Letter | Published:

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

Naturevolume 559pages8388 (2018) | Download Citation

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 catalysis1,2. 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.

Main

Within the field of organic chemistry, the efficient construction of C–N bonds is important owing to the prevalence of nitrogen-containing motifs in a wide array of natural products, pharmaceuticals and functional materials3,4,5. There are several notable routes to the formation of sp2 C–N bonds, including the Buchwald–Hartwig reaction1, Ullmann coupling6 and Chan–Lam amination7. However, sp3 C–N bond formation typically relies on classical methods, such as nucleophilic substitution reactions between nitrogen nucleophiles and alkyl halides8, Mitsunobu alkylations of alcohols using nitrogen nucleophiles9, reductive amination with carbonyls10 or olefin hydroamination11. Recently, several research groups have reported transition-metal-catalysed variants of the alkylation reaction of nitrogen nucleophiles with aliphatic halides12,13. In 1894, Curtius reported the rearrangement of acyl azides to form C–N-containing aliphatic substrates14. We questioned whether it might be possible to expand this concept to complex, medicinally relevant nitrogen-bearing fragments, thereby accelerating access to drug-like complexity in one step.

The synergistic merger of photoredox15 and transition metal catalysis (termed metallaphotoredox catalysis) has resulted in the development of many cross-coupling reactions that are now being widely adopted within the pharmaceutical sector16. The combination of nickel and photoredox catalysis has enabled the efficient construction of C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds using abundant alkyl carboxylic acids17 and alcohols18. Here we show that metallaphotoredox catalysis involving copper in place of nickel enables alkyl sp3 C–N bond formation in a generic sense without the use of alkyl halides or other prototypical electrophiles. More specifically, we hoped to merge the capacity of photoredox reactions to form alkyl radicals from iodonium carboxylates (derived in situ from carboxylic acids) with the long-established propensity of copper to participate in reductive elimination to form carbon–heteroatom bonds2. By taking advantage of the widely abundant nature of alkyl carboxylic acids and nitrogen nucleophiles such as heteroaromatics, sulfonamides, amides and anilines, we hoped to devise a new fragment coupling reaction that would be broadly useful yet mechanistically orthogonal to established alkylation reactions (Fig. 1). Recently, two methods have been reported with this aim in mind19,20, and these illustrate the capacity of copper to function in decarboxylative mechanisms.

Fig. 1: Decarboxylative nitrogen-nucleophile fragment coupling.
Fig. 1

a, An example of the Curtius14 rearrangement of acyl azides to form C–N-containing aliphatic substrates. b, 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 nitrogen nucleophiles are used to generate various N-alkyl products. Boc, tert-butoxycarbonyl; Ph, phenyl; X and Y, carbon or nitrogen atom.

A detailed mechanism for the proposed decarboxylative coupling of sp3 carbon with nitrogen nucleophiles is outlined in Fig. 2a. Excitation of photocatalyst Ir(F-Meppy)2(dtbbpy)PF6 (1) (F-Meppy = 2-(4-fluorophenyl)-5-(methyl)pyridine, dtbbpy = 4,4ʹ-di-tert-butyl-2,2ʹ-bipyridine) is known to generate the long-lived triplet-excited-state *Iriii complex 2 (with a lifetime, τ, of 1.1 μs)21. At the same time, we proposed that coordination of the nitrogen nucleophile 11 with a copper(i) precatalyst followed by deprotonation would readily form the copper(i)-amido species 3. The excited state *Iriii complex 2 (E1/2red [*Iriii/Irii] = 0.94 V versus the standard calomel electrode (SCE) in CH3CN)21 should rapidly oxidize this copper(i) complex 3 (E1/2red [Cuii(BPhen)2/Cui(BPhen)2] = 0.08 V versus SCE in DMF, BPhen = 4,7-diphenyl-1,10-phenanthroline)22 to generate the corresponding copper(ii)-amido system 4 and the corresponding iridium(ii) complex 5. At this stage we considered that iodomesitylene dicarboxylate 8 (which is preformed via the mixing of carboxylic acid 6 and iodomesitylene diacetate 7, see Supplementary Information) would be readily reduced by the newly formed iridium(ii) species 5 (E1/2red [Iriii/Irii] = −1.50 V versus SCE in CH3CN21, Ep [8/8] = −1.14 V versus SCE in CH3CN) to generate a carboxyl radical, which upon CO2 extrusion23,24 would produce the desired alkyl radical 9, while reconstituting the ground-state photocatalyst 1. At this stage, we anticipated that copper(ii)-amido complex 4 would capture alkyl radical 9 to form copper(iii) complex 10, which upon reductive elimination25 would yield the desired fragment-coupled sp3 C–N bearing adduct 12 and regenerate copper(i) catalyst 3.

Fig. 2: Catalytic cycles and control experiments.
Fig. 2

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 nitrogen nucleophile 11. b, Control experiments were performed with three different nitrogen 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. Cy, cyclohexyl; L, ligand; Mes, mesityl; Nu, nucleophile; SET, single-electron transfer; X, anionic ligand, such as a carboxylate; Y and Z, carbon or nitrogen atoms.

We first examined the proposed sp3 C–N coupling using three electronically disparate nitrogen nucleophiles (indole 11a, azaindole 11b and indazole 11c, Fig. 2b), along with cyclohexyl carboxylic acid 6 as the alkylating reagent, and a wide range of copper(i) and photoredox catalysts. The desired decarboxylative sp3 C–N coupling can be achieved in good to excellent efficiency for all three substrates (60%, 76% and 90% yield, respectively) using Ir(F-Meppy)2(dtbbpy)PF6 as the photocatalyst, CuTC (TC = thiophene-2-carboxylate) as the copper catalyst, BPhen or dOMe-Phen (dOMe-Phen = 4,7-dimethoxy-1,10-phenanthroline) as the ligand, BTMG (BTMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine) as the base, with exposure to 34-W blue light-emitting diodes (LEDs). Notably, a series of control experiments revealed that although the copper(i) catalyst is essential for the desired C–N bond formation in all cases, the absence of light and/or photocatalyst has a profound effect on reaction efficiency depending on the nitrogen nucleophile used. More specifically, the alkylation of indazole 11c is successful with or without photocatalysis (90% compared with 86% yield, respectively), whereas indole 11a and azaindole 11b achieve markedly improved yields and reaction times when light and the iridium photocatalyst are combined with copper (indole 11a, 60% compared with 7% yield; azaindole 11b, 76% compared with 47% yield). We speculate that a non-photonic mechanism is possible when copper(i)-amido species 3 is sufficiently electron-rich to undergo direct electron-transfer with the iodomesitylene dicarboxylate 8, thereby removing the requirement for a redox catalyst to act as an electron shuttle. However, when copper(i)-amido species 3 is not sufficiently reducing, or is formed slowly, the presence of a photoexcited electron-shuttle catalyst becomes essential to achieve useful efficiencies. Indeed, this latter case was found to be the most common, with non-photonic conditions leading to useful yields with only a small subset of substrates (yields for non-photonic conditions are reported in parentheses in Figs. 3 and 4). As such, the combination of copper and photoredox catalysts with light was identified as the superior protocol with which to evaluate a broad range of sp3 C–N cross-coupling reactions.

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

A wide variety of alkyl carboxylic acids can be cross-coupled with 3-chloroindazole. The carboxylic acid is added as part of step a, and the nitrogen nucleophile as part of step b. The protocol provides the product as a single regioisomer in all cases. The yields shown first are isolated yields of reactions conducted according to our standard protocol; yields shown in parentheses are for reactions that were conducted in the absence of light and a photocatalyst and were determined by 1H nuclear magnetic resonance (1H NMR) spectroscopy with an internal standard. See Supplementary Information for full experimental details, and Extended Data Fig. 1 for additional examples. All reactions were replicated at least twice for consistency. Ac, acetyl; BTMG, 2-tert-butyl-1,1,3,3-tetramethylguanidine; Cbz, carboxybenzyl; Et, ethyl; Me, methyl; NPhth, phthalimide; TC, thiophene-2-carboxylate; r.t., room temperature.

Fig. 4: Decarboxylative C–N couplings of cyclohexyl carboxylic acid with various nitrogen nucleophiles.
Fig. 4

This new C–N bond-forming protocol shows a markedly broad scope with respect to the nitrogen nucleophiles. Almost every class of important nitrogen heterocycle can provide N-alkylated products in good yields and excellent regioselectivity. Less nucleophilic substrates and complex drug molecules are all viable coupling partners. The yields shown first are isolated yields for the decarboxylative C–N coupling step; yields shown in parentheses are for reactions that were conducted in the absence of light and a photocatalyst and were determined by 1H NMR with an internal standard. See Supplementary Information for full experimental details, and Extended Data Figs. 24 for additional examples. aSingle regioisomer. Bn, benzyl; Pr, propyl.

Having established the preferred reaction conditions, we next examined the generality of this new C–N fragment coupling by exploring the scope of the carboxylic-acid alkylation partner (Fig. 3). Notably, a diverse range of alkyl carboxylic acids can be used in this new protocol to deliver the N-alkyl heteroaryl derivatives in good to excellent efficiency. It is important to highlight that in all cases the reactions were complete at room temperature within 1 h. Another feature of this protocol is that only one regioisomer of the product is produced for all cases shown in Fig. 3, which offers a notable advantage when compared to traditional N-alkylation reactions. Indeed, a broad series of differentially substituted primary alkyl acids can readily participate in this new C–N coupling (1321, 50–82% yield). Moreover, these mild reaction conditions are compatible with a range of common functional groups, such as terminal olefins (17, 64% yield), terminal alkynes (18, 80% yield), nitro groups (19, 50% yield), esters (21, 80% yield) and protected amines (16 and 20, 63% and 82% yield, respectively). In contrast to many established alkylation reactions, steric encumbrance proximal to the acid group is also well tolerated, as exemplified by the successful incorporation of a neopentyl system (15, 54% yield). Moreover, direct N-methylation (13, 65% yield) can also be realized by carrying out the C–N coupling protocol using commercial MesI(OAc)2 7. Finally, we successfully applied this coupling technology to three complex natural products that contain alcohols, ketones and internal alkenes. All were found to participate in decarboxylative N-alkylation with high efficiency (2224, 54%–76% yield).

We next sought to examine the scope of secondary alkyl carboxylic acids as alkylating agents. Importantly, a large array of ring-bearing carboxylates can be used to access N-cycloalkylation adducts in good to excellent efficiency (2631, 40%–85% yield). Moreover, this new transformation is not limited to cyclic systems, as exemplified by the rapid incorporation of acyclic secondary alkyl groups (25, 61% yield), a transformation that is not readily achieved using established alkylation protocols. An additional six examples using other secondary alkyl acids for this sp3 C–N coupling are detailed in Supplementary Information and Extended Data Fig. 1.

A notable feature of this decarboxylative C–N coupling method is the number of tertiary-carbon-bearing carboxylic acids that can be readily used to prepare heteroaryl N-tertiary alkyl derivatives with good to excellent efficiency (3236, 53%–80% yield). This is especially important given that the N-alkylation using tertiary alkyl halides can often be elusive, if not impossible, using traditional technologies. Given the recent interest in the incorporation of rigid bicyclic structures into drug-like compounds, such as the bicyclo[1.1.1]pentane core (as shown in product 36)26, we expect this light-mediated N-alkylation protocol to be immediately applicable to a large range of medicinal chemistry programs. Indeed, the capacity to access these bridged bicyclic aryl isosteres in only one operation using commercial carboxylic acids and iodomesitylene diacetate (at room temperature in less than 1 h) should enable the rapid adoption of this method.

Next, we turned our attention to the scope of the nitrogen-nucleophile component in this new catalytic alkylation protocol (Fig. 4). Almost every class of medicinally relevant nitrogen heterocycle, including, but not limited to, indazoles (37 and 38, 81% and 73% yield, respectively), azaindoles (39 and 40, 89% and 75% yield, respectively), indoles (41, 58% yield), pyrazoles (42 and 43, 98% and 68% yield, respectively), pyrroles (51, 75% yield), imidazoles (52, 68% yield), triazoles (53, 90% yield), benzimidazoles (54, 67% yield), benzotriazoles (55, 80% yield), purines (56, 60% yield) and carbazoles (57, 46% yield), can be successfully used to deliver N-alkyl products in good to excellent efficiency. Moreover, an additional 42 examples using other nitrogen heterocycles are detailed in Supplementary Information and Extended Data Figs. 2 and 3. For nucleophiles that are as acidic as or more acidic than pyrazoles (such as indazoles, triazoles and imidazoles), the addition of an exogenous base is not generally necessary. The carboxylate anion, which is generated upon the reduction of iodomesitylene dicarboxylate 8 (Fig. 2a), can function as a weak base. One notable feature is that this heterocycle C–N forming mechanism exhibits excellent regioselectivity (Fig. 4) with substrates that possess several N-alkylation sites (for example, pyrazoles, imidazoles, triazoles, indazoles and benzimidazoles). At this stage, we presume that the considerable steric bulk of the ligated copper complex ensures that the sp3 C–N coupling takes place at the least hindered site of these heteroaromatic nucleophiles. This outcome is in sharp contrast to classical alkylation methods that typically lead to regioisomeric mixtures. Several of these nitrogen heterocycles were also tested using our non-photonic conditions, and the corresponding yields are shown in parentheses in Fig. 4. It is clear that although C–N formation can be achieved with these nucleophiles in the absence of light (5157, 7–39% yield), the dual copper and photoredox protocol enables a more extensive scope and substantially higher efficiencies across the board, providing a more general protocol for this new C–N heterocyclic coupling reaction.

As shown in Fig. 4, this decarboxylative C–N coupling method is not limited to the cross-coupling of nitrogen heterocycles. Under our optimized conditions, a large selection of electron-deficient (and also less acidic) nitrogen nucleophiles, including anilines (44 and 45, 55% and 70%, respectively), aryl sulfonamides (46, 59% yield), alkyl sulfonamides (47, 51% yield), aryl amides (48, 79% yield), phthalimides (49, 61% yield) and cyclic carbamates (50, 71% yield), were found to participate readily in this sp3 C–N coupling. Notably, functional groups including aryl iodides (44, 55% yield), aryl bromides (46, 59% yield) and ketones (45, 70% yield) were readily tolerated, a useful feature with respect to further synthetic manipulation.

A long-established problem in the functionalization of primary amines with alkyl halides is the formation of polyalkylation products, given that the initial secondary amine adduct is more nucleophilic than the starting amine. Notably, as shown in Fig. 4, only monoalkylated products are obtained when primary amides, sulfonamides and anilines are used in this new copper-catalysed protocol (44–48, also see Supplementary Information for additional examples using primary alkyl acids). Moreover, an additional 27 examples using other electron-deficient nitrogen nucleophiles are detailed in Supplementary Information and Extended Data Fig. 3. As already highlighted, this coupling protocol does not appear to be negatively influenced by steric constraints, as ortho-substituted and ortho-,ortho-disubstituted anilines, sulfonamides and amides can be used readily (44, 46, and 48, 55%–79% yield).

To illustrate the utility of this new transformation with respect to drug discovery, we examined this decarboxylative sp3 C–N coupling using six known pharmaceuticals (Celebrex, Axitinib, Zelboraf, Actos, Rilutek and Skelaxin). Using three separate carboxylic acids, we were able to achieve decarboxylative alkylation in all cases in good to excellent yields (5863, 44%–90% yield). An additional ten examples of pharmaceutical functionalization using this technology are described in Supplementary Information and Extended Data Fig. 4.

For substrates with several nucleophilic sites, achieving regioselective monofunctionalization has been a long-standing challenge27. Therefore, we were pleased to find that this new alkylation technology can be applied sequentially to the same drug molecule to achieve selective alkylation at two discrete nitrogen positions through the judicious choice of reaction conditions. As demonstrated in Fig. 5a, heterocycle 64 contains both an indazole nitrogen and a primary amide; however, when the coupling protocol is performed without an exogenous base, regioselective N-alkylation of the indazole was observed in 80% yield. Moreover, we have carried out this regioselective N-alkylation step on a 7.4-mmol scale to prepare 1.45 g of the N-cyclohexyl indazole derivative 65. The origins of regioselectivity in this decarboxylative coupling arise from the relative acidity of the two N–H moieties in substrate 64 (that is, indazole and amide). More specifically, when no exogenous base is used, the carboxylate anion (formed by reduction of the iodomesitylene dicarboxylate 8) can function as a weak base and thereby selectively deprotonate the more acidic indazole nitrogen (pKa (indazole) <19.8 in DMSO28,29; pKa (phenyl acetamide) = 23.3 in DMSO28) upon coordination to the copper catalyst, which in turn leads to regioselective N-alkylation of the indazole N1 position. Perhaps most important, subsequent exposure of the resulting N-cyclohexyl indazole 65 to our coupling protocol with a second carboxylic acid in the presence of a strong organic base, BTTP (BTTP = tert-butyliminotri(pyrrolidino)phosphorane) leads to a second N-alkylation on the remaining amide nitrogen, again with a useful yield. We anticipate that the capacity to perform regioselective and sequential C–N coupling steps as a function of relative N–H acidities will have substantial benefit with respect to the step economy of building complex molecules, by removing the need to install and remove nitrogen protecting groups.

Fig. 5: Sequential C–N couplings and comparisons with nucleophilic substitutions.
Fig. 5

a, Sequential decarboxylative C–N couplings can be realized using indazole derivative 64 that contains two nucleophilic sites, demonstrating the construction of molecular complexity. The N,Nʹ-dialkylated product, which contains two different alkyl groups, can be easily generated through two C–N coupling reactions using 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.

Finally, to further showcase the utility of this new sp3 C–N coupling method, we performed a series of experiments to compare the decarboxylative protocol with traditional nucleophilic substitution reactions (Fig. 5b). Under various classical SN2 and SN1 alkylation conditions, tertiary alkyl bromide 67 and bromocyclopropane (68) failed to react with 3-chloroindazole to generate the desired N-alkyl products, which is consistent with a lack of literature precedent for using these alkyl bromides with indazole nucleophiles. By contrast, through decarboxylative C–N couplings using commercially available carboxylic acids 69 and 70 and our mild catalytic protocol, the desired N-alkyl products can be obtained in good yields and excellent regioselectivities within 30 min at room temperature using an integrated photoreactor30. As such, we anticipate that this new decarboxylative coupling strategy will provide a useful, complementary new approach to sp3 C–N alkylation.

Methods

Here we describe a typical procedure for the decarboxylative sp3 C–N coupling reaction; a summary of general conditions is included in Supplementary Information (Supplementary Fig. 36) and further experimental details are also provided in Supplementary Information.


Procedure for decarboxylative sp 3 C–N couplings

To a 20 ml or 40 ml vial equipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodomesitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by addition of the base. The solution was sonicated for 1–3 min until it became homogeneous. Next, the solution was degassed by sparging with nitrogen for 5–10 min before sealing with Parafilm. The reaction was stirred and irradiated using two 34-W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 h. The reaction mixture was removed from the light, cooled to ambient temperature, diluted with water (15 ml) and ethyl acetate (25 ml), and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel to afford the desired decarboxylative C–N coupling product. For aniline substrates, a solution of these nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene dicarboxylate is a liquid, its solution in dioxane was used.


Data availability

The findings of this study are available within the paper and its Supplementary Information.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

  2. 2.

    Bhunia, S., Pawar, G. G., Kumar, S. V., Jiang, Y. & Ma, D. Selected copper-based reactions for C–N, C–O, C–S, and C–C bond formation. Angew. Chem. Int. Ed. 56, 16136–16179 (2017).

  3. 3.

    Knölker, H.-J. (ed.) The Alkaloids: Chemistry and Biology Vol. 70 (Elsevier, San Diego, 2011).

  4. 4.

    Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

  5. 5.

    Ćirić-Marjanović, G. Recent advances in polyaniline research: polymerization mechanisms, structural aspects, properties and applications. Synth. Met. 177, 1–47 (2013).

  6. 6.

    Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525–3550 (2014).

  7. 7.

    Qiao, J. X. & Lam, P. Y. S. Copper-promoted carbon–heteroatom bond cross-coupling with boronic acids and derivatives. Synthesis 2011, 829–856 (2011).

  8. 8.

    Salvatore, R. N., Yoon, C. H. & Jung, K. W. Synthesis of secondary amines. Tetrahedron 57, 7785–7811 (2001).

  9. 9.

    Swamy, K. C. K., Kumar, N. N. B., Balaraman, E. & Kumar, K. V. P. P. Mitsunobu and related reactions: advances and applications. Chem. Rev. 109, 2551–2651 (2009).

  10. 10.

    Abdel-Magid, A. F. & Mehrman, S. J. A review on the use of sodium triacetoxyborohydride in the reductive amination of ketones and aldehydes. Org. Process Res. Dev. 10, 971–1031 (2006).

  11. 11.

    Huang, L., Arndt, M., Gooßen, K., Heydt, H. & Gooßen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).

  12. 12.

    Matier, C. D., Schwaben, J., Peters, J. C. & Fu, G. C. Copper-catalyzed alkylation of aliphatic amines induced by visible light. J. Am. Chem. Soc. 139, 17707–17710 (2017).

  13. 13.

    Peacock, D. M., Roos, C. B. & Hartwig, J. F. Palladium-catalyzed cross coupling of secondary and tertiary alkyl bromides with a nitrogen nucleophile. ACS Cent. Sci. 2, 647–652 (2016).

  14. 14.

    Curtius, T. 20. Hydrazide und azide organischer säuren I. Abhandlung. J. Prakt. Chem. 50, 275–294 (1894).

  15. 15.

    Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

  16. 16.

    Twilton, J., Le, C., Zhang, P., Shaw, M. H., Evans, R. W. & MacMillan, D. W. C. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

  17. 17.

    Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp3-carbons with aryl halides. Science 345, 437–440 (2014).

  18. 18.

    Zhang, X. & MacMillan, D. W. C. Alcohols as latent coupling fragments for metallaphotoredox catalysis: sp3–sp2 cross-coupling of oxalates with aryl halides. J. Am. Chem. Soc. 138, 13862–13865 (2016).

  19. 19.

    Zhao, W., Wurz, R. P., Peters, J. C. & Fu, G. C. Photoinduced, copper-catalyzed decarboxylative C–N coupling to generate protected amines: an alternative to the Curtius rearrangement. J. Am. Chem. Soc. 139, 12153–12156 (2017).

  20. 20.

    Mao, R., Frey, A., Balon, J. & Hu, X. Decarboxylative C(sp 3)–N cross-coupling via synergistic photoredox and copper catalysis. Nat. Catal. 1, 120–126 (2018).

  21. 21.

    Lowry, M. S. et al. Single-layer electroluminescent devices and photoinduced hydrogen production from an ionic iridium(III) complex. Chem. Mater. 17, 5712–5719 (2005).

  22. 22.

    Sanna, G., Pilo, M. I., Zoroddu, M. A. & Seeber, R. Electrochemical and spectroelectrochemical study of copper complexes with 1,10-phenanthrolines. Inorg. Chim. Acta 208, 153–158 (1993).

  23. 23.

    He, Z., Bae, M., Wu, J. & Jamison, T. F. Synthesis of highly functionalized polycyclic quinoxaline derivatives using visible-light photoredox catalysis. Angew. Chem. Int. Ed. 53, 14451–14455 (2014).

  24. 24.

    Minisci, F., Vismara, E., Fontana, F. & Barbosa, M. C. N. A new general method of homolytic alkylation of protonated heteroaromatic bases by carboxylic acids and iodosobenzene diacetate. Tetrahedr. Lett. 30, 4569–4572 (1989).

  25. 25.

    Tran, B. L., Li, B., Driess, M. & Hartwig, J. F. Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes. J. Am. Chem. Soc. 136, 2555–2563 (2014).

  26. 26.

    Stepan, A. F. et al. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J. Med. Chem. 55, 3414–3424 (2012).

  27. 27.

    Afagh, N. A. & Yudin, A. K. Chemoselectivity and the curious reactivity preferences of functional groups. Angew. Chem. Int. Ed. 49, 262–310 (2010).

  28. 28.

    Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456–463 (1988).

  29. 29.

    Lõkov, M. et al. On the basicity of conjugated nitrogen heterocycles in different media. Eur. J. Org. Chem. 4475–4489 (2017).

  30. 30.

    Le, C. C. et al. A general small-scale reactor to enable standardization and acceleration of photocatalytic reactions. ACS Cent. Sci. 3, 647–653 (2017).

Download references

Acknowledgements

This research was supported by the National Institutes of Health National Institute of General Medical Sciences (R01 GM103558-03) and gifts from Merck, Bristol-Myers Squibb, Eli Lilly, Genentech and Johnson & Johnson. X.Z. is grateful for a postdoctoral fellowship from the Shanghai Institute of Organic Chemistry. We thank C. Liu and Y. Y. Loh for assistance in preparing this manuscript.

Reviewer information

Nature thanks S. Bagley and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Yufan Liang, Xiaheng Zhang.

Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    • Yufan Liang
    • , Xiaheng Zhang
    •  & David W. C. MacMillan

Authors

  1. Search for Yufan Liang in:

  2. Search for Xiaheng Zhang in:

  3. Search for David W. C. MacMillan in:

Contributions

Y.L. and X.Z. performed and analysed the experiments. Y.L., X.Z. and D.W.C.M. designed the experiments. Y.L., X.Z. and D.W.C.M. prepared the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to David W. C. MacMillan.

Extended data figures and tables

  1. Extended Data Fig. 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 in all cases. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. d.r., diastereomeric ratio. #d.r. was determined by 1H NMR.

  2. Extended Data Fig. 2 Decarboxylative sp3 C–N couplings with a series of nitrogen heterocycles.

    Various nitrogen heterocycles, including indazoles, azaindoles, indoles and pyrazoles, can cross-couple with carboxylic acids with good efficiency. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. *Single regioisomer.

  3. Extended Data Fig. 3 Decarboxylative sp3 C–N couplings with a series of nitrogen nucleophiles.

    Various nitrogen nucleophiles, including nitrogen heterocycles, anilines, sulfonamides and amides, can cross-couple with carboxylic acids with good efficiency. All yields are isolated unless otherwise noted. All reactions were replicated at least twice for consistency. 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.

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

    Several drug molecules can cross-couple with carboxylic acids with good efficiency. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. *Single regioisomer.

Supplementary information

  1. Supplementary Information

    This file contains supplementary information 1-10

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41586-018-0234-8

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.