Synthesis of stable azomethine ylides by the rearrangement of 1,3-dipolar cycloadducts of 3,4-dihydroisoquinoline-2-oxides with DMAD

Article abstract of DOI:10.1016/j.tet.2005.11.040

1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were prepared according to a one-pot procedure involving the reaction of 2-(3,4- dimethoxyphenyl)-ethylamine with aromatic aldehydes in TFA at reflux. The tetrahydroisoquinolines were treated with H

Full text of DOI:10.1016/j.tet.2005.11.040

Tetrahedron 62 (2006) 1345–1350
Synthesis of stable azomethine ylides by the rearrangement of
1,3-dipolar cycloadducts of 3,4-dihydroisoquinoline-2-oxides
with DMAD
*
Necdet Cos¸kun and Selen Tunc¸man
˘
Department of Chemistry, Uludag University, 16059 Bursa, Turkey
Received 7 August 2005; revised 31 October 2005; accepted 17 November 2005
Available online 9 December 2005
Abstract—1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were prepared according to a one-pot procedure involving the reaction of
2-(3,4-dimethoxyphenyl)-ethylamine with aromatic aldehydes in TFA at reflux. The tetrahydroisoquinolines were treated with H2O2–WO42K
in methanol at room temperature to give the corresponding 3,4-dihydroisoquinoline-2-oxides. Treatment of these cyclic nitrones with
DMAD in toluene at room temperature gave the corresponding isoxazolo[3,2-a]isoquinolines. These compounds were heated in toluene at
reflux to give the corresponding ylides in high yields (Method A). The effect of the substituents on the rate of the rearrangement of such
compounds prompted us to discuss a new mechanism involving consecutive C–C bond heterolysis and 1,3-sigmatropic shift. A one-pot
reaction involving the treatment of the nitrones with equimolar amounts of DMAD in refluxing toluene also gave the ylides (Method B). The
structures of the prepared compounds were elucidated by spectral means and elemental analyses.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and their adducts with DMAD. It is known that nitrones
react with alkynes to give generally unstable adducts or
those, which are stable can be subjected to rearrangements
under thermal conditions. Rearrangements of DMAD
adducts of some heterocyclic N-oxides has been reviewed.1a
4,5-Dihydroimidazole N-oxides undergo 1,3-dipolar cyclo-
addition with alkyne dipolarophiles and the cycloadducts
were shown to convert to the corresponding ene-1,1-
diamines.7 The thermal reaction of some 4-isoxazoline
derivatives leading to isoquinoline-fused pyrroles has been
investigated and it was found that the pathway of the
rearrangement to pyrroles is consistent with a route
involving an acylaziridine.8
The synthetic utility of the 1,3-dipolar cycloaddition
reaction is evident from the number and the scope of
targets that can be prepared by this chemistry. Nitrones are
the most useful through their ability to generate nitrogen-
and oxygen based functionality from the cycloadducts.1 The
cycloadducts of di- and triarylimidazoline 3-oxides2 with a
variety of dipolarophiles3 give bicyclic compounds with
potentially interesting biological activity.4 On the other
hand, they are a source of new heterocyclic compounds via
interesting ring-opening reactions.5
Previously, we reported the synthesis of stable adducts of
D3-imidazoline 3-oxides with DMAD3d,e and 3-phenylpro-
panoic acid alkyl esters.3f Thermally and base-induced ring-
opening reactions of these adducts were demonstrated. As a
continuation of our interest in the ring-opening reactions of
4-isoxazolines,3d,e we prepared 1-aryl-3,4-dihydroisoquino-
line-2-oxides from the oxidation of 1-aryl-1,2,3,4-tetrahy-
droisoquinolines under the conditions recently reported6
2. Results and discussion
We report herein the synthesis of 1-aryltetrahydroisoquino-
lines 2a–e and their oxidation with H2O2–WO24K in
methanol at room temperature to give cyclic nitrones 3a–e.
Isolated or in situ formed 8,9-dimethoxy-10b-aryl-6,10b-
dihydro-5H-isoxazolo[3,2-a]isoquinoline-1,2-dicarboxylic
acid dimethyl esters 4a–e were shown to undergo
substituent–dependent rearrangement to novel stable 3,4-
dihydroisoquinolinium N-ylides 5a–e (Scheme 1). The
results are presented in Table 1. A new mechanism involving
consecutive C–C bond heterolysis and 1,3-sigmatropic shift
is discussed.
Keywords: Isoquinoline; 1-Aryl-1,2,3,4-tetrahydroisoquinoline; THI;
Pictet–Spengler; Oxidation with H2O2–tungstate; 3,4-Dihydroisoquinoline-
2-oxide; Rearrangement; Isoxazoloisoquinoline; Stable azomethine ylide;
4-Isoxazoline rearrangement mechanism; Alkyne; DMAD; Dipolar
cycloaddition; Synthesis; Heterocycles.
*
Corresponding author. Tel.: C90 44292561308; fax: C90 4428022;
e-mail: coskun@uludag.edu.tr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.040

1346
N. Cos¸kun, S. Tunc¸man / Tetrahedron 62 (2006) 1345–1350
Table 1. Synthesis of compounds 2a–e, 3a–e and 4a–e
corresponding nitrones 3a–e in toluene in the presence of
DMAD (see Table 2, Method B). It was shown that
isoxazolo[3,2-a]isoquinolines convert at different rates
to the corresponding ylides 5a–e. The structure of stable
3,4-dihydroisoquinolinium N-ylides 5a–e was deduced
from their elemental analyses and spectral data. The
compounds are highly coloured and soluble in diluted
acids with loss of their colours. The extraction of the acidic
water solutions of ylides 5 with CHCl3 again affords the free
ylides 5. Our preliminary experiments show that they react,
as expected, with dipolarophiles such as phenyl isocyanate.
1–5
Ar
Yield (%)
2
3
4
a
b
c
d
e
Ph
70a
85
80
70
60
43b
50
40
69
45
95c
97
96
98
97
3,4 (MeO)2C6H3
3-NO2C6H4
4-ClC6H4
3,4 (OCH2O)C6H3
a The reaction times were 3, 5.5, 2.5, 5, 5.5 h for 2a,b,c,d,e, respectively.
b The reaction times were 5.5, 17.5, 23, 21, 19 for 3a,b,c,d,e, respectively.
c The reaction times were 18, 5.5, 24, 18, 15 for 4a,b,c,d,e, respectively.
O
O
O
O
O
ii
i
NH
NH2
N
O
O
Ar
Ar
2
1
3
v
O
O
iv
iii
O
O
N
O
O
N
O
O
Ar
Ar
O
5
O
4
MeO2C
CO2Me
Scheme 1. Reagents and conditions: (i) ArCHO; TFA; reflux; (ii) H2O2–Na2WO4; MeOH; rt; (iii) DMAD; toluene; rt; (iv) toluene; reflux; (v) DMAD; toluene;
reflux.
2-(3,4-Dimethoxyphenyl)-ethylamine 1 was reacted with an
equimolar amount of the corresponding aromatic aldehyde
in refluxing TFA to give in good yields the corresponding
1-aryl-1,2,3,4-tetrahydroisoquinolines 2a–e.
On the other hand their reactions with amines as
diethylamine lead to the formation of corresponding 3,4-
dihydroisoquinoline. The 13C NMR spectroscopic assign-
ments specifically for 5e are shown in Figure 1.
Compounds 2 were treated with H2O2–WO24K in methanol
according to a method we have recently reported6 to give
3,4-dihydroisoquinoline-2-oxides 3a–e. The products were
purified by chromatographic methods and were recrystal-
lized from ethanol–ether (1/3).
110.2(6.73)
167.7
O
O
Nitrones 3a–e were reacted with DMAD in toluene at room
temperature to give quantitatively the corresponding
isoxazolo[3,2-a]isoquinolines 4a–e. The products were
purified by recrystallization from ethanol in the cases of
4a,c,e and preparative TLC in the cases of 4b,d. The NMR
as well as the infra red spectral data for compounds 4a–e are
in good agreement with those we have previously reported
for similar adducts.3d–f Isolated 4a–e were refluxed in
toluene for the times specified in Table 2 (Method A) to give
heretofore unreported exclusively stable azomethine ylides
5a–e. The methods available for generating azomethine
ylides, were discussed in a resent review.9 The same
products resulted from the direct heating of the
N
O
O
95.0
O
O
O
115.5(7.39)
O
O
167.8
172.5
180.53
Figure 1. Some 1H and 13C NMR assignments for compound 5e.10
Electron donating groups on the aromatic ring at C-10b of
compounds 4 increase the rate of rearrangement to ylides 5
while electron-withdrawing groups (see Table 2 for the
reaction times) decrease it.
Table 2. Synthesis of N-ylides 5a–e
Yield
Reaction time (h)
Method Aa
Method Bb
A
B
Aziridines are generally assumed to be involved in the
rearrangements of 4-isoxazolines.9 A similar approach
could be assumed for the conversion of compounds 4 to 5
as depicted in Scheme 2. The homolysis of N–O bond in
compounds 4 could give diradicals A, which could cyclize
to the corresponding aziridines B. Thermal ring-opening of
aziridine part of B could give ylides 5 (see Scheme 2).
5a
5b
5c
5d
5e
93
100
82
91
87
75
74
95
71
96
11
1.5
7
13
4
12
1.5
8
14
4.2
a Yields are based on the starting 4.
b Yields based on the starting 3.

N. Cos¸kun, S. Tunc¸man / Tetrahedron 62 (2006) 1345–1350
1347
O
O
O
O
O
N
N
N
O
O
O
Ar
O
Ar
Ar
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
A
4
O
5
N
O
O
Ar
MeO2C
CO2Me
B
Scheme 2. Probable aziridine involving mechanism for the rearrangement of isoxazoloisoquinolines 4.
O
O
O
O
O
O
O
O
O
CO2Me
CO2Me
C
N
N
N
O
O
CO2Me
Ar
Ar
Ar
MeO2C
CO2Me
A
5
4
Scheme 3. Probable C–C bond heterolysis involving mechanism for the rearrangement of isoxazoloisoquinolines 4.
However, the pronounced substituent effects discussed
above do not support the acylaziridine intermediate in the
rearrangement of 4-isoxazolines. It is expected that the
substituents on the 10b-phenyl will affect neither homolysis
nor heterolysis of the N–O bond in the isoxazoline part of
compounds 4. This prompted us to consider an alternative
mechanism outlined in Scheme 3. Electron donating groups
on the aromatic ring of 4 probably favour the C-3, C-4 bond
heterolysis to give zwitter ions A stabilised by resonance,
which in turn undergo 1,3-sigmatropic rearrangement to
give ylides 5a–e. The electron donating groups on the
aromatic ring at C-10b could stabilise the forming
azomethine ylides by their CR effects.
Mercury Plus 400 MHz spectrometer. UV/vis spectra of
compounds 5a–e were recorded on a Shimadzu UV-2100
spectrophotometer. TLC controls were performed using
silica gel coated aluminium sheets. Chloroform, petroleum
ether, methanol and acetone (45:40:10:5) solvent mixture
was used as an eluent system. Visualisation was effected
with UV light. The elemental analyses were performed on a
EuroEA 3000 CHNS analyser.
3.1. Synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinolines 2.
General procedure
To a solution of 2-(3,4-dimethoxyphenyl)-ethylamine
(5 mmol, 0.9062 g) in TFA (3 mL) the corresponding
aldehyde (5 mmol) was added and the solution was refluxed
for the time specified in Table 1. The reaction mixture was
poured onto ice and basified with sodium hydroxide. The
mixture was extracted with chloroform (3!10 mL) and
the combined extracts were dried over anhydrous Na2SO4.
The organic solvent was evaporated under vacuum and the
residue was crystallized from ethanol.
Thus, 1-aryltetrahydroisoquinolines prepared according to
Pictet–Spengler procedure from 2-(3,4-dimethoxyphenyl)-
ethylamine and the corresponding aromatic aldehydes were
oxidized to nitrones 3 the 1,3-dipolar cycloaddition products
of which with DMAD were shown to afford previously
unknown and stable 3,4-dihydroisoquinolinium N-ylides
when heated in toluene. A plausible mechanism involving
consecutive C–C bond heterolysis and 1,3-sigmatropic shift
was discussed.
3.1.1. 6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline 2a. RfZ0.31; yield 0.943 g, 70%; mp
110–111 8C; IR (KBr) nNH 3328 cmK1. (400 MHz,
CDCl3): d 1.87 (1H, s), 2.64–2.71 (1H, m), 2.82–2.90
(1H, m), 2.94–2.99 (1H, m), 3.11–3.17 (1H, m), 3.55 (3H,
s), 3.79 (3H, s), 4.97 (1H, s), 6.17 (1H, s), 6.56 (1H, s),
7.17–7.26 (5H, m). 13C NMR (100 MHz, CDCl3): d 29.7;
42.3; 56.3; 56.4; 61.9; 111.4; 111.9; 127.8; 128.1; 128.8;
3. Experimental
Melting points were recorded on an Electrothermal Digital
melting point apparatus. Infrared spectra were recorded on a
Mattson 1000 FTIR. NMR spectra were recorded on a

1348
N. Cos¸kun, S. Tunc¸man / Tetrahedron 62 (2006) 1345–1350
129.3; 130.3; 145.3; 147.5; 148.1. Anal. Calcd for
C17H19NO2 (269.34) C, 75.81; H, 7.11; N, 5.20; Found C,
75.75; H, 7.20; N, 5.30.
and the solvent evaporated. The purification was performed
by preparative TLC using silica gel as adsorbent and
chloroform, petroleum ether, methanol and acetone
(45:40:10:5) solvent mixture as an eluent.
3.1.2. 1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline 2b. RfZ0.23; yield 85%; mp
88–89 8C; IR (KBr) nNH 3567 cmK1. (400 MHz, CDCl3):
d 1.83 (1H, s), 2.71–2.77 (1H, m), 2.92–2.99 (1H, m),
3.03–3.1 (1H, m), 3.22–3.28 (1H, m), 3.66 (3H, s), 3.84 (3H,
s), 3.88 (3H, s), 3.89 (3H, s), 4.99 (1H, s), 6.28 (1H, s), 6.63
(1H, s), 6.78–6.83 (3H, m). 13C NMR (100 MHz, CDCl3): d
29.3; 42.2; 55.8; 55.8; 55.9; 56.0; 61.5; 110.7; 110.9; 111.4;
111.8; 121.3; 127.6; 130.1; 137.3; 147.0; 147.6; 148.3;
149.0. Anal. Calcd for C19H23NO4 (329.39) C, 69.28; H,
7.04; N, 4.25; Found C, 69.35; H, 6.88; N, 4.23.
3.2.1. 6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline-2-oxide 3a. RfZ0.51; yield 0.061 g, 43%;
mp 156–157 8C; IR (KBr) nC]N 1590 cmK1; nN–O
1286 cmK1. (400 MHz, CDCl3): d 3.15 (2H, t, JZ7.6 Hz),
3.62 (3H, s), 3.91 (3H, s), 4.26 (2H, t, JZ7.6 Hz), 6.36 (1H,
s), 6.76 (1H, s), 7.43–7.49 (3H, m), 7.56 (2H, d, JZ
7.02 Hz). (100 MHz, CDCl3): d 27.9; 56.3; 56.4; 59.8;
110.5; 110.6; 123.6; 125.7; 128.5; 129.6; 130.4; 131.4;
142.3; 147.9; 149.6. Anal. Calcd for C17H17NO3 (283.32) C,
72.07; H, 6.05; N, 4.94; Found C, 72.05; H, 5.99; N, 4.97.
3.1.3. 6,7-Dimethoxy-1-(3-nitrophenyl)-1,2,3,4-tetra-
hydroisoquinoline 2c. RfZ0.15; yield 1.257 g, 80%; mp
3.2.2. 1-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline N-oxide 3b. RfZ0.28; yield
109–111 8C; IR (KBr) nNH 3312 and 3256 cmK1
.
0.086 g, 50%; mp 165–166 8C; IR (KBr) nC]N 1590 cmK1
;
(400 MHz, CDCl3): d 1.77 (1H, s), 2.73–2.79 (1H, m),
2.91–2.98 (1H, m), 3.04–3.10 (1H, m), 3.14–3.20 (1H, m),
3.64 (3H, s), 3.89 (3H, s), 5.16 (1H, s), 6.17 (1H, s), 6.66
(1H, s), 7.49 (1H, t, JZ7.6 Hz), 7.61 (1H, d, JZ7.6 Hz),
8.12–8.17 (2H, m). 13C NMR (100 MHz, CDCl3): d 29.1;
41.6; 55.8; 55.9; 60.7; 110.7; 111.8; 122.5; 123.8; 127.9;
128.2; 129.3; 135.2; 147.2; 147.3; 148.1; 148.4. Anal. Calcd
for C17H18N2O4 (314.34) C, 64.96; H, 5.77; N, 8.91; Found
C, 64.94; H, 5.75; N, 9.02.
nN–O 1283 cmK1. (400 MHz, CDCl3): d 3.14 (2H, t,
JZ7.2 Hz), 3.65 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 3.93
(3H, s), 4.24 (2H, t, JZ7.2 Hz), 6.45 (1H, s), 6.75 (1H, s), 6.95
(1H, d, JZ8.4 Hz), 7.13 (1H, d, JZ8.4 Hz) 7.20 (1H, s). 13C
NMR (100 MHz, CDCl3): d 27.9; 56.1; 56.2; 56.3; 56.4; 59.8;
110.6; 110.8; 111.8; 113.5; 123.5; 123.6; 123.7; 125.9; 142.3;
147.9; 148.7; 149.6; 149.9. Anal. Calcd for C19H21NO5
(343.37) C, 66.46; H, 6.16; N, 4.08; Found C, 66.40; H, 6.34;
N, 4.06.
3.1.4. 1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline 2d. RfZ0.54; yield 1.063 g, 70%; mp
103–105 8C; IR (KBr) nNH 3242 cmK1. (400 MHz, CDCl3):
d 1.81 (1H, s), 2.71–2.77 (1H, m), 2.88–2.96 (1H, m),
3.01–3.07 (1H, m), 3.16–3.22 (1H, m), 3.64 (3H, s), 3.87
(3H, s), 5.02 (1H, s), 6.20 (1H, s), 6.63 (1H, s), 7.20 (2H, d,
JZ8.0 Hz), 7.29 (2H, d, JZ8.0 Hz). 13C NMR (100 MHz,
CDCl3): d 29.2; 41.8; 55.8; 55.9; 60.8; 110.8; 111.5; 127.7;
128.5; 129.3; 130.3; 133.1; 143.4; 147.1; 147.8. Anal. Calcd
for C17H18ClNO2 (303.78) C, 67.21; H, 5.97; N, 4.61;
Found C, 67.10; H, 5.97; N, 4.75.
3.2.3. 6,7-Dimethoxy-1-(3-nitrophenyl)-1,2,3,4-tetra-
hydroisoquinoline N-oxide 3c. RfZ0.54; yield 0.066 g,
40%; mp 172–173 8C; IR (KBr) nC]N 1584 cmK1; nN–O
1284 cmK1. (400 MHz, CDCl3): d 3.20 (2H, t, JZ7.6 Hz),
3.65 (3H, s), 3.95 (3H, s), 4.29 (2H, t, JZ7.6 Hz), 6.31 (1H,
s), 6.81 (1H, s), 7.69 (1H, t, JZ8.0 Hz), 8.01 (1H, d, JZ
8.0 Hz), 8.30 (1H, d, JZ8.0 Hz), 8.51 (1H, s). 13C NMR
(100 MHz, CDCl3): d 27.6; 56.2; 56.3; 59.9; 109.8; 110.8;
122.2; 124.2; 125.6; 125.7; 129.3; 132.8; 136.6; 139.7;
148.0; 148.1; 149.9. Anal. Calcd for C17H16N2O5 (328.32)
C, 62.19; H, 4.91; N, 8.53; Found C, 62.10; H, 4.95; N, 8.66.
3.1.5. 1-Benzo[1,3]dioxol-5-yl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline 2e. RfZ0.37; yield 0.940 g, 60%;
mp 133–134 8C; IR (KBr) nNH 3252 cmK1. (400 MHz,
CDCl3): d 1.76 (1H, s), 2.70–2.75 (1H, m), 2.88–2.95 (1H,
m), 3.0–3.06 (1H, m), 3.19–3.24 (1H, m), 3.67 (3H, s), 3.87
(3H, s), 4.97 (1H, s), 5.94 (2H, s), 6.28 (1H, s), 6.62 (1H, s),
6.71–6.77 (3H, m). 13C NMR (100 MHz, CDCl3): d 29.3;
41.9; 55.8; 55.9; 61.2; 101.0; 107.9; 109.2; 110.9; 111.42;
122.2; 127.7; 129.9; 139.1; 146.8; 147.1; 147.7; 147.7.
Anal. Calcd for C18H19NO4 (313.35) C, 68.99; H, 6.11; N,
4.47; Found C, 68.90; H, 5.99; N, 4.55.
3.2.4. 1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline N-oxide 3d. RfZ0.56; yield 0.110 g,
69%; mp 216–217 8C; IR (KBr) nC]N 1595 cmK1; nN–O
1284 cmK1. (400 MHz, CDCl3): d 3.15 (2H, t, JZ7.6 Hz),
3.65 (3H, s), 3.92 (3H, s), 4.25 (2H, t, JZ7.6 Hz), 6.35 (1H,
s), 6.76 (1H, s), 7.45 (2H, d, JZ8.4 Hz), 7.57 (2H, d, JZ
8.4 Hz). 13C NMR (100 MHz, CDCl3): d 27.9; 56.3; 56.4;
59.9; 110.3; 110.7; 123.1; 125.8; 128.8; 129.7; 132.0; 135.5;
141.3; 148.1; 149.7. Anal. Calcd for C17H16ClNO3 (317.77)
C, 64.26; H, 5.08; N, 4.41; Found C, 64.40; H, 5.03; N, 4.42.
3.2.5. 1-Benzo[1,3]dioxol-5-yl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline N-oxide 3e. RfZ0.56; yield
3.2. Synthesis of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline-2-oxides 3a–e. General procedure
0.074 g, 45%; mp 169–170 8C; IR (KBr) nC]N 1590 cmK1
;
nN–O 1288 cmK1. (400 MHz, CDCl3): d 3.13 (2H, t, JZ
8.0 Hz), 3.68 (3H, s), 3.91 (3H, s), 4.23 (2H, t, JZ8 Hz), 6.02
(2H, s), 6.44 (1H, s), 6.74 (1H, s), 6.89 (1H, d, JZ8.0 Hz),
6.98 (1H, d, JZ8.0 Hz), 7.16 (1H, s). 13C NMR (100 MHz,
CDCl3): d 27.9; 56.3; 56.4; 59.8; 101.6; 108.4; 110.5; 110.7;
111.0; 123.6; 123.7; 124.7; 125.8; 141.9; 147.7; 147.9; 148.6;
149.6. Anal. Calcd for C18H17NO5 (327.33) C, 66.05; H,
5.23; N, 4.28; Found C, 66.00; H, 5.20; N, 4.08.
To a solution of tetrahydroisoquinoline 2 (0.5 mmol) in
methanol (10 mL) H2O2 (35%, 2 mmol) was added in the
presence of Na2WO4$H2O (0.025 mmol, 8.3 mg). The
reaction mixture was stirred at room temperature for the
specified time. The solvent was evaporated and water
(15 mL) was added to the residue and extracted with
chloroform (3!10 mL). The combined extracts were dried

N. Cos¸kun, S. Tunc¸man / Tetrahedron 62 (2006) 1345–1350
1349
3.3. Synthesis of isoxazolo[3,2-a]isoquinolines 4a–e.
General procedure
153.6; 159.7; 163.5. Anal. Calcd for C23H22ClNO7 (459.88)
C, 60.07; H, 4.82; N, 3.05; Found C, 60.10; H, 4.83; N, 3.10.
To a solution of nitrone 3 (0.15 mmol) in toluene (10 mL)
DMAD (0.225 mmol, 0.032 g) was added and the reaction
mixture stirred for the specified time. The solvent was
evaporated under vacuum and the residue crystallized from
ethanol in the cases of 4a,c,e. Compounds 4b,d were
purified by preparative TLC.
3.3.5.
10b-Benzo[1,3]dioxol-5-yl-8,9-dimethoxy-
6,10b-dihydro-5H-isoxazolo[3, 2-a]isoquinoline-1,2-
dicarboxylic acid dimethyl ester 4e. RfZ0.86; yield
0.068 g, 97%; mp 122–123 8C; IR (KBr) nC]O 1749;
1716 cmK1; nC]C 1637 cmK1. (400 MHz, CDCl3): d 2.61–
2.67 (1H, m), 3.12–3.18 (1H, m), 3.25–3.32 (1H, m), 3.66–
3.77 (1H, m), 3.67 (3H, s), 3.71 (3H, s), 3.84 (3H, s), 3.87
(3H, s), 5.93 (2H, s), 6.60 (1H, s), 6.75 (1H, d, JZ8.4 Hz),
6.78 (1H, d, JZ8.4 Hz), 6.88 (1H, s) 7.02 (1H, s). 13C NMR
(100 MHz, CDCl3): d 23.7; 46.9; 52.2; 53.3: 56.0; 56.1;
77.1; 101.5; 107.8; 109.7; 110.8; 112.2; 114.9; 122.9; 126.6;
126.7; 136.8; 147.5; 147.7; 147.8; 148.5; 153.4; 159.8;
163.6. Anal. Calcd for C24H23NO9 (469.44) C, 61.40; H,
4.94; N, 2.98; Found C, 61.50; H, 5.10; N, 3.10.
3.3.1. 8,9-Dimethoxy-10b-phenyl-6,10b-dihydro-5H-iso-
xazolo[3,2-a]isoquinoline-1,2-dicarboxylic acid dimethyl
ester 4a. RfZ0.22; yield 0.061 g, 95%; mp 124–125 8C; IR
(KBr) nC]O 1758; 1712 cmK1; nC]C 1626 cmK1
.
(400 MHz, CDCl3): d 2.64–2.70 (1H, m), 3.14–3.22 (1H,
m), 3.26–3.33 (1H, m), 3.64–3.72 (1H, m), 3.66 (3H, s),
3.68 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 6.63 (1H, s), 6.99
(1H, s), 7.27–7.37 (5H, m). 13C NMR (100 MHz, CDCl3): d
23.8; 47.1; 52.2; 53.4: 56.0; 56.1; 77.3; 110.8; 112.3; 114.9;
126.6; 126.8; 128.2; 128.3; 129.1; 142.8; 147.7; 148.5;
153.5; 159.8; 163.6. Anal. Calcd for C23H23NO7 (425.43) C,
64.93; H, 5.45; N, 3.29; Found C, 65.10; H, 5.55; N, 3.40.
3.4. Synthesis of azomethine ylides 5a–e. Method A;
General procedure
A solution of compound 4 (0.1 mmol) in toluene (5 mL) was
refluxed for the specified time (see Table 2). The solvent
was evaporated under vacuum and the residue subjected to a
silica gel coated TLC plate and eluted with chloroform,
petroleum ether, methanol and acetone (45:40:10:5) solvent
mixture. The isolated product was crystallized from ethanol
ether mixture (1:5).
3.3.2.
10b-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-
6,10b-dihydro-5H-isoxazolo[3,2-a]isoquinoline-1,2-
dicarboxylic acid dimethyl ester 4b. RfZ0.89; yield
0.071 g, 97%; oil; IR (KBr) nC]O 1758; 1712 cmK1
;
nC]C 1626 cmK1. (400 MHz, CDCl3): d 2.60–2.70 (1H,
m), 3.15–3.22 (1H, m), 3.24–3.32 (1H, m), 3.64–3.72 (1H,
m), 3.67 (3H, s), 3.71 (3H, s), 3.79 (3H, s), 3.85 (3H, s), 3.86
(3H, s), 3.89 (3H, s), 6.62 (1H, s), 6.76 (1H, d, JZ8.4 Hz),
6.82 (1H, dd, JZ8.4, 2.0 Hz), 6.96 (1H, d, JZ2.0 Hz), 7.04
(1H, s). 13C NMR (100 MHz, CDCl3): d 23.7; 46.9; 52.3;
53.3: 56.0; 56.1; 77.0; 110.4; 110.8; 112.3; 112.4; 115.7;
121.9; 126.6; 126.7; 135.0; 147.6; 148.4; 148.7; 149.0;
152.9; 159.7; 163.8. Anal. Calcd for C25H27NO9 (485.48) C,
61.85; H, 5.61; N, 2.89; Found C, 61.80; H, 5.63; N, 2.89.
3.5. Synthesis of azomethine ylides 5a–e. Method B;
General procedure
To a solution of nitrone 3 (0.2 mmol) dissolved in toluene
(10 mL) DMAD was added and the mixture refluxed for the
specified time. The solvent was evaporated and the mixture
was subjected on a preparative TLC plate coated with silica
gel. The isolated coloured compounds were crystallized
from ethanol ether mixture (1:5).
3.3.3. 8,9-Dimethoxy-10b-(3-nitrophenyl)-6,10b-dihydro-
5H-isoxazolo[3,2-a]isoquinoline-1,2-dicarboxylic acid
dimethyl ester 4c. RfZ0.79; yield 0.068 g, 96%; mp
123–124 8C; IR (KBr) nC]O 1758; 1719 cmK1; nC]C
1644 cmK1. (400 MHz, CDCl3): d 2.72–2.77 (1H, m),
3.15–3.24 (1H, m), 3.25–3.31 (1H, m), 3.64–3.72 (1H, m),
3.67 (3H, s), 3.70 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 6.65
(1H, s), 6.89 (1H, s) 7.50 (1H, t, JZ8.2 Hz), 7.8 (1H, d, JZ
8.2 Hz), 8.16 (1H, d, JZ8.2 Hz), 8.25 (1H, s). 13C NMR
(100 MHz, CDCl3): d 23.9; 47.3; 52.5; 53.5: 56.1; 77.2;
111.2; 111.6; 114.1; 123.3; 124.1; 125.2; 126.8; 129.3;
135.2; 145.5; 148.1; 148.3; 148.9; 153.9; 159.5; 163.4.
Anal. Calcd for C23H22N2O9 (470.43) C, 58.72; H, 4.71; N,
5.95; Found C, 58.80; H, 4.90; N, 6.10.
3.5.1. Azomethine ylide 5a. RfZ0.5; yield; Method A,
0.040 g, 93%; Method B, 0.064 g, 75%; light red coloured
crystals; mp 228–229 8C; IR (KBr) nC]O 1726; 1664 cmK1
.
UV/vis lmax CHCl3 nm: 256.5, 313.5, 361.5, 455.1;
(400 MHz, CDCl3): d 3.25 (2H, t, JZ7.4 Hz), 3.52 (3H,
s), 3.63 (3H, s), 3.69 (3H, s), 4.16 (3H, s), 4.01–4.21 (1H,
m), 4.25–4.30 (1H, m), 6.57 (1H, s), 6.86 (1H, s), 7.44–7.53
(5H, m). (100 MHz, CDCl3): d 26.9; 50.8; 52.0; 54.3; 56.3;
56.8; 95.5; 110.5; 115.5; 121.0; 128.2; 128.5; 131.8; 131.9;
134.7; 148.3; 156.1; 164.3; 168.6; 171.1; 174.9. Anal. Calcd
for C23H23NO7 (425.43) C, 64.93; H, 5.45; N, 3.29; Found
C, 64.98; H, 5.60; N, 3.40.
3.5.2. Azomethine ylide 5b. RfZ0.47; yield; Method A,
0.049 g, 100%; Method B, 0.072 g, 74%; dark orange
3.3.4. 10b-(4-Chlorophenyl)-8,9-dimethoxy-6,10b-di-
hydro-5H-isoxazolo[3,2-a]isoquinoline-1,2-dicarboxylic
acid dimethyl ester 4d. RfZ0.74; yield 0.068 g, 98%; oil;
crystals; mp 128–129 8C; IR (KBr) nC]O 1725; 1665 cmK1
.
UV/vis lmax CHCl3 nm: 255.5, 391.5; (400 MHz, CDCl3): d
3.13 (2H, t, JZ6.4 Hz), 3.37 (3H, s), 3.71 (3H, s), 3.87 (6H,
s), 3.88 (3H, s), 3.98 (3H, s), 4.16 (2H, t, JZ6.4 Hz), 6.76
(1H, s), 6.86 (1H, d, JZ9.2 Hz), 6.91 (1H, d, JZ9.2 Hz),
6.98 (1H, s), 7.45 (1H, s). (100 MHz, CDCl3): d 26.6; 50.5;
51.8; 53.1; 56.0; 56.1; 56.2; 56.4; 96.1; 107.5; 109.9; 110.8;
115.3; 115.6; 121.9; 132.2; 139.1; 148.1; 148.6; 148.9;
154.8; 167.2; 167.6; 172.1; 180.3. Anal. Calcd for
IR (KBr) nC]O 1755; 1709 cmK1; nC]C 1638 cmK1
.
(400 MHz, CDCl3): d 2.63–2.0 (1H, m), 3.12–3.20 (1H,
m), 3.23–3.30 (1H, m), 3.64–3.72 (1H, m), 3.67 (3H, s),
3.69 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 6.62 (1H, s), 6.95
(1H, s), 7.28–7.32 (4H, m). 13C NMR (100 MHz, CDCl3): d
23.8; 47.2; 52.3; 53.4; 56.0; 56.1; 76.8; 110.9; 112.1; 114.6;
126.2; 126.8; 128.5; 130.5; 134.2; 141.5; 147.9; 148.7;

1350
N. Cos¸kun, S. Tunc¸man / Tetrahedron 62 (2006) 1345–1350
C25H27NO9 (485.48) C, 61.85; H, 5.61; N, 2.89; Found C,
61.90; H, 5.75; N, 3.00.
Acknowledgements
˘
Uludag University Research Fund and Turkish State
Planning Organization (DPT) are gratefully acknowledged
for the financial support (Project No 2001-2)
3.5.3. Azomethine ylide 5c. RfZ0.59; yield; Method A,
0.039 g, 82%; Method B, 0.090 g, 95%; dark red crystals;
mp 213–214 8C; IR (KBr) nC]O 1735; 1688 cmK1. UV/vis
lmax CHCl3 nm: 228.0, 233.0, 259.0, 315.5, 372.0, 469.0;
(400 MHz, CDCl3): d 3.16–3.24 (1H, m), 3.31–3.40 (1H,
m), 3.59 (3H, s), 3.63 (3H, s), 3.65 (3H, s), 4.03 (3H, s),
4.15–4.22 (1H, m), 4.24–4.32 (1H, m), 6.49 (1H, s), 6.89
(1H, s), 7.65 (1H, t, JZ8.0 Hz), 7.88 (1H, d, JZ8.0 Hz),
8.32 (1H, s), 8.37 (1H, d, JZ8.0 Hz). (100 MHz, CDCl3): d
26.8; 51.1; 52.1; 54.3; 56.5; 56.9; 92.1; 110.9; 114.5; 119.9;
123.9; 126.2; 129.4; 133.4; 134.3; 135.1; 147.6; 148.7;
156.9; 164.3; 168.1; 170.3; 171.5. Anal. Calcd for
C23H22N2O9 (470.43) C, 58.72; H, 4.71; N, 5.95; Found
C, 58.58; H, 4.80; N, 6.10.
References and notes
1. (a) Black, D. St. C.; Crozier, R. F.; Davis, V. C. Synthesis
1975, 205–221. (b) Padwa, A. Angew. Chem., Int. Ed. Engl.
1976, 15, 123–180. (c) Oppolzer, W. Angew. Chem., Int. Ed.
Engl. 1977, 16, 10–23. (d) Dell, C. P. J. Chem. Soc., Perkin
Trans. 1 1998, 3873–3905. (e) Martin, J. N.; Jones, R. C. F.
Synthetic Applications of 1,3-Dipolar Cycloaddition Chem-
istry toward Heterocycles and Natural Products. In Nitrones;
The Chemistry of Heterocyclic Compounds; Chichester: UK,
2002; Vol. 59, pp 1–81.
2. (a) Cos¸kun, N.; Su¨mengen, D. Synth. Commun. 1993, 23,
1699–1706. (b) Cos¸kun, N.; Asutay, O. Chim. Acta Turc. 1997,
25, 69. (c) Cos¸kun, N.; Asutay, O. Chim. Acta Turc. 1999, 27,
17–23.
3.5.4. Azomethine ylide 5d. RfZ0.67; yield; Method A,
0.042 g, 91%; Method B, 0.066 g, 71%; dark red crystals;
mp 178–179 8C; IR (KBr) nC]O 1727; 1665 cmK1. UV/vis
lmax CHCl3 nm: 258.0, 262.0, 366.5, 461.5; (400 MHz,
CDCl3): d 3.22–3.29 (2H, m), 3.54 (3H, s), 3.65 (3H, s), 3.71
(3H, s), 4.01 (3H, s), 4.17–4.25 (2H, m), 6.53 (1H, s),
6.86 (1H, s), 7.42 (4H, br s). 13C NMR (100 MHz, CDCl3): d
26.8; 51.0; 52.1; 54.4; 56.4; 56.9; 96.3; 110.6; 115.1;
120.6; 128.6; 130.1; 130.3; 134.9; 138.1; 148.4; 156.4;
164.3; 168.4; 170.9; 173.7. Anal. Calcd for C23H22ClNO7
(459.88) C, 60.07; H, 4.82; N, 3.05; Found C, 60.15; H,
5.01; N, 3.30.
3. (a) Cos¸kun, N. Tetrahedron Lett. 1997, 38, 2299–2302. (b)
Cos¸kun, N. Tetrahedron1997, 53, 13873–13882. (c) Cos¸kun, N.;
Ay, M. Heterocycles 1998, 48, 537–544. (d) Cos¸kun, N.;
¨ ¨
Tat, F. T.; Gu¨ven, O.O.; Ulku¨, D.; Arıcı, C. Tetrahedron Lett.
¨
¨ ¨
2000, 41, 5407–5409. (e) Cos¸kun, N.; Tat, F. T.; Gu¨ven, O.O.
Tetrahedron 2001, 57, 3413–3417. (f) Cos¸kun, N.; Yılmaz, B.
Synth. Commun. 2004, 34, 1617–1623. (g) Cos¸kun, N.; Tat, F. T.;
¨ ¨
Gu¨ven, O.O. Tetrahedron: Asymmetry 2001, 12, 1463–1467.
4. A series of tetrahydroimidazo compounds including tetrahy-
droimidazooxadiazolones were tested for their anticancer
activity and found to be quite active at 10K5 molar
concentrations.
3.5.5. Azomethine ylide 5e. RfZ0.59; yield; Method A,
0.41 g, 87%; Method B, 0.090 g, 96%; dark red crystals; mp
123–124 8C; IR (KBr) nC]O 1734; 1718 cmK1. UV/vis lmax
CHCl3 nm: 255.0, 297.5, 386.0; (400 MHz, CDCl3): d 3.08
(2H, t, JZ7.0 Hz), 3.40 (3H, s), 3.70 (3H, s), 3.84 (3H, s),
3.96 (3H, s), 4.08 (2H, t, JZ7.0 Hz), 5.98 (2H, s), 6.73 (1H,
s), 6.78 (1H, d, JZ8.4 Hz), 6.84 (1H, d, JZ8.4 Hz), 6.86
(1H, s), 7.40 (1H, s). 13C NMR (100 MHz, CDCl3): d 26.9;
50.9; 52.1; 53.3; 56.43; 56.6; 95.0; 102.1; 105.5; 108.4;
110.2; 115.5; 117.7; 122.2; 132.7; 140.7; 147.3; 148.1;
148.3; 155.0; 167.7; 167.8; 172.5; 180.5. Anal. Calcd for
C24H23NO9 (469.44) C, 61.40; H, 4.94; N, 2.98; Found C,
61.50; H, 5.10; N, 3.10.
5. (a)Cos¸kun, N.Turk. J.Chem. 2001, 25, 267–272. (b)Cos¸kun, N.;
Tat, F. T. Phosphorus Sulfur 2003, 178, 881–886.
6. Cos¸kun, N.; Parlar, A. Synth. Commun. 2005, 35, 2445–2451.
7. Jones,R.C.F.;Martin,J.N.;Smith,P.;Gelbrich, T.;Light,M. E.;
Hursthouse, M. B. Chem. Commun. 2000, 1949–1950.
8. Zhao, B. X.; Yu, Y.; Eguchi, S. Tetrahedron 1996, 52,
12049–12060.
9. Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7,
1105–1150.
10. The assignments shown in Figure 1 were made on the bases of
2D experiments as COSY, DEPT, HMQC, HMBC and
detailed NOESY1D.