Computational Study on the Mechanism and Origin of the Regioselectivity and Stereospecificity in Pd/SIPr-Catalyzed Ring-Opening Cross-Coupling of 2-Arylaziridines with Arylboronic Acids

Abstract

The mechanism, regioselectivity, and stereospecificity of Pd/NHC-catalyzed ring-opening cross-coupling of 2-arylaziridines with arylboronic acids (J. Am. Chem. Soc.136) is rationalized from density functional theory calculations. Pd(0)­SIPr complex, the active species, can be formed through the reduction of (η3-cinnamyl)­(Cl)­Pd­(II)­SIPr complex, where arylboronic acid in solution plays a key role. Then the Pd(0)­SIPr complex acts as the active species of the catalytic cycle that consists of the regioselective and stereospecific oxidative addition, proton transfer, rate-determining transmetalation, and reductive elimination. Transition states for the oxidative addition were systematically determined from a multicomponent artificial force induced reaction search and explained the regioselectivity and stereospecificity of the reaction. An energy decomposition analysis on the key transition states suggested that the interactions between Pd(0)­SIPr and 2-arylaziridines are important to the selectivity. The computed mechanism of the full catalytic cycle is consistent with the experimental data. Our detailed mechanistic survey provides important mechanistic insights for enantiospecific and regioselective ring-opening reactions of 2-arylaziridines.

Palladium‐Catalyzed Regioselective and Stereospecific Ring‐Opening Suzuki‐Miyaura Arylative Cross‐Coupling of 2‐Arylazetidines with Arylboronic Acids

“…In the lowest energy TS ( TS1 ), the ring opening occurs at the benzylic carbon position of 1 a , leading to the desired product of the reaction. The computed free energy barrier for the ring‐opening process is 14.9 kcal/mol, which is a larger barrier than that for the ring‐opening process for N ‐tosyl‐2‐phenylaziridine (7.4 kcal/mol), a three‐membered ring system [11c] . Since the ring component atoms of the azetidines have higher sp 3 ‐hybrized character than those of aziridines, the reacting point in the ring‐opening process of azetidine (i. e., the C(2) atom) is more sterically hindered, and the bond dissociation energy of the C(2)−N(1) is larger than that of aziridines.…”

Catalyst-controlled regiodivergent ring-opening C(sp3)–Si bond-forming reactions of 2-arylaziridines with silylborane enabled by synergistic palladium/copper dual catalysis

“…Aziridines have emerged as relatively new alkyl electrophiles in transition-metal-catalyzed regioselective ring-opening C–C13–18 and C–B19,20 cross-couplings with organoboron and organozinc nucleophiles to give β-organo- and borylated alkylamines, respectively. In conjunction with the fact that alkylamines bearing a C(sp 3 )–Si bond have been recognized as unique bioisosteres of pharmacological agents in medicinal chemistry,21 regiodivergent ring-opening C(sp 3 )–Si cross-coupling of aziridines with a silyl (pro)nucleophile would open up a new avenue to the preparation of a set of regioisomeric β-silyl-alkylamines.…”

Asymmetric Synthesis of β2‐Aryl Amino Acids through Pd‐Catalyzed Enantiospecific and Regioselective Ring‐Opening Suzuki–Miyaura Arylation of Aziridine‐2‐carboxylates

“…In the presence of an anionic Na tom, I2 can be stabilizedb yH 2 Oi ns olution. [20] The resulting intermediate, I2.3H 2 O,i s3 .4 kcal mol À1 more stable than I2.T hen, the proton transfer occurs through TS2 (À7.1 kcal mol À1 ), which is almost barrierless. The subsequenti ntermediate (I3.2H 2 O)i s1 7.3 kcal mol À1 more stable than the entry point of the free energy profile.…”

“…Then, regioselective and stereoinvertive aziridine ring opening occurs with a barrier of 6.6 kcal mol −1 ( TS1 ), giving I2 (−4.5 kcal mol −1 ). In the presence of an anionic N atom, I2 can be stabilized by H 2 O in solution . The resulting intermediate, I2.3H 2 O , is 3.4 kcal mol −1 more stable than I2 .…”

“…Scheme illustrates a plausible catalytic cycle based on the results obtained from experiments and computational studies. The reduction of Pd II with ArB(OH) 2 generates Pd 0 ‐L species . The coordination of a highly σ‐donating ligand allows for the exclusively regioselective oxidative addition at the more sterically‐hindered side (C‐2) in a stereoinvertive manner ( a in Scheme ).…”