A metal π-Lewis base activation model for Pd-catalyzed hydroamination of amines and 1,3-dienes

As a general mechanism proposal, a Pd(ii)–H migration insertion process is not able to well explicate the Pd-catalyzed hydroamination of amines and 1,3-dienes. Here we demonstrate that 1,3-dienes form electron-neutral and HOMO-raised η2-complexes with Pd(0) via π-Lewis base activation, which undergoes protonation with a variety of acidic sources, such as Brønsted acids, Lewis acid-activated indazoles, and Pd(ii) pre-catalyst triggered ammonium salts. The resultant π-allyl palladium complexes undergo the amination reaction to give the final observed products. FMO and NPA analyses have revealed the nature of Pd(0) mediated π-Lewis base activation of 1,3-dienes. The calculation results show that the π-Lewis base activation pathway is more favourable than the Pd(ii)–H species involved one in different reactions. Further control experiments corroborated our mechanistic proposal, and an efficient Pd(0) mediated hydroamination reaction was developed.


Alternative transition states structures in the π-Lewis base activation step
Fig. S1. The structure and energy difference of various π-lewis base activation transition states in Pd-catalyzed hydroamination of indazoles with isoprene.
As shown in Fig. S1, alternative transition state structures in the π-Lewis base activation step were considered. Due to the steric hindrance between methyl at isoprene and ligand, the relative free energy of 33-ts is 0.8 kcal/mol higher than that of 8-ts. Meanwhile, the cis-conformation isoprene involved transition state 34-ts is 8.8 kcal/mol higher than that of 8-ts. In 35-ts, phosphoric acid reacts with the adjacent carbon atom. and the relative free energy of 35-ts is 9.8 kcal/mol higher than that of 8-ts, indicating the vinylogy activation of diene is more favorable. It is consistent with the orbital analysis in Figure 2. Calculated results showed that all of these are much higher than that of 8-ts for the π-Lewis base activation process.

BEt3 mediated generation Pd(II)-H species
The ancillary Lewis acid BEt3 could facilitate the Pd(0)-catalyzed hydroamination of indazoles with isoprene to get N 1 -functionalized product 3b (Scheme 2a). For this Brønsted acid absent system, a BEt3 activating Pd(0) mechanism was proposed in the previous report. A small amount of BEt3 was expected to undergo oxidative addition with Pd(0) and the subsequent hydride elimination to deliver the Et2B-Pd(II)-H species. To evaluate the possibility of this pathway, we have calculated the free energy profile. As shown in Figure S3, the activation free energy of this pathway is up to 66.9 kcal/mol (referring to 7→39-ts). The extremely high activation free energy suggests this process is hard to occur in this reaction condition. Thus the possibility of the BEt3 mediated generation Pd(II)-H species pathway was excluded.  Fig. S4. The initial cycle of cationic Pd(II)−π-allyl mediated Pd-catalyzed hydroamination of aliphatic amine with diene. The data in parentheses represent the relative free energy, which is given in kcal/mol.

The initial cycle of cationic Pd(II)−π-allyl mediated Pd-catalyzed hydroamination
The main reaction mechanism of cationic Pd(II)−π-allyl mediated Pd-catalyzed hydroamination of aliphatic amine with diene was given in the text. The active complex 22 could be generated through S5 the initial cycle of cationic Pd(II)−π-allyl mediated Pd-catalyzed hydroamination ( Figure S4). The reaction starts from the amine 5 nucleophilic attack of the Pd(II)-π-allyl species 41 to give Pd(0) complex 25 and quaternary ammonium salt cation 44. Subsequently, the formation of Pd(II)-π-allyl species 22 via the π-Lewis base activation process between 44 and 25. The activation free energy for the initial cycle of cationic Pd(II)−π-allyl mediated Pd-catalyzed hydroamination is 17.2 kcal/mol (referring to 41→42-ts), indicating this process could proceed smoothly in the reaction condition. As shown in Fig. S5, alternative transition state structures in the generation of Pd(II)-H species via the oxidative protonation process were considered. Calculated results showed that all of these are much higher than that of 26-ts for the π-Lewis base activation process. Neutral aliphatic amine 5 direct oxidation addition with Pd complexes in hydroamination reaction was discussed. As shown in Figure S6, calculated results show that the energy barrier of oxidation addition with neutral amine 5 is up to 50.1 kcal/mol (referring to 25→48-ts). It suggests that the neutral amine 5 is insufficient to oxidize Pd(0) species. Moreover, the aliphatic amine 5 involved π-Lewis base activation process needs to overcome a high energy barrier of 49.6 kcal/mol (referring to 25→50-ts). These results emphasize the critical role of the cationic Pd(II) pre-catalyst triggered ammonium salt 6′. Fig. S7. The pre-activation of [Pd(π-allyl)Cl]2 in the neutral catalytic system. The data in parentheses represent the relative free energy, which is given in kcal/mol.

The pre-activation of [Pd(π-allyl)Cl]2 in the neutral catalytic system
In addition, the neutral [Pd(π-allyl)Cl]2 catalyst was also sufficient to mediate hydroamination reactions. Based on the above results, we anticipated that the pyrazole hydrochloride generated through reductive elimination with pyrazole could serve as an initial electrophile of the π-Lewis base activation mode. To validate this issue, we have calculated the pre-activation of [Pd(π-allyl)Cl]2 in this neutral catalytic system. As shown in Figure S7, [Pd(π-allyl)Cl]2 51 could directly afford allyl chloride (54) with an endothermic by 12.4 kcal/mol. However, the formation of pyrazole hydrochloride 53 via 52-ts is only endothermic by 4.0 kcal/mol. It suggests that the formation of pyrazole hydrochloride 53 is more thermodynamically favorable. And the generated pyrazole hydrochloride could drive the catalytic cycle via the π-Lewis base activation process to obtain desired hydroaminated products.