97 news & views © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. HOMOGENEOUS CATALYSIS Shining a light on amine synthesis Given the abundance of amines in pharmaceutical substances, new strategies for the formation of C–N bonds are highly sought after. Now, using a dual photoredox–copper catalysis system, a method for amine synthesis has been developed. Joyann S. Barber, Francesca M. Ippoliti and Neil K. Garg T he formation of C–N bonds is one of the most important transformations in organic chemistry, particularly in the pharmaceutical industry 1 . Although traditional methods such as alkylation or reductive amination remain popular, the use of transition metal-catalysed C–N bond forming reactions have become quintessential tools in modern synthesis. For example, the combination of aryl electrophiles and amine nucleophiles to forge C–N bonds, primarily due to breakthroughs by Ullmann, Buchwald and Hartwig, has become a remarkably reliable method to achieve aryl amination 2,3 . Comparable metal-catalysed methods to achieve the amination of alkyl electrophiles are less developed. Now, writing in Nature Catalysis, Hu and co-workers describe a general method for the alkylation of amines through the use of a dual photoredox–copper catalysis system that combines alkyl electrophiles and amines to form C–N bonds 4 . Drawing inspiration from works utilizing redox-active esters 5 , Hu and co-workers demonstrate that alkyl radicals can be generated via the excitation and fragmentation of N-hydroxyphthalimide esters using photoredox catalysis (Fig. 1a). Similar to the generation of alkyl radicals from alkyl halides as reported in ref. 6 , the alkyl radical generated by Hu and colleagues can subsequently be trapped by an amine nucleophile via copper catalysis. This dual photoredox–copper catalysis system uses Ru(bpy) 3 (PF 6 ) 2 as a photocatalyst, blue light-emitting diodes (LEDs) and CuBr, and notably employs carboxylic acid derivatives as the coupling partner, which are more abundant and stable than alkyl halides. Another important deviation from typical photoredox–transition metal relay catalysis 7,8 H N Me O 90% yield H N 78% yield N H N n = 1, 81% yield n = 2, 41% yield n = 9, 76% yield OMe n H N 40% yield OMe Br Ar H N 48% yield (from gabapentin) NHBoc R 2 R 1 O O PhthN Ru(bpy) 3 (PF 6 ) 2 (1 mol%) CuBr (20 mol%) Ligand (7.5 mol%) Et 3 N, CH 3 CN, RT, blue LEDs, 12 h H N R 2 R 1 N H O O OH OMe OMe Ligand R 2 R 1 Excitation and fragmentation –CO 2 Radical trapping and reductive elimination H N Cu I R 3 a b H N 88% yield H N 76% yield OMe OMe O O S H N 36% yield Ph O O H N 41% yield Ph O H N Et n-Bu 60% yield OMe H N 31% yield OMe H N 50% yield OMe C 8 F 17 H N 41% yield OMe MeO 2 C Varying amine functionality Varying alkyl functionality c O O N O O Ru(bpy) 3 (PF 6 ) 2 Et 3 N, CH 3 CN, RT blue LEDs, 12 h (41% yield) N NH Cu NCCH 3 + d H N N Ar H N 50% yield (from chlorambucil) N Cl Cl Ar H N 43% yield (from dehydrocholic acid) Me O H H H Me O O Me Ar H N 59% yield (from β-homoleucine) NHBoc i-Pr OMe = Ar Ar H N 41% yield (from ibuprofen) Me i-Pr R 3 –NH 2 + R 3 Fig. 1 | The decarboxylative coupling of aliphatic carboxylic acids and amines. a, The cross-coupling described by Hu and co-workers involves a dual photoredox–copper relay catalysis system 4 . The reaction proceeds through an alkyl radical intermediate and subsequent trapping with a copper amine complex generates the desired C–N bond. b, The scope with respect to both the amine and alkyl fragments encompasses a wide range of functional groups. c, Medicinally relevant molecules, such as natural products or pharmaceutical drugs, can be derivatized to form analogues. d, The in situ generation of a Cu(I) complex enabled mechanistic studies to support the notion that a Cu(I) species is operative. RT, room temperature. NATURE CATALYSIS | VOL 1 | FEBRUARY 2018 | 97–98 | www.nature.com/natcatal