Entering Chemical Space with Theoretical Underpinning of the Mechanistic Pathways in the Chan–Lam Amination

Abstract

Recent years have witnessed a growing interest in the development of efficient copper-based catalytic systems following the Chan−Lam (CL) reaction protocol for the C−N bond formation. Though CL amination has been widely explored experimentally, it is quite underdeveloped from a mechanistic standpoint. Extensive theoretical investigations are carried out to unravel the mechanistic pathways of the CL reaction. We report in detail the fundamental reaction steps involved in Cu-catalyzed carbon−heteroatom bond formation reactions, particularly the CLbased amination. An in-depth examination of this study provides some interesting insights into little known pathways such as the denucleation of dimeric copper acetate, the disproportionation of the Cu(II) complex, and the regeneration of Cu(II) from Cu(I) intermediates. The rate-determining step of 26.0 kcal mol −1 involves the disproportionation and reductive elimination of the Cu(II) intermediate. The mechanism for the inhibitory effect of pinacol (BPin) esters, off-cycle reaction routes, and influence of amine substrates are elaborated in this context. For a series of heteroarene substrates, it was observed that the catalyst generation energy span correlates with the experimentally observed reaction outcome. The calculated results are in agreement with the experimental observations based on spectroscopic and kinetic studies.

Copper-Catalyzed Homocoupling of Boronic Acids: A Focus on B-to-Cu and Cu-to-Cu Transmetalations

“…Relative to 3 +,n = 2 , transmetalation via TS-4 +,n = 2 requires us to overcome an overall Gibbs energy barrier of 16.2 kcal mol −1 to yield the transmetalated complex trans -[Cu II (Ph)(MeOH) 2 (μ-OH)B(OH) 2 ] + ( 5 + ). This is in good agreement with previous calculations related to boronate transmetalation reported on a parent Cu system [ 45 ]. From 3 +,n = 2 to TS-4 +,n=2 , the main contribution to the energy barrier is the formation of pre-complex 4 +,n = 2 .…”

“…The presence of a coordinating base (hydroxide and methoxide) enables the first B-to-Cu(II) transmetalation from aryl boronic acid to Cu II Cl 2 in methanol, while an excess of base is detrimental ( Scheme 3 ). This suggests the formation of heterobimetallic Cu-(μ-OH)-B intermediates as previously suggested [ 45 , 50 ] and as confirmed by our DFT calculations. In contrast with previous suggestions from the literature, a second B-to-Cu transmetalation to form bis-aryl Cu(II) complexes is kinetically prevented [ 6 , 7 , 9 ].…”

Copper-Catalyzed Homocoupling of Boronic Acids: A focus on B-to-Cu and Cu-to-Cu Transmetalations

“…The presence of a coordinating base (hydroxide, methoxide) enables the first B-to-Cu(II) transmetalation from aryl boronic acid to Cu II Cl2 in methanol, while an excess of base is detrimental. This suggests the formation of heterobimetallic Cu-(μ-OH)-B intermediates as previously suggested [45,50] and as confirmed by our DFT calculations. In contrast with previous suggestions from the literature, a second B-to-Cu transmetalation to form bis-aryl Cu(II) complexes is kinetically prevented.…”

“…This is in good agreement with previous calculations related to boronate transmetalation reported on a parent Cu system. [45] From 3 +,n=2 to TS-4 +,n=2 the main contribution to the energy barrier is the formation of pre-complex 4 +,n=2 . From cationic complex 5 + , coordination ).…”

Direct Chan–Lam Amination and Etherification of Aryl BMIDA Reagents

“…[1][2][3][4][5][6][7][8] In addition, arylboronic acids dominate this area, with comparatively few examples of other organoboron reagents, such as arylboronic acid pinacol esters (ArBPin) [9][10][11][12] and aryltrifluoroborates (ArBF 3 K). [13,14] In this latter case, based on the proposed mechanism of transmetalation, which involves a Lewis pairing of the Cu catalyst with the organoboron, [10,15] the ArBF 3 K reagent must first be hydrolyzed to a neutral organoboron, similar to that proposed for Suzuki-Miyaura cross-coupling with these reagents. [16] The ArBF 3 K can therefore be considered as a protected arylboronic acid undergoing a one-pot deprotection/Chan-Lam reaction.…”