Boron-Containing Enamine and Enamide Linchpins in the Synthesis of Nitrogen Heterocycles

Abstract

The use of α-boryl enamine and enamide linchpins in the synthesis of nitrogen heterocycles has been demonstrated. Boryl enamines provide ready access to the corresponding α-halo aldehydes, which undergo regioselective annulation to form borylated thiazoles. A condensation/amidation sequence converts α-boryl aldehydes into stable α-boryl enamides without concomitant C → N migration. We also show that palladium-catalyzed cyclization of α-boryl enamides leads to synthetically versatile isoindolones. These molecules can be subsequently used to access polycyclic scaffolds.

Towards the generalized iterative synthesis of small molecules

“…For example, many standard oxidations (Figure 5a), reductions (Figure 5b), and protecting group manipulations (Figure 5c) are well-tolerated. 145–151 Numerous other common synthetic transformations leave MIDA boronates intact, including aldol reactions, 145 carbonyl olefination reactions, 145 Mitsunobu reactions, 145 electrophilic substitution reactions, 149, 152 hydroborations and –stannylations, 151 Diels Alder cycloadditions (Figure 5j), 151, 153 and cyclopropanations. 147 A variety of transition metal-catalyzed reactions are also well-tolerated (Figure 5g), including Heck reactions, 147, 154 Grubbs metathesis, 147 Sonagashira couplings, 151 and Suzuki cross-couplings.…”

“…A variety of other heterocycle-forming reactions have also been developed using MIDA boronate-containing substrates. Making use of kinetically amphoteric molecules containing MIDA boronates and electrophilic ketones/aldehydes, Yudin has developed syntheses of borylated pyridazines/pyrroles, 156 imidazoles, 148 thiazoles, 149 imidazo[1,2-a]pyridines, 157 and many other motifs. 158 Watson has also developed a synthesis of 2-borylated indoles/benzofurans involving a palladium catalyzed cascade reaction with ethynyl BMIDA and 2-iodoanilines.…”

Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α‐Boryl Ketones

“…[13,15] Gratifyingly,t he reaction was also amenable for the formation of chlorinated, [25] brominated, [26] and iodinated [25] a-boryl ketones using NaClO 2 ,N BS,a nd I 2 as the halogen sources,r espectively (Scheme 1). [13,15] Gratifyingly,t he reaction was also amenable for the formation of chlorinated, [25] brominated, [26] and iodinated [25] a-boryl ketones using NaClO 2 ,N BS,a nd I 2 as the halogen sources,r espectively (Scheme 1).…”

“…Furthermore,Y udin [13] and Burke [14] independently reported the preparation of aboryl aldehydes by at wo-step synthesis that consisted of the epoxidation of alkenyl MIDA( N-methyliminodiacetyl) boronates followed by aL ewis acid-promoted 1,2-boryl migration ( Figure 1d). [13,15] [13,15] …”

Borylated oximes: versatile building blocks for organic synthesis

“…We have since reported a number of methods to circumvent the boryl migration through in situ trapping of the condensation intermediates. These include trapping the enamine intermediate via the addition of an acyl halide to produce C -boryl enamides, 26 or alternatively, trapping the imine species via reductive amination. 25 Herein, we present a new strategy to overcome 1,3-boryl migration.…”