Synthesis of N-hydroxymethyl-3-oxo-2-azabicyclo[2.2.1]hex-5-
enes (±)-6a–d
1-Propionyloxymethyl-2(1H)-pyridone 7b. Yield 3.7 g (65%),
oil; HRMS m/z: Found: Mϩ, 181.0713. C9H11NO3 requires M,
A mixture of lactam (±)-5a–d (10 mmol), paraformaldehyde (1
g) and potassium carbonate (0.2 g, 1.5 mmol) in water (20 cm3)
was reacted under sonication for 6 h at room temperature.
Extraction with CHCl3, drying (MgSO4), and removal of the
solvent in vacuo provided the crude N-hydroxymethyl analogue,
which was purified by silica gel TLC (Et2O) to give (±)-6a–d.
Methyl 2-hydroxymethyl-3-oxo-2-azabicyclo[2.2.0]hex-5-ene-
6-carboxylate 6a. Yield 228 mg (64%), prisms (from Et2O); mp
73–74 ЊC; HRMS m/z: Found: Mϩ, 183.0500. C8H9NO4
181.0739; νmax(film)/cmϪ1 1747 (C᎐O) and 1672 (NC᎐O);
᎐
᎐
δH (CDCl3) 1.13 (3 H, t, J 8, CH3), 2.40 (2 H, q, J 8, CH2CH3),
5.93 (2 H, s, NCH2), 6.20 (1 H, t, J4,5 = J5,6 = 7, 5-H), 6.60 (1 H,
d, J3,4 7, 3-H), 7.39 (1 H, t, J3,4 = J4,5 = 7, 4-H) and 7.60 (1 H,
dd, J5,6 7, J4,6 2, 6-H).
4-Methoxy-1-propionyloxymethyl-2(1H)-pyridone 7c. Yield
4.7 g (92%), prisms (from Et2O); mp 38–40 ЊC; HRMS m/z:
Found: Mϩ, 211.0838. C10H13NO4 requires M, 211.0845; νmax
-
(film)/cmϪ1 1743 (C᎐O) and 1665 (NC᎐O); δ (CDCl ) 1.13 (3
᎐
᎐
H
3
requires M, 183.0532; νmax(film)/cmϪ1 1752 (NC᎐O) and 1724
H, t, J 3.5, CH2CH3), 2.40 (2 H, q, J 3.5, CH2CH3), 3.80 (3 H, s,
OCH3), 5.76–6.10 (4 H, m, 3- and 5-H, NCH2) and 7.33–7.56 (1
H, m, 6-H).
᎐
(C᎐O); δ (CDCl ) 3.81 (3 H, s, CH ), 4.22 (1 H, dd, J 2.2,
᎐
H
3
3
1,4
J4,5 1.1, 4-H), 4.61 (1 H, dd, J1,5 2.5, J1,4 2.2, 1-H), 4.62 (1 H,
d, J 11.3, CH2), 4.87 (1 H, d, J 11.3, CH2) and 7.10 (1 H, dd,
J1,5 2.5, J4,5 1.1, 5-H); δC(CDCl3) 52.3 (CH3), 52.6 (C-1),
55.5 (C-4), 66.5 (CH2), 144.1 (C-6), 145.2 (C-5), 163.1 and
4-[1,1-(Ethylenedioxy)ethyl]-1-propionyloxymethyl-2(1H)-
pyridone 7d. Yield 2.1 g (48%), prisms (from Et2O); mp 83–
85 ЊC; HRMS m/z: Found: Mϩ, 267.1096. C13H17NO5 requires
M, 267.1107; νmax(film)/cmϪ1 1746 (C᎐O) and 1672 (NC᎐O);
166.9 (C᎐O).
᎐
᎐
᎐
2-Hydroxymethyl-3-oxo-2-azabicyclo[2.2.0]hex-5-ene
6b.
δH (CDCl3) 1.13 (3 H, t, J 8, CH2CH3), 1.57 (3 H, s, CH3), 2.40
(2 H, q, J 8, CH2CH3), 3.70–4.13 (4 H, m, CH2CH2), 5.86 (2 H,
s, NCH2), 6.23 (1 H, dd, J5,6 8, J3,5 2, 5-H), 6.68 (1 H, d, J3,5 2,
3-H) and 7.46 (1 H, d, J5,6 8, 6-H).
Yield 296 mg (75%), an oil; HRMS m/z: Found: Mϩ, 125.0528.
C6H7NO2 requires M, 125.0477; νmax(film)/cmϪ1 1731 (NC᎐O);
᎐
δH (CDCl3) 4.19 (1 H, br s, 4-H), 4.45 (1 H, t, J1,4 = J1,5 = 2.3,
1-H), 4.54 (1 H, d, J 11.2, CH2), 4.81 (1 H, d, J 11.2, CH2), 6.52
(1 H, t, J1,5 = J5,6 = 2.3, 5-H) and 6.67 (1 H, dd, J5,6 2.3, J1,6 1.3,
6-H); δC(CDCl3) 53.7 (C-1), 58.0 (C-4), 66.4 (CH2), 138.3
Synthesis of N-(propionyloxy)photopyridones (±)-8a–d
A solution of pyridones 7a–d (4 mmol) in benzene (1000 cm3)
under nitrogen was irradiated for 24 h. The solvent was
removed, and the residue was chromatographed on silica gel
[diethyl ether–hexane (1:1)] to afford the corresponding photo-
pyridones 8a–d.
(C-5), 142.5 (C-6) and 170.6 (C᎐O).
᎐
2-Hydroxymethyl-5-methoxy-3-oxo-2-azabicyclo[2.2.0]hex-5-
ene 6c. Yield 315 mg (85%), prisms (from Et2O); mp 70–72 ЊC;
HRMS m/z: Found: Mϩ, 155.0548. C7H9NO3 requires M,
155.0582; m/z 155 (Mϩ); νmax(film)/cmϪ1 1729 (NC᎐O);
Methyl 3-oxo-2-propionyloxymethyl-2-azabicyclo[2.2.0]hex-
5-ene-6-carboxylate 8a. Yield 640 mg (64%), oil; HRMS m/z:
᎐
δH (CDCl3) 3.67 (3 H, s, CH3), 4.24 (1 H, br s, 4-H), 4.28 (1 H,
br s, 1-H), 4.50–4.64 (2 H, m, CH2) and 5.18 (1 H, br s, 6-H); δC-
(CDCl3) 46.0 (C-1), 56.9 (CH3), 59.1 (C-4), 66.6 (CH2), 101.5
Found: Mϩ, 239.0794. C11H13NO5 requires M, 239.0811; νmax
-
(film)/cmϪ1 1772 (NC᎐O) and 1729 (C᎐O); δ (CDCl ) 1.13 (3
᎐
᎐
H
3
(C-6), 158.5 (C-5) and 169.3 (C᎐O).
H, t, J 7.6, CH2CH3), 2.30 (2 H, q, J 7.6, CH2CH3), 3.80 (3 H, s,
CO2CH3), 4.22 (1 H, dd, J4,5 1.1, J1,4 2.2, 4-H), 4.72 (1 H, dd,
J1,5 2.5, J1,4 2.2, 1-H), 5.13 (1 H, d, J 11.0, NCH2), 5.30 (1 H,
d, J 11.0, NCH2) and 7.14 (1 H, dd, J1,5 2.5, J4,5 1.1, 5-H);
δC(CDCl3) 8.7 (CH2CH3), 27.3 (CH2CH3), 51.9 (CO2CH3), 53.9
(C-1), 55.5 (C-4), 66.0 (NCH2), 144.2 (C-6), 146.0 (C-5),
᎐
5-[1,1-(Ethylenedioxy)ethyl]-2-hydroxymethyl-3-oxo-2-
azabicyclo[2.2.0]hex-5-ene 6d. Yield 287 mg (82%), prisms
(from Et2O); mp 72–73 ЊC; HRMS m/z: Found: Mϩ, 211.0852.
C10H13NO4 requires M, 211.0845; m/z 211 (Mϩ); νmax(film)/
cmϪ1 1743 (NC᎐O); δ (CDCl ) 1.53 (3 H, s, CH ), 4.00 (4 H,
᎐
H
3
3
s, CH2CH2), 4.20 (1 H, dd, J1,4 2.2, J4,6 1.2, 4-H), 4.32 (1 H,
d, J1,4 2.2, 1-H), 4.57 (1 H, d, J 11.4, NCH2), 4.81 (1 H, d, J
11.4, NCH2) and 6.50 (1 H, d, J4,6 1.2, 6-H); δC(CDCl3) 23.0
(CH3), 49.2 (C-1), 56.8 (C-4), 65.0 and 65.4 (CH2CH2), 66.5
(NCH2), 104.8 (CCH3), 134.4 (C-6), 152.2 (C-5) and 169.6
161.5, 167.4 and 173.6 (C᎐O).
᎐
3-Oxo-2-propionyloxymethyl-2-azabicyclo[2.2.0]hex-5-ene
8b. Yield 920 mg (92%), oil; HRMS m/z: Found: Mϩ, 181.0659.
C9H11NO3 requires M, 181.0738; νmax(film)/cmϪ1 1757 (NC᎐O)
᎐
and 1747 (C᎐O); δ (CDCl ) 1.15 (3 H, t, J 7.5, CH CH ), 2.36
᎐
H
3
2
3
(C᎐O).
᎐
(2 H, q, J 7.5, CH2CH3), 4.19 (1 H, br s, 4-H), 4.48 (1 H, t,
J1,4 = J1,5 = 2.6, 1-H), 5.14 (2 H, s, NCH2) and 6.50–6.55 (2 H,
m, CH᎐CH); δ (CDCl ) 8.9 (CH ), 27.3 (CH ), 55.2 (C-1), 58.5
᎐
C 3 3 2
(C-4), 65.7 (NCH2), 139.3 (C-5), 141.9 (C-6), 170.0 and 174.6
Synthesis of N-propionyloxymethyl-2(1H)-pyridones (±)-7a–d
A mixture of a pyridone (±)-4a–d (24 mmol), paraformaldehyde
(3.0 g) and potassium carbonate (1.5 g, 0.01 mol) in water (30
cm3) was treated under sonication for 3 h at room temperature.
After filtration of the reaction mixture, the aqueous layer was
extracted with CHCl3 (3 × 20 cm3). The combined organic layer
was concentrated to give the crude product, which was used for
the next step. Ethanol (40 cm3) and propionic anhydride (36
mmol) were added to the crude product and the mixture was
stirred at room temperature before being concentrated in vacuo,
and the residue was dissolved in CH2Cl2. The solution was
washed successively with saturated aq. NaHCO3, aq. HCl (2.7
mol dmϪ3), and saturated aq. NaCl. The organic layer was dried
over MgSO4 and was then concentrated in vacuo. The crude
product was chromatographed on a silica gel column eluted
with diethyl ether to give title products 7a–d.
(C᎐O).
᎐
5-Methoxy-3-oxo-2-propionyloxymethyl-2-azabicyclo[2.2.0]-
hex-5-ene 8c. Yield 980 mg (98%), yellow oil; HRMS m/z:
Found: Mϩ, 211.0827. C10H13NO4 requires M, 211.0844; νmax
(film)/cmϪ1 1762 (NC᎐O) and 1742 (C᎐O); δ (CDCl ) 1.15 (3
-
᎐
᎐
H
3
H, t, J 7.5, CH2CH3), 2.36 (2 H, q, J 7.5, CH2CH3), 3.66 (3 H, s,
OCH3), 4.25 (1 H, br s, 4-H), 4.30 (1 H, br s, 1-H), 5.06 (1 H, d,
J 11.2, NCH2), 5.07 (1 H, br s, 6-H) and 5.16 (1 H, d, J 11.2,
NCH2); δC(CDCl3) 8.9 (CH3), 27.3 (CH2), 47.7 (C-1), 56.9
(OCH3), 59.7 (C-4), 66.0 (NCH2), 101.0 (C-6), 158.9 (C-5),
168.8 and 174.6 (C᎐O).
᎐
5-[1,1-(Ethylenedioxy)ethyl]-3-oxo-2-propionyloxymethyl-2-
azabicyclo[2.2.0]hex-5-ene 8d. Yield 880 mg (88%), oil; HRMS
m/z: Found: Mϩ, 267.1114. C13H17NO5 requires M, 267.1109;
νmax(film)/cmϪ1 1762 (NC᎐O) and 1746 (C᎐O); δ (CDCl ) 1.15
Methyl 6-oxo-1-propionyloxymethyl-1,6-dihydropyridine-3-
carboxylate 7a. Yield 3.7 g (64%), prisms (from Et2O); mp 62–
63 ЊC; HRMS m/z: Found: Mϩ, 239.0810. C11H13NO5 requires
M, 239.0794; νmax(film)/cmϪ1 1748 (C᎐O), 1723 (C᎐O) and 1678
᎐
᎐
H
3
(3 H, t, J 7.5, CH2CH3), 1.52 (3 H, s, CH3), 2.35 (2 H, q, J 7.5,
CH2CH3), 3.92–4.03 (4 H, m, CH2CH2), 4.18 (1 H, br s, 4-H),
4.36 (1 H, d, J1,4 2.3, 1-H), 5.10 (1 H, d, J 11.2, NCH2), 5.16
(1 H, d, J 11.2, NCH2) and 6.36 (1 H, d, J4,6 1.0, 6-H); δC-
(CDCl3) 8.9 (CH2CH3), 23.1 (CCH3), 27.3 (CH2CH3), 50.7
(C-1), 57.2 (C-4), 64.9 and 65.3 (CH2CH2), 65.8 (NCH2), 104.8
᎐
᎐
(NC᎐O); δ (CDCl ) 1.14 (3 H, t, J 7, CH CH ), 2.42 (2 H, q, J
᎐
H
3
2
3
7, CH2CH3), 3.87 (3 H, s, CO2CH3), 5.89 (2 H, s, NCH2), 6.54 (1
H, d, J3,4 10, 3-H), 7.84 (1 H, dd, J3,4 10, J4,6 2, 4-H) and 8.37 (1
H, d, J4,6 2, 6-H).
(CCH ), 133.9 (C-6), 153.1 (C-5), 169.4 and 174.5 (C᎐O).
᎐
3
J. Chem. Soc., Perkin Trans. 1, 1997
1751