Journal of Medicinal Chemistry
Article
CDCl3) δ 168.0, 163.0, 137.5, 135.4, 130.0, 106.0, 72.0, 70.6, 70.6,
70.6, 68.9, 64.8, 59.1, 50.8, 17.2; IR νmax/cm−1 1748, 1652, 1592, 1561,
1196, 1099, 768; HRMS (ESI) calculated for C15H23NNaO6 [M +
Na]+ 336.14176, found 336.14193.
General Procedure for the Photooxygenation of 2-
Pyridones. The respective pyridone was dissolved in ca. 10 mL of
DCM in a reaction tube, TPP (1 mg) was added, and oxygen was
bubbled through the solution with vigorous stirring for 5 min. The
mixture was kept under an oxygen atmosphere with a balloon, cooled
to 0 °C, and irradiated for 1 h with a high-pressure sodium lamp. The
solution was concentrated in vacuo, and the residue was purified by
flash column chromatography.
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-{6-Oxo-2,3-dioxa-5-
azabicyclo[2.2.2]oct-7-en-5-yl}acetate, 17. Pyridone 11 (85 mg,
0.28 mmol); flash chromatography (20:1 DCM/MeOH v/v) yielded
the endoperoxide 17 as a clear oil (90 mg, 271 mmol, 95%). 1H NMR
(400 MHz, CDCl3) δ 6.96−6.89 (m, 1H), 6.73−6.66 (m, 1H), 5.81−
5.77 (m, 1H), 5.01−4.96 (m, 1H), 4.63 (d, J = 18.1 Hz, 1H), 4.34−
4.17 (m, 2H), 3.90 (d, J = 18.1 Hz, 1H), 3.74−3.43 (m, 10H), 3.33 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 168.7, 168.0, 135.2, 127.7, 84.5,
77.8, 71.9, 70.5,70.5, 70.5, 68.6, 64.6, 59.0, 43.9; IR νmax/cm−1 1744,
1704, 1447, 1202, 1098, 891; HRMS (ESI) calculated for
C14H21NNaO8 [M + Na]+ 354.11594, found 354.11597.
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-(6-Methyl-2-oxo-1,2-
dihydropyridin-1-yl)acetate, 13. 6-Methyl-2-pyridone, 2 (50 mg,
0.46 mmol), dissolved in 10 mL of DME, was cooled to 0 °C, and
NaH (60% suspension in oil, 19 mg, 0.48 mmol) was added. After the
mixture was stirred for 10 min, LiBr (80 mg, 0.92 mmol) was added,
and the mixture was stirred for 20 min. 2-[2-(2-Methoxyethoxy)-
ethoxy]ethyl 2-bromoacetate (157 mg, 0.55 mmol) was added. The
mixture was heated to 60 °C for 4 h, cooled to room temperature, and
filtered. The filtrate was concentrated in vacuo. Purification by flash
chromatography yielded the desired product as a colorless oil (40 mg,
0.13 mmol, 28%).
1H NMR (300 MHz, CDCl3) δ 7.18 (dd, J = 9.2, 6.8 Hz, 1H), 6.38
(d, J = 9.2 Hz, 1H), 5.98 (d, J = 6.7 Hz, 1H), 4.77 (s, 2H), 4.33−4.17
(m, 2H), 3.75−3.41 (m, 10H), 3.30 (s, 3H), 2.22 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.9, 163.3, 145.8, 139.5, 117.4, 106.7, 71.8,
70.5, 70.5, 70.4, 68.7, 64.6, 58.9, 45.3, 20.4; IR νmax/cm−1 1746, 1660,
1550, 1197, 1099, 794; HRMS (ESI) calcd for C15H23NNaO6 [M +
Na]+ 336.1418, found 336.1421.
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-{1-Methyl-6-oxo-2,3-
dioxa-5-azabicyclo[2.2.2]oct-7-en-5-yl}acetate, 18. Pyridone 12
(90 mg, 0.29 mmol); flash chromatography (20:1 DCM/MeOH v/
v) yielded the endoperoxide 18 as a slightly purple oil (70 mg, 0.20
mmol, 70%).
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-(3,5-Dimethyl-2-oxo-
1,2-dihydropyridin-1-yl)acetate, 14. 3,5-Dimethyl-2-pyridone, 8
(100 mg, 0.810 mmol), was alkylated according to the same procedure
described for product 13. Yield: 132 mg (0.404, 50%, colorless oil).
1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 1.1 Hz, 1H), 6.85 (s,
1H), 4.61 (s, 2H), 4.36−4.24 (m, 2H), 3.73−3.67 (m, 2H), 3.66−3.59
(m, 6H), 3.57−3.49 (m, 2H), 3.35 (s, 3H), 2.10 (s, 3H), 2.02 (d, J =
0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.2, 162.2, 140.4,
132.6, 129.4, 114.8, 72.0, 70.7, 70.7, 70.6, 68.9, 64.79, 59.1, 50.7, 17.2,
17.1; IR νmax/cm−1 1747, 1664, 1593, 1195, 1100, 1036; HRMS (ESI)
calcd for C16H25NNaO6 [M + Na]+ 350.1574, found 350.1579
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-(3,6-Dimethyl-2-oxo-
1,2-dihydropyridin-1-yl)acetate, 15. 3,6-Dimethyl-2-pyridone 5
(100 mg, 0.81 mmol) was dissolved in DME (9 mL) and cooled to
−20 °C. n-BuLi (2.5 M in hexane, 0.36 mL, 0.89 mmol) was slowly
added under an argon atmosphere, and the solution was stirred for 20
min. 2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-bromoacetate (347 mg,
1.22 mmol) in DME (0.5 mL) was added; the mixture was warmed to
room temperature and stirred overnight. Concentration under reduced
pressure and purification by flash chromatography (9:1 DCM/MeOH
v/v) yielded the product as a colorless oil (108 mg, 0.33 mmol, 41%).
1H NMR (300 MHz, CDCl3) δ 7.12 (dd, J = 6.9, 0.9 Hz, 1H), 5.98
(d, J = 6.9 Hz, 1H), 4.84 (s, 2H), 4.40−4.29 (m, 2H), 3.80−3.49 (m,
10H), 3.38 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.3, 163.8, 142.7, 137.0, 126.3, 106.4, 72.0, 70.7, 70.6,
70.6, 69.0, 64.7, 59.1, 45.8, 20.4, 17.1; IR νmax/cm−1 1747, 1651, 1568,
1194, 1101; HRMS (ESI) calcd for C16H25NNaO6 [M + Na]+
364.1731, found 364.1733.
1H NMR (300 MHz, CDCl3) δ 6.95 (dd, J = 7.8, 5.3 Hz, 1H), 6.45
(dd, J = 7.8, 1.8 Hz, 1H), 5.75 (dd, J = 5.3, 1.8 Hz, 1H), 4.72 (d, J =
18.1 Hz, 1H), 4.39−4.20 (m, 2H), 3.92 (d, J = 18.1 Hz, 1H), 3.75−
3.49 (m, 10H), 3.38 (s, 3H), 1.62 (s, 3H), 1.56 (s, 3H); 4.20 (m, 2H),
3.92 (d, J = 18.1 Hz, 1H), 3.75−3.49 (m, 10H), 3.38 (s, 3H), 1.62 (s,
3H), 1.56 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.6, 168.8,
134.7, 132.5, 84.7, 81.3, 71.8, 70.5, 70.5, 70.5, 68.6, 64.5, 59.0, 44.2,
14.5; IR νmax/cm−1 1747, 1705, 1448, 1201, 1104; HRMS (ESI) calcd
for C15H23NNaO8 [M + Na]+ 368.1316, found 368.1316; Rt = 4.9 min
(CN modified silica, 10% iprOH in hexanes, isocratic, 1 mL/min, then
gradient to 40% iprOH at 35 min, purity >95%).
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-{4-Methyl-6-oxo-2,3-
dioxa-5-azabicyclo[2.2.2]oct-7-en-5-yl}acetate, 19. Pyridone 13
(40 mg, 0.13 mmol); flash chromatography (20:1 DCM/MeOH v/
v) yielded the endoperoxide 19 as a clear oil (42 mg, 0.12 mmol,
95%).
1H NMR (400 MHz, CDCl3) δ 6.72−6.65 (m, 2H), 4.98 (dd, J =
4.5, 3.3 Hz, 1H), 4.60 (d, J = 18.2 Hz, 1H), 4.33−4.15 (m, 2H), 3.94
(d, J = 18.2 Hz, 1H), 3.73−3.45 (m, 10H), 3.34 (s, 3H), 1.70 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 169.2, 168.9, 140.0, 126.8, 89.2, 77.2,
72.0, 70.6, 70.6, 70.6, 68.8, 64.6, 59.1, 40.8, 17.0; IR νmax/cm−1 1744,
1703, 1400, 1196, 1100, 782; HRMS (ESI) C15H23NNaO8 [M + Na]+
368.1316, found 368.1315.
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-{1,8-Dimethyl-6-oxo-2,3-
dioxa-5-azabicyclo[2.2.2]oct-7-en-5-yl}acetate, 20. Pyridone 14
(100 mg, 0.305 mmol); flash chromatography (20:1 DCM/MeOH
v/v) yielded the endoperoxide 20 as a clear oil (82 mg, 0.23 mmol,
75%).
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-(3,5,6-Trimethyl-2-
oxo-1,2-dihydropyridin-1-yl)acetate, 16. 3,5,6-Trimethyl-2-pyri-
done, 6 (90 mg, 0.66 mmol), was dissolved in a mixture of dry DME
(6 mL) and dry DMF (1.5 mL). Under a nitrogen atmosphere, the
solution was cooled to 0 °C, sodium hydride (60% in oil, 28 mg, 0.69
mmol) was added, and the solution was stirred for 15 min. To this
mixture, LiBr (114 mg, 1.31 mmol) was added. The solution was
warmed to room temperature and stirred for 15 min. 2-[2-(2-
Methoxyethoxy)ethoxy]ethyl 2-bromoacetate (374 mg, 1.31 mmol)
was added, and the reaction mixture was heated to 65 °C overnight.
Concentration under reduced pressure followed by purification by
flash chromatography (9:1 DCM/MeOH v/v) yielded the product as a
colorless oil (150 mg, 0.44 mmol, 67%), purity >85%.
1H NMR (400 MHz, CDCl3) δ 6.03−5.99 (m, 1H), 5.48 (d, J = 2.1
Hz, 1H), 4.74 (d, J = 18.1 Hz, 1H), 4.30−4.25 (m, 2H), 3.85 (d, J =
18.2 Hz, 1H), 3.68 (t, J = 4.7 Hz, 2H), 3.64−3.58 (m, 6H), 3.56−3.48
(m, J = 5.7, 3.6 Hz, 2H), 3.35 (s, 3H), 2.07 (d, J = 1.8 Hz, 3H), 1.54 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 169.1, 145.7, 125.4, 88.9,
81.5, 72.0, 70.7, 70.7, 70.7, 68.8, 64.7, 59.1, 44.0, 17.6, 14.6; IR νmax
/
cm−1 1745, 1705, 1446, 1200, 1101; HRMS (ESI) calcd for
C16H25NNaO8 [M + Na]+ 382.1472, found 382.1473.
2-[2-(2-Methoxyethoxy)ethoxy]ethyl 2-{1,4-Dimethyl-6-oxo-2,3-
dioxa-5-azabicyclo[2.2.2]oct-7-en-5-yl}acetate, 21. Pyridone 15
(60 mg, 0.18 mmol); flash chromatography (20:1 DCM/MeOH v/
v) yielded the endoperoxide 21 as a clear oil (64 mg, 0.18 mmol,
97%), purity >90%.
1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 4.87 (s, 2H), 4.36−
4.23 (m, 2H), 3.71−3.65 (m, 2H), 3.65−3.57 (m, 6H), 3.55−3.47 (m,
2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.6, 163.1, 141.1,
138.9, 125.6, 112.4, 72.0, 70.6, 70.6, 70.6, 68.9, 64.6, 59.1, 46.0, 18.0,
16.9, 16.4; νmax/cm−1 1746, 1639, 1196, 1098; HRMS (ESI) calcd for
C17H27NNaO6 [M + Na]+ 350.1574, found 350.1577.
1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 7.8 Hz, 1H), 6.38 (d, J
= 7.8 Hz, 1H), 4.60 (d, J = 18.2 Hz, 1H), 4.32−4.16 (m, 2H), 3.94 (d,
J = 18.2 Hz, 1H), 3.71−3.46 (m, 10H), 3.34 (s, 3H), 1.67 (s, 3H), 1.57
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.2, 169.6, 139.9, 132.1,
89.6, 81.1, 72.4, 71.1, 71.0, 71.0, 69.3, 65.0, 59.5, 41.7, 17.7, 15.2; IR
10179
dx.doi.org/10.1021/jm4016137 | J. Med. Chem. 2013, 56, 10171−10182