Synthesis of indazole-N-oxides via the 1,7-electrocyclization of azomethine ylides

Article abstract of DOI:10.1016/j.tet.2004.08.026

The first examples of the 1,7-electrocyclization of azomethine ylides onto a nitro group, to give benz-1,2,6-oxadiazepine intermediates are reported. Subsequent ring contraction results in the formation of indazole-N-oxides. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.026

Tetrahedron 60 (2004) 9937–9944
Synthesis of indazole-N-oxides via the 1,7-electrocyclization of
azomethine ylides
a,
Miklos Nyerges, Andrea Viranyi, Weimin Zhang, Paul W. Groundwater, Gabor Blasko
a
b
b
c
*
´
´
´
´
a
´ ´ ˝
and Laszlo Toke
aDepartment of Organic Chemical Technology, Research Group of the Hungarian Academy of Sciences, Technical University of Budapest,
P.O. Box 91, H-1521 Budapest, Hungary
bSunderland Pharmacy School—Drug Deisgn and Molecular Modelling, University of Sunderland, Sunderland SR1 3SD, UK
cEGIS Pharmaceuticals Ltd, P.O. Box 100, H-1475 Budapest, Hungary
Received 14 June 2004; revised 20 July 2004; accepted 13 August 2004
Available online 15 September 2004
Abstract—The first examples of the 1,7-electrocyclization of azomethine ylides onto a nitro group, to give benz-1,2,6-oxadiazepine
intermediates are reported. Subsequent ring contraction results in the formation of indazole-N-oxides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
As part of our continuing work on the synthesis of the
pyrrolo[3,2-c]quinoline ring system of the martinelline
alkaloids (bradykinin receptor antagonist)1 we have investi-
gated the formation and reactions of the non-stabilised
azomethine ylide 2a. This azomethine ylide 2a was formed
by the reaction of o-nitrobenzaldehyde 1a with sarcosine in
refluxing benzene2 and, despite the presence of a large
excess of active dipolarophiles, for example, ethyl acrylate
or methyl vinyl ketone, we did not observe any trace of the
The indazole-N-oxide 5a and the isoxazolidine 7a probably
arise from the fragmentation of the unstable benz-1,2,6-
oxadiazepine intermediate 4, Scheme 1, formed by the
decarboxylative condensation5 of o-nitro-benzaldehyde 1
and sarcosine, followed by a 1,7-electrocyclization6 of the
non-stabilised azomethine ylide 2. As such, this represents
the first 1,7-electrocyclization of an azomethine ylide onto a
pendant nitro group. The seven-membered ring of 4
subsequently then undergoes a ring contraction, resulting
in the elimination of formaldehyde and the production of
2-methyl-2H-indazol-N-oxide 5a. The formaldehyde by-
product is then able to react with the excess sarcosine
present in the reaction mixture, resulting in the formation of
azomethine ylide 6, which can then react with the other
starting material, o-nitrobenzaldehyde 1, to yield the
3-methyl-5-aryl-oxazolidine 7a as the second product.3
Similar processes have been reported for the 1,7-electro-
cyclization of an azomethine imine and a nitrile ylide onto a
nitro group, leading to the formation of the corresponding
1
expected cycloadduct 3 in the H NMR spectrum of the
crude reaction mixture.
Two products, an indazole-N-oxide 5a and an oxazolidine
7a were, however, isolated after chromatographic separ-
ation (in 40 and 43% yields respectively) and their
structures confirmed by spectroscopic analysis, Scheme 1.
The isoxazoline product 7a was independently synthesized
by a method recently described by us,3 and was found to be
identical with the product 7a obtained from the reaction of
nitrobenzaldehyde 1a and sarcosine. The indazole-N-oxide
5a was deoxygenated in the presence of Pd-on-C, resulting
in the formation of the known 2-methyl-2H-indazole 8,
Scheme 2.4
benzotriazole-N-oxide7
and
1-acyloxyindazoles,8
respectively.
We have investigated the scope of this reaction via the
generation of further azomethine ylides and found that
substitution on the aromatic ring does not have a significant
effect, although the yields were somewhat lower than in the
unsubsubstituted case, Table 1. The reaction of o-nitro-
benzaldehyde 1a and N-benzylglycine 9 proceeded in a
Keywords: Cycloadditions; Electrocyclic reactions; Indazoles; Isoquino-
lines; Nitro compounds.
* Corresponding author. Tel.: C3614632213; fax: C3614633648;
e-mail: mnyerges@mail.bme.hu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.026

9938
M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
Scheme 1.
cycloadduct 17 (as a single isomer, shown by NOE
experiments to have syn-endo stereochemistry) and an
indazole-N-oxide, 16 were obtained, while in the absence of
the dipolarophile the N-oxide 16 was formed in quantitative
yield. In contrast to the examples described above, the
aldehyde in this case (which remains attached to the
indazole component), arising from the fragmentation of 15,
is not sufficiently reactive to act as a C]O dipolarophile in
a 1,3-dipolar cycloaddition process in competition with the
1,7-electrocyclization.
Scheme 2.
Table 1
With regard to the proposed mechanism we performed the
next series of experiments with 3,4-dihydro-1-(2-nitro-
phenyl)-N-substituted-isoquinolinium bromides 20
(prepared from the corresponding halide and 3,4-dihydro-
isoquinoline 18). In all cases the isoquinoline fused
indazole-N-oxide 22 was formed, Scheme 5, Table 2. In
one case (20a RZCO2CH3) the competitive formation of
the 1,3-dipolar cycloadduct 23 as a single isomer (the
relative stereochemistry of the which was again proven by
NOE experiments) was observed (ratio of 22a:23 approx.
3:1) due to the high reactivity of the electron-deficient C]O
double bond of the aldehyde by-product.
Entry
R1
R2
Reaction
time (h)
Products
1
2
3
4
H
H
CH3O
2
6
8
3
5a 40%
7a 43%
7b 30%
7c 38%
7d 33%
CH3O
OCH2O
Br
5b 32%
5c 34%
5d 37%
H
similar manner to give the analogue isoxazoline 10 and
2-benzyl-indazole-N-oxide 11, Scheme 3.
We next chose to form the azomethine ylide 14 from 6,7-
dimethoxy-3,4-dihydro-N-(2-nitrobenzyl)isoquinolinium
chloride 13 (prepared from 3,4-dimethoxy-6,7-dihydro-
isoquinoline 12 and 2-nitro-benzylchloride)9 by dehydro-
halogenation with triethylamine, Scheme 4.10 In the
presence of N-phenylmaleimide a 2:1 mixture of the
3. Experimental
Melting points were determined on a Gallenkamp apparatus
Scheme 3.

M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
9939
Scheme 4. Reagents and conditions: (i) 2-O2NC6H4CH2Cl, dry Et2O, 95%; (ii) Et3N, MeOH, rt, 85%; (iii) N-phenylmaleimide, Et3N, MeOH, rt, 58%.
Scheme 5. Reagents and conditions: (i) POCl3, P2O5, xylene, reflux; (ii) RCH2Br; (iii) Et3N, MeOH.
and are uncorrected. Column chromatography was per-
formed using Merck Kieselgel 60 70–230 mesh, TLC on
aluminium sheets coated with Kieselgel 60 F254. Plates were
stained with anisaldehyde solution (100 mL glacial acetic
acid, 2 mL cc. sulphuric acid and 1 mL anisaldehyde) and
heated at ca. 150 8C. IR spectra were measured on a
NICOLET FT-IR instrument. NMR spectra were obtained
on a Bruker 250 instrument. Chemical shifts are given
Table 2
Entry
R1
R2
R
Yield of 20
Yield of 22
1
2
3
4
5
6
Et
Et
Et
Me
Me
Et
H
H
H
H
Cl
Cl
–CO2Me
–CH2Ph
–CH]CH2
–CH]CH2
–CH]CH2
–CH]CH2
20a 97%
20b 95%
20c 92%
20d 88%
20e 94%
20f 96%
22a: 56%
22a: 66%
22a: 88%
22b: 95%
22c: 95%
22d: 92%

9940
M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
relative to dTMS. All solvents were purified according to
standard procedures and the amides 18 were prepared by the
method of Cortes et al.11
114.5 (quat.), 107.7 (CH), 104.8 (CH), 55.9 (CH3), 55.7
(CH3), 33.5 (CH3); nmax/cmK1 (KBr) 3428, 2940, 2832,
1665, 1612, 1500, 1457, 1436, 1398, 1362, 1341, 1270,
1217, 1167, 1131, 1051, 1013.
3.1. Reaction of 2-nitrobenzaldehydes with sarcosine.
General procedure
3.1.5. 3-Methyl-5-(30,40-methylenedioxy-60-nitrophenyl)-
oxazolidine (7c). As a pale yellow oil; dH (250 MHz,
CDCl3) 7.42 (1H, s, H-50), 7.16 (1H, s, H-20), 6.00 (2H, s,
OCH2O) 5.39 (1H, t, JZ6.3 Hz, H-5), 4.50 (1H, d,
JZ4.9 Hz, H-2), 4.30 (1H, d, JZ4.9 Hz, H-2), 3.46 (1H, dd,
JZ11.5, 6.3 Hz, H-4), 2.73 (1H, dd, JZ11.5, 6.3 Hz, H-4),
2.36 (3H, s, NCH3); dC (62.5 MHz, CDCl3) 152.5 (quat.),
146.6 (quat.), 140.3 (quat.), 137.4 (quat.), 105.8 (CH), 105.0
(CH), 102.8 (CH2), 89.1 (CH2), 73.9 (CH), 62.1 (CH2), 41.5
(CH3); nmax/cmK1 (liquid film) 2951, 2894, 1581, 1515,
1472, 1441, 1332, 1221, 1067, 1031, 1015; (Found:
252.0740. C11H12N2O5 requires 252.0746).
The appropriate 2-nitrobenzaldehyde (1 mmol) was dis-
solved in benzene or toluene (50 mL) and sarcosine (0.18 g,
2 mmol) was added. The reaction mixture was refluxed for
2–8 h and the water formed was removed with the aid of a
Dean–Stark trap. After cooling, the precipitated solid was
filtered off and all the solvent was removed in vacuo. The
resulting products were separated by column chromato-
graphy on silica, eluting with hexane–ethyl acetate (50:50 to
0:100). The corresponding yields are given in Table 1.
3.1.1. 3-Methyl-5-(20-nitrophenyl)oxazolidine (7a). As a
pale yellow oil; dH (250 MHz, CDCl3) 8.03 (1H, d,
JZ8.2 Hz, Ar–30H), 7.87 (1H, d, JZ8.2 Hz, Ar–60H), 7.65
(1H, t, JZ8.2 Hz, Ar–50H), 7.41 (1H, t, JZ8.2 Hz, Ar–
40H), 5.53 (1H, t, JZ6.7 Hz, H-5), 4.64 (1H, d, JZ5.1 Hz,
H-2), 4.47 (1H, d, JZ5.1 Hz, H-2), 3.62 (1H, dd, JZ11.6,
6.7 Hz, H-4), 2.80 (1H, dd, JZ11.6, 6.7 Hz, H-4), 2.49 (3H,
s, CH3); dC (62.5 MHz, CDCl3) 147.8 (quat., C-10), 139.3
(quat.), 133.8 (CH), 127.6 (CH), 127.0 (CH), 124.5 (CH),
89.3 (CH2, C-2), 73.3 (CH, C-5), 61.1 (CH2, C-4), 41.5
(N–CH3); nmax/cmK1 (liquid film) 2851, 2867, 2799, 1524,
1452, 1346, 1058; (HRMS Found: m/z 208.0822.
C10H12N2O3 requires 208.0835).
3.1.6. 2-Methyl-5,6-methylenedioxy)-2H-indazole-N-
oxide (5c). As a pale yellow powder; mp 118–9 8C;
[Found: C, 56.2; H, 4.3; N, 14.4. C9H8N2O3 requires C
56.25; H 4.2; N 14.6%]; dH (250 MHz, DMSO-d6) 8.23 (1H,
s, H-3), 7.40 (1H, s, H-7), 7.07 (1H, s, H-4), 6.18 (2H, s,
OCH2O), 3.46 (3H, s, NCH3); dC (62.5 MHz, DMSO-d6)
154.6 (quat.), 148.4 (quat.), 147.1 (CH), 144.1 (quat.), 114.5
(quat.), 107.6 (CH), 105.0 (CH), 102.7 (CH2), 33.4 (CH3);
nmax/cmK1 (KBr) 3422, 2942, 2838, 1664, 1611, 1504,
1453, 1402, 1364, 1343, 1212, 1167, 1132, 1011.
3.1.7. 3-Methyl-5-(30-bromo-60-nitrophenyl)oxazolidine
(7d). As a pale yellow oil; dH (250 MHz, CDCl3) 8.00
(1H, d, JZ2.0 Hz, H-20), 7.92 (1H, d, JZ8.7 Hz, H-50), 7.52
(1H, dd, JZ8.7, 2.0 Hz, H-40), 5.50 (1H, t, JZ6.7 Hz, H-5),
4.62 (1H, d, JZ5.2 Hz, H-2), 4.43 (1H, d, JZ5.2 Hz, H-2),
3.58 (1H, dd, JZ11.6, 6.7 Hz, H-4), 2.78 (1H, dd, JZ11.6,
6.7 Hz, H-4), 2.46 (3H, s, NCH3); dC (62.5 MHz, CDCl3)
141.5 (quat.), 138.1 (quat.), 131.1 (CH), 130.5 (CH), 129.5
(quat.), 126.4 (CH), 89.5 (CH2), 73.3 (CH), 62.0 (CH2), 41.6
(CH3); nmax/cmK1 (liquid film) 3432, 2951, 1662, 1611,
1501, 1458, 1431, 1367, 1279, 1168, 1132, 1051, 1009;
(Found: 252.9991. C10H11N2O3Br requires 285.9953).
3.1.2. 2-Methyl-2H-indazole-N-oxide (5a). As a pale
yellow powder, mp 90 8C [Found: C, 64.9; H, 5.6; N,
19.0. C8H8N2O requires C 64.8; H 5.45; N 18.9%]; dH
(250 MHz, DMSO-d6) 7.95 (1H, s, H-3), 7.60 (1H, d,
JZ8.1 Hz, H-7), 7.50 (1H, d, JZ8.1 Hz, H-4), 7.20 (1H, t,
JZ8.1 Hz, H-5), 7.06 (1H, t, JZ8.1 Hz, H-6), 3.95 (3H, s,
CH3); dC (62.5 MHz, DMSO-d6) 127.6 (quat.), 125.6 (CH),
123.0 (CH), 120.9 (CH), 115.1 (quat.), 112.2 (CH), 110.5
(CH), 33.0 (CH3); nmax/cmK1 (liquid film) 3224, 3098,
1670, 1622, 1510, 1458, 1374, 1240, 1178, 1112, 757.
3.1.3. 3-Methyl-5-(30,40-dimethoxy-60-nitrophenyl)oxa-
zolidine (7b). As a pale yellow oil; dH (250 MHz, CDCl3)
7.57 (1H, s, Ar–50H), 7.24 (1H, s, Ar–20H), 5.49 (1H, t,
JZ5.0 Hz, H-5), 4.54 (1H, d, JZ5.0 Hz, H-2), 4.35 (1H, d,
JZ5.0 Hz, H-2), 3.90 (3H, s, OCH3), 3.84 (3H, s, OCH3),
3.52 (1H, dd, JZ11.4, 5.0 Hz, H-4), 2.73 (1H, dd, JZ11.4,
5.0 Hz, H-4), 2.39 (3H, s, NCH3); dC (62.5 MHz, CDCl3)
153.6 (quat.), 147.3 (quat.), 138.6 (quat.), 134.8 (quat.),
107.8 (CH), 107.7 (CH), 89.1 (CH2), 73.7 (CH), 61.8 (CH2),
56.1 (OCH3), 56.0 (OCH3), 41.5 (CH3); nmax/cmK1 (liquid
film) 2949, 2896, 2857, 1580, 1518, 1471, 1440, 1336,
1275, 1220, 1067, 1030, 1015, 986; (HRMS Found: m/z
268.1021. C12H16N2O5 requires 268.1029).
3.1.8. 2-Methyl-5-bromo-2H-indazole-N-oxide (5d). As a
pale yellow powder, mp 130–1 8C; [Found: C, 42.6; H, 3.2;
N, 12.3. C8H7N2OBr requires C 42.3; H 3.1; N 12.3%]; dH
(250 MHz, DMSO-d6) 8.15 (1H, s, H-3), 7.85 (1H, s, H-4),
7.62 (1H, d, JZ8.5 Hz, H-7), 7.44 (1H, d, JZ8.5 Hz, H-6),
3.48 (3H, s, NCH3); dC (62.5 MHz, DMSO-d6) 137.6
(quat.), 132.0 (quat.) 124.6 (CH), 122.9 (CH), 120.1 (quat.),
119.2 (CH), 114.5 (CH), 33.5 (CH3); nmax/cmK1 (KBr)
3228, 3100, 1673, 1629, 1511, 1375, 1311, 1242, 1177,
1100.
3.1.9. 2-Methyl-2H-indazole (8).4 The indazole-N-oxide
5a (0.15 g, 1 mmol) was dissolved in ethanol (25 mL) and
palladium on charcoal (10%, 10 mg) was added. The
reaction mixture was stirred under an hydrogen atmosphere
(1 atm), at room temperature, for 12 h. The catalyst was then
filtered of with the aid of Celiteq and the solvent was
removed in vacuo to give the product as a colourless oil,
(0.13 g, 100%); dH (250 MHz, CDCl3) 7.81 (1H, s, H-3),
7.69 (1H, d, JZ8.7 Hz, H-7), 7.61 (1H, d, JZ8.7 Hz, H-4),
7.26 (1H, t, JZ8.7 Hz, H-6), 7.05 (1H, t, JZ8.7 Hz, H-5),
3.1.4. 2-Methyl-5,6-dimethoxy-2H-indazole-N-oxide
(5b). As a pale yellow powder, mp 122–3 8C [Found: C,
57.9; H, 5.8; N, 13.6. C10H12N2O3 requires C 57.7; H 5.8; N
13.5%]; dH (250 MHz, DMSO-d6) 8.24 (1H, s, H-3), 7.41
(1H, s, H-7), 7.08 (1H, s, H-4), 3.89 (3H, s, OCH3), 3.86
(3H, s, OCH3), 3.47 (3H, s, NCH3); dC (62.5 MHz, DMSO-
d6) 154.3 (quat.), 148.7 (quat.), 146.9 (CH), 144.2 (quat.),

M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
9941
4.14 (3H, s, CH3); dC (62.5 MHz, CDCl3) 127.3 (quat.),
125.8 (CH), 123.5 (CH), 121.6 (quat.), 121.5 (CH), 119.9
(CH), 116.9 (CH), 40.2 (CH3); nmax/cmK1 (nujol) 3416,
2932, 1730, 1628, 1517, 1386, 1300, 1159, 1009; m/z 42
(100%), 51 (52), 63 (57), 77 (18), 104 (6), 133 (M, 43).
3.1.12. 2,3-Dimethoxy-8-(2-nitrophe0ny0l)-10-phenyl-
8,8a,11a,11b-tetrahydro-6H-pyrrolo[3 ,4 :3,4]pyrrolo-
[2,1-a]isoquinoline-9,11(5H,10H)-dione (17). Isoquino-
linium, 3,4-dihydro-6,7-dimethoxy-2-[(2-nitrophenyl)-
methyl]-, chloride (13) (0.50 g, 1.4 mmol) and
N-phenylmaleimide (0.23 g, 1.4 mmol) were dissolved in
methanol (15 mL) and triethylamine (0.20 mL, 0.14 g,
1.4 mmol) was added. The reaction mixture was stirred
for 24 h at room temperature. The solvent was removed in
vacuo, and the residue was dissolved in dichloromethane
(30 mL) and it washed with water (3!20 mL). The organic
layer was dried over magnesium sulphate and evaporated to
give a pale brown solid which was further purified by
column chromatography on silica, eluting with ethyl
acetate–hexane (1:1). The product was obtained as a white
powder (0.41 g, 58%), mp 236–8 8C; [Found: C, 67.5; H,
5.0; N, 8.5. C28H25N3O6 requires C 67.3; H 5.0; N 8.4%]; dH
(250 MHz, CDCl3) 8.07 (1H, d, JZ7.7 Hz, H-30), 7.94 (1H,
d, JZ7.7 Hz, Ar–H), 7.66 (1H, t, JZ7.7 Hz, Ar–H), 7.46
(1H, t, JZ7.7 Hz, Ar–H), 7.43–7.30 (3H, m, Ar–H), 7.15
(2H, m, Ar–H), 6.81 (1H, s, H-1), 6.55 (1H, s, H-4), 5.13
(1H, s, H-11b), 4.95 (1H, d, JZ8.6 Hz, H-8), 4.01 (1H, t,
JZ8.6 Hz, H-8a), 3.93 (3H, s, CH3), 3.88 (3H, s, CH3), 3.73
(1H, d, JZ8.6 Hz, H-11a), 3.17 (1H, dt, JZ13.3, 4.5 Hz,
CH2), 3.00–2.70 (2H, m, CH2), 2.30 (1H, dd, JZ16.7,
3.9 Hz, CH2); dC (62.5 MHz, CDCl3) 177.6 (quat.), 174.7
(quat.), 149.7 (quat.), 148.3 (quat.), 148.2 (quat.), 133.6
(CH), 133.3 (quat.), 131.8 (quat.), 129.1 (2!CH), 129.0
(CH), 128.9 (CH), 128.5 (CH), 126.2 (2!CH), 126.1
(quat.), 125.8 (quat.), 125.2 (CH), 111.9 (C-4), 108.7 (C-1),
64.0 (C-11b), 59.1 (CH), 56.1 (CH3), 55.9 (CH3), 51.0 (CH),
49.0 (CH), 41.9 (CH2), 20.5 (CH2); nmax/cmK1 (KBr) 3099,
2992, 2931, 2834, 1714, 1515, 1450, 1376, 1357, 1253,
1182, 1099, 1020.
3.1.10. 3-Benzyl-5-(2-nitrophenyl)oxazolidine (10) and
2-benzyl-2H-indazole-N-oxide (11). To a solution of 2-
nitrobenzaldehyde (0.50 g, 3.3 mmol) in dry THF (50 mL)
was added N-benzylglycine (0.80 g, 4.97 mmol) and
˚
molecular sieves (4 A, 2 g). The reaction mixture was
heated at reflux for 5 h, under nitrogen. After cooling, the
solid was filtered off and the solvent was removed under
reduced pressure. The residue was purified by column
chromatography on silica, eluting with hexane–ethyl acetate
(from 80:20 to 0:100) to give two products; 10: as a yellow
solid (0.27 g, 29%), mp 133 8C; dH (CDCl3, 270 MHz): 8.03
(1H, dd, JZ7.9, 1.3 Hz, H-30), 07.90 (1H, d, JZ7.9 Hz,
H-60), 7.63 (1H, t, JZ7.9 Hz, H-5 ), 7.21–7.41 (6H, m, H-40
and Ar–H), 5.55 (1H, t, JZ6.6 Hz, H-5), 4.66 (1H, d,
JZ5.9 Hz, H-20), 4.59 (1H, d, JZ5.9 Hz, H-2), 3.72–3.80
(3H, m, Bn–CH2 and H-5), 2.82 (1H, dd, JZ11.9, 6.6 Hz,
H-5); dC (CDCl3, 67.5 MHz): 146.8 (quat.), 139.5 (quat.),
138.4 (quat.), 134.0 (CH), 128.7 (2!CH), 128.4 (2!CH),
127.8 (CH), 127.3 (CH), 127.1 (CH), 124.7 (CH), 87.4
(CH2), 73.3 (CH), 60.2 (CH2), 58.3 (CH2); nmax/cmK1
(KBr) 2921, 2855, 2801, 1527, 1455, 1368, 1347, 1166,
1052; (Found: 284.1132. C16H16N2O3 requires 284.1160);
11: as a white solid (0.33 g, 46%), mp 155–6 8C; dH (CDCl3,
270 MHz) 5.60 (2H, s, CH2), 7.06 (1H, t, JZ7.5 Hz, Ar–H),
7.21–7.45 (8H, m, Ar–H), 7.71 (1H, d, JZ8.0 Hz, Ar–H);
dC (CDCl3, 67.5 MHz) 49.5 (CH2), 108.6 (CH), 112.9 (CH),
116.0 (quat.), 120.2 (CH), 123.7 (CH), 126.3 (CH), 128.7
(3!CH) 129.0 (2!CH and 1 quat.), 133.7 (quat.); nmax
/
cmK1 (KBr) 3229, 3111, 1666, 1611, 1517, 1459, 1373,
1246, 1167, 1115; (Found: 224.0922. C14H12N2O requires
224.0950).
3.2. Synthesis of isoquinolines (19). General procedure
Phosphorus pentoxide (14.2 g, 0.1 mol) was suspended at
0 8C in dry xylene (300 mL) and freshly distilled phos-
phorus oxychloride (18.5 mL, 30.7 g, 0.2 M) was added
dropwise to the well-stirred mixture. To this mixture was
added the corresponding amide 18 and the reaction mixture
was stirred at reflux for 3 h followed by cooling to room
temperature. The xylene was decanted and the semi-solid
residue was stirred overnight with an excess of 10% aqueous
sodium hydroxide solution. The solid precipitate which
formed was filtered off and recrystallized from ethanol.
3.1.11. 4,5-Dimethoxy-2-[20-(200H-200-indazolyl-100-N-
oxide)ethyl]benzaldehyde (16). 6,7-Dimethoxy-3,4-
dihydro-2-(20-nitrobenzyl)isoquinolinium chloride (0.36 g,
1.0 mmol) was dissolved in methanol (5 mL) and triethyl-
amine (0.14 mL, 0.10 g, 1.0 mmol) was added. The reaction
mixture was stirred for 24 h at room temperature, then the
solvent was removed in vacuo. The residue was dissolved in
dichloromethane (30 mL) and washed with water (3!
20 mL). The organic layer was dried over magnesium
sulphate and evaporated to give the product as a pale brown
solid (0.28 g, 85%), mp 114–6 8C; [Found: C, 66.2; H, 5.6;
N, 8.5. C18H18N2O4 requires C 66.3; H 5.6; N 8.6%]; dH
(250 MHz, CDCl3) 10.06 (1H, s, CHO), 7.70 (1H, d,
JZ8.8 Hz, H-700), 7.44 (1H, d, JZ8.800Hz, H-400), 7.28 (1H,
s, H-300), 7.25 (1H, t, JZ8.8 Hz, H-5 ), 7.21 (1H, s, H-3),
7.07 (1H, t, JZ8.8 Hz, H-600), 6.51 (1H, s, H-6), 4.69 (2H, t,
JZ6.9 Hz, CH2), 3.92 (3H, s, OCH3), 3.65 (3H, s, OCH3),
3.64 (2H, t, JZ6.9 Hz, CH2); dC (62.5 MHz, CDCl3) 191.3
(CHO), 153.3 (quat.), 150.2 (quat.), 148.0 (quat.), 133.7
(quat.), 129.4 (quat.), 126.8 (quat.), 126.5 (CH), 123.7 (CH),
120.3 (CH), 115.7 (CH), 114.3 (CH), 112.6 (CH), 109.7
3.2.1. 6,7-Dimethoxy-1-(20-nitrophenyl)-3,4-dihydro-
isoquinoline (19a). As a pale yellow solid (58%), mp
112–3 8C (lit.11 110–2 8C); dH (250 MHz, CDCl3) 8.00 (1H,
d, JZ7.5 Hz, H-30), 7.67 (1H, t, JZ8.3 Hz, H-500), 7.54 (1H,
t, JZ8.3 Hz, H-40), 7.52 (1H, d, JZ8.3 Hz, H-6 ), 6.73 (1H,
s, H-8), 6.29 (1H, s, H-5), 3.86 (3H, s, OCH3), 3.79 (2H, t,
JZ7.6 Hz, CH2), 3.58 (3H, s, OCH3), 2.77 (2H, t,
JZ7.6 Hz, CH2); dC (62.5 MHz, CDCl3) 164.2 (quat.),
151.2 (quat.), 148.4 (quat.), 147.3 (quat.), 134.7 (quat.),
133.3 (CH), 131.3 (quat.), 130.9 (CH), 129.5 (CH), 124.2
(CH), 121.3 (quat.), 110.3 (CH), 109.1 (CH), 55.9 (CH3),
55.8 (CH3), 47.6 (CH2), 25.3 (CH2); nmax/cmK1 (KBr) 2966,
2836, 1606, 1568, 1526, 1353, 1324, 1284, 1270, 1215,
1123, 1024.
(CH), 56.1 (CH3), 56.0 (CH3), 47.6 (CH2), 31.7 (CH2); nmax
/
cmK1 (KBr) 2902, 1710, 1562, 1490, 1444, 1251, 1105,
1037.

9942
M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
3.2.2. 6,7-Diethoxy-1-(20-nitrophenyl)-3,4-dihydroiso-
quinoline (19b). As a pale yellow solid (65%), [Found: C,
67.2; H, 5.9; N, 8.4. C19H20N2O4 requires C 67.05; H 5.9; N
8.2%]; mp 118–20 8C; dH (250 MHz, CDCl3) 8.07 (1H, d,
1H, JZ7.8 Hz, H-30),0 7.68 (1H, t, JZ7.8 Hz, H-500), 7.68
(1H, t, JZ7.8 Hz, H-4 ), 7.58 (1H, d, JZ7.8 Hz, H-6 ), 6.76
(1H, s, H-8), 6.34 (1H, s, H-5), 4.14 (2H, q, JZ6.9 Hz,
OCH2), 3.83 (2H, m, 2!CH2), 2.80 (2H, t, JZ7.6 Hz,
CH2), 1.47 (3H, t, JZ6.9 Hz, CH3), 1.30 (3H, t, JZ6.9 Hz,
CH3); dC (62.5 MHz, CDCl3) 164.5 (quat.), 151.5 (quat.),
147.5 (quat.), 145.9 (quat.), 136.0 (quat.), 133.1 (CH), 131.2
(quat.), 129.9 (CH), 129.6 (CH), 124.0 (CH), 121.5 (quat.),
110.6 (CH), 109.8 (CH), 65.5 (CH2), 65.2 (CH2), 47.6
(CH2), 25.3 (CH2), 14.5 (2!CH3); nmax/cmK1 (KBr) 2968,
2830, 1611, 1564, 1525, 1320, 1283, 1271, 1215, 1175,
1122, 1054, 1021.
vacuo and the residue was triturated with dry diethyl ether.
The yellow precipitate was filtered off, washed with diethyl
ether and dried in vacuo.
3.3.1. Isoquinolinium, 3,4-dihydro-6,7-dimethoxy-2-[(2-
nitrophenyl)methyl]-, chloride (13). The title compound
was prepared via method A to give a yellow powder (95%),
mp 190–2 8C; [Found: C, 59.4; H, 5.1; N, 7.5.
C18H19N2O4Cl requires C 59.6; H 5.3; N 7.7%]; dH
(250 MHz, DMSO-d6) 9.25 (1H, s, H-10), 8.25 (1H, d,
JZ8.1 Hz, H-300), 7.87 (2H, m, H-40 and H-50), 7.76 (1H, d,
JZ8.1 Hz, H-6 ), 7.56 (1H, s, H-8), 7.21 (1H, s, H-5), 5.55
(2H, s, NCH2Ar), 3.99 (2H, t, JZ6.6 Hz, CH2), 3.97 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.20 (2H, t, JZ6.6 Hz, CH2);
dC (62.5 MHz, DMSO-d6) 165.8 (quat.), 157.7 (quat.),
148.5 (quat.), 148.1 (quat.), 134.9 (CH), 133.1 (CH), 132.4
(CH), 130.9 (CH), 127.0 (CH), 125.8 (quat.), 117.2 (quat.),
115.9 (CH), 111.5 (CH), 59.2 (ArCH2N), 56.7 (CH3), 56.0
(CH3), 48.3 (CH2), 25.0 (CH2); nmax/cmK1 (KBr) 3376,
3002, 2975, 1641, 1602, 1562, 1527, 1344, 1303, 1274,
1139, 1006.
3.2.3. 6,7-Dimethoxy-1-(50-chloro-20-nitrophenyl)-3,4-
dihydroisoquinoline (19c). As a yellow solid (72%), mp
128–9 8C; [Found: C, 60.0; H, 4.5; N, 8.0. C17H15N2O4Cl
requires C 59.9; H 4.4; N 8.1%]; dH (250 MHz, CDCl3) 8.04
(1H, d, JZ8.3 0Hz, H-30), 7.58 (1H, s, H-60), 7.56 (1H, d,
JZ8.3 Hz, H-4 ), 6.78 (1H, s, H-8), 6.31 (1H, s, H-5), 3.93
(3H, s, OCH3), 3.85 (2H, t, JZ7.5 Hz, CH2), 3.66 (3H, s,
OCH3), 2.83 (2H, t, JZ7.5 Hz, CH2); dC (62.5 MHz,
CDCl3) 163.3 (quat.), 151.4 (quat.), 147.5 (quat.), 146.7
(quat.), 140.0 (quat.), 136.5 (quat.), 131.4 (quat.), 131.1
(CH), 129.6 (CH), 125.7 (CH), 120.9 (quat.), 110.5 (CH),
108.8 (CH), 56.1 (CH3), 55.9 (CH3), 47.7 (CH2), 25.3
(CH2); nmax/cmK1 (KBr) 2986, 2947, 2904, 1606, 1564,
1523, 1397, 1357, 1312, 1213, 1132, 1111, 1087, 1039.
3.3.2. 6,7-Diethoxy-3,4-dihydro-2-(methoxycarbonyl-
methyl)-1-(20-nitrophenyl)isoquinolinium bromide
(20a). The title compound was prepared via method A to
give a yellow powder, mp 100–2 8C; [Found: C, 53.4; H,
5.2; N, 5.7. C22H25N2O6Br requires C 53.6; H 5.1; N 5.7%];
dH (250 MHz, DMSO-d6) 8.55 (1H, d, JZ8.0 Hz, H-30),
8.14 (1H, t, JZ8.0 Hz, H-500), 8.06 (1H, t, JZ8.0 Hz, H-40),
7.76 (1H, d, JZ8.0 Hz, H-6 ), 7.33 (1H, s, H-8), 6.18 (1H, s,
H-5), 4.18 (2H, s, CH2COO), 4.28 (4H, m, 2!CH2CH3),
3.76 (3H, s, COOCH3), 3.37 (4H, m, H-6 and H-7), 1.36
(3H, t, JZ6.7 Hz, CH2CH3), 1.11 (3H, t, JZ6.7 Hz,
CH2CH3); dC (62.5 MHz, DMSO-d6) 173.0 (quat.), 166.1
(quat.), 157.0 (quat.), 147.1 (quat.), 145.7 (quat.), 135.9
(CH), 135.2 (quat.), 133.9 (CH), 129.3 (CH), 126.6 (CH),
124.2 (quat.), 118.1 (CH), 115.0 (CH), 112.3 (quat.), 65.3
(CH2), 64.3 (CH2), 58.1 (CH2), 53.2 (CH3), 51.5 (CH2), 25.0
(CH2), 14.4 (CH3), 14.2 (CH3); nmax/cmK1 (KBr) 2988,
2955, 2913, 1720, 1625, 1523, 1375, 1234, 1222, 1137,
1039.
3.2.4. 6,7-Diethoxy-1-(50-chloro-20-nitrophenyl)-3,4-
hydroisoquinoline (19d). As a yellow solid (70%), mp
126–8 8C; [Found: C, 60.8; H, 5.1; N, 7.5. C19H19N2O4Cl
requires C 60.9; H 5.1; N 7.5%]; dH (250 MHz, CDCl3C
DMSO-d6) 8.06 (1H, d, JZ8.1 Hz, H-30), 7.59 (1H, d,
JZ8.1 Hz, H-40), 7.57 (1H, s, H-60), 6.78 (1H, s, H-8), 6.32
(1H, s, H-5), 4.14 (2H, q, JZ7.0 Hz, OCH2), 3.86 (4H, m,
2!CH2), 2.82 (2H, t, JZ7.5 Hz, CH2), 1.47 (3H, t,
JZ7.0 Hz, CH3), 1.32 (3H, t, JZ7.0 Hz, CH3); dC
(62.5 MHz, CDCl3Cd6-DMSO) 163.4 (quat.), 151.6
(quat.), 146.7 (quat.), 146.4 (quat.), 139.8 (quat.), 136.0
(quat.), 131.6 (quat.), 130.9 (CH), 129.6 (CH), 125.6 (CH),
120.6 (quat.), 111.7 (CH), 111.6 (CH), 65.0 (CH2), 64.2
(CH2), 47.4 (CH2), 25.1 (CH2), 14.4 (2!CH3); nmax/cmK1
(KBr) 2966, 2949, 2898, 2832, 1603, 1561, 1526, 1395,
1358, 1318, 1271, 1211, 1182, 1129, 1108, 1039.
3.3.3. Isoquinolinium, 6,7-diethoxy-3,4-dihydro-1-(2-
nitrophenyl)-2-(phenylmethyl)-, bromide (20b). 6,7-
Diethoxy-1-(20-nitrophenyl)-3,4-dihydroisoquinoline
(1.0 g, 2.9 mmol) was dissolved in dry toluene (10 mL) and
benzyl bromide (0.36 mL, 0.50 g, 3 mmol) was added. The
resulted solution was heated for 48 h at reflux under an
argon atmosphere. The solvent was removed in vacuo and
the residue was triturated with dry diethyl ether. The yellow
precipitate was filtered off, washed with diethyl ether and
dried in vacuo to give a yellow powder (1.45 g, 95%), mp
190–2 8C; [Found: C, 59.9; H, 5.1; N, 5.5. C26H27N2O4Br
requires C 60.0; H 5.3; N 5.5%]; dH (250 MHz, CDCl3) 8.92
(1H, d, JZ7.5 Hz, H-300), 8.47 (1H, d, JZ7.5 Hz, H-600), 8.18
(1H, t, JZ7.5 Hz, H-4 ), 8.08 (1H, t, JZ7.5 Hz, H-5 ), 7.35
(5H, s, ArH), 7.02 (1H, s, H-8), 6.09 (1H, s, H-5), 5.50 (1H,
d, JZ14.9 Hz, NCH2Ph), 5.07 (1H, d, JZ14.9 Hz,
NCH2Ph), 4.90–4.60 (1H, m, CH2CH2), 4.40–4.00 (4H, m,
2!CH2CH3), 3.88–3.52 (2H, m, CH2CH2), 3.50–3.15 (1H,
m, CH2CH2), 1.48 (3H, t, JZ6.5 Hz, CH3), 1.27 (3H, t,
JZ6.6 Hz, CH3); dC (62.5 MHz, CDCl3) 171.2 (quat.),
157.4 (quat.), 147.9 (quat.), 146.1 (quat.), 136.2 (CH), 134.3
3.3. Synthesis of quaternery salts. General procedures
Method A. The 3,4-dihydroisoquinoline (2.5 mmol) was
dissolved in dry diethyl ether (25 mL) and 2-nitro-
benzylchloride (0.44 g, 2.5 mmol) or methly bromoacetate
(0.28 mL, 0.46 g, 3.0 mmol) were added. The mixture was
left without stirring for 3 days at room temperature, under an
argon atmosphere. The yellow precipitate was filtered off,
washed with dry diethyl ether and dried in vacuo.
Method B. The 3,4-dihydroisoquinoline (2.5 mmol) was
dissolved in allyl bromide (4 mL). The resulting solution
was heated for 24 h under reflux, under an argon
atmosphere. The excess allyl bromide was removed in

M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
9943
(quat.), 133.8 (CH), 132.2 (CH), 131.7 (quat.), 129.5 (2!
CH), 129.4 (CH), 128.9 (2!CH), 125.6 (CH), 125.4 (quat.),
118.6 (quat.), 114.9 (CH), 112.1 (CH), 65.5 (CH2CH3), 65.1
(CH2CH3), 61.8 (CH2), 49.8 (CH2), 26.0 (CH2), 14.4 (CH3),
14.3 (CH3); nmax/cmK1 (KBr) 2979, 1602, 1552, 1525,
1386, 1342, 1272, 1213, 1186, 1029, 754.
2866, 1598, 1565, 1551, 1525, 1393, 1373, 1339, 1299,
1272, 1217, 1187, 1108, 1029.
3.3.7. 2-Allyl-6,7-diethoxy-3,4-dihydro-1-(20-nitro-50-
chlorophenyl)isoquinolinium bromide (20f). The title
compound was prepared via method B to give a yellow
powder (95%), mp 255 8C; [Found: C, 53.2; H, 4.9; N, 5.7
C22H24N2O4BrCl requires C 53.3; H 4.9; N 5.65%]; dH
(500 MHz, DMSO-d6) 8.54 (1H, d, JZ9.0 Hz, H-30), 8.31
(1H, d, JZ1.0 Hz, H-60), 8.14 (1H, dd, JZ9.0, 1.0 Hz,
H-40), 7.31 (1H, s, H-8), 6.32 (1H, s, H-5), 5.89–5.84 (1H,
m, allyl-H), 5.36–5.32 (2H, m, allyl-H), 4.39 (2H, m, allyl-
H), 4.29–4.22 (4H, m, 2!CH2CH3), 3.73 (2H, m, CH2),
3.41 (1H, m, CH2), 3.26 (1H, m, CH2), 1.35 (3H, t,
JZ7.0 Hz, CH3), 1.14 (3H, t, JZ7.0 Hz, CH3); dC
(75.5 MHz, DMSO-d6) 169.5 (quat.), 156.5 (quat.), 147.0
(quat.), 144.3 (quat.), 140.8.0 (quat.), 134.4 (quat.), 133.5
(CH), 129.6 (quat.), 129.2 (quat.), 128.3 (CH), 126.2 (CH),
121.7 (CH2), 118.1 (quat.), 115.1 (CH), 112.3 (CH), 65.0
(CH2), 64.4 (CH2), 59.8 (CH2), 49.7 (CH2), 24.8 (CH2), 14.3
(CH3), 14.1 (CH3); nmax/cmK1 (KBr) 2982, 2877, 1713,
1633, 1566, 1377, 1284, 1226, 1200, 1124, 1101, 1037.
3.3.4. 2-Allyl-6,7-diethoxy-3,4-dihydro-1-(20-nitro-
phenyl)isoquinolinium bromide (20c). The title compound
was prepared via method B to give a yellow powder, mp
245–7 8C; [Found: C, 57.0; H, 5.5; N, 6.0. C22H25N2O4Br
requires C 57.3; H 5.5; N 6.1%]; dH (250 MHz, CDCl3) 8.43
(1H, d, JZ7.5 Hz, H-300), 8.38 (1H, d, JZ7.5 Hz, H-600), 8.24
(1H, t, JZ7.5 Hz, H-4 ), 7.93 (1H, t, JZ7.5 Hz, H-5 ), 6.98
(1H, s, H-8), 6.09 (1H, s, H-5), 5.83–5.63 (1H, m, allyl-H),
5.48–5.23 (2H, m, allyl-H), 4.85–4.60 (2H, m, allyl-H),
4.39–4.18 (4H, m, 2!CH2CH3), 3.82–3.53 (2H, m, CH2),
3.29 (2H, m, CH2), 1.47 (3H, t, JZ6.9 Hz, CH3), 1.26 (3H,
t, JZ6.9 Hz, CH3); dC (62.5 MHz, CDCl3) 170.9 (quat.),
157.3 (quat.), 147.7 (quat.), 145.6 (quat.), 137.0 (quat.),
134.5 (quat.), 133.1 (CH), 131.8 (CH), 131.7 (quat.), 128.3
(CH), 125.2 (CH), 123.5 (CH2), 118.9 (CH), 115.3 (CH),
112.1 (CH), 65.5 (CH2), 65.2 (CH2), 61.1 (CH2), 50.1
(CH2), 25.9 (CH2), 14.4 (CH3), 14.3 (CH3); nmax/cmK1
(KBr) 2984, 2888, 1712, 1635, 1553, 1381, 1277, 1202,
1124, 1103, 1039.
3.3.8. 1,7-Electrocyclizations. General procedures. The
3,4-dihydro-1-(20-nitrophenyl)isoquinolinium
halide
(2.9 mmol) was dissolved in dry methanol (10 mL) and
triethylamine (0.42 mL, 0.30 g, 3.0 mmol) was added. The
reaction mixture was stirred for 24 h at room temperature.
The solvent was removed in vacuo, the residue was
dissolved in dichloromethane (50 mL) and washed with
water (3!20 mL) and brine (20 mL). The organic layer was
dried over magnesium sulphate and evaporated in vacuo.
The residue was further purified by column chromatography
on silica gel, eluting with acetone to give the product.
3.3.5. 2-Allyl-6,7-dimethoxy-3,4-dihydro-1-(20-nitro-
phenyl)isoquinolinium bromide (20d). The title com-
pound was prepared via method B to give a yellow powder,
mp 237–8 8C; [Found: C, 55.2; H, 4.7; N, 6.5
C20H21N2O4Br requires C 55.4; H 4.9; N 6.5%]; dH
(250 MHz, CDCl3) 8.89 (1H, d, JZ7.5 Hz, H-30), 8.46
(1H, d, JZ7.5 Hz, H-60), 8.14 (1H, t, JZ7.5 Hz, H-40), 8.00
(1H, t, JZ7.5 Hz, H-50), 7.03 (1H, s, H-8), 6.07 (1H, s, H-5),
5.91–5.80 (1H, m, allyl-H), 5.39–5.36 (2H, m, allyl-H),
4.89–4.69 (2H, m, allyl-H), 4.38 (1H, m, CH2), 4.17 (1H, m,
CH2), 4.05 (3H, s, OCH3), 3.66 (1H, m, CH2), 3.58 (3H, s,
OCH3), 3.41 (1H, m, CH2); dC (62.5 MHz, CDCl3) 170.7
(quat.), 157.0 (quat.), 148.3 (quat.), 145.5 (quat.), 135.9
(quat.), 134.0 (quat.), 133.1 (CH), 131.5 (CH), 131.4 (quat.),
128.0 (CH), 125.2 (CH), 123.3 (CH2), 118.8 (quat.), 112.5
(CH), 111.0 (CH), 60.9 (CH2), 56.7 (CH3), 55.8 (CH3), 49.4
(CH2), 25.6 (CH2); nmax/cmK1 (KBr) 3013, 2943, 1604,
1557, 1526, 1467, 1387, 1344, 1294, 1274, 1222, 1186,
1124, 1082.
3.3.9. 2,3-Diethoxy-5,6-dihydroindazolo[3,2-a]isoquino-
line-8-oxide (22a). The title compound was obtained as
an orange solid, mp 90 8C; [Found: C, 70.6; H, 6.1; N, 8.5.
C19H20N2O3 requires C 70.35; H 6.2; N 8.6%]; dH
(250 MHz, CDCl3) 7.87 (1H, d, JZ8.6 Hz, H-9), 7.71
(1H, d, JZ8.6 Hz, H-12), 7.38 (1H, s, H-1), 7.31 (1H, t,
JZ8.6 Hz, H-11), 7.16 (1H, t, JZ8.6 Hz, H-10), 6.81 (1H,
s, H-4), 4.57 (2H, t, JZ7.0 Hz, H-6), 4.15 (2H, q,
JZ7.3 Hz, OCH2), 4.12 (2H, q, JZ7.3 Hz, OCH2), 3.15
(2H, t, JZ7.0 Hz, H-5), 1.50 (3H, t, JZ7.3 Hz, CH3), 1.47
(3H, t, JZ7.3 Hz, CH3); dC (62.5 MHz, CDCl3) 149.5
(quat.), 148.1 (quat.), 131.3 (quat.), 127.0 (CH), 124.2
(quat.), 124.0 (CH), 120.1 (CH), 119.5 (quat.), 118.9 (quat.),
113.4 (CH), 112.9 (CH), 112.0 (quat.), 109.7 (CH), 65.1
(CH2), 64.7 (CH2), 39.9 (CH2), 27.6 (CH2), 14.8 (CH3), 14.7
(CH3); nmax/cmK1 (KBr) 2983, 2938, 1604, 1558, 1525,
1388, 1344, 1274, 1031.
3.3.6. 2-Allyl-6,7-dimethoxy-3,4-dihydro-1-(20-nitro-50-
chlorophenyl)isoquinolinium bromide (20e). The title
compound was prepared via method B to give a yellow
powder, mp 252–3 8C; [Found: C, 51.2; H, 4.5; N, 6.1
C20H20N2O4BrCl requires C 51.4; H 4.3; N 6.0%]; dH
(250 MHz, CDCl3) 9.01 (1H, s, H-60), 8.48 (1H, d,
JZ8.8 Hz, H-30), 7.98 (1H, d, JZ8.8 Hz, H-40), 7.07 (1H, s,
H-8), 6.11 (1H, s, H-5), 5.90–5.77 (1H, m, allyl-H), 5.44–
5.32 (2H, m, allyl-H), 4.88–4.32 (2H, m, allyl-H), 4.40 (1H,
m, CH2), 4.18 (1H, m, CH2), 4.10 (3H, s, OCH3), 3.71 (3H,
s, OCH3) 3.45 (2H, m, CH2); dC (62.5 MHz, CDCl3) 169.1
(quat.), 157.2 (quat.), 148.3 (quat.), 143.8 (quat.), 142.7
(quat.), 134.3 (quat.), 133.4 (CH), 131.0 (CH), 127.8 (CH),
126.8 (CH), 126.5 (CH), 123.4 (CH2), 118.4 (quat.), 112.4
(CH), 111.2 (CH), 61.0 (CH2), 56.7 (CH3), 56.0 (CH3), 49.6
(CH2), 25.5 (CH2); nmax/cmK1 (KBr) 3088, 2974, 2933,
3.3.10. 2,3-Dimethoxy-5,6-dihydroindazolo[3,2-a]iso-
quinoline-8-oxide (22b). The title compound was obtained
as an orange solid, mp 122–3 8C; [Found: C, 69.0; H, 5.6; N,
9.5 C17H16N2O3 requires C 68.9; H 5.4; N 9.45%]; dH
(250 MHz, CDCl3) 7.91 (1H, d, JZ8.6 Hz, H-9), 7.70 (1H,
d, JZ8.6 Hz, H-12), 7.39 (1H, s, H-1), 7.31 (1H, t,
JZ8.6 Hz, H-11), 7.20 (1H, t, JZ8.6 Hz, H-10), 6.87 (1H,
s, H-4), 4.58 (2H, t, JZ7.0 Hz, H-6), 4.01 (3H, s, CH3), 3.94
(3H, s, CH3), 3.21 (2H, t, JZ7.0 Hz, H-5); dC (62.5 MHz,
CDCl3) 149.3 (quat.), 147.8 (quat.), 131.7 (quat.), 129.4

9944
M. Nyerges et al. / Tetrahedron 60 (2004) 9937–9944
(CH), 125.9 (quat.), 123.5 (CH), 120.4 (CH), 120.1 (quat.),
118.1 (quat.), 112.4 (CH), 112.1 (quat.), 111.3 (CH), 106.6
[Found: C, 60.1; H, 5.7; N, 5.6. C25H28N2O9 requires C 59.99;
H 5.64; N 5.60%]; dH (250 MHz, CDCl3) 8.01 (1H, d,
JZ7.8 Hz, H-30), 7.57 (1H, dt, JZ7.8, 1.8 Hz, ArH), 7.49–
7.38 (2H, m, ArH), 6.71 (1H, s, H-10), 6.67 (1H, s, H-7),
4.87 (1H, d, JZ4.6 Hz, H-2), 4.08 (2H, q, JZ7.0 Hz,
OCH2), 4.00–3.77 (3H, m, H-3 and OCH2), 3.75 (OCH3),
3.53 (OCH3), 3.27–3.05 (3H, m, CH2), 2.75–2.62 (1H, m,
CH2), 1.43 (3H, t, JZ7.0 Hz, CH3), 1.31 (3H, t, JZ7.0 Hz
CH3); dC (62.5 MHz, CDCl3) 170.8 (quat.), 169.9 (quat.),
149.5 (quat.), 148.7 (quat.), 146.8 (quat.), 135.5 (quat.),
131.2 (CH), 129.7 (CH), 129.4 (CH), 127.7 (quat.), 126.0
(quat.), 124.4 (CH), 113.4 (CH), 112.0 (CH), 99.6 (quat.),
74.0 (CH), 71.5 (CH), 64.6 (CH2), 64.2 (CH2), 52.6 (CH3),
(CH), 55.7 (CH3), 55.5 (CH3), 39.1 (CH2), 27.0 (CH2); nmax
/
cmK1 (KBr) 3023, 2993, 2931, 2830, 1606, 1531, 1505,
1464, 1431, 1368, 1350, 1286, 1250, 1222, 1211, 1168,
1146, 1124, 1080, 1024.
3.3.11.
2,3-Dimethoxy-11-chloro-5,6-dihydroinda-
zolo[3,2-a]isoquinoline-8-oxide (22c). The title compound
was obtained as an orange solid, mp 133 8C; [Found: C,
61.7; H, 4.6; N, 8.5 C17H15N2O3Cl requires C 61.7; H 4.6; N
8.5%]; dH (250 MHz, CDCl3CDMSO-d6) 7.86 (1H, s,
H-12), 7.67 (1H, d, JZ9.2 Hz, H-9), 7.28 (1H, s, H-1), 7.22
(1H, d, JZ9.2 Hz, H-10), 6.87 (1H, s, H-4), 4.56 (2H, t,
JZ6.8 Hz, H-6), 4.02 (3H, s, OCH3), 3.94 (3H, s, OCH3),
3.21 (2H, t, JZ6.8 Hz, H-5); dC (62.5 MHz, CDCl3C
DMSO-d6) 148.9 (quat.), 148.3 (quat.), 129.2 (quat.), 127.8
(quat.), 127.2 (CH), 123.8 (quat.), 118.5 (CH), 118.2 (quat.),
117.4 (quat.), 114.2 (CH), 111.6 (quat.), 111.4 (CH), 106.7
52.4 (CH3), 50.1 (CH2), 28.3 (CH2), 14.7 (CH3!2); nmax
/
cmK1 (KBr) 1735 (C]O), 1535 (NO2), 1367 (NO2), 1263
(C–O).
Acknowledgements
(CH), 55.0 (CH3), 55.7 (CH3), 39.3 (CH2), 27.2 (CH2); nmax
/
cmK1 (KBr) 3380, 3005, 1610, 1538, 1506, 1489, 1470,
1359, 1281, 1221, 1205, 1161, 1076, 1054, 1012, 989.
This work was financially supported by the National
Foundation for Science and Research, Hungary (OTKA
Project No. T 032221). N. M. thanks the Hungarian
Academy of Sciences for a Bolyai J. fellowship.
3.3.12. 2,3-Diethoxy-11-chloro-5,6-dihydroindazolo[3,2-
a]isoquinoline-8-oxide (22d). The title compound was
obtained as an orange solid, mp 129–30 8C; [Found: C, 63.6;
H, 5.4; N, 7.6. C19H19N2O3Cl requires C 63.6; H 5.3; N
7.8%]; dH (250 MHz, CDCl3) 7.82 (1H, s, H-12), 7.68 (1H,
d, JZ9.2 Hz, H-9), 7.28 (1H, s, H-1), 7.21 (1H, d,
JZ9.2 Hz, H-10), 6.82 (1H, s, 1H, H-4), 4.56 (2H, t,
JZ7.0 Hz, H-6), 4.19 (2H, q, JZ7.0 Hz, OCH2), 4.16 (2H,
q, JZ7.0 Hz, OCH2), 3.17 (2H, t, JZ7.0 Hz, H-5), 1.53
(3H, t, JZ7.0 Hz, CH3), 1.49 (3H, t, JZ7.0 Hz, CH3); dC
(62.5 MHz, CDCl3) 148.8 (quat.), 147.8 (quat.), 129.0
(quat.), 127.7 (quat.), 127.1 (CH), 123.9 (quat.), 118.5 (CH),
118.1 (quat.), 117.8 (quat.), 114.0 (CH), 113.1 (CH), 111.5
(quat.), 109.3 (CH),64.9 (CH2), 64.2 (CH2), 39.3 (CH2),
27.1 (CH2), 14.4 (CH3), 14.3 (CH3); nmax/cmK1 (KBr) 2975,
2914, 2867, 1613, 1603, 1534, 1505, 1472, 1445, 1396,
1360, 1344, 1284, 1250, 1217, 1198, 1170, 1080, 1056.
References and notes
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´
3. Nyerges, M.; Fejes, I.; Viranyi, A.; Groundwater, P. W.; To˜ke,
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3.3.13. Dimethyl 8,9-diethoxy-10b-(2-nitrophenyl)-
2,3,6,10b-tetrahydro-5H-oxazolo[2,3-a]isoquinoline-2,3-
5. Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull. Chem.
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dicarboxylate
(23).
6,7,-Diethoxy-3,4-dihydro-2-
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bromide (20a) (0.49 g, 1.0 mmol) was dissolved in methanol
(5 mL) and triethylamine (0.14 mL, 0.10 g, 1.0 mmol) was
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temperature. The solvent was removed in vacuo, the residue
was dissolved in dichloromethane (30 mL) and washed with
water (3!20 mL). The organic layer was dried over
magnesium sulphate and evaporated to give a mixture of
10,11-diethoxy-7,8-dihydroindazolo[3,2-a]isoquinoline-5-
oxide 22a and the title compound, which was separated by
column chromatography, eluting with hexane–ethyl acetate
(2:1) to give a white powder (0.10 g, 20%), mp 168–170 8C;
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´
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