Isoxazole-embedded allylic zinc reagent for the diastereoselective preparation of highly functionalized aldol-type derivatives bearing a stereocontrolled quaternary center.

Highly functionalized aldol-type products bearing a β-quaternary center and a stereoselectively controlled γ-hydroxy function are readily prepared by the diastereoselective addition of an allylic zinc reagent embedded in an isoxazole ring to various aromatic and heteroaromatic aldehydes, in the presence of Lewis acids, such as MgCl2 or LaCl3⋅2 LiCl. After reductive cleavage of the N-O bond by using Fe, NH4Cl, aldol-type products bearing a stereocontrolled β-quaternary center and a γ-hydroxy group were observed. The benzylic reactivity of the isoxazolylmethylzinc reagent towards other electrophiles, such as acid chlorides, aryl and allylic halides, as well as aldehydes in the presence of BF3⋅OEt2 are also described.

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents.

In this review we summarize the most important procedures for the preparation of functionalized organzinc and organomagnesium reagents. In addition, new methods for the preparation of polyfunctional aryl- and heteroaryl zinc- and magnesium compounds, as well as new Pd-catalyzed cross-coupling reactions, are reported herein. Experimental details are given for the most important reactions in the Supporting Information File 1 of this article.

Pd- and Ni-catalyzed cross-coupling reactions of functionalized organozinc reagents with unsaturated thioethers.

A variety of unsaturated thioethers have been subjected to cross-coupling reactions with functionalized zinc reagents in the presence of a transition-metal catalyst. Three different catalytic systems based on Pd(OAc)(2) or [Ni(acac)(2)] and the ligands S-Phos or DPE-Phos gave the best results. N-Heterocyclic thioethers based on a pyridine, pyrimidine, pyrazine, pyridazine, triazine, benzothiazole, benzoxazole, pyrrole, or quinazoline ring, as well as thiomethylacetylenes, serve as electrophiles in this cross-coupling reaction.

Room temperature cross-coupling of highly functionalized organozinc reagents with thiomethylated N-heterocycles by nickel catalysis.

A variety of thiomethyl-substituted N-heterocycles such as pyridines, isoquinolines, pyrimidines, pyrazines, pyridazines, quinazolines, triazines, benzothiazoles, or benzoxazoles undergo smooth Ni-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, alkyl-, and benzylic zinc reagents using an inexpensive Ni(acac)(2)/DPE-Phos catalytic system at 25 degrees C.

Pd-catalyzed cross-coupling of functionalized organozinc reagents with thiomethyl-substituted heterocycles.

Various thiomethyl-substituted N-heterocycles (pyridines, pyrimidines, pyrazines, pyridazines, triazines, benzothiazoles, benzoxazoles, pyrazoles, benzindazoles, quinazolines, etc.) undergo smooth Pd-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, benzylic-, and alkylzinc reagents using Pd(OAc)(2)/S-Phos as the catalytic system mostly at 25 degrees C. No copper salt is required to perform these reactions.

Preparation of polyfunctional arylmagnesium, arylzinc, and benzylic zinc reagents by using magnesium in the presence of LiCl.

The presence of LiCl considerably facilitates the insertion of magnesium into various aromatic and heterocyclic bromides. Several functional groups, such as -OBoc, -OTs, -Cl, -F, -CF(3), -OMe, -NMe(2), and -N(2)NR(2), are well tolerated. The presence of a cyano group leads in some cases to competitive reduction of the organic halide to the corresponding ArH compound.

Polyfunctional benzylic zinc chlorides by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl2.

Benzylic zinc chlorides bearing various functional groups are smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl(2).

Palladium- and nickel-catalyzed cross-couplings of unsaturated halides bearing relatively acidic protons with organozinc reagents.

A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using Pd(OAc)2 (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups. A similar nickel-catalyzed reaction is described. The relative kinetic basicity of organozinc compounds as well as their stability toward acidic protons is also described.

One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates.

In situ generated aryl, heteroaryl, alkyl, or benzylic polyfunctional zinc reagents obtained by the addition of zinc and LiCl to the corresponding organic iodides undergo smooth Pd(0)-catalyzed cross-coupling reactions with aryl bromides, chlorides, and triflates in the presence of PEPPSI as a catalyst. This procedure avoids the manipulation of water and air-sensitive organozinc reagents and produces cross-coupling products in high yields.

Nickel-catalyzed cross-coupling reactions of benzylic zinc reagents with aromatic bromides, chlorides and tosylates.

Benzylic zinc reagents prepared by direct insertion of zinc to benzylic chlorides in the presence of LiCl undergo smooth cross-coupling reactions with aromatic chlorides, bromides and tosylates using Ni(acac)(2) and PPh(3) as a catalyst system.

A general preparation of polyfunctional benzylic zinc organometallic compounds.

A new method for the preparation of highly functionalized benzylic zinc chlorides by the direct insertion of zinc dust into the corresponding benzylic chlorides in the presence of LiCl is described without the formation of homocoupling products (<5 %). Various reactions of these benzylic zinc reagents with a broad range of electrophiles, which lead to polyfunctionalized products, are reported. In particular, the cross-coupling reactions of the benzylic zinc chlorides with aromatic chlorides, bromides, and tosylates in the presence of [Ni(acac)(2)] (acac=acetylacetonate) and PPh(3) proceeded in good to excellent yields to give the corresponding diaryl and heterodiaryl methanes.

LiCl-mediated preparation of highly functionalized benzylic zinc chlorides.

In the presence of zinc dust (1.5-2.0 equiv) and LiCl (1.