Abstract
A highly efficient, mild, and simple protocol is presented for the oxidative aromatization of Hantzsch 1, 4-dihydropyridines using the combination of Dess-Martin periodinane with molecular iodine or KBr. The in situ generated acetyl hypoiodite or bromite formed due to the reaction between Dess-Martin periodinane and molecular iodine or KBr respectively is supposed to be the responsible species for bringing about the oxidative aromatization of 1, 4dihydropyridines.
Highlights
The 1,4-DHP derived drugs such as nefidine, nitrendipine, and nimodipine are frequently used as cardiovascular agents (Ca2+ channel blockers) for the treatment of hypertension and angina pectoris diseases.2. This important class of calcium channel antagonists relaxes the cardiac muscle by decreasing the transmembrane calcium current on binding.3. The metabolism of these drugs involves an oxidative aromatization of 1, 4-DHP nucleus to the corresponding pyridine derivatives, which is catalyzed in the liver by cytochrome P-450.4 The pyridine derivatives are further metabolized leading to the cleavage of the ester groups
In continuation of our interest in hypervalent iodine reagents18, we report that DMP in combination with molecular iodine or KBr can serve as mild oxidant for the oxidative aromatization of the Hantzsch 1, 4-DHPs in high yields
A set of experiments was carried out first to define a standard procedure for this oxidation using the 1, 4-DHP 1a (R = C6H5-) as a model substrate
Summary
Hantzsch 1,4-dihydropyridine (DHP) structural subunit is contained in a growing number of both natural products and synthetic compounds with wide range of biological properties.1 For example, the 1,4-DHP derived drugs such as nefidine, nitrendipine, and nimodipine are frequently used as cardiovascular agents (Ca2+ channel blockers) for the treatment of hypertension and angina pectoris diseases.2 This important class of calcium channel antagonists relaxes the cardiac muscle by decreasing the transmembrane calcium current on binding.3 The metabolism of these drugs involves an oxidative aromatization of 1, 4-DHP nucleus to the corresponding pyridine derivatives, which is catalyzed in the liver by cytochrome P-450.4 The pyridine derivatives are further metabolized leading to the cleavage of the ester groups. The reaction of 1a (1 mmol) with DMP (1 mmol) in CH2Cl2 (10 mL) at room temperature stirring as well as under reflux conditions for 12 hrs did not produce the oxidation product 2a in appreciable yield.
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