Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones skeleton via intramolecular electrophilic cyclization

Article abstract of DOI:10.1016/j.tet.2004.09.015

An original alternative approach to isoquinolines based on the installation of a benzene nucleus on a performed heterocyclic ring. Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)- ones via intramolecular electrophilic cyclization of 3,4-disubstituted lactams is reported. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.015

Tetrahedron 60 (2004) 10637–10644
Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and
3,4-dihydroisoquinoline-1(2H)-ones skeleton via intramolecular
electrophilic cyclization
*
Min-Ruei Tsai, Ta-Chao Hung, Bo-Fong Chen, Chih-Ching Cheng and Nein-Chen Chang
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 22 July 2004; revised 7 September 2004; accepted 8 September 2004
Available online 29 September 2004
Abstract—An original alternative approach to isoquinolines based on the installation of a benzene nucleus on a performed heterocyclic ring.
Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones via intramolecular electrophilic
cyclization of 3,4-disubstituted lactams is reported.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
electron-donating groups often failed to cyclize or gave low
yields.8
The isoquinolone subunit is one of the most important
pharmacophores that is widely found in biologically active
molecules1 and natural products.2 This has encouraged the
development of a number of approaches for the synthesis of
the isoquinoline ring system and related heterocyclic
compounds, including isoquinolones. Bischler–Napier-
alski,3 Pictet–Spengler,4 and Pomeranz–Fritsch5 reactions
have been powerful methods for the synthesis of isoquino-
lines. Other procedures like the Curtius rearrangement of
cinnamic acids6 or methanolysis of 2-alkynylbenzonitriles7
to isoquinolones ring system were also reported. Although
these classical methods have been frequently employed in
the synthesis of isoquinoline or isoquinolone alkaloids, an
electron-donating group on the aromatic ring was still
required, such as alkoxy groups. Relatively strong acidic
conditions were employed to cyclize b-phenethylamines or
benzamide analog (Scheme 1). The substrates that lack of
2. Result and discussion
Recently, we developed a facile stepwise [3C3] annulation
reaction between N-benzyl-a-sulfonyl acetamide and
different a- or b-, aryl- or alkyl- substituted acyclic a,b-
unsaturated alkyl esters had lead to the corresponding
glutarimides in good yields. This method has been used for
the synthesis of natural products and potential biological
drugs.9
2.1. Retrosynthesis of 3,4-dihydroisoquinoline-1(2H)-
ones
Continuing our investigation on the application of the
synthesis of alkaloids, we disclose our preliminary finding
regarding a valuable alternative route for the preparation of
3,4-dihydrobenzo[g]isoquinoline-1(2H)-one and 3,4-
dihydroisoquinoline-1(2H)-one analogues. The key step of
the target structure construction was intramolecular
electrophilic cyclization of a suitably substituted lactam
(Scheme 2).
Scheme 1. Preparation of isoquinolone derivatives from b-phenethyl-
amines and benzamide analog.
Keywords: Stepwise [3C3] annulation; 3,4-Dihydrobenzo[g]isoquinoline-
1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones; Electrophilic
cyclization.
* Corresponding author. Tel.: C886 7 525 2000 3914; fax: C886 7 525
3913; e-mail: ncchang@mail.nsysu.edu.tw
Scheme 2. Retrosynthesis of 3,4-dihydroisoquinoline-1(2H)-ones.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.015

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M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
2.2. Synthesis of 3,4-disubstituted-d-lactam
2.3. Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-
ones and 3,4-dihydroisoquinoline-1(2H)-ones
Our synthetic studies commenced with the construction of
glutarimides 1, which were easily prepared via stepwise
[3C3] annulation of N-benzyl a-sulfonylacetamide A with
a,b-unsaturated ester9 B, followed by regioselective
reduction10 of C6 carbonyl (Scheme 3). Reaction of
d-lactam 2 with excess NaH and various alkyl halides
provided alkylated products 3 (Table 1).
With the desired lactams 3 in hand, we started to focus on
the intramolecular electrophilic cyclization. In the case of
lactams 3a, 3b, 3g, 3i, 3l, we accomplished the cyclization
by dissolving the lactams in 10% aqueous hydrochloric acid
and acetone followed by heating the resulting solution at
reflux temperature. The corresponding 3,4-dihydroisoquino-
line-1(2H)-ones 4a–b, and 3,4-dihydrobenzo[g]isoquino-
line-1(2H)-ones 5a–c were obtained in good yield
(Scheme 4).
Scheme 3.
Table 1. Treatment of 2 with 1.5 equiv NaH and various alkyl halides
Entry
1
Alkyl halides (R–X)
Product (yield, %)
Scheme 4. Intramolecular electrophilic cyclization.
3a 87
For entries 1–7 (R2ZH), only hydrolyzed products 6 were
found. However, treatment of compounds 6 with TiCl411 in
CH2Cl2 at reflux temperature for 4 h, the desired 3,4-
dihydrobenzo[g]isoquinoline-1(2H)-one derivatives 7a–g
were obtained in good yield (Table 2). The structures of
2
3
3b 90
3c 90
4
5
3d 85
3e 80
Table 2. Hydrolysis of acetal and intramolecular electrophiliccyclization
6
7
3f 87
3g 86a
8
9
3h 81
3i 83
Entry
Alkyl groups
Hydrolyzed
producta
Cyclized
productc
(yield, %)b
(yield, %)b
R1
H
CH3
H
Br
R2
H
H
H
H
H
H
H
R3
10
11
12
3j 75a
3k 86
3l 85
1
2
3
4
5
6
7
3c
3d
3e
3f
3h
3k
3j
H
H
Br
H
OMe
H
6a (91)
6b (85)
6c (83)
6dd (85)
6e (87)
6f (87)
6g (90)
7a (87)
7b (85)
7c (81)
7dd (80)
7e (83)
7fd (82)
7gd (60)
H
OMe
CO2Me
H
a All reaction were carried out under reflux temperature of acetone.
b Isolated yields.
Reagents and conditions: Alkyl halides (1.5 equiv), NaH (1.2 equiv),
solvent THF, reflux temperature.
a The compound decomposed during the separation on the silica gel. The
yield was crude yield.
c Dichloromethane.
d The structures were confirmed by single crystal X-ray analysis.

M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
10639
Figure 1. X-ray structures of 6d and 7d.
Scheme 6.
6d and 7d were confirmed by single crystal X-ray analysis
(Fig. 1).12
3. Conclusion
In conclusion, we developed an easy and alternative
approach to synthesize substituted 3,4-dihydrobenzo[g]iso-
quinoline-1(2H)-one and 3,4-dihydroisoquinoline-1(2H)-
one derivatives based on the construction of benzene ring
on a preformed d-lactam ring. This method is different from
the traditional procedures, which start from a substituted
benzene ring to the fused pyridine. It is noteworthy that in
entry 7 (Table 2), the cyclization still occurred in the
presence of a strong electron-withdrawing group (i.e. –
CO2Me) and provided 7g in reasonable yield. Further
application of this methodology in the synthesis of alkaloids
is currently underway in our laboratory.
To account for these results, we propose a mechanism which
involves (1) hydrolysis of the acetal to aldehyde I, (2)
elimination of p-toluenesulfinic acid to the a?b-unsaturated
lactam II, (3) intramolecular electrophilic cyclization
forming the cation intermediates III or IV and (4)
deprotonation and dehydration (Scheme 5). When R2
substituents can stabilize the carbon cation either by
electron donation or resonance, the target core structure
would form easily in acidic aqueous solution. Otherwise, a
Lewis acid has to be employed to promote the reaction
(Scheme 5).
4. Experimental
4.1. General
Melting points were determined with Fargo micro melting
point apparatus and are uncorrected. 1H NMR and 13C NMR
were recorded on Varian unity INOVA-500 spectrometer.
1H NMR spectra were recorded at indicated field strength as
solution in CDCl3 unless otherwise indicated. Chemical
shifts are given in parts per million (ppm, d) downfield from
TMS and are reference to CHCl3 (7.26 ppm) as internal
standard. 13C NMR spectra were recorded at indicated field
strength as solution in CDCl3 unless otherwise indicated.
Mass spectra were recorded by Brucker APEX II. Elemental
analyses were performed using a Perkin–Elmer 2400(II)
CHN analyzer. Infrared spectra (IR) were measured with a
Shimadzu IR-408 series FT-IR spectrophotometer. X-ray
data were performed by Rigaku AFC6S diffractometer.
Tetrahydrofuran was distilled prior to use. All other
reagents and solvents were obtained from commercial
sources and were used without any further purification.
Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Solutions of products in
organic solvents were dried with anhydrous magnesium
sulfate before concentration under vacuum.
Scheme 5. Proposed mechanism for cyclization.
Finally, in the presence of DDQ,13 5c and 7d could be
oxidized to the corresponding isoquinolones 8 and 9 in good
yields (Scheme 6).

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4.2. Procedure for alkylation of lactam 2
HRMS m/z (ESI, MCC1) calcd for C29H33NO5S 508.2079.
Found 508.2064.
A solution of lactam 2 (500 mg, 1.2 mmol) in THF (10 mL)
was added to a rapidly stirred suspension of sodium hydride
(96 mg, 2.4 mmol, 60%) in tetrahydrofuran (20 mL). After
the reaction mixture was stirred at room temperature for
15 min, alkyl halides were added. The resulting mixtures
were refluxed for 3–4 h, quenched with NH4Cl (1 mL),
filtered and concentrated under reduced pressure. The
residue was diluted with water (10 ml) and extracted with
ethyl acetate (3!20 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated.
Chromatography on silica gel (hexane/ethyl acetateZ3:1)
afforded the pure products.
4.2.4. 1-Benzyl-3-(4-bromobenzyl)-4-dimethoxymethyl-
3-(toluene-4-sulfonyl)piperidin-2-one (3f). 87% Yield;
yellow oil; IR (CHCl3, cmK1) 3034, 1656; 1H NMR
(500 MHz, CDCl3) d 7.73 (d, JZ9.0 Hz, 2H), 7.31–7.26
(m, 7H), 7.17 (d, JZ9.0 Hz, 2H), 7.12 (d, JZ7.0 Hz, 2H),
5.30 (d, JZ8.0 Hz, 1H), 4.56 (d, 15.0 Hz, 1H), 4.50 (d, JZ
15.0 Hz, 1H), 3.76 (d, JZ12.5 Hz, 1H), 3.66 (s, 3H), 3.42
(d, JZ12.5 Hz, 1H), 3.37 (s, 3H), 3.21 (dd, JZ8.0, 1.5 Hz,
1H), 2.89 (dt, JZ12.5, 5.0 Hz 1H), 2.71 (ddt, JZ13.5, 13.0,
5.0 Hz 1H), 2.46–2.41 (m, 1H), 2.44 (s, 3H), 1.88 (ddt, JZ
14.0, 12.5, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
164.13, 144.68, 136.04, 135.91, 134.37, 133.54 (2C),
130.11 (2C), 130.74 (2C), 128.80 (2C), 128.58 (2C),
127.62 (2C), 127.42, 120.99, 105.01, 77.17, 56.23, 53.17,
51.54, 46.74, 41.33, 37.91, 21.72, 21.07; HRMS m/z (ESI,
MCC1) calcd for C29H32NO5SBr 586.1185. Found
586.1166.
4.2.1. 1-Benzyl-4-dimethoxymethyl-3-(2-methyl allyl)-3-
(toluene-4-sulfonyl)piperidin-2-one (3a). 90% Yield; yel-
low oil; IR (CHCl3, cmK1) 3012, 1635; 1H NMR (500 MHz,
CDCl3) d 7.65 (d, JZ8.5 Hz, 2H), 7.36–7.24 (m, 7H), 5.16
(d, JZ7.0 Hz, 1H),4.9 (d, JZ15.0 Hz, 1H), 4.89 (s, 1H),
4.80 (s, 1H), 4.23 (d, JZ15.0 Hz, 1H), 3.53 (s, 3H), 3.47–
3.43 (m, 1H), 3.42 (s, 3H), 3.27 (dt, JZ12.5, 4.5 Hz 1H),
3.19 (d, JZ13.0 Hz, 1H), 2.92 (d, JZ13.0 Hz, 1H), 2.8 (ddt,
JZ13.5, 13.0, 7.0 Hz, 1H), 2.59 (ddd, JZ13.5, 10.0, 7.5 Hz
1H), 2.41 (s, 3H), 1.99 (ddt, JZ14.0, 7.0, 3.0 Hz, 1H), 1.49
(s, 3H); 13C NMR (125 MHz, CDCl3) d 164.81, 144.35,
139.92, 136.37, 136.03, 130.66 (2C), 128.64 (2C), 128.69
(2C), 127.92 (2C), 127.42, 117.07, 104.72, 75.2, 56.04,
53.82, 51.49, 46.93, 42.36, 40.74, 23.61, 21.67, 20.88;
HRMS m/z (ESI, MCC1) calcd for C26H33NO5S 472.2079.
Found 472.2106.
4.2.5. 1-Benzyl-3-(2-bromobenzyl)-4-dimethoxymethyl-
3-(toluene-4-sulfonyl)piperidin-2-one (3e). 80% Yield;
yellow oil; IR (CHCl3, cmK1) 3012, 1635; 1H NMR
(500 MHz, CDCl3) d 7.77 (d, JZ8.0 Hz, 2H), 7.51 (dd, JZ
8.0, 1.0 Hz, 1H), 7.40–7.33 (m, 7H), 6.95 (dt, JZ7.5,
1.0 Hz, 1H), 6.87 (dt, JZ7.5, 1.0 Hz, 1H), 6.61 (d, JZ
8.0 Hz, 1H), 5.19 (d, JZ5.5 Hz, 1H), 4.79 (d, JZ14.5 Hz,
1H), 4.61 (d, JZ14.5 Hz, 1H), 4.12 (d, JZ15.0 Hz, 1H),
3.56–3.53 (m, 1H), 3.50 (d, JZ15.0 Hz, 1H), 3.38 (s, 3H),
3.34 (s, 3H), 3.33–3.27 (m, 1H), 2.86 (ddt, JZ13.5, 13.0,
6.0 Hz, 1H), 2.51 (ddd, JZ13.0, 6.0, 3.0 Hz, 1H), 2.43 (s,
3H), 1.92 (ddt, JZ14.0, 6.0, 3.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 165.01, 144.75, 136.14, 135.67,
135.58, 133.27, 130.97, 128.91 (2C), 128.83 (2C), 128.67
(2C), 128.52 (2C), 127.72, 127.66, 127.08, 126.25, 104.58,
75.61, 56.03, 55.15, 52.11, 47.07, 42.22, 38.44, 21.68,
20.01; HRMS m/z (ESI, MCC1) calcd for C29H32NO5SBr
586.1185. Found 586.1179.
4.2.2. 1-Benzyl-3-(2-chloro allyl)-4-dimethoxymethyl-3-
(toluene-4-sulfonyl)piperidin-2-one (3b). 90% Yield;
yellow oil; IR (CHCl3, cmK1) 3012, 1635; 1H NMR
(500 MHz, CDCl3) d 7.64 (d, JZ8.0 Hz, 2H), 7.36–7.25 (m,
7H), 5.33 (d, JZ12.5 Hz, 1H), 5.18 (d, JZ8.0 Hz, 1H), 4.89
(d, JZ15.0 Hz, 1H), 4.23 (d, JZ15.0 Hz, 1H), 3.57 (d, JZ
13.5 Hz, 1H), 3.54 (s, 3H), 3.44–3.4 (m, 2H), 3.39 (s, 3H),
3.32–3.25 (m, 2H), 2.74 (ddt, JZ13.5, 13.0, 5.5 Hz, 1H),
2.64 (ddd, JZ12.0, 8.0, 2.5 Hz 1H), 2.41 (s, 3H), 1.99 (ddt,
JZ11.5, 8.0, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
164.01, 144.65, 136.42, 136.37, 135.63, 130.56 (2C),
128.73 (2C), 128.43 (2C), 127.92 (2C), 127.32, 119.18,
104.63, 74.74, 55.81, 52.78, 51.54, 46.65, 42.23, 42.11,
21.67, 21.27; HRMS m/z (ESI, MCC1) calcd for C25H31
NO5SCl 492.1533. Found 492.1606.
4.2.6. 1-Benzyl-4-dimethoxymethyl-3-(2-methoxy ben-
zyl)-3-(toluene-4-sulfonyl)piperidin-2-one (3h). 81%
Yield; yellow oil; IR (CHCl3, cmK1) 3016, 1628; 1H
NMR (500 MHz, CDCl3) d 7.72 (d, JZ8.0 Hz, 2H), 7.39–
7.24 (m, 9H), 7.14 (d, JZ2.5 Hz, 1H), 6.69 (d, JZ9.0 Hz,
1H), 5.16 (d, JZ3.0 Hz, 1H), 4.95 (d, JZ14.5 Hz, 1H), 4.35
(d, JZ14.5 Hz, 1H), 3.92 (d, JZ13.5 Hz, 1H), 3.78 (s, 3H),
3.52 (s, 3H), 3.42 (d, JZ14.0 Hz, 1H), 3.38 (s, 3H), 3.37–
3.32 (m, 1H), 3.08–3.04 (m, 1H), 2.83 (ddt, JZ14.0, 13.5,
6.0 Hz, 1H), 2.42 (s, 3H), 2.27 (dt, JZ12.5, 3.5 Hz, 1H),
1.84 (ddt, JZ14.0, 6.0, 3.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 164.79, 156.8, 144.45, 136.39, 136.29, 133.55,
130.79(2C), 128.7 (2C), 128.64(2C), 128.56 (2C), 128.55,
127.65 (2C), 127.33, 126.22, 112.75, 112.12, 104.39, 57.17,
55.51, 51.31, 46.73, 44.19, 31.54, 21.65, 19.53; HRMS m/z
(ESI, MCC1) calcd for C30H36NO6S 538.2185. Found
538.2259.
4.2.3. 1,3-Dibenzyl-4-dimethoxymethyl-3-(toluene-4-sul-
fonyl)piperidin-2-one (3c). 90% Yield; yellow oil; IR
(CHCl3, cmK1) 3014, 1641; 1H NMR (500 MHz, CDCl3) d
7.75 (d, JZ8.0 Hz, 2H), 7.30–7.25 (m, 7H), 7.19–7.14 (m,
5H), 5.31 (d, JZ8.0 Hz, 1H), 4.60 (d, JZ14.5 Hz, 1H), 4.48
(d, JZ14.5 Hz, 1H), 3.78 (d, JZ12.0 Hz, 1H), 3.65 (s, 3H),
3.52 (d, JZ12.0 Hz, 1H), 3.35 (s, 3H), 3.22 (dd, JZ5.5,
1.5 Hz, 1H), 2.9 (dt, JZ12.0, 4.5 Hz, 1H), 2.71 (ddt, JZ
13.5, 13.0, 5.5 Hz, 1H), 2.43 (s, 3H), 2.44 (ddd, JZ13.0,
8.0, 3.0 Hz, 1H), 1.86 (ddt, JZ14.0, 7.5, 3.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) d 164.38, 144.50, 136.20, 136.17,
135.33, 131.66 (2C), 130.73 (2C), 128.73 (2C), 128.52 (2C),
128.02 (2C), 127.68 (2C), 127.30, 126.77, 104.86, 77.44,
56.11, 52.88, 51.44, 46.65, 41.33, 38.61, 21.70, 21.07;
4.2.7. 1-Benzyl-4-dimethoxymethyl-3-(3-methoxy ben-
zyl)-3-(toluene-4-sulfonyl)piperidin-2-one (3i). 83%
Yield; yellow oil; IR (CHCl3, cmK1) 3017, 1633; 1H
NMR (500 MHz, CDCl3) d 7.75 (d, JZ8.5 Hz, 2H), 7.32–
7.25 (m, 7H), 7.17 (d, JZ7.0 Hz, 1H), 7.09 (t, JZ8.0 Hz,

M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
10641
1H), 6.9 (s, 1H), 6.73 (d, JZ8.0 Hz, 1H), 5.32 (d, JZ
8.0 Hz, 1H), 4.69 (d, JZ14.5 Hz, 1H), 4.45 (d, JZ14.5 Hz,
1H), 3.76 (d, JZ12.5 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 3H),
3.52 (d, JZ12.5 Hz, 1H), 3.35 (s, 3H), 3.23 (dd, JZ13.0,
5.0 Hz, 1H), 2.93 (dt, JZ13.0, 5.0 Hz, 1H) 2.73 (ddt, JZ
13.5, 13.5, 5.0 Hz, 1H), 2.48 (ddd, JZ8.5, 7.5, 2.5 Hz 1H),
2.44 (s, 3H), 1.86 (ddt, JZ13.5, 7.5, 3.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 164.41, 159.23, 144.45, 136.82,
136.27, 136.13, 130.66 (2C), 128.83, 128.73 (2C), 128.52
(3C), 127.51 (2C), 127.22, 124.01, 116.78, 112.7, 104.63,
56.04, 55.01, 52.68, 51.34, 46.55, 41.23, 38.61, 21.67,
21.07; HRMS m/z (ESI, MCC1) calcd for C30H36NO6S
538.2185. Found 538.2263.
2.49 (ddd, JZ13.0, 7.5, 2.5 Hz, 1H), 2.44 (s, 3H), 1.87 (ddt,
JZ13.5, 7.5, 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
164.61, 148.24, 147.73, 144.49, 136.30, 136.09, 130.70
(2C), 128.79 (2C), 128.60 (2C), 127.59, 127.38 (2C),
127.33, 124.17, 114.55, 110.57, 104.89, 77.52, 56.06, 55.68,
55.65, 53.01, 51.28, 46.67, 41.33, 38.19, 21.73, 21.12.;
HRMS m/z (ESI, MCC1–C2H6O2) calcd for C30H35NO5S
506.2236. Found (MCC1) 506.2259.
4.3. Procedure for hydrolysis of lactam 3 to 1,2,3,4-
tetrahydroisoquinoline derivatives 4 and 5
To a solution of lactam 3 (400 mg, 0.8 mmol) in acetone
(20 mL) was added 10% aqueous HCl (1 mL). The resulting
mixture was refluxed for 12 h and then evaporated. The
residue was dissolved with dichloromethane and the
mixture was basified with 2 N aqueous sodium hydroxide
in an ice bath. The organic layer was separated, and the
aqueous layer was extracted with dichloromethane. The
combined organic layers were washed with brine, dried, and
evaporated to give crude product. Chromatography on silica
gel (hexane/ethyl acetateZ4:1) afforded the pure products.
4.2.8. 4-[1-Benzyl-4-dimethoxymethyl-2-oxo-3-(toluene-
4-sulfonyl)piperidin-3-ylmethyl]benzoic acid methyl
ester (3j). 75% Yield; yellow oil; IR (CHCl3, cmK1
)
1
3026, 1714, 1220; H NMR (500 MHz, CDCl3) d 7.83 (d,
JZ8.0 Hz, 2H), 7.55 (d, JZ8.0 Hz, 2H), 7.37 (d, JZ
8.0 Hz, 2H), 7.32–7.27 (m, 5H), 7.17 (d, JZ8.0 Hz, 2H),
5.31 (d, JZ8.5 Hz, 1H), 4.65 (d, JZ15.0 Hz, 1H), 4.42 (d,
JZ15.0 Hz, 1H), 3.89 (s, 3H), 3.86 (d, JZ12.0 Hz, 1H),
3.66 (s, 3H), 3.54 (d, JZ12.0 Hz, 1H), 3.33 (s, 3H), 3.24 (dt,
JZ5.5, 4.0 Hz, 1H), 2.89 (dt, JZ12.5, 5.0 Hz, 1H), 2.72
(ddt, JZ13.5, 13.0, 5.5 Hz, 1H), 2.44 (s, 3H), 2.32 (ddd, JZ
11.5, 8.0, 3.0 Hz, 1H), 1.86 (ddt, JZ13.5, 8.0, 3.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) d 167.04, 164.18, 144.73,
141.01, 136.05, 135.88, 131.74 (2C), 130.76 (2C), 129.22
(2C), 128.82 (2C), 128.63, 128.59 (2C), 127.65 (2C),
127.45, 104.77, 77.17, 56.17, 52.68, 52.03, 51.53, 46.70,
41.32, 38.55, 21.74, 21.11.; HRMS m/z (ESI, MCC1) calcd
for C31H35NO7S 566.2134. Found (MCC1) 566.2145.
4.3.1. 2-Benzyl-7-chloro-3,4-dihydro-2H-isoquinolin-1-
one (4b). 85% Yield; yellow oil; IR (CHCl3, cmK1) 3030,
1
1656; H NMR (500 MHz, CDCl3) d 8.13 (d, JZ2.5 Hz,
1H), 7.38 (dd, JZ8.0, 2.5 Hz, 1H), 7.36–7.27 (m, 5H), 7.11
(d, JZ8.0 Hz, 1H), 4.79 (s, 2H), 3.48 (t, JZ6.5 Hz, 2H),
2.90 (t, JZ6.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) d
163.39, 137.10, 136.27, 133.15, 131.62, 130.89, 128.69
(2C), 128.47, 128.35, 128.06 (2C), 127.57, 50.54, 45.20,
27.51; HRMS m/z (ESI, MCC1) calcd for C16H14NOCl
272.0764. Found 272.0758.
4.2.9. 1-Benzyl-4-dimethoxymethyl-3-(4-methylbenzyl)-
3-(toluene-4-sulfonyl)piperidin-2-one (3d). 85% Yield;
4.3.2. 2-Benzyl-7-methyl-3,4-dihydro-2H-isoquinolin-1-
one (4a). 90% Yield; yellow oil; IR (CHCl3, cmK1) 3022,
1652; 1H NMR (500 MHz, CDCl3) d 7.97 (s, 1H), 7.33–7.27
(m, 5H), 7.23 (dd, JZ6.5, 1.0 Hz, 1H), 7.05 (d, JZ6.5 Hz,
1H), 4.79 (s, 2H), 3.46 (t, JZ6.5 Hz, 2H), 2.89 (t, JZ
6.5 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) d
164.81, 137.47, 136.76, 135.05, 132.43, 129.08, 128.81,
128.60 (2C), 128.01 (2C), 127.38, 126.80, 50.45, 45.51,
27.67, 21.06; HRMS m/z (EI, MC) calcd for C17H17NO
251.1310. Found 251.1316.
1
yellow oil; IR (CHCl3, cmK1) 3030, 1656, 1223; H NMR
(500 MHz, CDCl3) d 7.76 (d, JZ8.0 Hz, 2H), 7.31–7.27 (m,
5H), 7.19 (d, JZ8.0 Hz, 2H), 7.16 (d, JZ8.0 Hz, 2H), 6.98
(d, JZ8.0 Hz, 2H), 5.32 (d, JZ7.5 Hz, 1H), 4.62 (d, JZ
14.5 Hz, 1H), 4.49 (d, JZ14.5 Hz, 1H), 3.74 (d, JZ
12.5 Hz, 1H), 3.66 (s, 3H), 3.48 (d, JZ12.5 Hz, 1H), 3.37
(s, 3H), 3.22 (dd, JZ5.5, 1.5 Hz, 1H), 2.90 (dt, JZ12.5,
4.5 Hz, 1H), 2.72 (ddt, JZ13.5, 13.0, 5.5 Hz, 1H), 2.46
(ddd, JZ13.0, 8.0, 3.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s, 3H),
1.87 (ddt, JZ14.0, 7.5, 3.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 164.42, 144.44, 136.27, 136.24 (2C), 132.09,
131.52 (2C), 130.73 (2C), 128.75 (2C), 128.71 (2C), 128.48
(2C), 127.69 (2C), 127.27, 104.85, 77.48, 56.13, 52.93,
51.40, 46.65, 41.32, 38.21, 21.70, 21.05, 21.00; HRMS m/z
(ESI, MCC1) calcd for C30H35NO5S 522.2236. Found
(MCC1) 522.2261.
4.3.3. 2-Benzyl-7,8-dimethoxy-3,4-dihydro-2H-benzo-
[g]isoquinolin-1-one (5a). 95% Yield; white solid; mp
189–191 8C; IR (CHCl3, cmK1) 3030, 1653, 1235; 1H NMR
(500 MHz, CDCl3) d 8.54 (s, 1H), 7.43 (s, 1H), 7.36–7.28
(m, 5H), 7.22 (s, 1H), 7.06 (s, 1H), 4.85 (s, 2H), 4.01 (s, 3H),
4.01 (s, 3H) 3.53 (t, JZ6.5 Hz, 2H), 3.06 (t, JZ6.5 Hz, 2H);
13C NMR (125 MHz, CDCl3) d 164.98, 151.18, 149.49,
137.52, 132.85, 131.15, 128.62 (2C), 128.03 (2C), 127.87,
127.78, 127.39, 125.75, 123.50, 107.34,105.38, 55.92,
55.89, 50.57, 45.72, 28.44; HRMS m/z (EI, MC) calcd for
C22H21NO3 347.1521. Found 347.1516. Compound 5a was
recrystallized from ethyl acetate.
4.2.10. 1-Benzyl-3-(3,4-dimethoxybenzyl)-4-dimethoxy-
methyl-3-(toluene-4-sulfonyl)piperidin-2-one (3l). 85%
Yield; yellow oil; IR (CHCl3, cmK1) 3015, 1640, 1203;
1H NMR (500 MHz, CDCl3) d 7.74 (d, JZ8.0 Hz, 2H),
7.33–7.24 (m, 5H), 7.21 (d, JZ8.0 Hz, 2H), 6.90 (dd, JZ
8.0, 2.0 Hz, 1H), 6.86 (d, JZ2.0 Hz, 1H), 6.69 (d, JZ
8.0 Hz, 1H), 5.32 (d, JZ8.0 Hz, 1H), 4.77 (d, JZ15.0 Hz,
1H), 4.33 (d, JZ15.0 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H),
3.72 (d, JZ12.0 Hz, 1H), 3.66 (s, 3H), 3.47 (d, JZ12.0 Hz,
1H), 3.37 (s, 3H), 3.23 (dd, JZ11.0, 4.5 Hz, 1H), 2.93 (dt,
JZ12.5, 5.0 Hz, 1H), 2.72 (ddt, JZ13.5, 13.0, 5.5 Hz, 1H),
4.3.4. 2-Benzyl-8-methoxy-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (5b). 88% Yield; yellow oil; IR (CHCl3,
1
cmK1) 3030, 1629, 1494; H NMR (300 MHz, CDCl3) d
8.59 (s, 1H), 7.68 (d, JZ9.0 Hz, 1H), 7.52 (s, 1H), 7.36–
7.18 (m, 7H), 4.58 (s, 2H), 3.93 (s, 3H), 3.53 (t, JZ6.3 Hz,

10642
M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
2H), 3.06 (t, JZ6.3 Hz, 2H): 13C NMR (75 MHz, CDCl3) d
166.00, 158.79, 138.63, 134.48, 131.67, 129.84(2C),
129.59, 129.23(3C), 128.85, 128.62, 126.05, 122.14,
114.93, 107.97, 56.54, 51.78, 47.01, 29.55; HRMS m/z
(EI, MC) calcd for C21H19NO2 317.1416. Found 317.1409.
127.92 (2C), 127.67 (2C), 124.25, 50.83, 43.96, 31.06,
21.09; HRMS m/z (EI) calcd for C20H18BrNO2 383.0521.
Found (MC) 383.0518.
4.4.4. 1-Benzyl-3-(4-bromo-benzyl)-2-oxo-1,2,5,6-tetra-
hydropyridine-4-carbaldehyde (6d). 85% Yield; white
solid; IR (CHCl3, cmK1) 3030, 1655, 1227; 1H NMR
(500 MHz, CDCl3) d 10.36 (s, 1H), 7.42 (d, JZ8.0 Hz, 2H),
7.31–7.18 (m, 5H), 7.14 (d, JZ8.0 Hz, 2H), 4.65 (s, 2H),
4.22 (s, 2H), 3.31 (t, JZ7.0 Hz, 2H), 2.54 (t, JZ7.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 191.07, 164.32,
144.88, 139.26, 137.62, 136.53, 131.82 (2C), 130.32 (2C),
128.74 (2C), 127.87 (2C), 127.72, 120.52, 50.89, 43.93,
29.81, 20.91; LRMS m/z (EI, 30 eV): 383 (MC, 1%), 354
(2%), 288 (8%), 91 (100%). Anal. Calcd for C20H18BrNO2:
C, 62.51; H, 4.72; N, 3.65. Found: C, 62.45; H, 4.61; N,
4.05. Compound 6d was recrystallized from ethyl acetate as
a colorless prism.
4.3.5. 7-Benzyl-6,7-dihydro-5H-1-thia-7-aza-cyclopen-
ta[b]naphthalen-8-one (5c). 90% Yield; yellow oil; IR
(CHCl3, cmK1) 3012, 1635; 1H NMR (500 MHz, CDCl3) d
8.7 (s, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.34–7.25 (m, 6H),
4.84 (s, 2H), 3.52 (t, JZ6.5 Hz, 2H), 3.05 (t, JZ6.5 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 164.71, 141.95,
138.42, 137.45, 133.78, 130.02, 128.63 (2C), 128.02 (2C),
127.42, 125.93, 123.45, 123.21, 121.26, 50.52, 45.67, 28.55;
HRMS m/z (EI, MC) calcd for C18H15NOS 239.0874.
Found 239.871.
4.4. Procedure for hydrolysis of lactam 3 to 1-benzyl-3-
substituted-2-oxo-1,2,5,6-tetrahydropyridine-4-
carbaldehyde 6
Single-crystal X-ray diagram.14 Crystals of 6d were grown
by slow diffusion of n-hexane into a solution of 6d in ethyl
acetate to yield colorless prism. The compound crystallizes
in the monoclinic crystal system, space group P21/n(#14),
To a solution of lactam 3 (400 mg, 0.8 mmol) in acetone
(20 mL) was added 10% aqueous HCl (1 mL). The resulting
mixture was refluxed for 12 h and then evaporated. The
residue was dissolved with dichloromethane, and the
mixture was basified with 2 N aqueous sodium hydroxide
in an ice bath. The organic layer was separated, and the
aqueous layer was extracted with dichloromethane. The
combined organic layers were washed with brine, dried, and
evaporated to give the crude product. Chromatography on
silica gel (hexane/ethyl acetateZ4:1) afforded the pure
products.
˚
˚
˚
aZ14.142(3) A, bZ9.276(3) A, cZ19.066(4) A, bZ
92.99(2)8, VZ179.2(9) A , ZZ4, DcalcZ1.425 g/cm3,
3
˚
absorption coefficient 22.8 cmK1, F(000)Z784, 2q range
(8.8–13.88).
4.4.5. 1-Benzyl-3-(2-methoxybenzyl)-2-oxo-1,2,5,6-tetra-
hydropyridine-4-carbaldehyde (6e). 87% Yield; yellow
1
oil; IR (CHCl3, cmK1) 3022, 1663; H NMR (500 MHz,
CDCl3) d 10.43 (s, 1H), 7.36–7.18 (m, 7H), 6.92 (dd, JZ
0.5, 0.5 Hz, 1H), 6.83 (d, JZ8.0 Hz, 1H) 4.65 (s, 2H), 4.25
(s, 2H), 3.76 (s, 3H) 3.24 (t, JZ7.0 Hz, 2H), 2.48 (t, JZ
7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 192.30, 164.73,
157.06, 144.56, 138.18, 136.77, 130.91, 128.56 (2C),
127.88, 127.75 (2C), 127.44, 126.44, 120.67, 110.23,
54.84, 50.72, 43.95, 25.21, 20.72; HRMS m/z (EI, MC)
calcd for C21H21NO3 335.1521. Found 335.1517.
4.4.1. 1,3-Dibenzyl-2-oxo-1,2,5,6-tetrahydropyridine-4-
carbaldehyde (6a). 91% Yield; yellow oil; IR (CHCl3,
1
cmK1) 3022, 1635, 1220; H NMR (500 MHz, CDCl3) d
10.37 (s, 1H), 7.31–7.19 (m, 10H), 4.66 (s, 2H), 4.29 (s, 2H),
3.31 (t, JZ7.0 Hz, 2H), 2.54 (t, JZ7.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 191.43, 164.53, 145.48, 139.08,
138.68, 136.65, 128.77 (2C), 128.70 (2C), 128.50 (2C),
127.89 (2C), 127.63, 126.56, 50.87, 43.96, 30.27, 20.86;
HRMS m/z (EI, MC) calcd for C20H19NO2 305.1416. Found
305.3708.
4.4.6. 1-Benzyl-3-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetra-
hydropyridine-4-carbaldehyde (6f). 87% Yield; yellow
1
oil; IR (CHCl3, cmK1) 3032, 1673; H NMR (500 MHz,
CDCl3) d 10.39 (s, 1H), 7.30–7.16 (m, 7H), 6.84 (d, JZ
8.5 Hz, 2H), 4.65 (s, 2H), 4.21 (s, 2H), 3.79 (s, 3H), 3.30
(t, JZ7.0 Hz, 2H), 2.52 (t, JZ7.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 191.49, 164.58, 158.28, 145.87,
138.75, 136.67, 130.59, 129.57 (2C), 128.70 (2C), 127.88
(2C), 127.63, 114.17 (2C), 55.27, 50.86, 43.98, 29.42,
20.85; HRMS m/z (EI, MC) calcd for C21H21NO3 335.1521.
Found (MC) 335.1519.
4.4.2. 1-Benzyl-3-(4-methylbenzyl)-2-oxo-1,2,5,6-tetra-
hydropyridine-4-carbaldehyde (6b). 85% Yield; mp
126–128 8C; white solid; IR (CHCl3, cmK1) 3022, 1656;
1H NMR (500 MHz, CDCl3) d 10.38 (s, 1H), 7.31–7.10 (m,
9H), 4.65 (s, 2H), 4.23 (s, 2H), 3.30 (t, JZ7.0 Hz, 2H), 2.52
(t, JZ7.0 Hz, 2H), 2.32 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 191.52, 164.56, 145.73, 138.89, 136.70, 136.13,
135.60, 129.45 (2C), 128.68 (2C), 128.38 (2C), 127.90 (2C),
127.61, 50.84, 43.95, 29.85, 20.99, 20.84; HRMS m/z (EI,
MC) calcd for C21H21NO2 319.1572. Found 319.1569.
4.4.7. 4-(1-Benzyl-4-formyl-2-oxo-1,2,5,6-tetrahydro-
pyridin-3-ylmethyl)benzoic acid methyl ester (6g). 90%
Yield; yellow oil; IR (CHCl3, cmK1) 3030, 1683, 1652,
1611; 1H NMR (500 MHz, CDCl3) d 10.37 (s, 1H), 7.97 (dd,
JZ7.0, 2.0 Hz, 2H), 7.33–7.28 (m, 5H), 7.19 (dd, JZ7.0,
2.0 Hz, 2H), 4.65 (s, 2H), 4.33 (s, 2H), 3.91 (s, 3H), 3.32
(t, JZ7.0 Hz, 2H), 2.55 (t, JZ7.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 191.04, 166.85, 164.30, 144.52,
144.05, 139.58, 136.52, 130.09 (2C), 128.75 (2C), 128.56,
128.52 (2C), 127.90 (2C), 127.74, 52.09, 50.90, 43.92,
4.4.3. 1-Benzyl-3-(2-bromobenzyl)-2-oxo-1,2,5,6-tetra-
hydropyridine-4-carbaldehyde (6c). 83% Yield; yellow
1
oil; IR (CHCl3, cmK1) 3022, 1663; H NMR (500 MHz,
CDCl3) d 10.25 (s, 1H), 7.56 (dd, JZ8.0, 1.0 Hz, 1H), 7.31–
7.20 (m, 7H), 7.11–7.08 (m, 1H), 4.67 (s, 2H), 4.36 (s, 2H),
3.55 (t, JZ7.0 Hz, 2H), 2.55 (t, JZ7.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 191.42, 164.42, 143.91, 140.04,
138.17, 136.66, 132.99, 130.30, 128.70 (2C), 128.23,

M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
10643
30.40, 20.96; HRMS m/z (EI, MC) calcd for C22H21NO4
363.1471. Found 363.1465.
4.16. Compound 7d was recrystallized from ethyl acetate as
a colorless prism.
Single-crystal X-ray diagram.14 Crystals of 7d were grown
by slow diffusion of n-hexane into a solution of 7d in ethyl
acetate to yield colorless prism. The compound crystallizes
in the monoclinic crystal system, space group P21/c(#14),
4.5. Procedure for preparation of 1,2,3,4-tetrahydro-
isoquinolone derivatives 7
To solution of lactam 6 (200 mg, 0.66 mmol) in CH2Cl2
(20 mL) was added TiCl4 (124 mg, 0.66 mmol). The
resulting mixture were refluxed for 12 h and then evapor-
ated. The residue was dilute with water (10 mL) and
extracted with ethyl acetate (3!20 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated. Chromatography on silica gel (hexane/ethyl
acetateZ4:1) afforded the pure products.
˚
˚
˚
aZ14.350(3) A, bZ7.859(2) A, cZ14.201(4) A, bZ
3
99.34(2)8, VZ1580.4(7) A , ZZ4, DcalcZ1.539 g/cm3,
˚
absorption coefficient 26.12 cmK1, F(000)Z744, 2q range
(8.63–14.158).
4.5.5. 2-Benzyl-9-methoxy-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (7e). 83% Yield; yellow oil; IR (CHCl3,
cmK1) 3020,1232; 1H NMR (500 MHz, CDCl3) d 9.13
(s, 1H), 7.51 (s, 1H), 7.43 (t, JZ8.0 Hz, 1H), 7.31–7.25
(m, 6H), 6.01 (dd, JZ8.0, 2.5 Hz, 1H), 4.86 (s, 2H), 4.00
(s, 3H), 3.52 (t, JZ6.5 Hz, 2H), 3.08 (t, JZ6.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d 164.82, 156.74, 137.52, 136.40,
135.94, 134.92, 128.61 (2C), 128.25, 128.09 (2C), 127.40,
126.65, 124.62, 124.25, 119.09, 103.74, 55.49, 50.68, 45.62,
28.59; HRMS m/z (EI, MC) calcd for C21H19NO2 317.1416.
Found 317.1418.
4.5.1. 2-Benzyl-3,4-dihydro-2H-benzo[g]isoquinolin-1-
one (7a). 87% Yield; yellow oil; IR (CHCl3, cmK1) 3020,
1662, 1220; H NMR (500 MHz, CDCl3) d 8.68 (s, 1H),
1
7.96 (dd, JZ8.5, 2.0 Hz, 1H), 7.84 (d, JZ9.0 Hz, 1H), 7.56
(dd, JZ9.0, 2.0 Hz, 1H), 7.50 (s, 1H), 7.38–7.28 (m, 6H),
4.86 (s, 2H), 3.58 (t, JZ6.5 Hz, 2H), 3.11 (t, JZ6.5 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 164.34, 137.19,
135.77, 135.58, 130.93, 130.59, 129.47 (2C), 129.16,
128.70 (2C), 128.08 (2C), 127.85, 127.55, 124.20, 122.25,
50.70, 45.48, 28.58; HRMS m/z (EI, MC) calcd for
C20H17NO 287.1310. Found 287.1315.
4.5.6. 2-Benzyl-7-methoxy-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (7f). 82% Yield; white solid; IR (CHCl3,
1
cmK1) 3030, 16215, 1220; H NMR (500 MHz, CDCl3) d
4.5.2. 2-Benzyl-7-methyl-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (7b). 85% Yield; white solid; mp 123–
125 8C; IR (CHCl3, cmK1) 3022, 1656; 1H NMR (500 MHz,
CDCl3) d 8.66 (s, 1H), 7.86 (d, JZ8.5 Hz, 1H), 7.55 (s, 1H),
7.48 (s, 1H), 7.36–7.30 (m, 6H), 4.86 (s, 2H), 3.53 (t, JZ
6.5 Hz, 2H), 3.09 (t, JZ6.5 Hz, 2H), 2.52 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 164.87, 137.93, 137.42, 135.12,
134.35, 130.41, 129.30, 129.15, 128.64 (2C), 128.27,
128.05 (2C), 127.43, 126.59, 126.01, 124.37, 50.63, 45.65,
28.63, 21.91; HRMS m/z (EI, MC) calcd for C21H19NO
301.1467. Found 301.1462.
8.63 (s, 1H), 7.85 (d, JZ9.0 Hz, 1H), 7.46 (s, 1H), 7.37–
7.26 (m, 5H), 7.14 (dd, JZ9.0, 2.5 Hz, 1H), 7.07 (d, JZ
2.5 Hz, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 3.53 (t, JZ6.5 Hz,
2H), 3.08 (t, JZ6.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 164.89, 159.30, 137.49, 136.40, 135.02, 130.93, 129.34,
128.63 (2C), 128.06 (2C), 127.65, 127.41, 125.32, 123.85,
118.86, 105.01, 55.32, 50.59, 45.62, 28.67; HRMS m/z (EI,
MC) calcd for C21H19NO2 317.1416. Found 317.1409.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41.
Found: C, 79.23; H, 6.39; N, 4.81. Compound 7f was
recrystallized from ethyl acetate as a colorless prism.
4.5.3. 2-Benzyl-9-bromo-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (7c). 81% Yield; white solid; mp 146–
148 8C; IR (CHCl3, cmK1) 3022, 1227; 1H NMR (500 MHz,
CDCl3) d 9.09 (s, 1H), 7.76 (dd, JZ7.7, 1.0 Hz, 1H), 7.73
(d, JZ8.5 Hz, 1H), 7.59 (s, 1H), 7.29–7.37 (m, 6H), 4.87 (s,
2H), 3.56 (t, JZ6.0 Hz, 2H), 3.12 (t, JZ6.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d 164.20, 137.25, 135.97, 135.33,
131.09, 130.01, 128.90, 128.73, 128.69 (2C), 128.11 (2C),
127.53, 126.53, 126.94, 125.71, 124.30, 50.77, 45.46, 28.37;
HRMS m/z (EI, MC) calcd for C20H16NOBr 365.0415.
Found 365.0408.
Single-crystal X-ray diagram.14 Crystals of 7f were grown
by slow diffusion of n-hexane into a solution of 7f in ethyl
acetate to yield colorless prism. The compound crystallizes
in the triclinic crystal system, space group Pbca, aZ
12.0504(16) A, bZ8.0388(11) A, cZ33.425(4) A, aZ
90.008, bZ90.008, gZ90.008, ZZ8, DcalcZ1.302 g/cm3,
absorption coefficient 0.83 cmK1, F(000)Z1344.
˚
˚
˚
4.5.7. 2-Benzyl-1-oxo-1,2,3,4-tetrahydro-benzo[g]isoqui-
noline-7-carboxylic acid methyl ester (7g). 60% Yield;
yellow solid; mp 147–149 8C; IR (CHCl3, cmK1) 3018,
1
4.5.4. 2-Benzyl-7-bromo-3,4-dihydro-2H-benzo[g]iso-
quinolin-1-one (7d). 80% Yield; white solid; IR (CHCl3,
1721, 1629; H NMR (500 MHz, CDCl3) d 8.74 (s, 1H),
8.55 (s, 1H), 8.06 (dd, JZ8.5, 1.5 Hz, 1H), 8.01 (d, JZ
8.5 Hz, 1H), 7.70 (s, 1H), 7.36–7.29 (m, 5H), 4.87 (s, 2H),
3.99 (s, 3H), 3.57 (t, JZ6.5 Hz, 2H), 3.13 (t, JZ6.5 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 166.99, 164.21,
137.13, 135.17, 134.17, 133.88, 130.03, 129.58, 129.47,
129.21, 129.14, 128.70 (2C), 128.07 (2C), 127.56, 126.54,
125.26, 52.36, 50.75, 45.50, 28.53; HRMS m/z (EI, MC)
calcd for C22H19NO3 345.1359, found 345.1366. Anal.
Calcd for C22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C,
76.20; H, 5.41; N, 4.48. Compound 7g was recrystallized
from ethyl acetate as a colorless prism.
1
cmK1) 3030, 1220; H NMR (500 MHz, CDCl3) d 8.68
(s, 1H), 7.96 (d, JZ2.0 Hz, 1H), 7.84 (d, JZ9.0 Hz, 1H),
7.56 (dd, JZ9.0, 2.0 Hz, 1H), 7.50 (s, 1H), 7.38–7.28
(m, 5H), 4.86 (s, 2H), 3.58 (t, JZ6.5 Hz, 2H), 3.11 (t, JZ
6.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 164.34, 137.19,
135.77, 135.58, 130.93, 130.59, 129.47 (2C), 129.16,
128.70 (2C), 128.08 (2C), 127.85, 127.55, 124.20, 122.25,
50.70, 45.48, 28.58; LRMS m/z (EI, 30 eV): 365 (MC,
20%), 274 (9%), 91 (100%). Anal. Calcd for C20H16BrNO:
C, 65.59; H, 4.40; N, 3.82. Found: C, 65.45; H, 4.36; N,

10644
M.-R. Tsai et al. / Tetrahedron 60 (2004) 10637–10644
Single-crystal X-ray diagram.14 Crystals of 7g were grown
by slow diffusion of n-hexane into a solution of 7g in ethyl
acetate to yield colorless prism. The compound crystallizes
in the triclinic crystal system, space group P1(#1), aZ
References and notes
1. (a) Croisy-Delcey, M.; Croisy, A.; Carrez, D.; Huel, C.;
Chiaroni, A.; Ducrot, P.; Bisagni, E.; Jin, L.; Leclercq, G.
Bioorg. Med. Chem. 2000, 8, 2629. (b) Sulkowski, T. S.; Wille,
M. A. (American Home Products Corp.). US Patent 3,452,027,
1969; C.A. 1969, 71, 112830. (c) Coyne, W. E.; Cusic, J. W.
(Searle & Co.). US Patent 3,600,394, 1971; C.A. 1971, 75,
118241. (d) Kubo, K.; Ito, N.; Sozu, I.; Isomura, Y.; Homma,
H. Japan Kokai Tokkyo Koho 79, 163585, 1979; C.A. 1980,
93, 8037. (e) Kubo, K.; Ito, N.; Sozu, I.; Isomura, Y.; Homma,
H. Japan Kokai Tokkyo Koho 79, 92997, 1979; C.A. 1980, 92,
111036. (f) Kubo, K.; Ito, N.; Sozu, I.; Isomura, Y.; Homma,
H. Ger. Offen. 2,828,528, 1979; C.A. 1979, 90, 168468.
(g) Wakabayashi, T.; Watanabe, K. Japan Kokai Tokkyo Koho
78, 119879, 1978; C.A. 1979, 90, 152028.
˚
˚
˚
8.818(4) A, bZ12.692(4) A, cZ8.517(3) A, aZ107.82(2)8,
3
˚
bZ107.86(3)8, gZ82.04(3)8, VZ862.7(5) A , ZZ2, Dcalc
Z
1.330 g/cm3, absorption coefficient 0.88 cmK1, F(000)Z364,
2q range (9.2–17.68).
4.6. Procedure for preparation of isoquinolone
derivatives 8 and 9
To a solution of 5c (110 mg, 0.30 mmol) in 1,4-dioxane
(15 mL) was added DDQ (275 mg, 1.2 mmol). The resulting
mixture was refluxed for 24 h and then evaporated. The
residue was dilute with water (10 mL) and extracted with
ethyl acetate (3!20 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated.
Chromatography on silica gel (hexane/ethyl acetateZ4:1)
afforded the pure products.
2. (a) Matsui, T.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.;
Tukeda, H.; Odagaki, T.; Nagao, Y.; Ushio, Y.; Ohmoto, K.;
Iwamura, H.; Yamazaki, S.; Arai, Y.; Kawamura, M. J. Med.
Chem. 1992, 35, 3307. (b)Li,S. W.;Nair, M. G.;Edwards,D.M.;
Kisluick, R. L.; Gaument, Y.; Dev, I. K.; Duch, D. S.;
Humphreys, J.; Smith, G. K.; Ferone, R. J. Med. Chem. 1991,
34, 2746. (c) Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Brown,
S. J.; Jones, M.; Harrap, K. R. Eur. J. Cancer 1981, 17, 11.
3. Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 151–190.
4. Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Wiley: New York, 1951; Vol. 6, pp 74–150.
4.6.1. 2-Benzyl-7-bromo-2H-benzo[g]isoquinolin-1-one
(8). 70% Yield; white solid; mp 170–172 8C; IR (CHCl3,
1
cmK1) 3029, 1625, 1220; H NMR (500 MHz, CDCl3) d
9.01 (s, 1H), 8.08 (d, JZ2.0 Hz, 1H), 7.91 (d, JZ9.0 Hz,
1H), 7.85 (s, 1H), 7.56 (dd, JZ9.0, 2.0 Hz, 1H), 7.35–7.29
(m, 5H), 7.03 (d, JZ7.5 Hz, 1H), 6.58 (d, JZ7.5 Hz, 1H),
5.23 (s, 2H); 13C NMR (125 MHz, CDCl3) d 162.56, 136.77,
136.05, 133.86, 131.13, 130.92, 130.11, 129.54, 129.49,
129.41, 128.84 (2C), 127.96 (2C), 127.89, 124.98, 123.13,
122.66, 106.38, 51.53; HRMS m/z (EI, MC) calcd for
C20H14NOBr 363.0259. Found 363.0255. Compound 8 was
recrystallized from ethyl acetate.
5. Gensler, W. J. Adams, R., Ed.; Organic Reactions; Wiley:
New York, 1951; Vol. 6, pp 191–206.
6. Briet, N.; Brookes, M. H.; Davenport, R. J.; Galvin, F. C. A.;
Gilbert, P. J.; Mack, S. R.; Sabin, V. Tetrahedron 2002, 58, 5761.
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1999, 55, 13193.
8. Wang, X. J.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39,
6609 and the references therein.
4.6.2. 7-Benzyl-7,8-dihydrothieno[3,2-g]isoquinoline-8-
one (9). 65% White solid; yield; mp 150–152 8C; IR
(CHCl3, cmK1) 3030, 1640; 1H NMR (500 MHz, CDCl3) d
9.05 (s, 1H), 7.95 (s, 1H), 7.68 (d, JZ5.0 Hz, 1H), 7.42 (d,
JZ5.0 Hz, 1H), 7.35–7.29 (m, 5H), 7.04 (d, JZ7.5 Hz, 1H),
6.59 (d, JZ7.5 Hz, 1H), 5.26 (s, 2H); 13C NMR (125 MHz,
CDCl3) d 162.36, 142.91, 138.74, 137.01, 132.99, 131.31,
129.95, 128.80 (2C), 127.92 (2C), 127.78, 123.35, 123.31,
122.80, 120.00, 106.79, 51.57; HRMS m/z (EI, MC) calcd
for C18H13NOS 291.0718. Found 291.0712. Compound 9
was recrystallized from ethyl acetate
9. (a) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C.
Tetrahedron Lett. 2000, 41, 10273. (b) Huang, C. G.; Chang,
B. R.; Chang, N. C. Tetrahedron Lett. 2002, 43, 2721.
(c) Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett.
2002, 43, 3233. (d) Chang, M. Y.; Chen, S. T.; Chang, N. C.
Tetrahedron 2002, 58, 3623. (e) Chang, M. Y.; Chen, S. T.;
Chang, N. C. Tetrahedron 2002, 58, 5075. (f) Hsu, R. T.;
Cheng, L. M.; Chang, N. C.; Tai, H. M. J. Org. Chem. 2002,
67, 5044. (g) Chang, M. Y.; Chen, S. T.; Chang, N. C.
Heterocycles 2002, 57, 2321. (h) Lin, C. H.; Tsai, M. R.;
Wang, Y. S.; Chang, N. C. J. Org. Chem. 2003, 68, 5688.
(i) Chang, M. Y.; Chen, S. T.; Chang, N. C. Heterocycles 2003,
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Acknowledgements
The authors thank the National Science Council of the
Republic of China for financial support.
10. Cheng, C. Y.; Chang, B. R.; Tsai, M. R.; Chang, M. Y.; Chang,
N. C. Tetrahedron 2003, 59, 9383.
11. Tius, M. A.; Gomez-Galeno, J. Tetrahedron Lett. 1986, 27, 2571.
12. Compounds 6d, 7d, 7f, 7g were recrystallized from ethyl
acetate, and the X-ray crystallographic analysis succeeded in
confirming the structures.
Supplementary data
13. Komatsu, M.; Yamamoto, S.; Ohshiro, Y.; Agawa, T.
Tetrahedron Lett. 1981, 22, 3769.
Experimental procedures and photocopies of spectral data for
(1H NMR in CDCl3) were supported.
14. CCDC 243916-243919 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: C44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.09.
015.