Abstract
Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize the developing positive charge at the enone β-position. For the former, the closer the heteroatom is to the enone β-carbon, the faster the reaction. For the latter, greater resonance stabilization of the benzylic cationic charge accelerates the reaction. Thus, reaction rates are increased by the closer proximity of inductive electron-withdrawing elements, but if resonance effects are involved, then increased rates are observed with electron-donating ability. Evidence for these trends in isomeric substrates is presented, and the application of these insights has allowed for reaction conditions that provide improved reactivity with previously problematic substrates.
Highlights
Heteroaromatics routinely appear as key pharmacophores in small molecule drugs [1,2,3,4,5], as common motifs in natural products [6,7,8], and as important functional groups in materials [9]
Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize the developing positive charge at the enone β-position
We have contributed to this area by demonstrating that α-chiral heterocycles can be synthesized through 3,3-BINOL (6)-catalyzed conjugate addition of aryl, alkenyl, and alkynyl boronic acids and trifluoroborate salts to β-heteroaryl-appended enones and enals [87,88,89,90]
Summary
Heteroaromatics routinely appear as key pharmacophores in small molecule drugs [1,2,3,4,5], as common motifs in natural products [6,7,8], and as important functional groups in materials [9]. A control experiment of stirring the pyrrolyl-enone with just (NH4)2CO3 in toluene without light at 90 ◦C without a catalyst or organoboron nucleophile resulted in an unwanted reaction that produced a side product too unstable to isolate This indicated to us that the base has both an advantageous effect on the conjugate addition and an adverse effect on the starting material stability, creating a conflicted system. Though, in all of the pyrrole substrates (Figure 10) and some of the indole substrates (Figure 9), the boronic acids resulted in higher yields than their trifluoroborate counterparts These findings led us to b7eolife1v7e the base, (NH4)2CO3, could be helping to promote boroxine formation from the boronic acid or maintain a favorable pKa for the conjugate addition reaction to occur.
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