DBU-promoted cyclization of ortho -(3-hydroxy-1-alkynyl)benzamide: Synthesis of trans -3,4-dihydroisoquinolin-1(2 H)-ones and (E)-4-(1-alkenyl) isoquinolin-1(2 H)-ones

Article abstract of DOI:10.1021/jo2022907

DBU-promoted cyclization of ortho-(3-hydroxy-1-alkynyl)benzamide is presented, providing an efficientmethod for the synthesis of trans-3,4-dihydroisoquinolin-1(2H)-ones and (E)-4-(1-alkenyl)isoquinolin-1(2H)- ones under mild conditions.

Full text of DOI:10.1021/jo2022907

Note
pubs.acs.org/joc
DBU-Promoted Cyclization of ortho-(3-Hydroxy-1-alkynyl)benzamide:
Synthesis of trans-3,4-Dihydroisoquinolin-1(2H)-ones and
(E)-4-(1-Alkenyl)isoquinolin-1(2H)-ones
Wanli Chen,*,† Jing Cui,† Yinghong Zhu,‡ Xianchao Hu,† and Weimin Mo*,†
†Center of Analysis & Measurement, Zhejiang University of Technology, Hangzhou, 310014, P. R. China
‡College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou, 310014, P. R. China
S
* Supporting Information
ABSTRACT: DBU-promoted cyclization of ortho-(3-hydroxy-1-alkynyl)benzamide is presented, providing an efficient
method for the synthesis of trans-3,4-dihydroisoquinolin-1(2H)-ones and (E)-4-(1-alkenyl)isoquinolin-1(2H)-ones under mild
conditions.
ihydroisoquinolin-1(2H)-ones are an important class of
Scheme 1
D
heterocycles due to their applications as bioactive
compounds and synthetic intermediates in organic synthesis.1−9
However, there are only a few approaches about their synthesis.
The main known approach of dihydroisoquinolin-1(2H)-one
derivatives was the condensation of homophthalic anhydride
with imines and involves the acid- or base-catalyzed or thermal
conditions that often produce a cis-isomer or a mixture of cis- and
trans-isomers, favoring the cis-isomer.10−17 Afterward, BF3·Et2O,18
trimethyl orthoformate,19 and TiCl420 have been employed for the
preparation of thermodynamically more stable trans-isomers using
homophthalic anhydride reacted with imines. Recently, Murakami
has reported a nickel-catalyzed denitrogenative annulation
reactions of 2,3-benzotriazin-4(3H)-ones with 1,3-dienes and
alkenes to give dihydroisoquinolin-1(2H)-ones.21 Although these
methods are effective for the synthesis of some dihydroisoquinolin-
1(2H)-one derivatives, development of new and efficient method-
ologies for the stereoselective synthesis of dihydroisoquinolin-
1(2H)-one derivatives with different substituent groups from
simple, readily available starting materials remains an important
research theme in organic chemistry.
synthon of α,β-unsaturated ketones through propargyl
alcohol−enone isomerization. We envision that this kind of
aryl propargyl alcohol might be used as an efficient structure
unit in the construction of dihydroisoquinolin-1(2H)-ones
(Figure 1). This new subsequent intramolecular cyclization
Figure 1. Synthetic strategy.
Combining two or more reactions into one sequential reaction,
which usually involves a series of inter- or intramolecular processes
wherein the product of one reaction is programmed to be the
substrate for the next, represents an elegant and efficient way to
access novel and complex molecules from simple, readily available
approach may yield the thermodynamically more stable anti-
dihydroisoquinolin-1(2H)-ones with different substituent
groups.
As a first attempt, we chose 2-(3-hydroxy-3-phenyl-1-propynyl)-
N-(2-oxo-2-phenylethyl)-N-phenyl-benzamide (1a) as the starting
material, which could be easily prepared via a Sonogashira reaction
starting materials.22−27 Recently, Muller et al. have reported a Pd-
̈
catalyzed coupling and base-induced propargyl alcohol−enone
isomerization providing an efficient synthesis of α,β-unsaturated
ketones28,29 (Scheme 1), which could be further transformed to
some interesting heterocycles in a one-pot fashion.30−34
with 2-iodo-N-(2-oxo-2-phenylethyl)-N-phenylbenzamide and
1-phenyl-2-propyn-1-ol (Scheme 2).
In these reactions, the aryl propargyl alcohols with an
electron-withdrawing group were used as an efficient potential
Received: November 7, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 2
On the basis of the previous investigation, we initiated our
study by testing the reaction of 1a in the presence of various
bases and solvents (Table 1). Triethylamine could not promote
formation may be through an anti-dihydroisoquinolin-1(2H)-
one intermediate (Scheme 3).
To determine the scope of this transformation, we next
examined the reaction of 2-(3-hydroxy-1-pentynyl)-N-(2-oxo-2-
phenylethyl)-N-phenylbenzamide 1k, which has a methyl (alkyl
substituent) in alkyne unit. When using the above reaction
conditions, no reaction occurred. Then we further screened the
reaction conditions. Luckily, when we choose CH3CN as
solvent at elevated temperature (75 °C), a dihydroisoquinolin-
1(2H)-one compound 4a with an (E)-propenyl substituent was
obtained in a yield of 70%. The stereochemistry was established
a
Table 1. Base and Solvent Effect
1
on the basis of H NMR (the coupling constant for the vinyl
b
entry
base
solvent
time (h)
yield (%)
protons) and NOESY experiment (4a, Figure 2). Then we
further examined the scope of the reaction, and the results were
summarized in Table 3. Alkyl substitutes such as hydrogen,
methyl, propyl, and benzyl were all effective for this reaction,
and the corresponding dihydroisoquinolin-1(2H)-ones were
obtained in moderate yields.
1
2
3
4
5
6
7
8
Et3N
NaH
DBU
DBU
DBU
DBU
DBU
DBU
THF
48
1
0
55
85
THF
THF
16
12
44
17
17
27
c
THF
78
d
C2H5OH
CH3CN
DMF
35
70
50
75
On the basis of the above results and previous investigations,
a possible mechanism for the DBU-promoted cyclization of
ortho-(3-hydroxy-1-alkynyl)benzamide is shown in Scheme 4.
When the substrate has an aryl group (R3 = aryl), an initial base-
induced propargyl alcohol−enone isomerization provided the
intermediate A. Subsequently, the intramolecular attack at the
less sterically hindered side and capture of a hydrogen cation
afforded 2. While the substrate has an alkyl group (R3 = alkyl),
the above isomerization did not occur. At elevated temperature,
an initial base-induced 6-exo-dig afforded the intermediate B,
which could rearrange to C. Subsequent elimination a hydroxyl
and concurrence attack to the intramolecular carbonyl through
the six-membered ring transition state provided intermediate D.
Finally, leaving a benzoic acid anion36 and capture of a hydrogen
cation afforded the product 4.
Toluene
a
Substrate 1a (0.2 mmol) and base (2 equiv) in solvent (2 mL) under
b
c
atmosphere. Isolated yield based on 1a. The reaction temperature
was 60 °C. 27% of 1a was recovered.
d
the reaction. A strong base could trigger the expected reaction
and give anti-dihydroisoquinolin-1(2H)-one (3a) as the
product (entries 2−3, Table 1). The stereochemistry was
established on the coupling constant35 between protons H-3
and H-4 and was further confirmed by a NOESY experiment
(2a, Figure 2). A more competitive yield was obtained using
These trans-3,4-dihydroisoquinolin-1(2H)-ones bearing 1,5-
dicarbonyl functional groups and isoquinolin-1(2H)-ones with
an alkenyl functional group may be converted to other interesting
and useful structural units in organic synthesis.37−40 We treated 2a
with NH4OAc in CH3COOH to access 2,4,5-triphenylbenzo[c]-
[1,7]naphthyridin-6(5H)-one (5a) in moderate yield (Scheme 5).
In summary, we have developed an efficient method for
the synthesis of trans-3,4-dihydroisoquinolin-1(2H)-ones and
(E)-4-(1-alkeny)lisoquinolin-1(2H)-ones in moderate to good
yields under mild conditions. Further studies into the scope and
synthetic applications of this transformation are being carried
out in our laboratory.
Figure 2. NOE experiment of 2a, 3a, 4a, and 4i′.
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as the base (entry 3,
Table 1). Further examination of solvent choice showed that
THF was the suitable reaction medium for this reaction (entries
3−7, Table 1).
With the optimized reaction conditions in hand (Table 1,
entry 3), we further tried other aryl propargyl alcohols in the
reaction (Table 2). From the results in Table 2, we could see
that the reaction could proceed smoothly to afford anti-
dihydroisoquinolin-1(2H)-ones in moderate to good yields
under mild conditions. The reaction also exhibited an excellent
stereoselectivity. When 1j was used as the substrate, a tricycle
product 3a was obtained. NOESY experiment also demon-
strated the anti-configuration (3a, Figure 2). We think that its
EXPERIMENTAL SECTION
■
1
General Procedures. All H NMR and 13C NMR spectra were
measured in CDCl3 or DMSO-d6 and recorded on a 500 MHz (125 MHz
for 13C) spectrometer with TMS as the internal standard. Chemical
shifts are expressed in ppm and J-values are given in Hz. High-
resolution mass spectroscopy (HRMS) was carried out in electrospray
mode. Solvents were distilled before use.
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Note
Table 2. Synthesis of anti-Dihydroisoquinolin-1(2H)-ones 2
a
entry
1
R1/R2/Ar
time (h)
product
yield (%)
C6H5/C6H5/C6H5, 1a
16
11
16
16
16
16
16
16
17
2a
2b
2c
2d
2e
2f
85
78
67
75
72
67
b
2
C6H5/C6H5/p-ClC6H4, 1b
C6H5/C6H5/m-BrC6H4, 1c
p-CH3C6H4/C6H5/C6H5, 1d
p-CH3C6H4/C6H5/p-CH3C6H4, 1e
p-CH3C6H4/p-ClC6H4/p-CH3C6H4, 1f
p-ClC6H4/C6H5/p-CH3C6H4, 1g
C6H5/OEt/C6H5, 1h
3
4
5
6
7
8
9
2g
2h
80
c
79 (97:3)
c
Bu/OEt/C6H5, 1i
2i
58 (96:4)
a
b
c
1
Isolated yield based on 1. The reaction temperature was 0 °C. The ratio of trans/cis was determined by H NMR analysis
7.68 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz,
2H), 7.40 (t, J = 7.6 Hz, 2H), 7.34−7.30 (m, 4H), 7.21−7.19 (m, 1H),
7.15−7.07 (m, 5H), 5.78 (d, J = 5.0 Hz,1H), 5.33 (d, J = 17.3 Hz, 1H),
5.28 (d, J = 17.3 Hz, 1H), 4.56 (d, J = 5.9 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 194.1, 170.2, 142.6, 141.0, 139.5, 134.9, 133.9, 131.8,
128.9, 128.8, 128.5, 128.2, 128.1, 128.0, 127.8, 127.5, 127.1, 126.9,
120.5, 93.7, 84.1, 64.9, 56.4; HRMS-ESI [M + Na]+ Calcd for
C30H23NNaO3 468.1576, found 468.1585.
Scheme 3
2-[3-(4-Chlorophenyl)-3-hydroxy-1-propynyl]-N-(2-oxo-2-
phenylethyl)-N-phenylbenzamide (1b). Yellow solid (82 mg,
57%): mp 149−151 °C; H NMR (500 MHz, CDCl3) δ 7.92 (d, J =
1
Typical Procedure for Synthesis of 1. To a solution of 2-iodo-
N-phenylbenzamide (0.3 mmol) and substituted 2-propyn-1-ol
(1.2 equiv) in CH3CN (1 mL) were added CuI (2.9 mg. 0.015 mmol)
and PdCl2(PPh3)2 (10.5 mg, 0.015 mmol), and Et3N (1 mL) was then
added under a N2 atmosphere at room temperature. Then, the reaction
mixture was warmed to 80 °C and stirred until the reaction was
completed (monitored by TLC). After evaporation of reaction solvent,
saturated aqueous NH4Cl was added, extracted with ethyl acetate, and
dried over anhydrous MgSO4. After evaporation of ethyl acetate, chrom-
atography on silica gel (eluent: EtOAc/petroleum ether = 3/1) afforded 1
(for 1b, 1c, 1n, 1q, 1r, 30% catalyst was loaded and run at rt).
7.4 Hz, 2H), 7.62−7.58 (m, 3H), 7.46 (t, J = 7.7 Hz, 2H), 7.34−7.29
(m, 5H), 7.18−7.07 (m, 6H), 5.73 (d, J = 4.0 Hz, 1H), 5.36 (d, J =
17.3 Hz, 1H), 5.23 (d, J = 17.3 Hz, 1H), 4.76 (br, 1H); 13C NMR (125
MHz, CDCl3) δ 194.3, 170.1, 142.6, 139.7, 139.6, 134.9, 134.0, 133.8,
131.8, 129.0, 128.8, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.6,
127.0, 120.5, 93.2, 84.4, 64.3, 56.4; HRMS-ESI [M + Na]+ Calcd for
C30H22ClNNaO3 502.1186, found 502.1170.
2-[3-(3-Bromophenyl)-3-hydroxy-1-propynyl]-N-(2-oxo-2-
phenylethyl)-N-phenylbenzamide (1c). Yellow solid (25 mg,
1
16%): mp 74−76 °C; H NMR (500 MHz, CDCl3) δ 7.96 (d, J =
7.5 Hz, 2H), 7.87 (s, 1H), 7.61 (t, J = 6.8 Hz, 2H), 7.49−7.44 (m, 3H),
7.33−7.31 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.22−7.09 (m, 6H), 5.74 (s,
1H), 5.37 (d, J = 17.4 Hz, 1H), 5.30 (d, J = 17.4 Hz, 1H); 4.87 (br, 1H);
2-(3-Hydroxy-3-phenyl-1-propynyl)-N-(2-oxo-2-phenyleth-
yl)-N-phenylbenzamide (1a). Yellow solid (118 mg, 88%): mp
110−112 °C; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.3 Hz, 2H),
Table 3. Synthesis of Dihydroisoquinolin-1(2H)-ones 4
a
entry
R1/R2/R3
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
C6H5/C6H5/CH3, 1k
24
24
16
22
28
16
24
16
24
4a
70
p-CH3C6H4/C6H5/CH3, 1l
p-ClC6H4/C6H5/CH3, 1m
o-ClC6H4/C6H5/CH3, 1n
C6H5/C6H5/H, 1o
4b
4c
69
78
86
42
64
55
4d
4e
C6H5/C6H5/n-C3H7, 1p
p-CH3C6H4/C6H5/n-C3H7, 1q
p-ClC6H4/C6H5/n-C3H7,1r
C6H5/C6H5/CH2C6H5, 1s
4f
4g
4h
4i/4i′
66
b
50 (16:34)
a
b
Isolated yield based on 1. Determined by isolation.
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The Journal of Organic Chemistry
Note
Scheme 4
Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.45 (t, J =
7.7 Hz, 2H), 7.30−7.28 (m, 1H), 7.24−7.15 (m, 7H), 7.06 (d, J = 8.6
Hz, 2H), 5.71 (d, J = 3.6 Hz, 1H), 5.27 (d, J = 17.4 Hz, 1H), 5.20 (d,
J = 17.4 Hz, 1H), 4.40 (br, 1H), 2.34 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 194.0, 170.0, 141.1, 139.2, 138.1, 137.9, 134.8, 134.0, 133.1,
131.9, 129.4, 129.2, 129.0, 128.8, 128.7, 128.1, 128.0, 127.1, 126.8,
120.4, 94.0, 83.8, 64.7, 56.2, 21.2; HRMS-ESI [M + Na]+ Calcd for
C31H24ClNNaO3 516.1342, found 516.1322.
Scheme 5
Ethyl 2-[2-(3-Hydroxy-3-phenyl-1-propynyl)-N-
1
phenylbenzamido]acetate (1h). Yellow gum (103 mg, 83%): H
NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.6
Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.29−7.25 (m, 3H), 7.18−7.09 (m,
6H), 5.72 (s, 1H), 4.60 (d, J = 17.1 Hz, 1H), 4.54 (d, J = 17.1 Hz, 1H),
4.31 (br, 1H), 4.24−4.14 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.2, 169.5, 142.3, 141.0, 139.3, 131.7, 128.9,
128.5, 128.1, 127.8, 127.5, 127.0, 126.9, 120.4, 93.6, 83.9, 64.8, 61.7,
51.5, 14.0; HRMS-ESI [M + Na]+ Calcd for C26H23NNaO4 436.1525,
found 436.1511.
13C NMR (125 MHz, CDCl3) δ 194.3, 170.2, 143.3, 142.6, 139.6, 134.9,
134.0, 131.8, 131.1, 130.1, 130.0, 129.0, 128.8, 128.5, 128.2, 128.0, 127.9,
127.6, 127.1, 125.6, 122.5, 120.4, 93.0, 84.5, 64.2, 56.4; HRMS-ESI [M +
Na]+ Calcd for C30H22BrNNaO3 546.0681, found 546.0655.
2-(3-Hydroxy-3-phenyl-1-propynyl)-N-(2-oxo-2-phenylethyl)-
N-(p-tolyl)benzamide (1d). Yellow solid (113 mg, 82%): mp 70−72 °C;
1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 2H), 7.67 (d, J =
7.4 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.38 (t,
J = 7.4 Hz, 2H), 7.31−7.25 (m, 2H), 7.22−7.20 (m, 1H), 7.17 (d, J =
8.2 Hz, 2H), 7.12−7.09 (m, 2H), 6.89 (d, J = 8.2 Hz, 2H), 5.75 (d, J =
4.0 Hz, 1H), 5.28 (d, J = 17.3 Hz, 1H), 5.22 (d, J = 17.3 Hz, 1H), 4.70
(br, 1H), 2.16 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.2, 170.2,
141.1, 140.0, 139.7, 137.2, 135.0, 133.8, 131.7, 129.5, 128.7, 128.5,
128.3, 128.1, 128.0, 127.8, 127.7, 127.1, 126.9, 120.4, 93.6, 84.1, 64.9,
56.4, 20.9; HRMS-ESI [M + Na]+ Calcd for C31H25NNaO3 482.1732,
found 482.1720.
Ethyl 2-[N-Butyl-2-(3-hydroxy-3-phenyl-1-propynyl)-
benzamido]acetate (1i). Yellow solid (91 mg, 77%): mp 140−
1
142 °C; H NMR (500 MHz, DMSO, 80 °C) δ 7.54−7.20 (m, 9H),
5.82 (s, 1H), 5.60 (s, 1H), 4.19−3.90 (m, 4H), 3.42 (s, 1H), 1.52−
1.24 (m, 5H), 1.11−1.03 (m, 2H), 0.91−0.88 (m, 1H), 0.65 (t, J = 7.1
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 168.9, 168.5, 141.6, 138.9,
131.6, 131.4, 128.4, 128.1, 127.7, 127.1, 126.2, 126.0, 125.9, 119.0,
94.3, 81.6, 62.8, 60.3, 60.0. 49.9, 48.9, 46.5, 45.6, 29.4, 28.4, 19.2, 18.6,
13.6, 13.4, 13.0, 12.6; HRMS-ESI [M + Na]+ Calcd for C24H27NNaO4
416.1838, found 416.1818.
2-[3-Hydroxy-3-(p-tolyl)prop-1-ynyl]-N-(2-oxo-2-phenylethyl)-
N-(p-tolyl)benzamide (1e). Yellow solid (118 mg, 83%): mp 144−
1
2-(3-Hydroxy-3-phenyl-1-propynyl)-N-(2-oxopropyl)-N-
phenylbenzamide (1j). Yellow gum (92 mg, 80%): 1H NMR
(500 MHz, CDCl3) δ 7.66 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz,
2H), 7.34 (t, J = 7.3 Hz, 1H), 7.29−7.28 (m, 1H), 7.21−7.07 (m, 8H),
5.75 (s, 1H), 4.64 (d, J = 17.6 Hz, 1H), 4.60 (d, J = 17.6 Hz, 1H), 4.45
(br, 1H), 2.22 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.1, 169.9,
142.4, 141.0, 139.2, 131.8, 128.9, 128.5, 128.0, 127.8, 127.7, 127.4,
127.1, 126.8, 120.4, 93.6, 83.9, 64.8, 59.5, 27.5; HRMS-ESI [M + Na]+
Calcd for C25H21NNaO3 406.1419, found 406.1405.
146 °C; H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 7.4 Hz, 2H),
7.56−7.54 (m, 3H), 7.42 (t, J = 7.8 Hz, 2H), 7.28−7.25 (m, 1H),
7.22−7.20 (m, 1H), 7.18 (d, J = 8.1 Hz, 4H), 7.13−7.09 (m, 2H), 6.89
(d, J = 8.1 Hz, 2H), 5.72 (s, 1H), 5.29 (d, J = 17.4 Hz, 1H), 5.21 (d,
J = 17.4 Hz, 1H), 4.59 (br, 1H), 2.34 (s, 3H), 2.16 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 194.1, 170.2, 140.0, 139.7, 138.2, 137.7, 137.2,
135.0, 133.7, 131.7, 129.4, 129.1, 128.7, 128.3, 128.1, 127.7, 127.1,
126.9, 120.5, 93.8, 83.9, 64.7, 56.4, 21.1, 20.9; HRMS-ESI [M + Na]+
Calcd for C32H27NNaO3 496.1889, found 496.1875.
2-(3-Hydroxy-1-butynyl)-N-(2-oxo-2-phenylethyl)-N-phenyl-
N-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[3-hydroxy-3-(p-tolyl)-
1-propynyl]-N-(p-tolyl)benzamide (1f). Yellow solid (108 mg,
71%): mp 67−69 °C; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.5
Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.32−7.28
(m, 1H), 7.24−7.19 (m, 5H), 7.17−7.13 (m, 2H), 6.93 (d, J = 8.2 Hz,
2H), 5.72 (d, J = 5.0 Hz, 1H), 5.29 (d, J = 17.3 Hz, 1H), 5.17 (d, J =
17.3 Hz, 1H), 4.46 (br, 1H), 2.37 (s, 3H), 2.20 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 193.1, 170.2, 140.3, 139.9, 139.6, 138.1, 137.8,
137.3, 133.4, 131.8, 129.5, 129.2, 129.1, 128.4, 127.8, 127.7, 127.1,
126.9, 120.5, 93.8, 84.0, 64.8, 56.3, 21.2, 20.9; HRMS-ESI [M + Na]+
Calcd for C32H26ClNNaO3 530.1499, found 530.1473.
1
benzamide (1k). Yellow solid (101 mg, 88%): mp 150−152 °C; H
NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.4
Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.28−7.27
(m, 1H), 7.20−7.07 (m, 6H), 5.36 (s, 2H), 4.85 (q, J = 6.5 Hz, 1H),
4.27 (br, 1H), 1.60 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 194.0, 170.1, 142.6, 139.4, 134.9, 133.8, 131.6, 128.8, 128.7, 128.4,
128.1, 127.9, 127.5, 127.4, 127.1, 120.8, 95.9, 81.5, 58.6, 56.3, 23.9;
HRMS-ESI [M + H]+ Calcd for C25H22NO3 384.1600, found
384.1601.
2-(3-Hydroxy-1-butynyl)-N-(2-oxo-2-phenylethyl)-N-(p-
tolyl)benzamide (1l). Yellow solid (104 mg, 87%): mp 65−67 °C;
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 2H), 7.60
N-(4-Chlorophenyl)-2-[3-hydroxy-3-(p-tolyl)-1-propynyl]-N-
(2-oxo-2-phenylethyl)benzamide (1g). Yellow solid (107 mg,
72%): mp 69−71 °C; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.6
(t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.29−7.28 (m, 1H), 7.23
1588
dx.doi.org/10.1021/jo2022907 | J. Org. Chem. 2012, 77, 1585−1591

The Journal of Organic Chemistry
Note
(d, J = 8.3 Hz, 2H), 7.20−7.10 (m, 3H), 6.95 (d, J = 8.2 Hz, 2H), 5.34
(d, J = 17.4 Hz, 1H), 5.31 (d, J = 17.4 Hz, 1H), 4.85 (q, J = 6.5 Hz,
1H), 4.17 (br, 1H), 2.20 (s, 3H), 1.60 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 194.1, 170.3, 140.1, 139.7, 137.3, 135.0, 133.8,
131.6, 129.5, 128.8, 128.3, 128.1, 127.6, 127.5, 127.0, 120.7, 95.8, 81.6,
58.6, 56.4, 24.0, 20.9; HRMS-ESI [M + H]+ Calcd for C26H24NO3
398.1756, found 398.1741.
N-(4-Chlorophenyl)-2-(3-hydroxy-1-butynyl)-N-(2-oxo-2-
phenylethyl)benzamide (1m). Yellow solid (104 mg, 83%): mp
139−141 °C; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.5 Hz, 2H),
7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 8.7 Hz,
3H), 7.21−7.11 (m, 5H), 5.32 (s, 2H), 4.82 (q, J = 6.6 Hz, 1H), 4.14
(br, 1H), 1.58 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
193.9, 170.1, 141.2, 139.1, 134.8, 134.0, 133.2, 131.8, 129.3, 129.0,
128.8, 128.7, 128.1, 127.7, 127.0, 120.7, 96.1, 81.4, 58.6, 56.3, 23.9;
HRMS-ESI [M + H]+ Calcd for C25H21ClNO3 418.1210, found
418.1202.
N-(2-Chlorophenyl)-2-(3-hydroxy-1-butynyl)-N-(2-oxo-2-
phenylethyl)benzamide (1n). Yellow solid (114 mg, 91%): mp 73−
75 °C; 1H NMR (500 MHz, CDCl3) δ 8.03−8.00 (m, 2H), 7.93−7.89
(m, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.51−7.48 (m, 2H), 7.35−7.31 (m,
2H), 7.20−7.05 (m, 5H), 6.08 (d, J = 4.1 Hz, 0.5H), 6.05 (d, J = 4.1
Hz, 0.5H), 4.93−4.85 (m, 1H), 4.54−4.49 (m, 1.5H), 4.30 (d, J = 6.8
Hz, 0.5H), 1.65 (d, J = 6.6 Hz, 1.5H), 1.60 (d, J = 6.6 Hz, 1.5H); 13C
NMR (125 MHz, CDCl3) δ 194.2, 194.1, 170.2, 170.1, 139.6, 139.4,
139.3, 134.8, 134.0, 132.2, 132.1, 132.0, 131.6, 131.4, 129.7, 129.6,
128.9, 128.8, 128.7, 128.2, 128.1, 127.7, 127.6, 124.8, 124.7, 121.0,
96.4, 96.3, 81.7, 81.4, 58.9, 58.5, 54.4, 24.3,23.5; HRMS-ESI [M + H]+
Calcd for C25H21ClNO3 418.1210, found 418.1204.
2-(3-Hydroxy-4-phenyl-1-butynyl)-N-(2-oxo-2-phenylethyl)-
N-phenylbenzamide (1s). Yellow gum (83 mg, 60%): 1H NMR
(500 MHz, CDCl3) δ 8.0 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H),
7.47 (t, J = 7.7 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H), 7.35−7.32 (m, 4H),
7.27−7.20 (m, 3H), 7.17−7.08 (m, 5H), 5.35 (d, J = 17.6 Hz, 1H),
5.33 (d, J = 17.6 Hz, 1H), 4.91 (t, J = 6.5 Hz, 1H), 4.24 (br, 1H),
3.24−3.16 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 194.0, 170.0,
142.6, 139.3, 137.2, 134.9, 133.8, 131.7, 129.8, 128.8, 128.7, 128.4,
128.2, 128.1, 127.8, 127.6, 127.3, 127.1, 126.5, 120.7, 94.4, 83.3, 63.8,
56.3, 43.9; HRMS-ESI [M + H]+ Calcd for C31H26NO3 460.1913,
found 460.1920.
Typical Procedure for Synthesis of 2. To a solution of ortho-
(3-hydroxyalkynyl)benzamide (0.2 mmol) in THF (2 mL) was added
DBU (2 equiv) at room temperature. Then the reaction mixture
was warmed to 45 °C and stirred until the reaction was completed
(monitored by TLC). After evaporation of reaction solvent, chromatog-
raphy on silica gel (eluent: EtOAc/petroleum ether = 3/1) afforded 2
(for 2b run at 0 °C).
trans-3-Benzoyl-4-(2-oxo-2-phenylethyl)-2-phenyl-3,4-
dihydroisoquinolin-1(2H)-one (trans-2a). White solid (76 mg,
1
85%): mp 223−225 °C; H NMR (500 MHz, CDCl3) δ 8.32−8.28
(m, 3H), 8.07−8.05 (m, 2H), 7.67−7.62 (m, 2H), 7.56−7.52 (m, 4H),
7.45−7.39 (m, 2H), 7.33−7.20 (m, 5H), 7.03−7.01 (m, 1H), 5.83 (d,
J = 1.4 Hz, 1H), 4.16−4.03 (m, 2H), 3.39 (dd, J1 = 18.1 Hz, J2 =
2.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 198.3, 195.7, 164.9,
142.5, 137.4, 136.3, 134.0, 133.8, 132.5, 129.5, 129.2, 129.0, 128.9, 128.2,
128.1, 127.0, 126.8, 126.6, 68.3, 44.0, 37.8; HRMS-ESI [M + H]+ Calcd
for C30H24NO3 446.1756, found 446.1748.
trans-3-Benzoyl-4-[2-(4-chlorophenyl)-2-oxoethyl]-2-phenyl-
3,4-dihydroisoquinolin-1(2H)-one (trans-2b). White solid
2-(3-Hydroxy-1-propynyl)-N-(2-oxo-2-phenylethyl)-N-
phenylbenzamide (1o). Yellow solid (85 mg, 77%): mp 151−153 °C;
1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 7.7 Hz, 2H), 7.59 (t, J = 7.3
1
(75 mg, 78%): mp 209−211 °C; H NMR (500 MHz, CDCl3) δ
8.29−8.27 (m, 3H), 7.99 (d, J = 8.6 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H),
7.55 (t, J = 7.8 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.45−7.39 (m, 2H),
7.33−7.30 (m, 2H), 7.24−7.20 (m, 3H), 7.01−6.99 (m, 1H), 5.79 (s
Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 7.29−7.27 (m,
1H), 7.22−7.08 (m, 6H), 5.36 (s, 2H), 4.57 (s, 2H), 3.96 (br, 1H); 13
C
NMR (125 MHz, CDCl3) δ 194.1, 170.2, 142.6, 139.5, 134.9, 133.9,
131.6, 128.9, 128.8, 128.5, 128.1, 127.8, 127.6, 127.4, 127.1, 120.7, 92.3,
83.2, 56.4, 51.6; HRMS-ESI [M + H]+ Calcd for C24H20NO3 370.1443,
found 370.1449.
1H), 4.15−3.98 (m, 2H), 3.35 (dd, J1 = 18.4 Hz, J2 = 2.7 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 197.0, 195.6, 164.8, 142.5, 140.6, 137.2,
134.5, 134.0, 133.8, 132.5, 129.5, 129.3, 129.2, 129.1, 129.0, 128.9,
128.3, 127.1, 126.7, 126.5, 68.2, 43.9, 37.7; HRMS-ESI [M + H]+
Calcd for C30H23ClNO3 480.1366, found 480.1348.
2-(3-Hydroxy-1-hexynyl)-N-(2-oxo-2-phenylethyl)-N-phenyl-
1
benzamide (1p). Yellow gum (38 mg, 31%): H NMR (500 MHz,
trans-3-Benzoyl-4-[2-(3-bromophenyl)-2-oxoethyl]-2-phenyl-
CDCl3) δ 8.0 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J =
7.7 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 7.7 Hz, 1H), 7.20−
7.09 (m, 6H), 5.36 (d, J = 17.6 Hz, 1H), 5.34 (d, J = 17.6 Hz, 1H),
4.71 (t, J = 6.5 Hz, 1H), 4.07 (br, 1H), 1.91−1.81 (m, 2H), 1.65−1.57
(m, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
194.0, 170.1, 142.7, 139.4, 134.9, 133.9, 131.7, 128.9, 128.8, 128.4,
128.1, 127.9, 127.5, 127.4, 127.1, 120.9, 95.2, 82.4, 62.6, 56.3, 39.7,
18.5, 13.9; HRMS-ESI [M + H]+ Calcd for C27H26NO3 412.1913,
found 412.1905.
3,4-dihydroisoquinolin-1(2H)-one (trans-2c). White solid
1
(70 mg, 67%): mp 221−223 °C; H NMR (500 MHz, CDCl3) δ
8.29−8.27 (m, 3H), 8.20 (t, J = 1.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H),
7.79−7.77 (m, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H),
7.46−7.39 (m, 3H), 7.32 (t, J = 7.4 Hz, 2H), 7.25−7.21 (m, 3H),
7.02−7.00 (m, 1H), 5.78 (d, J = 1.4 Hz, 1H), 4.12−3.98 (m, 2H), 3.35
(dd, J1 = 18.4 Hz, J2 = 2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 196.9, 195.6, 164.8, 142.4, 137.9, 137.1, 136.8, 134.0, 133.8, 132.5,
131.2, 130.5, 129.5, 129.3, 129.1, 128.9, 128.3, 127.0, 126.6, 126.5,
123.4, 68.2, 44.0, 37.6; HRMS-ESI [M + H]+ Calcd for C30H23BrNO3
524.0861, found 524.0842.
2-(3-Hydroxy-1-hexynyl)-N-(2-oxo-2-phenylethyl)-N-(p-
tolyl)benzamide (1q). Yellow solid (60 mg, 47%): mp 110−112 °C;
1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.4
trans-3-Benzoyl-4-(2-oxo-2-phenylethyl)-2-(p-tolyl)-3,4-di-
hydroisoquinolin-1(2H)-one (trans-2d). White solid (69 mg,
Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.30−7.28 (m, 1H), 7.23 (d, J = 8.3
Hz, 2H), 7.20−7.09 (m, 3H), 6.95 (d, J = 8.2 Hz, 2H), 5.33 (d, J =
17.5 Hz, 1H), 5.31 (d, J = 17.5 Hz, 1H), 4.71 (t, J = 6.6 Hz, 1H), 4.08
(br, 1H), 2.20 (s, 3H), 1.90−1.82 (m, 2H), 1.65−1.57 (m, 2H), 1.00
(t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 194.1, 170.3,
140.1, 139.6, 137.3, 135.0, 133.8, 131.7, 129.5, 128.8, 128.3, 128.1, 127.7,
127.5, 127.0, 120.8, 95.1, 82.5, 62.6, 56.4, 39.7, 20.9, 18.5, 13.9; HRMS-
ESI [M + H]+ Calcd for C28H28NO3 426.2069, found 426.2056.
N-(4-Chlorophenyl)-2-(3-hydroxy-1-hexynyl)-N-(2-oxo-2-
phenylethyl)benzamide (1r). Yellow gum (112 mg, 84%): 1H
NMR (500 MHz, CDCl3) δ 8.0 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.4 Hz,
1H), 7.48 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.2 Hz, 3H), 7.21−7.12 (m,
5H), 5.32 (s, 2H), 4.68 (t, J = 6.4 Hz, 1H), 4.02 (br, 1H), 1.89−1.78
(m, 2H), 1.63−1.55 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 193.9, 170.0, 141.2, 139.1, 134.8, 134.0, 133.2, 131.9,
129.3, 129.1, 128.8, 128.7, 128.1, 127.7, 127.0, 120.8, 95.4, 82.3, 62.5,
56.3, 39.7, 18.5, 13.9; HRMS-ESI [M + H]+ Calcd for C27H25ClNO3
446.1523, found 446.1518.
1
75%): mp 249−251 °C; H NMR (500 MHz, CDCl3) δ 8.30−8.28
(m, 3H), 8.05 (d, J = 7.6 Hz, 2H), 7.67−7.61 (m, 2H), 7.55−7.52 (m,
4H), 7.42−7.38 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz,
2H), 7.02−7.00 (m, 1H), 5.78 (d, J = 1.1 Hz, 1H), 4.15−4.02 (m,
2H), 3.38 (dd, J1 = 17.9 Hz, J2 = 2.4 Hz, 1H), 2.29 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 198.3, 195.8, 164.9, 140.0, 137.4, 136.8, 136.3,
134.0, 133.9, 132.4, 129.8, 129.6, 129.1, 129.0, 128.9, 128.8, 128.2,
128.1, 126.6, 126.5, 68.4, 44.0, 37.7, 21.0; HRMS-ESI [M + H]+ Calcd
for C31H26NO3 460.1913, found 460.1902.
trans-3-Benzoyl-4-[2-oxo-2-(p-tolyl)ethyl]-2-(p-tolyl)-3,4-
dihydroisoquinolin-1(2H)-one (trans-2e). White solid (68 mg,
1
72%): mp 209−211 °C; H NMR (500 MHz, CDCl3) δ 8.30−8.27
(m, 3H), 7.95 (d, J = 8.2 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J =
7.5 Hz, 2H), 7.42−7.39 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.12 (d, J =
8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 7.01−7.00 (m, 1H), 5.77 (d, J =
1.3 Hz, 1H), 4.12−4.00 (m, 2H), 3.33 (dd, J1 = 18.1 Hz, J2 = 2.5 Hz,
1H), 2.46 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
1589
dx.doi.org/10.1021/jo2022907 | J. Org. Chem. 2012, 77, 1585−1591

The Journal of Organic Chemistry
Note
197.8, 195.8, 165.0, 145.0, 139.9, 137.5, 136.8, 133.8, 132.3, 129.8,
129.6, 129.1, 128.9, 128.8, 128.3, 128.1, 126.6, 126.5, 68.4, 43.8, 37.7,
21.7, 21.0; HRMS-ESI [M + H]+ Calcd for C32H28NO3 474.2069,
found 474.2062.
(m, 6H), 7.24 (s, 1H), 6.63 (d, J = 15.3 Hz, 1H), 6.03 (dq, J1 = 15.3
Hz, J2 = 6.6 Hz, 1H), 1.93 (dd, J1 = 6.6 Hz, J2 = 1.7 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 161.7, 141.4, 136.2, 132.4, 129.3, 128.8,
128.7, 128.1, 127.1, 126.9, 126.0, 124.3, 123.2, 116.3, 18.5; HRMS-ESI
[M + H]+ Calcd for C18H16NO 262.1232, found 262.1231.
(E)-4-(1-Propenyl)-2-(p-tolyl)isoquinolin-1(2H)-one (4b). Yel-
low solid (38 mg, 69%): mp 119−121 °C; 1H NMR (500 MHz,
CDCl3) δ 8.53 (d, J = 7.6 Hz, 1H), 7.78−7.70 (m, 2H), 7.56−7.53 (m,
1H), 7.34 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H),
6.63 (d, J = 15.3 Hz, 1H), 6.02 (dq, J1 = 15.3 Hz, J2 = 6.6 Hz, 1H),
2.44 (s, 3H), 1.92 (dd, J1 = 6.6 Hz, J2 = 1.7 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 161.8, 138.9, 138.0, 136.2, 132.3, 129.8, 129.0, 128.7,
128.0, 127.0, 126.6, 126.0, 124.4, 123.1, 116.1, 21.1, 18.5; HRMS-ESI
[M + H]+ Calcd for C19H18NO 276.1388, found 276.1381.
(E)-2-(4-Chlorophenyl)-4-(1-propenyl)isoquinolin-1(2H)-one
(4c). White solid (46 mg, 78%): mp 129−131 °C; 1H NMR
(500 MHz, CDCl3) δ 8.51 (d, J = 7.6 Hz, 1H), 7.78−7.72 (m, 2H),
7.56 (dt, J1 = 7.5 Hz, J2 = 1.3 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.42
(d, J = 8.7 Hz, 2H), 7.18 (s, 1H), 6.62 (d, J = 15.3 Hz, 1H), 6.03 (dq,
J1 = 15.3 Hz, J2 = 6.6 Hz, 1H), 1.93 (dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 161.6, 139.8, 136.1, 133.9, 132.6,
129.4, 128.7, 128.4, 128.3, 128.2, 127.3, 125.9, 124.2, 123.3, 116.7,
18.5; HRMS-ESI [M + H]+ Calcd for C18H15ClNO 296.0842, found
296.0838.
trans-3-(4-Chlorobenzoyl)-4-[2-oxo-2-(p-tolyl)ethyl]-2-(p-tolyl)-
3,4-dihydroisoquinolin-1(2H)-one (trans-2f). White solid (68 mg,
1
67%): mp 199−201 °C; H NMR (500 MHz, CDCl3) δ 8.29−8.26
(m, 3H), 7.95 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.43−7.40
(m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.10 (s, 4H), 7.02−7.00 (m, 1H),
5.73 (s, 1H), 4.08−4.02 (m, 2H), 3.36−3.30 (m, 1H), 2.47 (s, 3H),
2.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.9, 194.9, 164.9,
145.1, 140.5, 139.9, 137.3, 136.9, 133.7, 132.5, 132.2, 130.6, 129.9,
129.7, 129.5, 129.2, 128.9, 128.3, 128.2, 126.6, 126.5, 68.4, 43.8, 37.7,
21.7, 21.0; HRMS-ESI [M + H]+ Calcd for C32H27ClNO3 508.1679,
found 508.1658.
trans-3-Benzoyl-2-(4-chlorophenyl)-4-[2-oxo-2-(p-tolyl)-
ethyl]-3,4-dihydroisoquinolin-1(2H)-one (trans-2g). White solid
1
(79 mg, 80%): mp 219−221 °C; H NMR (500 MHz, CDCl3) δ
8.29−8.25 (m, 3H), 7.95 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H),
7.54 (t, J = 7.6 Hz, 2H), 7.44−7.39 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H),
7.26 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.02−7.01 (m, 1H),
5.79 (d, J = 1.0 Hz, 1H), 4.13−3.94 (m, 2H), 3.35 (dd, J1 = 18.3 Hz,
J2 = 2.8 Hz, 1H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.8,
195.6, 164.9, 145.2, 141.0, 137.5, 134.1, 133.7, 133.6, 132.6, 129.7,
129.3, 129.2, 129.1, 129.0, 128.9, 128.3, 128.2, 126.6, 68.3, 43.7, 37.8,
21.7; HRMS-ESI [M + H]+ Calcd for C31H25ClNO3 494.1523, found
494.1507.
(E)-2-(2-Chlorophenyl)-4-(1-propenyl)isoquinolin-1(2H)-one
(4d). White solid (51 mg, 86%): mp 130−132 °C; 1H NMR
(500 MHz, CDCl3) δ 8.53 (d, J = 7.6 Hz, 1H), 7.80−7.72 (m, 2H),
7.60−7.54 (m, 2H), 7.46−7.41 (m, 3H), 7.05 (s, 1H), 6.63 (d, J = 15.3
Hz, 1H), 6.03 (dq, J1 = 15.3 Hz, J2 = 6.6 Hz, 1H), 1.92 (dd, J1 = 6.6
Hz, J2 = 1.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.3, 138.8,
136.4, 132.6, 132.2, 130.5, 130.0, 129.7, 128.7, 128.4, 128.3, 127.9,
127.1, 125.9, 124.2, 123.4, 116.5, 18.5; HRMS-ESI [M + H]+ Calcd for
C18H15ClNO 296.0842, found 296.0831.
trans-Ethyl 1-Oxo-4-(2-oxo-2-phenylethyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (trans-2h). White gum
1
(65 mg, 79%): H NMR (500 MHz, CDCl3) δ 8.20 (dd, J1 = 7.7
Hz, J2 = 0.7 Hz, 1H), 7.96−7.94 (m, 2H), 7.60 (t, J = 7.3 Hz, 1H),
7.49−7.25 (m, 10H), 4.82 (d, J = 1.8 Hz, 1H), 4.25−4.22 (m, 1H),
4.14−4.09 (m, 2H), 3.70 (dd, J1 = 17.9 Hz, J2 = 9.2 Hz, 1H), 3.43 (dd,
J1 = 17.9 Hz, J2 = 4.7 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 197.4, 170.5, 163.9, 142.2, 138.7, 136.4, 133.7, 132.6,
129.2, 129.0, 128.8, 128.2, 128.1, 127.1, 126.6, 65.8, 61.9, 43.0, 37.4,
14.0; HRMS-ESI [M + H]+ Calcd for C26H24NO4 414.1705, found
414.1685.
2-Phenyl-4-vinylisoquinolin-1(2H)-one (4e). Yellow solid (21 mg,
1
42%): mp 89−91 °C; H NMR (500 MHz, CDCl3) δ 8.40 (d, J =
7.8 Hz, 1H), 7.79−7.73 (m, 2H), 7.59−7.52 (m, 3H), 7.49−7.43 (m,
3H), 7.34 (s, 1H), 6.99 (dd, J1 = 17.3 Hz, J2 = 10.8 Hz, 1H), 5.59 (dd,
J1 = 17.3 Hz, J2 = 1.1 Hz, 1H), 5.35 (dd, J1 = 10.8 Hz, J2 = 1.2 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 161.7, 141.3, 135.8, 132.6,
130.8, 129.3, 128.8, 128.2, 127.2, 126.9, 126.0, 123.0, 116.2, 116.0;
HRMS-ESI [M + H]+ Calcd for C17H14NO 248.1075, found 248.1069.
(E)-4-(1-Pentenyl)-2-phenylisoquinolin-1(2H)-one (4f). Yellow
trans-Ethyl 2-Butyl-1-oxo-4-(2-oxo-2-phenylethyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (trans-2i). White gum
1
(46 mg, 58%): H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 7.7 Hz,
1H), 7.90 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47−7.35 (m,
4H), 7.20 (d, J = 7.3 Hz, 1H), 4.42 (d, J = 1.3 Hz, 1H), 4.17−4.07 (m,
4H), 3.48 (dd, J1 = 18.0 Hz, J2 = 9.8 Hz, 1H), 3.19 (dd, J1 = 18.0 Hz,
J2 = 4.2 Hz, 1H), 2.95−2.90 (m, 1H), 1.43−1.39 (m, 2H), 1.31−1.26
(m, 2H), 1.11 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 197.6, 170.6, 164.2, 138.5, 136.4, 133.6, 132.2,
128.8, 128.5, 128.0, 127.9, 126.9, 61.8, 61.7, 46.8, 42.7, 36.6, 30.0, 20.2,
14.0, 13.6; HRMS-ESI [M + H]+ Calcd for C24H28NO4 394.2018,
found 394.2001.
1
solid (37 mg, 64%): mp 89−91 °C; H NMR (500 MHz, CDCl3) δ
8.53 (d, J = 7.6 Hz, 1H), 7.79−7.72 (m, 2H), 7.58−7.43 (m, 6H), 7.25
(s, 1H), 6.62 (d, J = 15.4 Hz, 1H), 6.02 (dt, J1 = 15.4 Hz, J2 = 6.9 Hz,
1H), 2.24 (dq, J1 = 6.9 Hz, J2 = 1.3 Hz, 2H), 1.57−1.50 (m, 2H), 0.99
(t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.7, 141.4,
136.2, 133.4, 132.4, 129.3, 128.7, 128.1, 127.1, 126.9, 126.0, 123.2,
116.3, 35.1, 22.5, 13.7; HRMS-ESI [M + H]+ Calcd for C20H20NO
290.1545, found 290.1538.
trans-2,5-Diphenyl-1,4a,5,10b-tetrahydrophenanthridine-
4,6-dione (trans-3a). White solid (19 mg, 25%): mp 223−225 °C;
1H NMR (500 MHz, CDCl3) δ 8.19 (dd, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H),
7.60−7.56 (m, 4H), 7.49−7.37 (m, 7H), 7.30 (t, J = 7.4 Hz, 1H), 7.20
(d, J = 7.6 Hz, 1H), 6.40 (d, J = 2.6 Hz, 1H), 4.74 (d, J = 4.9 Hz, 1H),
4.33 (s, 1H), 3.70 (d, J = 18.3 Hz, 1H), 3.44 (d, J = 18.3 Hz 1H); 13C
NMR (125 MHz, CDCl3) δ 194.7, 163.2, 155.9, 142.4, 137.9, 136.7,
132.3, 130.7, 130.6, 129.7, 129.0, 128.9, 127.9, 126.8, 126.7, 126.1,
125.6, 123.3, 67.9, 39.1, 30.1; HRMS-ESI [M + H]+ Calcd for
C25H20NO2 366.1494, found 366.1488.
(E)-4-(1-Pentenyl)-2-(p-tolyl)isoquinolin-1(2H)-one (4g). Yel-
low solid (33 mg, 55%): mp 88−90 °C; 1H NMR (500 MHz, CDCl3)
δ 8.53 (d, J = 7.6 Hz, 1H), 7.78−7.71 (m, 2H), 7.55 (dt, J1 = 7.5 Hz,
J2 = 1.1 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H),
7.23 (s, 1H), 6.62 (d, J = 15.4 Hz, 1H), 6.00 (dt, J1 = 15.4 Hz, J2 = 6.9
Hz, 1H), 2.44 (s, 3H), 2.24 (dq, J1 = 6.9 Hz, J2 = 1.2 Hz, 2H), 1.56−
1.49 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 161.8, 138.9, 138.0, 136.2, 133.3, 132.3, 129.9, 129.0, 128.7, 127.0,
126.6, 126.0 123.3, 123.1, 116.1, 35.1, 22.5, 21.1, 13.7; HRMS-ESI
[M + H]+ Calcd for C21H22NO 304.1701, found 304.1699.
Typical Procedure for Synthesis of 4. To a solution of ortho-
(3-hydroxyalkynyl)benzamide (0.2 mmol) in CH3CN (2 mL) was added
DBU (5 equiv) at room temperature. Then the reaction mixture was
warmed to 75 °C and stirred until the reaction was completed
(monitored by TLC). After evaporation of reaction solvent,
chromatography on silica gel (eluent: EtOAc/petroleum ether = 2/1)
afforded 4.
(E)-2-Phenyl-4-(1-propenyl)isoquinolin-1(2H)-one (4a). White
solid (37 mg, 70%): mp 121−123 °C; 1H NMR (500 MHz, CDCl3) δ
8.53 (dd, J1 = 8.0 Hz, J2 = 0.6 Hz, 1H), 7.79−7.72 (m, 2H), 7.57−7.42
(E)-2-(4-Chlorophenyl)-4-(1-pentenyl)isoquinolin-1(2H)-one
(4h). White solid (43 mg, 66%): mp 99−101 °C; 1H NMR (500 MHz,
CDCl3) δ 8.51 (d, J = 7.8 Hz, 1H), 7.78−7.72 (m, 2H), 7.56 (t, J =
7.0 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.19
(s, 1H), 6.60 (d, J = 15.4 Hz, 1H), 6.02 (dt, J1 = 15.4 Hz, J2 = 6.9 Hz,
1H), 2.24 (dq, J1 = 7.0 Hz, J2 = 1.2 Hz, 2H), 1.57−1.50 (m, 2H), 1.00
(t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.6, 139.8,
136.2, 133.9, 133.7, 132.6, 129.4, 128.7, 128.3, 128.2, 127.3, 125.9,
123.3, 123.1, 116.7, 35.1, 22.5, 13.7; HRMS-ESI [M + H]+ Calcd for
C20H19ClNO 324.1155, found 324.1145.
1590
dx.doi.org/10.1021/jo2022907 | J. Org. Chem. 2012, 77, 1585−1591

The Journal of Organic Chemistry
Note
(E)-2-Phenyl-4-(3-phenyl-1-propenyl)isoquinolin-1(2H)-one
(9) Bonnaud, B.; Carlessi, A.; Bigg, D. C. H. J. Heterocycl. Chem.
1993, 30, 257.
1
(4i). Yellow solid (11 mg, 16%): mp 158−160 °C; H NMR (500
MHz, CDCl3) δ 8.53 (d, J = 8.0 Hz, 1H), 7.78−7.73 (m, 2H), 7.58−
7.42 (m, 6H), 7.34 (t, J = 7.4 Hz, 2H), 7.28−7.24 (m, 4H), 6.70 (d, J =
15.3 Hz, 1H), 6.18 (dt, J1 = 15.3 Hz, J2 = 6.8 Hz, 1H), 3.60 (d, J = 6.8
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 161.6, 141.4, 139.8, 136.1,
132.4, 131.6, 129.2, 129.0, 128.7, 128.6, 128.5, 128.1, 127.1, 126.9,
126.3, 126.1, 124.4, 123.1, 115.7, 39.4; HRMS-ESI [M + H]+ Calcd for
C24H20NO 338.1545, found 338.1532.
(10) Azizian, J.; Mohammadi, A. A.; Karimi, A. R.;
Mohammadizadeh, M. R. J. Org. Chem. 2005, 70, 350.
(11) Wang, L.; Liu, J.; Tian, H.; Qian, C.; Sun, J. Adv. Synth. Catal.
2005, 347, 689.
(12) Karimi, A. R.; Pashazadeh, R. Synthesis 2010, 437.
(13) Yadav, J. S.; Reddy, B. V. S.; Reddy, A. R.; Narsaiah, A. V.
Synthesis 2007, 3191.
4-Cinnamyl-2-phenylisoquinolin-1(2H)-one (4i′). Yellow solid
(23 mg, 34%): mp 169−171 °C; 1H NMR (500 MHz, CDCl3) δ 8.57
(d, J = 8.0 Hz, 1H), 7.77−7.72 (m, 2H), 7.58−7.41 (m, 6H), 7.36 (d,
J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.11
(s, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.41 (dt, J1 = 15.9 Hz, J2 = 6.4 Hz,
1H), 3.65 (d, J = 6.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 161.8,
141.4, 137.1, 136.7, 132.5, 132.2, 130.5, 129.3, 128.8, 128.5, 128.0,
127.4, 127.3, 127.1, 126.9, 126.7, 126.2, 123.2, 114.5, 32.9; HRMS-ESI
[M + H]+ Calcd for C24H20NO 338.1545, found 338.1528.
(14) Yadav, J. S.; Reddy, B. V. S.; Saritha Raj, K.; Prasad, A. R.
Tetrahedron 2003, 59, 1805.
(15) Stoyanova, M. P.; Kozekov, I. D.; Palamareva, M. D.
J. Heterocycl. Chem. 2003, 40, 795.
(16) Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907.
(17) Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977, 42,
1111.
(18) Yu, N.; Bourel, L.; Deprez, B.; Gesquiere, J. C. Tetrahedron Lett.
1998, 39, 829.
Typical Procedure for Synthesis of 5a. To a solution of trans-3-
benzoyl-4-(2-oxo-2-phenylethyl)-2-phenyl-3,4-dihydroisoquinolin-1
(2H)-one 2a (80 mg, 0.18 mmol) in CH3COOH (2 mL) was added
NH4OAc (40 equiv) at room temperature. Then the reaction mixture
was refluxed for 48 h. After it cooled, saturated aqueous NaCl was
added, extracted with ethyl acetate, and dried over anhydrous MgSO4.
After evaporation of solvent, chromatography on silica gel (eluent:
EtOAc/petroleum ether = 3/1) afforded 5a in 60% yield.
(19) Yu, N.; Poulain, R.; Gesquiere, J. C. Synlett 2000, 355.
(20) Vara, Y.; Bello, T.; Aldaba, E.; Arrieta, A.; Pizarro, J. L.;
Arriortua, M. I.; Lopez, X.; Cossío, F. P. Org. Lett. 2008, 10, 4759.
(21) Miura, T.; Morimoto, M.; Yamauchi, M.; Murakami, M. J. Org.
Chem. 2010, 75, 5359.
(22) Ho, T. L. Tandem Organic Reactions; John Wiley & Sons:
New York, 1992.
(23) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reaction in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
(24) Posner, G. H. Chem. Rev. 1986, 86, 831.
(25) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96,
195.
2,4,5-Triphenylbenzo[c][1,7]naphthyridin-6(5H)-one (5a).
1
White solid (46 mg, 60%): mp 260−262 °C; H NMR (500 MHz,
CDCl3) δ 8.62 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 1H), 8.53 (d, J = 8.1 Hz,
1H), 8.49 (s, 1H), 8.17−8.16 (m, 2H), 7.93 (t, J = 7.3 Hz, 1H), 7.78 (t,
J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.18−
7.02 (m, 8H), 6.97−6.96 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
162.2, 151.1, 150.6, 141.0, 140.2, 138.6, 133.3, 132.7, 132.3, 130.4, 129.5,
129.3, 129.2, 128.8, 128.7, 128.2, 127.6, 127.5, 127.4, 127.0, 126.8, 122.6,
110.4; HRMS-ESI [M + H]+ Calcd for C30H21N2O 425.1654, found
425.1653.
(26) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(27) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(28) Muller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed.
̈
2000, 39, 1253.
(29) Braun, R. U.; Ansorge, M.; Muller, T. J. J. Chem.Eur. J. 2006,
̈
12, 9081.
(30) Braun, R. U.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2001, 3, 3297.
̈
ASSOCIATED CONTENT
(31) D’Souza, D. M.; Kiel, A.; Herten, D. P.; Muller, T. J. J. Chem.
̈
■
Eur. J. 2008, 14, 529.
S
* Supporting Information
1H and 13C NMR and NOESY spectra of selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(32) Braun, R. U.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2000, 2, 4181.
̈
(33) D’Souza, D. M.; Rominger, F.; Muller, T. J. J. Angew. Chem., Int.
Ed. 2005, 44, 153.
̈
(34) D’Souza, D. M.; Rominger, F.; Muller, T. J. J. Chem. Commun.
̈
2006, 4096.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chenwl@zjut.edu.cn, mowm@zjut.edu.cn.
(35) The typical coupling constants between between H-3 and H-4
of 3,4-dihydroisoquinolin-1(2H)-one analogues is 4−6 and 0−2 Hz
for the cis and trans stereoisomers, respectively. See references
11 and 20.
■
(36) After the reaction was completed, we could separate the benzoic
acid. See the Supporting Information.
(37) Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Lett. 2009,
11, 4176.
(38) Chen, Y.; Wan, J.; Wang, C.; Sun, C. Molecules 2008, 13,
2652.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
Zhejiang Province (Y4100662) and the Opening Foundation of
Zhejing Provincial Top Key Discipline is greatly appreciated.
(39) Navarro, C.; Csaky, A. G. Org. Lett. 2008, 10, 217.
(40) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res.
2004, 37, 21.
́
̈
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dx.doi.org/10.1021/jo2022907 | J. Org. Chem. 2012, 77, 1585−1591