
ASSOCIATED CONTENT
■
S
* Supporting Information
3-Hydroxy-2-methoxy-3-(naphthalen-2-yl)-2,3-dihydroisoquino-
line-1,4-dione (2t) and 3-(2-Naphthoyl)-3-hydroxy-2-methoxyisoin-
dolin-1-one (3t). Following the general procedure, 2t and 3t were
purified by silica gel chromatography (EA/PE = 20/80): yield 88%, 293
mg, isomers (2t/3t ratio 1:2) are reported together, white solid; some
Spectral data for all new compounds. The material is available
free of charge via the Internet at The Supporting Information is
available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.5b00576.
1
peaks of two isomers overlapped H NMR (600 MHz, CDCl3) major
AUTHOR INFORMATION
isomer 3t δ7.84−7.89 (m, 3H), 7.67−7.75 (m, 2H), 7.39−7.52 (m, 4H),
7.21−7.24 (m, 2H), 6.03 (s, 1H), 4.12 (s, 3H); minor isomer 2t δ 8.40
(d, J = 7.8 Hz, 1H), δ 8.01 (d, J = 7.6 Hz, 1H), 7.81−7.89 (m, 2H), 7.67−
7.75 (m, 1H), 7.39−7.52 (m, 4H), 7.21−7.24 (m, 2H), 4.62 (s, 1H),
3.57 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 199.2, 164.4, 144.6, 139.7,
133.7, 133.5, 133.3, 132.5, 130.9, 130.8, 130.2, 129.9, 129.2, 128.7, 128.5,
127.7, 127.6, 126.7, 126.5, 126.3, 125.8, 125.2, 125.1, 124.5, 124.2, 123.9,
122.4, 91.8, 66.6, 64.6; HRMS (ESI) m/z calcd for C20H16NO4+ [M +
H+] 334.1074, found 334.1070.
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Corresponding Authors
*E-mail: duyunfeier@tju.edu.cn.
*E-mail: kangzhao@tju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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3-Hydroxy-2-methoxy-6-nitro-3-phenyl-2,3-dihydroisoquinoline-
1,4-dione (2u) and 3-Benzoyl-3-hydroxy-2-methoxy-5-nitroisoindo-
lin-1-one (3u). Following the general procedure, 2u and 3u were
purified by silica gel chromatography (EA/PE = 20/80): yield 78%, 256
We acknowledge the National Natural Science Foundation of
China (#21472136) and the National Basic Research Project
(2014CB932201) for financial support.
1
mg, isomers (2u/3u ratio 3:1) are reported together, white solid; H
NMR (600 MHz, CDCl3) major isomer 2u δ 8.75 (s, 1H), 8.61 (q, J =
8.6 Hz, 2H), 7.40 (s, 2H), 7.38−7.33 (m, 3H), 4.88 (s, 1H), 4.09 (s, 3H),
minor isomer 3u δ 8.46 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 8.09 (d, J = 8.3
Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.8
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DOI: 10.1021/acs.joc.5b00576
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The Journal of Organic Chemistry
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1
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DOI: 10.1021/acs.joc.5b00576
J. Org. Chem. XXXX, XXX, XXX−XXX