James L. Douthwaite,Ruheng Zhao,Eunjae Shim,Babak Mahjour,Paul M. Zimmerman,Tim Cernak
Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds
Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp3)–C(sp2) bonds following preactivation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl3, and GaCl3. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl3 supports the decarbonylation event, thereby improving reaction selectivity.
Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds

Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp3)–C(sp2) bonds following preactivation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl3, and GaCl3. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl3 supports the decarbonylation event, thereby improving reaction selectivity.

Carbon–carbon bonds are ubiquitous in natural and synthetic products; therefore, new reactions that forge this critical bond expand access to chemical space. Producing carbon–carbon bonds from readily available feedstocks is particularly impactful. The C(sp3)–C(sp2) substructure is often synthesized from an organometallic reagent and an alkyl or aryl (pseudo)halide via cross-coupling with palladium, nickel, copper, iron, cobalt, or other metal catalysts. Recently, nickel catalysis has found complementary utility in reductive C(sp3)–C(sp2) couplings. These methods have a valued place in the synthetic chemist’s toolbox and would be augmented by related reactions that use abundant feedstocks, such as amines and acids. We recently mapped the coupling of amine and acid building blocks to identify unknown but impactful amine–acid coupling reactions for development as an alternative to amide coupling (Figure 1A). We identified C(sp3)–C(sp2) bonds as the sixth most prevalent substructure in DrugBank molecules (Figure 1B). Furthermore, analysis of building blocks in the MilliporeSigma catalog shows C(sp3)-amines access a complementary chemical space to that of C(sp3)-halides and C(sp3)-boronates (Figure 1C). Likewise, C(sp2)-carboxylic acids probe chemical space uncharted by C(sp2)-halides and C(sp2)-boronates. As such, a transformation which could unite amines and acids to form a C(sp3)–C(sp2) bond would be valuable. We envisioned the amine–acid C(sp3)–C(sp2) coupling could be achieved through reductive cross-coupling of carboxylic acids activated as N-acyl-glutarimides with alkyl amine-derived pyridinium salts. Using these coupling partners, we embarked on a high-throughput experimentation (HTE) optimization campaign (Figure 2A). A 96-reaction array comprising three solvents, four nickel precatalysts, and eight diverse nitrogen and phosphorus ligands was performed (Figure 2A, entry 1). Probenecid-derived N-acyl-glutarimide 1 and phenethylamine-derived pyridinium salt 2 coupled to form product 3 in 17 of the 96 reactions. The most productive reaction used NiBr2·DME and 4,4′-di-tert-butyl-2,2′-bipyridine L1 in NMP (N-methyl-2-pyrrolidone), and was repeated on 0.25 mmol scale to give 23% yield by 1H NMR. No ketone product was observed, despite the array containing some similar conditions to those reported by Matsuo and Yu for ketone formation from aryl N-acyl-succinimides and alkylpyridinium salts (see also Table S20). We next surveyed 24 diverse nitrogen ligands (Figure 2A, entry 2). Most bipyridine and phenanthroline ligands gave a similar performance to that of L1, with pyridine-2-carboxamidine (L2) giving 3 in 26% 1H NMR yield upon scale-up. An evaluation of carboxamidine and oxalamide ligands, Ni(II) precatalysts and reductants (Figure 2A entry 3) led to a 31% 1H NMR yield using carboxamidine L3 and confirmed Mn to be the preferential reductant. An extended screen of ligands revealed 5,5′-dimethyl-2,2′-bipyridine L4 as a preferred ligand for the protocol, which yielded 3 in 38% (Figure S18). Further examination of ligands, Ni-precatalysts, temperature, concentration, stoichiometry, order of addition, and addition of water gave no significant increase in yield (see the Supporting Information). Additives have been shown to have a significant impact on Ni-catalyzed coupling reactions. Therefore, we surveyed inorganic and organic additives in the presence and absence of LiCl (Figure 2A, entry 4). We saw an increase in performance to 71% yield when 1.5 equiv of phthalimide 4 was added to the reaction. Adjustment of the stoichiometry of 2 and 4 increased the NMR yield to 76% (63% isolated). Replacement of 4 with 2 equiv of glutarimide reduced the yield to 27%, and other imide and hydantoin additives surveyed did not significantly increase the yield (Figure S21). With our optimized conditions, we explored the substrate scope of the reaction (Figure 3). Other primary alkylpyridinium salts successfully coupled to 1 (3, 5–8). Alternative acids with electron-withdrawing groups could also be coupled (9–16), and the reaction was tolerant of alkene (7), phenol (10, 11), ether (8, 12), aryl chloride (3, 9, 13, 15), aryl fluoride (11, 12), and tert-butyl carbamate (14, 16, 17, 18) functionalities. Quinoline-derived glutarimides were also successfully coupled (15, 16, 20). Electron-rich acids gave lower yields (17–19), likely for two reasons—slower oxidative addition of N-acyl-glutarimide to the Ni catalyst and increased formation of ketone products—which suggests that decarbonylation is slower for electron-rich substrates. Amines are common in drug molecules and, therefore, provide a handle for late-stage diversification. We exemplified such amine–acid couplings on a protected form of lysine (20 and 21), adapalene (22), an atorvastatin precursor (23 and 24), amlodipine (25 and 26), and fluvoxamine (27 and 28). We also applied our methodology to the gram-scale synthesis of the anxiolytic drug pipequaline 29 in 48% yield over two steps after Boc deprotection of the piperidine nitrogen. Additional scope exploration is presented in Figure S34, and all data is available in a machine-readable format. Some substrate pairs yielded significant amounts of ketone (cf.32) in addition to the target decarbonylated C–C product. To increase the selectivity for C–C product in such pairs, 30 was subjected to coupling with 2 in the presence of various metal salt additives selected to promote decarbonylation (Table S9). We identified 0.5 equiv of RuCl3 to be optimal and applied these conditions to the selective coupling of naphthyl (31 and 33) and quinoline (34) derivatives (Figure 4A). Additionally, RuCl3 boosted performance to give 35 in 58% isolated yield. We applied these conditions to the synthesis of vinyl derivative 36 in 43% yield, with no ketone product detected. This is in stark contrast to the reaction without RuCl3, which gives a complete selectivity for the ketone. Comparing 31 with 35 or 3 with 31 suggests the substrate plays a role in determining the relative rates of radical addition and decarbonylation and, hence, selectivity. Variation of the vessel volume or purging with N2 had little impact on reaction yield and selectivity, while a CO atmosphere prevented reactivity (Table S22). Control experiments show that RuCl3 alone does not catalyze the reaction (Figure 4B) and does not decarbonylate ketone 37 to 33 (Figure 4C). We believe that RuCl3 plays a role in promoting decarbonylation during the Ni-catalytic cycle and that ketone 37, itself, is not a likely intermediate in the formation of 33. With the above conditions, secondary alkyl and benzylpyridinium salts generally gave lower yields (Table S14). Kinetic studies revealed that secondary alkylpyridinium salts were consumed twice as fast as primary substrates, and benzyl substrates were consumed four times as fast (Figures S28 and S29), which led to the competing formation of unproductive dihydropyridine side products that result from alkyl radical addition to the pyridinium. Yield was increased by switching the ligand to 5,5′-bis(trifluoromethyl)-2,2′-bipyridine L5, which was identified through a ligand screen (Figure S32), and optimization of the temperature to 40 °C (Table S16). We found that 0.5 equiv of GaCl3 and 0.5 equiv of RuCl3 further increased the yield when added to the reaction in concert (Table S17). Using these conditions, 39–43 derived from secondary pyridinium salts were synthesized in satisfactory yield (Figure 5). These conditions were also applied to a benzylpyridinium substrate to yield 44, which is a challenging case due to the rapid decomposition of the benzyl C–N bond. To investigate the role of 4, we subjected N-acyl phthalimide 45 to a coupling with 2. Product 3 was obtained in 37% and 40% yield in the absence and presence of phthalimide additive, respectively (Figure 6A). This suggests 4 does not improve yield through a transamidation reaction with 1 to give 45. This is supported by density functional theory (DFT) calculations (see the Supporting Information for full details), which show the energy barrier for the oxidative addition of 1 to be more than 6 kcal/mol lower than that of 45 (TS-1 versus TS-45, Figure 6B). The possibility of 4 facilitating decarbonylation was evaluated, but DFT simulations showed comparable decarbonylation rates for Ni-glutarimide and Ni-phthalimide complexes (Figures S47 and S48). Instead, 4 may play a role in the prevention of unproductive Ni oligomerization or the formation of off-cycle N-acyl-imide Ni complexes. On the basis of literature precedent, mechanistic studies, and additional DFT calculations (see the Supporting Information), we propose a possible reaction pathway (Figure 6C). Oxidative addition of 1 to Ni(0) I generates Ni(II) complex II, which undergoes decarbonylation to III. Radical trapping experiments confirm SET reduction of TPP to form an alkyl radical (Figures S40 and S41), with kinetic data supporting a Ni complex as the primary reductant rather than Mn (Figure S42). Currently, we cannot confirm a radical rebound or radical chain pathway. Addition of the alkyl radical gives IV, which reductively eliminates to yield product 3 and Ni(I) complex V, with Mn regenerating the active catalyst. In conclusion, we have developed a formal cross-coupling of amines and carboxylic acids to form new C(sp3)–C(sp2) bonds. HTE enabled identification of the key additives phthalimide 4 to improve yield and RuCl3 to improve selectivity for the C–C product. Scope exploration suggests the rate of decarbonylation and, hence, selectivity is primarily determined by the electronics of the acid substrate. C–C selectivity is greatest for electron-deficient acids, which suggests fast decarbonylation, and ketone selectivity is greatest for electron-rich acids, which suggests slow decarbonylation and is consistent with the work of Matsuo and Yu. (see the Supporting Information for comparison of the two protocols). To guide future applications of this method, we advise use of the conditions in Figure 3 for primary alkylpyridinium salts in the first instance, with RuCl3 being added to unselective or low yielding reactions, as in Figure 4. For secondary alkylpyridinium salts, the conditions in Figure 5 should be applied. Overall, this new amine–acid coupling can expand accessible chemical space, as exemplified through the late-stage diversification of multiple amine or acid-containing drugs.