Cascade Reductive Friedel–Crafts Alkylation Catalyzed by Robust Iridium(III) Hydride Complexes Containing a Protic Triazolylidene Ligand

Abstract

The synthesis of complex molecules like active pharmaceutical ingredients typically requires multiple single-step reactions, in series or in a modular fashion, with laborious purification and potentially unstable intermediates. Cascade processes offer attractive synthetic remediation as they reduce time, energy, and waste associated with multistep syntheses. For example, triarylmethanes are traditionally prepared via several synthetic steps, and only a handful of cascade routes are known with limitations due to high catalyst loadings. Here, we present an expedient catalytic cascade process to produce triarylmethanes. For this purpose, we have developed a bifunctional iridium system as the efficient catalyst to build heterotriaryl synthons via reductive Friedel–Crafts alkylation from ketones, arenes, and hydrogen. The catalytically active species were generated in situ from a robust triazolyl iridium­(III) hydride complex and acid and is composed of a metal-bound hydride and a proximal ligand-bound proton for reversible dihydrogen release. These complexes catalyze the direct hydrogenation of ketones at slow rates followed by dehydration. Appropriate adjustment of the conditions successfully intercepts this dehydration and leads instead to efficient C–C coupling and Friedel–Crafts alkylation. The scope of this cascade process includes a variety of carbonyl substrates such as aldehydes, (alkyl)­(aryl)­ketones, and diaryl ketones as precursor electrophiles with arenes and heteroarenes for Friedel–Crafts coupling. The reported method has been validated in a swift one-step synthesis of the core structure of a potent antibacterial agent. Excellent yields and exquisite selectivities were achieved for this cascade process with unprecedentedly low iridium loadings (0.02 mol %). Moreover, the catalytic activity of the protic system is significantly higher than that of an N-methylated analogue, confirming the benefit of the Ir–H/N–H hydride-proton system for high catalytic performance.

Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones

“…The reaction of benzoic acid with phenylboronic acid and Boc2O in the presence of a palladium catalyst gave benzophenone (1) via a mixed acid anhydride. 33 When 1 was subjected directly to the diverging conditions of Figure 2 without isolation in one pot, diphenylmethane (2A) and tetraphenylmethane (3A) were successfully synthesized in 70% and 43% yields from benzoic acid, respectively. We also attempted a deoxygenative allylation of diarylketones (Figure 5B).…”

“…Meanwhile, recent attention has been focused on the deoxygenative transformation of aromatic carbonyls, which has been extensively studied by the Li group and others. [29][30][31][32][33] Regarding this field of research, we have also developed a deoxygenative C-P bond formation of aromatic esters (Figure 1C). 34 In this reaction, an aromatic ester reacts with phosphine oxide in the presence of a palladium catalyst to give an acylphosphine oxide species as the intermediate.…”

“…Meanwhile, recent attention has been focused on the deoxygenative transformation of aromatic carbonyls, which has been extensively studied by the Li group and others. [29][30][31][32][33] Regarding this eld of research, we have also developed a deoxygenative C-P bond formation of aromatic esters (Fig. 1C).…”

Cu-catalyzed cycloaddition of aryl azides to 1-iodobuta-1,3-diynes: an experimental and quantum chemical study of unusual regiochemistry

“…24 Additionally, several examples of the formation of 1,5-disubstituted triazoles from terminal alkynes using basic conditions have been reported. 25,26…”

4-Phenyl-1,2,3-triazoles as Versatile Ligands for Cationic Cyclometalated Iridium(III) Complexes

“…4-Phenyl- and 4-(pyrid-2′-yl)-1,2,3-triazoles and the corresponding triazolylidenes have been widely used in recent years as monodentate or chelating ligands in coordination and organometallic chemistry. Thanks to their great versatility, metal complexes derived from such ligands (e.g., iridium­(III), − platinum­(IV), , ruthenium­(II), ,, palladium­(II), gold­(I), − silver­(I), and rhodium­(II)) have been utilized for homogeneous catalysis or as luminescent materials. When dealing with emissive heteroleptic complexes, the carbene-type chelators are normally employed as ancillary ligands. − …”