(Chief Bee)
12-10-03 12:13
No 475987
(Rated as: excellent)
Anyone with access to reference #14 and #15?
Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole
Eur. J. Med. Chem. 35, 187-203 (2000)
Chemistry
The safrole derived target compounds were prepared from Piperonal 15, obtained in ca. 75% overall yield from the natural safrole 7, using base catalysed isomerization of the double bond [14] followed by oxidative cleavage [15]. Employing the oxidative Yamada’s procedure [16] compound 15 was ‘one-pot’ converted, in 90% yield, to the corresponding methyl ester 16 by treatment with 2.6 eq. of KOH and 1.3 eq. of iodine in methanol at 0 °C.
Methyl 3,4-methylenedioxybenzoate 16
To a solution of piperonal 15 (0.45 g, 3.0 mmol) in absolute methanol (4 mL) cooled at 0°C, were successively added methanolic solutions (each 3 mL) of iodine (1.00 g, 3.9 mmol) and KOH (0.44 g, 7.8 mmol) at 0°C. After stirring for 1.5 h at 0°C, small amounts of saturated NaHSO3 solution were added until the disappearance of the brown colour. Next, the methanol was almost totally evaporated under reduced pressure. To the residue was added water, and the desired methyl 3,4-methylenedioxybenzoate 16 was obtained by filtration, in 90% yield, as a white solid, mp 53°C.
3-(3',4'-Methylenedioxyphenyl)propan-1-o
A solution of 0.92 g (5.7 mmol) of safrole 7 in 25 mL of dry THF, at room temperature, was treated with 6 mL (6 mmol) of a 1 M solution of BH3.THF, under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 h. Then, methanol was added dropwise until no further gas was evolved, and 2.4 mL of a 10% aqueous NaOH solution (6 mmol) and 2.4 mL of 30% aqueous H2O2 solution were added at 0°C. The suspension formed was maintained at 60°C for 4 h. After cooling, the reaction mixture was partitioned between ethyl ether (20 mL) and water (10 mL), followed by separation of the organic phase. The aqueous layer was further extracted with ethyl ether (3x10 mL) and the organic extracts were combined, treated with 10 mL of a 10% aqueous HCl solution and submitted to the usual work-up which furnished compound 20 as a yellow oil, 78% yield (Rf ethyl acetate: hexane 30% = 0.35).
3-(3',4'-Methylenedioxyphenyl) propanoic acid 21 [15]
An 8 N solution of Jones reagent [19] (ca. 10 mL) was added dropwise to a solution of 1.15 g (6.4 mmol) of alcohol 20 in 10 mL of acetone at 0°C. After 1 h 10 mL of isopropanol was added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue which was diluted with 50 mL of a mixture of diethylether/water (2:1). The organic layer was separated, dried and evaporated to give 1.14 g (92%) of the acid 21 as a white solid, mp 81–82°C (Rf acetone:toluene 30% = 0.47).
Methyl 3-(3',4'-methylenedioxyphenyl) propanoate 22
To a solution of 0.580 g (3 mmol) of the acid 21 in 10 mL of MeOH were added 0.3 mL of concentrated H2SO4 and the reaction mixture was refluxed for 2 h, when analysis by TLC indicated the end of the reaction. Then, the solvent was concentrated at reduced pressure and the residue obtained was neutralized with 10% aqueous NaHCO3 solution. Extraction of the aqueous phase with ethyl acetate (3x10 mL), followed by the usual work-up of organic layers, furnished 0.62 g (90%) of the corresponding ester derivative 22 as a light yellow oil, (Rf acetone:toluene 30% = 0.81).
References:
[14] Barreiro E.J., Lima M.E.F., J. Pharm. Sci. 81 (1992) 1219–1222.
[15] Barreiro E.J., Costa P.R.R., Coelho F.A.S., de Farias F.M.C., J. Chem. Res. (M) (1985) 2301–2332.
[16] Yamada S., Tetrahedron Lett. 33 (1992) 4329–4332. DOI:10.1016/S0040-4039(00)74252-3
[19] Hudlicky M., Oxidations in Organic Chemistry, American Chemical Society, Washington DC, 1990, p. 273.
(Hive Bee)
12-11-03 16:47
No 476260
(Rated as: excellent)
J. Pharm. Sci. 81 (1992) 1219–1222 (http://lego.chemistry.tripod.com/Journa
Barreiro E.J., Lima M.E.F.,
The synthesis and anti-inflammatory properties of a new Sulindac analogue synthesized from natural safrole
...
2: Safrole
7: Isosafrole
...
Isomerization of 2 to 710:
To 80.0 g (0.49 mmol, Lego's voice: probably 0.49 mol meant) of 2 was added 100 ml of a 3 N solution of potassium hydroxide in n-butyl alcohol and the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into a solution of 12 ml of concentrated HCl and 52 ml of ice water. After neutralization with additional concentrated HCl, the organic layer was extracted with three 35-ml portions of ethyl acetate. After usual workup, a white oily residue was obtained and distilled to furnish 78.4 (96-98%) of the styrene derivative (7) as a colorless oil. An analytical sample showed spectroscopic data identical with those reported27.
2-Methyl-5,6-(methylendioxy)-1-idanone (9) - A modification of an earlier procedure18 was used. To 14,5 ml (185 mmol) of dry dimethylformamide was added in a dropwise manner with vigorous stirring 3.5 ml (37.03 mmol) of recently distilled POCl3. The mixture was stirred at this temperature for 3 h, then cooled to room temperature and poured into 200 ml of ice water. The aqueous layer was made basic by addition of 7 N aqueous sodium hydroxide solution and stirred at room temperature overnight. Finally, the aqueous layer was treated with three 50-ml portions of ethyl ether, and the organic layers were combined and submitted to the usual workup to provide a pale brown viscous oil as product. Chromatographic purification on a silical gel column with ethyl acetate as eluant gave 5.0 g (85%) of indanone (9) as a pale yellow solid.
...
10. For other examples of the use of safrole in the synthesis of bioactive compounds see Barreiro, E.; Costa, P. R. R.; Mello, R. T.; Barros, P. R. An. Acad. Brasil. Cienc. 1981, 53, 65-67
...
18. Witiak, D.T.; Wiliams, D. R.; Kakodkar, S.V. J. Org. Chem., 1974, 39, 1242-1247
...
27. Barreiro, E. J.; Costa, P. R. R.; Coelho, F. A. S.; Farias, F. M. C., J. Chem. Res. 1985, 2301-2332
J. Chem. Res. (M) (1985) 2301–2332 (http://lego.chemistry.tripod.com/Journa
Barreiro E.J., Costa P.R.R., Coelho F.A.S., de Farias F.M.C.
Prostaglandin Analogues. 2
Synthesis of new prostanoid derivatives from safrole isoalted from sassafras oil
The candle that burns twice as bright burns half as long
(Chief Bee)
12-11-03 23:56
No 476339
Very nice! Do you think you could post the following synthetic sequences from the J. Chem. Res. article (I have a hard time reading that small print)...
6 -> 7 -> 8 as well as 6 -> 14 -> 15
Optional: 14 -> 26 and 7 -> 30 -> 30a
The Hive - Clandestine Chemists Without Borders