Allylic C-H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis

Abstract

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).

Fig. 1.. Reaction design and development.

(A) Merging the benefits of classic aminations (cyclic secondary amines) and C–H aminations (unactivated olefins) (middle) inspired the development of a fragment-coupling C–H amination to furnish complex tertiary amines (this work; bottom-middle). The challenges associated with basic amines in electrophilic metal-mediated catalysis include undesired Pd(II)-coordination that competes with C–H cleavage (bottom left). Our strategy uses catalyst turnover to regulate generation of secondary amine nucleophiles (bottom right). (B) Reaction development and optimization studies using secondary amine-BF₃ complexes. All reactions were run on a 0.2-mmol scale open to air and moisture. All aminations proceeded in >20:1 linear:branched (L:B) and >20:1 E:Z selectivity, and free tertiary amines were isolated by means of a basic workup followed by column chromatography. Isolated yields are the average of two experiments. *Dibutyl phosphate. †The amine-BF₃ was complexed in the reaction vial without purification and was then subjected to AACC catalysis (supplementary materials). ‡Yield was determined by crude ¹H NMR analysis using benzotrifluoride as an internal standard.

Fig. 2.. AACC reaction scope.

(A) Aliphatic cyclic and acyclic amine scope, including the top five aliphatic tertiary amines found in medicinal chemistry (B) Terminal olefin scope. All reactions were run under ambient conditions. Unless otherwise indicated, all reactions were run on a 0.2-mmol scale using amine-BF₃ (1 equivalent), olefin (1 equivalent), Pd(OAc)₂ (10 mol %), (±)-MeO-SOX (10 mol %), 2,5-dimethyl-1,4-benzoquinone (2,5-DMBQ) (1.1 equivalents), and dbp in solvent (1 M) at 45 °C for 48 hours, followed by basic workup. All amination products were formed in >20:1 L:B and >20:1 E/Z selectivity, and isolated yields of the free tertiary amine products are the average of three experiments. *25% dbp in dioxane. †50% dbp in dioxane. ‡25% dbp in toluene (in some cases, toluene diminishes diene by-product formation). §50% dbp in toluene. ¶5% dbp in dioxane. #0.5 equivalents of amine-BF₃. **0.4-mmol scale. ††5 mol % (±)-MeO-SOX·Pd(OAc)₂. ‡‡0.167 M. §§0.4 M. ¶¶12 hours. ##24 hours. ***72 hours. †††Average of two experiments.

Fig. 3.. Synthesis of complex tertiary aliphatic amine drugs and drug derivatives.

(A and B) All reactions were run under ambient conditions. Unless otherwise indicated all reactions were run on a 0.2-mmol scale using amine-BF₃ (1 equivalent), olefin (1 equivalent), Pd(OAc)₂ (10 mol %), (±)-MeO-SOX (10 mol %), 2,5-DMBQ (1.1 equivalents), and dbp in solvent (1 M) at 45 °C for 48 hours, followed by basic workup. All amination products were formed in >20:1 L:B and >20:1 E/Z selectivity, and isolated yields of the free tertiary amine products are the average of three experiments. *25% dbp in dioxane. †50% dbp in dioxane. ‡25% dbp in toluene. §50% dbp in toluene. ¶50% dbp in methyl tert-butyl ether. #50% dbp in benzene. **5% dbp in dioxane. ††5 mol % (±)-MeO-SOX·Pd(OAc)₂. ‡‡24 hours. §§72 hours. ¶¶Average of two experiments.

Fig. 4.. Mechanistic studies and proposed mechanism.

(A) Reaction profile monitored by quantitative ¹H NMR analysis using benzotrifluoride as an internal standard. All time points (excluding t = 0 h and 48 hours) are the average of three experiments, with error bars indicating one standard deviation. The identity of 1·HBF₄ was confirmed by matching its spectra to authentic material; however, we cannot exclude that other counterions (X) may be present. (B) Experiments to investigate the formation of free secondary amine nucleophile and the role of free tertiary amine in proton transfer as well as experiments to investigate reactivity at 5 mol % catalyst loading (cat. loading). See supplementary materials for details. *Yield was determined by crude ¹H NMR analysis using mesitylene as an internal standard. (C) Proposed mechanism for AACC. 2,5-DMHQ, 2,5-dimethylhydroquinone.