Dang et al.
2
3
(EI, 70 eV): m/z ) 232 (M+, 10), 143 (5), 131 (7), 115 (9), 28
(100). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06.
Found: C, 66.99; H, 6.70; N, 12.03.
2.65 (m, 1 H, CH2), 2.88 (dd, J ) 15 Hz, J ) 7 Hz, 1 H, CH),
3.95-4.03 (m, 2 H, CH, OCH2), 4.56-4.62 (m, 1 H, CH2), 7.16-
3
7.28 (m, 2 H, Ar), 7.56 (d, J ) 8 Hz, 1 H, Ar), 7.67 (br s, 1 H,
Ar). 13C NMR (75 MHz, CDCl3): δ ) 21.3, 22.3, 22.8, 50.5, 67.9,
122.9, 126.3, 128.2, 130.6, 136.0, 138.1, 150.7, 153.4. MS (EI, 70
eV): m/z ) 230 (M+, 100), 143 (78), 128 (51), 117 (40), 114 (42).
Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.16. Found:
C, 67.66; H, 6.27; N, 11.70.
General Procedure for the Cyclization of Dilithiated Hydra-
zones with Epibromohydrin. To a THF solution (40 mL) of 6
(4.0 mmol) was added n-butyllithium (9.0 mmol, 2.5 M) at -78
°C. After being stirred for 1 h at -78 °C, the mixture was stirred
for 10 min at 20 °C. To the solution was added 2 (4.4 mmol) at
-78 °C. The reaction mixture was allowed to warm to 20 °C over
16 h. Subsequently, a saturated aqueous solution of NH4Cl was
added. The organic and the aqueous layers were extracted with
EtOAc (2 × 30 mL). The combined organic layers were dried (Na2-
SO4) and filtered, and the solvent of the filtrate was removed in
vacuo. The residue was purified by chromatography (silica gel,
n-heptane/ EtOAc, 4:1f 1:1).
2-Phenyl-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-7-one (7a).
Starting with 6a (0.41 g, 2.0 mmol), THF (10 mL), n-BuLi (2.0
mL, 5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol), 7a was
isolated as a yellow solid (0.200 g, 46%). Mp ) 199 °C. IR (KBr,
cm-1): ν˜ ) 2901 (w), 1757 (s), 1402 (s). UV-vis (acetonitrile,
nm): λmax (log ꢀ) 206.92 (4.0), 218.22 (4.0), 281.41 (4.2). 1H NMR
(300 MHz, CDCl3): δ ) 1.78 (dddd, 2J ) 12 Hz, 3J ) 6 Hz, 3J )
2-(3-Methoxyphenyl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]py-
ridazin-7-one (7e). Starting with 6e (0.47 g, 2.0 mmol), n-BuLi
(2.0 mL, 5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in
THF (10 mL), 7e was isolated as a yellow solid (0.31 g, 62%). Mp
) 157 °C. IR (KBr, cm-1): ν˜ ) 3431 (w), 2951 (w), 2912 (w),
1759 (s), 1710 (w), 1604 (m), 1573 (m), 1464 (m), 1404 (s). UV-
vis (acetonitrile, nm): λmax (log ꢀ): 216.76 (4.3), 282.04 (4.2). 1H
NMR (300 MHz, CDCl3): δ ) 1.77-1.78 (m, 1 H, CH2), 2.33-
2
2.34 (m, 1 H, CH2), 2.52-2.65 (m, 1 H, CH2), 2.86 (dd, J ) 18
3
Hz, J ) 7 Hz, 1 H, CH), 3.82 (s, 3 H, OCH3), 3.99-4.04 (m, 2
H, CH, OCH2), 4.61-4.63 (m, 1 H, CH2), 6.92 (dd, 3J ) 8 Hz, 4J
3
) 2 Hz, 1 H, Ar), 7.27 (t, J ) 8 Hz, 1 H, Ar), 7.33-7.38 (m, 2
H, Ar). 13C NMR (75 MHz, CDCl3): δ ) 22.3, 22.7, 50.5, 55.3,
67.9, 110.9, 115.7, 118.2, 129.2, 137.5, 150.3, 153.2, 159.6. MS
(EI, 70 eV): m/z ) 246 (M+, 100), 159 (14), 144 (15), 133 (20),
77 (14). Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38.
Found: C, 63.31; H, 6.43; N, 11.06.
2
3
3
7 Hz, 1 H, CH2), 2.35 (dddd, J ) 12 Hz, J ) 6 Hz, J ) 7 Hz,
2
3
3
1 H, CH2), 2.60 (ddd, J ) 25 Hz, J ) 7 Hz, J ) 6 Hz, 1 H,
2
3
3
CH2), 2.88 (ddd, J ) 12 Hz, J ) 7 Hz, J ) 7 Hz, 1 H, CH),
3.95-4.04 (m, 2 H, CH, OCH2), 4.58-4.62 (m, 1 H, CH2), 7.34-
7.39 (m, 3 H, Ar), 7.79-7.83 (m, 2 H, Ar). 13C NMR (75 MHz,
CDCl3): δ ) 22.2, 22.3, 50.4, 67.9, 125.7, 128.3, 129.7, 136.1,
150.5, 153.3. MS (EI, 70 eV): m/z ) 216 (M+, 40), 206 (23), 161
(100), 133 (24), 105 (20). Anal. Calcd for C12H12N2O2: C, 66.65;
H, 5.59; N, 12.96. Found: C, 66.14; H, 5.68; N, 12.83.
2-(o-Tolyl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-7-
one (7f). Starting with 6f (0.44 g, 2.0 mmol), n-BuLi (2.0 mL, 5.0
mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in THF (10 mL),
7f was isolated as an orange oil (0.11 g, 24%). IR (KBr, cm-1): ν˜
) 3432 (s), 3124 (w), 3100 (w), 3061 (w), 2934 (s), 1761 (s), 1702
(s), 1601 (m), 1556 (m), 1456 (s). 1H NMR (300 MHz, CDCl3): δ
) 1.29-1.34 (m, 1 H, CH2), 2.29-2.42 (m, 4 H, CH2, CH3), 2.57-
2.63 (m, 1 H, CH2), 4.04-4.26 (m, 3 H, CH, OCH2), 4.64 (m, 1
H, CH2), 7.19-7.28 (m, 4 H, Ar). 13C NMR (75 MHz, CDCl3): δ
) 20.2, 22.7, 26.0, 50.3, 67.9, 125.5, 127.6, 128.6, 130.7, 135.6,
137.2, 153.4, 154.2. MS (EI, 70 eV): m/z ) 230 (M+, 50), 144
(60), 130 (50), 91 (19), 28 (100).
2-(p-Tolyl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-7-
one (7b). Starting with 6b (0.44 g, 2.0 mmol), n-BuLi (2.0 mL,
5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in THF (10
mL), 7b was isolated as a yellow solid (0.31 g, 56%): mp ) 222
°C. IR (KBr, cm-1): ν˜ ) 2361 (w), 2336 (w), 1755 (s), 1611 (w),
1467 (m), 1405 (s). UV-vis (acetonitrile, nm): λmax (log ꢀ) 209.24
(4.0), 214.60 (4.0), 220.28 (4.0), 283.68 (4.2). 1H NMR (300 MHz,
CDCl3): δ ) 1.73-1.84 (m, 1 H, CH2), 2.29-2.38 (m, 4 H, CH2,
CH3), 2.53-2.65 (m, 1 H, CH2), 2.88 (dd, 2J ) 18 Hz, 3J ) 6 Hz,
1 H, CH), 3.96-4.04 (m, 2 H, CH, OCH2), 4.56-4.63 (m, 1 H,
2-(Naphth-1-yl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-
7-one (7g). Starting with 6g (0.51 g, 2.0 mmol), n-BuLi (2.0 mL,
5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in THF (10
mL), 7g was isolated as an orange solid (0.27 g, 52%). Mp ) 66
°C. IR (KBr, cm-1): ν˜ ) 3437 (m), 3052 (w), 2928 (m), 2870
(m), 1774 (s), 1701 (s), 1600 (w), 1507 (m). UV-vis (acetonitrile,
nm): λmax (log ꢀ) 221.72 (4.6). 1H NMR (300 MHz, CDCl3): δ )
1.80-1.97 (m, 1 H, CH2), 2.26-2.34 (m, 1 H, CH2), 2.67-2.79
3
4
3
CH2), 7.17 (dd, J ) 8 Hz, J ) 2 Hz, 2 H, Ar), 7.71 (dd, J ) 8
Hz, J ) 2 Hz, 2 H, Ar). 13C NMR (75 MHz, CDCl3): δ ) 21.2,
4
22.2, 22.9, 50.5, 67.9, 125.7, 129.0, 133.3, 139.9, 150.5, 153.4.
MS (EI, 70 eV): m/z ) 230 (M+, 17), 160 (12), 143 (5), 91 (4),
28 (100).
3
(m, 1 H, CH2), 4.04-4.17 (m, 2 H, CH, OCH2), 4.63 (q, J ) 7
Hz, 2 H, CH2), 7.43-7.54 (m, 4 H, Ar), 7.83-7.88 (m, 2 H, Ar),
2-(4-Methoxyphenyl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]py-
ridazin-7-one (7c). Starting with 6c (0.47 g, 2.0 mmol), n-BuLi
(2.0 mL, 5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in
THF (10 mL), 7c was isolated as a yellow solid (0.20 g, 41%). Mp
) 209 °C. IR (KBr, cm-1): ν˜ ) 3034 (w), 2963 (w), 2935 (w),
2911 (w), 2844 (w), 1750 (s), 1607 (s), 1513 (m), 1467 (m), 1407
(s). UV-vis (acetonitrile, nm): λmax (log ꢀ) 287.90 (4.3). 1H NMR
(300 MHz, CDCl3): δ ) 1.31 - 1.36 (m, 1 H, CH2), 2.34 (m, 1
8.12 (d, J ) 7 Hz, 1 H, Ar). 13C NMR (75 MHz, CDCl3): δ )
3
22.7, 26.7, 50.4, 68.0, 124.8, 125.1, 125.7, 125.9, 126.7, 128.3,
129.4, 130.5, 133.6, 135.2, 153.4, 153.5. MS (EI, 70 eV): m/z )
266 (M+, 60), 194 (47), 180 (100), 167 (80), 152 (62).
2-(Naphth-2-yl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-
7-one (7h). Starting with 6h (0.51 g, 2.0 mmol), n-BuLi (2.0 mL,
5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in THF (10
mL), 7h was isolated as an orange solid (0.17 g, 31%). Mp ) 184
°C. IR (KBr, cm-1): ν˜ ) 3432 (m), 2955 (m), 2928 (m), 1758 (s),
1504 (m), 1470 (m), 1405 (s). UV-vis (acetonitrile, nm): λmax
(log ꢀ) 214.59 (4.3), 226.51 (4.3), 235.69 (4.3), 265.18 (4.2), 273.23
(4.2), 300.56 (4.2). 1H NMR (300 MHz, CDCl3): δ ) 1.86-1.92
(m, 1 H, CH2), 2.41-2.47 (m, 1 H, CH2), 2.70-2.83 (m, 1 H, CH2),
3.10 (dd, J ) 19 Hz, J ) 5 Hz, 1 H, CH2), 4.04-4.14 (m, 2 H,
CH, OCH2), 4.66-4.70 (m, 1 H, CH2), 7.47-7.54 (m, 3 H, Ar),
7.82 - 7.88 (m, 2 H, Ar), 8.13-8.18 (m, 2 H, Ar). 13C NMR (75
MHz, CDCl3): δ ) 22.2, 23.0, 50.7, 68.0, 123.2, 125.5, 126.4,
127.0, 127.7, 128.1, 128.6, 132.9, 133.6, 134.0, 150.2, 153.3. MS
(EI, 70 eV): m/z ) 266 (M+, 42), 209 (100), 180 (20), 152 (64),
127 (80).
2
3
H, CH2), 2.53-2.65 (m, 1 H, CH2), 2.87 (dd, J ) 18 Hz, J ) 6
Hz, 1 H, CH), 3.81 (s, 3 H, OCH3), 3.99-4.05 (m, 2 H, CH, OCH2),
4.62 (m, 1 H, CH2), 6.89 (dd, 3J ) 7 Hz, 4J ) 2 Hz, 2 H, Ar), 7.77
(dd, 3J ) 7 Hz, 4J ) 2 Hz, 2 H, Ar). 13C NMR (75 MHz, CDCl3):
δ ) 22.2, 23.1, 50.5, 55.3, 67.9, 113.7, 127.3, 128.8, 150.3, 153.4,
161.0. MS (EI, 70 eV): m/z ) 246 (M+, 65), 189 (34), 175 (21),
135 (65), 28 (100).
2
3
2-(m-Tolyl)-3,4,4a,5-tetrahydrooxazolo[3,4-b]pyridazin-7-
one (7d). Starting with 6d (0.44 g, 2.0 mmol), n-BuLi (2.0 mL,
5.0 mmol), and epibromohydrin (0.25 mL, 3.0 mmol) in THF (10
mL), 7d was isolated as a yellow solid (0.25 g, 53%). Mp ) 168
°C. IR (KBr, cm-1): ν˜ ) 3495 (w), 3409 (w), 3038 (w), 2912
(m), 1756 (s), 1602 (m), 1464 (m). UV-vis (acetonitrile, nm): λmax
(log ꢀ) 210.28 (4.2), 282.40 (4.2). 1H NMR (300 MHz, CDCl3): δ
) 1.72-1.80 (m, 1 H, CH2), 2.30-2.39 (m, 4 H, CH2, CH3), 2.53-
7i. To a THF solution (40 mL) of 6i (6.0 mmol, 1.02 g) was
added n-butyllithium (6.0 mL, 2.5 M) at -78 °C. After being stirred
2300 J. Org. Chem., Vol. 71, No. 6, 2006