The Journal of Organic Chemistry
Article
20% EtOAc/Hex as an amorphous yellow solid (45 mg, 88% with [Pt];
47 mg, 91% with [Au]). 1H NMR (CDCl3, 400 MHz): δ 2.00−1.93 (m,
4H); 2.30 (s, 3H); 2.77 (t, J = 6.0 Hz, 2H); 2.87 (t, J = 6.4 Hz, 2H);
3.27−3.21 (m, 4H); 5.88 (s, 1H); 6.97 (s, 1H). 13C NMR (CDCl3, 100
MHz): δ 18.6, 20.5, 20.7, 21.6, 27.8, 49.5, 50.0, 106.7, 108.1, 108.9,
118.0, 121.7, 145.8, 151.0, 153.1, 162.6. HRMS (FAB+): calcd for
C16H17NO2 255.1259, measured 255.1255 [M].
5.21−5.14 (m, 2H); 5.84−5.76 (m, 1H); 5.90 (s, 1H); 6.40 (s, 1H); 7.16
(s, 1H). 13C NMR (CDCl3, 100 MHz): δ 22.0, 28.0, 28.5, 32.4, 39.7,
49.2, 53.8, 79.7, 97.4, 108.2, 108.5, 116.7, 119.7, 123.8, 131.5, 148.6,
153.7, 155.2, 155.9, 162.2. HRMS (FAB+): calcd for C22H28N2O4
384.2049, measured 384.2046 [M].
6,7,8,9-Tetrahydro-2-oxo-4-(propyl-2-tert-butoxycarbonyl-
amino)-9-(2-propen-1-yl)-2H-pyrano[3,2-g]quinoline (43). Com-
pound 43 was eluted with 20% EtOAc/Hex as an amorphous pale yellow
solid (60 mg, 75% with [Pt]; 73 mg, 92% with [Au]). 1H NMR (CDCl3,
400 MHz): δ 1.13 (d, J = 6.8 Hz, 3H); 1.40 (s, 9H); 1.94 (quint, J =
5.6 Hz, 2H); 2.55−2.50 (m, 1H); 2.79 (t, J = 6.0 Hz, 2H); 3.03−3.01 (m,
1H); 3.34 (t, J = 6.0 Hz, 2H); 3.86 (d, J = 4.4 Hz, 2H) 3.96 (quint, J = 6.8
Hz, 1H); 4.61 (br s, 1H); 5.17−5.10 (m, 2H); 5.81−5.72 (m, 1H); 5.85
(s, 1H); 6.34 (s, 1H); 7.36 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ
20.4, 21.9, 27.9, 28.4, 39.9, 46.0, 49.2, 53.7, 79.4, 97.1, 108.4, 109.2,
116.5, 119.6, 124.4, 131.5, 148.4, 153.3, 155.0, 155.2, 162.2. HRMS
(FAB+): calcd for C23H30N2O4 398.2206, measured 398.2215 [M].
7,8,9,10-Tetrahydro-2-oxo-4-(ethyl-tert-butoxycarbonylami-
no)-7-(2-propen-1-yl)-2H-pyrano[3,2-f ]quinoline (45). Com-
pound 45 was eluted with 20% EtOAc/Hex as an amorphous pale
yellow solid (71 mg, 74% with [Pt]; 86 mg, 90% with [Au]). 1H NMR
(CDCl3, 400 MHz): δ 1.44 (s, 9H); 2.05−1.95 (m, 2H); 2.92−2.87 (m,
4H); 3.42−3.34 (m, 4H); 3.97−3.95 (m, 2H); 4.85 (s, 1H); 5.19−5.14
(m, 2H); 5.87−5.78 (m, 1H); 5.92 (s, 1H); 6.52 (d, J = 9.2 Hz, 1H); 7.36
(d, J = 8.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 20.6, 21.0, 28.4,
32.5, 39.9, 49.0, 53.9, 79.6, 108.0, 108.3, 108.5, 116.4, 123.0, 132.2,
148.4, 152.5, 154.2, 155.9, 162.3. HRMS (FAB+): calcd for C22H24N2O4
384.2049, measured 384.2041 [M].
4-Methylpyrano[2,3-a]carbazol-2(5H)-one (30). Compound
30 was eluted with 50% EtOAc/Hex as an amorphous pale yellow solid
(isolated as a 5:1 mixture of 30:31 with [Pt] 69 mg, 69%. Isolated as a
1
1.7:1 mixture of 30:31 with [Au] 92 mg, 92%). H NMR (DMSO-d6,
400 MHz): δ 2.86 (s, 3H); 6.35 (s, 1H); 7.19 (d, J = 8.4 Hz, 1H); 7.24 (t,
J = 7.6 Hz, 1H); 7.43 (dt, J = 8.0 Hz, J = 0.8 Hz, 1H); 7.71 (d, J = 8.4 Hz,
1H); 8.16 (d, J = 7.6 Hz, 1H); 8.36 (d, J = 8.4 Hz, 1H); 11.14 (s, 1H).
13C NMR (DMSO-d6, 100 MHz): δ 22.6, 106.0, 108.4, 112.2, 112.6,
119.6, 119.8, 119.9, 121.6, 124.1, 125.4, 135.0, 140.3, 152.9, 153.0, 159.9.
HRMS (FAB+): calcd for C16H12NO2 250.0868, measured 250.0864
[M+1].
4-Methylpyrano[2,3-b]carbazol-2(10H)-one (31). Compound
31 was eluted with 30% EtOAc/Hex as an amorphous white solid
(isolated as a 5:1 mixture of 30:31 with [Pt] 69 mg, 69%. Isolated as a
1
1.7:1 mixture of 30:31 with [Au] 92 mg, 92%). H NMR (DMSO-d6,
400 MHz): δ 2.56 (s, 3H); 6.23 (d, J = 1.2 Hz, 1H); 7.23 (dt, J = 7.6 Hz,
J = 0.8 Hz, 1H); 7.38 (s, 1H); 7.43 (dt, J = 8.0 Hz, J = 1.2 Hz, 1H); 7.51
(d, J = 8.0 Hz, 1H); 8.23 (d, J = 8.0 Hz, 1H); 8.55 (s, 1H); 11.63 (s, 1H).
13C NMR (DMSO-d6, 100 MHz): 18.7, 97.2, 110.5, 111.2, 112.5, 117.2,
119.5, 120.3, 120.6, 122.2, 126.3, 140.9, 142.0, 152.1, 154.3, 160.5.
HRMS (FAB+): calcd for C16H12NO2 250.0868, measured 250.0864
[M+1].
7,8,9,10-Tetrahydro-2-oxo-4-(ethyl-tert-butoxycarbonylami-
no)-2H-pyrano[3,2-f ]quinoline (PV139). To an oven-dried vial was
added 7,8,9,10-tetrahydro-2-oxo-4-(ethyl-tert-butoxycarbonylamino)-7-
(2-propen-1-yl)-2H-pyrano[3,2-f ]quinoline (45) (306 mg, 0.79 mmol)
followed by THF (18 mL). To the resulting solution were added N,N′-
dimethylbarbituric acid (370 mg, 2.37 mmol) and Pd(PPh3)4 (92 mg,
0.079 mmol, 10 mol %). The mixture was then sealed with a Teflon
screw-cap under an atmosphere of argon and heated to 80 °C for 12 h.
Upon consumption of the starting material, the reaction mixture was
concentrated, and the resulting residue was purified by flash column
chromatography (eluting with 30% EtOAc/Hex) to afford 7,8,9,10-
tetrahydro-2-oxo-4-(ethyl-tert-butoxycarbonylamino)-2H-pyrano-
[3,2-f]quinoline (250 mg, 0.73 mmol) as an amorphous yellow solid,
92%. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H); 1.95−1.92 (m, 2H);
2.87−2.85 (m, 4H); 3.41−3.33 (m, 4H); 4.64 (br s, 1H); 4.87 (br s,
1H); 5.92 (s, 1H); 6.39 (d, J = 8.4 Hz, 1H); 7.28 (d, J = 9.2 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ 20.0, 20.7, 28.4, 32.6, 39.9, 41.2, 79.6,
107.3, 108.2, 109.1, 111.0, 122.8, 148.5, 153.2, 154.4, 155.9, 162.2. This
material (222 mg, 0.65 mmol) in DCM (3.75 mL) was added TFA (1.20
mL) slowly at 0 °C. The reaction stirred for 15 min at 0 °C, at which time
the starting material had been fully consumed. The solvent was removed
in vacuo, and the residue was purified via HPLC eluting with MeCN/
H2O (the water contained 0.1% TFA). The fractions containing the
product were pooled and evaporated. The residue was then lyophilized
to afford 7,8,9,10-tetrahydro-2-oxo-4-(2-aminoethyl)-2H-pyrano-
[3,2-f]quinoline (PV139 TFA salt) as an amorphous yellow solid
2,3,6,7-Tetrahydro-9-(ethyl-2-tert-butoxycarbonylamino)-
1H,5H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (35).
Compound 35 was eluted with 30% EtOAc/Hex as an amorphous
pale yellow solid (229 mg, 91% with [Pt]; 73 mg, 95% with [Au]). 1H
NMR (CDCl3, 300 MHz): δ 1.44 (s, 9H); 1.97 (quint, J = 6.3 Hz, 4H);
2.78 (t, J = 6.6 Hz, 2H); 2.91−2.83 (m, 4H); 3.25 (quart, J = 6.0 Hz,
4H); 3.43 (quart, J = 6.3 Hz, 2H); 4.64 (br s, 1H); 5.89 (s, 1H); 7.04 (s,
1H). 13C NMR (CDCl3, 75 MHz): δ 20.6, 20.8, 21.7, 28.0, 28.5, 32.4,
39.8, 49.6, 50.0, 79.7, 107.0, 107.9, 118.3, 121.6, 146.0, 151.5, 154.0,
155.9, 162.4. HRMS (FAB+): calcd for C22H28N2O4 384.2049,
measured 384.2048 [M].
2,3,6,7-Tetrahydro-9-(propyl-2-tert-butoxycarbonylamino)-
1H,5H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (37).
Compound 37 was eluted with 20% EtOAc/Hex as an amorphous
1
pale yellow solid (70 mg, 88% with [Pt]; 72 mg, 90% with [Au]). H
NMR (CDCl3, 400 MHz): δ 1.15 (d, J = 6.4 Hz, 3H); 1.44 (s, 9H);
1.98−1.96 (m, 4H); 2.58−2.53 (m, 1H); 2.80 (t, J = 6.0 Hz, 2H); 2.88 (t,
J = 6.4 Hz, 2H); 3.03 (br s, 1H); 3.28−3.23 (m, 4H); 4.01−3.97 (m,
1H); 4.47 (br s, 1H); 5.87 (s, 1H); 7.27 (s, 1H, overlaps with residual
solvent peak). 13C NMR (CDCl3, 75 MHz): δ. 20.6, 20.8, 21.7, 27.9,
28.5, 40.0, 46.2, 49.6, 50.1, 79.5, 106.9, 108.3, 108.8, 118.3, 122.2, 146.0,
151.5, 153.5, 155.2, 162.5. HRMS (FAB+): calcd for C23H30N2O4
398.2206, measured 398.2193 [M].
2,3,6,7-Tetrahydro-9-(methyl-tert-butoxycarbonylamino)-
1H,5H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (39).
Compound 39 was eluted with 30% EtOAc/Hex as an amorphous
1
(130 mg, 0.36 mmol, 55%). H NMR (CD3OD, 400 MHz): δ 1.90
1
pale yellow solid (65 mg, 88% with [Pt]; 67 mg, 90% with [Au]). H
(quint, J = 8.4 Hz, 2H); 2.79 (t, J = 8.4 Hz, 2H); 3.06 (t, J = 9.6 Hz, 2H);
3.32−3.22 (m, 4H); 5.93 (s, 1H); 6.52 (d, J = 12.0 Hz, 1H); 7.31 (d, J =
11.6 Hz, 1H). 13C NMR (CD3OD, 75 MHz): δ 20.0, 20.5, 29.5, 38.6,
40.7, 106.4, 106.8, 107.9, 111.6, 122.7, 150.2, 153.4, 153.5, 163.3. 19F
NMR (CDCl3, 300 MHz): δ −76.51. HRMS (FAB+): calcd for
C14H17N2O2 245.1290, measured 245.1283 [M − trifluoroacetate].
9-(2-Aminoethyl)-2,3,6,7-tetrahydro-1H,5H,11H-[1]-
benzopyrano[6,7,8-ij]quinolizin-11-one (FFN511 TFA Salt). To a
solution of 2,3,6,7-tetrahydro-9-(ethyl-2-tert-butoxycarbonylamino)-
1H,5H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (35)
(177 mg, 0.46 mmol) in DCM (6 mL) was added TFA (2 mL) slowly at
0 °C. The reaction was stirred for 10 min at 0 °C, at which time the starting
material had been fully consumed. The solvent was removed in vacuo,
and the residue was quenched with satd NaHCO3 (aq) (∼20 mL).
The resulting solution was extracted with 10% MeOH/CHCl3 (6 ×10 mL).
NMR (CDCl3, 300 MHz): δ 1.47 (s, 9H); 1.96 (quint, J = 6.3 Hz, 4H);
2.75 (t, J = 6.6 Hz, 2H); 2.87 (t, J = 6.6 Hz, 2H); 3.25 (quart, J = 5.7 Hz,
4H); 4.40 (d, J = 6.0 Hz, 2H); 4.84 (br s, 1H); 6.01 (s, 1H); 6.98 (s, 1H).
13C NMR (CDCl3, 75 MHz): δ 20.6, 20.8, 21.7, 27.9, 28.5, 41.0, 49.7,
50.1, 80.4, 105.7, 106.8, 107.1, 118.3, 120.9, 146.1, 151.4, 152.9, 155.7,
162.6. HRMS (FAB+): calcd for C21H26N2O4 370.1893, measured
370.1879 [M]
6,7,8,9-Tetrahydro-2-oxo-4-(ethyl-tert-butoxycarbonylami-
no)-9-(2-propen-1-yl)-2H-pyrano[3,2-g]quinoline (41). Com-
pound 41 was eluted with 30% EtOAc/Hex as an amorphous pale
yellow solid (290 mg, 76% with [Pt]; 72 mg, 93% with [Au]). 1H NMR
(CDCl3, 400 MHz): δ 1.45 (s, 9H); 1.98 (quint, J = 6.0 Hz, 2H); 2.80 (t,
J = 6.0 Hz, 2H); 2.87 (t, J = 6.8 Hz, 2H); 3.38 (t, J = 6.8 Hz, 2H); 3.46−
3.42 (m, 2H); 3.91 (dd, J = 2.8 Hz, J = 2.0 Hz, 2H); 4.66 (br s, 1H)
J
dx.doi.org/10.1021/jo3006842 | J. Org. Chem. XXXX, XXX, XXX−XXX