(Na2SO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (70% EtOAc/hexane) to give
7a (147 mg, 0.58 mmol, 85%) as a yellow solid.
pounds 4a and 5a in 76% and 94% yield by treatment
with NBS in dioxane at room temperature within 1 min.
Piperidine of monopiperidinyl compounds 6a and 7a
was substituted by methanol in the presence of H2SO4
in low yields. The resulting methoxy compound 7i could
be changed to methylaziridinyl compound by SNAr of
methylaziridine. We anticipate that the alkylamino
compounds that cannot be prepared by the debromination
reaction can be prepared from methoxy compound. From
7i, 7a and 7e were obtained 60% and 32%, respectively.
A comparison of chemical shifts in 1H NMR and Rf
values of 7-alkylamino compounds (5a -h ) with 6-alky-
lamino compounds (4a -h ) shows general tendencies.7
The peaks of H-4 of 5a -h appeared in more downfield
than those of H-4 of 4a -h .9 The peaks of H-6 of 7a -h
appeared in more upfield than those of H-7 of 6a -h .9 In
addition, the 6-hydro- or 6-bromo-7-alkylamino com-
pounds (5a -h ) or (7a -h ), respectively, have larger Rf
values than the 7-hydro- or bromo-6-alkylamino com-
pounds (4a -h ) or (6a -h ) in the eluent condition of ethyl
acetate/hexane.
In conclusion, 7-alkylamino-2-methylquinoline-5,8-di-
ones were synthesized by the new synthetic routes
nucleophilic substitution of amines and debrominations
from 6,7-dibromo-2-methylquinoline-5,8-dione. Some
alkylamino compounds cannot be prepared by this syn-
thetic route due to their instability during debromination.
But, these compounds could be prepared by another
pathway via methoxyquinoline-5,8-diones in low yields.
However, this new synthetic route presented in this
paper would be useful and efficient to synthesize quino-
linediones and to study their biological activities.
2-Meth yl-7-p ip er id in ylqu in olin e-5,8-d ion e (7a ): mp 157-
1
158 °C; H NMR (200 MHz, CDCl3) δ 8.24 (d, J ) 7.8 Hz, 1H),
7.47 (d, J ) 8.2 Hz, 1H), 6.01 (s, 1H), 3.56 (bs, 4H), 2.73 (s, 3H),
1.73 (bs, 6H); 13C NMR (50 MHz, CDCl3) δ 182.1, 182.0, 162.9,
154.0, 148.0, 133.8, 127.5, 126.9, 108.3, 50.4, 25.7, 24.9, 24.2;
MS (EI) 256 (M+, 100), 227, 213, 201, 189, 174, 161, 145, 117,
101, 84, 41. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N,
10.93. Found: C, 70.07; H, 6.61; N, 11.11.
Meth od B. In Acetic Acid w ith Sca ven ger . Concentrated
HBr (48%, 2.0 mL) was excessively added to the mixture of 5b
(228 mg, 0.85 mmol), aniline (0.5 mL), and acetic acid (10 mL)
in a two-neck flask (100 mL) with stirring at 20 °C. The mixture
was refluxed for 1 h, basified with aqueous NaHCO3, and
extracted with EtOAc. The organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography (70% EtOAc/hexane) to give 7b (98 mg, 0.52
mmol, 62%) as a yellow solid.
7-Am in o-2-m eth ylqu in olin e-5,8-d ion e (7b): mp 224-225
1
°C; H NMR (200 MHz, CDCl3) δ 8.29 (d, J ) 8.2 Hz, 1H), 7.50
(d, J ) 8.6 Hz, 1H), 6.03 (s, 1H), 5.35 (bs, 2H), 2.74 (s, 3H);13
C
NMR (50 MHz, DMSO-d6 + CDCl3) δ179.7, 178.6, 160.1, 147.9,
143.9, 131.8, 126.2, 125.8, 100.4, 22.6; MS (EI) 188 (M+, 100),
132, 119, 104, 93, 64, 52, 32. Anal. Calcd for C10H8N2O2: C,
63.82; H, 4.28; N, 14.89. Found: C, 63.44; H, 4.63; N, 15.28.
7-Meth oxy-2-m eth ylqu in olin e-5,8-d ion e (7i). Compound
7a (344 mg, 1.34 mmol) was dissolved in methanol (20 mL) at
20 °C, and H2SO4 (1 mL) was added. The mixture was refluxed
for 2 h, concentrated in vacuo, neutralized by NaHCO3, and
extracted with EtOAc. The organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography (50% EtOAc/hexane) to give 7i (85 mg, 0.42
mmol, 31%) as a yellow solid: mp 170-172 °C; 1H NMR (400
MHz, CDCl3) δ 8.30 (d, J ) 8.0 Hz, 1H), 7.54 (d, J ) 8.0 Hz,
1H), 6.21 (s, 3H), 3.95 (s, 3H), 2.78 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 183.7, 178.4, 164.5, 160.7, 146.3, 134.4, 127.9, 126.9,
109.1, 56.6, 25.1; MS (EI) 203 (M+, 100), 174, 145, 132, 117, 104,
77, 64, 53, 39. Anal. Calcd for C11H9NO3: C, 65.02; H, 4.46; N,
6.89. Found: C, 65.02; H, 4.49; N, 7.17.
Exp er im en ta l Section
Gen er a l P r oced u r e for 4a -h a n d 5a -h . Piperidine (0.7
mL, 7.08 mmol, 5 equiv) or piperidine (1.2 equiv) and triethy-
lamine (5 equiv) were added to the mixture of 3 (460 mg, 1.39
mmol) and THF (15 mL) with stirring at 20 °C. The mixture
was stirred for 5 min and was concentrated in vacuo at 20 °C in
a water bath. The residue was purified by flash column chro-
matography (40% EtOAc/hexane) to give 5a (226 mg, 0.675
mmol, 47%) as a red solid and 4a (183 mg, 0.546 mmol, 39%) as
a red solid.
6-Meth oxy-2-m eth ylqu in olin e-5,8-d ion e (6i). Compound
6i was prepared by the same method as for 7i in 37% yield: mp
1
204-206 °C; H NMR (400 MHz, CDCl3) δ 8.32 (d, J ) 8.0 Hz,
1H), 7.56 (d, J ) 8.0 Hz, 1H), 6.34 (s, 3H), 3.97 (s, 3H), 2.78 (s,
3H);13C NMR (100 MHz, CDCl3) δ 182.9, 179.1, 165.0, 159.6,
146.7, 134.4, 126.9, 125.4, 109.9, 56.3, 24.9; MS (EI) 203 (M+,
100), 188, 175, 145, 117, 104, 77, 69, 53, 39. Anal. Calcd for
C11H9NO3: C, 65.02; H, 4.46; N, 6.89. Found: C, 65.32; H, 4.55;
N, 7.10.
6-Br om o-2-m eth yl-7-p ip er id in ylqu in olin e-5,8-d ion e (5a ):
1
mp 122-124 °C; H NMR (200 MHz, CDCl3) δ 8.31 (d, J ) 8.0
Hz, 1H), 7.48 (d, J ) 8.0 Hz, 1H), 3.59 (bs, 4H), 2.74 (s, 3H),
1.77 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 179.6, 176.5, 163.4,
153.0, 146.1, 134.3, 127.2, 125.5, 113.4, 53.0, 26.3, 24.5, 23.6;
MS (EI) 336 (M+, 100), 334 (M+), 255, 253, 227, 225, 197, 195,
174, 117, 89, 84, 41. Anal. Calcd for C15H15BrN2O2: C, 53.75;
H, 4.51; N, 8.36. Found: C, 53.53; H, 4.57; N, 8.02.
2-Meth yl-7-m eth ylazir idin ylqu in olin e-5,8-dion e (7e). Com-
pound 7i (85 mg, 0.42 mmol) was dissolved in chloroform (10
mL) at 20 °C, and triethylamine (1 mL) was added. The mixture
was refluxed for 5 h and was concentrated in vacuo. The residue
was purified by flash column chromatography (50% EtOAc/
hexane) to give 7e (31 mg, 0.14 mmol, 32%) as a yellow solid:
1
mp 106-107 °C; H NMR (200 MHz, CDCl3) δ 8.03 (d, J ) 8.0
7-Br om o-2-m eth yl-6-p ip er id in ylqu in olin e-5,8-d ion e (4a ):
1
Hz, 1H), 7.40 (d, J ) 8.0 Hz, 1H), 6.14 (s, 1H), 2.64 (s, 3H), 2.25-
2.40 (m, 1H), 2.10-2.20 (m, 2H), 1.37 (d, J ) 5.4 Hz, 3H); 13C
NMR (50 MHz, CDCl3) δ 183.4, 180.0, 163.7, 157.8, 146.6, 134.0,
127.4, 126.9, 117.4, 36.3, 34.4, 24.8, 17.3; MS (CI) 229 (M+ + 1),
215, 201, 189, 57, 43; HRMS m/z (EI) 228.0917, calcd for
C13H12N2O2 228.0899.
mp 134-135 °C; H NMR (200 MHz, CDCl3) δ 8.20 (d, J ) 8.0
Hz, 1H), 7.45 (d, J ) 8.0 Hz, 1H), 3.56 (bs, 4H), 2.75 (s, 3H),
1.76 (bs, 6H); 13C NMR (50 MHz, CDCl3) δ 181.2, 176.7, 164.9,
152.5, 146.5, 135.0, 126.7, 125.9, 116.4, 53.4, 26.7, 25.2, 23.9;
MS (EI) 336 (M+, 100), 334 (M+), 281, 257, 227, 173, 116, 89,
41. Anal. Calcd for C15H15BrN2O2: C, 53.75; H, 4.51; N, 8.36.
Found: C, 53.79; H, 4.66; N, 8.11.
Ack n ow led gm en t. This research was supported by
the grant of ChemOn, Co., Ltd. (2001).
Gen er a l P r oced u r e for 6a -h a n d 7a -h . Meth od A. In
Dioxa n e w ith ou t Sca ven ger . Concentrated HBr (48%, 0.1 mL,
1.3 equiv) was added to the mixture of 5a (226 mg, 0.68 mmol)
and dioxane (10 mL) in a two-neck flask (100 mL) with stirring
at 20 °C. The mixture was stirred for 5 min at 60 °C in a water
bath, concentrated in vacuo, basified with aqueous NaHCO3 (10
mL), and extracted with EtOAc. The organic layer was dried
Su p p or tin g In for m a tion Ava ila ble: Characterization of
the rest of the compounds synthesized and1H and 13C NMR
spectra of 4a -h , 5a -h , 6a -c,f-i, 7a -c,e-i, and 8a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Detail data are in the Supporting Information.
J O0257039
J . Org. Chem, Vol. 67, No. 15, 2002 5393