ChemInform Abstract: Approaches to Iodinated Derivatives of Vanillin and Isovanillin.

Abstract

Previously unknown 5‐iodovanillin ethers like (VI) and (VIII) are prepared by a three‐step strategy consisting of ether cleavage, regioselective methylation and subsequent O‐alkylation.

Inhibition of Bacterial Dihydrofolate Reductase by 6‐Alkyl‐2,4‐diaminopyrimidines

“…Compounds 8 and (±)-10a-b were then coupled to generate racemic 11a-c and 12a-c as depicted in Scheme 2. Since both 1a and 1b demonstrated excellent inhibitory properties in our previous studies, [5,6] the propyl-and isobutenyl-substituted compounds 11a-c and 12a-c were targeted. The synthesis of DAP derivatives 8a-c involved a seven-step sequence from commercially available 5-iodovanillin (2).…”

“…Finally, the dihydrophthalazine coupling partners (±)-10a-b were obtained by reacting phthalazine (9) with the propyl and isobutenyl Grignard reagents, followed by N-acylation with acryloyl chloride in the presence of triethylamine as described in earlier reports. [5,6] The final coupling reactions involving 8a-c and 10a-b were accomplished using a palladium acetate-promoted Heck coupling in the presence of N-ethylpiperidine in anhydrous DMF solvent at 140 °C (see Scheme 2). Purification of the products by flash chromatography, followed by recrystallization, afforded the final racemic compounds 11 and 12 in yields ranging from 78-85%.…”

“…4760) and heated to 165°C for 16 h. The reaction was cooled, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography on a 70cm × 3-cm silica gel column eluted with dichloromethane:methanol:triethylamine (95:5:1) to give 8a as a white solid 3-{5-[(2,4-Diamino-6-methyl-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl}-1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (11a)-To a stirred solution of 1.00 g (2.50 mmol) of 8a in 8 mL of dry DMF under nitrogen was added 627 mg (2.75 mmol, 1.10 equiv) of (±)-1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one [(±)-10a] [6] dissolved in 1 mL of DMF, followed by 310 mg (0.38 mL, 2.75 mmol, 1.10 equiv) of N-ethylpiperidine. To this solution was added 20 mg (0.089 mmol) of palladium(II) acetate, and the reaction mixture was heated at 140°C for 20 h. Isolation of the expected product was achieved by pouring the cooled reaction mixture directly onto a 50-cm × 2.5-cm silica gel flash chromatography column packed in dichloromethane.…”

“…Impurities were eluted using dichloromethane, and the final product was collected using dichloromethane:methanol:triethylamine (97:3:1) as the eluent. Evaporation of the solvent gave a pale yellow solid, which was further purified using a 15-cm × 2-cm silica gel column, packed with dichloromethane and eluted with dichloromethane:methanol:triethylamine 1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (11b)-This compound was prepared as above using 1.00 g (2.42 mmol) of 8b, 606 mg (2.66 mmol, 1.10 equiv) of (±)-10a, [6] 2,3-dimethoxyphenyl}-1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (11c)-This compound was prepared as above using 1.00 g (2.34 mmol) of 8c, 587 g (2.57 mmol, 1.10 equiv) of (±)-10a, [6] (E)-3-{5-[(2,4-Diamino-6-methyl-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl}-1-(1-isobutenyl-2(1H)-phthalazinyl)-2-propen-1-one (12a)-This compound was prepared as above using 1.00 g (2.50 mmol) of 8a, 660 mg (2.75 mmol, 1.10 equiv) of (±)-1-(1-isobutenyl-2(1H)-phthalazinyl)-2-propen-1-one [(±)-10b], [6]…”

“…1.5.1.3). Our recently reported [4][5][6] library of dihydrophthalazine-containing compounds has demonstrated potency against DHFR in Bacillus anthracis. We are also monitoring the broad-spectrum potency of this series, and in particular for antistaphylococcal activity.…”