Tetraborylation of p-Benzynes Generated by the Masamune-Bergman Cyclization through Reaction Design Based on the Reaction Path Network

Abstract

Designing the reactant molecule of an initial reaction, based on quantum chemical pathway exploration, enabled us to access a new reaction, i.e., the tetraborylation reaction of p-benzynes generated from 1,2-diethynylbenzene derivatives, using bis(pinacolato)diborane(4) (B₂pin₂). Based on the reaction path network generated via the artificial-force-induced reaction (AFIR) method, desired and undesired paths were identified and used to modify the chemical structure of the reactant. After the in silico screening, the optimal structure of the reactant was determined to be a 1,2-diethynylbenzene derivative with a butylene linker. The reaction of the optimized reactant and its derivatives with an excess of B₂pin₂ gave the tetraborylated products in good yields (up to 58%). It is quite intriguing that the two carbons of p-benzyne behave formally as dicarbenes in this reaction.

Figure 1

Our concept of theoretical-calculation-based modification of the initial reactant to develop a new reaction affords the desired product. SM: starting material, SM-mod: modified starting material, Int.: intermediate, Int-mod: modified intermediate, and Prod. A and B: Products.

Figure 2

Reaction path network and the lowest energy pathways for the reaction of enediyne 1a with 1 equiv (a,b) or 2 equiv (c,d) of B2eg2 at the UB3LYP/6-31G level of theory. Nodes (circles) and edges (lines) represent obtained equilibrium structures and reaction paths connecting them, respectively. In (a,c), the color of the nodes represents their Gibbs energy at 300 K. In (b,d), the bracketed numbers indicate the Gibbs energy of each species, and the red numbers indicate activation energy in kJ/mol at 300 K.

Figure 3

In silico analysis of the activation energies of the Masamune–Bergman cyclization of enediynes 1a–8a at the UB3LYP-D3BJ/6-31G(d,p) level of theory at 298.15 K.

Figure 4

ORTEP drawing of 9c obtained from an X-ray crystallographic analysis. One of two independent molecules is shown. Thermal ellipsoids are shown at 50% probability, and hydrogen atoms are omitted for clarity.

Figure 5

(a) Reaction diagram for the tetraborylation reaction of 6a with B₂pin₂ calculated at the (U)B3LYP-D3BJ/6-311+G(2d,p)//(U)B3LYP-D3BJ/6-31G(d,p) level of theory with the solvent effect (SMD = 1,2-dichlorobenzene) at 413.15 K. (b–d) Structures of TS2, Int1, and TS3 with distances and angles.