9106
C. Vitry et al. / Tetrahedron 57 52001) 9101±9108
4.1.5. 6-[4S)-2-Benzyl-1-hydroxyethyl]-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 48). Imide 10 01 g, 3.5
mmol), zinc powder 01.8 g) and 12N HCl 04.7 mL) were
heated at 1008C for 5 h. After cooling, zinc powder 01.3 g)
was added and the mixture was stirred for 12 h at room
temperature. Zinc in excess was ®ltered, the ®ltrate was
basi®ed with aqueous ammonia and extracted with
CH2Cl2. The organic layers were dried over MgSO4, ®ltered
and evaporated under vacuum to afford an oil. The crude
product was puri®ed by chromatography on silica gel
0CH2Cl2/EtOH, 95/5) to give 8 00.57 g, 60% yield) as a
yellow oil.
hydro-5-oxo-1,6-naphthyridinium iodide 414). The
above compound 13 01.12 g, 4 mmol) was heated to re¯ux
for 12 h in a mixture of methyl iodide 05 mL, large excess)
and acetonitrile 05 mL). After concentration at 2/3 of the
initial volume ether was added. The obtained precipitate
was ®ltered. Yellow solid: 1.43 g. Yield 85%. IR 0KBr):
1
1648 cm21. H NMR 0200 MHz): 9.03 0q, 1H); 8.71 0q,
1H); 7.79 0d, 1H, J8.0 Hz); 7.52 0q, 1H); 7.28±7.10 0m,
5H); 6.63 0d, 1H, J8.0 Hz); 4.17 0s, 3H); 3.65 0d, 2H); 3.14
0d, 2H).
4.1.10. 1-Methyl-6-[4S)-2-benzyl-1-hydroxyethyl]-1,4,5,6-
tetrahydro-1,6-naphthyridin-5-one 45). The above pyri-
dinium salt 14 00.422 g, 1 mmol) was dissolved in degassed
water 05 mL) at 408C. At rt, under argon, Na2CO3 00.53 g,
5 mmol) was added, followed by the dropwise addition of a
solution of sodium dithionite 00.70 g, 4 mmol) in degassed
water 03 mL). After stirring for 30 min, the precipitate was
®ltered, washed with degassed water and dried. A yellow
light solid was obtained: 2.66 g Yield 90%. IR 0KBr)
4.1.6.
6-[4S)-2-Benzyl-1-hydroxyethyl]-6,7-dihydro-1-
methyl-5-oxo-5H-pyrrolo[3,4-b]pyridinium tosylate 411).
Compound 8 01.07 g, 4 mmol) was dissolved in acetonitrile
05 mL) and methyl tosylate 00.75 g, 4 mmol) was added.
The reaction mixture was heated to re¯ux of acetonitrile
for 12 h. After evaporation of the two-thirds of the solvent
under vacuum, ether was added dropwise until precipitation
of a salt which was ®ltered and washed with ether to afford
11 01.54 g, 85% yield) as a pale yellow solid 0mp 608C). IR
0KBr) 1697 cm21. 1H NMR 0200 MHz, DMSO-d6): 9.14 0d,
1H, J5.0 Hz); 8.74 0d, 1H, J7.7 Hz); 8.16 0tapp, 1H); 7.45
0d, 2H, J8 Hz); 7.30±7.13 0m, 5H); 7.09 0d, 2H, J
8.0 Hz); 5.03 0s, 2H); 4.68±4.48 0m, 1H); 4.34 0s, 3H);
3.75±3.60 0m, 3H); 3.10±2.80 0m, 2H); 2.57 0s, 3H).
Anal. calcd for C24H26N2O5S: C, 63,41; H, 5.77; N, 6.17.
Found: C, 63.45; H, 5.85; N, 6.02.
1
1645 cm21. H NMR 0500 MHz, CD3CN): 7.30±7.18 0m,
5H); 7.16 0d, 1H, J7.75 Hz); 5.84 0dt, 1H, J1.70 and
8.10 Hz); 5.77 0d, 1H, J7.75 Hz); 4.95±4.86 0m, 1H);
4.67 0dt, 1H, J3.55 and 8.00 Hz); 3.90±3.72 0m, 3H);
3.20±3.10 0m, 4H); 2.95 0s, 3H). Spectrum in the presence
of 1 equiv. of Mg0ClO4)2 0500 MHz, CD3CN): 7.34 0d, 1H,
J7.75 Hz); 7.30±7.15 0m, 5H); 6.11 0d, 1H, J7.75 Hz);
5.88 0dt, 1H, J1.60 and 8.00 Hz); 5.20±5.07 0m, 1H); 4.76
0dt, 1H, J3.55 and 8.00 Hz); 4.00±3.90 0m, 2H); 3.25±
3.05 0m, 4H); 3.00 0s, 3H).
4.1.7. 1-Methyl-6-[4S)-2-benzyl-1-hydroxyethyl]-1,4,6,7-
tetrahydro-5H-pyrrolo[3,4-b]pyridin-5-one 44). The
pyridinium salt 11 00.455 g, 1 mmol) was placed under
argon and dissolved in degassed water 05 mL) at 408C.
After cooling to rt, Na2CO3 00.53 g, 5 mmol) and a solution
of sodium dithionite 00.7 g, 4 mmol) in degassed water
03 mL) were added. The reaction mixture was vigorously
stirred for 0.5 h and ®ltrated. The precipitate was washed
with degassed water and dried under vacuum to afford
4.1.11. 3-[43-Methoxycarbonylpyridin)3-yl]propanol 416).
A suspension of 2-methylnicotinic acid 01.51 g, 11 mmol) in
dry THF 0100 mL) under argon was cooled at 2788C. A
LDA solution 024 mmol) was added dropwise and the
purple reaction mixture was held at 2788C for 0.5 h and
then at 08C for 1 h. After recooling to 2788C, 1-bromo-2-
[0tetrahydropyran-2-yl)oxy]ethane 14 03.45 g, 16.5 mmol)
was added dropwise to this solution at 2558C and the
reaction mixture was allowed to rise slowly rt for 16 h.
The solvent was evaporated under reduced pressure. The
residue was dissolved in a solution of HCl in methanol
05% w/w, 100 mL) and the resulting mixture was heated
to re¯ux for 24 h. After removal of the solvent, the residue
was taken up with water, neutralised with NaHCO3, and
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, ®ltered and concentrated under vacuum
to give a brown liquid. A ¯ash chromatography on silica gel
0CH2Cl2/MeOH, 98/2) afforded 16 02.14 g, 60% yield) as a
1
model 4 00.242 g, 85% yield) as a pale green solid. H
NMR 0500 MHz, CD3 CN): 7.35±7.20 0m, 5H); 5.81 0dt,
1H, J1.7 and 8.1 Hz); 4.66 0dt, 1H, J3.3 and 8.0 Hz);
4.27±4.08 0m, 1H); 3.95±3.80 0m, 2H); 3.69±3.63 0m, 3H);
3.01±2.86 0m, 4H); 2.84 0s, 3H).
Spectrum in the presence of 1 equiv. Mg0ClO4)2 0500 MHz,
CD3CN): 7.35±7.20 0m, 5H); 5.84 0dt, 1H, J1.6 and
8.1 Hz); 4.72 0dt, 1H, J3.3 and 8.0 Hz); 4.54±4.42 0m,
1H); 4.10±3.90 0m, 2H); 3.75±3.67 0m, 2H); 3.07±2.85
0m, 4H); 2.89 0s, 3H).
1
yellow liquid. IR 0®lm) 1727 cm21. H NMR 0200 MHz,
CDCl3): 8.59 0dd, 1H, J4.8 and 1.7 Hz); 8.14 0dd, 1H,
J7.9 and 1.7 Hz); 7.19 0dd, 1H, J4.8 and 7.9 Hz); 3.88
0s, 3H); 3.78 0br, 1H); 3.61 0tapp, 2H); 3.25 0tapp, 2H, J
7.1 Hz): 1. 98 0qapp, 2H). Anal. calcd for C10H13NO3: C,
61.54; H, 6.67; N, 7.18. Found: C, 61.45; H,7.92; N, 7.07.
4.1.8. 6-[4S)-2-Benzyl-1-hydroxyethyl]-5,6-dihydro-1,6-
naphthyridin-5-one 413). Compound 127 02.79 g, 10
mmol) was heated to re¯ux in a mixture of ethanol/water:
95/5 020 mL) for 48 h. After evaporation of the solvents the
obtained solid was puri®ed by chromatography on silica gel
0CH2Cl2/EtOH: 95/5) leading to 1.45 g of a yellow solid.
4.1.12. 3-[43-Methoxycarbonylpyridin)-2-yl]propanal 417).
A 150 mL three-necked round-bottom ¯ask under argon
was equipped with a thermometer and two pressure-
equalising dropping funnel containing freshly distilled
dimethylsulfoxide 01.33 mL, 18.5 mmol) diluted in
CH2Cl2 05 mL) and alcohol 16 01.5 g, 7.7 mmol) diluted
in CH2Cl2 05 mL), respectively. A solution of oxalyl
Yield 52%. IR 0KBr): 1645 cm21 1H NMR 0200 MHz
.
CDCl3): 8.70 0q, 1H); 8.39 0q, 1H); 7.28 0d, 1H, J
8.0 Hz); 7.20±7.05 0m, 6H); 6.58 0d, 1H, J8.0 Hz); 5.20
0m, 1H); 3.93 0d, 2H); 3.13 0d, 2H).
4.1.9. 6-[4S)-2-Benzyl-1-hydroxyethyl]-1-methyl-5,6-di-