A novel synthesis of 5,6-dihydroindazolo[3,2-a]isoquinolines and their relative compounds via tin(II) chloride dihydrate as reducing agent

Article abstract of DOI:10.1002/jccs.200500135

A series of 1-(2-nitrophenyl)-3,4-dihydroisoquinolines were reduced under very mild reaction conditions in the presence of Tin(II) chloride dihydrate (SnCl₂·2H₂O) to give 5,6-dihydroindazolo[3,2-a] isoquinolines 4a-h. A mechanism for

Full text of DOI:10.1002/jccs.200500135

Journal of the Chinese Chemical Society, 2005, 52, 965-974
965
A Novel Synthesis of 5,6-Dihydroindazolo[3,2-a]isoquinolines and Their
Relative Compounds via Tin(II) Chloride Dihydrate as Reducing Agent
Chen-Yuan Kuoab
(
) and Ming-Jung Wuc* (
)
aDepartment of Chemical Engineering, Yung-Ta Institute of Technology and Commerce,
Pingtung, Taiwan, R.O.C.
bGraduate Institute of Pharmaceutical Science, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
cFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
A series of 1-(2-nitrophenyl)-3,4-dihydroisoquinolines were reduced under very mild reaction conditions
in the presence of Tin(II) chloride dihydrate (SnCl2·2H2O) to give 5,6-dihydroindazolo[3,2-a]isoquinolines
4a-h. A mechanism for this reaction is proposed.
Keywords: Isoquinoline; Bischler-Napieralski; Indazole.
INTRODUCTION
The synthesis of isoquinolines and their derivatives has
lines 4a-h is shown in Scheme I. The treatment of 2-phenyl
ethylamine with 2-nitrobenzoylchloride gave N-phenyleth-
yl-2-nitrobenzamide 1a in 80% yield. Compound 1a was then
converted to 1-(2-nitrophenyl)-3,4-dihydroisoquinoline 2a
in 90% yield following the Bischler-Napieralski21 reaction
conditions. Finally, compound 2a was treated with SnCl2·
2H2O in ethyl acetate to give 1-(2-aminophenyl)isoquinoline
3a and 5,6-dihydroindazolo[3,2-a]isoquinoline 4a. It was
found that the treatment of 2a with SnCl2·2H2O at 80 °C gave
1-(2-aminophenyl)isoquinoline 3a in 66% yield along with
5,6-dihydroindazolo[3,2-a]isoquinoline 4a in 28% yield. In-
terestingly, when an ethyl acetate solution of SnCl2·2H2O
was added dropwise into the solution of 2a, compound 4a
was obtained in 79% yield as the only product. In order to
gain a further understanding of the reaction, seven other 1-
(2-nitrophenyl)-3,4-dihydroisoquinolines 2b-h were synthe-
sized. Treating 2b-h with SnCl2·2H2O under different reac-
tion conditions gave compounds 3 and 4 in different ratios,
respectively. The results are summarized in Table 1.
received much attention1-5 due to their widespread occur-
rence in nature6-8 and broad biological activities.9-15 The pyr-
azolo[4,3-c]isoquinoline and pyrazolo[3,4-c]isoquinolines
and their derivatives have been found to exibit biological
activity as anti-inflammatory, antiallergic, and anti viral
agents.16 Also, indolo[1,2-b]indazoles have shown high ac-
tivity against proliferation of cancer cell lines.17 All of these
compounds contain a pyrazolomoiety.
In 1977, Reddy reported that the treatment of 1-(2-ni-
trophenyl)isoquinolines with triethylphosphite gave inda-
zolo[3,2-a]isoquinolines.18 Recently, a similar result was ob-
served by Stanforth.19 Both of them suggested that the forma-
tion of indazolo[3,2-a]isoquinolines involve a nitrene inter-
mediate. Since these compounds contain a similar structure
moiety to that of pyrazolo[4,3-c]isoquinolines and pyrazolo-
[3,4-c]isoquinolines, they may also exhibit biological activ-
ity. During our investigation on the synthesis of isoquinolines
and their derivatives, we found that the reaction of 1-(2-
nitrophenyl)isoquinolines with SnCl2·2H2O not only gave
1-(2-aminophenyl)isoquinolines20 but also resulted in the
formation of indazolo[3,2-a]isoquinolines. In this paper, we
report an efficient synthesis of 5,6-dihydroindazolo[3,2-
a]isoquinolines 4a-h by the reaction of 1-(2-nitrophenyl)iso-
quinolines with SnCl2·2H2O.
The IR spectroscopic data of compound 4a shows the
1
presence of a C=N bond absorption at 1620 cm-1. In the H
NMR spectrum, all 12 protons are visible. The downfield sig-
nals at d 7.19-8.05 suggested the presence of 8 aromatic (con-
jugated C=C) protons, and the two triplets at d 4.67 (2H) and
3.28 (2H) were both observed downfield compared with cor-
responding signals of 1-(2-aminophenyl)isoquinoline 3a at d
3.85 and 2.78. This is because these two groups of hydrogens
of 4a are in a more polar environment (Fig. 1). 13C NMR
spectra indicated that this molecule contains 15 carbon sig-
nals, including 13 sp2 carbons at d 117.8 - d 148.5 (d 148.5 for
C=N, and the others for C=C); compared with 1-(2-amino-
phenyl)isoquinoline 3, the carbon (C=N) of 4a is at higher
RESULTS AND DISCUSSIONS
The synthesis of 5,6-dihydroindazolo[3,2-a]isoquino-

966 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Kuo and Wu
Scheme I
COOH
NO2
COCl
1a: R1=R2=R=H
NO2
1b: R1=OCH3 R2=R=H
1c: R1=R2=OCH3 R=H
1d: R1=R2=H R=OCH3
1e: R1=R=OCH3 R2=H
1f: R1= R2=H R=OCH3
1g: R1= R2=H R=Cl
+ (COCl)2
R
R
COCl
R2
R2
R1
NO2
Py.
+
NH2
NH
1h: R1= R2=OCH3 R=Cl
R1
O
R
NO2
R
R2
R2
R2
SnCl2 2H2O
POCl3
CH3CN, 800C
N
N
N
+
R1
R1
R1
NO2
NH2
N
R
R
R
2
4
3
Table 1. Reaction of 1-(2-nitrophenyl)-3,4-dihydroisoquinolines
with SnCl2·2H2O
field than that of 3a (at d 167.6). This could be due to the reso-
nance structure of 4a on the right in Fig. 1. In addition, the
mass spectra indicated that the molecular weight of 4a is 220.
Finally, elemental analysis showed the molecule formula of
4a is C15H12N2·1/4H2O. Hence, the structure of 4a was as-
signed as 5,6-dihydroindazolo[3,2-a]isoquinoline (more de-
tailed spectral data is shown in the experimental section).
Vedejs reported10 that the reduction of 2c with Fe/HCl gave
3c and an intensely yellow impurity that could not be sepa-
rated well enough to give satisfactory analysis or spectra and
he thought it was an indazole N-oxide. According to our ob-
servation, the impurity they obtained could be compound
4c.
Entry Reactant Reducing agent Temp (°C) Yields [%] 3:4
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
NaBH4
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
SnCl2·2H2O
80a
rtb
66:28
00:79
10:75
60:23
00:75
22:55
80:00
00:45
36:40
< 5c
68:25
00:20
45:18
65:22
00:17
45:15
78:10
00:10
55:13
00:58
55:38
00:46
72:14
80b
80a
rtb
80b
80a
rtb
9
80b
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
80a
rtb
To explain the different ratios of the products formation
under different reaction conditions, a reasonable mechanism
is proposed as shown in Scheme II. Treatment of compound 2
with SnCl2·2H2O in ethyl acetate would generate a nitroso in-
termediate which would undergo further reduction by tin
80b
80a
rtb
80b
80a
rtb
2f
2f
2g
2g
2h
2h
4
5
80b
rtb
R2
R1
3
R2
R1
6
N
80a
rtb
N
2
1
N
N
7
80a
10
a All reactions were carried out using General Procedure C.
b All reactions were carried out using General Procedure D.
c Product is 3c.
R
8
R
9
Fig. 1.

Synthesis of 5,6-Dihydroindazolo[3,2-a]isoquinoline
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 967
Scheme II
R2
R2
R1
b
N
N
+ SnCl 2 2H2O
R1
NO2
O
N
R
R
a
R2
N
R1
R2
N
OH
N
R1
NH3+Cl-
R
H-
R
R2
R1
R2
R1
NaOH
H
N
N
Sn
N
N
OH
R2
R1
N
R
R
NH2
R
chloride to give the amino adduct. However, under the condi-
tions of slow addition of SnCl2·2H2O to the solution of 2, the
free electron pair on N1 would be allowed to add to the nitroso
group. Further reduction of the azomethine and elimination
of a hydroxide would give, 5,6-dihydroindazolo[3,2-a]iso-
quinolines 4. When the C-ring bears an electron-donating
group, such as a methoxy group, it would reduce the electro-
philicity of the nitroso group towards the nucleophilic addi-
tion, and therefore, a large amount of reduction products,
compounds 3d-f, would be formed and compounds 4d-f
would be obtained in lower yields. On the other hand, if the
C-ring bears an electron-withdrawing group, such as a chloro
group, the electrophilicity of the nitroso group toward the
nucleophilic addition would be enhanced, and therefore,
compounds 4g-h would be obtained in higher yields than in
the case of those compounds in which the C-ring bears an
electron-donating group. However, contrary to expectations,
the yields of compounds 4g-h were lower than those of com-
pounds 4a-c.
CONCLUSIONS
An efficient synthesis of indazolo[3,2-a]isoquinolines
has been developed by the reaction of 1-(2-nitrophenyl)-3,4-
dihydroisoquinolines with tin(II) chloride at room tempera-
ture. This methodology would allow us to prepare a variety of
indazolo[3,2-a]isoquinolines in moderate to good yields.
Only the compounds bearing electron-donating groups at the
C-ring gave low yields. A reasonable mechanism was pro-
posed as shown in Scheme II.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded at 400 and
100 MHz or 200 and 50 MHz, respectively. High-resolution
mass spectra were recorded on a double focusing magnetic
sector mass spectrometer using EI at 70 eV. IR spectra were
recorded on a SHIMADZU IR 470. UV data were recorded

968 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Kuo and Wu
with methanol as solvent on a SHIMADZU UV-1201. All re-
N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1c)
actions were monitored by analytical TLC (silica gel 60 F254
,
Light yellow needles, mp 142-143 °C, Rf = 0.57
(EtOAc/n-Hexane = 2:1), lmax (MeOH) = 275 nm; IR (cm-1)
3300 NH, 3010 (Aromatic CH), 2950 2830 (aliphatic CH),
Merck). The residues were purified by flash chromatography
(230-400 mm). All melting points are uncorrected.
1
1640 (NHC=O), 1530 (NO2), 1360 (NO2); H NMR (400
N-Phenylethyl-2-nitrobenzamides (1a-c)10,20-21 (General
procedure A1)
MHz, CDCl3) d 8.05 (1H, dd, J = 8.0, 1.2 Hz, H-3¢), 7.62 (1H,
dd, J = 7.2, 1.2 Hz, H-6¢), 7.56 (1H, dd, J = 8.0, 1.2 Hz, H-4¢),
7.42 (1H, d, J = 1.2 Hz, H-5¢), 6.80 (3H, s, H-1,5,6), 5.78 (1H,
br s, NH), 4.09 (3H, s, OCH3), 4.04 (3H, s, OCH3), 3.74 (2H,
2-Nitrobenzoyl chloride (5.01 g, 27.7 mmol) was dis-
solved in dry benzene (30 mL) and added dropwise to a
stirred solution of phenethylamine (3.63 g, 30 mmol) and
pyridine (3.0 g, 38 mmol) in dry benzene (80 mL). The mix-
ture was continuously stirred at room temperature overnight
and then poured into water (200 mL). The solution was fil-
tered and the solid was washed with 1.0 N HCl (80 mL), 1.0 N
NaOH (80 mL), and water (80 mL). Recrystallization of the
crude product from ethanol afforded 1a (4.50 g). The mother
layer was evaporated and the residue was recrystallized from
ethanol to afford white crystals 1a (1.51 g). Totally, com-
pound 1a was obtained in 80% yield (6.01 g): mp 114-115 °C,
lmax (MeOH) = 250 nm; IR (cm-1) 3300 (NH), 3000 (aromatic
CH), 2920 (aliphatic CH), 1650 (NHC=O), 1510, 1360
(NO2); 1H NMR (400 MHz, CDCl3) d 8.03 (1H, d, J = 8.4 Hz,
H-3¢), 7.63 (1H, dd, J = 7.2, 1.2 Hz, H-6¢), 7.55 (1H, dd, J =
8.0, 1.2 Hz, H-4¢), 7.40 (1H, d, J = 1.2 Hz, H-5¢), 7.2-7.3 (5H,
m, H-2,3,4,5,6), 5.83 (NH, br s), 3.74 (2H, q, J = 6.8 Hz,
NCH2), 2.96 (2H, t, J = 6.8 Hz, NCH2CH2); 13C NMR (100
MHz, CDCl3) d 166.4 (C=O), 146.5 (C-NO2), 138.6 (C-1¢),
133.6 (C-1), 133 (C-4¢), 130 (C-3¢), 128.8 (C-5¢), 128.7 (C-
3,5), 128.6 (C-4), 126.6 (C-2,6), 124.5 (C-6¢), 41.2 (CH2-N),
35.3 (CH2CH2N). EI-MS m/z (%) = 270 (M+, 27.6), 253 (100)
[M+-OH]. Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N,
10.36. Found: C, 65.97; H, 5.18; N, 10.38. Using the same
process, we also obtained 1b and 1c in good yields.
q, J = 6.4 Hz, NCH2), 2.85 (2H, t, J = 6.4 Hz, NCH2CH2); 13
C
NMR (100 MHz, CDCl3) d 166.4 (C=O), 149.0 (C-3), 147.6
(C-4), 146.4 (C-NO2), 133.6 (C-1), 133.0 (C-1¢), 131.1 (C-
3¢), 130.3 (C-4¢), 128.5 (C-5¢), 124.5 (C-6¢), 120.6 (C-6),
112.1 (C-5), 111.4 (C-2), 55.85 (OCH3), 55.80 (OCH3), 41.29
(NCH2), 34.77 (NCH2CH2). EI-MS m/z (%) = 330 (35) [M+],
164 (100) [M+-C7H6N2O3], 151 (74) [M+-C8H7N2O3]. Anal.
Calcd for C17H18N2O5: C, 61.81; H, 5.49; N, 8.48. Found: C,
62.01; H, 5.36; N, 8.47.
N-phenylethyl-2-nitrobenzamide (1d-1h) (General Proce-
dure A2)
A mixture of 5-methoxy-2-nitrobenzoic acid or 5-chlo-
ro-2-nitrobenzoic acid, oxalyl chloride, and dry benzene was
stirred at 50-60 °C for 2 h. The excess oxalyl chloride was re-
moved under reduced pressure. The resulting acid chloride
was dissolved in dry benzene, and added dropwise to a stirred
solution of phenethylamine and pyridine in dry benzene. The
mixture was continuously stirred at room temperature over-
night and then poured into water (200 mL). The solution was
filtered and the solid was washed with 0.5 N HCl (100 mL),
0.5 N NaOH (100 mL), and water (100 mL); the crude prod-
uct was recrystallized from EtOAc/n-hexane. The mother liq-
uid was evaporated and the residue was recrystallized from
EtOAc/n-hexane. The crystals were combined.
N-(4-methoxyphenethyl)-2-nitrobenzamide (1b)
1
White needles, mp 123-124 °C; H NMR (400 MHz,
N-phenylethyl-5-methoxy-2-nitrobenzamide (1d)
1
CDCl3) d 8.01 (1H, dd, J = 8.0, 1.2 Hz, H-3¢), 7.62 (1H, m,
H-6¢), 7.54 (1H, m, H-4¢), 7.40 (1H, dd, J = 7.6, 1.6 Hz, H-5¢),
7.16 (2H, m, H-2,6), 6.84 (2H, dd, J = 6.4, 2.0 Hz, H-3,5),
5.90 (1H, br s, NH), 3.77 (3H, s, OCH3), 3.67 (2H, t, J = 6.8
Hz, NCH2), 2.89 (2H, t, J = 6.8 Hz, NCH2CH2); 13C NMR
(100 MHz, CDCl3, ppm) d 166.4 (C=O), 158.3 (C-4), 146.5
(C-NO2), 133.7 (C-1), 133.1 (C-1¢), 130.6 (C-3¢), 130.4 (C-
4¢), 129.8 (C-5¢), 128.6 (C-6¢), 124.6 (C-2,6), 114.1 (C-3,5),
55.3 (OCH3), 41.4 (NCH2), 34.4 (NCH2CH2). EI-MS m/z (%)
= 300 (M+, 100). Anal. Calcd for C16H16N2O4: C, 63.99; H,
5.37; N, 9.33. Found: C, 63.58; H, 5.41; N, 9.32.
White needles, mp 126-127 °C, H NMR (400 MHz,
CDCl3) d 8.10 (1H, d, J = 9.2 Hz, H-3¢), 7.20-7.33 (5H, m, H-
2,3,4,5,6), 6.94 (1H, dd, J = 9.2, 2.4 Hz, H-4¢), 6.80 (1H, d, J
= 2.4 Hz, H-6¢), 5.79 (1H, br s, NH), 3.87 (3H, s, OCH3), 3.74
(2H, t, J = 6.8 Hz, NCH2), 2.96 (2H, t, J = 6.8 Hz, NCH2CH2);
13C NMR (100 MHz, CDCl3) d 166.6 (C=O), 163.7 (C-5¢),
138.6 (C-NO2), 135.6 (C-1¢), 128.9 (C-3¢), 128.6 (C-3,5),
127.2 (C-4), 126.6 (C-2,6), 114.9 (C-6¢), 113.7 (C-4¢), 56.1
(OCH3), 41.1 (NCH2), 35.2 (NCH2CH2). EI-MS m/z (%) =
300 (32) [M+]. Anal. Calcd for C16H16N2O4: C, 63.99; H,
5.37; N, 9.33. Found: C, 63.94; H, 5.34; N, 9.30.

Synthesis of 5,6-Dihydroindazolo[3,2-a]isoquinoline
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 969
N-(4-methoxyphenylethyl)-5-methoxy-2-nitrobenzamide
(1e)
6.8 Hz, NCH2), 2.91 (2H, t, J = 6.8 Hz, NCH2CH2); 13C NMR
(100 MHz, CDCl3) d 165.0 (C=O), 149.1 (C-3), 147.8 (C-4),
140.4 (C-NO2), 134.5 (C-1¢), 130.9 (C-1), 130.4 (C-Cl), 128.9
(C-3¢), 126.1 (C-6¢), 120.7 (C-4¢), 120.6 (C-6), 111.9 (C-5),
111.4 (C-2), 55.9 (OCH3), 55.8 (OCH3), 41.4 (NCH2), 34.8
(NCH2CH2). EI-MS m/z (%) = 366 (35) [M++2], 364 (100)
[M+]. Anal. Calcd for C17H17N2O5Cl: C, 55.82; H, 4.70; N,
7.68. Found: C, 56.12; H, 4.92; N, 7.69.
1
White needles, mp 124-125 °C, H NMR (400 MHz,
CDCl3) d 8.10 (1H, d, J = 7.6 Hz, H-3¢), 7.17 (2H, m, H-2,6),
6.95 (1H, dd, J = 9.2, 2.8 Hz, H-4¢), 6.83-6.85 (2H, m, H-3,5),
6.81 (1H, d, J = 2.8Hz, H-6¢), 5.77 (1H, br s, NH), 3.87 (3H, s,
OCH3), 3.77 (3H, s, OCH3), 3.70 (2H, q, J = 6.8 Hz, NCH2),
2.90 (2H, t, J = 6.8 Hz, NCH2CH2); 13C NMR (100 MHz,
CDCl3) d 166.6 (C=O), 163.7 (C-5¢), 159.9 (C-4), 135.6 (C-
NO2), 130.6 (C-1¢), 129.8 (C-1), 127.2 (C-3¢), 126.8 (C-2,6),
117.0 (C-3,5), 114.9 (C-6¢), 113.7 (C-4¢), 56.1 (OCH3), 55.2
(OCH3), 41.3 (NCH2), 34.3 (NCH2CH2). EI-MS m/z (%) =
330 (67) [M+]. Anal. Calcd for C17H18N2O5: C, 61.81; H,
5.49; N, 8.48. Found: C, 62.87; H, 5.52; N, 8.43.
1-(2-Nitrophenyl)-3,4-dihydroisoquinolines (2a-2h)10,20-21
General Procedure B
To a stirred solution of N-phenylethyl-2-nitrobenz-
amide 1a (3.49 g, 12.9 mmol) in dry CH3CN (80 mL) was
added POCl3 (4.99 g, 32 mmol) dropwise, and the stirring
was continued for 1 h at room temperature. The resulting
mixture was heated to reflux and stirred for approximately 5
h. After removal of the solvent in vacuo, CHCl3 (40 mL) and
H2O (40 mL) were added, and the aqueous phase was ad-
justed with aqueous 10 N NaOH to pH 12. The organic layer
was washed with saturated aqueous NaHCO3 (3 ´ 100 mL),
dried over anhydrous Na2SO4, and the solvent was removed
in vacuo. 1-(2-Nitro-phenyl)-3,4-dihydroisoquinoline 2a pre-
cipitated on addition of n-hexane. Recrystallization of the
crude product from EtOAc/n-Hexane, afforded colorless
crystals 2a (2.92 g, 90.1%), mp 66-68 °C, IR (cm-1) 3000 (Ar-
omatic CH), 2920 (aliphatic CH), 1620 (C=N), 1510, 1350
(NO2); 1H NMR (400 MHz, CDCl3 ppm) d 8.14 (1H, dd, J =
8.0, 1.2 Hz, H-3¢), 7.76 (1H, dd, J = 7.6, 1.2 Hz, H-6¢), 7.63
(1H, dd, J = 7.6, 1.2 Hz, H-4¢), 7.59 (1H, dd, J = 7.6, 1.2 Hz,
H-5¢), 7.35 (1H, dd, J = 7.6, 1.2 Hz, H-8), 7.28 (1H, d, J = 8.4
Hz, H-7), 7.16 (1H, d, J = 7.6 Hz, H-6), 6.81 (1H, d, J = 7.2
Hz, H-5), 3.91 (2H, t, J = 7.2 Hz, NCH2), 2.93 (2H, t, J = 7.2
Hz, NCH2CH2); 13C NMR (100 MHz, CDCl3) d 165.2 (C=N),
148.2 (C-NO2), 137.5 (C-1¢), 135.0 (CH-5¢), 133.5 (C-4a),
131.09 (C-8a), 131.07 (C-3¢), 129.6 (CH), 128.8 (CH), 127.5
(CH), 126.9 (CH), 125.4 (CH-6¢), 124.4 (CH-4¢), 47.7 (CH2-
N), 25.6 (CH2-CH2-N). EI-MS m/z (%) = 252 (67.5) [M+],
222 (100) [M+-NO]. Anal. Calcd for C15H12N2O2·H2O: C,
66.67; H, 5.18; N, 10.36. Found: C, 65.83; H, 5.36; N, 10.02.
Using the same process we also obtained 2b-2h in good
yields.
N-(3,4-dimethoxyphenylethyl)-5-methoxy-2-nitrobenz-
amide (1f)
1
Light yellow needles, mp 150-151 °C, H NMR (400
MHz, CDCl3) d 8.10 (1H, d, J = 9.2 Hz, H-3¢), 6.94 (1H, dd, J
= 9.2, 2.8 Hz, H-4¢), 6.80-6.82 (4H, m, H-2,5,6,6¢), 5.86 (1H,
br s, NH), 3.88 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.86 (3H,
s, OCH3), 3.72 (2H, q, J = 6.8 Hz, NCH2), 2.91 (2H, t, J = 6.8
Hz, NCH2CH2); 13C NMR (100 MHz, CDCl3) d 166.6 (C=O),
163.7 (C-5¢), 149 (C-3), 147.6 (C-4), 138.7 (C-NO2), 135.6
(C-1¢), 131.1 (C-1), 127.2 (C-3¢), 120.6 (C-6¢), 114.8 (C-4¢),
114.7 (C-6), 113.7 (C-5), 111.4 (C-2), 56.1 (OCH3), 55.9
(OCH3), 55.8 (OCH3), 41.2 (NCH2), 34.8 (NCH2CH2). EI-
MS m/z (%) = 360 (100) [M+]. Anal. Calcd for C18H20N2O6:
C, 59.99; H, 5.59; N, 7.77. Found: C, 59.83; H, 5.67; N, 7.74.
N-(phenethyl)-5-chloro-2-nitrobenzamide (1g)
White needles, mp 97-98 °C, 1H NMR (400 MHz, CDCl3)
d 8.00 (1H, d, J = 8.8 Hz, H-3¢), 7.50 (1H, dd, J = 8.8, 2.0 Hz,
H-4¢), 7.22-7.35 (6H, m, H-2,3,5,6,5¢,6¢), 5.87 (1H, br s, NH),
3.73 (2H, q, J = 6.8 Hz, NCH2), 2.96 (2H, t, J = 6.8 Hz,
NCH2CH2); 13C NMR (100 MHz, CDCl3) d 165.1 (C=O),
144.5 (C-NO2), 140.3 (C-1¢), 138.4 (C-1), 134.5 (C-Cl), 130.3
(C-3¢), 128.8 (C-2,6), 128.7 (C-3,5), 126.7 (C-4), 126.0 (C-
4¢), 41.2 (NCH2), 35.2 (NCH2CH2). EI-MS m/z (%) = 306
(1.78) [M++2], 304 (7.62) [M+]. Anal. Calcd for C15H13N2O3Cl:
C, 59.12; H, 4.30; N, 9.19. Found: C, 59.33; H, 4.28; N, 9.27.
N-(3,4-dimethoxyphenethyl)-5-chloro-2-nitrobenzamide
(1h)
7-Methoxy-1-(2-nitrophenyl)-3,4-dihydroisoquinoline (2b)
White solid, mp 54-55 °C, 1H NMR (400 MHz, CDCl3)
d 8.11 (1H, dd, J = 8.0, 1.2 Hz, H-3¢), 7.72 (1H, dd, J = 7.6,
1.2 Hz, H-6¢), 7.55-7.62 (2H, m, H-4¢,5¢), 7.20 (1H,d, J = 8.4
Hz, H-5), 6.90 (1H, dd, J = 8.4, 2.8 Hz, H-6), 6.35 (1H, d, J =
2.4 Hz, H-8), 3.88 (2H, t, J = 7.2 Hz, NCH2), 3.66 (3H, s,
1
White needles, mp 134-136 °C, H NMR (400 MHz,
CDCl3) d 8.00 (1H, d, J = 8.8 Hz, H-3¢), 7.50 (1H, dd, J = 8.8,
2.4 Hz, H-4¢), 7.37 (1H, d, J = 2.4 Hz, H-6¢), 5.83 (1H, br s,
NH), 3.86 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.71 (2H, q, J =

970 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Kuo and Wu
OCH3), 2.84 (2H, t, J = 7.2 Hz, NCH2CH2); 13C NMR (100
MHz, CDCl3) d 165.1 (C=N), 158.3 (C-7), 148.2 (C-NO2),
134.8 (CH-5¢), 133.6 (C-4a), 131.1 (C-8a), 129.64 (CH),
129.59 (CH), 129.49 (CH), 128.4 (CH), 124.5 (C-5), 115.8
(C-8), 111.9 (C-6), 55.3 (OCH3), 48.1 (CH2-N), 24.8 (CH2-
CH2-N). Anal. Calcd for C16H14N2O3: C, 68.08; H, 5.00; N,
9.92. Found: C, 67.93; H, 5.05; N, 9.83.
OCH3), 2.87 (2H, NCH2CH2); 13C NMR (100 MHz, CDCl3,
ppm) d 165.7 (C=N), 163.8 (C-5¢), 158.4 (C-7), 140.8 (C-
NO2), 137.3 (C-1¢), 129.5 (C-8a), 129.5 (C-4a), 128.4 (C-5),
115.8 (CH-4¢), 115.5 (CH-6¢), 115.0 (CH-6), 111.8 (CH-8),
56.1 (OCH3), 55.4 (OCH3), 47.9 (CH2-N), 24.8 (CH2CH2N).
EI-MS m/z (%) = 312 (29) [M+], 282 (77) [M+-NO], 265 (100)
[M+-NO2-H], 251 (13) [M+-NO-OCH3]. Anal. Calcd for
C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C, 64.45; H,
5.15; N, 8.81.
6,7-Dimethoxy-1-(2-nitrophenyl)-3,4-dihydroisoquinoline
(2c)
Yellow needles, mp 116-117 °C, Rf = 0.60 (EtOAc/n-
Hexane 2:1). IR (cm-1) 3010 (Aromatic CH), 2963 (aliphatic
6,7-Dimethoxy-1-(5-methoxy-2-nitrophenyl)-3,4-dihydro-
isoquinoline (2f)
1
CH), 1605 (C=N), 1524, 1352 (NO2); H NMR (400 MHz,
Yellow crystals, mp 122-123 °C, 1H NMR (400 MHz,
CDCl3) d 8.15 (1H, dd, J = 8.8 Hz, 0.4 Hz, H-3¢), 7.04 (2H, m,
H-4¢,6¢), 6.79 (1H, s, H-5), 6.32 (1H, s, H-8), 3.94 (5H, s,
OCH3-5¢, NCH2), 3.93 (3H, s, OCH3), 3.63 (3H, s, OCH3),
2.88 (2H, NCH2CH2); 13C NMR (100 MHz, CDCl3) d 165.3
(C=N), 163.7 (C-5¢), 151.8 (C-7), 147.6 (C-6), 141.1 (C-
NO2), 136.8 (C-1¢), 131.6 (C-8a), 127.1 (C-4a), 121.3 (C-3¢),
115.5 (CH-4¢), 115.2 (CH-6¢), 110.6 (CH-5), 109.2 (CH-8),
56.2 (2OCH3), 56.0 (OCH3), 47.1 (CH2-N), 25.4 (CH2-
CH2N), Anal. Calcd for C18H18N2O5: C, 63.13; H, 5.30; N,
8.18. Found: C, 62.08; H, 5.32; N, 8.00.
CDCl3) d 8.10 (1H, dd, J = 7.6, 0.4 Hz, H-3¢), 7.56-7.76 (3H,
m, H-4¢,5¢,6¢), 6.77 (1H, s, H-5), 6.32 (1H, s, H-8), 3.92 (3H,
s, OCH3), 3.85 (2H, t, J = 7.6 Hz, NCH2), 3.63 (3H, s, OCH3),
2.83 (2H, t, J = 7.6 Hz, NCH2CH2); 13C NMR (100 MHz,
CDCl3) d 164.5 (C=N), 151.6 (C-7), 147.6 (C-NO2), 143.0
(C-6), 133.8 (CH-5¢), 133.4 (C-4a), 131.7 (C-8a), 131.1
(CH-3¢), 129.7 (CH-5¢), 124.4 (CH-4¢), 121.5 (CH-6¢), 110.6
(CH-8), 109.5 (CH-5), 56.2 (OCH3), 56.1 (OCH3), 47.7
(CH2-N), 25.5 (CH2CH2N). EI-MS m/z (%) = 312 (100) [M+],
282 (17) [M+-NO], 251 (24) [M+-NO-OCH3], 235 (28)
[M+-NO2-OCH3], 180 (16) [M+-C6H4O], Anal. Calcd for
C17H16N2O4·H2O: C, 61.81; H, 5.45; N, 8.48. Found: C,
61.79; H, 5.54; N, 8.39.
1-(5-Chloro-2-nitrophenyl)-3,4-dihydroisoquinoline (2g)
Colorless crystals, mp 128-129 °C, 1H NMR (400 MHz,
CDCl3) d 8.08 (1H, dd, J = 8.8, Hz, H-3¢), 7.56 (1H, dd, J =
8.8, 2.0 Hz, H-4¢), 7.56 (1H, d, J = 1.6 Hz, H-6¢), 7.37 (1H, d,
J = 7.6 Hz, H-8), 7.27 (1H, d, J = 7.2 Hz, H-6), 7.17 (1H, d, J
= 7.2 Hz, H-5), 6.80 (1H, d, J = 7.6 Hz, H-7), 3.90 (2H, t, J =
7.2 Hz, NCH2), 2.91 (2H, t, J = 7.2 Hz, NCH2CH2); 13C NMR
(100 MHz, CDCl3) d 164.2 (C=O), 146.4 (C-NO2), 140.2
(C-5¢), 137.4 (C-1¢), 136.7 (C-3¢), 131.3 (C-6¢), 131.2 (C-4¢),
129.6 (C-8a), 128.4 (C-4a),127.7 (C-5), 127.0 (C-8), 125.9
(C-6), 125.2 (C-7), 47.8 (NCH2), 25.6 (NCH2CH2). EI-MS
m/z (%) = 288 (7) [M++2], 286 (22) [M+], 256 (100) [M+-NO].
Anal. Calcd for C15H12N2O2Cl·1/2H2O: C, 60.92; H, 4.09; N,
9.47. Found: C, 63.13; H, 4.22; N, 9.71.
1-(5-Methoxy-2-nitrophenyl)-3,4-dihydroisoquinoline (2d)
1
Brownish crystals, mp 142-143 °C, H NMR (400
MHz, CDCl3) d 8.17 (1H, d, J = 9.2 Hz, H-3¢), 7.34 (1H, td, J
= 7.6, 1.2 Hz, H-6), 7.26 (1H, d, J = 7.6 Hz, H-8), 7.13 (1H,
td, J = 7.6, 0.8 Hz, H-7), 6.99-7.04 (2H, m, H-5,4¢), 6.78 (1H,
d, J = 7.6 Hz, H-6¢), 3.91 (5H, s, OCH3, NCH2), 2.93 (2H, t, J
= 6.8 Hz, NCH2CH2); 13C NMR (100 MHz, CDCl3) d 165.6
(C=N), 163.7 (C-5¢), 140.8 (C-NO2), 137.6 (C-1¢), 137.4 (C-
8a), 131.1 (C-4a), 128.8 (C-5), 127.5 (CH-7), 127.1 (CH-6),
126.9 (CH-8), 125.2 (CH-3¢), 115.4 (CH-6¢), 114.9 (CH-4¢),
56.1 (OCH3), 47.5 (CH2-N), 25.6 (CH2-CH2-N). Anal. Calcd
for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found: C, 67.25;
H, 4.96; N, 9.74.
6,7-Dimethoxy-1-(5-chloro-2-nitrophenyl)-3,4-dihydroiso-
quinoline (2h)
7-Methoxy-1-(5-methoxy-2-nitrophenyl)-3,4-dihydroiso-
quinoline (2e)
Greenish crystals, mp 166-168 °C, 1H NMR (400 MHz,
CDCl3) d 8.08 (1H, dd, J = 8.0, 0.8 Hz, H-3¢), 7.58 (1H, d, J =
2.0 Hz, H-6¢), 7.56 (1H, dd, J = 8.0, 2.0 Hz, H-4¢), 6.77 (1H, s,
H-5), 6.30 (1H, s, H-8), 3.93 (3H, s, OCH3), 3.84 (2H, t, J =
7.2 Hz, NCH2), 3.72 (3H, s, OCH3), 2.83 (2H, t, J = 7.2 Hz,
NCH2CH2); 13C NMR (100 MHz, CDCl3) d 163.5 (C-6,7),
151.6 (C=N), 146.4 (C-NO2), 140.1 (C-5¢), 136.5 (C-1¢),
Greenish crystals, mp 119-120 °C, 1H NMR (400 MHz,
CDCl3) d 8.17 (1H, d, J = 8.8 Hz, H-3¢), 7.18 (1H, d, J = 8.8
Hz, H-5), 7.03 (1H, d, J = 8.8 Hz, H-4¢), 6.99 (1H, d, J = 2.8
Hz, H-6¢), 6.90 (1H, dd, J = 8.4, 2.8 Hz, H-6), 6.33 (1H, dd, J
= 8.4, 2.8 Hz, H-8), 3.92 (5H, m, OCH3, NCH2), 3.66 (3H, s,

Synthesis of 5,6-Dihydroindazolo[3,2-a]isoquinoline
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 971
131.6 (C-3¢), 131.2 (C-6¢), 129.7 (C-4¢), 125.8 (C-8a), 121.0
(C-4a), 110.6 (C-5), 108.9 (C-8), 56.2 (OCH3), 56.0 (OCH3),
47.8 (NCH2), 25.6 (NCH2CH2). EI-MS m/z (%) = 348 (36)
[M++2], 346 (100) [M+], 316 (17) [M+-NO]. Anal. Calcd for
C17H15N2O4Cl: C, 58.88; H, 4.36; N, 8.08. Found: C, 59.09;
H, 4.92; N, 8.03.
(CH2CH2N). EI-MS m/z (%) = 252 (23) [M+], 251 (100)
[M+-H], 236 (47) [M+-NH2], 221 (68) [M+-OCH3]. Anal.
Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C,
75.51; H, 6.41; N, 10.68.
6,7-Dimethoxy-1-(2-aminophenyl)-3,4-dihydroisoquinoline
(3c)
1-(2-Aminophenyl)-3,4-dihydroisoquinolines (3a-3h)
General Procedure C
The same process afforded 3c (~75%), 4c (trace).
Pale yellow crystal, mp 159-160 °C, IR (cm-1) 3419,
3308 (NH2), 2920, 2911 (aliphatic CH), 1530 NO2, 1355
NO2; 1H NMR (400 MHz, CDCl3) d 7.18 (1H, dd, J = 8.0, 1.2
Hz, H-6¢), 7.12 (1H, d, J = 1.2 Hz, H-4¢), 6.81 (1H, s, H-5),
6.75 (1H, dd, J = 8.0, 1.2 Hz, H-5¢), 6.74 (1H, s, H-8), 6.69
(1H, dd, J = 7.6, 1.2 Hz, H-3¢), 3.95 (3H, s, OCH3), 3.83 (2H,
t, J = 7.2 Hz, CH2-N), 3.73 (3H, s, OH3), 2.73 (2H, t, J = 7.2
Hz, CH2CH2N); 13C NMR (100 MHz, CDCl3) d 166.96
(C=N), 150.77 (C-7), 146.73 (C-6), 146.85 (C-NH2), 132.55
(C-1¢), 130.94 (C-4a), 129.85 (C-8a), 121.80 (CH), 121.43
(CH), 116.77 (CH-5), 116.63 (CH-8), 111.73 (CH-4¢), 110.02
(CH-3¢), 56.03 (OCH3), 55.94 (OCH3), 46.91 (CH2-N), 25.78
(CH2-CH2-N). EI-MS m/z (%) = 282 (37) [M+], 281 (100)
[M+-H], 266 (11) [M+-NH2], 251 (51) [M+-OCH3]. Anal.
Calcd for C17H18N2O2: C, 72.34; H, 6.38; N, 9.92. Found: C,
71.26; H, 6.46; N, 9.81.
The 1-(2-nitrophenyl)-3,4-dihydroisoquinoline 2a (1.105
g, 4.4 mmol) and SnCl2·2H2O (5.96 g, 26.4 mmol) in dry
EtOAc (150 mL) were refluxed until completion of the reac-
tion (30 h). To this mixture were added with stirring H2O (20
mL) and 10 N NaOH (5 mL), and the resulting solution was
carefully poured into saturated aqueous NaHCO3 (100 mL).
After extraction with EtOAc (3 ´ 50 mL), the combined or-
ganic layers were filtered, dried over MgSO4 (3 h), and evap-
orated in vacuo. Pure product was obtained by recrystalliza-
tion of the crude product from EtOAc/n-Hexane, affording a
pale yellow solid, mp 84-85 °C 3a (0.75 g, 76.8%) and 4a
(15%).
1-(2-Aminophenyl)-3,4-dihydroisoquinolines (3a)
1H NMR (400 MHz, CDCl3) d 7.38 (1H, dd, J = 7.2, 1.6
Hz, H-6¢) d 7.15-7.30 (5H, m, H-5,6,7,8,4¢), 6.78 (1H, dd, J
= 8.0, 1.2 Hz, H-5¢), 6.68 (1H, dd, J = 7.6, 1.2 Hz, H-3¢),
3.85 (2H, t, J = 7.2 Hz, CH2-N), 2.78 (2H, t, J = 7.2 Hz,
CH2CH2N); 13C NMR (100 MHz, CDCl3) d 167.55 (C=N),
146.85 (C-NH2), 138.84 (C-1¢), 131.09 (C-4a), 130.56 (C-
8a), 129.88 (CH), 129.10 (CH), 128.21 (CH), 127.24 (CH),
126.48 (CH), 121.51 (CH), 116.71 (CH-5), 116.66 (CH-8),
46.97 (CH2-N), 26.19 (CH2-CH2-N). EI-MS m/z (%) = 222
(49) [M+], 221 (100) [M+-H], 220 (54) [M+-2H], 206 (8)
[M+-NH2]. Anal. Calcd for C15H14N2: C, 81.08; H, 6.30; N,
12.61. Found: C, 79.60; H, 6.31; N, 12.29.
1-(5-Methoxy-2-aminophenyl)-3,4-dihydroisoquinoline
(3d)
1
Yellowish solid, mp 67-68 °C, H NMR (400 MHz,
CDCl3) d 7.40 (1H, dd, J = 8.0, 1.2 Hz, H-6), 7.26-7.35 (3H,
m, H-5,7,8), 6.85 (1H, dd, J = 8.8, 2.8 Hz, H-4¢), 6.82 (1H, d,
J = 2.8 Hz, H-6¢), 6.76 (1H, d, J = 8.8 Hz, H-3¢), 4.47 (2H, br,
NH2), 3.90 (2H, t, J = 7.2 Hz, CH2-N), 3.74 (3H, s), 2.82 (2H,
t, J = 7.2 Hz, CH2CH2N); 13C NMR (100 MHz, CDCl3) d
167.1 (C=N), 151.2 (C-5¢), 140.3 (C-NH2), 138.6 (C-1¢),
130.5 (C-4a), 128.8 (C-8a), 127.9 (CH), 127.2 (CH), 126.5
(CH), 122.7 (CH), 117.9 (CH-3¢), 116.6 (CH-6¢), 115.7 (CH-
4¢), 55.8 (OCH3), 47.1 (CH2N), 26.0 (CH2CH2N). EI-MS m/z
(%) = 252 (31) [M+], 251 (100) [M+-H], 236 (9) [M+-NH2],
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10.
Found: C, 75.72; H, 6.47; N, 10.72.
7-Methoxy-1-(2-aminophenyl)-3,4-dihydroisoquinoline
(3b)
The same process afforded 3b (~60%), 4b (23%).
Pale yellow solid, mp 118-120 °C, 1H NMR (400 MHz,
CDCl3) d 7.15-7.22 (3H, m, H-5,4¢,6¢), 6.94 (1H, dd, J = 8.0,
2.8 Hz, H-6), 6.84 (1H, d, J = 2.8 Hz, H-8), 6.77 (1H, dd, J =
8.0, 0.8 Hz, H-3¢), 3.83 (2H, t, J = 7.2 Hz, CH2N), 3.71 (3H, s,
OCH3), 2.71 (2H, t, J = 7.2 Hz, CH2CH2N); 13C NMR (100
MHz, CDCl3) d 167.6 (C=N), 158.0 (C-7), 146.8 (C-NH2),
131.1 (C-1¢), 130.9 (C-4a), 130.1 (C-8a), 129.6 (CH), 128.1
(CH), 120.9 (CH), 116.9 (CH-5¢), 116.8 (CH-3¢), 116.5
(CH-6), 113.9 (CH-8), 55.4 (OCH3), 47.1 (CH2N), 25.3
7-Methoxy-1-(5-methoxy-2-aminophenyl)-3,4-dihydroiso-
quinoline (3e)
1
Yellowish liquid, H NMR (400 MHz, CDCl3) d 7.18
(1H, d, J = 8.0 Hz, H-5), 6.95 (1H, dd, J = 8.0, 2.8 Hz, H-6),
6.83 (1H, d, J = 2.8 Hz, H-8), 6.82 (1H, dd, J = 8.8, 2.8 Hz,
H-4¢), 6.77 (1H, d, J = 2.8 Hz, H-6¢), 6.74 (1H, d, J = 8.8 Hz,
H-3¢), 3.85 (2H, t, J = 7.2 Hz, CH2-N), 3.72 (3H, s, OCH3),

972 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Kuo and Wu
3.70 (3H, s, OCH3), 2.73 (2H, t, J = 7.2 Hz, CH2CH2N); 13
C
130.0 (C-3¢), 121.4 (C-6¢), 121.1 (C-4¢), 118.1 (C-8a), 111.6
(C-4a), 110.2 (C-5), 56.2 (OCH3), 56.1 (OCH3), 46.7 (NCH2),
25.8 (NCH2CH2). EI-MS m/z (%) = 318 (32) [M++2], 316
(100) [M+]. Anal. Calcd for C17H17N2O2Cl: C, 64.46; H, 5.41;
N, 8.84. Found: C, 64.01; H, 5.38; N, 8.69.
NMR (100 MHz, CDCl3) d 167.1 (C=N), 158.2 (C-7), 151.3
(C-5¢), 140.4 (C-NH2), 130.7 (C-1¢), 129.5 (C-4a), 128.1 (C-
8a), 122.4 (CH-5), 118.2 (CH-6), 117.0 (CH-8), 116.6 (CH-
3¢), 115.5 (CH-4¢), 113.6 (CH-6¢), 55.9 (OCH3), 55.4 (OCH3),
47.4 (CH2N), 25.2 (CH2CH2N). EI-MS m/z (%) = 282 (38)
[M+], 281 (100) [M+-H], 266 (33) [M+-NH2], 251 (33) [M+-
OCH3], Anal. Calcd for C17H18N2O2·0.5H2O: C, 70.08; H,
6.57; N, 9.61. Found: C, 70.80; H, 6.44; N, 9.29.
5,6-Dihydroindazo[3,2-a]isoquinolines (4a-4h)
General Procedure D
Tin(II) chloride dihydrate (2.7 g, 12 mmol) was dis-
solved in ethyl acetate (150 mL), and the resulting mixture
was added dropwise to a stirred solution of 1-(2-nitrophen-
yl)-3,4-dihydroisoquinoline 2a (0.502 g, 2 mmol) in ethyl ac-
etate (50 mL). The mixtures were continuously stirred at
room temperature overnight. To this mixture were added with
stirring H2O (15 mL) and 10 N NaOH (5 mL), and the result-
ing solution was carefully poured into saturated aqueous
NaHCO3 (100 mL). After extraction with EtOAc (3 ´ 40 mL),
the combined organic layers were filtered, dried over MgSO4
(3 h), and evaporated in vacuo. The crude products were sep-
arated by a flash column (EtOAc/n-Hexane 2:1), affording
colorless liquid compound 4a (0.35 g, 79.9%). IR (cm-1) 3000
(Aromatic CH), 2920 (aliphatic CH), 1620 (broad C=C C=N);
1H NMR (400 MHz, CDCl3) d 8.05 (1H, dd, J = 8.8 Hz, 1.2
Hz, H-8), 7.97 (1H, d, J = 7.6 Hz, H-1), 7.78 (1H, dd, J = 8.8,
0.8 Hz, H-11), 7.29-7.42 (4H, m, H-2,3,4,10), 7.19 (1H, ddd,
J = 8.8, 6.8, 1.2 Hz, H-9), 4.67 (2H, t, J = 7.2 Hz, H-6), 3.28
(2H, t, J = 7.2 Hz, H-5); 13C NMR (100 MHz, CDCl3) d
148.45 (C=N), 131.96 (C-N), 130.62 (C-4a), 128.25 (C-1a),
127.92 (C-11a), 127.84 (CH), 127.68 (CH), 126.11 (CH),
123.88 (CH), 122.37 (CH), 120.33 (CH), 118.19 (CH-8),
117.75 (CH-11), 47.81 (CH2N), 29.13 (CH2-5). EI-MS m/z
(%) = 220 (100) [M+], 219 (37) [M+-H], 218 (20) [M+-2H].
Anal. Calcd for C15H12N2·1/4H2O: C, 80.18; H, 5.57; N,
12.47. Found: C, 80.24; H, 5.68; N, 12.52.
6,7-Dimethoxy-1-(5-methoxy-2-aminophenyl)-3,4-dihydro-
isoquinoline (3f)
1
Yellowish solid, mp 110-111 °C, H NMR (400 MHz,
CDCl3) d 6.83 (1H, s, H-8), 6.82 (1H, dd, J = 8.8, 3.6 Hz,
H-4¢), 6.78 (1H, s, H-5), 6.77 (1H, d, J = 3.6 Hz, H-6¢), 6.75
(1H, d, J = 8.8 Hz, H-3¢), 4.40 (2H, br, NH2), 3.95 (3H, s,
OCH3), 3.85 (2H, t, J = 7.2 Hz, CH2-N), 3.74 (3H, s, OCH3),
3.70 (3H, s, OCH3), 2.74 (2H, t, J = 7.2 Hz, CH2CH2N); 13
C
NMR (100 MHz, CDCl3) d 166.8 (C=N), 151.3 (C-7), 151.2
(C-6), 147.1 (C-5¢), 140.4 (C-NH2), 132.6 (C-1¢), 122.3 (C-
4a), 121.4 (C-8a), 118.3 (CH-5), 117.3 (CH-8), 115.3 (CH-
3¢), 111.7 (CH-4¢), 110.1 (CH-6¢), 56.1 (OCH3), 56.0 (OCH3),
55.9 (OCH3), 46.7 (CH2N), 25.8 (CH2CH2N). EI-MS m/z (%)
= 312 (37) [M+], 311 (100) [M+-H], 296 (23) [M+-NH2], 281
(35) [M+-OCH3], Anal. Calcd for C18H20N2O3: C, 69.21; H,
6.45; N, 8.97. Found: C, 69.01; H, 6.51; N, 8.91.
(5-Chloro-2-aminophenyl)-3,4-dihydroisoquinoline (3g)
Pale yellow solid, mp 105-107 °C, 1H NMR (200 MHz,
CDCl3) d 7.15-7.20 (4H, m, H-5,6,7,8), 6.91-7.13 (3H, m,
H-3¢,4¢,6¢), 3.55 (2H, t, J = 7.2 Hz, CH2N), 2.80 (2H, t, J = 7.2
Hz, CH2CH2N); 13C NMR (50 MHz, CDCl3) d 166.4 (C=N),
145.2 (C-NH2), 131.4 (C-1¢), 130.8 (C-4a), 130.0 (C-8a),
129.7 (CH), 129.4 (CH), 128.5 (CH), 121.2 (CH), 116.1 (CH-
5¢), 115.8 (CH-3¢), 113.5 (CH-6), 111.9 (CH-8), 47.6 (CH2N),
25.6 (CH2CH2N). EI-MS m/z (%) = 258 (34) [M++2], 256
(100) [M+]. Anal. Calcd for C15H13N2Cl: C, 70.18; H, 5.10; N,
10.91. Found: C, 70.01; H, 5.02; N, 10.77.
Using the same process we obtained 4b (~75%), 4c
(~45%), 4d (~20%), 4e (~17%), 4f (~10%), 4g (~60%), 4h
(~45%).
2-Methoxy-5,6-dihydroindazolo[3,2-a]isoquinoline (4b)
1
6,7-Dimethoxy-1-(5-chloro-2-aminophenyl)-3,4-dihydro-
isoquinoline (3h)
White powder, mp 82-83 °C, H NMR (400 MHz,
CDCl3) d 8.00 (1H, d, J = 8.4 Hz, H-8), 7.74 (1H, dd, J = 8.8
Hz, 1.2 Hz, H-11), 7.50 (1H, d, J = 2.8 Hz, H-4), 7.34 (1H,
ddd, J = 8.8, 6.8, 1.2 Hz, H-10), 7.24 (1H, d, J = 8.0 Hz, H-1),
7.18 (1H, ddd, J = 8.4, 6.8, 1.2 Hz, H-9), 6.84 (1H, dd, J = 8.0,
2.8 Hz, H-3), 4.60 (2H, t, J = 7.2 Hz, H-6), 3.91 (3H, s,
OCH3), 3.21 (2H, t, J = 7.2 Hz, H-5); 13C NMR (100 MHz,
CDCl3) d 159.1 (C-2), 148.45 (C=N), 131.2 (C-N), 130.5
(C-4a), 129.1 (C-1a), 128.9 (C-11a), 126.0 (CH), 124.11
1
Yellowish crystals, mp 160-162 °C, H NMR (400
MHz, CDCl3) d 7.20 (1H, d, J = 1.8 Hz, H-6¢), 7.13 (1H, dd, J
= 8.4, 1.8 Hz, H-4¢), 6.78 (1H, s, H-5), 6.76 (1H, s, H-8), 6.72
(1H, d, J = 8.4, H-3¢), 3.95 (3H, s, OCH3), 3.82 (2H, t, J = 7.6
Hz, NCH2), 3.76 (3H, s, OCH3), 2.74 (2H, t, J = 7.6 Hz,
NCH2CH2); 13C NMR (100 MHz, CDCl3) d 166.2 (C-6,7),
147.2 (C=N), 145.5 (C-NH2), 132.8 (C-5¢), 130.5 (C-1¢),

Synthesis of 5,6-Dihydroindazolo[3,2-a]isoquinoline
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 973
CH), 122.4 (CH), 120.2 (CH), 117.9 (CH), 112.9 (CH-11),
109.8 (CH-8), 55.5 (OCH3), 48.2 (CH2-N), 28.4 (CH2-5).
EI-MS m/z (%) = 250 (100) [M+], 219 (7) [M+-OCH3]. Anal.
Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C,
76.51; H, 5.71; N, 10.65.
121.1 (CH), 119.3 (CH), 118.1 (CH), 111.7 (CH), 109.9 (CH-
11), 97.5 (CH-8), 55.6 (OCH3), 55.5 (OCH3), 48.2 (CH2-N),
28.5 (CH2-5). IE-MS m/z (%) = 280 (100) [M+], 265 (46)
[M+-CH3]. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N,
9.99. Found: C, 72.29; H, 6.08; N, 9.88.
2,3-Dimethoxy-5,6-dihydroindazolo[3,2-a]isoquinoline
2,3,10-Trimethoxy-5,6-dihydroindazolo[3,2-a]isoquinoline
(4c)
(4f)
1
1
White powder, mp 177-179 °C, H NMR (400 MHz,
Pale yellow powder, mp 150-152 °C, H NMR (400
CDCl3) d 8.00 (1H, dd, J = 8.8, 1.2 Hz, H-8), 7.75 (1H, dd,
8.4, 1.2 Hz, H-11), 7.50 (1H, s, H-1), 7.34 (1H, ddd, J = 8.8,
6.8, 1.2 Hz, H-9), 7.18 (1H, ddd J = 8.4, 6.8, 1.2 Hz, H-10),
6.85 (1H, s, H-4), 4.6 (2H, t, J = 7.2 Hz, H-6), 4.01 (3H, s,
MHz, CDCl3) d 7.63 (1H, d, J = 9.2 Hz, H-8), 7.40 (1H, s,
H-1), 7.19 (1H, d, J = 2.4 Hz, H-11), 7.04 (1H, dd, J = 9.2 Hz,
2.4 Hz, H-9), 6.99 (1H, s, H-4), 4.60 (2H, t, J = 7.2 Hz, H-6),
4.1 (3H, s, OCH3), 3.91 (6H, s, 2OCH3), 3.20 (2H, t, J = 7.2
Hz, H-5); 13C NMR (100 MHz, CDCl3) d 155.5 (C-10), 148.5
(C-2), 148.4 (C-3), 145.1 (C=N), 129.9 (=C-N), 124.8 (C-
4a), 121.1 (C-1a), 119.9 (CH), 119.2 (CH), 117.3 (CH), 111.7
(C-11a), 107.4 (CH-11), 97.7 (CH-8), 56.3 (OCH3), 56.1
(OCH3), 55.5 (OCH3), 47.9 (CH2-N), 29.0 (CH2-5). IE-MS
m/z (%) = 310 (100) [M+], 295 (46) [M+-CH3]. Anal. Calcd
for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.34;
H, 5.76; N, 9.17.
OCH3), 3.95 (3H, s, OCH3), 3.21 (2H, t, J = 7.2 Hz, H-5); 13
C
NMR (100 MHz, CDCl3) d 148.9 (C-2), 148.5 (C-3), 148.3
(C=N), 130.8 (=C-N), 126.1 (C-4a), 124.9 (C-1a), 122.0 (C-
11a), 120.1 (CH), 117.7 (CH), 117.5 (CH), 111.6 (CH-11),
107.5 (CH-8), 56.2 (OCH3), 56.1 (OCH3), 47.9 (CH2-N), 28.8
(CH2-5). FRB-MS m/z (%) = 280 (100) [M+]. Anal. Calcd for
C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.26; H,
5.93; N, 9.67.
10-Methoxy-5,6-dihydroindazolo[3,2-a]isoquinoline (4d)
Yellowish powder, mp 61-62 °C, 1H NMR (400 MHz,
CDCl3) d 7.90 (1H, d, J = 7.6 Hz, H-3), 7.66 (1H, d, J = 9.2
Hz, H-8), 7.43 (1H, ddd, J = 7.6, 6.8, 1.2 Hz, H-2), 7.33 (1H,
d, J = 6.8 Hz, H-1), 7.27 (1H, dd, J = 7.6, 1.2 Hz, H-4), 7.22
(1H, d, J = 2.4 Hz, H-11), 7.06 (1H, dd, J = 9.2, 2.4 Hz, H-9),
4.60 (2H, t, J = 7.2 Hz, H-6), 3.91 (3H, s, OCH3), 3.26 (2H, t,
J = 7.2 Hz, H-5); 13C NMR (100 MHz, CDCl3) d 155.8 (C-
10), 145.2 (C=N), 131.8 (=C-N), 129.7 (C-4a), 128.35 (C-
8a), 128.30 (CH), 127.6 (CH), 127.3 (CH), 123.3 (CH), 120.3
(C-11a), 119.2 (CH), 118.1 (CH-11), 97.5 (CH-8), 55.5 (OCH3),
47.9 (CH2-N), 29.4 (CH2-5). EI-MS m/z (%) = 250 (100)
[M+], 235 (18) [M+-CH3]. Anal. Calcd for C16H14N2O·H2O:
C, 71.64; H, 5.97; N, 10.44. Found: C, 71.64; H, 6.07; N,
10.25.
10-Chloro-5,6-dihydroindazolo[3,2-a]isoquinoline (4g)
1
Yellowish powder, mp 108-110 °C, H NMR (400
MHz, CDCl3) d 8.00 (1H, d, J = 0.8 Hz, H-8), 7.88 (1H, d, J =
8.4 Hz, H-11), 7.67 (1H, dd, J = 8.4, 0.8 Hz, H-9), 7.42 (1H,
ddd, J = 8.8, 6.8, 2.0 Hz, H-2), 7.25-7.34 (3H, m, H-1,3,4),
4.64 (2H, t, J = 7.2 Hz, H-6), 3.28 (2H, t, J = 7.2 Hz, H-5); 13
C
NMR (100 MHz, CDCl3) d 146.9 (C=N), 131.8 (C-N), 130.5
(C-Cl), 128.3 (C-4a), 128.1 (C-1a), 127.9 (C-11a), 127.8
(CH), 127.4 CH), 127.3 (CH), 123.7 (CH-2), 119.28 (CH-8),
119.26 (CH-9), 118.5 (CH-11), 47.9 (CH2-N), 29.0 (CH2-5).
EI-MS m/z (%) = 254 (100) [M+], 219 (15) [M+-Cl]. Anal.
Calcd for C15H11N2Cl: C, 70.73; H, 4.35; N, 11.00. Found: C,
70.04; H, 4.48; N, 10.76.
2,3-Dimethoxy-10-chloro-5,6-dihydroindazolo[3,2-a]iso-
quinoline (4h)
1
2,10-Dimethoxy-5,6-dihydroindazolo[3,2-a]isoquinoline
Yellowish powder, mp 162-163 °C, H NMR (400
(4e)
MHz, CDCl3) d 7.91 (1H, d, J = 0.8 Hz, H-11), 7.67 (1H, dd, J
= 9.2, 0.8 Hz, H-9), 7.37 (1H, s, H-1), 7.29 (1H, dd, J = 9.2
Hz, H-8), 6.86 (1H, s, H-4), 4.64 (2H, t, J = 7.2 Hz, H-6), 4.04
(3H, s, OCH3), 3.96 (3H, s, OCH3), 3.22 (2H, t, J = 7.2 Hz,
H-5); 13C NMR (100 MHz, CDCl3) d 149.1 (C-2), 148.6
(C-3), 146.9 (C=N), 130.5 (C-N), 127.8 (C-4a), 125.1 (C-1a),
120.0 (C-11a), 119.1 (CH), 118.9 CH), 118.0 (CH), 111.6
(CH-2), 107.6 (CH-8), 107.4 (CH-9), 56.4 (OCH3), 56.1
(OCH3), 47.9 (CH2-N), 28.6 (CH2-5). EI-MS m/z (%) = 316
1
Yellowish powder, mp 138-140 °C, H NMR (400
MHz, CDCl3) d 7.64 (1H, d, J = 9.2 Hz, H-8), 7.42 (1H, d, J =
2.4 Hz, H-1), 7.27 (1H, d, J = 8.0 Hz, H-4), 7.22 (1H, d, J =
2.4 Hz, H-11), 7.04 (1H, dd, J = 9.2, 2.4 Hz, H-9), 6.82 (1H,
dd, J = 8.0, 2.4 Hz, H-3), 4.60 (2H, t, J = 7.2 Hz, H-6), 3.91
(6H, s, OCH3), 3.20 (2H, t, J = 7.2 Hz, H-5); 13C NMR (100
MHz, CDCl3) d 159.04 (C-1), 155.8 (C-10), 145.1 (C=N),
130.4 (=C-N), 129.3 (C-4a), 129.1 (C-1a), 124.1 (C-11a),

974 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Kuo and Wu
(38) [M++2], 314 (100) [M+], 299 (23) [M+-CH3]. Anal.
Calcd for C17H15N2O2Cl·0.5H2O: C, 63.06; H, 4.98; N, 8.65.
Found: C, 64.63; H, 5.13; N, 8.66.
39(2), 189-194.
9. Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67(1),
86-94.
10. Vedejs, E.; Trapencieris, P.; Suna, E. J. Org. Chem. 1999,
64(18), 6724-6729.
11. Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002,
67(10), 3437-3444.
Received October 7, 2004.
12. Pedrosa, R.; Andres, C.; Iglesias, J. M. A.; Perez-Encabo, J.
M. J. Am. Chem. Soc. 2001, 123(9), 1817-1821.
13. Xu, X. Y.; Qin, G. W.; Xu, R. S.; Zhu, X. Z. Tetrahedron
1998, 54, 14179.
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