Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis

Abstract

Over the past three decades, considerable progress has been made in the development of methods to construct sp carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis. However, the incorporation of alkyl substrates to form sp C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

The Persistent Radical Effect in Organic Synthesis

“…[290] Based on this seminal work, other radical Cu-catalyzed CÀN bond formations at activated CÀHs ites with amides,s ulfonamides,i mides, [293] carbamates, [294] sulfoximines, [295] and Weinreb amides [296] as the nucleophilic Nsources have been developed. Recently,c arboxylic acids in combination with alkyl chlorides [297] and hypervalent iodine [298] were established in such couplings.M oreover,s uch aminations can be combined with ar adical addition to aC =Cd ouble bond where uncatalyzed radical C À Cb ond formation precedes the Cucatalyzed C À Nbond formation. [299] NorOarylations of aryl iodides can also be conducted by radical-metal crossover chemistry (Ullmann-type coupling).…”

Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

“…In 1994, Della and co‐workers demonstrated that when lead(IV) acetate was used as the promoter with benzene as the reaction solvent, 28 could be converted to methyl 3‐phenylbicyclo[1.1.1]pentane‐1‐carboxylate ( 49 p ) in 69% yield (Scheme ) . MacMillan and co‐workers reported an iridium‐copper dual catalyst strategy to achieve decarboxylative C−N coupling of 28 to achieve the indazole adduct 49 q in 80% yield with blue LED and 20% yield in dark (Scheme ) …”

Der “Persistent Radical Effect” in der organischen Chemie

“…[290] Basierend auf dieser wegbereitenden Arbeit wurden weitere radikalische Cu-katalysierte C-N-Bindungsknüpfungen an aktivierten C-H-Positionen mit Amiden, Sulfonamiden, Imiden, [293] Carbamaten, [294] Sulfoximinen [295] und Weinreb-Amiden [296] als nukleophile N-Quellen entwickelt. Vor kurzem wurden Carbonsäuren in Kombination mit Alkylchloriden [297] und hypervalentem Iod [298] in solchen Kupplungen etabliert. Außerdem kçnnen solche Aminierungen mit der radikalischen Addition an eine C = C-Doppelbindung kombiniert werden, bei welchen eine unkatalysierte radikalische C-C-der Cu-katalysierten C-N-Bindungsknüpfung vorausgeht.…”