Application of ring-closing metathesis for the synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones

Article abstract of DOI:10.1248/cpb.59.1169

Cycloaddition reaction between toluamides and benzonitriles was applied to prepare the 3-arylisoquinolines, and their chemical transformation to the dienes 4 was performed. The ring-closing metathesis (RCM) reaction afforded the desired heterocyclic compo

Full text of DOI:10.1248/cpb.59.1169

September 2011
Note
Chem. Pharm. Bull. 59(9) 1169—1173 (2011)
1169
Application of Ring-Closing Metathesis for the Synthesis of
Benzo[3,4]azepino[1,2-b]isoquinolin-9-ones
Hue Thi My VAN,# Daulat Bikram KHADKA,# Thanh Nguyen LE, Su Hui YANG, and Won-Jea CHO*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University; Gwangju 500–757,
Korea. Received April 6, 2011; accepted June 28, 2011; published online July 14, 2011
Cycloaddition reaction between toluamides and benzonitriles was applied to prepare the 3-arylisoquino-
lines, and their chemical transformation to the dienes 4 was performed. The ring-closing metathesis (RCM) reac-
tion afforded the desired heterocyclic compounds, benzo[3,4]azepino[1,2-b]isoquinolinones 5 in good yield.
Key words ring-closing metathesis; benzo[3,4]azepino[1,2-b]isoquinolinone; 3-arylisoquinoline; chemical shift difference
In order to heal cancer, chemotherapeutic treatments have a key intermediate for the RCM reaction.
been investigated over the last several decades.1,2) Conforma-
The synthetic approach of using the RCM reaction to pre-
tion studies and synthesis of medium-sized heterocyclic pare the seven-membered ring was based on the synthesis of
compounds, which have been investigated as the scaffolds of 3-arylisoquinolines 4 that contain olefins at the appropriate
many biologically interesting structures, have received more positions. To synthesize the 3-arylisoquinoline 6a, a coupling
attention.3—5) Recently, we studied the synthesis of 3-aryliso- reaction between N,N-diethyl-o-toluamide 7a and benzoni-
quinoline derivatives such as indeno[1,2-c]isoquinolines,6,7) trile 8a was performed (Chart 2).10) Generally, the chemical
isoindolo[2,1-b]isoquinolines,8) benz[b]oxepines9) and benzo- yield of this reaction is low (33 to 49%) due to the unknown
[c]phenanthridinones10) as constrained structures through side product and it is quite dependent on the substitution pat-
molecular modeling to find plausible antitumor agents. The tern of aromatic rings of the starting materials.10) As a part of
diversely rigidified 3-arylisoquinoline analogs exhibited our continuous research on natural alkaloids synthesis, in-
promising cytotoxicities and topoisomerase I inhibitory ac- cluding biological evaluation of 3-arylisoquinolines, the cou-
tivities.11) We also reported the convenient synthesis of proto- pling reaction of o-toluamides with benzonitriles was utilized
berberines using ring-closing metathesis (RCM) as shown in to provide the desired molecules.27) Significant increases in
Fig. 1.12)
the topoisomerase I inhibitory activities of these compounds
Seven-membered heterocyclic rings are considered attrac- were observed through conversion of flexible 3-aryl rings to
tive molecules due to the points of structural determination rigid forms such as isoindolo[2,1-b]isoquinolinones, benz-
of natural products as well as their interesting pharmacologi- [b]oxepines, 12-oxobenzo[c]phenanthridinones and indeno-
cal actions.3—5)
[1,2-c]isoquinolines, and molecular docking studies were
In this paper we applied RCM13—26) for the formation of used to explain the potency of these compounds.11) The
seven-membered benzo[3,4]azepino[1,2-b]isoquinolinone 5, above coupling reaction has advantages as a synthetic tool
and the retrosynthetic pathway of benzo[3,4]azepino[1,2- for the construction of 3-arylisoquinolines because it is easi-
b]isoquinolinone 5 is depicted in Chart 1. The coupling reac- ly adaptable to starting materials with diverse aromatic ring
tion of toluamide 7 with benzonitrile 8 afforded the 3- substitutions and it is a one-pot procedure for the construc-
arylisoquinolinone 6, which could be modified to diene 4 as tion of all essential carbon atoms in the desired molecules.
Fig. 1. Structural Modification of 3-Arylisoquinolinone to Protoberberine 3 and Benzo[3,4]azepino[1,2-b]isoquinolinone 5 via Ring-Closing Metathesis
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: wjcho@jnu.ac.kr
#
These authors contributed equally to this work.

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Vol. 59, No. 9
Chart 1. Retrosynthetic Pathway of Benzo[3,4]azepino[1,2-b]isoquinolinone 5
Chart 2. Synthesis of Benzo[3,4]azepino[1,2-b]isoquinolinone 5
Next, the amide 6a was reacted with allyl bromide and tained. 4,5-Dimethoxy toluamides 7b and benzonitriles 8b
K2CO3 in N,N-dimethylformamide (DMF) to provide the N- also provided the corresponding coupling products 6b in
allyl compound 9a in 67% yield without giving an O-allyl 49% yield. The reactions for the preparation of 9b, 10b, 11b,
product. When we tried to get an alkyl group such as methyl 4b, and 5b were also conducted following similar procedures
or PMB, only N-alkylated compounds were obtained. applied for 5a.
Methoxymethyl (MOM) was removed from 9a with 10%
The structures of benzoazepinoisoquinolones were deter-
HCl to afford the alcohol 10a, which was then reacted with mined by 1D 1H-, 13C-NMR and 2D 1H–1H correlation spec-
PDC in CH2Cl2 to furnish the aldehyde 11a in 99% yield. troscopy (COSY), H–13C heteronuclear single quantum co-
1
Wittig reactions of the aldehyde 11a with Ph3PCH3Br and n- herence (HSQC), heteronuclear multiple bond coherence
BuLi in tetrahydrofuran (THF) gave the desired olefin 4a in (HMBC) spectra (spectral data of 5a is compiled in Table 1).
79% yield. Finally, RCM reaction of 4a with 1st generation 1H-NMR spectrum of 5a revealed H10 proton signaled at d
Grubbs catalyst in CH2Cl2 furnished the desired cyclized 8.42 (d, Jꢀ8 Hz, 1H) and rest of aromatic protons between
product 5a in 66% yield. When we carried out this reaction 7.67—6.89 ppm. H14 and benzylic protons appeared as sin-
using 2nd generation catalyst, the similar result was ob- glet at 6.54 and 5.14 ppm respectively. Ethylene protons H5

September 2011
1171
Table 1. 1H- and 13C-NMR Data and HMBC Correlations of 5a
Carbon
No.
HMBC
H→C
dC
dH
1
2
3
4
4a
5
6
131.21
114.90
159.22
114.36
137.45
134.46
129.99
39.53
7.67 (d, Jꢀ8.5)
7.03 (dd, Jꢀ3, 8.7)
3, 4a, 14a
3, 4, 14b
6.89 (d, Jꢀ3)
2, 3, 5, 14b
6.82 (d, Jꢀ10)
6.49—6.44 (m)
a: 5.74 (dd, Jꢀ8, 13.5)
b: 3.53 (dd, Jꢀ6.5, 13.5)
4, 4a, 7, 14b
4a, 7
5, 6, 9, 14a
5, 6, 9, 14a
7
9
9a
10
11
12
13
13a
14
14a
14b
1ꢁ
2ꢁ
3ꢁ
4ꢁ
5ꢁ
6ꢁ
7ꢁ
161.27
124.03
127.91
126.25
132.11
125.92
136.57
107.48
142.67
128.87
136.36
127.91
128.67
128.18
128.67
127.91
70.14
8.42 (d, Jꢀ8)
9, 12, 13a
9a, 13
10, 13a
7.50—7.34 (m)
7.61 (t, Jꢀ7.5)
7.50—7.34 (m)
9a, 11, 14
6.54 (s)
9a, 13, 13a, 14a, 14b
Fig. 3. HSQC Spectrum of 5a Showing Correlations between Geminal
Protons H7a and H7b with C7
7.50—7.34 (m)
7.50—7.34 (m)
7.50—7.34 (m)
7.50—7.34 (m)
7.50—7.34 (m)
5.14 (s)
1ꢁ, 3ꢁ, 6ꢁ
2ꢁ
2ꢁ, 6ꢁ
6ꢁ
1ꢁ, 2ꢁ, 5ꢁ
3, 1ꢁ, 2ꢁ, 6ꢁ
1
Fig. 4. A Portion of H–1H COSY Spectrum of 5a Showing Correlations
between Nonequivalent Geminal Protons H7a and H7b
Fig. 2. A Portion of 1H-NMR Spectrum of 5a Showing Nonequivalence of
Geminal Protons H7a and H7b
and H6 of the azepine ring, showed up at d 6.82 (d, Jꢀ10 Hz,
1H) and at d 6.49—6.44 (m, 1H). Interestingly, methylene
protons labeled as H7a and H7b signaled as doublets of dou-
blets centered at d 5.74 (Jꢀ8, 13.5 Hz, 1H) and 3.53 (Jꢀ6.5,
Fig. 5. Selected HMBC Correlations of 5a
13.5 Hz, 1H) respectively (Fig. 2). HSQC cross peaks of and of azocine ring bridging biphenyl group have also been
H7a/C7 and H7b/C7 corroborated that the protons are at- reported.28,29)
1
tached to the same carbon C7 (Fig. 3). Furthermore, H–1H
In addition, formation of azepine ring by RCM of olefin 4
COSY correlation peaks of H7a/H7b and H7b/H7a en- was established by HMBC analysis (Fig. 5). HMBC correla-
forced that the geminal protons lie in different magnetic en- tion peaks, H5/C7, H6/C4a and H7a,b/C5, clearly indicated
vironment (Fig. 4). Difference in chemical shifts of geminal, that seven membered ring was formed by intramolecular
methylene protons of azepine ring adjoined to naphthoquinone olefin metathesis. In the similar manner, the spectral data of

1172
Vol. 59, No. 9
(400 mg, 3 mmol) in DMF (20 ml) and allyl bromide (240 mg, 2 mmol) to
give compound 9b as yellow oil (252 mg, 62%). IR (cmꢂ1): 1650 (CꢀO).
1H-NMR (300 MHz, CDCl3) d: 7.84 (s, 1H), 7.02 (s, 1H), 6.82 (s, 1H), 6.74
(s, 1 H), 6.32 (s, 1H), 6.04 (d, 2H), 5.82 (m, 1H), 5.08 (dd, 1H), 4.80 (dd,
1H), 4.69 (m, 1H), 4.59 (d, 2H), 4.29 (s, 2H), 4.24 (m, 1H), 4.02 (s, 3H),
azepine derivatives 5b were in total agreement with the pro-
posed structure.
In conclusion, cycloaddition reaction between toluamides
7a, b and benzonitriles 8a, b was utilized to prepare the 3-
arylisoquinolines 6a, b, which retain the main template for 3.98 (s, 3H), 3.25 (s, 3H). EI-MS, m/z (%): 439 (Mꢃ
, 76). HR-MS-EI (Calcd
for C24H25NO7): 439.1631, Found 439.1633.
the RCM reaction, to construct the seven-membered hetero-
2-Allyl-3-(4-benzyloxy-2-hydroxymethylphenyl)-2H-isoquinolin-1-one
(10a) To a solution of compound 9a (700 mg, 0.84 mmol) in THF (15 ml)
was added 10% HCl (10 ml), and the reaction was refluxed for 2 h. After
cooling to room temperature, the reaction mixture was poured into water and
extracted with ethyl acetate. The ethyl acetate extracts were washed with
water and brine and dried over anhydrous sodium sulfate. After removal of
the solvent in vacuo the residue was purified by column chromatography on
silica gel with n-hexane–ethyl acetate (1 : 2) to produce the alcohol 10a as
yellow oil (421 mg, 67%). IR (cmꢂ1): 3300 (OH), 1641 (CꢀO). 1H-NMR
(300 MHz, CDCl3) d: 8.41 (d, 1H), 7.62 (m, 1H), 7.49—7.37 (m, 8H), 7.18
(d, 1H), 6.93 (dd, 1H), 6.39 (s, 1H), 5.77 (m, 1H), 5.14 (s, 2H), 5.02 (dd,
1H), 4.76 (dd, 1H), 4.63 (m, 1H), 4.51 (d, 2H), 4.22 (m, 1H). EI-MS, m/z
(%): 397 (Mꢃ
cyclic compounds, benzo[3,4]azepino[1,2-b]isoquinolinones
5a, b. The conventional transformation of 3-arylisoquino-
lines 6a, b to dienes 4a, b was carried out and the subsequent
RCM reaction furnished the desired benzo[3,4]azepino[1,2-
b]isoquinolinones 5a, b in 66% and 85% yield, respectively.
We believe that the RCM reaction could be an efficient
method for the preparation of heterocyclic medium-sized
rings.
Experimental
Melting points were determined by the capillary method on an Elec-
trothermal IA9200 digital melting point apparatus and were uncorrected. 1H-
NMR spectra were obtained at 300 or 500 MHz, using Varian 300 or Kjui
500-Inova 500 FT spectrometer at the Korea Basic Science Institute and
were reported in ppm, downfield from the peak of the internal standard,
tetramethylsilane. The data are reported as follows: chemical shift, number
of protons, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multi-
plet, b: broadened). 1H–1H COSY, HSQC and HMBC spectra were obtained
using Kjui 500-Inova 500 FT spectrometer. IR spectra were recorded on a
JASCO-FT IR spectrometer using CHCl3 or KBr pellets. Mass spectra were
obtained on JEOL JNS-DX 303 using the electron-impact (EI) method. Col-
umn chromatography was performed on Merck silica gel 60 (70—230
mesh). TLC was performed using plates coated with silica gel 60 F254 that
were purchased from Merck.
3-(4-Benzyloxy-2-methoxymethoxymethyl-phenyl)-2H-isoquinolin-1-
one (6a) A solution of N,N-diethylbenzamide 7a (1.6 g, 8.0 mmol) and
benzonitrile 8a (3.4 g, 12 mmol) in dry THF (20 ml) were added drop wise to
a solution of n-butyllithium (5 ml of 2.5 M in hexane, 12.5 mmol) in THF
(20 ml) at ꢂ70 °C, and then the reaction mixture was stirred at the same
temperature for 6 h. The reaction was quenched with water, extracted with
ethyl acetate and dried over sodium sulfate. After removal of the solvent, the
residue was purified by column chromatography with n-hexane–ethyl acetate
(1 : 1) to afford compound 6a as pale yellow needles (1.04 g, 33%). mp:
130—131 °C (Et2O). IR (cmꢂ1): 3400 (NH), 1657 (CꢀO). 1H-NMR
(300 MHz, CDCl3) d: 9.74 (s, 1H), 8.40 (m, 1H), 7.67 (m, 1H), 7.58—7.36
, 100). HR-MS-EI (Calcd for C26H23NO3): 397.1678, Found
397.1677.
2-Allyl-3-(6-hydroxymethylbenzo[1,3]dioxol-5-yl)-6,7-dimethoxyiso-
quinolin-1(2H)-one (10b) The procedure described for compound 10a
was used with compound 9b (230 mg, 0.52 mmol) in THF (15 ml) and 10%
HCl (10 ml) to give the alcohol 10b as colorless needles (145 mg, 70%). mp
185—189 °C (Et
2O). IR (cmꢂ1): 3300 (OH), 1641 (CꢀO). 1H-NMR
(300 MHz, CDCl3) d: 7.80 (s, 1H), 7.08 (s, 1H), 6.81 (s, 1H), 6.72 (s, 1H),
6.32 (s, 1H), 6.04 (d, 2H), 5.80 (m, 1H), 5.06 (dd, 1H), 4.78 (dd, 1H), 4.57
(m, 1H), 4.40 (s, 2H), 4.31 (m, 1H), 4.00 (s, 3H), 3.97 (s, 3H). EI-MS, m/z
(%): 395 (Mꢃ
, 100). HR-MS-EI (Calcd for C22H21NO6): 395.1369, Found
395.1366.
2-(2-Allyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-5-benzyloxybenzalde-
hyde (11a) To a solution of alcohol 10a (400 mg, 1.0 mmol) in methylene
chloride (30 ml) was added PDC (760 mg, 2 mmol), and the mixture was
stirred for 2 h at room temperature. The reaction mixture was filtered off and
the filtrate was washed with CH2Cl2. The solvent was evaporated off, and the
residue was purified by column chromatography on silica gel with n-
hexane–ethyl acetate (2 : 1) to afford the aldehyde 11a as a brown oil
(390 mg, 99%). IR (cm
ꢂ1): 1700, 1640 (CꢀO). 1H-NMR (300 MHz, CDCl3)
d: 9.89 (s, 1H), 8.47 (d, 1H), 7.67—7.30 (m, 11H), 6.42 (s, 1H), 5.78 (m,
1H), 5.19 (s, 2H), 5.03 (dd, 1H), 4.73 (dd, 1H), 4.50 (m, 2H). EI-MS, m/z
(%): 395 (Mꢃ, 23). HR-MS-EI (Calcd for C26H21NO3): 395.1521, Found
395.1524.
6-(2-Allyl-1,2-dihydro-6,7-dimethoxy-1-oxoisoquinolin-3-
(m, 8H), 7.12 (d, 1H), 7.02 (m, 1H), 6.51 (s, 1H), 5.13 (s, 2H), 4.78 (s, 2H), yl)benzo[d][1,3]dioxole-5-carbaldehyde (11b) The procedure described
4.55 (s, 2H), 3.41 (s, 3H). EI-MS: m/z 401 (Mꢃ, 86). High resolution (HR)-
MS-EI (Calcd for C25H23NO4): 401.1627, Found 401.1623.
for compound 11a was used with alcohol 10b (125 mg, 0.32 mmol) and
PDC (240 mg, 0.65 mmol) in CH
2Cl2 (20 ml) to give the aldehyde 11b as
colorless needles (88 mg, 71%). IR (cmꢂ1): 1700, 1640 (CꢀO). 1H-NMR
(300 MHz, CDCl3) d: 9.78 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.08 (s, 1H),
6.84 (s, 1H), 6.32 (s, 1H), 6.14 (d, 2H), 5.82 (m, 1H), 5.06 (dd, 1H), 4.79
(dd, 1H), 4.51—4.44 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H). EI-MS, m/z (%):
393(Mꢃ, 46). HR-MS-EI (Calcd for C22H19NO6): 393.1212, Found
393.1215.
6,7-Dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-
2H-isoquinolin-1-one (6b) The procedure described for compound 6a
was used with N,N-diethyl-4,5-dimethoxy-2-methylbenzamide 7b (1.51 g,
6 mmol) and benzonitrile 8b (11.66 g, 7.5 mmol) in the presence of n-BuLi
(6 ml of 2.5 M in hexane, 15 mmol) to give compound 6b as bright yellow
solid (1.2 g, 49%). mp 151.0—154.2 °C (Et2O). IR (cmꢂ1): 3400 (NH), 1657
1
(CꢀO). H-NMR (300 MHz, CDCl3) d: 9.62 (s, 1H), 7.78 (s, 1H), 6.97 (s,
2-Allyl-3-(4-benzyloxy-2-vinylphenyl)-2H-isoquinolin-1-one (4a) To
1H), 6.95 (s,1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.06 (s, 2H), 4.80 (s, 2H), 4.46 a solution of methyltriphenylphosphonium bromide (1.6 g, 4.5 mmol) in dry
(s, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.44 (s, 3H). EI-MS, m/z (%): 399 (Mꢃ,
75). HR-MS-EI (Calcd for C21H21NO7): 399.1318, Found 399.1312.
2-Allyl-3-(4-benzyloxy-2-methoxymethoxymethylphenyl)-2H-iso-
THF (30 ml) was added n-butyllithium (1.8 ml of 2.5 M in hexane, 4.5 mmol)
at 0 °C, and the solution was stirred at 0 °C for 1 h. To this mixture was
added the aldehyde 11a (350 mg, 0.9 mmol) in THF (10 ml); the resulting
mixture was stirred at room temperature for 1 h, quenched with water, and
extracted with ethyl acetate. The combined organic layers were washed with
quinolin-1-one (9a) To
a solution of 3-arylisoquinoline 6a (1.0 g,
2.5 mmol) and K2CO3 (1.05 g, 7.5 mmol) in DMF (20 ml) was added allyl
bromide (600 mg, 5 mmol). The mixture was stirred at room temperature for water and brine and dried over sodium sulfate. After removing the solvent,
12 h, quenched with water, and extracted with ethyl acetate. The combined
ethyl acetate extracts were washed with water and brine and dried over anhy-
drous sodium sulfate. After removing the solvent in vacuo, the residue was
purified by column chromatography on silica gel with n-hexane–ethyl ace-
tate (2 : 1) to give compound 9a as yellow oil (735 mg, 67%). IR (cmꢂ1):
1650 (CO). 1H-NMR (300 MHz, CDCl3) d: 8.46 (d, 1H), 7.64 (m, 1H),
7.51—7.37 (m, 8H), 7.21 (m, 2H), 6.95 (dd, 1H), 6.39 (s, 1H), 5.80 (m, 1H),
5.14 (s, 2H), 5.05 (dd, 1H), 4.80 (dd, 1H), 4.74 (m, 1H), 4.58 (m, 2H), 4.39
(s, 2H), 4.18 (m, 1H), 3.27 (s, 3H). EI-MS, m/z (%): 441 (Mꢃ, 65). HR-MS-
EI (Calcd for C28H27NO4): 441.1940, Found 441.1941.
the residue was purified by column chromatography with n-hexane–ethyl
acetate (3 : 1) to afford the olefin 4a as a brown oil (281 mg, 79%). 1
(300 MHz, CDCl3) d: 8.47 (d, 1H), 7.64 (m, 1H), 7.50—7.25 (m, 8H), 7.19
(d, 1H), 6.94 (dd, 1H), 6.50 (dd, Jꢀ17.0, 10.0 Hz, 1H), 6.39 (s, 1H), 5.72 (m,
1H), 5.68 (d, Jꢀ17.0 Hz, 1H), 5.22 (d, Jꢀ10.0 Hz, 1H), 5.14 (s, 2H), 5.01
(m, 1H), 4.81 (m, 2H), 4.08 (m, 1H). EI-MS, m/z (%): 393 (Mꢃ
H-NMR
, 86). HR-
MS-EI (Calcd for C27H23NO2): 393.1729, Found 393.1726.
2-Allyl-6,7-dimethoxy-3-(6-vinylbenzo[1,3]dioxol-5-yl)-2H-isoquino-
lin-1-one (4b) The procedure described for compound 4a was used with
the aldehyde 11b (88 mg, 0.224 mmol) and methyltriphenylphosphonium
bromide (430 mg, 1.12 mmol) and n-butyllithium (0.5 ml of 2.5 M in hexane,
1.25 mmol) in dry THF (30 ml) to afford the olefin 4b as yellow oil (56 mg,
75%). 1H-NMR (300 MHz, CDCl3) d: 7.80 (s, 1H), 7.11 (s, 1H), 7.08 (s,
2-Allyl-6,7-dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-
5-yl)-2H-isoquinolin-1-one (9b) The procedure described for compound
9a was used with 3-arylisoquinoline 6b (373 mg, 0.93 mmol) and K2CO3

September 2011
1173
6) Van H. T. M., Le Q. M., Lee K. Y., Lee E. S., Kwon Y., Kim T. S., Le
T. N., Lee S. H., Cho W. J., Bioorg. Med. Chem. Lett., 17, 5763—5767
(2007).
7) Cho W. J., Le Q. M., My Van H. T., Youl Lee K., Kang B. Y., Lee E.
S., Lee S. K., Kwon Y., Bioorg. Med. Chem. Lett., 17, 3531—3534
(2007).
1H), 6.71 (s, 1H), 6.43 (dd, Jꢀ17.0, 10.0 Hz, 1H), 6.23 (s, 1H), 6.04 (d, 2H),
5.79 (m, 1H), 5.58 (d, Jꢀ17.0 Hz, 1H), 5.12 (d, Jꢀ10.0 Hz, 1H), 5.01 (d,
1H), 4.84—4.74 (m, 2H), 4.10 (m,1H), 4.01 (s, 3H). 3.95 (s, 3H). EI-MS,
m/z (%): 391 (Mꢃ, 88). HR-MS-EI (Calcd for C23H21NO5): 391.1420, Found
391.1422.
3-Benzyloxy-7H-benzo[3,4]azepino[1,2-b]isoquinolin-9-one (5a) The
reaction mixture of compound 4a (170 mg, 0.43 mmol) and 1st generation
Grubbs catalyst (70 mg, 20%) in CH2Cl2 (15 ml) was stirred for 2 h at room
temperature and filtered off. The filtrate was washed with CH2Cl2. The sol-
vent was evaporated off, and the residue was purified by column chromatog-
raphy on silica gel with n-hexane–ethyl acetate (2 : 1) to afford the azepine
5a as brown needles (104 mg, 66%). mp 187—189 °C (Et2O). IR (cmꢂ1):
1640 (CꢀO). 1H-NMR (500 MHz, CDCl3) d: 8.42 (d, Jꢀ8 Hz, 1H), 7.67 (d,
Jꢀ8.5 Hz, 1H), 761 (t, Jꢀ7.5 Hz, 1H), 7.50—7.34 (m, 7H), 7.03 (dd, Jꢀ3,
8.7 Hz, 1H), 6.89 (d, Jꢀ3 Hz, 1H), 6.82 (d, Jꢀ10 Hz, 1H), 6.54 (s, 1H),
6.49—6.44 (m, 1H), 5.74 (dd, Jꢀ8, 13.5 Hz, 1H), 5.14 (s, 2H), 3.53 (dd,
Jꢀ6.5, 13.5 Hz, 1H). 13C-NMR (75 MHz, CDCl3) d: 161.2, 159.2, 142.6,
137.4, 136.5, 136.3, 134.4, 132.1, 131.2, 129.9, 128.6, 128.1, 127.9, 127.4,
126.2, 125.9, 124.0, 114.9, 114.3, 107.4, 70.1, 39.5. EI-MS, m/z (%): 365
(Mꢃ, 56). HR-MS-EI (Calcd for C25H19NO2): 365.1416, Found 365.1416.
11,12-Dimethoxy-2,3-[1,3-dioxol])-7H-benzo[3,4]azepino[1,2-b]iso-
quinolin-9-one (5b) The procedure described for compound 5a was used
with the olefin 4b (55 mg, 0.14 mmol) and 1st generation Grubbs catalyst
(23 mg, 20%) in CH2Cl2 (15 ml) to produce the azepine 5b as brown needles
(43 mg, 85%). mp 128—132 °C (Et2O). 1H-NMR (300 MHz, CDCl3) d: 7.79
(s 1H), 7.19 (s, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 6.75 (d, Jꢀ9.6 Hz, 1H), 6.48
(s, 1H), 6.44—6.36 (m, 1H), 6.07 (d, Jꢀ5.5 Hz, 2H), 5.75 (dd, Jꢀ7.5,
13.3 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 3.49 (dd, Jꢀ6.6, 13.2 Hz, 1H). 13C-
NMR (CDCl3) d: 160.3, 153.4, 148.9, 148.2, 147.2, 134.0, 132.1, 130.9,
128.5, 128.5, 128.3, 118.2, 109.3, 108.4, 107.5, 107.0, 105.8, 101.7, 56.1,
56.0, 39.6. EI-MS, m/z (%): 363 (Mꢃ, 69). HR-MS-EI (Calcd for
C21H17NO5): 363.1107, Found 363.1105.
8) Van H. T. M., Cho W. J., Bioorg. Med. Chem. Lett., 19, 2551—2554
(2009).
9) Lee S. H., Van H. T. M., Yang S. H., Lee K. T., Kwon Y., Cho W. J.,
Bioorg. Med. Chem. Lett., 19, 2444—2447 (2009).
10) Le T. N., Gang S. G., Cho W. J., J. Org. Chem., 69, 2768—2772
(2004).
11) Khadka D. B., Cho W. J., Bioorg. Med. Chem., 19, 724—734 (2011).
12) Van H. T. M., Yang S. H., Khadka D. B., Kim Y. C., Cho W. J., Tetra-
hedron, 65, 10142—10148 (2009).
13) Alcaide B., Almendros P., Luna A., Chem. Rev., 109, 3817—3858
(2009).
14) Vieille-Petit L., Luan X., Gatti M., Blumentritt S., Linden A., Clavier
H., Nolan S. P., Dorta R., Chem. Commun., 25, 3783—3785 (2009).
15) Rudolf G. C., Hamilton A., Orpen A. G., Owen G. R., Chem. Com-
mun., 5, 553—555 (2009).
16) Benitez D., Tkatchouk E., Goddard W. A., Chem. Commun., 46,
6194—6196 (2008).
17) Mwangi M. T., Schulz M. D., Bowden N. B., Org. Lett., 11, 33—36
(2009).
18) Sohn J. H., Kim K. H., Lee H. Y., No Z. S., Ihee H., J. Am. Chem.
Soc., 130, 16506—16507 (2008).
19) Polshettiwar V., Varma R. S., J. Org. Chem., 73, 7417—7419 (2008).
20) Rix D., Caijo F., Laurent I., Boeda F., Clavier H., Nolan S. P., Mauduit
M., J. Org. Chem., 73, 4225—4228 (2008).
21) Vehlow K., Wang D., Buchmeiser M. R., Blechert S., Angew. Chem.
Int. Ed. Engl., 47, 2615—2618 (2008).
22) Brass S., Gerber H. D., Dorr S., Diederich W. E., Tetrahedron, 62,
1777—1786 (2006).
Acknowledgement This work was supported by Korea Research Foun-
23) Delhaye L., Merschaert A., Diker K., Houpis I. N., Synthesis, 9,
1437—1442 (2006).
dation Grant (KRF-2009-0071379).
24) Rix D., Caijo F., Laurent I., Gulajski L., Grela K., Mauduit M., Chem.
Commun., 36, 3771—3773 (2007).
25) Chen S. W., Kim J. H., Song C. E., Lee S. G., Org. Lett., 9, 3845—
3848 (2007).
26) Webster C. E., J. Am. Chem. Soc., 129, 7490—7491 (2007).
27) Le T. N., Gang S. G., Cho W. J., Tetrahedron Lett., 45, 2763—2766
(2004).
28) Camara C. A., Pinto A. C., Vargas M. D., Zukerman-Schpector J.,
Tetrahedron, 58, 6135—6140 (2002).
References
1) Damia G., D’Incalci M., Eur. J. Cancer, 45, 2768—2781 (2009).
2) Pollard J. R., Mortimore M., J. Med. Chem., 52, 2629—2651 (2009).
3) Hassner A., Amit B., Marks V., Gottlieb H. E., J. Org. Chem., 68,
6853—6858 (2003).
4) Qadir M., Cobb J., Sheldrake P. W., Whittall N., White A. J. P., Hii K.
K., Horton P. N., Hursthouse M. B., J. Org. Chem., 70, 1545—1551
(2005).
5) Tabata H., Suzuki H., Akiba K., Takahashi H., Natsugari H., J. Org.
Chem., 75, 5984—5993 (2010).
29) Jeffs P. W., Hansen J. F., Brine G. A., J. Org. Chem., 40, 2883—2890
(1975).