Transition metal-free cascade reactions of alkynols to afford isoquinolin-1(2H)-one and dihydroisobenzofuran derivatives

Article abstract of DOI:10.1021/jo5006312

Transition metal-free cascade reactions of alkynols with imines have been achieved using potassium tert-butoxide as catalyst. Switching the reaction solvent gives two kinds of products in good yield: isoquinolin-1(2H)-one derivatives and dihydroisobenzofuran derivatives. This approach was used to generate the natural product 8-oxypseudopalmatine in a two-step procedure from commercially available starting materials. Additionally, multicomponent reactions of alkynols, aldehydes, and amines were also successfully achieved to afford isoquinolin-1(2H)-one derivatives.

Full text of DOI:10.1021/jo5006312

Article
pubs.acs.org/joc
Transition Metal-Free Cascade Reactions of Alkynols to Afford
Isoquinolin-1(2H)‑one and Dihydroisobenzofuran Derivatives
Deng Yuan Li, Ke Ji Shi, Xiao Feng Mao, Guo Rong Chen, and Pei Nian Liu*
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab for Advanced Materials and Institute of Fine Chemicals, East
China University of Science and Technology, Meilong Road 130, Shanghai, 200237 China
S
* Supporting Information
ABSTRACT: Transition metal-free cascade reactions of alkynols with imines have been achieved using potassium tert-butoxide
as catalyst. Switching the reaction solvent gives two kinds of products in good yield: isoquinolin-1(2H)-one derivatives and
dihydroisobenzofuran derivatives. This approach was used to generate the natural product 8-oxypseudopalmatine in a two-step
procedure from commercially available starting materials. Additionally, multicomponent reactions of alkynols, aldehydes, and
amines were also successfully achieved to afford isoquinolin-1(2H)-one derivatives.
Recently, we communicated the cascade reactions of exo-
cyclic enol ethers with imines in the presence of potassium tert-
butoxide (t-BuOK) to afford isoquinolin-1(2H)-one products
in DMSO, or dihydroisobenzofuran products in THF (Scheme
1a).17 Although the reactions gave good yields, the preparation
of exo-cyclic enol ethers from alkynols usually require metal
catalysts such as Ln[N(SiMe3)2]3 (Ln = La, Sm, Y, Lu, Nd),18
HgO19 Pd(OAc)2/PdCl2,20 Ag2CO3,21 AuCl,22 Cu(OTf)2,23
Cu(NHC)(Me) complex,24 {M[N(SiMe3)2]2} (M = Ca, Sr,
Ba),25 or stoichiometric NaH,26 which makes the protocol
cumbersome. Herein we report the successful cascade reactions
from alkynols and imines directly to afford the isoquinolin-
1(2H)-ones in DMSO and dihydroisobenzofuran derivatives in
THF with t-BuOK as the single catalyst (Scheme 1b).
Moreover, the transition metal-free, three-component reactions
of alkynols, aldehydes and amines were also successfully
achieved to give isoquinolin-1(2H)-ones (Scheme 1c). The
easy availability of alkynol starting materials makes this
approach much more efficient and practical than the protocol
via the previously reported functionalization of exo-cyclic enol
ethers.
INTRODUCTION
■
Direct transformations of alkynols have attracted extensive
interest as methods for highly efficient synthesis of complex
compounds, including bioactive compounds and natural
products.1 These reactions usually require transition metal
catalysts,2 such as tungsten,3 gold,4 platinum,5 palladium,6 and
copper.7 The reactions often involve cascade processes that
start with intermolecular hydroalkoxylation of alkynes and
continue via prins-type cyclization,2c,g Diels−Alder reaction,4a−c
Povarov reaction,5a or other transformations.2d−f,3a,b,4d−f,5c−g
Very few transition metal-free cascade reactions of alkynols
have been reported.8
Isoquinolin-1(2H)-one derivatives show strong antihyper-
tensive activity9 and antitumor activity via different mecha-
nisms.10 In fact, isoquinolin-1(2H)-ones are the frequently used
scaffolds for pharmaceutical drugs and natural products.11 In
recent years, diverse synthetic approaches to construct
isoquinolin-1(2H)-one frameworks have been exploited,12−16
while they are achieved usually by the cycloaddition reaction of
benzamides and alkynes using transition metal catalysts such as
Ni,13 Cu,14 Rh,15 and Ru.16 Thus, there remains a need for
conceptually novel and versatile methodologies for the
synthesis of isoquinolin-1(2H)-one from readily available
building blocks with selective control of the substitution
patterns.
Received: March 18, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Scheme 1. Synthesis of Isoquinolin-1(2H)-ones and Dihydroisobenzofuran Derivatives
a
Table 1. Reactions of Alkynol 1a and Imine 2a under Various Conditions
b
b
entry
temp (°C)
time (h)
solvent
yield (3a, %)
yield (4a, %)
1
2
3
4
5
6
7
8
9
80
80
80
80
80
80
80
60
rt
4
4
t-BuOH
dioxane
toluene
CH3CN
NMP
0
0
0
0
4
trace
trace
trace
44
trace
trace
trace
15
4
4
4
DMF
4
DMSO
DMSO
DMSO
DMSO
THF
63
28
6
76
trace
trace
trace
74
6
89
c
10
rt
6
45
11
80
80
110
rt
4
24
d
12
4
THF
trace
trace
29
89
d
13
4
THF
92
d
14
24
THF
17
a
b
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), t-BuOK (0.04 mmol), solvent (1.0 mL), unless otherwise noted. Determined by 1H NMR
c
d
integration using PhSiMe3 as the internal standard. t-BuOK (0.02 mmol) was used. t-BuOK (0.24 mmol) was used.
8 and 9). Decreasing the catalyst loading of t-BuOK to 10 mol
% remarkably reduced the yield of 3a (entry 10).
RESULTS AND DISCUSSION
■
We began designing the new cascade processes by reacting
alkynol 1a and imine 2a in the presence of t-BuOK (20 mol %)
at 80 °C (oil bath temperature). As shown in Table 1, when t-
BuOH, 1,4-dioxane, toluene, acetonitrile, or NMP were used as
solvents, no desired products were obtained after 4 h (entries
1−5). When polar aprotic DMF was used as the solvent, the
cascade reaction of 1a and 2a gave 3-(4-methoxyphenyl)-2-
phenylisoquinolin-1(2H)-one (3a) in 44% yield, together with
the dihydroisobenzofuran product 4a in 15% yield (entry 6).
Changing the solvent to DMSO increased the yield of 3a to
63%, while also giving 4a in 28% yield (entry 7). Decreasing the
reaction temperature to 60 °C or room temperature
substantially enhanced the yield of product 3a to 76% or
89%, respectively, while formation of 4a was inhibited (entries
Changing the reaction solvent from DMSO to THF led to
the dihydroisobenzofuran product 4a in 74% yield and
dramatically decreased the yield of 3a to 24% (entry 11).
The fact that changing solvent generated different products
from the same starting material illustrates the solvent
dependence of the cascade reaction pathway. Further
optimization of the reaction conditions by increasing the
temperature and catalyst dosage of t-BuOK led to 92% yield
after 4 h (entries 12 and 13). In contrast, performing the
reaction at room temperature in THF gave only 17% yield even
after 24 h (entry 14).
To explore the scope of the cascade reactions, a wide range
of imines were reacted with various alkynols in DMSO at room
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a
Table 2. Reactions of Alkynols (1) and Imines (2) To Afford Isoquinolin-1(2H)-ones (3) in the Presence of t-BuOK
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), t-BuOK (0.04 mmol), DMSO (1.0 mL), room temperature, 6 h, unless otherwise noted.
b
Isolated yields are shown. THF was used as solvent at 80 °C for 6 h.
Scheme 2. Synthesis of the Natural Product 8-Oxypseudopalmatine (6)
temperature with t-BuOK (20 mol %) as the catalyst. As shown
in Table 2, N-phenylmethanimines substituted with benzene
rings bearing electron-donating functional groups such as OMe,
SMe, Me, piperidinyl, or morpholinyl reacted with 1a to afford
the products 3a−3g in 73−91% isolated yields. These results
indicate that electron-donating groups on the benzene ring do
not inhibit the reaction. It is noteworthy that when N-
phenylmethanimine was substituted with simple phenyl, 4-
bromophenyl, or a pyridyl group or naphthyl group, the
corresponding imines reacted with 1a only in THF to give the
products 3h−3k in 78−83% yields. In contrast, when the 1-
phenylmethanimine was substituted on the N atom with
aromatic groups (4-Me-Ph, 4-MeO-Ph, 3,5-Me2-Ph) or
aliphatic groups (Me, n-propyl, cyclohexyl), the corresponding
imines reacted smoothly with 1a in DMSO to give products
3l−3q in 80−93% yields.
Next the substrate scope with respect to alkynols was
examined. Alkynols with various aryl substituents, such as 4-F-
Ph, 4-Cl-Ph, 4-Me-Ph, and 5-MeO-Ph, participated in the
cascade reactions to give 3r−3u in 76−92% yields. In contrast,
alkynols with a dimethoxyl or similar −OCHH2O- substituent
generated 3v and 3w only in low yields of 62% or 63%,
respectively. Alkynols carrying methyl or phenyl substitutions
on the benzylic carbon reacted with imine 2a to yield 3x in 66%
yield and 3y in 63% yield. Interestingly, reacting 1a with a cyclic
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a
Table 3. Reactions of Alkynols (1) and Imines (2) To Afford Dihydroisobenzofuran Derivatives (4) in the Presence of t-BuOK
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), t-BuOK (0.24 mmol), THF (1.0 mL), 110 °C, 4 h. Isolated yields are shown.
imine produced the product 3z in 52% yield, which represents
the skeleton of protoberberine alkaloids.27
ogous analogues of 3-arylideneisobenzofuran-1(3H)-one com-
pounds in the Z-configuration.17 As shown in Table 3, various
imines with electron-donating substituents on the benzene ring
such as OMe, NMe2, pyrrolidinyl, piperidinyl, or morpholinyl
reacted efficiently with alkynol 1a to give the corresponding
products 4a−4f in up to 95% yield.
In order to demonstrate the synthetic usefulness of our
cascade reaction, we applied it to the synthesis of the alkaloid 8-
oxypseudopalmatine. Previous methods to synthesize this
compound, which is found naturally in Stephama suberosa
Forman (Menispermaceae),28,29 require complicated starting
materials29b,e and lengthy sequences with low overall yields.29d
To use our approach, we first transformed the commercially
available bromide 5 into alkynol 1b in 94% yield, which was
then reacted with the commercially available imine 2b in
DMSO with 20% mol t-BuOK as the catalyst. The alkaloid 8-
oxypseudopalmatine 6 was obtained in 30% isolated yield
(Scheme 2). In this way, our approach allowed the total
synthesis of the natural product 8-oxypseudopalmatine in a
two-step procedure and 28% total yield from commercial
reagents, demonstrating the great potential of this cascade
reaction for constructing complex compounds including natural
products.
We also tested the ability of a range of alkynols to react with
N,N-dimethyl-4-((phenylimino)methyl)aniline 2c. Alkynols
carrying 2-OMe, 2-Cl, 3-Cl, 4-Me, 4-OMe, 4-Cl, or naphthyl
at the R2 position afforded 4g−4m in 84−92% yield. Alkynols
carrying 4-Me, 4-Cl, or 5-OMe at the R1 position reacted with
imine 2c to give 4n−4p in 85−92% yields. Alkynols with a
cyclic −OCHH2O− substituent or pyridyl moiety smoothly
reacted with 2c to produce 4q in 72% yield and 4r in 78% yield,
respectively. Finally, we applied the cascade reaction to the
natural product derivatization: an alkynol derived from
cholesterol reacted with imine 2c in THF in the presence of
t-BuOK, affording the desired product 4s in 80% yield.
The multicomponent reaction (MCR) is a one-pot reaction
with three or more starting materials to form a product, in
which all or most of the atoms contribute to the newly
constructed product.30 Multicomponent reactions offer the
unique opportunity of building up complex molecules with
To explore the cascade reactions further, we reacted a variety
of alkynols with various imines in THF at 110 °C (in sealed
tubes) in the presence of 1.2 equiv of t-BuOK. A cascade
cyclization/addition/elimination occurred to give the vinyl-
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Table 4. Optimization of Multicomponent Cascade Reaction of Alkynol 1a, Aldehyde 7a, and Amine 8a under Various
a
Conditions
b
entry
base
solvent
additive
temp (°C)
yied (3a′, %)
1
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KHMDS
KOH
DMSO
DMF
toluene
CH2Cl2
THF

rt
rt
31
c
2

84 (81)
3

rt
0
4

rt
0
5

rt
0
6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF

rt
40
10
75
74
68
44
30
35
7

rt
8
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK

60
80
0
9

10
12
13
14

DCC
4 Å MS
18-Crown-6
rt
rt
rt
a
Reaction conditions: 1a (0.2 mmol), 7a (0.24 mmol), 8a (0.24 mmol), t-BuOK (0.24 mmol), solvent (1.0 mL), unless otherwise noted.
Determined by H NMR integration using PhSiMe3 as the internal standard. Isolated yield is shown.
b
c
1
exceptional high synthetic efficiency and diversity with high
stereoselectivity, from simple and easily available materials.
Upon our interest in the development of multicomponent
reactions, we explored the possibility of synthesizing
isoquinolin-1(2H)-one derivatives in a one-pot reaction from
alkynols, aldehydes, and amines.
and 3k were obtained in 79% and 73% yields, respectively.
Likewise, the reactions of alkynol 1a with methyl- or methoxy-
substituted amines and benzaldehydes proceeded smoothly to
generate the corresponding products 3l, 3m, 3a′, 3c′, and 3d′
in 72−85% yields.
Subsequently, a variety of alkynols substituted with various
substituents such as F, Cl, Me, MeO at position R1 were
examined in the reactions with aldehyde 7a and aniline, giving
the isoquinolin-1(2H)-ones product 3r−t and 3u in 67−75%
yields. Interestingly, the steric hindered secondary alcohol with
Me, Ph at position R2 were applied to the reactions with
aldehyde 7a and aniline, the products 3x and 3y were obtained
in 58% and 51% yields, respectively.
On the basis of the reaction mechanism described for the
cascade reaction of exo-cyclic enol ether and imine catalyzed by
t-BuOK,17 we proposed the mechanism for the reactions of
alkynols and imines as depicted in Scheme 3. First,
deprotonation of alkynol by t-BuOK generates the benzyloxide
anion A, which may undergo the nucleophilic attack on the
alkynyl moiety to form the alkene anion B. After the protolysis,
the exo-cyclic enol ether product C is formed, and this
intermediate has been detected in the reactions. Then the
deprotonated exo-cyclic enol ether D can be added to imine 2
to produce E and F. When the solvent is THF, proton H1 of
intermediate F can be selectively deprotonated to undergo the
elimination to produce the product 4. When the solvent is
DMSO, H2 of F can be deprotonated to undergo the
intramolecular sp3 C−O bond cleavage, leading to I after the
proton exchange. After the intramolecular nucleophilic addition
and C−C cleavage, the isoquinolin-1(2H)-one product 3 can
be generated with Ar1−CH3 as the byproduct.
Considered one equivalent of H2O was generated to
decompose one equivalent of t-BuOK in the MCR process,
1.2 equiv t-BuOK was used to initiate our studies for the
reaction of alkynol 1a, aldehyde 7a, and aniline 8a in DMSO at
room temperature. As shown in Table 4, the reaction led to the
formation of the desired product isoquinolin-1(2H)-one 3a′ in
31% yield (entry 1). This result encouraged us to explore the
reaction conditions further. When the DMSO was changed to
DMF, the yield of 3a′ drastically increased to 84% (entry 2).
However, toluene, THF, and CH2Cl2 were inefficient for the
reaction (entries 3−5). When the base t-BuOK was replaced by
KHMDS or KOH, the results led to the decreased 40% or 10%
yields of 3a′ (entries 6 and 7). The increase of reaction
temperature was negative to the one-pot reaction (entries 8−
10). With DCC, 4 Å MS was added to the reaction mixture, and
worse results were observed (entries 12−13). Finally, the
additive 18-Crown-6 also showed a negative effect to the
reaction, forming product 3a′ (entry 14).
On the basis of the optimal conditions for the multi-
component reaction to form isoquinolin-1(2H)-ones 3, the
scope of this MCR was surveyed by probing the alkynols, the
aldehydes, and the amines substrates (Table 5). A wide range of
aldehydes substituted with various electron-donating substitu-
ents such as MeO, MeS, piperidinyl, or morpholinyl benzene
ring were applicable to the reaction, giving the isoquinolin-
1(2H)-ones product in 63−79% yields (3a, 3b, 3d and 3e).
Multisubstituted aldehydes were also tolerated to generate
corresponding products 3f and 3b′ in 68% and 69% yields,
respectively. When benzaldehyde or 2-naphthaldehyde under-
went the process with alkynol 1a and aniline, the products 3h
CONCLUSION
■
In summary, for the first time, we have developed the transition
metal-free cascade reactions to convert alkynols and imines into
derivatives of isoquinolin-1(2H)-one or dihydroisobenzofuran
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Table 5. Reactions of Alkynols (1), Aldehydes (7) and Amines (8) To Afford Isoquinolin-1(2H)-ones (3) in the Presence of t-
a
BuOK
a
Reaction conditions: 1 (0.25 mmol), 7 (0.30 mmol), 8 (0.30 mmol), t-BuOK (0.30 mmol), DMF (1.5 mL), room temperature, 8 h, unless
otherwise noted. Isolated yields are shown.
Typical Procedure for the Cascade Reactions of Alkynols (1)
and Imines (2) To Afford Isoquinolin-1(2H)-ones (3). To a
mixture of alkynols (0.20 mmol) and imines (0.24 mmol) in DMSO
(1.0 mL) at room temperature was added t-BuOK (0.04 mmol, 1 M in
THF) via a syringe. The reaction mixture was stirred under nitrogen
atmosphere, and the progress was monitored using TLC detection.
After 6 h, the reaction mixture was diluted with saturated aq NH4Cl (3
mL) and extracted with EtOAc (3 × 5 mL). The combined organic
phase was washed with saturated brine (15 mL) and dried over
anhydrous Na2SO4. After filtration and evaporation of the solvent in
vacuum, the crude product was purified by column chromatography
on silica gel to afford the isoquinolin-1(2H)-one 3. The products 3s−z
are new compounds, and the other products are known compounds.17
(The syntheses of isoquinolin-1(2H)-ones 3a−z were carried out
using this procedure unless otherwise indicated.)
using t-BuOK as the catalyst. The type of product depends on
the solvent used: DMSO or THF, which demonstrated the
solvent effect in the cascade process. On the basis of the
cascade reaction, we accomplished the synthesis of alkaloid 8-
oxypseudopalmatine in a two-step procedure, suggesting the
usefulness of this method for constructing complex compounds
including natural products. Additionally, the multicomponent
reactions of alkynols, aldehydes, and amines were successfully
achieved to afford the isoquinolin-1(2H)-ones. The cascade
processes provide highly concise and effective protocols to the
related complex compounds including the natural products.
EXPERIMENTAL SECTION
■
All manipulations were carried out under nitrogen atmosphere using
standard Schlenk techniques, unless otherwise stated. Solvents DMSO
and DMF were dried by the 4 Å molecular sieves and degassed with
the nitrogen bubbling. THF was distilled under nitrogen from sodium
benzophenone. Potassium tert-butoxide (1 M in THF) used in the
catalytic reactions was purchased from a commercial source. The
alkynols23,31 and imines32 were prepared according to the reported
literature methods. Other chemicals were obtained from commercial
3-(4-Methoxyphenyl)-2-phenylisoquinolin-1(2H)-one (3a). Col-
umn chromatography (eluent = petroleum ether/ethyl acetate 5:1 v/
v) on silica gel gave a white solid (58 mg, 88% yield). Mp: 187−189
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.45 (d, J = 8.00 Hz, 1H),
7.66−7.70 (m, 1H), 7.55 (d, J = 7.80 Hz, 1H), 7.48−7.56 (m, 1H)
7.27−7.30 (m, 2H), 7.19−7.21 (m, 1H), 7.12 (d, J = 7.24 Hz, 2H),
7.07 (d, J = 8.72 Hz, 2H), 6.68 (d, J = 8.72 Hz, 2H), 6.57 (s, 1H), 3.74
(s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.3, 159.3, 143.5,
139.3, 137.0, 132.8, 130.6, 129.5, 128.4, 127.7, 126.8, 126.0, 125.4,
1
sources, and were used without further purification. H NMR spectra
were recorded using TMS as internal standard. Chemical shifts in
13C{1H} NMR spectra were internally referenced to CHCl3 (δ = 77.1
ppm).
+
113.3, 107.8, 55.3; HRMS (ESI, TOF) calcd for C22H18NO2 [M +
H]+: 328.1332, found: 328.1333.
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Scheme 3. Proposed Mechanism of the Cascade Reactions of Alkynols and Imines
3-(4-(Methylthio)phenyl)-2-phenylisoquinolin-1(2H)-one (3b).
Column chromatography (eluent = petroleum ether/ethyl acetate
10:1 v/v) on silica gel gave a white solid (50 mg, 73% yield). Mp:
155−157 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.45 (d, J = 8.04
Hz, 1H), 7.67−7.70 (m, 1H), 7.56 (d, J = 7.84 Hz, 1H), 7.49−7.53
(m, 1H), 7.27−7.31 (m, 2H), 7.22−7.24 (m, 1H), 7.12 (d, J = 7.84
Hz, 2H), 7.07 (d, J = 8.32 Hz, 2H), 7.02 (d, J = 8.44 Hz, 2H), 6.58 (s,
1H), 2.42 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 162.2,
142.2, 138.1, 138.0, 135.8, 131.9, 131.8, 128.6, 128.4, 127.8, 127.4,
126.8, 126.0, 125.1, 124.4, 124.3, 107.0, 14.3; HRMS (ESI, TOF) calcd
for C22H18NOS+ [M + H]+: 344.1104, found: 344.1107.
2-Phenyl-3-(p-tolyl)isoquinolin-1(2H)-one (3c). Column chroma-
tography (eluent = petroleum ether/ethyl acetate 10:1 v/v) on silica
gel gave a white solid (55 mg, 89% yield). Mp: 189−190 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): δ 8.45 (d, J = 8.08 Hz, 1H), 7.66−7.70 (m,
1H), 7.55 (d, J = 7.84 Hz, 1H), 7.48−7.52 (m, 1H), 7.26−7.30 (m,
2H), 7.19−7.21 (m, 1H), 7.13 (d, J = 7.08 Hz, 2H), 7.04 (d, J = 8.12
Hz, 2H), 6.97 (d, J = 8.00 Hz, 2H), 6.58 (s, 1H), 2.26 (s, 3H); 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ 163.3, 143.8, 139.3, 138.0, 137.0,
133.5, 132.9, 129.5, 129.2, 128.7, 128.6, 128.5, 127.7, 126.9, 126.1,
125.4, 107.9, 21.3; HRMS (ESI, TOF) calcd for C22H18NO+ [M +
H]+: 312.1383, found: 312.1390.
2:1 v/v) on silica gel gave a white solid (67 mg, 88% yield). Mp: 282−
284 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.44 (d, J = 8.08 Hz,
1H), 7.65−7.69 (m, 1H), 7.54 (d, J = 7.84 Hz, 1H), 7.47−7.51 (m,
1H), 7.27−7.31 (m, 2H), 7.20−7.24 (m, 1H), 7.14 (d, J = 7.04 Hz,
2H), 7.05 (d, J = 8.80 Hz, 2H), 6.67 (d, J = 8.84 Hz, 2H), 6.56 (s, 1H),
3.82 (t, J = 4.88 Hz, 4H), 3.11 (t, J = 4.84 Hz, 4H); 13C NMR (100.6
MHz, CDCl3, 25 °C): δ 163.4, 150.6, 143.7, 139.4, 137.1, 132.8, 130.3,
129.5, 128.8, 128.4, 127.7, 127.5, 126.8, 126.0, 125.3, 114.3, 107.7,
+
66.8, 48.6; HRMS (ESI, TOF) calcd for C25H23N2O2 [M + H]+:
383.1754, found: 383.1760.
3-(3,4-Dimethoxyphenyl)-2-phenylisoquinolin-1(2H)-one (3f).
Column chromatography (eluent = petroleum ether/ethyl acetate
3:1 v/v) on silica gel gave a white solid (65 mg, 91% yield). Mp: 182−
184 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.45 (d, J = 8.04 Hz,
1H), 7.67−7.71 (m, 1H), 7.56 (d, J = 7.76 Hz, 1H), 7.48−7.52 (m,
1H), 7.27−7.32 (m, 2H), 7.20−7.24 (m, 1H), 7.15 (d, J = 7.12 Hz,
2H), 6.85−6.87 (m, 1H), 6.71 (d, J = 8.32 Hz, 1H), 6.62 (s, 1H), 6.51
(d, J = 2.00 Hz, 1H), 3.83 (s, 3H), 3.62 (s, 3H); 13C NMR (100.6
MHz, CDCl3, 25 °C): δ 163.3, 148.9, 148.1, 143.4, 139.4, 136.9, 132.9,
129.5, 128.9, 128.8, 128.4, 127.8, 126.9, 126.0, 125.4, 122.1, 112.7,
110.4, 107.8, 55.9, 55.8; HRMS (ESI, TOF) calcd for C23H20NO3+ [M
+ H]+: 358.1438, found: 358.1445.
2-Phenyl-3-(4-(piperidin-1-yl)phenyl)isoquinolin-1(2H)-one (3d).
Column chromatography (eluent = petroleum ether/ethyl acetate
3:1 v/v) on silica gel gave a white solid (58 mg, 76% yield). Mp: 181−
183 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.44 (d, J = 8.04 Hz,
1H), 7.64−7.68 (m, 1H), 7.54 (d, J = 7.76 Hz, 1H), 7.45−7.49 (m,
1H), 7.26−7.30 (m, 2H), 7.19−7.23 (m, 1H), 7.13 (d, J = 7.08 Hz,
2H), 7.00 (d, J = 8.84 Hz, 2H), 6.68 (d, J = 8.84 Hz, 2H), 6.57 (s, 1H),
3.12 (t, J = 5.64 Hz, 4H), 1.62−1.68 (m, 4H), 1.54−1.58 (m, 2H); 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ 163.5, 151.4, 144.0, 139.5, 137.2,
132.8, 130.2, 129.5, 128.7, 128.4, 127.6, 126.6, 126.3, 126.0, 125.2,
114.9, 107.5, 49.8, 25.7, 24.3; HRMS (ESI, TOF) calcd for
C26H25N2O+ [M + H]+: 381.1961, found: 381.1961.
2-Phenyl-3-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one (3g).
Column chromatography (eluent = petroleum ether/ethyl acetate
2:1 v/v) on silica gel gave a foamed white solid (63 mg, 81% yield). 1H
NMR (400 MHz, CDCl3, 25 °C): δ 8.46 (d, J = 8.04 Hz, 1H), 7.68−
7.72 (m, 1H), 7.58 (d, J = 7.76 Hz, 1H), 7.50−7.54 (m, 1H), 7.29−
7.33 (m, 2H), 7.22−7.26 (m, 1H), 7.16 (d, J = 7.12 Hz, 2H), 6.65 (s,
1H), 6.36 (s, 2H), 3.78 (s, 3H), 3.68 (s, 6H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 162.2, 151.6, 142.4, 138.4, 136.9, 135.8, 132.0, 130.5,
128.3, 127.8, 127.5, 126.8, 126.1, 125.1, 124.5, 106.8, 106.0, 60.0, 55.2;
+
HRMS (ESI, TOF) calcd for C24H22NO4 [M + H]+: 388.1543,
found: 388.1544.
2,3-Diphenylisoquinolin-1(2H)-one (3h). The compound was
prepared from (2-(phenylethynyl)phenyl)methanol (41.6 mg, 0.20
mmol) and N-benzylidene aniline (43.5 mg, 0.24 mmol) in the
3-(4-Morpholinophenyl)-2-phenylisoquinolin-1(2H)-one (3e).
Column chromatography (eluent = petroleum ether/ethyl acetate
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presence of t-BuOK (0.04 mmol) in THF at 80 °C for 4 h. The
product 3h was obtained as a white solid (46 mg, 78% yield) after
column chromatography (eluent = petroleum ether/ethyl acetate 10:1
128.4, 128.1, 128.0, 127.0, 126.1, 125.5, 114.0, 107.8, 55.4; HRMS
+
(ESI, TOF) calcd for C22H18NO2 [M + H]+: 328.1332, found:
328.1336.
1
v/v). Mp: 177−179 °C; H NMR (400 MHz, CDCl3, 25 °C): δ 8.47
2-(3,5-Dimethylphenyl)-3-phenylisoquinolin-1(2H)-one (3n). Col-
umn chromatography (eluent = petroleum ether/ethyl acetate 10:1 v/
v) on silica gel gave a white solid (52 mg, 80% yield). Mp: 138−140
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.46 (d, J = 8.04 Hz, 1H),
7.66−7.70 (m, 1H), 7.55 (d, J = 7.80 Hz, 1H), 7.49−7.53 (m, 1H),
7.16−7.20 (m, 5H), 6.81 (s, 1H), 6.73 (s, 2H), 6.58 (s, 1H), 2.19 (s,
6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.3, 143.9, 138.8,
138.3, 136.9, 136.4, 132.8, 129.5, 129.3, 128.5, 128.1, 127.8, 127.1,
126.9, 126.1, 125.5, 107.8, 21.2; HRMS (ESI, TOF) calcd for
C23H20NO+ [M + H]+: 326.1539, found: 326.1545.
(d, J = 8.08 Hz, 1H), 7.68−7.72 (m, 1H), 7.57 (d, J = 7.80 Hz, 1H),
7.50−7.54 (m, 1H), 7.25−7.29 (m, 2H), 7.11−7.22 (m, 8H), 6.61 (s,
1H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.2, 143.6, 139.1,
136.8, 136.3, 132.9, 129.5, 129.4, 128.7, 128.4, 128.1, 127.9, 127.8,
127.0, 126.1, 125.5, 108.0; HRMS (ESI, TOF) calcd for C21H16NO+
[M + H]+: 298.1226, found: 298.1232.
3-(4-Bromophenyl)-2-phenylisoquinolin-1(2H)-one (3i). The com-
pound was prepared from (2-(phenylethynyl)phenyl)methanol (41.6
mg, 0.20 mmol) and N-(4-bromobenzylidene)aniline (62.4 mg, 0.24
mmol) in the presence of t-BuOK (0.04 mmol) in THF at 80 °C for 4
h. The product 3i was obtained as a white solid (60 mg, 80% yield)
after column chromatography (eluent = petroleum ether/ethyl acetate
2-Methyl-3-phenylisoquinolin-1(2H)-one (3o). Column chroma-
tography (eluent = petroleum ether/ethyl acetate 10:1 v/v) on silica
1
gel gave a white solid (44 mg, 93% yield). Mp: 58−60 °C; H NMR
1
10:1 v/v). Mp: 190−192 °C; H NMR (400 MHz, CDCl3, 25 °C): δ
(400 MHz, CDCl3, 25 °C): δ 8.46 (d, J = 7.72 Hz, 1H), 7.62−7.66 (m,
1H), 7.51 (s, 1H), 7.47−7.49 (m, 4H), 7.40−7.42 (m, 2H), 6.46 (s,
1H), 3.43 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.5,
144.0, 136.5, 136.3, 132.4, 129.1, 128.9, 128.8, 128.0, 126.7, 126.0,
125.0, 107.6, 34.3; HRMS (ESI, TOF) calcd for C16H14NO+ [M +
H]+: 236.1070, found: 236.1056.
8.46 (d, J = 8.04 Hz, 1H), 7.68−7.72 (m, 1H), 7.56 (d, J = 7.84 Hz,
1H), 7.51−7.53 (m, 1H), 7.28−7.32 (m, 4H), 7.22−7.24 (m, 1H),
7.11 (d, J = 7.08 Hz, 2H), 7.04 (d, J = 8.52 Hz, 2H), 6.58 (s, 1H); 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ 163.1, 142.4, 138.9, 136.6, 135.2,
133.0, 131.2, 130.9, 129.4,129.0, 128.5, 128.0, 127.3, 126.2, 125.6,
122.5, 108.2; HRMS (ESI, TOF) calcd for C21H15BrNO+ [M + H]+:
376.0332, found: 376.0338.
3-Phenyl-2-propylisoquinolin-1(2H)-one (3p). Column chroma-
tography (eluent = petroleum ether/ethyl acetate 10:1 v/v) on silica
1
2-Phenyl-3-(pyridin-4-yl)isoquinolin-1(2H)-one (3j). The com-
pound was prepared from (2-(phenylethynyl)phenyl)methanol (41.6
mg, 0.20 mmol) and N-(pyridin-4-ylmethylene)aniline (43.7 mg, 0.24
mmol) in the presence of t-BuOK (0.04 mmol) in THF at 80 °C for 4
h. The product 3j was obtained as a white solid (50 mg, 83% yield)
after column chromatography (eluent = petroleum ether/ethyl acetate
gel gave a pale-yellow oil (47 mg, 90% yield). H NMR (400 MHz,
CDCl3, 25 °C): δ 8.45 (d, J = 7.56 Hz, 1H), 7.61−7.65 (m, 1H),
7.45−7.50 (m, 5H), 7.39−7.43 (m, 2H), 6.40 (s, 1H), 3.90 (t, J = 7.76
Hz, 2H), 1.55−1.64 (m, 2H), 0.73 (t, J = 7.44 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 162.9, 143.8, 136.4, 132.3, 129.1,
128.9, 128.5, 128.0, 126.6, 125.8, 125.3, 107.8, 47.2, 22.2, 11.3; HRMS
(ESI, TOF) calcd for C18H18NO+ [M + H]+: 264.1383, found:
264.1383.
2-Cyclohexyl-3-phenylisoquinolin-1(2H)-one (3q). Column chro-
matography (eluent = petroleum ether/ethyl acetate 25:1 v/v) on
silica gel gave a white solid (48 mg, 80% yield). Mp: 120−122 °C; 1H
NMR (400 MHz, CDCl3, 25 °C): δ 8.41 (d, J = 7.92 Hz, 1H), 7.59−
7.63 (m, 1H), 7.43−7.47 (m, 5H), 7.36−7.39 (m, 2H), 6.35 (s, 1H),
3.69−3.77 (m, 1H), 2.76−2.86 (m, 2H), 1.74 (d, J = 13.32 Hz, 2H),
1.65 (d, J = 14.68 Hz, 2H), 1.51 (d, J = 13.16 Hz, 1H), 1.18−1.28 (m,
1H), 0.89−0.99 (m, 2H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
163.5, 144.7, 137.4, 136.2, 132.2, 128.9, 128.6, 128.5, 127.8, 126.8,
126.6, 125.6, 108.2, 62.0, 28.9, 26.4, 25.2; HRMS (ESI, TOF) calcd for
C21H22NO+ [M + H]+: 304.1696, found: 304.1699.
6-Fluoro-3-(4-methoxyphenyl)-2-phenylisoquinolin-1(2H)-one
(3r). Column chromatography (eluent = petroleum ether/ethyl acetate
5:1 v/v) on silica gel gave a white solid (64 mg, 92% yield). Mp: 207−
209 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.09 (dd, J1 = 2.72 Hz,
J2 = 9.28 Hz, 1H), 7.54−7.57 (m, 1H), 7.39−7.44 (m, 1H), 7.26−7.29
(m, 2H), 7.20−7.24 (m, 1H), 7.11 (d, J = 7.16 Hz, 2H), 7.06 (d, J =
8.80 Hz, 2H), 6.68 (d, J = 8.76 Hz, 2H), 6.56 (s, 1H), 3.74 (s, 3H);
13C NMR (100.6 MHz, CDCl3, 25 °C): δ 162.5 (d, JC−F = 3.64 Hz),
1
10:1 v/v). Mp: 201−203 °C; H NMR (400 MHz, CDCl3, 25 °C): δ
8.48 (d, J = 8.04 Hz, 1H), 8.44 (d, J = 6.08 Hz, 2H), 7.71−7.75 (m,
1H), 7.55−7.61 (m, 2H), 7.29−7.33 (m, 2H), 7.24−7.27 (m, 1H),
7.14 (d, J = 7.00 Hz, 2H), 7.08 (d, J = 6.08 Hz, 2H), 6.64 (s, 1H); 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ 162.9, 149.6, 143.9, 140.9, 138.5,
136.3, 133.1, 129.3, 129.0, 128.5, 128.3, 127.8, 126.5, 125.8, 123.6,
108.8; HRMS (ESI, TOF) calcd for C20H15N2O+ [M + H]+: 299.1179,
found: 299.1189.
3-(Naphthalen-2-yl)-2-phenylisoquinolin-1(2H)-one (3k). The
compound was prepared from (2-(phenylethynyl)phenyl)methanol
(41.6 mg, 0.20 mmol) and N-(naphthalen-2-ylmethylene)aniline (55.5
mg, 0.24 mmol) in the presence of t-BuOK (0.04 mmol) in THF at 80
°C for 4 h. The product 3k was obtained as a white solid (57 mg, 82%
yield) after column chromatography (eluent = petroleum ether/ethyl
acetate 10:1 v/v). Mp: 196−198 °C; 1H NMR (400 MHz, CDCl3, 25
°C): δ 8.49 (d, J = Hz, 1H), 7.69−7.80 (m, 4H), 7.59 (d, J = 7.76 Hz,
1H), 7.51−7.56 (m, 2H), 7.44−7.49 (m, 2H), 7.12−7.25 (m, 6H),
6.71 (s, 1H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.2, 143.6,
139.1, 136.9, 133.9, 132.9, 132.8, 132.5, 129.5, 128.8, 128.6, 128.5,
128.1, 127.8, 127.7, 127.3, 127.1, 126.8, 126.6, 126.5, 126.2, 125.5,
108.5; HRMS (ESI, TOF) calcd for C25H18NO+ [M + H]+: 348.1383,
found: 348.1383.
3-Phenyl-2-(p-tolyl)isoquinolin-1(2H)-one (3l). Column chroma-
tography (eluent = petroleum ether/ethyl acetate 10:1 v/v) on silica
gel gave a white solid (54 mg, 87% yield). Mp: 158−160 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): δ 8.46 (d, J = 8.04 Hz, 1H), 7.66−7.70 (m,
1H), 7.55 (d, J = 7.76 Hz, 1H), 7.48−7.50 (m, 1H), 7.16−7.19 (m,
5H), 7.06 (d, J = 8.20 Hz, 2H), 6.99 (d, J = 8.04 Hz, 2H), 6.58 (s, 1H),
2.27 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.3, 143.8,
137.5, 136.8, 136.5, 136.4, 132.8, 129.4, 129.3, 129.1, 128.4, 128.0,
127.9, 126.9, 126.1, 125.5, 107.9, 21.2; HRMS (ESI, TOF) calcd for
C22H18NO+ [M + H]+: 312.1383, found: 312.1389.
161.6 (d, JC−F = 247.01 Hz), 159.4, 142.9 (d, JC−F = 2.40 Hz), 139.1,
133.6 (d, JC−F = 2.13 Hz), 130.7, 129.4, 128.8, 128.4 (d, JC−F = 21.90
Hz), 128.4, 127.9, 127.0 (d, JC−F =8.01 Hz), 121.7 (d, JC−F = 23.75
Hz), 113.6, 113.4, 107.1, 55.3; HRMS (ESI, TOF) calcd for
+
C22H17FNO2 [M + H]+: 346.1238, found: 346.1245.
6-Chloro-3-(4-methoxyphenyl)-2-phenylisoquinolin-1(2H)-one
(3s). Column chromatography (eluent = petroleum ether/ethyl acetate
5:1 v/v) on silica gel gave a white solid (55 mg, 76% yield). Mp: 218−
220 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.41 (d, J = 2.16 Hz,
1H), 7.62 (dd, J1 = 8.44 Hz, J2 = 2.20 Hz, 1H), 7.49 (d, J = 8.44 Hz,
1H), 7.27−7.31 (m, 2H), 7.21−7.24 (m, 1H), 7.10 (d, J = 7.20 Hz,
2H), 7.06 (d, J = 8.76 Hz, 2H), 6.68 (d, J = 8.80 Hz, 2H), 6.54 (s, 1H),
3.74 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 162.3, 159.4,
143.9, 139.0, 135.4, 133.3, 132.7, 130.6, 129.4, 128.9, 128.4, 127.9,
127.6, 126.5, 113.4, 107.1, 55.3; HRMS (EI, TOF) calcd for
C22H16ClNO2 [M]+: 361.0870, found: 361.0869.
2-(4-Methoxyphenyl)-3-phenylisoquinolin-1(2H)-one (3m). Col-
umn chromatography (eluent = petroleum ether/ethyl acetate 5:1 v/v)
on silica gel gave a white solid (60 mg, 92% yield). Mp: 174−176 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ 8.46 (d, J = 8.00 Hz, 1H),
7.66−7.70 (m, 1H), 7.55 (d, J = 7.84 Hz, 1H), 7.48−7.52 (m, 1H),
7.16−7.20 (m, 5H), 7.02 (d, J = 8.80 Hz, 2H), 6.70 (d, J = 8.76 Hz,
2H), 6.58 (s, 1H), 3.74 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25
°C): δ 163.5, 158.7, 144.0, 136.8, 136.4, 132.8, 131.9, 130.3, 129.4,
3-(4-Methoxyphenyl)-6-methyl-2-phenylisoquinolin-1(2H)-one
(3t). Column chromatography (eluent = petroleum ether/ethyl acetate
5:1 v/v) on silica gel gave a white solid (60 mg, 88% yield). Mp: 238−
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240 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.24 (s, 1H), 7.50 (dd,
J1 = 8.24 Hz, J2 = 1.72 Hz, 1H), 7.46 (d, J = 8.04 Hz, 1H), 7.26−7.30
(m, 2H), 7.19−7.22 (m, 1H), 7.11 (d, J = 7.16 Hz, 2H), 7.06 (d, J =
8.76 Hz, 2H), 6.68 (d, J = 8.76 Hz, 2H), 6,54 (s, 1H), 3.74 (s, 3H),
2.51 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 163.3, 159.2,
142.6, 139.5, 137.0, 134.7, 134.4, 130.7, 129.6, 129.0, 128.8, 128.0,
127.7, 126.0, 125.3, 113.3, 107.7, 55.3, 21.7; HRMS (EI, TOF) calcd
for C23H19NO2 [M]+: 341.1416, found: 341.1415.
7-Methoxy-3-(4-methoxyphenyl)-2-phenylisoquinolin-1(2H)-one
(3u). Column chromatography (eluent = petroleum ether/ethyl
acetate 5:1 v/v) on silica gel gave a white solid (59 mg, 83% yield).
Mp: 180−182 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.36 (d, J =
8.88 Hz, 1H), 7.25−7.29 (m, 2H), 7.18−7.22 (m, 1H), 7.11 (d, J =
7.20 Hz, 2H), 7.06−7.08 (m, 3H), 6.91 (d, J = 2.40 Hz, 1H), 6.68 (d, J
= 8.72 Hz, 2H), 6.49 (s, 1H), 3.93 (s, 3H), 3.74 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 163.3, 163.0, 159.3, 144.2, 139.4,
139.1, 130.6, 129.6, 128.9, 128.7, 127.6, 119.2, 116.3, 113.3, 107.6,
106.9, 55.7. 55.3; HRMS (EI, TOF) calcd for C23H19NO3 [M]+:
357.1365, found: 357.1369.
7-(4-Methoxyphenyl)-6-phenyl-[1,3]dioxolo[4,5-g]isoquinolin-
5(6H)-one (3v). Column chromatography (eluent = petroleum ether/
ethyl acetate 5:1 v/v) on silica gel gave a white solid (46 mg, 62%
yield). Mp: 228−230 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.79
(s, 1H), 7.26−7.29 (m, 2H), 7.18−7.22 (m, 1H), 7.11 (d, J = 7.48 Hz,
2H), 7.05 (d, J = 8.72 Hz, 2H), 6.89 (s, 1H), 6.67 (d, J = 8.76 Hz, 2H),
6.45 (s, 1H), 6.10 (s, 2H), 3.74 (s, 3H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 162.5, 159.2, 152.4, 147.9, 142.3, 139.4, 134.3, 130.7,
129.5, 128.8, 127.7, 120.8, 113.3, 107.7, 106.3, 103.9, 101.8, 55.3;
HRMS (EI, TOF) calcd for C23H17NO4 [M]+: 371.1158, found:
371.1160.
°C): δ 162.3, 137.5, 136.7, 135.6, 132.4, 130.4, 129.4, 128.1, 127.6,
126.7, 126.4, 125.2, 125.1, 103.0, 39.8, 28.7; HRMS (ESI, TOF) calcd
for C17H14NO+ [M + H]+: 248.1070, found: 248.1069.
(4,5-Dimethoxy-2-(phenylethynyl)phenyl)methanol (1b). To a
mixture of the (2-bromo-4,5-dimethoxyphenyl)methanol (494.2 mg,
2.0 mmol) in DMF (10 mL) at room temperature were added
PdCl2(PPh3)2 (7.1 mg, 0.01 mmol) and CuI (1.9 mg, 0.01 mmol)
under nitrogen. After the reaction mixture was stirred for 5 min, N,N-
diisopropylamine (815.2 g, 8.0 mmol) was added via a syringe. The
reaction mixture was then heated to 70 °C. A solution of the
phenylacetylene (1.5 equiv) in DMF (5 mL) was added dropwise over
10 min, the mixture was allowed to stir at 70 °C for several hours, and
the progress was monitored using TLC detection. After 2 h, the
reaction mixture was washed with saturated aq NH4Cl and brine and
then extracted with EtOAc (3 × 25 mL). The combined organic
extract was washed with saturated brine (50 mL) and dried over
anhydrous MgSO4. After filtration and evaporation of the solvent in
vacuum, the crude product was purified by column chromatography
(eluent = petroleum ether/ethyl acetate 5:1 v/v) on silica gel to give
1b as a white solid (504 mg, 94% yield). Mp: 104−106 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): δ 7.51−7.53 (m, 2H), 7.34−7.37 (m, 3H),
7.02 (d, J = 8.32 Hz, 2H), 4.86 (d, J = 6.40 Hz, 2H), 3.93 (s, 3H), 3.91
(s, 3H), 2.06 (t, J = 6.12 Hz, 1H); 13C NMR (100.6 MHz, CDCl3, 25
°C): δ 149.7, 148.1, 136.3, 131.5, 128.5, 128.4, 123.2, 114.5, 113.2,
110.7, 92.8, 87.0, 63.8, 56.2, 56.0; HRMS (EI, TOF) calcd for
C17H16O3 [M]+: 268.1099, found: 268.1100.
2,3,10,11-Tetramethoxy-5H-isoquinolino[3,2-a]isoquinolin-
8(6H)-one (6). The compound was prepared from (4,5-dimethoxy-2-
(phenylethynyl)phenyl)methanol (1b, 134.2 mg, 0.50 mmol) and 6,7-
dimethoxy-3,4-dihydroisoquinoline (2b, 114.7 mg, 0.60 mmol) in the
presence of t-BuOK (0.10 mmol) in DMSO at room temperature for
48 h. The product 6 was obtained as a white solid (55 mg 30% yield)
after column chromatography (eluent = petroleum ether/ethyl acetate
6,7-Dimethoxy-3-(4-methoxyphenyl)-2-phenylisoquinolin-1(2H)-
one (3w). Column chromatography (eluent = petroleum ether/ethyl
acetate 5:1 v/v) on silica gel gave a white solid (46 mg, 60% yield).
1
1
Mp: 188−190 °C; H NMR (400 MHz, CDCl3, 25 °C): δ 7.83 (s,
1:2 v/v). Mp: 178−180 °C; H NMR (400 MHz, CDCl3, 25 °C): δ
1H), 7.26−7.30 (m, 2H), 7.19−7.23 (m, 1H), 7.12 (d, J = 7.08 Hz,
2H), 7.06 (d, J = 8.76 Hz, 2H), 6.91 (s, 1H), 6.69 (d, J = 8.76 Hz, 2H),
6.50 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.74 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 162.7, 159.2, 154.0, 149.4, 142.2,
139.5, 132.5, 130.7, 129.6, 129.0, 128.7, 127.6, 119.2, 113.3, 108.3,
107.4, 106.1, 56.3, 55.3; HRMS (ESI, TOF) calcd for C24H22NO4+ [M
+ H]+: 388.1543, found: 388.1541.
7.81 (s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 6.75 (s, 1H),
4.37 (t, J = 6.12 Hz, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.99 (s, 3H), 3.95
(s, 3H), 2.95 (t, J = 6.12 Hz, 2H); 13C NMR (100.6 MHz, CDCl3, 25
°C): δ 161.6, 153.6, 150.2, 149.1, 148.5, 136.3, 132.3, 128.5, 122.6,
118.7, 110.6, 107.9, 107.7, 106.0, 101.3, 56.4, 56.3, 56.2, 39.9, 28.2;
HRMS (EI, TOF) calcd for C21H21NO5 [M]+: 367.1420, found:
367.1418.
3-(4-Methoxyphenyl)-4-methyl-2-phenylisoquinolin-1(2H)-one
(3x). Column chromatography (eluent = petroleum ether/ethyl
acetate 10:1 v/v) on silica gel gave a white solid (45 mg, 66%
yield). Mp: 239−241 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.54
(d, J = 7.96 Hz, 1H), 7.76 (d, J = 3.56 Hz, 2H), 7.53−7.57 (m, 1H),
7.20−7.24 (m, 2H), 7.12−7.16 (m, 1H), 7.02 (d, J = 7.20 Hz, 2H),
6.96 (d, J = 8.68 Hz, 2H), 6.70 (d, J = 8.68 Hz, 2H), 3.73 (s, 3H), 2.11
(s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 162.8, 158.9, 140.1,
140.0, 137.8, 132.8, 131.9, 129.6, 128.7, 127.8, 127.6, 126.8, 125.9,
123.5, 113.3, 110.9, 55.2, 15.1; HRMS (EI, TOF) calcd for C23H19NO2
[M]+: 341.1416, found: 341.1418.
Typical Procedure for the Reactions of Alkynols (1) and
Imines (2) To Afford Dihydroisobenzofuran Derivatives (4). To
a mixture of alkynols (0.20 mmol) and imines (0.24 mmol) in THF
(1.0 mL) at room temperature was added t-BuOK (0.24 mmol, 1 M in
THF) via a syringe. The reaction mixture was then heated to 110 °C
in a sealed tube under nitrogen atmosphere and stirred for 4 h. After
the mixture cooled to ambient temperature, it was diluted with
saturated aq NH4Cl (3 mL) and extracted with EtOAc (3 × 5 mL).
The combined organic phase was washed with saturated brine (15
mL) and dried over anhydrous Na2SO4. After filtration and
evaporation of the solvent in vacuum, the crude product was purified
by column chromatography on silica gel to afford the dihydroiso-
benzofuran derivatives 4. The products 4j and 4m−4s are new
compounds and the other products are known compounds.17 (The
syntheisis of dihydroisobenzofuran derivatives 4a−4s were carried out
using this procedure unless otherwise indicated.)
3-(4-Methoxyphenyl)-2,4-diphenylisoquinolin-1(2H)-one (3y).
Column chromatography (eluent = petroleum ether/ethyl acetate
5:1 v/v) on silica gel gave a white solid (51 mg, 63% yield). Mp: 213−
215 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.56 (d, J = 7.84 Hz,
1H), 7.57−7.60 (m, 1H), 7.50−7.54 (m, 1H), 7.20−7.26 (m, 5H),
7.12−7.18 (m, 4H), 7.10 (d, J = 7.40 Hz, 2H), 6.78 (d, J = 8.64 Hz,
2H), 6.42 (d, J = 8.64 Hz, 2H), 3.60 (s, 3H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 162.9, 158.3, 141.0, 139.7, 137.8, 136.7, 132.6, 132.4,
131.7, 129.6, 128.8, 128.4, 128.1, 127.6, 127.3, 126.9, 125.7, 125.6,
(1Z,3Z)-1-Benzylidene-3-(4-methoxybenzylidene)-1,3-
dihydroisobenzofuran(4a). Column chromatography (eluent =
petroleum ether/ethyl acetate 50:1 v/v) on silica gel gave a yellow
1
solid (55 mg, 85% yield). Mp: 115−117 °C; H NMR (400 MHz,
+
119.2, 112.7, 55.0; HRMS (ESI, TOF) calcd for C28H22NO2 [M +
CDCl3, 25 °C): δ 7.90 (d, J = 7.40 Hz, 2H), 7.86 (d, J = 8.84 Hz, 2H),
7.61−7.66 (m, 2H), 7.39−7.45 (m, 4H), 7.23−7.27 (m, 1H), 6.97 (d, J
= 8.84 Hz, 2H), 6.17 (s, 1H), 6.15 (s, 1H), 3.87 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 158.5, 152.0, 150.5, 135.3, 134.1,
133.6, 129.9, 129.3, 128.9, 128.7, 128.4, 127.9, 126.5, 120.0, 119.7,
114.2, 99.6, 99.2, 55.5; HRMS (ESI, TOF) calcd for C23H19O2+ [M +
H]+: 327.1380, found: 327.1389.
H]+: 404.1645, found: 404.1649.
5H-Isoquinolino[3,2-a]isoquinolin-8(6H)-one (3z). Column chro-
matography (eluent = petroleum ether/ethyl acetate 5:1 v/v) on silica
1
gel gave a white solid (26 mg, 52%). Mp: 80−82 °C; H NMR (400
MHz, CDCl3, 25 °C): δ 8.45 (d, J = 8.08 Hz, 1H), 7.83−7.85 (m, 1H),
7.62−7.66 (m, 1H), 7.58 (d, J = 7.56 Hz, 1H), 7.45−7.49 (m, 1H),
7.36−7.38 (m, 2H), 7.27−7.29 (m, 1H), 7.04 (s, 1H), 4.39 (t, J = 6.12
Hz, 2H), 3.03 (t, J = 6.16 Hz, 2H); 13C NMR (100.6 MHz, CDCl3, 25
4-((Z)-((Z)-3-Benzylidene-isobenzofuran-1(3H)-ylidene)methyl)-
N,N-dimethylaniline (4b). Column chromatography (eluent =
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1
petroleum ether/ethyl acetate 40:1 v/v) on silica gel gave a yellow
solid (64 mg, 95% yield). Mp: 145−147 °C; H NMR (400 MHz,
solid (62 mg, 87% yield) Mp: 162−164 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 7.82 (d, J = 8.56 Hz, 4H), 7.59−7.63 (m, 2H),
7.35−7.38 (m, 2H), 7.25 (d, J = 8.60 Hz, 2H), 6.80 (d, J = 8.92 Hz,
2H), 6.13 (s, 1H), 6.12 (s, 1H), 3.04 (s, 6H), 2.40 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 151.7, 149.4, 149.3, 136.0, 134.4,
133.5, 132.7, 129.7, 129.4, 129.0, 128.4, 128.3, 123.6, 119.8, 119.4,
112.6, 100.2, 98.6, 40.7, 21.5; HRMS (ESI, TOF) calcd for
C25H24NO+ [M + H]+: 354.1852, found: 354.1855.
1
CDCl3, 25 °C): δ 7.92 (d, J = 7.32 Hz, 2H), 7.82 (d, J = 8.88 Hz, 2H),
7.60−7.64 (m, 2H) 7.36−7.45 (m, 4H), 7.222−7.25 (m, 1H), 6.79 (d,
J = 8.92 Hz, 2H), 6.14 (s, 2H), 3.03 (s, 6H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 152.3, 149.3, 135.6, 134.4, 133.3, 129.8, 129.2, 128.6,
128.4, 126.2, 123.5, 119.9, 119.4, 112.5, 100.5, 98.5, 40.6; HRMS (ESI,
TOF) calcd for C24H22NO+ [M + H]+: 340.1696, found: 340.1705.
1-(4-((Z)-((Z)-3-Benzylidene-isobenzofuran-1(3H)-ylidene)-
methyl)phenyl)pyrrolidine (4c). Column chromatography (eluent =
petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a yellow
4-((Z)-((Z)-3-(4-Methoxybenzylidene)isobenzofuran-1(3H)-
ylidene)methyl)-N,N-dimethylaniline (4i). Column chromatography
(eluent = petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a
1
1
solid (69 mg, 94% yield). Mp: 193−195 °C; H NMR (400 MHz,
yellow solid (63 mg, 85% yield). Mp: 156−158 °C; H NMR (400
CDCl3, 25 °C): δ 7.93 (d, J = 7.36 Hz, 2H), 7.82 (d, J = 8.76 Hz, 2H),
7.59−7.64 (m, 2H), 7.33−7.45 (m, 4H), 7.21−7.26 (m, 1H), 6.63 (d, J
= 8.84 Hz, 2H), 6.14 (s, 1H), 6.13 (s, 1H), 3.37 (t, J = 6.52 Hz, 4H),
2.04 (t, J = 6.52 Hz, 4H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
152.4, 148.8, 146.8, 135.6, 134.6, 133.2, 129.9, 129.1, 128.6, 128.3,
128.2, 126.1, 122.4, 119.9, 119.3, 111.8, 100.9, 98.3, 47.7, 25.6; HRMS
(ESI, TOF) calcd for C26H24NO+ [M + H]+: 366.1852, found:
366.1860.
MHz, CDCl3, 25 °C): δ 7.87 (d, J = 8.80 Hz, 2H), 7.81 (d, J = 8.88
Hz, 2H), 7.59−7.62 (m, 2H), 7.35−7.37 (m, 2H), 6.98 (d, J = 8.84
Hz, 2H), 6.80 (d, J = 8.64 Hz, 2H), 6.12 (s, 1H), 6.10 (s, 1H), 3.88 (s,
3H), 3.03 (s, 6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 158.1,
150.9, 149.5, 149.2, 134.2, 133.6, 129.6, 128.8, 128.4, 123.7, 119.6,
119.4, 114.1, 112.6, 99.9, 98.3, 55.5, 40.7; HRMS (ESI, TOF) calcd for
+
C25H24NO2 [M + H]+: 370.1802, found: 370.1810.
4-((Z)-((Z)-3-(4-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)-
methyl)-N,N-dimethylaniline (4j). Column chromatography (eluent =
petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a pale-yellow
1-(4-((Z)-((Z)-3-Benzylidene-isobenzofuran-1(3H)-ylidene)-
methyl)phenyl)piperidine (4d). Column chromatography (eluent =
petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a yellow
1
solid (66 mg, 88% yield). Mp: 170−172 °C; H NMR (400 MHz,
1
solid (68 mg, 90% yield). Mp: 141−143 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 7.84 (d, J = 8.60 Hz, 2H), 7.78 (d, J = 8.88 Hz, 2H),
7.60−7.63 (m, 2H), 7.35−7.42 (m, 4H), 6.79 (d, J = 8.92 Hz, 2H),
6.16 (s, 1H), 6.08 (s, 1H), 3.04 (s, 6H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 152.7, 149.4, 149.2, 134.5, 134.2, 133.1, 131.4, 129.8,
129.4, 128.7, 128.4, 123.3, 119.9, 119.4, 112.6, 100.9, 97.3, 40.6;
HRMS (EI, TOF) calcd for C24H20ClNO [M]+: 373.1233, found:
373.1230.
CDCl3, 25 °C): δ 7.91 (d, J = 7.32 Hz, 2H), 7.82 (d, J = 8.84 Hz, 2H),
7.60−7.65 (m, 2H), 7.37−7.45 (m, 4H), 7.22−7.26 (m, 1H), 6.98 (d, J
= 8.88 Hz, 2H), 6.15 (s, 1H), 6.14 (s, 1H), 3.25 (t, J = 5.60 Hz, 4H),
1.71- 1.77 (m, 4H), 1.59−1.64 (m, 2H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 152.2, 150.7, 149.9, 135.4, 134.3, 133.5, 129.6, 129.2,
128.6, 128.4, 126.3, 125.7, 119.9, 119.5, 116.1, 100.2, 98.8, 50.3, 25.9,
24.5; HRMS (ESI, TOF) calcd for C27H26NO+ [M + H]+: 380.2009,
found: 380.2017.
4-((Z)-((Z)-3-(2-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)-
methyl)-N,N-dimethylaniline (4k). Column chromatography (eluent
= petroleum ether/ethyl acetate 40:1 v/v) on silica gel gave a yellow
4-(4-((Z)-((Z)-3-Benzylidene-isobenzofuran-1(3H)-ylidene)-
methyl)phenyl)morpholine (4e). Column chromatography (eluent =
petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a yellow
1
solid (64 mg, 85% yield). Mp: 152−154 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 8.55 (dd, J1= 7.96 Hz, J2 = 1.12 Hz, 1H), 7.78 (d, J =
8.80 Hz, 2H), 7.72 (d, J = 7.04 Hz, 1H), 7.61 (d, J = 7.16 Hz, 1H),
7.37−7.44 (m, 4H), 7.14−7.18 (m, 1H), 6.76 (d, J = 8.84 Hz, 2H),
6.55 (s, 1H), 6.16 (s, 1H), 3.02 (s, 6H); 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 153.6, 149.4, 149.0, 134.6, 133.4, 133.2, 132.4, 129.8,
129.7, 129.6, 128.5, 127.1, 126.8, 123.2, 120.4, 119.4, 112.5, 101.2,
94.0, 40.6; HRMS (ESI, TOF) calcd for C24H21ClNO+ [M + H]+:
374.1306, found: 374.1306.
1
solid (67 mg, 88% yield). Mp: 192−194 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 7.91 (d, J = 7.52 Hz, 2H), 7.85 (d, J = 8.80 Hz, 2H),
7.61−7.66 (m, 2H), 7.39−7.45 (m, 4H), 7.23−7.26 (m, 1H), 6.97 (d, J
= 8.84 Hz, 2H), 6.17 (s, 1H), 6.14 (s, 1H), 3.90 (t, J = 4.80 Hz, 4H),
3.24 (t, J = 7.76 Hz, 4H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
152.1, 150.3, 149.8, 135.4, 134.2, 133.6, 129.6, 129.2, 128.8, 128.6,
128.4, 126.8, 126.4, 120.0, 119.6, 115.5, 99.8, 99.1, 67.0, 49.1; HRMS
+
(ESI, TOF) calcd for C26H24NO2 [M + H]+: 382.1802, found:
4-((Z)-((Z)-3-(2-Methoxybenzylidene)isobenzofuran-1(3H)-
ylidene)methyl)-N,N-dimethylaniline (4l). Column chromatography
(eluent = petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a
382.1803.
(1Z,3Z)-1-Benzylidene-3-(3,4-dimethoxybenzylidene)-1,3-dihy-
droisobenzofuran (4f). Column chromatography (eluent = petroleum
ether/ethyl acetate 15:1 v/v) on silica gel gave a yellow solid (48 mg,
68% yield). Mp: 152−154 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ
7.89 (d, J = 7.32 Hz, 2H), 7.62−7.67 (m, 3H), 7.35−7.43 (m, 4H),
7.29−7.31 (m, 1H), 7.21−7.25 (m, 1H), 6.92 (d, J = 8.36 Hz, 1H),
6.18 (s, 1H), 6.16 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 152.1, 150.5, 149.1, 148.2, 135.3,
134.1, 133.7, 129.3, 129.0, 128.6, 128.4, 128.2, 126.6, 121.9, 119.9,
119.6, 111.3, 111.2, 100.0, 99.3, 56.3, 56.0; HRMS (ESI, TOF) calcd
1
yellow solid (64 mg, 87% yield). Mp: 182−184 °C; H NMR (400
MHz, CDCl3, 25 °C): δ 8.50 (dd, J1 = 7.72 Hz, J2 = 1.48 Hz, 1H), 7.81
(d, J = 8.84 Hz, 2H), 7.69−7.71 (m, 1H), 7.58−7.60 (m, 1H), 7.35−
7.38 (m, 2H), 7.21−7.23 (m, 1H), 7.10−7.13 (m, 1H), 6.93 (d, J =
8.08 Hz, 1H), 6.78 (d, J = 8.88 Hz, 2H), 6.59 (s, 1H), 6.12 (s, 1H),
3.92 (s, 3H), 3.02 (s, 6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
156.3, 152.4, 149.4, 149.3, 134.4, 133.8, 129.7, 129.2, 129.0, 128.3,
127.3, 124.6, 123.7, 120.9, 120.2, 119.3, 112.6, 110.6, 100.2, 92.2, 55.8,
40.6; HRMS (ESI, TOF) calcd for C25H24NO2+ [M + H]+: 370.1802,
found: 370.1775.
+
for C24H21O3 [M + H]+: 357.1485, found: 357.1495.
N,N-Dimethyl-4-((Z)-((Z)-3-(naphthalen-2-ylmethylene)-
isobenzofuran-1(3H)-ylidene)methyl)aniline (4g). Column chroma-
tography (eluent = petroleum ether/ethyl acetate 50:1 v/v) on silica
gel gave a yellow solid (72 mg, 92% yield). Mp: 159−161 °C; H
4-((Z)-((Z)-3-(3-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)-
methyl)-N,N-dimethylaniline (4m). Column chromatography (eluent
= petroleum ether/ethyl acetate 50:1 v/v) on silica gel gave a yellow
solid (63 mg, 84% yield). Mp: 119−121 °C; H NMR (400 MHz,
1
1
NMR (400 MHz, CDCl3, 25 °C): δ 8.55 (s, 1H),7.90−7.94 (m, 4H),
7.82−7.87 (m, 2H), 7.67−7.69 (m, 1H), 7.62−7.64 (m, 1H), 7.38−
7.50 (m, 4H), 6.86 (d, J = 8.84 Hz, 2H), 6.29 (s, 1H), 6.19 (s, 1H),
3.06 (s, 6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 151.7, 148.4,
148.3, 133.4, 133.0, 132.3, 132.1, 131.2, 128.8, 128.2, 127.4, 127.1,
126.9, 126.7, 126.2, 125.7, 125.1, 124.5, 122.5, 118.9, 118.4, 111.5,
99.7, 97.6, 39.6; HRMS (ESI, TOF) calcd for C28H24NO+ [M + H]+:
390.1852, found: 390.1861.
CDCl3, 25 °C): δ 8.22 (t, J = 1.68 Hz, 1H), 7.82 (d, J = 8.88 Hz, 2H),
7.63 (dd, J1 = 7.28 Hz, J2 = 4.48 Hz, 2H), 7.52 (d, J = 7.76 Hz, 1H),
7.35−7.43 (m, 2H), 7.29−7.33 (m, 1H), 7.20 (dd, J1= 7.96 Hz, J2 =
1.00 Hz, 1H), 6.84 (d, J = 8.80 Hz, 2H), 6.19 (s, 1H), 6.08 (s, 1H),
3.03 (s, 6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 153.3, 149.5,
149.0, 137.4, 134.6, 134.5, 132.9, 129.8, 129.6, 129.5, 128.4, 127.8,
126.5, 126.0, 123.1, 120.0 119.4, 112.7, 101.3, 97.1, 40.6; HRMS (EI,
TOF) calcd for C24H20ClNO [M]+: 373.1233, found: 373.1229.
4-((Z)-((Z)-3-Benzylidene-5-chloroisobenzofuran-1(3H)-ylidene)-
methyl)-N,N-dimethylaniline (4n). Column chromatography (eluent
= petroleum ether/ethyl acetate 50:1 v/v) on silica gel gave a yellow
N,N-Dimethyl-4-((Z)-((Z)-3-(4-methylbenzylidene)isobenzofuran-
1(3H)-ylidene)methyl)aniline (4h). Column chromatography (eluent
= petroleum ether/ethyl acetate 30:1 v/v) on silica gel gave a yellow
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1
solid (67 mg, 90% yield). Mp: 166−168 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 7.90 (d, J = 7.48 Hz, 2H), 7.79 (d, J = 8.88 Hz, 2H),
7.60 (d, J = 1.48 Hz, 1H), 7.51 (d, J = 8.32 Hz, 1H), 7.42−7.46 (m,
2H), 7.34 (dd, J1 = 8.32 Hz, J2 = 1.72 Hz, 1H), 7.24−7.27 (m, 1H),
6.78 (d, J = 8.88 Hz, 2H), 6.11 (s, 2H), 3.03 (s, 6H); 13C NMR (100.6
MHz, CDCl3, 25 °C): δ 151.1, 149.4, 148.4, 135.1, 134.9, 134.2, 132.9,
129.8, 129.5, 128.7, 128.5, 126.6, 123.1, 120.5, 119.9, 112. 5, 101.1,
99.6, 40.6; HRMS (EI, TOF) calcd for C24H20ClNO [M]+: 373.1233,
found: 373,1234.
24.4, 24.0, 23.0, 22.7, 20.9, 19.2, 18.9, 12.0; HRMS (EI, TOF) calcd
for C51H65NO2 [M]+: 723.5015, found: 723.4990.
Multicomponent Cascade Reactions of Alkynols (1),
Aldehydes (7) and Amines (8) To Afford Isoquinolin-1(2H)-
ones (3). To a mixture of alkynols (0.25 mmol), aldehydes (0.30
mmol), and amines (0.30 mmol) in DMF (1.5 mL) at room
temperature was added t-BuOK (0.30 mmol, 1 M in THF) via a
syringe. The reaction mixture was stirred under nitrogen atmosphere,
and the progress was monitored using TLC detection. After 8 h, the
reaction mixture was diluted with saturated aq NH4Cl (3 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic phase was
washed with saturated brine (15 mL) and dried over anhydrous
Na2SO4. After filtration and evaporation of the solvent in vacuum, the
crude product was purified by column chromatography on silica gel to
afford the isoquinolin-1(2H)-one 3. The products 3a′−3d′ are new
compounds, and the other products are known compounds.17 (The
synthesis of isoquinolin-1(2H)-ones 3a, 3b, 3d−3f, 3h, 3k−3m, 3r−-
3u, 3x, 3y and 3a′−3d′ were also carried out using this procedure
unless otherwise indicated.)
4-((Z)-((Z)-3-Benzylidene-5-methylisobenzofuran-1(3H)-ylidene)-
methyl)-N,N-dimethylaniline (4o). Column chromatography (eluent
= petroleum ether/ethyl acetate 50:1 v/v) on silica gel gave a yellow
1
solid (60 mg, 85% yield). Mp: 168−170 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 7.91 (d, J = 7.84 Hz, 2H), 7.81 (d, J = 8.72 Hz, 2H),
7.50 (d, J = 7.96 Hz, 1H), 7.41−7.44 (m, 3H), 7.20−7.25 (m, 2H),
6.79 (d, J = 8.64 Hz, 2H), 6.11 (s, 1H), 6.08 (s, 1H), 3.02 (s, 6H), 2.45
(s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 152.3, 149.5, 149.2,
138.6, 135.7, 133.7, 132.2, 130.6, 129.6, 128.6, 128.4, 126.1, 123.8,
120.0, 119.2, 112.7, 99.7, 98.3, 40.7, 21.8; HRMS (EI, TOF) calcd for
C25H23NO [M]+: 353.1780, found: 353.1781.
3-(4-Methoxyphenyl)-2-(p-tolyl)isoquinolin-1(2H)-one (3a′). Col-
umn chromatography (eluent = petroleum ether/ethyl acetate 10:1 v/
v) on silica gel gave a white solid (69 mg, 81% yield). Mp: 212−214
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.44 (d, J = 8.08 Hz, 1H),
7.65−7.69 (m, 1H), 7.54 (d, J = 7.76 Hz, 1H), 7.47−7.51 (m, 1H),
7.06−7.10 (m, 4H), 6.99 (d, J = 8.24 Hz, 2H), 6.70 (d, J = 8.80 Hz,
2H), 6.55 (s, 1H), 3.75 (s, 3H), 2.29 (s, 3H).13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 163.4, 159.2, 143.6, 137.4, 137.0, 136.6, 132.7, 130.6,
129.4, 129.1, 128.9, 128.4, 126.7, 126.0, 125.4, 113.3, 107.7, 55.3, 21.2;
4-((Z)-((Z)-3-Benzylidene-6-methoxyisobenzofuran-1(3H)-
ylidene)methyl)-N,N-dimethylaniline (4p). Column chromatography
(eluent = petroleum ether/ethyl acetate 25:1 v/v) on silica gel gave a
1
yellow solid (68 mg, 92% yield). Mp: 177−179 °C; H NMR (400
MHz, CDCl3, 25 °C): δ 7.88 (d, J = 7.52 Hz, 2H), 7.82 (d, J = 8.84
Hz, 2H), 7.52 (d, J = 8.52 Hz, 1H), 7.40−7.43 (m, 2H), 7.21 (t. J =
7.36 Hz, 1H), 7.02 (d, J = 2.04 Hz, 1H), 6.95 (dd, J1 = 8.52 Hz, J2 =
2.20 Hz, 1H), 6.79 (d, J = 8.88 Hz, 2H), 6.10 (s, 1H), 6.00 (s, 1H),
3.90 (s, 3H), 3.02 (s, 6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
161.1, 152.3, 149.4, 149.2, 136.1, 135.9, 129.8, 128.6, 128.1, 126.7,
125.8, 123.4, 121.2, 117.4, 112.6, 102.0, 100.5, 97.1, 55.8, 40.6; HRMS
(EI, TOF) calcd for C25H23NO2 [M]+: 369.1729, found: 369.1732.
4-((Z)-((Z)-7-Benzylidene-[1,3]dioxolo[4,5-f]isobenzofuran-5(7H)-
ylidene)methyl)-N,N-dimethylaniline (4q). Column chromatography
(eluent = petroleum ether/ethyl acetate 25:1 v/v) on silica gel gave a
+
HRMS (ESI, TOF) calcd for C23H20NO2 [M + H]+: 342.1489,
found: 342.1494.
3-(2-Bromo-4,5-dimethoxyphenyl)-2-phenylisoquinolin-1(2H)-
one (3b′). Column chromatography (eluent = petroleum ether/ethyl
acetate 5:1 v/v) on silica gel gave a white solid (75 mg, 69% yield).
Mp: 186−188 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.48 (d, J =
7.96 Hz, 1H), 7.69−7.73 (m, 1H), 7.58 (d, J = 84 Hz, 1H), 7.52−7.56
(m, 1H), 7.19−7.26 (m, 5H), 6.88 (s, 1H), 6.60 (s, 1H), 6.56 (s, 1H),
3.81 (s, 3H), 3.70 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
163.2, 149.5, 147.7, 141.7, 138.8, 136.6, 132.9, 129.2, 129.1, 128.8,
128.5, 128.3, 127.3, 126.3, 125.9, 114.8, 114.6, 114.5, 108.8, 56.2;
HRMS (EI, TOF) calcd for C23H18BrNO3 [M]+: 435.0470, found:
435.0469.
1
yellow solid (55 mg, 72% yield). Mp: 206−208 °C; H NMR (400
MHz, CDCl3, 25 °C): δ 7.87 (d, J = 7.48 Hz, 2H), 7.78 (d, J = 8.88
Hz, 2H), 7.39−7.43 (m, 2H), 7.19−7.23 (m, 1H), 6.99 (s, 1H), 6.96
(s, 1H), 6.78 (d, J = 8.88 Hz, 2H), 6.06 (s, 2H), 5.93 (s, 2H), 3.02 (s,
6H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 152.3, 149.9, 149.3,
149.2, 135.7, 129.5, 128.6, 128.2, 128.1, 125.9, 123.6, 112.6, 102.0,
99.3, 99.2, 98.9, 97.3, 40.7; HRMS (EI, TOF) calcd for C25H21NO3
[M]+: 383.1521, found: 383.1523.
2,3-Di-p-tolylisoquinolin-1(2H)-one (3c′). Column chromatogra-
phy (eluent = petroleum ether/ethyl acetate 10:1 v/v) on silica gel
1
gave a white solid (69 mg, 85% yield). Mp: 202−204 °C; H NMR
4-((Z)-((Z)-7-Benzylidenefuro[3,4-b]pyridin-5(7H)-ylidene)-
methyl)-N,N-dimethylaniline (4r). Column chromatography (eluent =
petroleum ether/ethyl acetate 10:1 v/v) on silica gel gave a yellow
(400 MHz, CDCl3, 25 °C): δ 8.44 (d, J = 8.08 Hz, 1H), 7.65−7.69 (m,
1H), 7.54 (d, J = 7.80 Hz, 1H), 7.47−7.51 (m, 1H), 7.04−7.08 (m,
4H), 6.97−7.00 (m, 4H), 6.56 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H); 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ 163.4, 143.9, 137.9, 137.4, 136.9,
136.6, 132.8, 129.4, 129.2,129.1, 128.6, 128.4, 126.8, 126.0, 125.4,
107.8, 21.3; HRMS (ESI, TOF) calcd for C23H20NO+ [M + H]+:
326.1539, found: 326.1542.
1
solid (53 mg, 78% yield). Mp: 144−146 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ 8.59 (dd, J1 = 4.72 Hz, J2 = 1.32 Hz, 1H), 7.96 (d, J
= 7.36 Hz, 2H), 7.89 (dd, J1 = 7.88 Hz, J2 = 1.32 Hz, 1H), 7.83 (d, J =
8.88 Hz, 2H), 7.43−7.47 (m, 2H), 7.27−7.30 (m, 2H), 6.80 (d, J =
8.96 Hz, 2H), 6.63 (s, 1H), 6.16 (s, 1H), 3.04 (s, 6H); 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 151.9, 150.4, 149.7, 146.7, 135.0,
130.1, 129.0, 128.7, 128.3, 127.2, 126.9, 123.5, 122.8, 112.5, 102.9,
100.3, 40.6; HRMS (EI, TOF) calcd for C23H20N2O [M]+: 340.1576,
found: 340.1577.
2,3-Bis(4-methoxyphenyl)isoquinolin-1(2H)-one (3d′). Column
chromatography (eluent = petroleum ether/ethyl acetate 5:1 v/v)
on silica gel gave a white solid (76 mg, 78% yield). Mp: 205−207 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ 8.44 (d, J = 8.00 Hz, 1H),
7.65−7.69 (m, 1H), 7.47−7.55 (m, 2H), 7.08 (d, J = 8.76 Hz, 2H),
7.02 (d, J = 8.76 Hz, 2H), 6.79 (d, J = 8.88 Hz, 2H), 6.70 (d, J = 8.88
Hz, 2H), 6.56 (s, 1H), 3.76 (s, 3H), 3.76 (s, 3H); 13C NMR (100.6
MHz, CDCl3, 25 °C): δ 163.6, 159.2, 158.6, 143.8, 137.0, 132.8, 132.0,
130.6, 130.3, 128.9, 128.4, 126.8, 126.0, 125.3, 114.0, 113.3, 107.6,
4-((Z)-((Z)-3-(4-(((3R,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-
((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-
decahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)benzylidene)-
isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethylaniline (4s). Col-
umn chromatography (eluent = petroleum ether/ethyl acetate 30:1 v/
v) on silica gel gave a yellow solid (116 mg, 80% yield). Mp: 96−98
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.79−7.84 (m, 4H), 7.58−
7.60 (m, 2H), 7.32−7.38 (m, 2H), 6.98 (d, J = 8.72 Hz, 2H), 6.80 (d, J
= 8.68 Hz, 2H), 6.11 (s, 1H), 6.09 (s, 1H), 5.32 (br, 1H), 4.60 (s, 1H),
3.03 (s, 6H), 2.56 (d, J = 14.56 Hz, 1H), 2.41 (d, J = 15.08 Hz, 1H),
1.95−2.04 (m, 3H), 1.76−1.85 (m, 2H), 0.83−1.68 (m, 33H), 0.69 (s,
3H); 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 156.4, 150.8, 149.5,
149.2, 138.8, 134.2, 133.7, 129.6, 129.5, 128.8, 128.4, 128.3, 122.4,
123.8, 119.6, 119.4, 117.1, 112.7, 99.8, 98.5, 73.3, 56.9, 56.3, 50.0, 42.5,
40.7, 39.9, 39.7, 37.1, 36.5, 36.3, 36.0, 33.3, 32.0, 29.8, 28.4, 28.2, 26.0,
+
55.4, 55.3; HRMS (ESI, TOF) calcd for C23H20NO3 [M + H]+:
358.1438, found: 358.1441.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H spectra for products 3a−3z, 3a′−3d′, 4a−4s and 6, 13C
NMR spectra for new compounds 3s−3z, 3a′−3d′, 4j, 4m−s
and 6. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Article
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AUTHOR INFORMATION
Corresponding Author
*E-mail: liupn@ecust.edu.cn
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Project Nos. 21172069, 21190033, and
21372072), the Innovation Program of Shanghai Municipal
Education Commission (Project No. 12ZZ050), the Basic
Research Program of the Shanghai Committee of Science and
Technology (Project No. 13NM1400802), NCET (NCET-13-
0798), and the Fundamental Research Funds for the Central
Universities.
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