Direct inter- and intramolecular addition of amides to arylalkenes promoted by KOt-Bu/DMF

Article abstract of DOI:10.1021/jo501179t

Direct addition of tetrahydroisoquinoline derived amides to arylalkenes has been achieved in the presence of KOt-Bu/DMF. Both intermolecular and intramolecular reactions could occur in good yields. α-Amido alkyl radicals are proposed to be generated under the reaction conditions. The reaction is efficient for the synthesis of seven-membered nitrogen heterocycles. A homoprotoberberine was prepared conveniently via this method.

Full text of DOI:10.1021/jo501179t

Article
pubs.acs.org/joc
Direct Inter- and Intramolecular Addition of Amides to Arylalkenes
Promoted by KOt‑Bu/DMF
Wei-juan Wang, Xu Zhao, Lang Tong, Jia-hua Chen, Xue-jing Zhang,* and Ming Yan*
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, China
S
* Supporting Information
ABSTRACT: Direct addition of tetrahydroisoquinoline de-
rived amides to arylalkenes has been achieved in the presence
of KOt-Bu/DMF. Both intermolecular and intramolecular
reactions could occur in good yields. α-Amido alkyl radicals are
proposed to be generated under the reaction conditions. The
reaction is efficient for the synthesis of seven-membered
nitrogen heterocycles. A homoprotoberberine was prepared
conveniently via this method.
1,2,3,4-tetrahydroisoquinoline and explored its reaction with
KOt-Bu/DMF. The reaction gave 3aa with excellent yield.
These results obviously indicated that KOt-Bu promoted the
cleavage of the C−N bond of 1a. In addition, we also found
that 4 did not react with styrene in the presence of KOt-Bu/
DMF. Thus, the addition of 1a to styrene must occur before
the C−N cleavage. NaOt-Bu and LiOt-Bu were found to be
completely inefficient (Table 1, entries 2 and 3).9,10 The
replacement of DMF with DMSO led to a poor yield (Table 1,
entry 4). Other solvents such as DMA, toluene, dioxane, and
HOt-Bu were incompatible (Table 1, entries 5−8). The
decrease of reaction temperature led to a slightly lower yield
(Table 1, entry 9). Higher reaction temperature (120 °C) did
not give improved yield (Table 1, entry 10). The decrease of
the loading of KOt-Bu and styrene led to lower yield (Table 1,
entries 11−13). The radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidinooxy) inhibited the reaction (Table 1,
entry 15). The reaction was also inhibited in the presence of
oxygen (Table 1, entry 16). The results undoubtedly implicated
a free radical reaction pathway.
To explore the influence of acyl groups, a number of N-acyl
tetrahydroisoquinolines 1b−1h were prepared and examined in
the reaction with styrene 2a.11 The results are summarized in
Scheme 1. When 1-(3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-
methoxyphenyl)ethanone was explored, the reaction gave 3ba
in good yield (67%). The substitution with a nitro group
inhibited the reaction. Although the complete consumption of
1c was observed, almost no expected product 3ca could be
isolated from the complicated reaction mixture. A series of N-
heteroaryl carboxyl substrates 1d−1f were also examined. N-1-
Methyl-pyrrole-2-carboxyl tetrahydroisoquinoline 1e gave the
best yield. N-Pivaloyl tetrahydroisoquinoline 1h also gave the
product in good yield; however, N-acetyl tetrahydroisoquino-
INTRODUCTION
■
The synthesis of nitrogen heterocycles is of great interest for
synthetic and medicinal chemists because of their abundance in
natural products and drugs.1 Although many methods have
been developed for the synthesis of nitrogen heterocycles, new
and efficient methods are still desirable considering their
structural diversity. In recent years, there have been increasing
interests in the direct functionalizations of the α C−H bond of
amines or amides.2−6 The strategy provides superior advantages
over the traditional methods in terms of short synthetic steps
and readily available substrates. Most of these transformations
proceed via the iminium intermediates generated in situ by the
oxidation of amines or amides. The α-amido alkyl radicals
formed by the hydrogen abstraction are also reactive
intermediates for further functionalizations, but successful
examples are limited because they are readily oxidized to
iminium ions in the presence of oxidants.6
Recently, we found that KOt-Bu/DMF promotes the
intramolecular additions of α-aryl substituted tertiary amines
to alkenes or ketones.7 The α-amino alkyl radicals were
proposed to be the crucial intermediates. However, the
intermolecular addition of tertiary amines to alkenes was not
successful. We speculate that more electron-deficient α-amido
alkyl radicals possess better reactivity with alkenes. Herein, we
report inter- and intramolecular addition of tetrahydroisoquino-
line derived amides to alkenes promoted by KOt-Bu/DMF.
RESULTS AND DISCUSSION
■
Initially, we examined the reaction of N-benzoyltetrahydro-
isoquinoline 1a with styrene 2a in the presence of KOt-Bu/
DMF. Product 3aa was obtained in 79% yield, together with 5%
of 4 (Table 1, entry 1). The cleavage of the C−N bond of
tetrahydroisoquinolines was previously reported in the presence
of a strong base.8 In the absence of the styrene 2a, the reaction
of 1a with KOt-Bu/DMF gave 4 in 40% yield. We also
synthesized the key intermediate 2-benzoyl-1-(2-phenylethyl)-
Received: May 20, 2014
Published: August 29, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
Scheme 2. Reaction of N-Benzoyltetrahydroisoquinoline 1a
with Alkenes 2b−2k
b
entry
base (equiv)
solvent
T (°C)
yield (%)
1
2
KOt-Bu (3.0)
NaOt-Bu (3.0)
LiOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (1.5)
KOt-Bu (0.75)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
DMF
DMF
DMF
DMSO
DMA
toluene
dioxane
HOt-Bu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
90
90
90
90
90
90
90
60
120
90
90
90
90
90
90
83 (79)
5
3
0
4
24
0
5
6
0
7
0
8
0
9
55
72
73
37
62
78
0
10
11
12
c
13
d
14
e
15
f
16
trace
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), base (n equiv),
b
solvent (1.2 mL), T °C, 0.5 h. Yields of 3aa were obtained by GC
with n-dodecane as the internal standard. The values in the
parentheses are the isolated yields after column chromatography.
c
d
e
1.0 equiv of 2a was used. 3.0 equiv of 2a was used. TEMPO (3.0
f
equiv) was added. The reaction was carried out with an O2 balloon.
Scheme 1. Intermolecular Reaction of
Tetrahydroisoquinolines 1b−1h with Styrene 2a
good yields. The substitution on styrene with a methyl group
led to lower yields, while the reaction of 4-methoxyl styrene 2e
mainly gave the ring-opening product 4. The reaction of 4-
trifluoromethyl 2f did not provide the product 3af.13 The
reaction of 2-vinylthiophene 2g gave the product 3ag in 20%
yield. The reaction of 4-vinylpyridine 2h led to a poor result.13
The reaction of 1-vinylnaphthalene 2i and 2-vinylnaphthalene
2j afforded the products 3ai and 3aj in excellent yields. α,α-
Diphenylethylene 2k is also applicable. The product 3ak was
obtained in good yield.
The intramolecular reactions of tetrahydroisoquinoline
derivatives 5a−5i were also investigated (Scheme 3). We
were pleased to find that the 7-endo cyclization occurred
exclusively, and seven-membered products 6a−6i were
obtained in good yields. We treated the product 6a with
KOt-Bu/DMF at 150 °C. No ring-opening product was
observed even after 24 h. The fact demonstrates that the
products 6a−6i with a fused-ring structure are resistant to the
base-promoted C−N cleavage. The reaction proceeds well with
β-methyl, β-propyl, and α-methyl alkenes. Surprisingly, the
ring-opening reaction did not occur in these cases. β,β-
Dimethyl, cyclohexyl, and cyclopentyl alkenes are also suitable
substrates. Spirocyclic products 6f−6g were obtained in good
yields. The para- and meta-methyl substitutions at the phenyl
ring were also examined. The reaction provided the expected
products 6h and 6i in comparable yields with 6a.
line only provided a trace amount of the product and most of
1g was recovered.
Furthermore, we examined the intermolecular reactions of N-
benzoyltetrahydroisoquinoline 1a with alkenes 2b−2k, and the
results are summarized in Scheme 2.12 The reaction of 4-fluoro
and 4-chloro styrenes 2b and 2c gave products 3ab and 3ac in
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Scheme 3. Intramolecular Cyclization of
Scheme 5. Proposed Reaction Mechanism
Tetrahydroisoquinoline Derivatives 5a−5i
The reaction of β-phenyl alkene 5j gave the debenzylation
and ring-opening product 7 in moderate yield. The byproduct
toluene was detected in the reaction mixture via GC-MS
analysis. To the best of our knowledge, such a debenzylation
was not reported previously.13 On the other hand, β-chloro
alkene 5k underwent a dechlorination and ring-opening
reaction to give product 8 (Scheme 4).14
probably resistant to the base-promoted C−N cleavage due to
its fused-ring structure.
Furthermore, the reaction was applied to the synthesis of a
homoprotoberberine bearing a fused tetrahydroisoquinoline
and azepine structure (Scheme 6). Dimethoxy substituted
tetrahydroisoquinoline 5l was treated under the standard
reaction conditions. The cyclization product 6l was obtained
in excellent yield. After a reduction, a homoprotoberberine 9
was produced in good yield. The method represents a new
strategy for the synthesis of these biologically interesting
natural products.16,17
Scheme 4. Intramolecular Cyclization of
Tetrahydroisoquinoline Derivatives 5j−5k
CONCLUSIONS
■
In summary, we have developed inter- and intramolecular
additions of tetrahydroisoquinoline derived amides and alkenes
promoted by KOt-Bu/DMF. α-Substituted amides could be
conveniently prepared in moderate to good yields. In addition,
the intramolecular reaction provided a new synthetic pathway
for seven-membered nitrogen heterocycles. The method is
demonstrated to be highly efficient for the synthesis of
homoprotoberberines. A radical cyclization mechanism is
suggested on the basis of experiment data and previous study.
Further expanding the substrate scope and applying to the
synthesis of drugs and natural products are currently underway
in our laboratory.
On the basis of the experiment data and our previous study,7
the reaction mechanism of intermolecular and intramolecular
addition of amides to alkenes is proposed (Scheme 5). The
DMF radical generated in the KOt-Bu/DMF system abstracts a
hydrogen from 1a to provide α-amido alkyl radical A.15 A adds
to alkene to give a radical intermediate B, which abstracts a
hydrogen from DMF. The intermediate C undergoes a base-
promoted C−N cleavage reaction to provide the final product
3aa.8 In the case of intramolecular reaction, the product 6a is
EXPERIMENTAL SECTION
General Information. The H NMR spectra were recorded on a
■
1
400 MHz spectrometer, and resonances (δ) are given in parts per
million (ppm) relative to the singlets at δ 0.0 and δ 7.26 for
tetramethylsilane and chloroform, respectively. Peaks are labeled as
single (s), broad singlet (br), doublet (d), triplet (t), double doublet
(dd), and multiplet (m), and all coupling constants (J) are absolute
values given in hertz (Hz). 13C NMR spectra were recorded at 75
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Scheme 6. Synthesis of a Homoprotoberberine
MHz with complete proton decoupling. Chemical shifts are reported
in ppm relative to the central line of the heptalet at 77.0 ppm for
CDCl3. High-resolution mass spectra (HRMS) were acquired using an
electron spray ionization time-of-flight (ESI-TOF) mass spectrometer
in positive mode. The IR spectra were recorded as thin films with KBr
and reported in wavenumbers (cm−1). Melting points were
determined with a commercially available melting point apparatus.
All reagents were used without further purification as received from
commercial suppliers unless otherwise noted. All solvents were dried
and distilled prior to use according to the standard protocols.
General Procedure for the Preparation of Substrates (1a−
1h, 5l′, 5h′, and 5i′). Compound 1 was synthesized according to a
known procedure.18 To a solution of benzoic acid (1230.0 mg, 10
mmol) and triethylamine (1.53 mL, 11 mmol) in CH2Cl2 (20.0 mL)
was added pivaloyl chloride (1.36 mL, 11 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 1 h. To this solution was
slowly added a mixture of triethylamine (1.53 mL, 11 mmol) and
1,2,3,4-tetrahydroisoquinoline (1.38 mL, 11 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 0.5 h. Then, the
reaction mixture was quenched with water. The organic layer was
washed with 10% HCl (aq), saturated NaHCO3 (aq), and brine. The
organic layer was dried over MgSO4 and removed under reduced
pressure. The residue was purified by column chromatography
(petroleum ether:EtOAc = 5:1) to give 1a as a colorless oil (2017.1
mg, 85%).
N-(3-Phenyl-1-(2-vinylphenyl)propyl)benzamide (3aa). White
solid (27.0 mg, 79%), mp 124.5−125.3 °C. H NMR (400 MHz,
1
CDCl3): δ 7.74−7.60 (m, 2H), 7.54−7.44 (m, 2H), 7.39 (dd, J = 10.2,
4.6 Hz, 2H), 7.36−7.27 (m, 4H), 7.18 (dd, J = 6.8, 3.4 Hz, 3H), 7.15−
7.06 (m, 1H), 6.32 (d, J = 7.8 Hz, 1H), 5.62 (dd, J = 17.2 Hz, 1H),
5.55 (dd, J = 14.6, 7.7 Hz, 1H), 5.34 (dd, J = 1.4 Hz, 1H), 2.79−2.59
(m, 2H), 2.36−2.16 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 166.5,
141.4, 139.0, 137.2, 134.5, 134.4, 131.5, 128.5, 128.4, 128.1, 127.7,
127.0, 126.9, 126.0, 125.3, 117.1, 50.1, 37.6, 32.7. IR (KBr) ν/cm−1:
3285, 3065, 3024, 2855, 2924, 2950, 1603, 1578, 1552, 1490, 1451,
1432, 1369, 1313, 984, 925, 777, 749, 701. HRMS (ESI) calculated for
C24H23NNaO [M + Na]+: 364.1672, found: 364.1671.
4-Methoxy-N-(3-phenyl-1-(2-vinylphenyl)propyl)benzamide
1
(3ba). White solid (24.9 mg, 67%), mp 147.8−149.7 °C. H NMR
(400 MHz, CDCl3): δ 7.64 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 5.9, 2.9
Hz, 1H), 7.33 (d, J = 5.0 Hz, 1H), 7.30−7.20 (m, 4H), 7.16 (s, 4H),
6.84 (d, J = 8.7 Hz, 2H), 6.44 (d, J = 7.7 Hz, 1H), 5.60 (d, J = 17.2 Hz,
1H), 5.52 (d, J = 7.0 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H), 3.79 (s, 3H),
2.76−2.54 (m, 2H), 2.31−2.10 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 166.1, 162.2, 141.5, 139.3, 137.1, 134.5, 128.8, 128.5, 128.4,
128.1, 127.6, 126.9, 126.7, 126.0, 125.4, 117.0, 113.7, 55.4, 50.0, 37.6,
32.7. IR (KBr) ν/cm−1: 3288, 3028, 2934, 2838, 1627, 1606, 1532,
1504, 1313, 1253, 1177, 1028, 988, 926, 845, 763. HRMS (ESI)
calculated for C25H26NO2 [M + H]+: 372.1958, found: 372.1958.
N-(3-Phenyl-1-(2-vinylphenyl)propyl)isonicotinamide (3da).
1
White solid (21.6 mg, 63%), mp 124.5−125.6 °C. H NMR (400
(3,4-Dihydroisoquinolin-2(1H)-yl)(1-methyl-1H-pyrrol-2-yl)meth-
1
MHz, CDCl3): δ 8.64 (d, J = 5.9 Hz, 2H), 7.50 (dd, J = 5.3, 3.7 Hz,
1H), 7.46 (dd, J = 4.5, 1.5 Hz, 2H), 7.35−7.25 (m, 5H), 7.22−7.14
(m, 3H), 7.09 (dd, J = 17.2, 10.9 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H),
5.62 (dd, J = 17.2, 1.3 Hz, 1H), 5.53 (dd, J = 14.6, 7.6 Hz, 1H), 5.34
(dd, J = 10.9, 1.3 Hz, 1H), 2.75−2.61 (m, 2H), 2.34−2.17 (m, 2H).
13C NMR (100 MHz, CDCl3): δ 164.9, 150.3, 141.6, 141.2, 138.6,
anone (1e). White solid (1562.0 mg, 65%), mp 100.1−101.5 °C. H
NMR (400 MHz, CDCl3): δ 7.21−7.15 (m, 3H), 7.12 (d, J = 3.1 Hz,
1H), 6.74−6.68 (m, 1H), 6.43 (dd, J = 3.8, 1.6 Hz, 1H), 6.11 (dd, J =
3.8, 2.6 Hz, 1H), 4.88 (s, 2H), 3.96 (t, J = 5.9 Hz, 2H), 3.80 (s, 3H),
2.95 (t, J = 5.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 163.3, 134.6,
133.3, 128.8, 126.7, 126.6, 126.5, 126.4, 125.2, 113.0, 107.0, 35.8, 29.2.
IR (KBr) v/cm−1: 3113, 2923, 1615, 1530, 1434, 1244, 748. HRMS
(ESI) calculated for C15H17N2O [M + H]+: 241.1335, found:
241.1335.
137.1, 134.2, 128.6, 128.4, 128.1, 127.9, 127.0, 126.2, 125.4, 121.0,
117.4, 50.4, 37.2, 32.7. IR (KBr) ν/cm−1: 3303, 3061, 3024, 2927,
2862, 1640, 1599, 1545, 1490, 1325, 991, 931, 754, 700. HRMS (ESI)
calculated for C23H23N2O [M + H]+: 343.1797, found: 343.1805.
1-Methyl-N-(3-phenyl-1-(2-vinylphenyl)propyl)-1H-pyrrole-2-
carboxamide (3ea). White solid (27.5 mg, 80%), mp 113.2−114.3 °C.
1H NMR (400 MHz, CDCl3): δ 7.52−7.44 (m, 1H), 7.35−7.26 (m,
3H), 7.24 (d, J = 6.8 Hz, 2H), 7.18 (t, J = 7.1 Hz, 3H), 7.09 (dd, J =
17.2, 10.9 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H), 6.45 (dd, J = 3.9, 1.6 Hz,
1H), 6.14−5.99 (m, 2H), 5.61 (dd, J = 17.2, 1.4 Hz, 1H), 5.44 (dd, J =
14.6, 7.7 Hz, 1H), 5.32 (dd, J = 10.9, 1.4 Hz, 1H), 3.91 (s, 3H), 2.80−
2.67 (m, 1H), 2.67−2.57 (m, 1H), 2.24−2.08 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 161.0, 141.4, 139.4, 136.9, 134.4, 128.5, 128.4,
128.0, 127.9, 127.5, 126.9, 126.0, 125.7, 125.2, 117.0, 111.3, 107.1,
49.3, 37.9, 36.7, 32.7. IR (KBr) ν/cm−1: 3317, 3025, 2924, 2857, 1614,
1538, 1510, 1464, 1412, 1258, 1143, 1007, 909, 750, 728, 670. HRMS
(ESI) calculated for C23H25N2O [M + H]+: 345.1961, found:
345.1960.
2-(6,7-Dimethoxy-1,2,h3,4-tetrahydroisoquinoline-2-carbonyl)
Benzaldehyde (5l′). White solid (2765.6 mg, 85%), mp 139.7−140.6
°C. Atropisomer. 1H NMR (400 MHz, CDCl3): δ 10.08 (s, 1H), 10.03
(s, 0.7H), 7.97 (m, 1.7H), 7.71−7.64 (m, 1.7H), 7.60 (td, J = 7.6, 1.0
Hz, 1.7H), 7.44−7.36 (m, 1.7H), 6.68 (d, J = 10.6 Hz, 1.7H), 6.59 (s,
1H), 6.31 (s, 0.7H), 4.91 (s, 2H), 4.26 (s, 1.4H), 4.07 (t, J = 6.0 Hz,
1.4H), 3.89 (s, 2.9H), 3.86 (d, J = 3.9 Hz, 5.4H), 3.75 (s, 2H), 3.43 (t,
J = 5.9 Hz, 2H), 2.95 (t, J = 5.9 Hz, 1.4H), 2.69 (t, J = 5.8 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 190.6, 190.5, 168.5, 168.2, 148.1,
148.0(6)19, 147.9, 147.7, 147.7, 138.7, 138.6, 134.2(9)19, 134.2(7)19,
132.9, 132.8, 130.4, 129.5(1)19, 129.5, 127.1, 127.0, 126.5, 125.3,
124.4, 123.7, 111.8, 111.4, 109.4, 108.7, 56.0(1)19, 59.9(9)19,
55.9(6)19, 55.9(2)19, 48.7, 44.7, 44.0, 40.1, 28.8, 27.9. IR (KBr) ν/
cm−1: 3030, 2930, 2820, 2720, 1650, 1530, 1450, 750. HRMS (ESI)
calculated for C19H20NO4 [M + H]+: 326.1381, found: 326.1387.
General Procedure for the Intermolecular Reaction of 1a−1l
and 2a−2k Promoted by KOt-Bu/DMF. To a dried 10 mL reaction
tube was added 1a (23.5 mg, 0.1 mmol), KOt-Bu (33.7 mg, 0.3
mmol), 2a (23.0 μL, 0.2 mmol), and DMF (1.0 mL). The mixture was
stirred at 90 °C for 0.5 h under an argon atmosphere. After being
cooled down to room temperature, the reaction mixture was diluted
with CH2Cl2 (10 mL) and washed with water (10 mL × 2). After
being washed with brine and dried over MgSO4, the organic layer was
removed under reduced pressure. The residue was purified by column
chromatography (petroleum ether:EtOAc = 10:1) to give 3aa as a
white solid (27.0 mg, yield: 79%).
N-(3-Phenyl-1-(2-vinylphenyl)propyl)benzamide (3fa). White
1
solid (13.9 mg, 42%), mp 122.8−123.3 °C. H NMR (400 MHz,
CDCl3): δ 7.48 (dd, J = 7.1, 1.9 Hz, 1H), 7.40 (dd, J = 1.7, 0.7 Hz,
1H), 7.35 (dd, J = 7.5, 1.6 Hz, 1H), 7.29 (m, 2H), 7.25 (m, 2H), 7.17
(dd, J = 7.2, 5.3 Hz, 3H), 7.09 (dt, J = 12.8, 11.9 Hz, 2H), 6.58 (d, J =
8.2 Hz, 1H), 6.47 (dd, J = 3.5, 1.8 Hz, 1H), 5.60 (dd, J = 17.2, 1.5 Hz,
1H), 5.50 (dd, J = 14.8, 8.1 Hz, 1H), 5.32 (dd, J = 10.9, 1.4 Hz, 1H),
2.75−2.59 (m, 2H), 2.30−2.13 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 157.5, 147.9, 143.8, 141.2, 138.8, 137.1, 134.3, 128.4, 128.3,
128.1, 127.7, 126.9, 126.0, 125.3, 117.2, 114.4, 112.2, 50.0, 37.8, 32.7.
IR (KBr) ν/cm−1: 3300, 3030, 2930, 2850, 1640, 1590, 1471, 991, 912,
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690, 750. HRMS (ESI) calculated for C22H22NO2.(M + H)+:
332.1645, found: 332.1648.
127.1, 126.9, 126.8, 126.0, 125.9, 125.6, 125.5, 125.3, 123.6, 117.3,
50.4, 37.2, 29.9. IR (KBr) ν/cm−1: 3295, 3052, 2925, 2855, 1635,
1631, 1601, 1313, 990, 914, 774, 751. HRMS (ESI) calculated for
C28H26NO [M + H]+: 392.2009, found: 392.2009.
N-(3-Phenyl-1-(2-vinylphenyl)propyl)pivalamide (3ha). White
solid (19.9 mg, 62%), mp 117.5−118.3 °C. 1H NMR (400 MHz,
CDCl3): δ 7.46 (dd, J = 4.9, 2.8 Hz, 1H), 7.30−7.20 (m, 5H), 7.16 (t, J
= 8.6 Hz, 3H), 7.03 (dd, J = 17.2, 10.9 Hz, 1H), 5.86 (d, J = 7.6 Hz,
1H), 5.59 (dd, J = 17.2, 1.4 Hz, 1H), 5.36−5.23 (m, 2H), 2.72−2.50
(m, 2H), 2.19−2.02 (m, 2H), 1.15 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 177.4, 141.5, 139.3, 137.1, 134.5, 128.5, 128.4, 128.0, 127.5,
126.9, 126.0, 125.1, 116.9, 49.4, 38.7, 37.6, 32.7, 27.6. IR (KBr) ν/
cm−1: 3341, 3084, 3063, 3027, 2988, 2964, 2926, 2869, 1625, 1396,
1362, 1209, 918, 754, 700. HRMS (ESI) calculated for C22H28NO (M
+ H)+: 322.2159, found: 322.2165.
N-(3-(Naphthalen-2-yl)-1-(2-vinylphenyl)propyl)benzamide (3aj).
1
White solid (36.0 mg, 92%), mp 138.7−139.5 °C. H NMR (400
MHz, CDCl3): δ 7.76 (m, 3H), 7.62 (dd, J = 7.4, 6.1 Hz, 3H), 7.51
(dd, J = 7.0, 2.1 Hz, 1H), 7.47−7.40 (m, 3H), 7.38−7.29 (m, 5H),
7.27−7.22 (m, 1H), 7.19−7.11 (m, 1H), 6.37 (d, J = 7.9 Hz, 1H),
5.67−5.56 (m, 2H), 5.32 (dd, J = 10.9, 1.4 Hz, 1H), 2.94−2.76 (m,
2H), 2.43−2.25 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 166.5,
138.9, 137.2, 134.4, 134.3, 133.7, 132.1, 131.4, 128.5, 128.1(1),19
128.1, 127.7, 127.6, 127.5, 127.2, 127.0, 126.9, 126.5, 126.0, 125.4,
125.3, 117.2, 50.2, 37.4, 32.9. IR (KBr) ν/cm−1: 3289, 3057, 2924,
2854, 1635, 1600, 1533, 1313, 989, 908, 774, 749, 695. HRMS (ESI)
calculated for C28H26NO [M + H]+: 392.2010, found: 392.2009.
N-(3,3-Diphenyl-1-(2-vinylphenyl)propyl)benzamide (3ak). White
N-(3-(4-Fluorophenyl)-1-(2-vinylphenyl)propyl)benzamide (3ab).
1
White solid (24.1 mg, 67%), mp 106.7−108.5 °C. H NMR (400
MHz, CDCl3): δ 7.71 (d, J = 7.3 Hz, 2H), 7.55−7.45 (m, 2H), 7.40 (t,
J = 7.5 Hz, 2H), 7.37−7.27 (m, 3H), 7.19−7.06 (m, 3H), 6.95 (t, J =
8.7 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H), 5.62 (dd, J = 17.2, 1.2 Hz, 1H),
5.53 (d, J = 7.3 Hz, 1H), 5.33 (dd, J = 10.9, 1.2 Hz, 1H), 2.75−2.56
(m, 2H), 2.33−2.22 (m, 1H), 2.22−2.11 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 166.5, 162.6 (d, J = 242), 138.7, 137.3, 136.9 (d, J =
3), 134.4, 134.3, 131.5, 129.8(d, J = 8), 128.6, 128.1, 127.8, 127.1,
126.9, 125.3, 117.3, 115.2 (d, J = 21), 49.8, 37.7, 32.9. IR (KBr) ν/
cm−1: 3335, 3276, 3059, 2924, 2851, 1634, 1536, 1509, 1491, 1450,
1315, 1224, 994, 914, 829, 755, 747, 692. HRMS (ESI) calculated for
C24H23FNO [M + H]+: 360.1751, found: 360.1758.
1
solid (30.5 mg, 73%), mp 179.5−180.4 °C. H NMR (400 MHz,
CDCl3): δ 7.63−7.56 (m, 2H), 7.46 (dd, J = 9.5, 5.1 Hz, 2H), 7.37 (t, J
= 7.5 Hz, 2H), 7.28 (dd, J = 6.7, 4.3 Hz, 6H), 7.24 (dd, J = 6.2, 4.5 Hz,
4H), 7.18 (tdd, J = 6.8, 4.6, 2.0 Hz, 3H), 6.75 (dd, J = 17.2, 10.9 Hz,
1H), 6.30 (d, J = 7.5 Hz, 1H), 5.52 (dd, J = 17.2, 1.4 Hz, 1H), 5.44
(dd, J = 14.1, 7.7 Hz, 1H), 5.17 (dd, J = 10.9, 1.4 Hz, 1H), 3.95 (t, J =
7.6 Hz, 1H), 2.80−2.73 (m, 1H), 2.62−2.52 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 166.3, 144.5, 143.7, 138.9, 137.0, 134.3, 134.2, 131.5,
128.7, 128.6, 128.0, 127.7, 126.9, 126.5, 125.4, 117.0, 49.3, 48.3, 41.6.
IR (KBr) ν/cm−1: 3299, 3058, 3025, 1636, 1538, 1493, 1311, 993, 911,
756, 749, 697. HRMS (ESI) calculated for C30H28NO [M + H]+:
418.2156, found: 418.2165.
N-(3-(4-Chlorophenyl)-1-(2-vinylphenyl)propyl)benzamide (3ac).
1
White solid (25.1 mg, 70%), mp 128.3−129.1 °C. H NMR (400
MHz, CDCl3): δ 7.73−7.64 (m, 2H), 7.50−7.44 (m, 2H), 7.39 (t, J =
7.4 Hz, 2H), 7.34−7.30 (m, 1H), 7.29−7.27 (m, 1H), 7.27−7.19 (m,
3H), 7.11 (m, 3H), 6.27 (d, J = 7.5 Hz, 1H), 5.60 (dd, J = 17.2, 1.4 Hz,
1H), 5.53 (dd, J = 14.8, 7.5 Hz, 1H), 5.33 (dd, J = 10.9, 1.3 Hz, 1H),
2.72−2.57 (m, 2H), 2.33−2.22 (m, 1H), 2.22−2.12 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 166.5, 139.8, 138.7, 137.3, 134.4, 134.3,
131.8, 131.6, 129.8, 128.6, 128.5, 128.1, 127.8, 127.1, 126.9, 125.3,
117.3, 49.9, 37.4, 32.1. IR (KBr) ν/cm−1: 3310, 3057, 2927, 2852,
1633, 153.8, 1491, 1450, 990, 909, 820, 751, 697. HRMS (ESI)
calculated for C24H23ClNO [M + H]+: 376.1459, found: 376.1463.
N-(3-p-Tolyl-1-(2-vinylphenyl)propyl)benzamide (3ad). White
solid (18.5 mg, 52%), mp 128.1−128.6 °C. 1H NMR (400 MHz,
CDCl3): δ 7.70−7.61 (m, 2H), 7.52−7.43 (m, 2H), 7.43−7.26 (m,
5H), 7.14 (dd, J = 17.2, 11.0 Hz, 1H), 7.08 (s, 4H), 6.31 (d, J = 7.9 Hz,
1H), 5.62 (dd, J = 17.2, 1.4 Hz, 1H), 5.54 (dd, J = 14.5, 7.7 Hz, 1H),
5.34 (dd, J = 10.9, 1.4 Hz, 1H), 2.73−2.61 (m, 2H), 2.31 (s, 3H),
2.27−2.13 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 166.6, 139.2,
138.3, 137.1, 135.5, 134.5, 131.4, 129.2, 128.5, 128.3, 128.1, 127.6,
127.0, 126.9, 125.4, 117.1, 50.2, 37.6, 32.3, 21.0. IR (KBr) ν/cm−1:
3311, 3063, 2962, 2915, 2853, 1634, 1545, 1491, 1325, 989, 929, 812,
768, 693. HRMS (ESI) calculated for C25H26NO [M + H]+: 356.2002,
found: 356.2009.
N-(2-Vinylbenzyl)benzamide (4). White solid (9.5 mg, 40%), mp
99.7−100.5 °C. H NMR (400 MHz, CDCl3): δ 7.79−7.68 (m, 2H),
1
7.55 (d, J = 7.9 Hz, 1H), 7.51−7.45 (m, 1H), 7.44−7.36 (m, 2H), 7.30
(dt, J = 8.7, 7.4 Hz, 3H), 7.01 (dd, J = 17.3, 11.0 Hz, 1H), 6.26 (s,
1H), 5.70 (dd, J = 17.3, 1.2 Hz, 1H), 5.36 (dd, J = 11.0, 1.2 Hz, 1H),
4.70 (d, J = 5.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 167.1,
137.2, 134.7, 134.4, 133.8, 131.5, 129.6, 128.6, 128.3, 128.1, 126.9,
126.3, 116.9, 42.3. IR (KBr) ν/cm−1: 3341, 3058, 2921, 1640, 1578,
1548, 1480, 1310, 981, 917, 768, 695. HRMS (ESI) calculated for
C16H16NO [M + H]+: 238.1226, found: 238.1225.
General Procedure for the Preparation of 5a−5g, 5j−5l.
Compound 5a was synthesized according to a known procedure.20
A
mixture of MePPh3Br (1970.0 mg, 5.5 mmol) and KOt-Bu (650.0 mg,
5.75 mmol) in dry THF (10 mL) was stirred at room temperature for
1 h. After addition of 5a′ (1330.0 mg, 5 mmol), the reaction mixture
was stirred at room temperature for 1 h. The solvent was then
evaporated under reduced pressure. The residue was purified by
column chromatography (petroleum ether:EtOAc = 10:1) over silica
gel to give 5a as a colorless oil (1053.3 mg, yield: 80%).
(3,4-Dihydroisoquinolin-2(1H)-yl)(2-vinylphenyl)methanone (5a).
1
Colorless oil (1053.3 mg, 80%). Atropisomer. H NMR (400 MHz,
N-(3-(Thiophen-2-yl)-1-(2-vinylphenyl)propyl)benzamide (3ag).
Yellow solid (6.9 mg, 20%), mp 120.1−120.8 °C. 1H NMR (400
MHz, CDCl3): δ 7.74−7.64 (m, 2H), 7.52−7.44 (m, 2H), 7.42−7.32
(m, 3H), 7.31−7.28 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.20−7.13 (m,
1H), 7.13−7.09 (m, 1H), 6.90 (dd, J = 5.1, 3.5 Hz, 1H), 6.81 (d, J =
2.5 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 5.60 (m, 2H), 5.35 (dd, J = 10.9,
1.3 Hz, 1H), 2.98−2.83 (m, 2H), 2.40−2.21 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 166.6, 144.1, 138.7, 137.2, 134.4, 134.3, 131.5, 128.5,
128.1, 127.8, 127.1, 127.0, 126.9, 125.4, 124.5, 123.3, 117.3, 49.9, 37.7,
26.9. IR (KBr) ν/cm−1: 3314, 3065, 2924, 2852, 1634, 1578, 1540,
1491, 1450, 1324, 991, 930, 773, 696. HRMS (ESI) calculated for
C22H22NOS (M + H)+: 348.1412, found: 348.1417.
CDCl3): δ 7.60 (t, J = 8.2 Hz, 1.6H), 7.37 (m, 1.6H), 7.30 (m, 1.6H),
7.21 (m, 6H), 7.11 (dd, J = 11.5, 6.8 Hz, 1.6H), 6.74 (m, 2.2H), 5.74
(m, 1.6H), 5.28 (m, 1H), 5.22 (d, J = 11.0 Hz, 0.6H), 4.95 (d, J = 15.5
Hz, 2H), 4.32 (s, 1.2H), 4.05 (m, 1.2H), 3.41 (t, J = 5.9 Hz, 2H), 2.97
(t, J = 5.4 Hz, 1.2H), 2.75 (t, J = 5.7 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 170.1, 169.8, 135.5, 135.4, 134.6, 134.4, 133.9, 133.6, 133.4,
132.8, 132.7, 129.2, 129.1, 128.9, 128.7, 128.1, 128.0, 126.9, 126.8,
126.7, 126.6, 126.5, 126.4, 126.3, 126.0, 125.6, 125.5, 116.8, 116.7,
48.7, 44.5, 44.2, 39.9, 29.5, 28.5. IR (KBr) v/cm−1: 3022, 3057, 2927,
2852, 1633, 1538, 1491, 1450, 990, 909, 820, 751, 697. HRMS (ESI)
calculated for C18H18NO [M + H]+: 264.1375, found: 264.1383.
(3,4-Dihydroisoquinolin-2(1H)-yl)(2-(prop-1-enyl)phenyl)-
methanone (5b). Colorless oil (1109.4 mg, 80%). Atropisomer and
Z/E isomer. 1H NMR (400 MHz, CDCl3): δ 7.48 (m, 2.2H), 7.37 (m,
3.6H), 7.33 (d, J = 7.5 Hz, 3H), 7.28 (m, 6.5H), 7.20 (m, 8.8H), 7.15
(m, 5.9H), 7.10 (dd, J = 9.8, 5.8 Hz, 5.3H), 6.81 (t, J = 7.0 Hz, 1.8H),
6.40 (m, 3.8H), 6.20 (m, 2.6H), 5.81 (m, 1.6H), 5.65 (m, 1.1H), 4.92
(m, 5.1H), 4.30 (d, J = 7.2 Hz, 3.1H), 4.03 (m, 3.7H), 3.40 (m, 4.8H),
2.95 (mz, 3.8H), 2.73 (d, J = 5.4 Hz, 5.1H), 1.84 (dd, J = 7.1, 1.7 Hz,
3.5H), 1.81 (dd, J = 6.6, 1.4 Hz, 2.9H), 1.71 (dd, J = 7.1, 1.7 Hz, 3H),
N-(3-(Naphthalen-1-yl)-1-(2-vinylphenyl)propyl)benzamide (3ai).
1
White solid (36.4 mg, 93%), mp 145.1−146.3 °C. H NMR (400
MHz, CDCl3): δ 7.89 (dd, J = 5.3, 4.3 Hz, 1H), 7.83 (dd, J = 6.8, 2.7
Hz, 1H), 7.70 (t, J = 7.1 Hz, 3H), 7.54−7.26 (m, 11H), 7.17 (dd, J =
17.2, 10.9 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 5.71−5.56 (m, 2H), 5.31
(dd, J = 10.9, 1.3 Hz, 1H), 3.27−3.14 (m, 1H), 3.13−3.01 (m, 1H),
2.49−2.24 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 166.6, 139.0,
137.5, 137.4, 134.5, 133.9, 131.7, 131.5, 128.8, 128.6, 128.1, 127.8,
8561
dx.doi.org/10.1021/jo501179t | J. Org. Chem. 2014, 79, 8557−8565

The Journal of Organic Chemistry
Article
1.63 (dd, J = 6.5, 1.4 Hz, 1.9H). 13C NMR (100 MHz, CDCl3): δ
170.3, 170.2, 169.9, 169.8, 136.4, 136.3, 134.8, 134.7, 134.6, 134.5,
134.4, 134.1, 133.9, 133.0, 132.8, 129.5, 128.7, 128.6(8)19, 128.6(5)19,
128.6, 128.5, 127.6, 127.5, 127.1, 127.0, 126.9, 126.8, 126.6, 126.5,
126.4, 126.3, 126.2, 126.1, 126.0, 125.8, 125.6, 125.5, 48.8, 48.6, 44.4,
44.3, 44.2, 44.1, 39.9, 39.8, 29.4, 28.5, 18.8, 18.5, 14.6, 14.5. IR (KBr)
v/cm−1: 3022, 2960, 2933, 2870, 2850, 1636, 1450, 1429, 1368, 1299,
964, 752. HRMS (ESI) calculated for C19H20NO [M + H]+: 278.1531,
found: 278.1539.
1.83 (s, 1H), 1.52 (m, 10H). 13C NMR (100 MHz, CDCl3): δ 170.6,
170.0, 145.2, 145.1, 136.4, 136.3, 134.9, 134.8, 134.5, 134.0,
132.9(4)19, 132.9(1)19, 130.0, 129.8, 129.0, 128.5, 128.4, 126.6(1)19,
126.6, 126.5(8)19, 126.5, 126.2, 126.1(5)19, 126.1, 125.9, 119.1, 118.7,
48.6, 44.3, 44.1, 39.7, 37.4, 37.1, 29.7, 29.6, 29.4, 28.7, 28.5, 28.3, 27.9,
27.7, 26.5, 26.4. IR (KBr) ν/cm−1: 3061, 3023, 2926, 2851, 1637,
1482, 1447, 1428, 1299, 1257, 1148, 843, 749. HRMS (ESI) calculated
for C23H26NO [M + H]+: 332.2001, found: 332.2009.
(2-(Cyclopentylidenemethyl)phenyl)(3,4-dihydroisoquinolin-
2(1H)-yl)methanone (5g). Colorless oil (1111.0 mg, 70%).
(3,4-Dihydroisoquinolin-2(1H)-yl)(2-(pent-1-enyl)phenyl)-
1
methanone (5c). Colorless oil (992.6 mg, 65%). Atropisomer and Z/
Atropisomer. H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.9 Hz,
1
E isomer. H NMR (400 MHz, CDCl3): δ 7.51 (m, 1H), 7.38−7.34
1H), 7.38 (d, J = 7.7 Hz, 1H), 7.36−7.29 (m, 2H), 7.22−7.16 (m,
6H), 7.13 (m, 3H), 7.06 (m, 3H), 6.75 (d, J = 7.4 Hz, 1H), 6.35−6.29
(m, 1H), 6.22−6.15 (m, 1H), 4.93 (m, 2H), 4.42−4.30 (m, 1H), 4.26
(s, 2H), 3.69−3.59 (m, 1H), 3.37 (t, J = 5.8 Hz, 2H), 3.03−2.84 (m,
3H), 2.71 (t, J = 5.8 Hz, 2H), 2.55−2.38 (m, 4H), 2.27 (m, 4H), 1.78
(m, 4H), 1.51−1.28 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 170.6,
170.1, 149.5, 149.4, 135.8, 135.7, 135.4, 134.4, 133.9, 133.1, 133.0,
129.0, 128.7, 128.6, 128.0, 127.9, 126.6, 126.5(7)19, 126.5, 126.3,
126.2, 126.1, 126.0, 125.7, 117.3, 117.0, 48.7, 44.4, 44.1, 39.8, 35.6,
34.9, 31.3, 30.9, 29.4, 28.7, 27.0, 26.7, 25.5, 25.3. IR (KBr) ν/cm−1:
3060, 3023, 2950, 2866, 1635, 1480, 1449, 1428, 1299, 1256, 1148,
832,749. HRMS (ESI) calculated for C22H24NO [M + H]+: 318.1845,
found: 318.1852.
(m, 2.2H), 7.33 (dd, J = 6.3, 3.2 Hz, 2H), 7.29 (dd, J = 6.2, 3.3 Hz,
1H), 7.27 (d, J = 1.2 Hz, 1H), 7.24 (dd, J = 7.3, 1.3 Hz, 2H), 7.22−
7.17 (m, 5.3H), 7.15 (dd, J = 7.2, 3.4 Hz, 4H), 7.08 (q, J = 4.0 Hz,
3H), 6.83−6.76 (m, 1H), 6.47−6.10 (m, 4H), 5.71 (m, 1H), 5.59 (m,
0.72H), 4.87 (m, 3.5H), 4.30 (s, 2.4H), 3.98 (s, 2H), 3.40 (d, J = 3.6
Hz, 3.5H), 2.95 (dt, J = 12.1, 6.0 Hz, 2.6H), 2.73 (t, J = 5.8 Hz, 3.6H),
2.33−2.16 (m, 2.7H), 2.16−2.04 (m, 2.3H), 1.96 (m, 1H), 1.42 (m,
3.8H), 1.34−1.20 (m, 2.6H), 0.95−0.77 (m, 8.6H). 13C NMR (100
MHz, CDCl3): δ 170.4, 170.3, 170.0, 169.9, 136.4, 136.3, 134.9,
134.8(2)19, 134.8, 134.7(4)19, 134.7, 134.6(4)19, 134.6, 134.5, 134.4,
134.3, 134.1, 133.9(4)19, 133.9, 132.9, 132.8, 129.4(4)19, 129.4(2)19,
129.1, 129.0, 128.9(5)19, 128.9(2)19, 128.7, 128.6, 128.5, 127.0, 126.8,
126.7, 126.6, 126.5(6)19, 126.5, 126.4, 126.3(4)19, 126.3, 126.2(6)19,
126.2(4)19, 126.2(2)19, 126.1, 126.0, 125.9, 125.8, 125.7, 125.6, 48.7,
48.6, 44.4, 44.3, 44.2, 39.9, 39.8, 35.2, 35.1, 30.7, 30.6, 29.5, 29.4, 28.5,
23.1, 22.9, 22.4, 22.1, 14.0, 13.9, 13.7, 13.6. IR (KBr) ν/cm−1: 3030,
2962, 3935, 2877, 2854, 1632, 1510, 1450, 1430, 970, 751. HRMS
(ESI) calculated for C21H24NO [M + H]+: 306.1845, found: 306.1852.
(3,4-Dihydroisoquinolin-2(1H)-yl)(2-(prop-1-en-2-yl)phenyl)-
(E)-(3,4-Dihydroisoquinolin-2(1H)-yl)(2-styrylphenyl)methanone
(5j). White solid (1272.9 mg, 75%), mp 82.3−85.5 °C. 1H NMR (400
MHz, CDCl3): δ 7.69 (m, 0.7H), 7.38 (m, 1.7H), 7.33−7.23 (m,
5.1H), 7.23−7.15 (m, 8.5H), 7.15−7.05 (m, 5.1H), 7.01 (m, 2.1H),
6.76 (dd, J = 15.8, 7.5 Hz, 0.7H), 6.66−6.57 (m, 1H), 6.53 (m, 0.7H),
5.14−4.79 (m, 2H), 4.36 (d, J = 11.9 Hz, 1.4H), 4.13 (s, 1H), 3.97 (d,
J = 5.4 Hz, 1H), 3.45 (d, J = 5.7 Hz, 2H), 2.94 (m, 1.4H), 2.72 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 170.2, 170.1, 169.8, 169.7,
136.9, 136.7, 136.6, 136.5, 136.4, 135.7, 135.6, 134.6, 134.5,
134.4(4)19, 134.4(3)19, 134.2, 133.9, 133.8, 132.9, 132.8, 132.7,
132.0, 131.5, 131.3, 129.8, 129.4, 129.3, 129.1, 129.0, 128.9(1)19,
128.9, 128.7, 128.6(9)19, 128.6(4)19, 128.6, 128.4, 128.2, 128.0, 127.9,
127.8, 127.6, 127.5, 127.4(5)19, 127.3, 127.1, 126.9, 126.8(7)19,
126.8(4)19, 126.8, 126.7(7)19, 126.6(5)19, 126.5(6)19, 126.4,
126.3(7)19, 126.3, 126.0, 125.9, 125.7, 125.6, 125.0, 48.9, 48.8, 44.6,
44.5, 44.3, 44.2, 40.1, 39.9, 29.8, 29.5, 29.4, 28.6. IR (KBr) v/cm−1:
3023, 2925, 2841, 1634, 1495, 1448, 1429, 1256, 962, 762. HRMS
(ESI) calculated for C24H22NO [M + H]+: 340.1689, found: 340.1696.
(E)-(2-(2-Chlorovinyl)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)-
methanone (5k). Colorless oil (893.4 mg, 60%). Atropisomer and Z/
E isomer. 1H NMR (400 MHz, CDCl3): δ 7.95−7.87 (m, 0.7H),
7.47−7.05 (m, 12H), 6.92−6.56 (m, 3H), 6.30 (d, J = 8.1 Hz, 0.4H),
6.15 (d, J = 8.0 Hz, 0.3H), 4.92 (s, 2H), 4.32 (d, J = 9.6 Hz, 1.4H),
4.01 (m, 1.4H), 3.42 (dd, J = 12.4, 6.4 Hz, 2H), 2.97 (dd, J = 14.3, 6.2
Hz, 1.4H), 2.75 (d, J = 5.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
169.7, 169.6, 169.3, 169.2, 136.5, 136.4, 135.1, 135.0, 134.5, 134.4,
133.8, 133.7, 132.7, 132.6, 132.5, 131.7, 131.6, 130.1, 130.0, 129.6,
129.5, 129.4(5)19, 129.4, 129.1, 128.9, 128.8, 128.7, 128.4, 128.3(8)19,
127.0, 126.9, 126.8, 127.7(8)19, 126.7, 126.6(4)19, 126.6, 126.4,
126.3(8)19, 126.3(6)19, 126.1, 126.0(6)19, 126.0, 125.9, 125.8, 121.4,
121.3, 120.0, 48.8(8)19, 48.8(6)19, 44.6, 44.5, 44.3, 44.2, 29.5, 29.4,
28.5. IR (KBr) v/cm−1: 3067, 2926, 1634, 1430, 1299, 1258, 979, 750.
HRMS (ESI) calculated for C18H17ClNO [M + H]+: 298.0988, found:
298.0993.
1
methanone (5d). Colorless oil (693.4 mg, 50%). Atropisomer. H
NMR (400 MHz, CDCl3): δ 7.38−7.34 (m, 1H), 7.34−7.31 (m,
1.7H), 7.30 (dd, J = 4.4, 3.0 Hz, 1.7H), 7.29−7.27 (m, 1H), 7.27−7.26
(m, 0.7H), 7.26−7.22 (m, 1H), 7.21 (dd, J = 6.1, 3.0 Hz, 0.7H), 7.19−
7.16 (m, 1.7H), 7.16−7.11 (m, 2.7H), 7.09 (dd, J = 11.2, 4.9 Hz, 2H),
6.82 (d, J = 7.4 Hz, 0.7H), 5.15−5.11 (m, 1H), 5.08 (d, J = 0.7 Hz,
1H), 4.98 (dd, J = 3.0, 1.5 Hz, 0.7H), 4.96 (s, 0.7H), 4.67 (s, 0.7H),
4.34 (s, 1.7H), 4.15−4.00 (m, 0.7H), 3.90−3.74 (m, 0.7H), 3.42 (m,
2H), 2.91 (d, J = 5.5 Hz, 1.7H), 2.75 (s, 2H), 2.10 (s, 3H), 1.97 (s,
2H), 1.31 (s, 0.7H). 13C NMR (100 MHz, CDCl3): δ 170.8, 170.3,
143.7, 143.3, 140.6, 140.5, 134.8, 134.6, 133.9, 132.8, 132.7, 129.0,
128.9, 128.6, 128.0, 127.9, 127.5, 127.4, 126.8(3)19, 126.8, 126.7(8)19,
126.7(6)19, 126.7, 126.6, 126.5, 126.3, 126.2, 125.9, 116.1, 116.0, 48.9,
44.5, 44.3, 39.8, 29.5, 28.2, 23.6, 23.5. IR (KBr) ν/cm−1: 3063, 2960,
2870, 2850, 1630, 1530, 1480, 1360, 890, 750. HRMS (ESI) calculated
for C19H20NO [M + H]+: 278.1532, found: 278.1539.
(3,4-Dihydroisoquinolin-2(1H)-yl)(2-(2-methylprop-1-enyl)-
phenyl)methanone (5e). Colorless oil (947.0 mg, 65%). Atropisomer.
1H NMR (400 MHz, CDCl3): δ 7.38−7.32 (m, 2H), 7.27 (m, 5.4H),
7.21 (t, J = 7.0 Hz, 3H), 7.18−7.13 (m, 2.7H), 7.13−7.07 (m, 2H),
6.80 (d, J = 7.1 Hz, 1H), 6.23 (s, 0.9H), 6.07 (s, 1H), 5.00 (s, 0.9H),
4.84 (s, 0.9H), 4.39 (s, 1H), 4.26 (d, J = 3.5 Hz, 1.8H), 3.60 (s, 1H),
3.38 (d, J = 3.5 Hz, 1.8H), 3.01−2.85 (m, 2H), 2.72 (d, J = 4.2 Hz,
2H), 1.82 (s, 5.4H), 1.59 (d, J = 1.1 Hz, 3H), 1.45 (d, J = 1.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 170.6, 170.1, 137.5, 137.4, 136.3,
136.2, 135.3, 135.1, 134.5, 133.9, 133.0, 132.9(7)19, 129.8, 129.6,
129.0, 128.6, 128.5, 126.8, 126.6, 126.5(7)19, 126.5(5)19, 126.5, 126.6,
126.1, 126.0, 125.7, 122.2, 121.7, 77.4, 77.1, 76.7, 48.7, 44.2, 44.1, 39.8,
29.4, 28.7, 26.5, 25.7, 19.5, 19.1. IR (KBr) ν/cm−1: 3063, 2972, 2929,
2870, 2852, 1635, 1483, 1450, 1428, 1369, 1335, 1300, 850, 751.
HRMS (ESI) calculated for C20H22NO [M + H]+: 292.1686, found:
292.1696.
(2-(Cyclohexylidenemethyl)phenyl)(3,4-dihydroisoquinolin-
2(1H)-yl)methanone (5f). Colorless oil (1209.2 mg, 70%). Atro-
pisomer. 1H NMR (400 MHz, CDCl3): δ 7.36−7.30 (m, 2H), 7.27 (d,
J = 6.4 Hz, 3H), 7.21 (t, J = 8.2 Hz, 5H), 7.13 (m, 6H), 6.82 (d, J = 7.3
Hz, 1H), 6.19 (s, 1H), 6.08 (s, 1H), 5.06 (m, 1H), 4.77 (m, 1H), 4.28
(m, 3H), 3.72 (s, 1H), 3.39 (d, J = 5.0 Hz, 2H), 2.93 (s, 2H), 2.74 (t, J
= 5.6 Hz, 2H), 2.30 (d, J = 5.8 Hz, 2H), 2.18 (s, 4H), 2.05 (m, 3H),
(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(2-vinylphenyl)-
1
methanone (5l). Colorless oil (1293.6 mg, 80%). Atropisomer. H
NMR (400 MHz, CDCl3): δ 7.61 (t, J = 7.3 Hz, 1.7H), 7.38 (t, J = 7.5
Hz, 1.7H), 7.34−7.28 (m, 1.7H), 7.24 (t, J = 8.0 Hz, 1.7H), 6.80−6.64
(m, 3.4H), 6.59 (s, 1H), 6.33 (s, 0.7H), 5.75 (m, 1.7H), 5.30 (d, J =
11.1 Hz, 1H), 5.24 (d, J = 11.0 Hz, 0.7H), 4.88 (m, 2H), 4.26 (s,
1.4H), 4.13−4.02 (m, 0.7H), 4.01−3.93 (m, 0.7H), 3.90−3.82 (m,
8.2H), 3.75 (s, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.90 (s, 1.4H), 2.68 (t, J
= 5.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 170.0, 169.7, 148.0,
147.9, 147.8, 147.7, 135.5, 135.4, 134.3, 133.5, 133.4, 129.1, 129.0,
128.0, 126.5, 126.4, 126.2, 125.6, 125.5, 125.4, 124.6, 124.4, 116.7,
116.6, 111.6, 111.4, 109.4, 108.8, 56.0, 48.4, 44.6, 43.8, 39.9, 28.9, 28.1.
8562
dx.doi.org/10.1021/jo501179t | J. Org. Chem. 2014, 79, 8557−8565

The Journal of Organic Chemistry
Article
IR (KBr) ν/cm−1: 3061, 2934, 2835, 1632, 1518, 1485, 1450, 1432,
1012, 918, 754. HRMS (ESI) calculated for C20H22NO3 [M + H]+:
324.1587, found: 324.1594.
CDCl3): δ 170.8, 141.2, 137.4, 136.3, 135.3, 133.7, 129.0, 128.9, 128.3,
127.8, 126.9, 126.6, 126.1, 55.6, 39.9, 39.6, 30.9, 29.0, 21.5. Trans
isomer: 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, J = 7.4, 1.5 Hz, 1H),
7.46−7.34 (m, 2H), 7.22 (dd, J = 10.0, 2.5 Hz, 2H), 7.16 (m, 2H),
6.87 (d, J = 7.4 Hz, 1H), 4.38 (m, 1H), 3.88 (d, J = 11.3 Hz, 1H),
3.36−3.15 (m, 2H), 3.12−3.00 (m, 1H), 2.99−2.90 (m, 1H), 2.51 (d, J
= 13.3 Hz, 1H), 2.26−2.12 (m, 1H), 0.87 (d, J = 6.7 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 171.1, 136.6, 136.0, 135.7, 135.0, 130.6,
129.6, 128.6, 128.2, 127.7, 127.5, 127.2, 126.1, 62.8, 42.9, 42.7, 39.0,
28.8, 16.4. IR (KBr) ν/cm−1: 3033, 2960, 2930, 2871, 1635, 1603,
1400, 1380, 771, 756. HRMS (ESI) calculated for C19H20NO [M +
H]+: 278.1539, found: 278.1538.
General Procedure for the Preparation of 5h and 5i. A
mixture of potassium vinyltrifluoroborate (1000.0 mg, 7.5 mmol),
PdCl2 (17.8 mg, 0.1 mmol), PPh3 (78.7 mg, 0.3 mmol), Cs2CO3
(3930.0 mg, 15 mmol), and 5h′ (1650.0 mg, 5 mmol) in THF/H2O
(9:1, 10 mL) was stirred and heated at 85 °C in a sealed tube. After 22
h, the reaction mixture was cooled to room temperature and diluted
with H2O (15 mL). After extraction with CH2Cl2 (15 mL × 3) and
evaporation in vacuo, the crude product was obtained. The crude was
purified by silica gel chromatography (petroleum ether:EtOAc = 10:1)
to give 5h as a colorless oil (1250.0 g, yield: 90%).21
14-Propyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
(3,4-Dihydroisoquinolin-2(1H)-yl)(4-methyl-2-vinylphenyl)-
isoquinolin-8(13H)-one (6c). White solid (26.6 mg, 87%), mp 158.3−
1
1
methanone (5h). Colorless oil (1178.8 mg, 85%). Atropisomer. H
159.5 °C. Cis isomer: H NMR (400 MHz, CDCl3): δ 7.69 (dd, J =
NMR (400 MHz, CDCl3): δ 7.41 (d, J = 9.0 Hz, 1.7H), 7.21 (t, J = 6.9
Hz, 3H), 7.17 (d, J = 4.1 Hz, 2.7H), 7.14 (d, J = 2.3 Hz, 2.1H), 7.11 (s,
1.7H), 6.85 (d, J = 7.5 Hz, 0.7H), 6.70 (m, 1.7H), 5.74 (m, 1.7H), 5.27
(m, 1H), 5.20 (m, 0.7H), 4.94 (d, 2H), 4.33 (d, 1.4H), 4.00 (s, 1.4H),
3.43 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.7 Hz, 1.4H), 2.76 (t, J = 5.8 Hz,
2H), 2.39 (s, 5.1H). 13C NMR (100 MHz, CDCl3): δ 170.4, 170.0,
139.0, 138.9, 134.7, 134.3, 133.9, 133.7, 133.6, 133.2, 132.9, 132.8,
132.8, 132.7, 129.1, 129.0, 128.8, 128.7, 128.6, 126.8, 126.7, 126.6,
126.5(2)a, 126.5, 126.3, 126.1, 126.0, 125.9, 116.3, 116.2, 48.7, 44.5,
44.2, 39.9, 29.5, 28.5, 21.4. IR(KBr) ν/cm−1: 3030, 2960, 2930, 2870,
2850, 1636, 1584, 1496, 1431, 1256, 990, 930, 820, 735. HRMS (ESI)
calculated for C19H20NO [M + H]+: 278.1531, found: 278.1539.
(3,4-Dihydroisoquinolin-2(1H)-yl)(5-methyl-2-vinylphenyl)-
7.5, 1.3 Hz, 1H), 7.41 (td, J = 7.4, 1.4 Hz, 1H), 7.34 (dt, J = 7.5, 3.8
Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.19−7.11 (m, 3H), 7.03−6.95 (m,
1H), 4.74−4.63 (m, 2H), 3.42−3.32 (m, 1H), 3.01 (m, 1H), 2.95−
2.86 (m, 2H), 2.64−2.56 (m, 1H), 2.49 (m, 1H), 1.55−1.42 (m, 1H),
1.28−1.14 (m, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.4, 137.5, 136.1, 135.6, 134.2, 130.8, 128.8, 128.7, 128.3,
127.2, 126.6, 126.5, 125.9, 58.1, 47.8, 39.2, 37.5, 33.2, 29.2, 20.5, 14.0.
1
Trans isomer: H NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 7.4, 1.5
Hz, 1H), 7.44−7.35 (m, 2H), 7.24 (d, J = 4.0 Hz, 2H), 7.19−7.12 (m,
2H), 6.88 (d, J = 7.4 Hz, 1H), 4.36 (m, 1H), 3.91 (d, J = 11.3 Hz, 1H),
3.22 (m, 1H), 3.14−3.02 (m, 2H), 2.93 (m, 1H), 2.78 (d, J = 13.5 Hz,
1H), 2.03−1.92 (m, 1H), 1.61−1.49 (m, 1H), 1.22−1.03 (m, 3H),
0.80 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.1, 136.8,
136.1, 136.0, 135.0, 130.6, 129.5, 128.7, 128.6, 127.7, 127.5, 127.1,
126.0, 62.0, 48.1, 42.9, 34.1, 30.6, 28.9, 20.7, 14.1. IR (KBr) ν/cm−1:
3000, 2941, 2927, 2868, 2852, 1632, 1570, 1459, 1419, 1255, 741.
HRMS (ESI) calculated for C21H24NO [M + H]+: 306.1846, found:
306.1852.
1
methanone (5i). Colorless oil (1178.8 mg, 85%). Atropisomer. H
NMR (400 MHz, CDCl3): δ 7.48 (t, J = 8.2 Hz, 1.7H), 7.19 (dd, J =
7.0, 4.5 Hz, 3H), 7.15 (d, J = 5.0 Hz, 2.7H), 7.09 (d, J = 6.4 Hz, 2.1H),
7.04 (d, J = 10.2 Hz, 1.7H), 6.82 (d, J = 7.4 Hz, 0.7H), 6.67 (m, 1.7H),
5.68 (t, J = 17.2 Hz, 1.7H), 5.26−5.19 (m, 1H), 5.15 (d, J = 11.4 Hz,
0.7H), 4.93 (d, 2H), 4.32 (d, 1.4H), 4.07 (d, J = 5.7 Hz, 0.7H), 3.99−
3.86 (m, 0.7H), 3.42 (t, J = 5.9 Hz, 2H), 2.96 (d, J = 3.5 Hz, 1.4H),
2.75 (t, J = 5.3 Hz, 2H), 2.34 (s, 3H), 2.32 (s, 2.1H). 13C NMR (100
MHz, CDCl3): δ 170.3, 169.9, 138.1, 135.5, 135.3, 134.6, 133.9, 133.4,
133.3, 132.9, 132.8, 131.6, 131.5, 130.1, 130.0, 128.9, 128.7, 126.9,
126.8, 126.7(5)19, 126.7(3)19, 126.6, 126.0, 125.5, 125.4, 115.7, 115.6,
48.6, 44.4, 44.2, 39.9, 29.5, 28.5, 21.2, 21.1. IR (KBr) ν/cm−1: 3021,
2922, 2860, 1636, 1583, 1495, 1436, 1259, 1207, 987, 930, 827, 751.
HRMS (ESI) calculated for C19H20NO [M + H]+: 278.1533, found:
278.1539.
General Procedure for the Intramolecular Cyclization
Reaction of 5a−5k Promoted by KOt-Bu/DMF. To a dried 10
mL reaction tube was added 5a (26.3 mg, 0.1 mmol), KOt-Bu (33.7
mg, 0.3 mmol), and DMF (1.0 mL). The mixture was stirred at 90 °C
for 0.5 h under an argon atmosphere. After being cooled down to
room temperature, the reaction mixture was diluted with CH2Cl2 (10
mL) and washed with water (10 mL × 2) and brine (10 mL × 1).
After being dried over MgSO4, the organic layer was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (petroleum ether:EtOAc = 5:1) to give 6a as a white solid (16.6
mg, yield: 63%).
5,6,14,14a-Tetrahydrobenzo[5,6]azepino[2,1-a]isoquinolin-8-
(13H)-one (6a). White solid (16.6 mg, 63%), mp 129.0−129.9 °C. 1H
NMR (400 MHz, CDCl3): δ 7.70 (m, 1H), 7.39 (m, 2H), 7.18 (m,
4H), 6.95 (d, J = 7.1 Hz, 1H), 4.50 (dd, J = 12.3, 5.3 Hz, 1H), 3.92
(dd, J = 8.9, 4.0 Hz, 2H), 2.99 (m, 3H), 2.76 (dd, J = 13.7, 6.4 Hz,
1H), 2.16 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 170.6, 137.4,
136.1, 136.1, 135.2, 131.0, 128.8, 128.4, 128.3, 127.2, 127.0, 126.7,
126.1, 55.5, 39.8, 39.5, 30.9, 29.0. IR (KBr) ν/cm−1: 2927, 2910, 2861,
1639, 1603, 1457, 1425, 1230, 749. HRMS (ESI) calculated for
C18H18NO [M + H]+: 264.1383, found: 264.1380.
11-Methyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one (6b). White solid (20.5 mg, 74%), mp 132.3−
133.1 °C. Cis isomer: 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.7
Hz, 1H), 7.17 (m, 4H), 7.03 (s, 1H), 6.97 (d, J = 7.0 Hz, 1H), 4.51
(dd, J = 12.3, 5.4 Hz, 1H), 3.92 (s, 2H), 2.96 (s, 3H), 2.71 (dd, J =
13.7, 6.1 Hz, 1H), 2.40 (s, 3H), 2.15 (m, 2H). 13C NMR (100 MHz,
13-Methyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one (6d). White solid (13.9 mg, 50%), mp 135.3−
1
136.1 °C. H NMR (400 MHz, CDCl3): δ 7.67 (dd, J = 7.5, 1.3 Hz,
1H), 7.49 (td, J = 7.6, 1.4 Hz, 1H), 7.39−7.30 (m, 2H), 7.21−7.12 (m,
3H), 6.95 (d, J = 7.2 Hz, 1H), 4.44 (dd, J = 12.6, 5.1 Hz, 1H), 4.01−
3.86 (m, 2H), 3.27−3.16 (m, 1H), 2.97 (t, J = 6.0 Hz, 2H), 2.24 (m,
1H), 1.82 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.5, 140.6, 136.3, 136.0, 135.1, 130.9, 128.4, 128.3, 127.0,
126.9, 126.7, 126.1, 123.8, 55.8, 49.0, 39.5, 33.4, 29.0, 17.1. IR (KBr)
ν/cm−1: 3025, 2959, 2924, 2854, 1642, 1602, 1456, 1416, 1301, 757.
HRMS (ESI) calculated for C19H20NO [M + H]+: 278.1539, found:
278.1541.
14,14-Dimethyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one (6e). White solid (17.5 mg, 60%), mp 138.4−
1
140.1 °C. H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 7.5, 1.2 Hz,
1H), 7.43 (td, J = 7.4, 1.5 Hz, 1H), 7.37 (dt, J = 7.5, 3.8 Hz, 1H),
7.25−7.16 (m, 3H), 7.15−7.09 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H),
4.39−4.28 (m, 1H), 4.15 (s, 1H), 3.34 (m, 1H), 3.27−3.16 (m, 1H),
3.00 (d, J = 13.1 Hz, 1H), 2.92−2.84 (m, 1H), 2.43 (d, J = 13.1 Hz,
1H), 0.95 (s, 3H), 0.86 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
172.3, 136.8, 136.6, 135.9, 133.1, 130.7, 129.1, 128.9, 128.8, 128.0,
127.4, 127.1, 125.8, 64.9, 47.3, 45.4, 42.4, 28.6, 25.1, 23.0. IR (KBr) ν/
cm−1: 3058, 2925, 2902, 2844, 1623, 1597, 1435, 1395, 1375, 1301,
759. HRMS (ESI) calculated for C20H22NO [M + H]+: 292.1696,
found: 292.1695.
13,14a-Dihydro-5H-spiro[benzo[5,6]azepino[2,1-a]isoquinoline-
14,1′-cyclohexan]-8(6H)-one (6f). White solid (23.9 mg, 72%), mp
223.3−224.5 °C. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 6.9 Hz,
1H), 7.39 (m, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.15 (m, 2H), 6.81 (d, J =
7.5 Hz, 1H), 4.26 (dd, J = 12.8, 5.2 Hz, 1H), 4.04 (s, 1H), 3.37 (m,
1H), 3.27−3.14 (m, 2H), 2.86 (dd, J = 15.3, 3.5 Hz, 1H), 2.62 (d, J =
13.3 Hz, 1H), 1.791.59 (m, 4H), 1.46 (m, 2H), 1.25 (m, 2H), 0.93−
0.80 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 172.1, 137.4, 136.9,
136.1, 132.8, 130.7, 129.7, 129.2, 128.7, 127.8, 127.5, 127.1, 125.7,
66.4, 48.3, 42.6, 38.3, 31.3, 29.0, 28.5, 25.6, 22.2, 21.1. IR (KBr) ν/
cm−1: 3031, 3001, 2933, 2863, 1630, 1601, 1457, 1395, 757, 722.
8563
dx.doi.org/10.1021/jo501179t | J. Org. Chem. 2014, 79, 8557−8565

The Journal of Organic Chemistry
Article
HRMS (ESI) calculated for C23H26NO [M + H]+: 332.2009, found:
332.2013.
2,3-Dimethoxy-5,6,8,13,14,14a-hexahydrobenzo[5,6]azepino-
1
[2,1-a]isoquinoline (9). White solid (24.8 mg, 80%). H NMR (400
MHz, CDCl3): δ 7.20−7.10 (m, 4H), 6.55 (d, J = 13.1 Hz, 2H), 4.46
(d, J = 14.7 Hz, 1H), 4.23−4.15 (m, 1H), 3.95 (d, J = 14.8 Hz, 1H),
3.84 (s, 3H), 3.81 (s, 3H), 3.24−3.14 (m, 1H), 3.00−2.90 (m, 1H),
2.88−2.81 (m, 1H), 2.69−2.62 (m, 1H), 2.61−2.50 (m, 2H), 1.97−
1.86 (m, 2H). 13C NMR (100 MHz, CDCl3):δ 147.5, 147.0, 142.4,
138.7, 132.2, 129.6, 128.4, 127.5, 126.0, 125.9, 111.4, 109.9, 65.4, 60.5,
56.0, 55.8, 42.6, 35.0, 31.2, 29.0.16c
13,14a-Dihydro-5H-spiro[benzo[5,6]azepino[2,1-a]isoquinoline-
14,1′-cyclopentan]-8(6H)-one (6g). White solid (23.2 mg, 73%), mp
195.1−197.0 °C. 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, J = 7.5, 1.4
Hz, 1H), 7.43 (td, J = 7.4, 1.5 Hz, 1H), 7.38 (td, J = 7.5, 1.1 Hz, 1H),
7.26−7.20 (m, 2H), 7.19−7.10 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 4.40
(s, 1H), 4.27 (m, 1H), 3.31 (m, 1H), 3.14−3.04 (m, 1H), 2.88 (m
2H), 2.68 (m, 1H), 1.77−1.63 (m, 2H), 1.53 (m, 2H), 1.42 (m, 3H),
1.11−1.02 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 171.8, 137.8,
136.9, 136.0, 133.1, 130.7, 129.3, 129.1, 128.7, 127.7, 127.5, 127.2,
126.0, 62.7, 57.0, 42.6, 42.2, 32.8, 31.2, 28.7, 23.5, 21.9. IR (KBr) ν/
cm−1: 2956, 2873, 1631, 1601, 1457, 1399, 761. HRMS (ESI)
calculated for C22H24NO [M + H]+: 318.1852, found: 318.1854.
11-Methyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one (6h). White solid (16.6 mg, 60%), mp 175.1−
(1-Phenethyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)-
methanone (Intermediate C). Colorless oil (48.0 mg, 70%).
1
Atropisomer. H NMR (400 MHz, CDCl3): δ 8.08 (m, 1H), 7.56
(m, 0.5H), 7.43 (m, 8H), 7.25 (m, 4H), 7.15 (m, 6H), 7.08 (d, J = 7.0
Hz, 1H), 7.03 (d, J = 7.0 Hz, 0.5H), 6.87 (d, J = 7.1 Hz, 0.5H), 5.93
(dd, J = 9.3, 5.0 Hz, 1H), 4.86 (d, J = 5.1 Hz, 1H), 3.79 (m, 1H), 3.51
(m, 1H), 3.37 (m, 0.5H), 3.16 (m, 0.5H), 2.88 (m, 3H), 2.69 (m,
1.5H), 2.42 (m, 0.5H), 2.22 (m, 2.5H), 1.98 (m, 0.5H). 13C NMR
(100 MHz, CDCl3): δ 171.1, 170.6, 141.8, 141.0, 137.5, 137.1, 136.7,
136.4, 133.9, 133.4, 133.0, 130.1, 129.9, 129.5, 129.4, 128.9, 128.7,
128.5, 128.4, 128.2, 127.6, 127.2, 127.0, 126.7, 126.5, 126.2, 126.1,
126.0, 58.2, 52.4, 41.1, 39.1, 38.6, 35.8, 32.8, 29.7, 29.4, 28.0. HRMS
(ESI) calculated for C24H23NO [M + H]+: 342.1850, found:
342.1852.22
1
176.0 °C. H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.7 Hz, 1H),
7.22−7.12 (m, 4H), 7.03 (s, 1H), 6.97 (d, J = 7.0 Hz, 1H), 4.51 (dd, J
= 12.3, 5.4 Hz, 1H), 3.96−3.85 (m, 2H), 3.04−2.91 (m, 3H), 2.71 (dd,
J = 13.7, 6.1 Hz, 1H), 2.40 (s, 3H), 2.25−2.09 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 170.8, 141.2, 137.4, 136.3, 135.3, 133.3, 129.0,
128.9, 128.3, 127.8, 126.9, 126.6, 126.1, 55.6, 39.9, 39.6, 30.9, 29.0,
21.5. IR (KBr) ν/cm−1: 2960, 2930, 2870, 2850, 1630, 1608, 1500,
1450, 840. HRMS (ESI) calculated for C19H20NO [M + H]+:
278.1539, found: 278.1539.
10-Methyl-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one(6i). White solid (18.3 mg, 66%), mp 140.3−
140.9 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1H), 7.24−7.12 (m,
4H), 7.10 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 4.51 (dd, J =
12.2, 5.4 Hz, 1H), 3.92 (s, 2H), 2.97 (d, J = 5.6 Hz, 3H), 2.73 (dd, J =
13.8, 6.1 Hz, 1H), 2.37 (s, 3H), 2.21−2.07 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 170.8, 136.9, 136.2, 135.9, 135.3, 134.4, 131.6, 129.3,
128.3, 128.2, 126.9, 126.7, 126.1, 55.6, 39.8, 39.5, 30.4, 29.0, 21.0. IR
(KBr) ν/cm−1: 3305, 2933, 2837, 1629, 1606, 1531, 1504, 1453, 1252,
1177, 1030, 844, 763. HRMS (ESI) calculated for C19H20NO [M +
H]+: 278.1539, found: 278.1539.
ASSOCIATED CONTENT
* Supporting Information
■
S
The tentative reaction mechanism for the formation of
compounds 7 and 8 and 1H and 13C NMR spectra of
compounds 3aa−3ak, 3ba−3ha, 6a−6i, 6l, 7−9 and
intermediate C. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: yanming@mail.sysu.edu.cn (M.Y.).
*E-mail: zhangxj33@mail.sysu.edu.cn (X.-j.Z.).
■
2,3-Dimethoxy-5,6,14,14a-tetrahydrobenzo[5,6]azepino[2,1-a]-
isoquinolin-8(13H)-one (6l). White solid (29.4 mg, 91%), mp 149.0−
Notes
1
150.5 °C. H NMR (400 MHz, CDCl3): δ 7.70 (dd, J = 7.5, 1.3 Hz,
The authors declare no competing financial interest.
1H), 7.41 (m, 2H), 7.22 (d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 6.47 (s,
1H), 4.45 (dd, J = 12.2, 5.3 Hz, 1H), 4.02−3.95 (m, 1H), 3.89 (d, J =
11.1 Hz, 3H), 3.84 (dd, J = 9.1, 3.7 Hz, 1H), 3.76 (d, J = 16.7 Hz, 3H),
3.06−2.98 (m, 1H), 2.92−2.87 (m, 2H), 2.77 (dd, J = 13.6, 6.2 Hz,
1H), 2.26−2.09 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 170.5,
147.9, 147.7, 137.3, 136.2, 130.9, 128.7, 128.2, 127.7, 127.2, 127.1,
111.3, 109.3, 56.0, 55.9, 55.1, 39.6, 39.1, 30.8, 28.5. IR (KBr) ν/cm−1:
3030, 2962, 2931, 2870, 2853, 1630, 1598, 1457, 1420, 752. HRMS
(ESI) calculated for C20H22NO3 [M + H]+: 324.1588, found:
324.1594.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21202208, 21172270) and the Guangdong Engineering
Research Center of Chiral Drugs for financial support of this
study.
REFERENCES
■
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1
52%), mp 177.2−178.1 °C. H NMR (400 MHz, CDCl3): δ 9.23 (s,
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1606, 992, 913, 763. HRMS (ESI) calculated for C18H16NO [M +
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