Synthesis of 5-substituted pyrrolo[1,2-b]pyridazines with antioxidant properties

Article abstract of DOI:10.1002/1521-4184(200101)334:1<21::AID-ARDP21>3.0.CO;2-W

5-Substituted pyrrolo[1,2-b]pyridazines have been prepared by cyclisation of pyridazine with diphenylcyclopropenone followed by further functionalisations in the pyrrolo[1,2-b]pyridazine 5-position. Several compound exhibit profound inhibition of lipid pe

Full text of DOI:10.1002/1521-4184(200101)334:1<21::AID-ARDP21>3.0.CO;2-W

Pyrrolo[1,2-b]pyridazines as Antioxidants
21
Synthesis of 5-Substituted Pyrrolo[1,2-b]pyridazines with
Antioxidant Properties
a)
a)
a)
b)
b)
b)
c)
Ole Benny Østby , Lise-Lotte Gundersen , Frode Rise , Øyvind Antonsen , Kjetil Fosnes , Vibeke Larsen , Aalt Bast ,
c)
c)
Ilse Custers , and Guido R. M. M. Haenen
a) Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, N-0315 Oslo, Norway
b) Hedmark College, Department of Agriculture and Natural Science, N-2322 Ridabu, Norway
c) University Maastricht, Faculty of Medicine, Dept. of Pharmacology and Toxicology, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Key Words: Pyrrolo[1,2-b]pyridazines; antioxidants; lipid peroxidation
Summary
5-Substituted pyrrolo[1,2-b]pyridazines have been prepared by
cyclisation of pyridazine with diphenylcyclopropenone followed
by further functionalisations in the pyrrolo[1,2-b]pyridazine 5-po-
sition. Several compound exhibit profound inhibition of lipid
peroxidation in vitro. Lipid peroxidation of boiled rat liver mi-
crosomes was induced by ascorbic acid/FeSO4 and the peroxida-
Scheme 1
tion was determined by measuring the thiobarbituric acid reactive
material.
The triflate 11 was available when the pyrrolo[1,2-b]pyri-
dazin-5-ol 3 was reacted with triflic anhydride in the presence
of 4-(N,N-dimethylamino)pyridine (DMAP) at low tempera-
Introduction
tures. Sodium hydride was a much less efficient base in this
reaction, and the use of ethereal solvents (THF, DME, or
Free radical mediated processes have been implicated in
diethyl ether) instead of dichloromethane resulted in exten-
numerous serious pathological conditions and development
[1]
sive polymerisation. Reaction of the pyrrolo[1,2-b]pyridazin-
of novel antioxidants may therefor lead to new drugs . We
5-ol 3 with tosyl chloride in the presence of DMAP and
triethylamine gave the tosylate 12. It has been reported that
5-chloropyrrolo[1,2-b]pyridazine 15* is formed when pyr-
rolo[1,2-b]pyridazin-5-ol 3 is reacted with phosphorus oxy-
have recently reported derivatives of 1-indolizinols which are
strong inhibitors of lipid peroxidation in vitro, and hence may
have a therapeutic potential as antioxidants / radical scaven-
[2,3]
gers
. Indolizinyl esters, ethers, carbonates, and car-
[5]
[2]
[3]
chloride , but this procedure gave, in our hands, only the
bamates
as well as sulfonates
were active, and we
phosphate 14 after work-up using ethanol. Work-up without
nucleophilic solvents gave compound 13 (Scheme 2).
proposed that the compounds were not cleaved to indolizinols
but that they inhibited peroxidation themselves by an electron
donation mechanism . An extension of this work is the
[2]
study of azaindolizines, and in this paper we report synthesis
and antioxidant properties of 5-substituted pyrrolo[1,2-
b]pyridazines (1-substituted 5-azaindolizines).
Results and Discussion
We chose to prepare the pyrrolo[1,2-b]pyridazines 4–12 by
cyclization of pyridazine 1 with diphenylcyclopropenone 2
[4]
to give the pyrrolo[1,2-b]pyridazin-5-ol 3
followed by
further functionalisation of the hydroxy group (Scheme 1,
Table 1). The esters 4–6, ethers 7 and 8, carbonate 9, and
Scheme 2
carbamate 10 were prepared essentially as reported before for
[2,4]
———
similar structures
; treatment of the intermediate hydroxy
*
Lown and Matsumoto actually reported the synthesis of 5-chloropyr-
compound 3 with acid chloride or anhydride, alkyl halide,
chloroformate, or isocyanate in the presence of a suitable
base.
rolo[1,2-b]pyridazin 16 (see Scheme 2) from pyrrolo[1,2-b]pyridazin-5-
ol [5], but later Weidner et al. showed that the hydroxy group in the starting
material must have been situated in the indolizine 1-position [4]
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0101/0021 $17.50 +.50/0

22
Gundersen and co-workers
Table 1. Synthesis and antioxidant properties of pyrrolo[1,2-b]pyridazine derivatives.
a IC50 (mM) is the concentration which causes 50% inhibition of lipid peroxidation after 30 min. The values are given as
the mean of 3 separate experiments and the accuracy of the data is within 25%.
The ability of the indolizine derivatives to inhibit lipid must be considered as potent antioxidants. In the same assay,
peroxidation in vitro was examined and the results are sum-
the IC value for rutin was found to be 10 µM and cyanidine
50
marised in Table 1. The testing was performed as we have
had an IC value of 27 µM. The acetate 4 and triflate 11 were
50
[2]
described before . Lipid peroxidation of boiled rat liver
extremely active. Comparison of the esters 4, 5, and 6, as well
as the sulfonates 11 and 12 indicate that increased lipo-
philisity, lowers the activity. The same trend is seen before
microsomes was induced by ascorbic acid/FeSO and the
4
peroxidation was determined by measuring the thiobarbituric
acid reactive material. Except for the phosphate 14, all com-
when benzoindolizines were much less active than indol-
[2]
pounds examined had IC values well below 100 µM and izines
.
50
Arch. Pharm. Pharm. Med. Chem. 334, 21–24 (2001)

Pyrrolo[1,2-b]pyridazines as Antioxidants
23
Yield 45%; mp 210–214 °C; 1H NMR (CDCl3, 200 MHz) δ 1.67 (m, 4H,
CH2), 2.53 (m, 4H, CH2), 6.51 (dd, J = 9.0 and 4.4 Hz, 2H), 7.25–7.50 (m,
20H, Ph), 7.59 (dd, J = 9.0 and 1.8 Hz, 2H) and 8.00 (dd, J = 4.4 and 1.8 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ 26.3, 35.6, 111.6, 119.3, 121.6, 126.0,
126.1, 126.5, 129.0, 129.7, 130.2, 130.3, 131.2, 132.7, 134.2, 144.1 and
174.0; MS (EI) 682 (12%, M+), 368 (4), 287 (49), 286 (100), 285 (30), 271
(23), 270 (49), 269 (23) and 178 (33).
Acknowledgements
The purchase of the 200, 300, and 500 MHz Bruker Spectrospin Avance
instruments was made possible through financial support from The Research
Council of Norway (NFR). The assistance in the lipid peroxidation experi-
ments of Mrs. D. H. Veening-Griffioen, Mr. N. Cuiper and Mr. M. A. J. G.
Fischer is gratefully acknowledged
5-Methoxy -6,7-diphenylpyrrolo[1,2-b]pyridazine 7
Experimental
A mixture of diphenylcyclopropenone (464 mg, 2.25 mmol) and pyrid-
azine (0.163 ml, 2.25 mmol) in dry 1,2-dichloroethane (25 ml) was refluxed
under N2-atm. for 14 h and evaporated in vacuo. The residue was dissolved
in dry THF (50 ml). Sodium hydride (119 mg, 4.95 mmol) was added and
the mixture was stirred at ambient temperature for 1 h before iodomethane
(703 mg, 4.95 mmol) was added dropwise. After further stirring for for 26 h,
the reaction was quenched by the addition of saturated aqueous NH4Cl-so-
lution (1 ml). The mixture was extracted with EtOAc (50 ml) and the organic
extract was washed with water (2×50 ml), dried (MgSO4) and evaporated in
vacuo. The product was purified by flash chromatography eluting with
EtOAc-hexane (1:19).
1
The H NMR spectra were recorded at 500 MHz with a Bruker Avance
DRX 500 instrument, at 300 MHz with a Bruker Avance DPX 300 instrument
or at 200 MHz with a Bruker Avance DPX 200 or a Varian Gemini 200
instrument and the 13C NMR spectra were recorded at 125, 75 or 50 MHz
using the above mentioned spectrometers. Mass spectra were recorded at 70
eV ionising voltage with a VG Prospec instrument, and are presented as m/z
(% rel. int.). Methane was used for chemical ionisation (CI). Elemental
analyses were performed by Ilse Beetz Mikroanalytisches Laboratorium,
Kronach, Germany. Melting points are uncorrected. Silica gel for flash
chromatography was purchased from Merck, Darmstadt, Germany (Merck
No. 9385). THF was distilled from Na/benzophenone. 1,2-Dichloroethane
and triethylamine were distilled from calcium hydride. All other reagents
were commercially available and used as received. The lipid peroxidation
Yield 54%; mp 111–112 °C; 1H NMR (acetone-d6, 500 MHz) δ 3.73 (s,
3H, OCH3), 6.51 (dd, J = 9.0 and 4.4 Hz, 1H, H-3), 7.2–7.4 (m, 6H, Ph), 7.4
(m, 2H, Ph), 7.4–7.5 (m, 2H, Ph) and 7.9–8.0 (m, 2H, H-2 and H-4); 13C
NMR (acetone-d6, 125MHz) δ 62.7, 109.1, 117.1, 119.0, 123.7, 125.7, 127.4,
128.0, 128.7, 128.9, 131.1, 131.5, 134.0, 136.3, and 149.2; MS (EI) 300
(70%, M+), 285 (100), 255 (2), 178 (5), 176 (5), 143 (3), 134 (4), 128 (4),
107 (17), and 79 (14); HRMS: Calcd. for C20H16N2O 300.1263, found
300.1265.
inhibition tests were performed as previously reported [2]
.
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl Acetate 4
Synthesis see ref. [4]. Yield 55%; 1H NMR (CDCl3, 300 MHz) δ 2.25 (s,
3H, CH3), 6.50 (dd, J = 9.1 and 4.4 Hz, 1H), 7.18–7.35 (m, 8H, Ph),
7.43–7.50 (m, 2H, Ph), 7.59 (dd, J = 9.1 and 1.8 Hz, 1H) and 7.97 (dd, J = 4.4
and 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.6, 109.6, 117.3, 119.4,
124.0, 124.1, 124.4, 126.9, 127.7, 128.1, 128.3, 129.8, 130.1, 130.7, 132.2,
142.1 and 169.7; MS (EI) 328 (15%, M+), 286 (100), 285 (32), 255 (8), 178
(21), 176 (16), 152 (9), 126 (5) and 107 (9).
5-Ethoxy -6,7-diphenylpyrrolo[1,2-b]pyridazine 8
A mixture of diphenylcyclopropenone (206 mg, 1.00 mmol) and pyrid-
azine (80 mg, 1.0 mmol) in dry 1,2-dichloroethane (20 ml) was refluxed
under N2-atm. for 24 h and evaporated under a stream of N2-gas. The residue
was dissolved in dry THF (20 ml), sodium hydride (53 mg of a ca. 55%
suspension in mineral oil, ca. 2.2 mmol) was added and the resulting mixture
was stirred for 1 h before addition of iodoethane (343 mg, 2.20 mmol). After
further stirring for 26 h, the reaction was quenched by addition of saturated
aqueousNH4Cl-solution (1 ml). The mixture was extracted with diethyl ether
(100 ml) and the organic extract was washed with water (2×30 ml), dried
(MgSO4) and evaporated in vacuo. The product was purified by flash
chromatography eluting with EtOAc-hexane (1:19) followed by EtOAc-hex-
ane (1:9).
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl Palmitate 5
A mixture of diphenylcyclopropenone (103 mg, 0.50 mmol) and pyrid-
azine (36 µl, 0.50 mmol) in dry 1,2-dichloroethane (20 ml) was refluxed
under N2-atm. for 2 h and cooled to 0 °C before 4-(N,N-dimethylamino)pyri-
dine (3.0 mg, 0.024 mmol), triethylamine (72 mg, 0.53 mmol), and palmitoyl
chloride (180 µl, 0.580 mmol) were added. The resulting mixture was stirred
for 16 h while reaching ambient temperature. Chloroform (30 ml) was added
and the reaction mixture washed with saturated aqueous CuSO4 solution
(4×25 ml), saturated aqueous NaHCO3 solution (2×15 ml), and brine
(15 ml), dried (MgSO4) and evaporated in vacuo. The product was purified
by flash chromatography eluting with EtOAc-hexane (1:5).
Yield 52%; mp 108–109 °C; (Found: C, 79.82 H, 5.59. C21H18N2O
1
requires C, 80.23; H, 5.76%); H NMR (acetone-d6, 200 MHz) δ 1.19 (t,
J = 7.0 Hz, 3H, CH3), 3.89 (q, J = 7.0 Hz, 2H, CH2), 6.56 (dd, J = 8.8 and
4.6 Hz, 1H), 7.2–7.5 (m, 10H, Ph) and 7.9–8.0 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 15.5, 70.7, 107.9, 117.3, 118.8, 123.1, 124.6, 126.4, 127.3, 128.0,
128.0, 130.2, 130.3, 130.6, 133.1, 133.9 and 141.9; MS (EI) 314 (40%, M+),
286 (23), 285 (100), 257 (2), 255 (3), 178 (6), 176 (5), 107 (11), and 99 (15).
Yield 46%; mp 68–72 °C; 1H NMR (CDCl3, 500 MHz) δ 0.81 (t, J = 6.9
Hz, 3H, CH3), 1.19–1.24 (m, 24H, CH2), 1.58–1.62 (m, 2H, CH2), 2.46 (t,
J = 7.5 Hz, 2H, CH2), 6.45 (dd, J = 9.1 and 4.4 Hz, 1H), 7.17–7.43 (m, 10H,
Ph), 7.52 (dd, J = 9.1 and 1.8 Hz, 1H) and 7.93 (dd, J = 4.4 and 1.8 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 14.2, 22.7, 25.0, 29.1, 29.2, 29.4, 29.4, 29.6,
29.6, 29.7, 29.7, 31.9, 34.0, 35.3, 109.5, 117.2, 119.5, 123.8, 124.1, 124.5,
126.9, 127.6, 128.1, 128.2, 129.7, 130.1, 130.6, 132.1, 142.1 and 172.6; MS
(EI) 524 (2%, M+), 287 (25), 286 (100), 270 (2), 178 (4) and 107 (4).
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl Methylcarbonate 9
A mixture of diphenylcyclopropenone (103 mg, 0.50 mmol) and pyrid-
azine (36 µl, 0.50 mmol) in dry 1,2-dichloroethane (30 ml) was refluxed
under N2-atm. for 2 h and evaporated in vacuo. The residue was dissolved in
1,2-dimethoxyethane (30 ml) and sodium hydride (49 mg of a ca. 55%
suspension in mineral oil, ca. 1.1 mmol) and methyl chloroformate (150 µl,
2.00 mmol) were added. After stirring for 16 h, the reaction mixture was
evaporated in vacuo and the product was purified by flash chromatography
eluting with EtOAc-hexane (1:2).
Bis(6,7-diphenylpyrrolo[1,2-b]pyridazin-5-yl ) Adipate 6
A mixture of diphenylcyclopropenone (103 mg, 0.5 mmol) and pyridazine
(0.036 ml, 0.50 mmol) in dry 1,2-dichloroethane (20 ml) was refluxed under
N2-atm. for 2 h and cooled to ambient temperature before 4-(N,N-dimethyl-
amino)pyridine (3.0 mg, 0.024 mmol), triethylamine (38 µl, 0.27 mmol) and
adipoyl chloride (39 µl, 0.27 mmol) were added. The resulting mixture was
stirred for 16 h. Chloroform (30 ml) was added and the reaction mixture
washed with saturated aqueous CuSO4 solution (4×15 ml), saturated aqueous
NaHCO3 solution (2×15 ml), and brine (15 ml), dried (MgSO4) and evapo-
rated in vacuo. The product was purified by flash chromatography eluting
with EtOAc-hexane (1:1).
Yield 61%; mp 124–128 °C; 1H NMR (CDCl3, 500 MHz) δ 3.82 (s, 3H,
CH3), 6.54 (dd, J = 9.1 and 4.4 Hz, 1H), 7.22–7.49 (m, 10H, Ph), 7.70 (dd,
J = 9.1 and 1.8 Hz, 1H) and 7.99 (dd, J = 4.4 and 1.8 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 55.8, 109.8, 117.1, 119.2, 123.8, 124.2, 124.7, 127.0,
127.7, 128.1, 128.4, 129.7, 130.1, 130.7, 131.8, 142.1 and 154.4; MS (EI)
344 (45%, M+), 300 (7), 286 (18), 285 (80), 183 (34), 149 (100), 141 (65),
and 107 (25); HRMS: Calcd. for C21H16N2O3 344.1161, found 344.1159.
Arch. Pharm. Pharm. Med. Chem. 334, 21–24 (2001)

24
Gundersen and co-workers
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl N-Phenylcarbamate 10
128.0, 128.3, 129.0, 129.4, 130.2, 130.7, 130.9, 131.1, 142.5, and 144.8; MS
(EI): 440 (4%, M+), 285 (100), 107 (12), and 79 (9).
A mixture of diphenylcyclopropenone (103 mg, 0.50 mmol) and pyrid-
azine (36 µl, 0.50 mmol) in dry 1,2-dichloroethane (30 ml) was refluxed
under N2-atm. for 2 h and cooled to 0 °C before 4-(N,N-dimethylamino)pyri-
dine (153 mg, 1.26 mmol) and phenyl isocyanate (220 µl, 2.00 mmol) in
1,2-dichloroethane (10 ml) were added. After stirring for 12 h at 0–5 °C and
at ambient temperature for 8 h, the reaction mixture was evaporated in vacuo
and the product was purified by flash chromatography eluting with EtOAc-
hexane (1:3).
Dichloro 6,7-diphenylpyrrolo[1,2-b]pyridazin-5-yl Phosphate 13
A mixture of diphenylcyclopropenone (309 mg, 1.50 mmol) and pyrid-
azine (120 mg, 1.50 mmol) in methanol (8 ml) was refluxed under N2-atm.
for 3 h and set aside in the refrigerator for 24 h. The crystals formed was
filtered off, dissolved in phosphorus oxychloride (2 ml), refluxed under
N2-atm. for 3 h and the mixture was evaporated in vacuo. The residue was
crystallised from dichloromethane-hexane.
Yield 52%; mp 175 °C; 1H NMR (CDCl3, 500 MHz) δ 6.47 (dd, J = 9.0
and 4.2 Hz, 1H), 6.78–7.43 (m, 15H, Ph), 7.67 (dd, J = 9.0 and 1.4 Hz, 1H)
and 7.94 (dd, J = 4.2 and 1.4 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 109.6,
118.0, 118.7, 119.9, 124.0, 124.1, 124.2, 124.8, 127.1, 127.8, 128.3, 128.5,
129.3, 130.0, 130.4, 130.9, 132.3, 137.4, 142.3 and 178.0; MS (EI) 405 (1%,
M+), 287 (22), 286 (100), 285 (12), 257 (8), 178 (18), 119 (41), 107 (5), and
91 (20); HRMS: Calcd. for C26H19N3O2 405.1477, found 405.1474.
Yield 69%; 1H NMR (CDCl3, 200 MHz) δ 6.88 (ddd, J = 9.2, 4.4 and 1.7
Hz, 1H), 7.20–7.50 (m, 10H, Ph), 8.09 (dd, J = 9.2 and 1.7 Hz, 1H, H-4) and
8.18 (dd, J = 4.4 and 1.7 Hz, 1H, H-2); MS (EI) 404/402 (55/55%, M+), 285
(100), 176 (8), 134 (8), 107 (20), and 79 (18); HRMS: Calcd. for
C19H13Cl2N2OP 402.009, found 402.009.
Diethyl 6,7-diphenylpyrrolo[1,2-b]pyridazin-5-yl Phosphate 14
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl Triflate 11
A mixture of diphenylcyclopropenone (309 mg, 1.50 mmol) and pyrid-
azine (120 mg, 1.50 mmol) in methanol (8 ml) was refluxed under N2-atm.
for 3 h and set aside in the refrigerator for 24 h. The crystals formed was
filtered off, dissolved in phosphorus oxychloride (2.0 ml) and refluxed under
N2-atm. for 3 h before the mixture was evaporated in vacuo. The residue was
crystallised from dichloromethane-hexane and the crystals formed was
stirred in abs. ethanol (2.0 ml) under N2-atm. for 24 h. The mixture was
evaporated in vacuo and the product was purified by flash chromatography
eluting with EtOAc-hexane (1:1).
Yield 59%; (Found: C, 64.91; H, 5.43. C23H23N2O4P requires C, 65.40;
H, 5.49%); 1H NMR (CDCl3, 200 MHz) δ 1.10 (dt, J = 7.1 and 1.1 Hz, 6H,
CH3), 3.7–4.0 (m, 4H, CH2), 6.45 (ddd, J = 9.1, 4.4 and 0.8 Hz, 1H), 7.1–7.5
(m, 10H, Ar), 7.89 (dd, J = 4.4 and 1.8 Hz, 1H) and 7.98 (dd, J = 9.1 and 1.8
Hz, 1H); 13C NMR (acetone-d6, 125 MHz) δ 15.8, 64.7, 117.1, 119.2, 123.6,
124.8, 126.1, 127.4, 127.9, 128.3, 128.5, 130.4, 131.1, 132.6 and 142.9; MS
(EI): 422 (100%, M+), 394 (10), 366 (14), 348 (6), 285 (25), 270 (7), 255 (3),
228 (1), 198 (1), 178 (7), 126 (1), 107 (11), and 79 (9); HRMS: Calcd. for
C23H23N2O4P 422.1395, found 422.1400.
A mixture of diphenylcyclopropenone (206 mg, 1.00 mmol) and pyrid-
azine (80 mg, 1.0 mmol) in dry 1,2-dichloroethane (10 ml) was refluxed
under N2-atm. for 15 h and cooled to ambient temperature before 4-(N,N-di-
methylamino)pyridine (184 mg, 1.50 mmol) and dichloromethane (40 ml)
were added. The resulting mixture was stirred under N2-atm. at ambient
temperature for 1 h and cooled to –78 °C before trifluoromethanesulfonic
anhydride (141 mg, 0.50 mmol) was added. After stirring at –78 °C for 1 h,
the reaction mixture was allowed to reach ambient temperature and evapo-
rated in vacuo. The product was purified by flash chromatography eluting
with EtOAc-hexane (1:39).
Yield 55%; mp 118–124 °C; (Found: C, 57.43; H, 3.28. C20H13F3N2O3S
requires C, 57.42; H, 3.13%); 1H NMR (acetone-d6, 300 MHz) δ 7.03 (dd,
J = 9.3 and 4.4 Hz, 1H), 7.3–7.6 (m, 10H, Ph), 8.10 (dd, J = 9.3 and 1.7 Hz,
1H) and 8.29 (dd, J = 4.4 and 1.7 Hz, 1H); 13C NMR (acetone-d6, 75 MHz)
δ 113.5, 118.8, 119.3 (q, JCF = 320 Hz), 120.6, 122.6, 124.7, 125.3, 128.6,
128.9, 128.9, 129.3, 130.0, 131.4, 131.4, 131.8 and 144.1; MS (EI): 418
(13%, M+), 285 (100), 182 (14), 178 (11), 156 (6), 142 (5), 128 (8), 122 (8),
107 (14), and 79 (12).
References
6,7-Diphenylpyrrolo[1,2-b]pyridazin-5-yl Tosylate 12
[1] B. Halliwell, Drugs, 1991, 42, 569–605; C. A. Rice-Evans, A. T.
Diplock, Free Radical Biol. Med. 1993, 15, 77–96; A. Bast, Drug News
Perspect. 1994, 7, 465–472; B. Halliwell, Chem. Edu. 1995, 123–124.
A mixture of diphenylcyclopropenone (516 mg, 2.50 mmol) and pyrid-
azine (200 mg, 2.50 mmol) in dry 1,2-dichloroethane (140 ml) was refluxed
under a N2-atm. for 24 h and cooled to 0 °C before 4-(N,N-dimethyl-
amino)pyridine (61 mg, 0.50 mmol), triethylamine (506 mg, 5.00 mmol) and
toluene-4-sulfonyl chloride (953 mg, 5.00 mmol) were added, and the
resulting mixture was stirred at 0 °C for 1 h and at ambient temperature for
24 h. The reaction mixture was washed with water (25 ml) and saturated
aqueous NaHCO3 (25 ml), dried (MgSO4) and evaporated in vacuo. The
product was purified by flash chromatography eluting with EtOAc-hexane
(1:4).
Yield 55%; (Found: C, 71.19; H, 4.47. C26H20N2O3S requires C, 70.89;
H, 4.58%); 1H NMR (CDCl3, 200 MHz) δ 2.31 (s, 3H, CH3), 6.83 (dd, J = 9.2
and 4.4 Hz, 1H), 6.85–6.93 (m, 2H), 7.00–7.40 (m, 12H, Ar), 7.97 (dd, J = 9.2
and 1.8 Hz, 1H) and 8.13 (dd, J = 4.4 and 1.8 Hz, 1H); 13C NMR (CDCl3,
75MHz) δ 21.5, 110.8, 119.2, 119.7, 122.5, 123.6, 125.7, 126.5, 127.7, 127.7,
[2] A. I. Nasir, L.-L. Gundersen, F. Rise, Ø. Antonsen, T. Kristensen, B.
Langhelle, A. Bast, I. Custers, G. R. M. M. Haenen, H. Wikström,
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[3] O. B. Østby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M.
Haenen. Eur. J. Org. Chem. 2000, 9, 3763–3770.
[4] C. H. Weidner, F. M. Michaels, D. J. Beltman, C. J. Montgomery, D.
H. Wadsworth, B. T. Briggs, M. L. Picone, J. Org. Chem. 1991, 56,
5594–5602.
[5] J. W. Lown, K. Matsumoto, Can. J. Chem. 1971, 49, 1165–1175.
Received: August 25, 2000 [FP518]
Arch. Pharm. Pharm. Med. Chem. 334, 21–24 (2001)