Palladium-Catalyzed Aminocarbonylation of Isoquinolines Utilizing Chloroform-COware Chemistry

Abstract

The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for in or ex situ generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this “Chloroform-COware” technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.

Carbonylative Transformations Using a DMAP-Based Pd-Catalyst through Ex Situ CO Generation

“…[1,3]­Dioxolo­[4,5- g ]­isoquinolin-5­(6 H )-one was prepared according to a previously reported procedure . [1,3]­Dioxolo­[4,5- g ]­isoquinolin-5­(6 H )-one (200 mg, 1 equiv) was taken in a 50 mL round-bottom flask, charged with a magnetic stirring bar, and was dissolved in 15 mL DMF.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 8.57 (dd, J = 4.5, 1.5 Hz, 1H), 7.80 (dd, J = 8.1, 1.5 Hz, 1H), 7.17 Synthesis of 1-Morpholino-4-iodoisoquinoline (1l). 11 1-Morpholino-4-iodoisoquinoline (1l) was prepared according to our previously reported procedure and obtained as a white solid; mp 135−137 °C. Synthesis of the Complex [Pd(DMAP) 2 (OAc) 2 ] (3).…”

“…Morpholino(quinolin-3-yl)methanone (2m). 11 2m was prepared following general procedure A from 1c (77 mg, 0.3 mmol). The crude reaction mixture was purified by silica gel column chromatography (MeOH/CH 2 Cl 2 2:98) to obtain the product as a white oil (62 mg, 85%).…”

“…Our continuous efforts in contributing toward safe and effective carbonyl insertion have intrigued us in exploring phosphine-free catalytic systems. Recently, we have addressed the issue of safe and easy handling of such reactions through “Chloroform-COware” chemistry, where chloroform has been used as a cheap and widely available ex situ CO precursor employed in a two-chamber setup . Such a design facilitates the smooth release of CO gas from chloroform in one chamber, while in the other chamber, carbonylative transformations are carried out under mild conditions.…”

“…Synthesis of 4-Iodoisoquinoline (1e) 11. 4-Iodoisoquinoline (1e) was prepared according to a previously reported procedure and obtained as a white solid; mp 89−91 °C 1.…”