Optimization of the reaction conditions. Our initial exploration focused on accomplishing the selective oxidative amination of allylbenzene with dipropyl-amine (see Tables S1 to S4 for more details). When employing Pd(OAc)2 as a catalyst, BQ as oxidant, PPh3 as ligand and toluene as solvent, the expected amination product was afforded in 60% yield. The blank control experiments indicated that the combination of phosphine ligands and oxidative quinone oxidants dominated this novel amination process. Considering the indispensable effect of phosphine ligands and quinone oxidants, the optimal association of ligands and oxidants was inspected cautiously, as shown in Tables S3. Several quinone oxidants including BQ, 2,6-DMBQ etc. were combined with different mono-dentate and bidentate phosphine ligands. The results revealed that the combination of 2,6-DMBQ and DPPE achieved the effective construction of allylamines in 90% yield. We suspected that in the air, the phosphorus ligands would be slowly oxidized, and at the same time, some of the olefins will be isomerized into internal olefins. The examination of atmosphere and the loading of catalyst and ligand suggested that the combination of 5 mol% Pd(OAc)2 and 10 mol% DPPP was the optimal choice under N2 atmosphere, allowing the exclusive formation of 3 in 94% yield, and the olefin usage could be reduced to 1.2 equivalents.
Substrate scope of aliphatic amines and olefines. Under the optimized conditions, a wide range of aliphatic amines were then investigated for amination with allylbenzene (Fig. 2). Various alkyl chain amines could be converted into the corresponding products in 70%-94% yields and excellent stereoselectivities (3-10). Substrates with functional group (cyano and hydroxyl) appending to the alkyl chain were well accommodated under the mild conditions, giving the desired 3-(cinnamyl(methyl)amino)propanenitrile (7) and 𝛅-hydroxylamine derivative (8). To our delight, amino alcohols and amino acid esters could also be compatible with this type of reaction, converting to the target products (11-14) in 59%-72% yields with excellent regio- and stereoselectivities. Next, a variety of readily available cyclic amines, such as hexamethyleneimine, 3-pyrroline and substituted piperidines also underwent the amination and transformed to the corresponding products (15-24) in moderate to good yields. Nortropinone and (1S,4S)-2-Boc-2,5-diazabicyclo [2.2.1] heptane with bridged skeleton proceeded the amination process efficiently to afford the corresponding allylic amines (22 and 23) in 59% and 89% yields, respectively. Notably, when 3-pyrroline was employed in the reaction, the aromatization product 1-cinnamyl-1H-pyrrole (24) was obtained in 75% yield. Fused heterocyclic amine, morpholine, thiomorpholine and different substituted piperazines were also tolerated in this reaction system, delivering the expected products (25-31) in 43%-85% yields. For the substrates containing multiple N-H sites, the amination exclusively occurred on the less steric hindrance and more electron-rich site. For example, evaluation of decahydroisoquinoline derivative bearing two N-H sites (N1 and N4) indicated that preferential amination at the N1 site over the N4 site, probably due to the stronger nucleophilicity of N1 and the larger steric hindrance of N4 (32, 86% yield). Moreover, various N-substituted benzylamine substrates could also convert to the cross-coupling products in good yields (55 to 92%) with excellent stereoselectivities (33-43).
In addition to the great applicability of aliphatic amine substrates, a variety of simple olefins were compatible with this process (Fig. 2). Various substituted allylbenzenes were tolerated, delivering high yields and sole stereoselectivities (44-58). Substituents at the ortho-, meta-, or para-positions on the allylbenzenes could be accommodated. The effect of steric hindrance on the reaction was almost negligible. It was noteworthy that substituting the phenyl ring with electron-withdrawing groups generally led to higher yields and efficiency comparing with electron-rich substrates. For instance, 95% yield of the product could be obtained for p-CF3 substituted allylbenzene, whereas the allylbenzene (49) with a p-OCH3 substituent was formed only in 84% yield. Moreover, heterocyclic olefin was also suitable for the reaction and the desired allylic amine (59) was formed in 83% yield. When slightly adjusting the reaction conditions, the feedstock alkene, such as 1-octene and several functionalized alkenes could participate well in this oxidative amination, generating the corresponding products (60-65).
Synthetic applications. Considering the widespread presence of alkylamines in small molecular drugs and natural products, the efficient synthesis and late-stage functionalization of such compounds could indeed manifest the utility of this oxidative amination. Under the standard conditions, a series of pharmaceutical agents and bioactive molecules, such as cytisine, amoxapine (CCDC 2038362), desloratadine, dehydroabietylamine, sitagliptin, atomoxetine, desipramine, estrone, (+)-allylated-𝜹-tocopherol underwent the oxidative amination effectively to afford the corresponding allylamine derivatives (66-75) in satisfactory yields (35 to 79%) with excellent regio- and stereoselectivities (Fig. 3A). Moreover, the synthesis of bioactive molecules was also feasible. Notably, the product 76 naftifine28, a commercially available antifungal drug, could be obtained directly from the amination of allylbenzene and 1-methyl-aminomethyl naphthalene in one single step in 85% yield (Fig. 3B). Cinnarizine (77) and flunarizine (6) (78) were accessed in a two-step sequence proceeding in 92% and 86% yields, respectively (Fig. 3C). The product 79, which was formulated from benzyl-protected tryptamine and allylbenzene via this oxidative amination reaction, was an AC1 inhibitor29 (Adenylyl cyclase type I (AC1) belongs to the family of adenylyl cyclases, which are associated with neuropathic and inflammatory pain) (Fig. 3D). Additionally, abamine SG derivatives30 80, an effective inhibitor in the biosynthesis of abscisic acid, was assembled in 79% yield with two steps (Fig. 3E).
Substrate scope of aromatic amines and olefines. We next investigated extension of the Pd-catalyzed oxidative amination of olefins with aromatic amines (Fig. 4). The basicity and affinity of aromatic amines are comparatively weaker than those of aliphatic ones, leading to a decrease in their coordination to transition-metal. The employ of monodentate phosphorus ligand could maintain the activity of the catalyst, and O2 could be used as the terminal oxidant to complete the catalytic cycle. The substrate applicability of primary anilines for intermolecular amination was first investigated. Both halogen and electron-donating-substituted anilines can achieve moderate to high yields (50% to 81%). Substituents at either ortho-, meta-, or para-position on the anilines could be accommodated, and higher yields were obtained with large steric hindrance on anilines. The range of different types of nitrogen substituted anilines for intermolecular amination was subsequently probed (94 to 101). Notably, the 3-anilinopropionitrile was also suitable for the reaction to give the desired product 98, which could proceed downstream synthetic manipulation. Various substituted allylbenzenes were tolerated in this transformation, and the corresponding products were obtained in 70 to 85% yields with sole stereoselectivities. Skipped dienes, 2-methyl-3-phenyl-1-propene, and heterocyclic olefins were also well tolerated in this transformation, and the desired allylic amines (108, 113, and 114) were obtained in moderate to high yields. Moreover, the reactions of unactivated simple aliphatic alkenes afforded the desired products in synthetically useful yields. Under modified reaction conditions, the scope of the intramolecular amination was then evaluated. The substrate 118 bearing various electron-rich or electron-deficient functionalities on the aryl ring underwent the reaction effectively to afford the corresponding tetrahydropyrrole and piperidine derivatives (119 to 130) in 35-98% yields with excellent regioselectivities.
Mechanistic investigations. To gain more insight into the palladium-catalyzed oxidative amination of olefins, kinetic analysis experiments for allylbenzene were conducted under optimal reaction conditions. The rate data indicated a first-order dependence on the concentration of Pd catalyst, DPPP and allylbenzene (Fig. 5A), which revealed that the formation of π-allylpalladium complex through the C-H activation of olefins should be the rate-determining step. However, dipropylamine, which could easily coordinate with the palladium catalyst and suppressed the formation of π-allylpalladium complex, indicated a zero-order in this reaction. This result suggested that the coordination of DPPP with the palladium catalyst was much stronger than dipropylamine, and the toxic effect of amine could be ignored. Inter- and intramolecular competitive kinetic isotopic effect (KIE) studies were also explored (Fig. 5B). The results exhibited a high KIE (kH/kD) value of 4.6 and 2.8 for inter- and intramolecular competitions respectively, implying that the allylic C-H cleavage contributes to the rate-determining step. A preliminary Hammett study was performed to investigate the electronic effect on substituents appended to the olefines (Fig. 5C). A ρ value of 0.5355 was obtained for a series of substituted allylbenzenes, indicating that electron-withdrawing groups produced an increase in the amination reaction rate. This is consistent with the mechanism of C-H activation, and the electron-poor olefins could promote the ligand exchange with the palladium complex31. Alternatively, the electron-withdrawing substituents would increase the activity of the allylpalladium intermediate, accelerating subsequent functionalization.
Combining the aforementioned kinetics and Hammett experiments, a proposed catalytic cycle was shown in Fig. 5D. The combination of phosphorus ligands and palladium catalyst is the key to avoid the catalyst being poisoned by Lewis basic amines, after the highly active allyl-palladium intermediate was generated via C-H activation, amines underwent a nucleophilic attack on the allyl position, leading to the target product. It is worth noting that when the nucleophile was aromatic amines, Pd(0) could be oxidized to Pd(II) by oxygen as the terminal oxidant, generating H2O as the sole side-product.