Dormer et al.
azabicyclo[3.2.1]octane (2.8 mL, 15.4 mmol), H SO (38 µL,
5
2
1
5.8, 50.1, 42.3, 39.9, 39.7, 37.2, 36.5, 35.9, 35.6, 31.9, 31.6,
8.2, 26.0, 24.2, 21.0, 19.4, 18.7, 11.8; FTIR (CH Cl ) 1610,
552, 1521, 1502 cm-1
-(4-Ch lor obu tyl)-1,8-n a p h th yr id in e (3k ). The general
procedure was followed with the use of 2-aminonicotinaldehyde
2.50 g, 20.5 mmol), 95% 1,3,3-trimethyl-6-azabicyclo[3.2.1]-
octane (4.0 mL, 22 mmol), H SO (57 µL, 1.0 mmol), EtOH
12.5 mL), and a 2.72 M solution of 6-chloro-2-hexanone in
2
4
2
2
0.68 mmol) and methanol (8.0 mL) in a bath at 65 °C was
added a 0.848 M solution 2-amino-5-chlorobenzaldehyde in
methanol (16.5 mL, 14.0 mmol) over 60 min. The solution was
aged for an additional 60 min, whereupon it was concentrated.
.
2
1
(
H NMR indicated an 84:16 ratio of naphthyridine isomers.
Chromatography on silica gel (50:50 cyclohexane/CH
80 cyclohexane/CH Cl ), yielded the title compound as an oil
(2.37 g, 77%): H NMR (CD OD, 400 MHz) δ 8.19 (d, J ) 8.5,
2 2
Cl f 20:
2
4
(
2
2
1
1
ethanol (8.3 mL, 22.6 mmol). Gas chromatography and
NMR indicated a 93:7 ratio of naphthyridine isomers. Con-
centration and chromatography on silica gel (CH Cl f 10:90
EtOAc/ CH Cl ) yielded the title compound as an oil (3.15 g,
0%): H NMR (CD OD, 400 MHz) δ 9.03 (dd, J ) 4.3, 1.9,
H), 8.11 (dd, J ) 8.1, 1.9, 1H), 8.06 (d, J ) 8.2, 1H), 7.39 (dd,
H
3
1H), 7.94 (d, J ) 9.0, 1H), 7.90 (d, J ) 2.3, 1H), 7.68 (dd, J )
9.0, 2.3, 1H), 7.46 (d, J , ) 8.5, 1H), 2.95 (t, J ) 7.8, 1H), 1.79-
2
2
1
3
1.74 (m, 2H), 1.46-1.40 (m, 2H), 0.9733 (t, J ) 7.4, 3H);
NMR (CD
129.0, 127.5, 126.1, 122.3; FTIR (CH
C
2
2
1
7
1
3
3
OD, 100 MHz) δ 163.6, 145.5, 136.1, 131.2, 130.1,
Cl ) 1602, 1556, 1490
12 2
cm . Anal. Calcd for C12H N : C, 71.07; H, 6.42; N, 6.38.
2
2
-
1
J ) 8.1, 4.3, 1H), 7.35 (d, J ) 8.3, 1H), 3.55 (t, J ) 6.7, 2H),
3
.04 (t, J ) 7.6, 2H), 2.07-2.01 (m, 2H), 1.99-1.82 (m, 2H);
Found: C, 70.88; H, 6.35; N, 6.32.
1
3
C NMR (CD
36.8, 122.5, 121.5, 121.1, 44.8, 38.3, 32.2, 26.4.
-[2-(1,8-Naph th yr idin -2-yl)eth yl]-1,8-n aph th r yidin e (7).
3
OD, 100 MHz) δ 165.9, 156.0, 153.4, 137.1,
2-Bu tyl-5H-ch r om en o[2,3-b]p yr id in -5-on e (16). To a
solution of 98% 2-hexanone (1.24 mL, 9.85 mmol), 95% 1,3,3-
trimethyl-6-azabicyclo[3.2.1]octane (1.8 mL, 10.0 mmol),
1
2
The general procedure was followed with the use of 2-ami-
nonicotinaldehyde (2.50 g, 20.5 mmol), 95% 1,3,3-trimethyl-
2 4
H SO (25 µL, 0.45 mmol) and ethanol (10.0 mL) in a bath at
65 °C was added a slurry of 97% 2-amino-3-formylchromone
(1.75 g, 8.97 mmol) in ethanol (16.5 mL) over 80 min. The
solution was aged an additional 60 min, whereupon it was
6
-azabicyclo[3.2.1]octane (4.0 mL, 22 mmol), H
mmol), EtOH (12.5 mL), and a 1.36 M solution of 2,5-hexadione
6.37 mL, 8.66 mmol) in ethanol. HPLC indicated a 95:05:0
2 4
SO (57 µL, 1.0
1
(
concentrated. H NMR indicated an 80:20 ratio of regioisomers.
ratio of 7, 8, and 9, respectively. After aging at 65 °C for 60
min, the reaction was cooled to 0 °C and n-heptane (10 mL)
was added over 10 min. The slurry was aged an additional 40
min at 0 °C, whereupon the crystals were filtered and washed
Chromatography on silica gel (10:90 hexanes/CH
CH Cl ), yielded the title compound, which crystallized upon
2 2
Cl f 100%
2
2
solvent-switching to n-heptane. The resultant crystals were
filtered and washed with n-heptane, yielding the title com-
1
with n-heptane, yielding the title compound as a tan solid (1.15
pound as a white solid (1.59 g, 70%): mp ) 58.0-59.0 °C; H
1
g, 48%): mp ) 256.5-258.5 °C; ( H NMR (CD
3
OD, 400 MHz)
3
NMR (CDCl , 400 MHz) δ 8.61 (d, J ) 8.0, 1H), 8.32 (dd, J )
δ 8.97 (dd, J ) 4.3, 1.9, 2H), 8.36 (dd, J ) 8.2, 1.9, 2H), 8.3 (d,
J ) 8.4, 2H), 7.6 (d, J ) 8.3, 2H), 7.56 (dd, J ) 8.2, 4.3, 2H),
8.0, 1.7, 1H), 7.79-7.75 (m, 1H), 7.62 (broad d, J ) 7.9, 1H),
7.45-7.41 (m, 1H), 7.30 (d, J ) 8.0, 1H), 2.94 (t, J ) 7.7, 2H),
1.84-1.78 (m, 2H), 1.49-1.39 (m, 2H), 0.97 (t, J ) 7.3, 1H);
1
3
3
1
1
.62 (s, 4H); C NMR (CD
3
OD, 100 MHz) δ 165.6, 154.6, 153.1,
Cl ) 1606,
: C, 75.50; H, 4.93;
1
3
38.2, 138.0, 123.2, 122.0, 121.6, 37.4; FTIR (CH
2
2
C NMR (CD
137.3, 135.3, 126.6, 124.5, 121.7, 120.6, 118.4, 114.4, 38.5, 31.5,
22.5, 13.8; FTIR (CH Cl ) 1664, 1617, 1606, 1587, 1559, 1463
cm . Anal. Calcd for C12 : C, 75.87; H, 5.97; N, 5.53.
3
OD, 100 MHz) δ 177.5, 169.2, 160.1, 155.7,
-
1
552, 1498 cm . Anal. Calcd for C18
14 2
H N
N, 19.57. Found: C, 75.09; H, 4.78; N, 19.39.
2
2
-
1
12 2
H N
2
-Bu tyl-6,8-d ibr om oqu in olin e (11). The general proce-
Found: C, 75.92; H, 5.93; N, 5.39.
dure was followed with the use of 2-amino-3,5-dibromoben-
zaldehyde (2.70 g, 9.68 mmol), 95% 1,3,3-trimethyl-6-azabicyclo-
8-Meth yl-7,8-d ih yd r o-6H-cyclop en ta [b]-1,8-n a p h th yr i-
d in e (18). Under nitrogen, a solution of 2-aminonicitinalde-
hyde (2.50 g, 20.5 mmol), pyrrolidine (1.9 mL, 22.8 mmol) and
[
3.2.1]octane (1.9 mL, 10.6 mmol), H
2 4
SO (27 µL, 0.49 mmol),
EtOH (9.2 mL), and a 2.72 M solution of 2-hexanone in ethanol
1
(
3.9 mL, 10.6 mmol). H NMR indicated an 88:12 ratio of
naphthyridine isomers. Concentration and chromatography on
silica gel (90:10 hexanes/CH Cl f 80:20 hexanes/CH Cl
yielded the title compound as an oil (2.59 g, 78%): H NMR
CDCl
2 4
H SO (57 µL, 1.0 mmol) in ethanol (18 mL) was stirred at 24
°C. To this solution was added 2-methylcyclopentanone (2.42
mL, 22.5 mmol) over 35 min. The solution was aged at 24 °C
for an additional 18 h, whereupon it was concentrated. Chro-
matography on silica gel (CH Cl2 f 30:70 EtOAc/CH Cl )
2
2
2
2
)
1
(
1
7
7
3
, 400 MHz) δ 8.12 (d, J ) 2.1, 1H), 7.95 (d, J ) 8.4,
H), 7.90 (d, J ) 2.1, 1H), 7.36 (d, J ) 8.4, 1H), 3.03 (t, J )
.8, 2H), 1.90-1.82 (m, 2H), 1.50-1.44 (m, 2H), 0.99 (t, J )
2
2
2
yielded the title compound, which crystallized upon solvent
switching to n-heptane. The resultant crystals were filtered
and washed with n-heptane, yielding the title compound as a
1
3
.3, 3H); C NMR (CDCl
3
, 100 MHz) δ 164.7, 143.8, 135.5,
1
1
35.4, 129.4, 128.6, 125.8, 123.1, 118.6, 38.9, 31.4, 22.6, 14.0;
white solid (2.88 g, 76%): mp ) 94.1-95.6 °C; H NMR
-
1
FTIR (CH
for C12
3
2
Cl
: C, 45.51; H, 3.82; N, 4.08. Found: C, 45.33; H,
.65; N, 4.03.
Eth yl 3-(6,8-Dibr om oqu in olin -2-yl)bu ta n oa te (12). The
2
) 1605, 1590, 1544, 1482,1444 cm . Anal. Calcd
(CD OD, 400 MHz) δ 8.96 (dd, J ) 4.2, 1.9, 1H), 8.06 (dd, J )
3
H
12
N
2
8.1, 1.9, 1H), 7.84 (s, 1H), 7.36 (dd, J ) 8.1, 4.2, 1H), 3.36-
3.30 (m, 1H), 3.05-2.94 (m, 2H), 2.50-2.41 (m, 1H), 1.79-
1.72 (m, 1H), 1.49 (d, J ) 6.9, 3H); 13C NMR (CD
OD, 100
3
general procedure was followed with the use of 2-amino-3,5-
dibromobenzaldehyde (2.39 g, 8.58 mmol), 95% 1,3,3-trimethyl-
MHz) δ 174.8, 156.3, 151.8, 136.7, 136.6, 130.7, 121.7, 121.1,
40.9, 33.1, 28.7, 18.1; FTIR (CH Cl ) 1629, 1602, 1563, 1486,
2
2
-
1
6
0
4
-azabicyclo[3.2.1]octane (2.1 mL, 11.7 mmol), H
2
SO
4
(29 µL,
1455 cm .
.52 mmol), EtOH (10.0 mL), and a 2.78 M solution of ethyl
9-Me t h yl-6,7,8,9-t e t r a h yd r ob e n zo[b]-1,8-n a p h t h yr i-
d in e (20). Under nitrogen, a solution of 2-aminonicitinalde-
hyde (1.31 g, 10.7 mmol), 99% 2-methylcyclohexanone (2.6 mL,
21,2 mmol), TABO (2.1 mL, 11.8 mmol) and H SO (30 µL,
-acetylbutyrate in ethanol (4.2 mL, 11.7 mmol). 1H NMR
indicated an 89:11 ratio of naphthyridine isomers. Concentra-
tion and chromatography on silica gel (90:10 n-heptane/MTBE)
2
4
yielded an 89:11 mixture of 12 and the corresponding regio-
0.54 mmol) in ethanol (5 mL) was heated to 70 °C for 40 h,
whereupon additional 2-methylcylcohexanone (1.3 mL, 10.6
mmol) was added. The solution was aged at 70 °C for an
additional 48 h, whereupon it was concentrated. Chromatog-
raphy on silica gel (50:50 CH Cl /EtOAc) yielded the title
1
isomer, respectively, as an oil (2.90 g, 75% yield of 12):
NMR (Major isomer, CDCl
H
3
, 400 MHz) 8.14 (d, J ) 2.0, 1H),
7
1
7
.95 (d, J ) 8.4, 1H), 7.89 (d, J ) 2.0, 1H), 7.35 (d, J ) 8.4,
H), 4.13 (q, J ) 7.1, 2H), 3.07 (t, J ) 7.4, 2H), 2.49 (t, J )
.4, 2H), 2.23 (t, J ) 7.4, 2H), 1.26 (t, J ) 7.1, 3H); 13C NMR
2
2
compound, which crystallized upon solvent-switching to n-
heptane. The resultant crystals were filtered and washed with
(CDCl
3
, 100 MHz) δ 173.4, 163.1, 143.6, 135.6, 129.3, 128.5,
25.8, 123.0, 118.7, 60.3, 37.9, 33.6, 23.9, 14.3; FTIR (CH Cl
729, 1605, 1590, 1544, 1482, 1444 cm-1
-Bu tyl-6-ch lor oqu in olin e (14). To a solution of 98%
1
1
2
2
)
n-heptane, yielding the title compound as a white solid (1.15
.
1
g, 58%): mp ) 99.8-102.3 °C; H NMR (CDCl
3
, 400 MHz) δ
2
8.97 (dd, J ) 4.2, 1.9, 1H), 8.02 (dd, J ) 8.1, 1.9, 1H), 7.76 (s,
1H), 7.33 (dd, J ) 8.1, 4.2, 1H), 3.26-3.15 (m, 1H), 2.96 (t, J
2
-hexanone (1.9 mL, 15.4 mmol), 95% 1,3,3-trimethyl-6-
4
76 J . Org. Chem., Vol. 68, No. 2, 2003