T. Lebl et al. / Tetrahedron 66 (2010) 9694e9702
9701
then cooled and the solution concentrated in vacuo. The residue was
purified by distillation.
procedure A. Mp 168e169 ꢂC; 1H NMR (300 MHz, CDCl3):
d
¼8.73
(dd, 3J¼7.9 Hz, 4J¼2.0 Hz, 1H, C4-H), 8.51 (dd, 3J¼4.5 Hz, 4J¼2.0 Hz,
1H, C2-H), 7.53e7.50 (m, 2H, AreH), 7.28e7.24 (m, 2H, AreH, C3-H),
7.17e7.13 (m, 1H, AreH), 3.08e2.93 (m, 2H, C6-H2), 2.64e2.59 (m,
2H, C10-H2), 1.87e1.79 (m, 2H, C8-H2), 1.67e1.60 (m, 2H, C7-H2),
4.3.1. 13-(3-Chlorophenyl)-8,9,10,11-tetrahydro-5H-pyrido[2,3-b][1]
azacycloundecine-5,6,12-(7H,13H)-trione (1b). The title compound
1b (257 mg, 0.720 mmol, 72%) was afforded as a yellow solid using
general procedure B.
1.59e1.52 (m, 2H, C9-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼176.5
(C5), 155.4 (C10a), 151.9 (C2), 151.1 (C11a), 140.8 (C10), 136.1 (C4),
135.3 (C30), 130.7 (Ar), 129.8 (Ar), 129.4 (Ar), 127.7 (Ar), 124.9 (C5a),
119.6 (C3), 119.3 (C4a), 32.2 (C10), 32.0 (C8), 26.7 (C7), 25.5 (C9),
24.1 (C6); IR (KBr): nmax¼2932 (m), 1617 (s) (C]O), 1589 (m), 1542
(w), 1475 (m), 1425 (m), 1296 (m), 785 (m), 750 (w) cmꢁ1; LRMS
Mp 115e116 ꢂC; 1H NMR (300 MHz, CDCl3):
d
¼8.29 (dd,
3J¼4.9 Hz, 4J¼2.0 Hz, 1H, C2-H), 8.04 (dd, 3J¼7.7 Hz, 4J¼2.0 Hz, 1H,
C4-H), 7.34e7.30 (m, 1H, AreH), 7.29e7.23 (m, 2H, AreH), 7.22e7.17
(m, 1H, AreH), 7.14e7.09 (m, 1H, C3-H), 3.44e3.30 (m, 1H, C7-H),
2.65e2.54 (m, 1H, C70-H), 2.34e2.21 (m, 1H, C11-H), 2.07e1.98 (m,
1H, C110-H), 1.92e1.78 (m, 1H, C8-H), 1.69e1.46 (m, 4H, C80-H, C10-
H2, C9-H), 1.22e1.08 (m, 1H, C90-H); 13C NMR (75.5 MHz, CDCl3):
(ESþ): m/z (%) 347.13 (100) [M35ClþNa]þ; HRMS (ESþ): m/z calcd for
35
C19
H
ClN2NaO [M35ClþNa]þ: 347.0927; found: 347.0913.
17
d
¼201.5 (C6), 188.8 (C5), 175.5 (C12), 151.6 (C2), 151.4 (C13a), 142.6
4.3.4. 12-(3-Chlorophenyl)-6,7,8,9,10,11-hexahydrocycloocta[b][1,8]
naphthyridin-5(12H)-one (2c). The title compound 2c (5.43 g,
16.0 mmol, 51%) was afforded as a cream solid using general pro-
(C10), 139.2 (C4), 135.1 (C30), 130.5 (Ar), 129.9 (Ar), 128.8 (Ar), 128.0
(Ar), 126.0 (C4a), 121.8 (C3), 36.0 (C11), 34.3 (C7), 25.0 (C9), 22.5
(C10), 21.5 (C8); IR (KBr): nmax 2944 (m), 1710 (s) (C]O), 1686 (s)
(C]O), 1655 (s) (C]O), 1589 (s), 1475 (m), 1423 (m), 1364 (m), 1266
cedure A. Mp 190e191 ꢂC; 1H NMR (300 MHz, CDCl3):
d¼8.74 (dd,
3J¼7.6 Hz, 4J¼1.9 Hz, 1H, C4-H), 8.51 (dd, 3J¼4.6 Hz, 4J¼1.9 Hz, 1H,
C2-H), 7.55e7.50 (m, 2H, AreH), 7.31e7.25 (m, 2H, AreH, C3-H),
7.21e7.18 (m, 1H, AreH), 2.96e2.83 (m, 2H, C6-H2), 2.74e2.69 (m,
2H, C11-H2), 1.81e1.73 (m, 2H, C7-H2), 1.56e1.42 (m, 6H, C10-H2,
(s), 741 (s) cmꢁ1; LRMS (ESþ): m/z (%) 379.18 (100) [M35ClþNa]þ;
HRMS (ESþ): m/z calcd for C19
H
ClN2NaO3 [M35ClþNa]þ:
35
17
379.0835; found: 379.0825.
C8-H2, C9-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼177.0 (C5), 151.9 (C2),
4.3.2. 14-(3-Chlorophenyl)-7,8,9,10,11,12-hexahydropyrido[2,3-b][1]
azacyclododecine-5,6,13-(14H)-trione (1c). Method 1: The title
compound 1c (89 mg, 0.24 mmol, 24%) was afforded as a yellow oil
using general procedure B with an additional 20 h stirring at room
151.7 (C12a), 151.6 (C11a), 140.6 (C10), 136.0 (C4), 135.3 (C30), 130.5
(Ar), 130.1 (Ar), 129.6 (Ar), 128.1 (Ar), 123.4 (C5a), 119.5 (C3), 119.2
(C4a), 29.6 (C8), 29.5 (C7), 29.2 (C11), 27.6 (C10), 25.7 (C9), 25.2
(C6); IR (KBr): nmax¼1617 (s) (C]O), 1588 (m), 1543 (m), 1475 (m),
1426 (m), 1266 (s), 745 (s) cmꢁ1; LRMS (ESþ): m/z (%) 361.11 (100)
temperature. 1H NMR (300 MHz, CDCl3):
d
¼8.41 (dd, 3J¼4.8 Hz,
4J¼2.0 Hz, 1H, C2-H), 8.01 (dd, 3J¼7.7 Hz, 4J¼2.0 Hz, 1H, C4-H),
7.57e7.53 (m, 1H, AreH), 7.46e7.41 (m, 3H, AreH), 7.23 (dd, 3J¼7.7,
4.8 Hz, 1H, C3-H), 3.96e3.41 (m, 1H, C7-H), 2.53e1.39 (m, 11H, C70-
H, C12-H2, C8-H2, C9-H2, C11-H2, C10-H2); 13C NMR (75.5 MHz,
[M35ClþNa]þ,
699.27
(25)
[2M35ClþNa]þ,
363.15
(10)
[[M37ClþNa]þ, 701.28 (10) [M35ClþM37ClþNa]þ; HRMS (ESþ): m/z
35
calcd for C20
H
ClN2O [M35ClþH]þ: 339.1264; found: 339.1268.
20
CDCl3):
d
¼199.6 (C6), 187.8 (C5), 173.7 (C13), 150.8 (C14a), 150.5
4.3.5. (E)-1-Cycloheptenylpyrrolidine13 (3b). The title compound 3b
(C2), 142.0 (C10), 139.2 (C4), 135.0 (C30), 130.4e129.0 (4ꢃAr), 126.5
(C4a), 121.6 (C3), 34.2 (C12), 26.0 (C7), 24.8 (C9), 24.5 (C10), 23.3
(C11), 21.2 (C8); IR (NaCl): nmax¼2932 (m), 1693 (s) (C]O), 1665 (s)
(C]O),1591 (s), 1475 (w), 1420 (m), 1368 (m), 1274 (m) cmꢁ1; LRMS
(9.20 g, 55.7 mmol, 62%) was afforded as a yellow oil after distil-
lation using general procedure C. 1H NMR (300 MHz, CDCl3):
d
¼4.47
(br s, 1H, C2-H), 2.97e2.91 (m, 4H, C20-H2), 2.49e2.45 (m, 4H, C3-
H2, C7-H2), 1.84e1.80 (m, 4H, C30-H2), 1.73e1.62 (m, 6H, C4-H2, C6-
H2, C5-H2); LRMS (ESþ): m/z (%) 166.15 (100) [MþH]þ.
(ESþ): m/z (%) 393.19 (100) [M35ClþNa]þ; HRMS (ESþ): m/z calcd for
35
C20
H
ClN2NaO3 [M35ClþNa]þ: 393.0982; found: 393.0967.
19
When 4.0 equiv of m-CPBA was used, 1c was obtained as a yel-
4.3.6. (E)-1-Cyclooctenylpyrrolidine13 (3c). The title compound 3c
(13.9 g, 77.5 mmol, 86%) was afforded as a yellow oil after distil-
low oil (133 mg, 0.360 mmol, 36%). In addition, aldehyde 5 (116 mg,
0.300 mmol, 30%) and 2c (115 mg) were isolated from this reaction.
Method 2: A. Sodium periodate (321 mg, 1.50 mmol, 3.00 equiv)
was stirred in H2O (0.750 mL) and 2 N sulfuric acid (100
0.100 mmol, 20 mol %). After the solid had dissolved, the solution
was cooled to 0 ꢂC. Ruthenium(III) chloride hydrate (519
g,
lation using general procedure C. 1H NMR (300 MHz, CDCl3):
d¼4.27
(br s,1H, C2-H), 3.15e3.08 (m, 4H, C20-H2), 2.52e2.43 (m, 4H, C3-H2,
C8-H2), 2.28e2.17 (m, 2H, C4-H2), 2.01e1.91 (m, 4H, C30-H2),
1.68e1.54 (m, 6H, C5-H2, C7-H2, C6-H2); LRMS (ESþ): m/z (%) 180.12
(100) [MþH]þ.
mL,
m
0.00300 mmol, 0.5 mol %) was then added and the reaction was
stirred until the colour turned bright yellow. Ethyl acetate (3 mL)
and acetonitrile (3 mL) were added and stirring was continued for
a further 5 min 2c (169 mg, 0.500 mmol, 1.00 equiv) was then
added to the reaction and the slurry was stirred at room temper-
ature for 24 h. The reaction mixture was poured into a mixture of
saturated NaHCO3 solution (10.0 mL) and saturated sodium thio-
sulfate solution (10.0 mL). The phases were separated, and the
aqueous layer was extracted with ethyl acetate (3ꢃ20.0 mL). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by flash column chroma-
tography using silica gel (4:6, ethyl acetate/hexane) to afford 1c
(30.0 mg, 0.0800 mmol, 16%) as a white solid; B. Method 2A was
repeated using ruthenium(III) chloride hydrate (5.19 mg,
0.0300 mmol, 5.0 mol %) to afford 1c (69.0 mg, 0.190 mmol, 37%) as
a white solid.
4.3.7. 6-(1-(3-Chlorophenyl)-3-hydroxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-1,8-naphthyridin-3-yl)-hexanal (5). The title compound
5
(116 mg, 0.300 mmol, 30%) was afforded as a yellow solid using
general procedure B with an additional 20 h stirring at room
temperature.
Mp 93e94 ꢂC; 1H NMR (400 MHz, CDCl3):
d
¼9.73 (t, 3J¼1.4 Hz,
1H, C12-H), 8.47 (dd, 3J¼4.8 Hz, 4J¼1.9 Hz, 1H, C2-H), 8.29 (dd,
3J¼7.6 Hz, 4J¼1.9 Hz, 1H, C4-H), 7.48e7.47 (m, 2H, C50-H and C40-H),
7.22e7.18 (m, 2H, C60-H and C3-H), 7.11 (br s, 1H, C20-H), 2.41 (td,
3J¼7.2 Hz, 4J¼1.4 Hz, 1H, C11-H), 2.09e1.94 (m, 2H, C7-H), 1.64e1.56
(m, 2H, C10-H2), 1.54e1.40 (m, 2H, C8-H2), 1.35e1.24 (m, 2H, C9-
H2); 13C NMR (100.6 MHz, CDCl3):
d
¼202.5 (C12), 193.6 (C5), 173.1
(C13), 154.8 (C2), 154.4 (C1a), 137.4 (C10), 137.2 (C4), 135.5 (C30),
130.9 (C50), 129.7 (C40 and C3), 127.5 (C20), 120.3 (C60), 115.8 (C4a),
83.4 (C6), 43.9 (C11), 41.1 (C7), 29.0 (C10), 23.1 (C8), 22.0 (C11); IR
(NaCl): nmax¼3409 (OH), 2926 (m), 1722 (s) (C]O), 1688 (s) (C]O),
1587 (s), 1469 (w), 1435 (m), 1346 (m), 1174 (CeN), 773 (s), 732
(s) cmꢁ1; LRMS (ESþ): m/z (%) 408.8 (100) [M35ClþNa]þ, 440.8 (30)
4.3.3. 11-(3-Chlorophenyl)-6,7,8,9,10,11-hexahydro-5H-cyclohepta
[b][1,8]naphthyridin-5-one (2b). The title compound 2b (4.08 g,
12.6 mmol, 40%) was afforded as a cream solid using general