Synthesis and chemistry of unusual bicyclic endoperoxides containing the pyridazine ring

Article abstract of DOI:10.1021/jo0345300

Inverse-Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with unsaturated bicyclic endoperoxides gave the bicyclic endoperoxides containing the pyridazine ring. The NEt ₃ and CoTPP (TPP = tetraphenylporphyrin) catalyzed reac

Full text of DOI:10.1021/jo0345300

Syn th esis a n d Ch em istr y of Un u su a l Bicyclic En d op er oxid es
Con ta in in g th e P yr id a zin e Rin g
Galip O¨ zer,† Nurullah Sarac¸ogˇlu,† and Metin Balci*,‡
Department of Chemistry, Faculty of Art and Sciences, Atatu¨rk University, 25240 Erzurum, Turkey, and
Department of Chemistry, Faculty of Art and Sciences, Middle East Technical University,
06531 Ankara, Turkey
mbalci@metu.edu.tr
Received April 25, 2003
Inverse-Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with unsaturated
bicyclic endoperoxides gave the bicyclic endoperoxides containing the pyridazine ring. The NEt3
and CoTPP (TPP ) tetraphenylporphyrin) catalyzed reaction of endoperoxide 8 resulted in the
formation of hydroxy ketone 11 and cis-diol 9. Cleavage of the peroxide linkage in 8 with thiourea
provided cis-diol 9. Oxidation of hydroxy ketone 11 and cis-diol 9 led to the phthalazine-5,8-dione
10. Furthermore, the various transformations of the other endoperoxides 19, 20, 22, 23, and 30
resulted in the formation of pyridazine derivatives.
In tr od u ction
The pyridazine (1) nucleus is of considerable interest
because of its synthetic applications1 and important
pharmacological activities,2 most of them related to the
cardiovascular system.2a,3 This six-membered heterocycle
is also an integral part of many polynuclear heterocycles.
Bicyclic endoperoxides, whose oxygen-oxygen (O-O)
bond often plays a key role in the activity of a number of
chemically and biologically relevant substances, are an
important class of compounds.4,5 For example, the pros-
taglandin endoperoxide (2) is a key intermediate in the
biosynthesis of prostaglandins, prostacyclins, thrombox-
anes, and leukotrienes from fatty acids. Another example
is the potent antimalarial 1,2,4-trioxane, artemisinin (3),
and other related semisynthetic derivatives.6
pyridazine and peroxide units and their chemical trans-
formations.7 The methodology is based on the inverse-
Diels-Alder reaction of tetrazine8 with unsaturated
bicyclic endoperoxides. With electron-withdrawing sub-
stituents (R ) COOCH3, CF3, etc.), the reactivity of
tetrazines is particularly high. Since some endoperoxides
were not stable at the room temperature, the reactions
were run at lower temperatures. To increase the reactiv-
ity of the tetrazine ring in the Diels-Alder reactions with
inverse electron demand, we have used dimethyl 1,2,4,5-
tetraazine-3,6-dicarboxylate as the diene component.
In this paper, we report on the first synthesis of the
phthalazine-type bicyclic endoperoxides containing both
† Atatu¨rk University.
Resu lts a n d Discu ssion
‡ Middle East Technical University.
(1) (a) Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu K. R.
Tetrahedron 2002, 58, 9933-9940. (b) Tisler, M.; Stanovnik B. In
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: San Diego,
1990; Vol. 49, p 1. (c) Coates, W. J .; McKillop A. Synthesis 1993, 334-
342.
(2) (a) Heinisch, G.; Kopelent H. In Progress in Medicinal Chemistry;
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Pharm. Fr. 1997, 55, 2-69.
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2000, 56, 2473-2479. (b) Campos, M.; Estevez, I.; Ravina, E.; Orallo,
F. Gen. Pharmacol. 1998, 30, 201-207.
2,3-Dioxabicyclo[2.2.2]oct-5-ene5 (5) reacted with tet-
razine 4 in dry methylene chloride to give the isomeric
adduct 7, which is formed upon nitrogen extrusion from
the initially formed tetracyclic adduct followed by a 1,3-
hydrogen shift. Oxidation of the 1,4-dihydropyridazine
mixture under the same reaction conditions with phen-
yliodosyl bis(trifluoroacetate) (PIFA)9 produced the aro-
matized compound 8 in a 83% overall yield (Scheme 1).
(4) (a) Donkers, R. L.; Workentin, M. S. Chem. Eur. J . 2001, 7,
4012-4020. (b) Clennan, E. L.; Foote C. S. In Organic Peroxides; Ando
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10.1021/jo0345300 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003
J . Org. Chem. 2003, 68, 7009-7015
7009

O¨ zer et al.
SCHEME 1
SCHEME 2
bond breaks in this reaction, it preserves the configura-
tion of alkoxy carbon atoms. Oxidation of diol 9 with
active MnO2 resulted in the formation of phthalazine-
quinone 10 in a yield of 61%.
The triethylamine-catalyzed reaction5,14 of the endo-
peroxide 8 in CHCl3 provided a mixture of the expected
hyroxy ketone 11 and diol 9 in a 3:2 ratio (Scheme 1).
The formation of the diol 9 can be rationalized by a
mechanism in which the tertiary amine probably attacks
the peroxide linkage directly and acts as a reducing
reagent14b,15 and reduces the peroxide linkage to diol 9.
Next, we treated endoperoxide 8 with cobalt(II) tetra-
phenylporphyrin (CoTPP)16,17 and also obtained a mixture
consisting of 9 and 11 in a 1:4 ratio.
In an analogous manner, we synthesized the endo-
peroxide 13 starting from the cyclopentadiene endoper-
oxide 12 (Scheme 2).18 All efforts to obtain the corre-
sponding pyridazine derivative 17 failed. However, the
synthesis of 14, a reduction product of 17, was readily
accomplished by two different approaches. Selective
reduction of the peroxide linkage in 13 with thiourea
followed by oxidation with PIFA and acetylation resulted
in the formation of 14 (15% overall yield). In the second
approach, we started from cis-1,3-diacetoxycyclopent-2-
ene 15,18 which was synthesized from the reduction of
cyclopentadiene endoperoxide with thiourea followed by
acetylation. An addition of 15 to tetrazine 4 gave the 1,4-
dihydropyridazine derivative 16 (Scheme 2).
After successful isolation and characterization of the
bicyclic endoperoxide 8, we turned our attention to the
chemistry of the peroxide functionality. We were inter-
ested in the synthesis of phthalazine derivatives,10
especially phthalazinequinone 10. The parent compound,
phthalazine-5,8-quinone, was first synthesized by Parrick
et al.11 Some derivatives of this skeleton were used as
medication for the treatment of inflammation, migraine,
and shock.12 Furthermore, other analogues have been
shown to be effective in their DNA-degrading ability.13
The peroxide linkage is highly susceptible to reductive
cleavage by a variety of reductants.5 Selective reduction
of the peroxide linkage in 8 was performed with thiourea
under very mild conditions to produce the cis-diol 9 in
56% yield (Scheme 1). Since only the oxygen-oxygen
(12) Boutherin-Falson, O.; Desquand-Billiald, S.; Favrou, A.; Finet,
M.; Tembo, O.; Torregrosa, J .-L.; Yannic-Arnoult, S.; PCT Int. Appl.
CODEN: PIXXD2 WO 9721432 A1 19970619 CAN 127:121758 AN
1997:516337, 1997, 82 pp.
(13) (a) Shaikh, I. A.; J ohnson, F.; Grollman, A. P. J . Med. Chem.
1986, 29, 1329-40. (b) Krapcho, A. P.; Maresch, M. J .; Helgason, A.
L.; Rosner, K. E.; Hacker, M. P.; Spinelli, S.; Menta, E.; Oliva, A. J .
Heterocycl. Chem. 1993, 30, 1597-1606.
(14) (a) Kornblum, N.; DeLaMare, H. E. J . Am. Chem. Soc. 1951,
73, 880-881. (b) Kelly, D. R.; Bansal, H.; Morgan, J . J . G. Tetrahedron
Lett. 2002, 43, 9331-9333. (c) Mete, E.; Altundas, R.; Secen, H.; Balci,
M. Turk. J . Chem. 2003, 27, 145-153.
(15) For a similar reduction, see: Dastan, A.; Saracoglu, N.; Balci,
M. Eur. J . Org. Chem. 2001, 3519-3522.
(16) (a) Boyd, J . D.; Foote, C. S.; Imagawa, D. K. J . Am. Chem. Soc.
1980, 102, 3641-3642. (b) Su¨tbeyaz, Y.; Secen, H.; Balci, M. J . Org.
Chem. 1988, 53, 2312-2317.
(17) For the reaction of saturated bicyclic endoperoxides with
CoTPP, see: Balci, M.; Akbulut, N. Tetrahedron 1985, 41, 1315-1322.
(18) (a) Schenck, G. O.; Dunlap, E. D. Angew. Chem. 1956, 68, 248-
249. (b) Kanoko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876-
877.
(10) For phthalazine and their biological importance, see: (a)
Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longmans: Oxford,
1997. (b) Tsoungas, P. G.; Searcey, M. Tetrahedron Lett. 2001, 42,
6589-6592. (c) Brzezinski, J . Z.; Browski, H. B.; Epsztajn, J . Tetra-
hedron 1996, 52, 3261-3272. (d) Eguchi, Y.; Sasaki, F.; Takashima,
Y.; Nakajima, M.; Ishikawa, M. Chem. Pharm. Bull. 1991, 39, 795. (e)
Cherkez, S.; Herzig, J .; Yellin, H. J . Med. Chem. 1986, 29, 947. (f)
Scheffler, G.; Engel, J .; Kutscher, B.; Sheldrick, W. S.; Bell, P. Arch.
Pharm. (Weinheim) 1988, 321, 205. (g) Yamaguchi, M.; Kamei, K.;
Koga, T.; Akima, M.; Kuroki, T.; Ohi, N. J . Med. Chem. 1993, 36, 4052.
(h) Bavin, E. M.; Drain, D. J .; Seiler, M.; Seymour, D. E. J . Pharm.
Pharmacol. 1952, 4, 844. (i) Sugimoto A.; Tanaka, H.; Eguchi, Y.; Ito,
S.; Takashima, Y.; Ishikawa, M. J . Med. Chem. 1984, 27, 1300. (j)
Mylari, B. L.; Beyer, T. A.; Scott, P. J .; Aldinger, C. E.; Dee, M. F.;
Siegel, T. W.; Zembrowski, J . J . Med. Chem. 1992, 35, 457.
(11) Parrick, J .; Ragunathan, R. J . Chem. Soc., Perkin Trans. 1 1993,
211-216.
7010 J . Org. Chem., Vol. 68, No. 18, 2003

Unusual Bicyclic Endoperoxides Containing the Pyridazine Ring
SCHEME 3
SCHEME 4
The assignment of the relative configuration of 16 was
accomplished by 1H- and 13C NMR spectral data and NOE
measurements. The stereochemistry of doubly allylic
proton H4a was confirmed by the observation of NOE
effects. Irradiation at the resonance signal of the doubly
allylic proton H4a (at 3.60 ppm) caused a signal enhance-
ment at the resonance signal of the adjacent proton H5
at 5.54 ppm and the methylenic proton H6endo at 1.91
ppm. However, there was no signal enhancement at the
resonance signal of the proton H7 indicating the cis
orientation of the proton H4a with respect to the acetyl
groups. The oxidation of 1,4-dihydropyridazine derivative
16 supplied the compound 14 in 52% yield (Scheme 2).
In a similar manner, the synthesis of 20 (Scheme 3)
and 23 (Scheme 4) was achieved upon the addition of the
endoperoxides 18 and 2119 to tetrazine 4 followed by
PIFA oxidation. Although the stereochemistry of 1,4-
dihydropyridazine endoperoxides 19 and 22 was not
determined, we assume that tetrazine approaches the
endocyclic double bond unit in 18 and 21 also from the
exo-face, the sterically less crowded face of the molecule,
to form the products 19 and 22, respectively.
The reaction of 22 and 23 with thiourea furnished the
cyclization products 24 and 25a , respectively. One of the
hydroxy groups of the diol formed upon the reduction of
22 (23) with thiourea attacks the neighboring ester group
to form the lactone 24 (25a ).
Treatment of 22 with CoTPP or thermolysis at 77 °C
produced the isomeric pyranyl pyridazine derivative 26a
(in a ration of 1:1) as the major product besides the
lactone 27 (Scheme 4). For the characterization of 26a ,
the isomeric mixture was converted to the methoxyl
derivative 26b. The CoTPP-catalyzed reaction as well as
the thermolysis of the bicyclic endoperoxides can lead to
the formation of the products derived from an initial C-C
cleavage.16b,20 We assume that the primarily formed open-
chain aldehyde 28 underwent intramolecular cyclization
where the hydroxyl group attacks either ester carbonyl
group or the aldehyde carbonyl group to produce the
transesterification product 27 and the pyranyl derivative
26a , respectively (Scheme 4).
tetrazine with CHT-endoperoxide 29 in methylene chlo-
ride at room temperature for 1 day. Tetrazine 4 was only
added to the double bond, which was incorporated into
the six-membered ring and exclusively produced 30
(Scheme 5).
The exo-configuration of the proton H7 was supported
by a NOE experiment. The irradiation of the doubly
allylic proton in the pyridazine ring at 3.50 ppm caused
an enhancement of the bridgehead proton H8 at 5.07 ppm
and one of the methylene protons at 2.70 ppm. This
finding indicated that the tetrazine approached the
double bond in 29 from the exo-face of the molecule.
The base-catalyzed rearrangement of the endoperoxide
30 with NEt3 produced a complex mixture that under-
went polymerization or decomposition upon treatment
with any column material. However, an isolable product
32 was obtained by the treatment of 30 with thiourea.
The CoTPP-catalyzed reaction of endoperoxide 30 or
its thermolysis gave the isomeric pyranyl pyridazine
derivative 33 (in a 3:7 ratio). The exact position of the
double bond in 33 was determined by double resonance
experiments. The position of the double bond provides
As the last endoperoxide we studied the reaction of the
cycloheptatriene endoperoxide 2919,21 with tetrazine 4.
The addition was accomplished by the treatment of
(19) Adam, W.; Balci, M. J . Am. Chem. Soc. 1979, 101, 7537-7541.
(c) Adam, W.; Balci, M. J . Am. Chem. Soc. 1979, 101, 7541-7547.
(20) For C-C cleavage of the endoperoxides upon threatment with
CoTPP or thermolysis reactions, see: (a) O¨ zer, G.; Sarac¸ogˇlu, N.; Balci,
M. Heterocycles 2000, 53, 761-764. (b) Sengul, M. E.; Simsek, N.; Balci,
M. Eur. J . Org. Chem. 2000, 1359-1363. (c) Hathaway, S. H.; Paquette,
L. A. Tetrahedron 1985, 41, 2037-2043. (d) Paquette, L. A.; Carr, R.
V. C.; Arnold, E.; Clardy, J . J . Org. Chem. 1980, 45, 4907-4913.
(21) Mori, A.; Takeshita, H. Chem. Lett. 1978, 395-396. (b) Kende
A. S.; Chu, J . Y. C. Tetrahedron Lett. 1970, 11, 4837-4840. (c) Adam,
W.; Balci, M. Angew. Chem. 1978, 90, 1014-1015.
J . Org. Chem, Vol. 68, No. 18, 2003 7011

O¨ zer et al.
SCHEME 5
pounds, such as the phthalazine and pyridazine deriva-
tives.
Exp er im en ta l Section
Gen er a l Meth od s. Solvents were concentrated at reduced
pressure. Melting points were determined on a capillary
melting apparatus and are uncorrected. Infrared spectra were
recorded on a FT-IR spectrometer. 1H NMR and 13C NMR
spectra were recorded on a 200 (50) MHz spectrometer and
are reported in δ units with SiMe4 as internal standard. Mass
spectra (electron impact) were recorded at 70 eV on an MS
spectrometer.
Dim eth yl 9,10-Dioxa-4,5-diazatr icyclo[6.2.2.02,7]dodeca-
2,4,6-tr ien e-3,6-d ica r boxyla te (8). A solution of endoperox-
ide 5 (60 mg, 0.53 mmol), tetrazine 4 (150 mg, 0.75 mmol),
and PIFA (270 mg, 0.63 mmol) in 15 mL of CH2Cl2 was stirred
at room temperature for 4 days. The reaction mixture was
diluted with water, and the aqueous solution was extracted
with CH2Cl2 (3 × 50 mL), washed with water, and dried over
CaCl2. After removal of the solvent, the residue was filtered
on a short silica gel column (15 g) eluting with CCl4/hexane
(1:1), and 112 mg of iodobenzene was obtained as the first
fraction. Further elution with ethyl acetate/hexane (1:4)
furnished the product 8 (125 mg, 83%): pale yellow crystals
from CHCl3/ether; mp 133-134 °C; 1H NMR (200 MHz, CDCl3)
δ 6.15 (m, OCH, 2H), 4.11 (s, OCH3, 6H), 2.67 (AA′ part of
AA′XX′ methylene, 2H), 1.66 (XX′ part of AA′XX′ system,
methylene, 2H); 13C NMR (50 MHz, CDCl3) δ 164.4 (CO) 146.7,
139.2, 69.7, 54.1, 21.0; IR (KBr, cm-1) 3000, 2930, 2845, 1720,
1440, 1365, 1270, 1235, 1215, 1170, 1055, 925; Mass spectrum
m/z (M+) 280 (88), 264 (13), 249 (100), 233 (35), 222 (100), 190
(65), 175 (38), 163 (65). Anal. Calcd for C12H12N2O6: C, 51.43;
H, 4.32; N, 10.00. Found: C, 51.33; H, 4.16; N, 9.89.
SCHEME 6
Th iou r ea Red u ction of 8: Dim eth yl 5R(S),8S(R)-5,8-
Dih yd r oxy-5,6,7,8-tetr a h yd r op h th a la zin e-1,4-d ica r boxy-
la te (9). To a stirred solution of 8 (200 mg, 0,72 mmol) in 10
mL of methanol was added a solution of thiourea (162 mg, 2.14
mmol) in methanol. After the addition was complete, stirring
was continued for 2 h. The precipitated sulfur was filtrated
and the solvent was evaporated. Crystallization of the residue
(152 mg) from CH2Cl2/ether gave a dark brown powder (116
mg, 56%): mp 115-117 °C; 1H NMR (200 MHz, CDCl3) δ 4.92
(m, OCH, 2H), 4.26 (m, OH, 2H), 3.99 (s, OCH3, 6H), 2.15-
1.85 (m, methylene, 4H); 13C NMR (50 MHz, CDCl3) δ 168.2,
155.3, 141.0, 65.4, 55.7, 28.4; IR (KBr, cm-1) 3285, 3157, 2953,
2876, 2723, 1753, 1625, 1548, 1446, 1395, 1293, 1268, 1191,
1165, 1089, 1038, 961, 834. Anal. Calcd for C12H14N2O6: C,
51.06; H, 5.00; N, 9.93. Found: C, 51.25; H, 4.90; N, 9.83.
Oxid a tion of 9: Dim eth yl 5,8-Dioxo-5,6,7,8-tetr a h y-
d r op h th a la zin e-1,4-d ica r boxyla te (10). To a solution of diol
9 (or a mixture of 9 and 11) (100 mg, 0.36 mmol) in 50 mL of
CH2Cl2 was added 620 mg (7.14 mmol) of MnO2. The reaction
mixture was stirred at rt for 6 days. The solids were removed
by filtration, and the solvent was evaporated. The crystalliza-
tion of the residue from CH2Cl2/ether gave 10 as brown powder
(60 mg, 61%): mp 163-166 °C; 1H NMR (200 MHz, CDCl3) δ
7.15 (s, dCH, 2H), 4.13 (s, OCH3, 6H); 13C NMR (50 MHz,
information about the cleavage mode of CoTPP catalyzed
reaction or thermolysis. Presumably such reactions of the
decomposition of endoperoxides, proceed via radical
pathways. The formation of the isomeric 33 is reasonably
understood in terms of the mechanism outlined in
Scheme 6.
The radical, depicted as 34 resulting from the electron-
transfer reaction between Co2+ species and endoperoxide,
serves as a key intermediate. Cleavage of the C-C bond
can form the allylic radical 35. Subsequently, the proton
abstraction and ring closure of an open-chain aldehyde
ultimately delivers the isomeric pyranosyl derivative 33.
The other possible intermediate 36, which is a vinyl
radical, will not be as stable as the radical 35.
CDCl3) δ 183.7, 166.2, 153.3, 140.2, 124.6, 55.9; IR (KBr, cm-1
)
3068, 2960, 1753, 1702, 1607, 1445, 1391, 1375, 1291, 1260,
1221, 1183, 1106, 1067, 967, 859. Anal. Calcd for C12H8N2O6:
C, 52.18; H, 2.92; N, 10.14. Found: C, 52.07; H, 2.85; N, 10.01.
CoTP P -Ca ta lyzed Rea ction of 9,10-Dioxa -4,5-d ia za tr i-
cyclo[6.2.2.02,7]d od eca -2,4,6-tr ien e-3,6-d ica r boxylic Acid
Dim eth yl Ester (8). To a magnetically stirred solution of the
endoperoxide 8 (250 mg, 0.89 mmol) in CH2Cl2 (50 mL) was
added a catalytic amount of cobalt meso-tetraphenylporphyrin
(CoTPP) at room temperature. The mixture was stirred for 3
days at rt and then evaporated. Chromatography of residue
on silica gel (30 g) eluting with CH2Cl2/acetone (95:5) yielded
the hydroxy ketone 11 as the first fraction.
In conclusion, we have described a simple method of
access to bicyclic endoperoxides containing the pyridazine
ring in which allow diverse transformations of the
peroxide functional group. Transformations of these
endoperoxides open a new way to heterocyclic com-
7012 J . Org. Chem., Vol. 68, No. 18, 2003

Unusual Bicyclic Endoperoxides Containing the Pyridazine Ring
Dim eth yl 5-h yd r oxy-8-oxo-5,6,7,8-tetr a h yd r op h th a la -
zin e-1,4-d ica r boxyla te (11): dark brown powder from CH2-
Cl2/ether (132 mg, 47%); mp 135-137 °C; 1H NMR (200 MHz,
CDCl3) δ 5.17 (q, J ) 7.7 Hz, H5, 1H), 4.10 (s, OCH3, 3H), 4.08
(br.s, OH, 1H), 4.04 (s, OCH3, 3H), 3.25-3.07 (ddd, A part of
AB system, J ) 17.4 Hz, 12.6 Hz, 4.9 Hz, H7a, 1H), 2.76-2.63
(dt, B part of AB system, J ) 17.4, 4.2 Hz, H7b, 1H), 2.56-
2.24 (m, H6, 2H); 13C NMR (50 MHz, CDCl3) δ 196.7, 167.6,
167.3, 154.8, 154.1, 143.6, 126.9, 63.6, 56.1, 55.5, 35.3, 30.5;
IR (KBr, cm-1) 3234, 2953, 2851, 2697, 1753, 1702, 1548, 1446,
1395, 1344, 1293, 1268, 1217, 1165, 1114, 1063, 961, 885. Anal.
Calcd for C12H12N2O6: C, 51.43; H, 4.32; N, 10.00. Found: C,
51.25; H, 4.22; N, 10.15.
resulting mixture was added 310 mg (4.08 mmol) of thiourea
in 40 mL of methanol and the mixture stirred for 3 h. After
the precipitated sulfur was filtrated, the solvent was evapo-
rated. The crude product (650 mg) was dissolved in 10 mL of
pyridine, and Ac2O (2 g, 0.02 mol) was added to the resulting
mixture. The reaction mixture was stirred at rt for 16 h. The
mixture was cooled to 0 °C, 100 mL of 1 N HCl solution was
added, and the mixture was extracted with ethyl acetate (3 ×
50 mL). The organic extracts were washed with NaHCO3
solution (100 mL) and water (100 mL) and then dried (MgSO4).
After removal of the solvent, the crude product (354 mg) was
oxidized with PIFA (600 mg, 1.39 mmol) in 30 mL of CH2Cl2
for 1 h. The reaction mixture was diluted with water, and the
aqueous solution was extracted with CH2Cl2 (3 × 30 mL),
washed with water, and dried over MgSO4. After removal of
the solvent, the residue was filtered on a short Florisil column
(10 g) eluting with CH2Cl2 (50 mL) to give 270 mg of
iodobenzene as the first fraction. Further elution with ethyl
acetate (100 mL) furnished the product 14 (140 mg, 15%,
overall yield).
Continued elution with CH2Cl2/acetone (60:40) afforded the
cis-diol 9 (36 mg, 13%).
NEt3-Ca ta lyzed Rea r r a n gem en t of Dim eth yl 9,10-Di-
oxa -4,5-d ia za tr icyclo[6.2.2.02,7]d od eca -2,4,6-tr ien e-3,6-d i-
ca r boxyla te (8). A solution of the endoperoxide 8 (100 mg,
0.36 mmol) in 20 mL of CH2Cl2 containing 3 drops of triethyl-
amine was stirred at room temperature for 4 h. After removal
of the solvent, the 1H NMR of the residue showed the formation
of a mixture of 9/11 (3:2) in quantitative yield. The mixture
was separated as described above or used for the synthesis of
10 without further purification.
Syn th esis of Dim eth yl 5R(S),7S(R)-5,7-Bis(a cetyloxy)-
6,7-d ih yd r o-5H-cyclop en ta [d ]p yr id a zin e-1,4-d ica r boxy-
la te (14). Meth od A. A solution of 1,4-diacetoxycyclopentene
15 (592 mg, 3.22 mmol) and tetrazine 4 (700 mg, 3.50 mmol)
in 15 mL of CH2Cl2 was stirred at room temperature for 96 h.
Filtration of the residue on a short Florisil column (8 g) eluting
with ethyl acetate (100 mL) furnished d im et h yl 5,7-
bis(a cet yloxy)-4a ,5,6,7-t et r a h yd r o-2H-cyclop en t a [d ]p y-
Dim eth yl 10,11-Dioxa-4,5-diazatr icyclo[7.2.2.02,7]tr ideca-
2,4,6-tr ien e-3,6-d ica r boxyla te (20). A solution of endoper-
oxide 18 (250 mg, 1.98 mmol) and tetrazine 4 (471 mg, 2.38
mmol) in 15 mL of CH2Cl2 was stirred at room temperature
for 45 h. After removal of the solvent, the residue was filtered
on a short Florisil column (5 g) eluting with CH2Cl2 (150 mL)
to furnish the crude product 19 (522 mg). The oxidation of the
crude product (522 mg) to 23 was realized as described for the
preparation of 8: pale yellow crystals (216 mg, 37%) from
1
CHCl3/ether; mp 135-136 °C; H NMR (200 MHz, CDCl3) δ
5.79 (m, H1, 1H), 4.84-4.77 (m, H9, 1H), 4.06 (s, OCH3, 3H),
4.05 (s, OCH3, 3H), 3.60 (d, A part of AB-system, J )19.7 Hz,
H
8a, 1H), 3.57 (dd, B part of AB-system, J ) 19.7, 5.2 Hz, H8b,
r id a zin e-1,4-d ica r boxyla te (16): colorless crystals (1.11 g,
98%) from CH2Cl2/ether; mp 131-132 °C; 1H NMR (200 MHz,
CDCl3) δ 8.45 (bs, NH, 1H), 6.21 (bd, J ) 5.8 Hz, H7, 1H), 5.54
(ddd, J ) 8.1, 5.0, 3.0 Hz, H5, 1H), 3.85 (s, OCH3, 3H), 3.81 (s,
OCH3, 3H), 3.60, (d, J ) 5.0 Hz, H4a, 1H), 2.33 (ddd, A part of
AB system, J ) 15.8, 8.1, 5.8 Hz, H6a, 1H), 2.10 (s, CH3, 3H),
2.06 (s, CH3, 3H), 1.91 (bd, B part of AB system, J )15.8 Hz,
1H), 2.80-2.61 (m, CH2, 1H), 2.40-2.21 (m, CH2, 2H), 1.60-
1.43 (m, CH2, 1H); 13C NMR (50 MHz, CDCl3) δ 166.9, 166.7,
156.1, 151.9, 144.9, 141.0, 79.2, 76.7, 55.6, 55.4, 40.6, 25.3, 22.6;
IR (KBr, cm-1) 2940, 2890, 1730, 1440, 1240, 1215, 1150, 990,
950, 815, 765; MS m/z (M+) 294 (35) 279 (18), 263 (69), 237
(88), 206 (100). Anal. Calcd for C13H14N2O6: C, 53.06; H, 4.80;
N, 9.52. Found: C, 52.75; H, 4.57; N, 9.43.
H
6b, 1H); 13C NMR (50 MHz, CDCl3) δ ) 172.2, 171.9, 165.8,
Dim eth yl 12,13-Dioxa-4,5-diazatr icyclo[6.3.2.02,7]tr ideca-
2,5-d ien e-3,6-d ica r boxyla te (22). A solution of the endop-
eroxide 21 (126 mg, 1 mmol) and tetrazine 4 (198 mg, 1 mmol)
in 20 mL of CH2Cl2 was stirred at room temperature for 24 h.
The residue was filtered on a short Florisil column (5 g).
Elution with CCl4 (40 mL) furnished the endoperoxide 22: pale
yellow colorless crystals from CCl4 (222 mg, 75%); mp 131-
162.7, 132.1, 126.6, 120.4, 77.8, 74.2, 55.0, 54.6, 43.6, 39.9, 23.1
(2 × CH3); IR (KBr, cm-1) 3340, 2995, 2940, 1720, 1590, 1430,
1240, 1125, 1110, 1030, 940, 815. Anal. Calcd for C15H18N2O8:
C, 50.85; H, 5.12; N, 7.91. Found: C, 50.98; H, 5.22; N, 8.03.
A solution of 16 (520 mg, 1.47 mmol) and PIFA (900 mg,
2.1 mmol) in 25 mL of CH2Cl2 was stirred at room temperature
for 3 h. The reaction mixture was diluted with water, and the
aqueous solution was extracted with CH2Cl2 (75 mL), washed
with water, and dried over MgSO4. After removal of the
solvent, the residue was filtered on a short Florisil column (10
g) eluting with CH2Cl2 (100 mL), and 320 mg of iodobenzene
was obtained as the first fraction. Further elution with ethyl
acetate (100 mL) furnished the product 14 (270 mg, 52%) as
1
133 °C; H NMR (200 MHz, CDCl3) δ 8.73 (bs, NH, 1H), 5.73
(m, H1, 1H), 5.68 (m, H8, 1H), 3.80 (s, OCH3, 3H), 3.76 (s,
OCH3, 3H), 2.67 (s, H7, 1H), 2.18-1.17 (m, CH2, 6H); 13C NMR
(50 MHz, CDCl3) δ 165.2, 162.7, 132.2, 129.8, 114.2, 77.7, 77.2,
54.8, 54.4, 37.0, 36.8, 34.8, 21.8; IR (KBr, cm-1) 3285, 2973,
2953, 2927, 1753, 1702, 1625, 1472, 1446, 1370, 1293, 1268,
1242, 1191, 1140, 1114, 1089, 1063, 961, 808. Anal. Calcd for
1
pale yellow crystals from CH2Cl2/ether: mp 170-171 °C; H
C
13H16N2O6: C, 52.70; H, 5.44; N, 9.46. Found: C, 52.85; H,
NMR (200 MHz, CDCl3) δ 6.60 (dd, J ) 7.7, 2.8 Hz, H5 and
H7, 2H), 4.05 (s, OCH3, 6H), 3.06 (dt, A part of AB system, J
) 15.7, 7.7 Hz, H6a, 1H), 2.09 (dt, B part of AB system, J )
15.7 Hz, 2.8 Hz, H6b, 1H), 2.06 (s, CH3, 6H); 13C NMR (50 MHz,
CDCl3) δ 171.3, 165.1, 152.6, 145.6, 77.8, 55.5, 41.3, 22.5; IR
(KBr, cm-1) 2995, 2940, 1720, 1425, 1365, 1250, 1200, 1050,
1030, 950, 810, 780; MS m/z (M+) 352 (48) 321 (7), 279 (33),
250 (61), 237 (45), 220 (100), 207 (20), 192 (81). Anal. Calcd
for C15H16N2O8: C, 51.14; H, 4.58; N, 7.95. Found: C, 51.00;
H, 4.67; N, 8.09.
5.57; N, 9.61.
Dim eth yl 12,13-Dioxa-4,5-diazatr icyclo[6.3.2.02,7]tr ideca-
2,4,6-tr ien e-3,6-d ica r boxyla te (23). The pyridazine deriva-
tive 22 (645 mg, 2.2 mmol) was oxidized with PIFA (1.2 g, 2.8
mmol) as described for the preparation of 8. The residue was
crystallized from CH2Cl2/ether to give pale yellow crystals (440
mg, 57%): mp 141-142 °C: 1H NMR (200 MHz, CDCl3) δ 6.05
(m, H1 and H8, 2H), 4.09 (s, OCH3, 6H), 2.30 (m, CH2, 4H),
1.75-1.16 (m, CH2, 1H), 0.78-0.59 (m, CH2, 1H); 13C NMR
(50 MHz, CDCl3) δ 164.4, 148.0, 137.0, 76.7, 54.1, 32.0, 19.1;
IR (KBr, cm-1) 3030, 2930, 2920, 2860, 1725, 1440, 1370, 1285,
1235, 1230, 1200, 1140, 1010, 780; MS m/z (M+) 294 (8) 280
(4), 262 (100), 247 (23), 232 (52), 204 (35). Anal. Calcd for
Meth od B. To a solution of cyclopentadiene (203 mg, 3.07
mmol) in 50 mL of CCl4 was added 10 mg of TPP. The resulting
mixture was irradiated with a projection lamp (150 W) while
dry oxygen was being passed through the solution, and the
mixture was stirred for 2.5 h at -20 °C. Later, to the stirred
solution of cyclopentadiene endoperoxide 12 was added 507
mg (2.56 mmol) of tetrazine 4 at 10 °C. After complete addition
(1-2 min), the mixture was stirred for 3.5 h at 10 °C. To the
C
13H14N2O6: C, 53.06; H, 4.80; N, 9.52. Found: C, 53.24; H,
4.91; N, 9.67.
Th iou r ea Red u ction of 22: Meth yl 5a R(S),6R(S),9a S-
(R)-6-H yd r oxy-2-oxo-2,3,5a ,6,7,8,9,9a -oct a h yd r o-1-oxa -
J . Org. Chem, Vol. 68, No. 18, 2003 7013

O¨ zer et al.
3,4-d ia za ben zo[cd ]a zu len e-5-ca r boxyla te (24). A solution
of 22 (210 mg, 0.7 mmol) and thiourea (320 mg, 4.2 mmol) in
10 mL of methanol was stirred at -30 °C. At the same
temperature, stirring was continued for 4 days. The precipi-
tated sulfur was filtrated, and the solvent was evaporated. The
residue was crystallized from methanol to give 24 (51 mg, 27%)
as yellow crystals: mp 149-151 °C; 1H NMR (200 MHz,
CDCl3) δ 9.21 (s, NH, 1H), 5.07 (bt, J ) 5.5 Hz, H9a,1H), 4.17
(m, H6, 1H), 3.94 (m, H5a, 1H), 3.87 (s, OCH3, 3H), 2.36 (m,
OH, 1H), 2.35-1.24 (m, 6H), 2.10-1.89 (m, 3H), 1.61-1.51 (m,
1H); 13C NMR (50 MHz, DMSO-d6) δ 166.9, 166.6, 134.1, 131.5,
p yr id a zin e-3-ca r boxyla te (27): 1H NMR (200 MHz, CDCl3)
δ 9.75 (bs, 1H), 8.43 (s, 1H), 5.70 (m, 1H), 4.09 (s, OCH3, 3H),
2.60 (t, J ) 6.5 Hz, 2H), 2.00-1.74 (m, 4H); 13C NMR (50 MHz,
CDCl3) δ 202.5, 166.4, 165.5, 153.9, 151.9, 148.2, 124.0, 81.0,
55.6, 44.7, 35.1, 19.5; IR (KBr, cm-1) 3463, 3080, 2953, 2876,
2723, 2263, 1778, 1727, 1600, 1446, 1421, 1344, 1268, 1217,
1114, 1063, 987, 910. Anal. Calcd for C12H12N2O5: C, 54.55;
H, 4.58; N, 10.60. Found: C, 54.34; H, 2.32; N, 10.45.
4-(6-Meth oxytetr a h yd r op yr a n -2-yl)p yr id a zin e-3,6-d i-
ca r boxylic Acid Dim eth yl Ester (cis/tr a n s-26b). A solution
of cis/ trans-26a (1:1 ratio, 180 mg, 0.61 mmol) and p-
toluensulfonic acid (20 mg, 0.066 mmol) in 20 mL of methanol
was refluxed for 12 h. After evaporation of the solvent, 50 mL
of CH2Cl2 was added to the residue. The formed organic layer
was separated, washed with water (2 × 50 mL), and dried over
anhydrous CaCl2, and the solvent was evaporated. The residue
was chromatographed on a short neutral Al2O3 column (15 g,
activity 3). Elution with ether (100 mL) gave a mixture of cis/
trans-26b as a brown oil (133 mg, 71%, 3:7 ratio): 1H NMR
(200 MHz, CDCl3) δ 8.51 (s, 2H), 5.30 (dd, J ) 11.2 Hz, 1.6
Hz, 1H), 5.07 (dd, J ) 11.0 Hz, 1.7 Hz, 1H), 4.87 (m, 1H), 4.06
(s, OCH3, 3H), 4.04 (s, OCH3, 3H), 3.46 (s, OCH3, 3H), 3.31 (s,
OCH3, 3H), 2.08-1.21 (m, 6H); 13C NMR (50 MHz, CDCl3) δ
166.8, 166.6, 165.9, 165.8, 154.4, 153.0, 152.7, 146.3, 145.4,
127.8, 127.6, 105.6, 101.0, 74.4, 67.8, 58.1, 56.8, 55.2 (2), 55.1
(2C), 35.0, 34.1, 32.5, 31.2, 24.4, 20.2. Anal. Calcd for
129.0, 82.9, 71.1, 53.5, 37.9 (2C), 33.5, 17.8; IR (KBr, cm-1
)
3565, 3514, 3361, 3285, 2953, 2876, 1778, 1753, 1727, 1702,
1625, 1600, 1472, 1446, 1395, 1370, 1293, 1268, 1217, 1140,
1114, 1063, 987.
Th iou r ea Red u ction of 23: Meth yl 6R(S),9a S(R)-6-
H yd r oxy-2-oxo-2,6,7,8,9,9a -h exa h yd r o-1-oxa -3,4-d ia za -
ben zo[cd ]a zu len e-5-ca r boxyla te (25a ). To a stirred solution
of 23 (100 mg, 0,34 mmol) in 10 mL of CH2Cl2 was added a
solution of thiourea (104 mg, 1.36 mmol) in 10 mL of methanol.
After the addition was complete, stirring was continued for 4
days. The precipitated sulfur was filtrated, and the solvent
was evaporated. The residue was crystallized from methanol
to give 25a as a yellow crystals (47 mg, 53%): mp 186-188
°C); 1H NMR (200 MHz, DMSO-d6) δ 6.35 (d, J ) 5.1 Hz, OH,-
1H), 5.72 (dd, H9a, J ) 9.3 Hz, 5.1 Hz, 1H), 5.0 (m, H6, 1H),
3.89 (s, OCH3, 3H), 2.37-2.31 (m, 1H), 2.10-1.89 (m, 3H),
1.61-1.51 (m, 2H); 13C NMR (50 MHz, DMSO-d6) δ 168.5 (+),
167.4 (+), 154.3 (+), 149.3 (+), 146.9 (+), 140.9 (+), 82.2 (-),
C
14H18N2O6: C, 54.19; H, 5.85; N, 9.03. Found: C, 54.03; H,
5.75; N, 9.18.
CoTP P -Ca ta lyzed Rea ction of 22. The CoTPP-catalyzed
reaction of 22 was performed as described for 8. After 2 h, the
71.1 (-), 54.5 (-), 38.5 (+), 31.8 (+), 23.7 (+); IR (KBr, cm-1
)
3463, 3412, 3029, 2953, 2876, 1804, 1753, 1625, 1574, 1446,
1395, 1344, 1293, 1242, 1191, 1140, 1114, 1089, 1063, 1012,
987, 936, 859.
products 26a and 27 were formed in
a ratio of 5:1 in
quantitative yield.
Dim eth yl 1R(S),7S(R),8R(S)-12,13-Dioxa -4,5-d ia za tr i-
cyclo[6.3.2.02,7]tr id eca -2,5,9-tr ien e-3,6-d ica r boxyla te (30).
A solution of endoperoxide 29 (176 mg, 1.98 mmol) and
tetrazine 4 (283 mg, 1.43 mmol) in 15 mL of CHCl3 was stirred
at room temperature for 27 h. After removal of the solvent,
the residue was chromatographed on a short neutral Al2O3
column (15 g, activity 3). Elution with CHCl3 gave 30 as pale
yellow crystals from CH2Cl2/ether (230 mg, 55%): mp 99-100
6-Acet oxy-2-oxo-2,6,7,8,9,9a -h exa h yd r o-1-oxa -3,4-d i-
a za ben zo[cd ]a zu len e-5-ca r boxylic Acid Meth yl Ester
(25b). To a stirred solution of 25a (90 mg, 0.34 mmol) in 1.5
g pyridine was added Ac2O (300 mg, 2.94 mmol) at 0 °C. The
reaction mixture was stirred at the room temperature for 18
h. The mixture was cooled to 0 °C, 40 mL of 2 N HCl solution
was added, and the mixture was extracted with ethyl acetate
(3 × 35 mL). The combined organic layers were washed with
NaHCO3 solution (2 × 50 mL) and water (100 mL) and then
dried (Na2SO4). The residue was chromatographed on a short
silica gel column (5 g). Elution with CHCl3 gave 25b as
colorless crystals from CH2Cl2/ether (54 mg, 37%): mp 181-
1
°C; H NMR (200 MHz, CDCl3) δ 8.39 (bs, NH, 1H), 6.25 (bd,
J ) 3.1 Hz, OCH, 1H), 6.10-6.02 (m, dCH, 1H), 5.88-5.79
(m, dCH, 1H), 5.07 (m, OCH, 1H), 3.90 (s, OCH3, 3H), 3.85 (s,
OCH3, 3H), 3.50 (s, CH, 1H), 3.05 (bd, A part of AB system, J
) 18.8 Hz, CH2, 1H), 2.78 (dt, B part of AB system, J ) 18.8,
5.3 Hz, CH2, 1H); 13C NMR (50 MHz, CDCl3) δ 164.6, 161.4,
138.9, 133.0, 128.1, 125.03, 115.0, 80.7, 73.4, 53.5, 53.0, 37.3,
34.7; IR (KBr, cm-1) 3390, 3020, 2940, 2880, 2840, 1700, 1595,
1450, 1335, 1250, 1110, 900; MS m/z (M+) 294 (28), 276 (30),
265 (81), 250 (100), 235 (94), 225 (47), 217 (49), 205 (49), 193
(56). Anal. Calcd for C13H14N2O6: C, 53.06; H, 4.80; N, 9.52.
Found: C, 52.93; H, 4.66; N, 9.43.
1
182 °C); H NMR (200 MHz, CDCl3) δ 6.19 (dd, J ) 10.1 Hz,
1.8 Hz, H6, 1H), 5.55 (dd, J ) 12.2 Hz, 4.5 Hz, H9a, 1H), 4.06
(s, OCH3, 3H), 2.70-2.60 (m, 1H), 2.16 (s, OCCH3, 3H), 2.33-
1.25 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 170.6, 167.4, 166.4,
153.7, 149.8, 146.4, 136.3, 81.4, 72.7, 55.3, 34.9, 32.9, 23.8, 22.5;
IR (KBr, cm-1) 3004, 2978, 2953, 2902, 1829, 1778, 1600, 1446,
1395, 1319, 1242, 1140, 1063, 1038, 910, 808. Anal. Calcd for
C
14H14N2O6: C, 54.90; H, 4.61; N, 9.15. Found: C, 54.74; H,
Dim et h yl 1R(S),8S(R)-12,13-Dioxa -4,5-d ia za t r icyclo-
[6.3.2.02,7]tr id eca -2,4,6,9-tetr a en e-3,6-d ica r boxyla te (31).
The oxidation of 30 to 31 was carried out as described for 8
starting with 310 mg (1 mmol) of 30 and 500 mg (1.16 mmol)
of PIFA. The residue (310 mg) was crystallized from CH2Cl2/
ether to give pale yellow crystals (120 mg, 34%): mp 155-
156 °C; 1H NMR (200 MHz, CDCl3) δ 6.36-6.27 (m, 3H), 5.80
(dt, B part of AB-system, J ) 10.2, 3.6 Hz, dCH, 1H), 4.10 (s,
OCH3, 6H), 3.30 (bd, A part of AB-system, J ) 20.0 Hz, CH2,
1H), 2.68 (bd, B part of AB-system, J ) 20.0 Hz, CH2, 1H);
13C NMR (50 MHz, CDCl3) δ 165.8 (2C), 150.0, 147.4, 141.7,
471; N, 9.34.
Th er m olysis Rea ction of 22. A magnetically stirred
solution of the endoperoxide 22 (300 mg, 1 mmol) in CCl4 (40
mL) was refluxed for 10 h. While the lactone 27 was separated
as a yellow viscose oil (41 mg, 14%), pyranyl pyridazine
derivative cis/ trans-26a remained in CCl4 solution. The
solvent was removed and the cis/ trans-26a was obtained as
the pale brown oil (230 mg, 77%). Thermolysis products (cis/
trans-26a and 27) were not stable toward column materials,
and crystallization failed.
Dim et h yl 4-(6-h yd r oxyt et r a h yd r op yr a n -2-yl)p yr id a -
zin e-3,6-d ica r boxyla te (cis/tr a n s-26a ): 1H NMR (200 MHz,
CDCl3) δ 8.38 (s, 1H), 8.30 (s, 1H), 5.40 (m, 2H), 4.99 (d, J )
10 Hz, 1H), 4.88 (d, J ) 8.6 Hz, 1H), 4.02 (s, OCH3, 3H), 4.01
(s, OCH3, 3H), 3.99 (s, OCH3, 3H), 3.98 (s, OCH3, 3H), 2.09-
1.19 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 166.7 (2C), 165.9,
165.7, 154.3, 154.1, 153.5, 152.7, 146.5, 145.8, 127.9 (2C), 98.8,
94.2, 74.5, 67.7, 55.3 (4C), 34.7, 33.9 (2C), 31.3, 24.4, 19.5.
137.2, 134.3, 130.0, 76.6, 74.3, 55.7 (2C), 37.4; IR (KBr, cm-1
)
3035, 2925, 2900, 1765, 1440, 1415, 1362, 1320, 1310, 1270,
1230, 1164, 1100, 1025, 975, 945, 825. Anal. Calcd for
C
13H12N2O6: C, 53.43; H, 4.14; N, 9.59. Found: C, 53.45; H,
4.08; N, 9.68.
Th iou r ea Red u ction of 30: Meth yl 2-Oxo-2,8,9,9a -tet-
r a h yd r o-1-oxa -3,4-d ia za b e n zo[cd ]a zu le n e -5-ca r b oxy-
la te (32). To a stirred solution of 30 (100 mg, 0,34 mmol) in
10 mL of CHCl3 was added a solution of thiourea (52 mg, 0.68
Met h yl 7-oxo-5-(4-oxob u t yl)-5,7-d ih yd r ofu r o[3,4-c]-
7014 J . Org. Chem., Vol. 68, No. 18, 2003

Unusual Bicyclic Endoperoxides Containing the Pyridazine Ring
mmol) in 10 mL of methanol. After the addition was complete,
stirring was continued for 18 h. The precipitated sulfur was
filtrated, and the solvent was evaporated. The residue was
chromatographed on a short silica gel column (5 g). Elution
with CHCl3 gave 32 as yellow crystals (65 mg, 77%) from CH2-
Cl2/ether: mp 136-137 °C; 1H NMR (200 MHz, CDCl3) δ 6.96
(dt, A part of AB system, H6, J ) 12.3 Hz, 2.2 Hz, 1H), 6.58
(dt, B part of AB system, H7, J ) 12.3 Hz, 4.4 Hz, 1H), 5.50
(dd, J ) 12.1 Hz, 2.9 Hz, H9a, 1H), 4.06 (s, OCH3, 3H), 2.91-
2.70 (m, 3H), 2.01-1.83 (m, 1H); 13C NMR (50 MHz, CDCl3) δ
167.3, 166.6, 151.9, 149.7, 147.8, 146.0, 131.2, 121.9, 80.4, 55.6,
30.6, 30.5; IR (KBr, cm-1) 3285, 2953, 2927, 1804, 1753, 1727,
1625, 1600, 1497, 1446, 1395, 1344, 1293, 1263, 1217, 1140,
1114, 1012, 961, 936. Anal. Calcd for C12H10N2O4: C, 58.54;
H, 4.09; N, 11.38. Found: C, 58.41; H, 4.00; N, 11.23.
mixture was stirred for 1 day at rt, and then the solvent was
evaporated. Cleavage product cis/ trans-33 was formed quan-
1
titatively. The H NMR analysis of the crude product showed
the presence of a mixture of cis/ trans-33 in a ratio of 3:7. The
crystallization of the residue from methanol gave cis/ trans-
33 (55 mg, 55%): 1H NMR (200 MHz, CDCl3) δ 8.50 (s, 1H),
8.37 (s, 1H), 5.92-5.71 (m, 6H), 5.46 (m, 1H), 5.28 (m, 1H),
4.07 (s, OCH3, 3H), 4.06 (s, OCH3, 3H), 4.05 (s, OCH3, 3H),
4.03 (s, OCH3, 3H), 3.98 (d, OH, 1H), 3.88 (m, OH, 1H), 2.59-
2.14 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 166.9 (2C), 160.0,
165.9, 154.5, 154.2, 154.1, 153.3, 144.9, 144.8, 128.8, 128.6,
128.2, 127.3 (2C), 125.8, 95.2, 92.5, 73.3, 67.7, 55.5 (4C, OCH3),
33.7, 32.0.
Ack n ow led gm en t. We are indebted to the Depart-
ment of Chemistry and Atatu¨rk University (Project No.
2001/28) and the Turkish Academy of Sciences for
financial support of this work.
CoTP P -Catalyzed Reaction 30: Dim eth yl 4-(6-Hydr oxy-
5,6-d ih yd r o-2H -p yr a n -2-yl)p yr id a zin e -3,6-d ica r b oxy-
la te (33). To a magnetically stirred solution of the endoper-
oxide 30 (100 mg, 0.34 mmol) in CH2Cl2 (20 mL) was added a
catalytic amount 10 mg of CoTPP at room temperature. The
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J . Org. Chem, Vol. 68, No. 18, 2003 7015