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