R. Risgaard et al. / Bioorg. Med. Chem. 22 (2014) 381–392
389
Compound 13 LC/MS: ELSD: 100.0%; UV: 100.0%; MH+ 291.8. 1H
4.1.22. (2S,4aR,10aR)-9-Methoxy-4-propyl-2-pyrazol-1-
ylmethyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-
b][1,4]oxazine (18)
NMR (500 MHz, CDCl3) d 0.85 (t, J = 7,3 Hz, 3H), 1.45–1.59 (m, 2H),
2.24–2.32 (m, 3H), 2.43 (dd, J = 16.9, J = 10.6, 1H), 2.60 (dd, J = 11.8,
J = 15.4, 1H), 2.73 (m, 1H), 2.79 (d, J = 11.18, 1H), 3.10–3.19 (m, 2H),
3,55 (dd, J = 6.35, J = 11.64, 1H), (3.58–3.66 (m, 2H), 3.74 (s, 3H),
3.78 (br s, 1H), 6.61 (d, J = 8.21, 1H), 6.66 (d, J = 7.92, 1H), 7.05 (t,
J = 7.88, 1H). 13C NMR (500 MHz, CDCl3) d: 157.5 135.8, 127.1,
123.4, 121.2, 107.7, 76.9, 76.0, 64.7, 60.9, 55,7, 55.6, 53.4, 33.9,
30.1, 18.7, 12.4.
NaH (5.0 mg, 0.18 mmol) was added to a solution of 16 (42 mg,
0.09 mmol) and pyrazol (18.4 mg, 0.27 mmol) in DMF (1.0 mL). The
solution was heated at 130 °C for 30 min using microwave condi-
tions. The reaction was quenched with brine (10 mL) and EtOAc
(10 mL) was added. The phases were separated and the organic
phase washed with additional brine and concentrated. The product
was purified by silica gel chromatography. Yield: 33 mg (95%) of
compound 18 as an oil. LC/MS: ELSD: 100.0%; UV: 100.0%; MH+
328.0. Anal. Calcd for C20H28N3O2Clꢂ3.5H2O: C, 54.42; H, 7.90; N,
9.52. Found: C, 54.35; H, 7.57; N, 9.25. 1H NMR (500 MHz,
DMSO-d6) d 0.95 (t, J = 7,34 Hz, 3H), 1.67–1.82 (m, 2H), 2.33 (dd,
J = 16.80, J = 10.21, 1H), 2.99–3.08 (mm, 2H), 3.32–3.52 (m, 7H),
3.77 (s, 3H), 4.35–4.42 (m, 1H), 4.44–4.51 (m, 1H), 4.69 (dd,
J = 14.29, J = 6.06, 1H), 5.13 (dd, J = 14.33, J = 9.29, 1H), 6.27 (t,
J = 1.87, 1H), 6.78 (d, J = 7.60, 1H), 6.82 (d, J = 7.98, 1H), 7.18 (t,
J = 7.78, 1H), 7.50 (d, J = 1.70, 1H), 7.92 (d, J = 2.08, 1H).
4.1.19. Toluene-4-sulfonic acid (2S,4aR,10aR)-9-methoxy-4-
propyl-3,4,4a,5,10,10a-hexahydro-2H-naptho[2,3-b][1,4]oxazin-
2-ylmethyl ester (15)
Compound 15 was synthesized from 13 (294 mg, 1.01 mmol) as
described for 16. Yield: 330 mg (73%) of compound 15 as yellow/
brown oil. LC/MS: ELSD: 100.0%; UV: 29.6%; MH+ 446.0. 1H NMR
(500 MHz, CDCl3) d 0.92 (t, J = 7,34 Hz, 3H), 1.39–1.59 (m, 2H),
2.16 (t, J = 10.89, 1H), 2.21–2.34 (m, 2H), 2.37 (dd, J = 17.40,
J = 6.52, 1H), 2.47 (s, 3H), 2.60 (dd, J = 15.01, J = 11.89, 1H), 2.71–
2.81 (m, 1H), 2.61–2.68 (m, 1H), 2.89 (d, J = 12.13, 1H), 3.10 (dd,
J = 16.91, J = 5.81, 1H), 3.17 (dd, J = 11.25, J = 4.90, 1H), 3.55 (dd,
J = 15.76 J = 9.46, 1H), 3.82 (s, 3H), 3.87–3.94 (m, 1H), 4.04 (dd,
J = 10.30, J = 4.92, 1H), 4.10 (dd, J = 10.30, J = 5.35, 1H), 6.68 (d,
J = 8.17, 1H), 6.72 (d, J = 7.56, 1H), 7.12 (t, J = 7.91, 1H), 7.37 (d,
J = 7.84, 2H), 7.83 (d, J = 8.12, 2H).
4.1.23. (2R,4aR,10aR)-4-Propyl-2-pyrazol-1-ylmethyl-
3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazin-9-ol
(19)
Compound 19 was synthesized from 17 as described for 20 from
18. Yield: 7.5 mg (29%) of compound 19 as an oil. 1H NMR
(500 MHz, DMSO-d6)
d 0.96 (t, J = 7,27 Hz, 3H), 1.54–1.67
4.1.20. Toluene-4-sulfonic acid (2R,4aR,10aR)-9-methoxy-4-
propyl-3,4,4a,5,10,10a-hexahydro-2H-naptho[2,3-b][1,4]oxazin-
2-ylmethyl ester (16)
(m, 1H), 1.70–1.82 (m, 1H) 2.41 (dd, J = 16.92, J = 10.69, 1H), 2.51
(br s, 1H), 2.85 (t, J = 13.90, 2H), 2.97–3.14 (m, 2H), 3.34–3.71 (m,
3H), 3.92–3.99 (m, 1H), 4.25–4.42 (m, 3H), 6.29 (s, 1H), 6.60 (dd,
J = 7.45, 1H), 6.66 (d, J = 7.66, 1H), 6.99 (t, J = 7.89, 1H), 7.51 (s,
1H), 7.75 (d, J = 1.53, 1H); HRMS C19H26N3O2 [M+H+] calcd
328.2020, found 328.2011.
TsCl (343 mg, 1.80 mmol) was added to a solution of 14 (116 mg,
0.40 mmol) in pyridine (5.5 mL, 68 mmol). The solution was stirred
at rt for 4 h and quenched by addition of water (0.4 mL). EtOAc
(18.0 mL) and satd NaHCO3 (7.4 mL) were added. The phases were
separated and the organic phase extracted with satd NaHCO3
(7.4 mL) and washed with brine, and concentrated. The crude prod-
uct was purified by silica gel chromatography to afford 118 mg
(quantitative) of 16. LC/MS: ELSD: 100.0%; UV: 100.0%; MH+
446.0. Mp: 139.3–141.6. Anal. Calcd for C23H29NO5S: C, 64.01; H,
6.77; N, 3.25. Found: C, 64.67; H, 7.18; N, 3.02. 1H NMR
(500 MHz, CDCl3) d 0.86 (t, J = 7,44 Hz, 3H), 1.30–1.48 (m, 2H),
2.11–2.17 (m, 1H), 2.21–2.27 (mm, 1H), 2.26 (s, 3H), 2.31 (dd,
J = 16.65, J = 5.98, 1H), 2.45 (dd, J = 16.15, J = 4.57, 1H), 2.51 (dd,
J = 12.15, J = 8.08, 1H), 2.61–2.68 (m, 1H), 2.78 (d, J = 12.15, 1H),
2.92 (dd, J = 16.77, J = 11.22, 1H), 3.09 (dd, J = 16.05, J = 10.88, 1H),
3.18–3.24 (m, 1H), 3.81 (s, 3H), 4.03–4.09 (m, 1H), 4.31 (dd,
J = 10.34, J = 6.08, 1H), 4.52 (dd, J = 10.34, J = 7.76, 1H), 6.66 (d,
J = 8.15, 1H), 6.67 (d, J = 7.87, 1H), 7.09 (t, J = 7.90, 1H), 7.28 (d,
J = 7.98, 2H), 7.82 (d, J = 7.98, 2H). 13C NMR (500 MHz, CDCl3) d:
157.4, 145.3, 135.6, 133.2, 130.2, 128.5, 127.1, 123.2, 121.2, 107.6,
71.3, 70.8, 68.4, 61.6, 55.7, 54.6, 51.5, 33.8, 30.1, 21.8, 19.1, 12.2.
4.1.24. (2S,4aR,10aR)-4-Propyl-2-pyrazol-1-ylmethyl-
3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazin-9-ol
(20)
KF and thiophenol were added to 18 (21 mg, 0.06 mmol) dis-
solved in DMA. The reaction mixture was heated to 210 °C for
1 h using microwave heating, and then concentrated. The resulting
mixture was purified with silica gel chromatography (eluent: 0–5%
MeOH in EtOAc) and 20 was further purified by HPLC. Yield: 12 mg
(60%) of 20 as an oil. 1H NMR (500 MHz, DMSO-d6) d 0.77
(t, J = 7,27 Hz, 3H), 1.41–1.62 (m, 2H), 2.14 (dd, J = 16.67,
J = 10.24, 1H), 2.31 (br s, 1H), 2.77–2.94 (m, 3H), 3.19–3.32 (m,
4H), 3.38 (d, J = 13.28, 3H), 4.15 (dd, J = 16.23, J = 10.05, 1H),
4.22–4.34 (m, 2H), 4.70 (dd, J = 14.11, J = 9.45 1H), 6.09 (s, 1H),
6.43 (dd, J = 7.62, 1H), 6.48 (d, J = 7.99, 1H), 6.81 (t, J = 7.62, 1H),
7.31 (s, 1H), 7.63 (s, 1H); HRMS
328.2020, found 328.2016.
C
19H26N3O2 [M+H+] calcd
4.1.25. (2R,4aR,10aR)-2-(3-Phenyl-pyrazol-1-ylmethyl)-4-
propyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-
b][1,4]oxazin-9-ol (21)
4.1.21. (2R,4aR,10aR)-9-Methoxy-4-propyl-2-pyrazol-1-
ylmethyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-
b][1,4]oxazine (17)
NaH (4.3 mg, 0.18 mmol) was added to a solution of 15 (42 mg,
0.09 mmol) and 3-phenyl-pyrazol (38.9 mg, 0.27 mmol) in DMF
(1 mL). The solution was heated at 130 °C for 30 min using micro-
wave heating. The reaction was quenched with saturated NaHCO3
(10 mL) and EtOAc (15 mL) was added. The phases were separated
and the organic phase extracted with NaHCO3 (10 mL) and concen-
trated. Yield: 60 mg of the crude intermediate (2R,4aR,10aR)-
9-methoxy-2-(3-phenyl-pyrazol-1-ylmethyl)-4-propyl-
3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazine. LC/MS:
ELSD: 99.9%; UV: 71.5%; MH+ 418.1. This intermediate was dis-
solved in DMA (6.3 mL), and KF (11 mg, 0.18 mmol) and thiophenol
(0.07 mL, 0.68 mmol) were added. The solution was heated at
210 °C for 1 h using microwave heating. The mixture was purified
Compound 17 was synthesized from compound 15 as described
for 18 from 16. Yield: 20 mg (59%) of compound 17 as a white solid.
LC/MS: ELSD: 100.0%; UV: 100.0%; MH+ 328.0. Anal. Calcd for C20-
H28N3O2Clꢂ2H2O: C, 58.00; H, 7.73; N, 10.14. Found: C, 58.47; H,
7.39; N, 10.04. 1H NMR (500 MHz, DMSO-d6) d 0.95 (t, J = 7,34 Hz,
3H), 1.63–1.81 (m, 2H), 2.39 (dd, J = 16.71, J = 10.83, 1H), 2.90–
3.06 (mm, 2H), 3.07–3.19 (m, 2H), 3.30–3.40 (m, 3H), 3.48 (dd,
J = 16.03, J = 5.34, 1H), 3.65 (s, 1H) 3.76 (s, 3H), 4.08–4.16 (m,
1H), 4.29 (dd, J = 14.32, J = 6.74, 1H), 4.39 (dd, J = 14.32, J = 4.29,
1H), 4.43–4.49 (m, 1H), 6.28 (t, J = 2.04, 1H), 6.76 (d, J = 7.93, 1H),
6.82 (d, J = 8.21, 1H), 7.17 (t, J = 8.00, 1H), 7.50 (d, J = 1.89, 1H),
7.74 (d, J = 2.23, 1H).