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 sp² carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis^1,2. However, the incorporation of alkyl substrates to form sp³ 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.

Extended Data Figure 1. Decarboxylative sp³ C–N couplings with a series of secondary alkyl acids

An array of secondary alkyl carboxylic acids can be cross-coupled with 3-chloroindazole. The protocol provides the product as a single regioisomer for all cases. All yields are isolated. See Supplementary Information for full experimental details. d.r., diastereomeric ratio. ^#d.r. was determined by ¹H NMR.

Extended Data Figure 2. Decarboxylative sp³ C–N couplings with a series of N-heterocycles

A variety of N-heterocycles, including indazoles, azaindoles, indoles, and pyrazoles, can cross-couple with carboxylic acids in good efficiency. All yields are isolated. See Supplementary Information for full experimental details. *Single regioisomer.

Extended Data Figure 3. Decarboxylative sp³ C–N couplings with a series of N-nucleophiles

A variety of N-nucleophiles, including N-heterocycles, anilines, sulfonamides, and amides, can cross-couple with carboxylic acids in good efficiency. All yields are isolated unless otherwise noted. See Supplementary Information for full experimental details. ^#Yield was determined by ¹⁹F NMR with an internal standard. ^&Yield was determined by gas chromatography analysis with an internal standard. *Single regioisomer.

Extended Data Figure 4. Decarboxylative sp³ C–N couplings with a series of pharmaceutical compounds

A number of drug molecules can cross-couple with carboxylic acids in good efficiency. All yields are isolated. See Supplementary Information for full experimental details. *Single regioisomer.

Figure 1. Decarboxylative N-nucleophile fragment coupling

A general platform for decarboxylative sp³ C–N coupling can be realized by the combination of copper catalysis and photoredox catalysis. A broad range of readily available carboxylic acids and N-nucleophiles are employed to generate a variety of N-alkyl products. Ph, phenyl; Boc, tert-butoxycarbonyl; X and Y, carbon or nitrogen atom.

Figure 2. Catalytic cycles and control experiments

a, A proposed mechanism is outlined. Photocatalyst 1 is excited by visible light to produce a long-lived triplet excited state (2), which can readily oxidize copper(I) catalyst 3 to yield copper(II) species 4. The reduced iridium(II) complex 5 can then be oxidized by iodomesitylene dicarboxylate 8, which is derived from the reaction of carboxylic acid 6 and iodomesitylene diacetate 7, to release alkyl radical 9 and photocatalyst 1. Concurrently in the copper catalytic cycle, copper(II)-amido complex 4 can capture alkyl radical 9 to form the highly unstable copper(III) complex 10. Reductive elimination from complex 10 provides the desired sp³ C–N coupled product and regenerates the copper(I) catalyst 3 after coordination with the N-nucleophile 11. b, Control experiments were performed with three different N-nucleophiles. In all cases, the presence of both the copper(I) catalyst and the photoredox catalyst under light irradiation conditions is crucial to achieve the best efficiency for the C–N coupling reactions. SET, single-electron transfer; Mes, mesityl; L, ligand; Cy, cyclohexyl; Nu, nucleophile; X, anionic ligand, such as a carboxylate; Y and Z, carbon or nitrogen atom.

Figure 3. Decarboxylative C–N couplings of 3-chloroindazole with a range of alkyl carboxylic acids

A wide variety of alkyl carboxylic acids can be cross-coupled with 3-chloroindazole. The carboxylic acid is added in (a) and the N-nucleophile in (b). The protocol provides the product as a single regioisomer for all cases. All yields are isolated. In the absence of light and the photocatalyst, the yields of these compounds are: 13, 42% yield; 14, 70% yield; 25, 48% yield; 26, 34% yield; 27, 80% yield; 28, 56% yield; 29, 86% yield; 31, 44% yield; 32, 62% yield; 33, 38% yield; 34, 26% yield; 35, 32% yield; 36, 20% yield. These yields were determined by ¹H nuclear magnetic resonance (¹H NMR) spectroscopy with an internal standard. See Supplementary Information for full experimental details. See Extended Data Figure 1 for additional examples. TC, thiophene-2-carboxylate; Me, methyl; Ac, acetyl; Et, ethyl; Cbz, carboxybenzyl; NPhth, phthalimide.

Figure 4. Decarboxylative C–N couplings of cyclohexyl carboxylic acid with a variety of N-nucleophiles

This new C–N bond-forming protocol shows a strikingly broad scope with respect to the N-nucleophiles. Almost every single class of important N-heterocycles can provide N-alkylated products in good yields and excellent regioselectivity. Less nucleophilic substrates and complex drug molecules are all viable coupling partners. All yields are isolated yields for the decarboxylative C–N coupling step.*Single regioisomer. ^#The yields of reactions that were conducted in the absence of light and a photocatalyst are shown in the parentheses and determined by ¹H NMR with an internal standard. See Supplementary Information for full experimental details. See Extended Data Figures 2–4 for additional examples. Pr, propyl; Bn, benzyl.

Figure 5. Sequential C–N couplings and comparisons with nucleophillic substitutions

a, Sequential decarboxylative C–N couplings can be realized using indazole derivative 64 bearing two nucleophilic sites. The N,N′-dialkylated product bearing two different alkyl groups can be easily generated via two C–N coupling reactions employing different alkyl acids under different reaction conditions. All yields in this section are isolated yields for the decarboxylative C–N coupling step. b, Comparing the current decarboxylative C–N coupling protocol with classical nucleophilic substitution methods using two alkyl electrophiles demonstrates the complementary nature of this new method. All yields in this section were determined by ¹H NMR studies with an internal standard. See Supplementary Information for full experimental details and additional examples. BTTP, tert-butylimino-tri(pyrrolidino)phosphorane; r.r., regiomeric ratio.