Regio- and chemoselective multiple functionalization of chloropyrazine derivatives. Application to the synthesis of coelenterazine.

Successive regio- and chemoselective metalations of chloropyrazines using TMPMgCl x LiCl and TMPZnCl x LiCl furnish, after trapping with electrophiles, highly functionalized pyrazines in high yields. Application to a synthesis of coelenterazine, a bioluminescent natural product in jellyfish Aequorea victoria, in nine steps (9% overall yield) is reported.

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.

Kinetics of bromine-magnesium exchange reactions in heteroaryl bromides.

Competition experiments are reported which compare the relative reactivities of bromoheteroarenes toward i-PrMgCl x LiCl in THF at 0 degrees C.

Synthesis of fully substituted pyrazoles via regio- and chemoselective metalations.

The full functionalization of the pyrazole ring was achieved by successive regioselective metalations using TMPMgCl x LiCl and TMP(2)Mg x 2 LiCl. Trapping with various electrophiles led to trisubstituted pyrazoles. An application to the synthesis of the acaricide Tebufenpyrad is reported.

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.

2,3-Functionalization of furans, benzofurans and thiophenes via magnesiation and sulfoxide-magnesium exchange.

The use of TMPMgCl.LiCl and iPrMgCl.LiCl allows a sequential 2,3-difunctionalization of various 2-arylsulfinyl furans, thiophenes and benzofurans.

TMPZnCl.LiCl: a new active selective base for the directed zincation of sensitive aromatics and heteroaromatics.

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using TMPZnCl.LiCl, a new exceptionally mild and efficient base. Activated arenes and heteroarenes are metalated at room temperature.

Kinetics of bromine-magnesium exchange reactions in substituted bromobenzenes.

Competition experiments have been performed to determine the relative reactivities of substituted bromobenzenes, bromonaphthalenes, and 9-bromoanthracene toward i-PrMgCl x LiCl in THF at 0 degrees C. The rates of the bromine-magnesium exchange reactions are accelerated by electron-acceptor substituents, the activating efficiency of which increases in the order para < meta << ortho. The activation free enthalpies of the bromine-magnesium exchange reactions correlate fairly (r(2) = 0.

LiCl-mediated preparation of functionalized benzylic indium(III) halides and highly chemoselective palladium-catalyzed cross-coupling in a protic cosolvent.

Sensitive functional groups such as COR, CHO, or CH(2)OH can be present in benzylic indium reagents prepared by the direct insertion of indium in the presence of LiCl. These reagents undergo palladium-catalyzed cross-coupling reactions in the presence of a protic cosolvent after activation with iPrMgCl x LiCl (see scheme). Remarkable chemoselectivities are achieved by using various electrophiles containing NH or OH groups.

Aluminum bases for the highly chemoselective preparation of aryl and heteroaryl aluminum compounds.

Selective C-H activation with a series of neutral aluminum trisamide bases led to a wide range of polyfunctional aryl and heteroaryl aluminum reagents. Ester and cyano groups are stable under the reaction conditions for this direct alumination, and donor oxygen substituents are efficient directing groups. High metalation regioselectivities were observed with O,S and N,S heterocycles (see example).

Regio- and chemoselective metalation of chloropyrimidine derivatives with TMPMgCl x LiCl and TMP(2)Zn x 2 MgCl(2) x 2 LiCl.

Efficient zincation and magnesiation of chlorinated pyrimidines can be performed at convenient temperatures (e.g., 25 and 55 degrees C) by using TMPMgCl x LiCl and TMP(2)Zn x 2 MgCl(2) x 2 LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) as effective bases.

Regio- and chemoselective synthesis of fully substituted thiophenes.

A full functionalization of all four positions of the thiophene ring was achieved. Starting from readily available 2,5-dichlorothiophene, successive magnesiations of the 3- and 4-positions using TMPMgCl x LiCl furnish, after trapping with various electrophiles, 3,4-difunctionalized dichlorothiophenes. Subsequent dechlorination and metalation or magnesium insertion into the C-Cl bond provides fully functionalized thiophenes in high yields.

Efficient mono- and bis-functionalization of 3,6-dichloropyridazine using (tmp)2Zn.2MgCl2.2LiCl.

3,6-Dichloropyridazine undergoes a smooth metallation using (tmp)2Zn.2MgCl2.2LiCl.

Direct zincation of functionalized aromatics and heterocycles by using a magnesium base in the presence of ZnCl2.

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)(2)Mg2 LiCl (TMP=2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl(2). The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine.

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.

High temperature metalation of functionalized aromatics and heteroaromatics using (tmp)2Zn x 2 MgCl2 x 2 LiCl and microwave irradiation.

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using (tmp)2Zn x 2 MgCl2 x 2 LiCl and microwave irradiation. Ester and cyano functions as well as ketones are compatible with the high temperatures of the zincation. The resulting bis-organo zinc species undergo a number of subsequent reactions leading to highly functionalized aromatics and heteroaromatics in good to excellent yields.

Regio- and chemoselective magnesiation of protected uracils and thiouracils using TMPMgCl x LiCl and TMP(2)Mg x 2 LiCl.

Two successive regio- and chemoselective magnesiations using TMPMgCl x LiCl and TMP(2)Mg x 2 LiCl enable the full functionalization of protected uracils and thiouracils in good to excellent yields.

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.