Massimo Giannerini

Direct catalytic cross-coupling of organolithium compounds

Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of natural products, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagents and organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivity of common organolithium reagents have largely prohibited their use as a viable partner in direct catalytic cross-coupling. Here we report that in the presence of a Pd-phosphine catalyst, a wide range of alkyl-, aryl- and heteroaryl-lithium reagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mild conditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation of key alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions for medicinal chemistry and material science. A general and selective palladium-catalysed cross-coupling of aryl- and alkenyl-bromides with a wide range of alkyl-, aryl- and heteroaryl-lithium reagents is reported. The process proceeds quickly at room temperature, and avoids the notorious lithium–halogen exchange and homocoupling side-reactions commonly associated with these extremely reactive organometallic compounds.

Palladium-catalysed direct cross-coupling of secondary alkyllithium reagents

Palladium-catalysed cross-coupling of secondary C(sp3) organometallic reagents has been a long-standing challenge in organic synthesis, due to the problems associated with undesired isomerisation or the formation of reduction products. Based on our recently developed catalytic C–C bond formation with organolithium reagents, herein we present a Pd-catalysed cross-coupling of secondary alkyllithium reagents with aryl and alkenyl bromides. The reaction proceeds at room temperature and on short timescales with high selectivity and yields. This methodology is also applicable to hindered aryl bromides, which are a major challenge in the field of metal catalysed cross-coupling reactions.

Catalytic Direct Cross-Coupling of Organolithium Compounds with Aryl Chlorides

Palladium-catalyzed direct cross-coupling of aryl chlorides with a wide range of (hetero)aryl lithium compounds is reported. The use of Pd-PEPPSI-IPent or Pd2(dba)3/XPhos as the catalyst allows for the preparation of biaryl and heterobiaryl compounds in high yields under mild conditions (room temperature to 40 °C) with short reaction times.

Palladium-catalysed direct cross-coupling of organolithium reagents with aryl and vinyl triflates.

A palladium-catalysed cross-coupling of organolithium reagents with aryl and vinyl triflates is presented. The reaction proceeds at 50 or 70 °C with short reaction times, and the corresponding products are obtained with moderate to high yields, with a variety of alkyl and (hetero)aryl lithium reagents.

Z-Selective copper-catalyzed asymmetric allylic alkylation with Grignard reagents.

Allylic gem-dichlorides undergo regio- and enanantioselective (er up to 99:1) copper-catalyzed allylic alkylation with Grignard reagents affording chiral Z-vinyl chlorides. This highly versatile class of synthons can be subjected to Suzuki cross coupling affording optically active Z-alkenes and 1,3-cis,trans dienes.

Palladium-Catalyzed C(sp(3)) C(sp(2)) Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)Aryl Halides

The palladium-catalyzed direct cross-coupling of a range of organic chlorides and bromides with the bifunctional C(sp(3))-(trimethylsilyl)methyllithium reagent is reported. The use of Pd-PEPPSI-IPent as the catalyst allows for the preparation of structurally diverse and synthetically versatile benzyl- and allylsilanes in high yields under mild conditions (room temperature) with short reaction times.

Palladium-Catalyzed, tert-Butyllithium-Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A.

A palladium-catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium-halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst-induced remote point-to-axial chirality transfer.

tBuLi-Mediated One-Pot Direct Highly Selective Cross-Coupling of Two Distinct Aryl Bromides.

A Pd-catalyzed direct cross-coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst allows for the efficient one-pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross-coupling is the use of an ortho-substituted bromide that undergoes lithium-halogen exchange preferentially.

Catalyst-controlled reverse selectivity in C-C bond formation

An efficient and highly α-selective copper-catalyzed allylic alkylation of allylic halides with organolithium reagents is presented. The use of N-heterocyclic carbenes as ligands is key to reverse the common γ-selectivity of this transformation and gives rise to the corresponding linear products with high levels of regioselectivity.