Fused pyridine derivatives R 0450 Practical Outcome of Azaphthalimide Reduction with Zn/AcOH at Various Temperatures. -The regioselective reduction of azaphthalimides (I) can be stopped at the stage of products (II), whereas in the case of azaphthalimides (IV) only reduction products (V) are obtained. -(PARCHINSKY, V. Z.; KOLEDA, V. V.; USHAKOVA, O.; TALISMANOVA, T. D.; KRAVCHENKO, D. V.; KRASAVIN*, M.; Lett. Org.

Reduction of 4-aza-and 5-azaphthalimides with Zn dust in acetic acid resulted in two distinct outcomes: i) in the 4-aza series, the reduction process stopped at the stage of 3-hydroxy-4-azaisoindolin-1ones (isolated in 69-90% yield), presumably, stabilized by an intramolecular hydrogen bond; more forcing condition (110°C, 2 days) are required to obtain 4-azaisoindolin-1-ones; ii) in the 5-aza series, even at low temperatures (~10°C), overreduction could not be avoided; practical yields of 4-azaisoindolin-1-ones (59-85%) were achieved using elevated temperatures (50°C). The method described offers a practical alternative to hitherto reported sodium borohydride reduction of 4-azaphthalimides, which suffers from poor selectivity and isolated yields. Reductive manipulation of 5-azaphthalimides was studied for the first time.Isomeric azaphthalimide moieties (1 and 2) are present as an essential structural feature in a number of pharmacologically active compounds among which antibacterial [1], metalloprotease inhibitory [2], analgesic [3], and antihypertensive [4] are notable. Benzene ring-fused (i.e. quinolinebased) azaphthalimides have been reported by some of us as potent caspase-3 inhibitors [5]. Additionally, azaphthalimides are of interest as bioisosteric phthalimide replacement in an ongoing worldwide effort [6] to develop anticancer and immune disease treatments based on analogs of thalidomide-the notoriously teratogenic drug that has been approved for use in oncology [7]. RESULTS AND DISCUSSION4-Azaphthalimides (1) and 5-azaphthalimides (2) used in this study were prepared by a literature method [16]. Reduction of 1 with 5 equiv. of Zn dust in acetic acid (5 mL/mmol) at room temperature for 8 h resulted in a clean