The Kumada cross-coupling allows direct Pd-catalyzed carbon-carbon bond formation between unsaturated halides and organomagnesium reagents (without further transmetalation steps) [1,2] and is therefore a highly atom-economical cross-coupling reaction.[3] Most of these cross-couplings follow a standard mechanism (oxidative addition, ligand exchange, reductive elimination), [4] although an alternative pathway is possible, as was shown by Kambe et al. for Kumada cross-couplings in the presence of dienes.[5] Recently, Buchwald and co-workers have shown that when an appropriate phosphine ligand [6] and low temperatures are used, functionalized aryl and heteroaryl iodides undergo a smooth cross-coupling with functionalized arylmagnesium halides. [7,8] Herein, we wish to report a new radical catalysis which makes it possible to perform a Kumada cross-coupling using aryl bromides at room temperature within a few minutes in the presence of an alkyl iodide. In preliminary experiments we observed that the reaction of PhMgCl (1 a), prepared by the insertion of magnesium in the presence of lithium chloride, [9] reacts slowly with 4-bromoanisole (2 a) in the presence of Pd(OAc) 2 and S-Phos (S-Phos = 2-dicyclohexylphosphanyl-2',6'dimethoxyphenyl) [10] or PEPPSI (PEPPSI = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride), [11] leading to 4-methoxybiphenyl (3 a). A conversion of only 8 % was observed at 0 8C after 15 minutes. In strong contrast, the reaction of PhMgCl (1 a), prepared by I/Mg exchange using iPrMgCl·LiCl, [12] provided 3 a with 82 % conversion after 15 minutes (Scheme 1, top). This difference was attributed to the presence of 1.1 equivalents of iPrI obtained as a side product in the I/Mg exchange. Thus, the cross-coupling of arylmagnesium halide 1 b, prepared from 3-iodobenzotrifluoride (4 a) by I/Mg exchange with the bromoaryl ketone 2 b, furnished the functionalized biphenyl 3 b within 5 min at 25 8C as a single product (87 % yield, Scheme 1, bottom). Interestingly, when the Grignard reagent 1 b was prepared from the corresponding aryl bromide 4 b by Br/Mg exchange, no acceleration was observed and the biphenyl 3 b was isolated in only 46 % yield after 1 hour. [13] This demonstrates the accelerating effect of iPrI. We have found that a range of alkyl iodides such as MeI, 1-iodoadamantane, neopentyl iodide, and cyclohexyl iodide give similar rate enhancement. [14] In subsequent experiments, however, we used isopropyl iodide (1.1-1.2 equiv), [15] since it is produced in the I/Mg exchange and since the abovementioned iodides displayed comparable catalytic activity.As shown in the bottom equation of Scheme 1, the presence of iPrI considerably enhances the functional-group tolerance of this Kumada cross-coupling. By using this procedure, a range of functionalized arylmagnesium species were efficiently coupled with functionalized aryl and heteroaryl bromides. Thus, the reaction of 3-trifluoromethylphenylmagnesium chloride (1 b, 1.1 equiv) with 2-bromobenzonitrile (2 c, 1.0 eq...

Pump it up! The sluggish reactivity of organozinc reagents in additions to aldehydes, ketones, and CO2 can be increased by MgCl2, which is usually generated in the preparation of the zinc reagent. The direct reaction with CO2, in particular, opens an expeditious route to phenylacetic acid derivatives, as demonstrated in a short synthesis of ibuprofen (see scheme).

A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated halides bearing an acidic NH or OH function, using Pd(OAc)(2) (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups.

An efficient, high-yielding, and transition-metal-free synthesis of diaryl sulfones from arylsulfinic acid salts and diaryliodonium salts has been developed. The mild reaction conditions tolerate a range of functional groups, and unsymmetrical diaryliodonium salts show high chemoselectivity.

Various methods for the preparation of organozinc compounds have been reported. [3] However, polyfunctional zinc reagents of type RZnX (X = halide) [4] or R 2 Zn are highly sensitive to moisture and air. These properties represent a serious drawback for their practical use in the laboratory and on an industrial scale. Thus, the availability of more easy to handle organozinc compounds is highly desirable. Since their reactivity is strongly influenced by the presence of salts, [5] we anticipated that the presence of appropriate metallic salts may lead to an improved stability towards air and water. Charette et al. have already demonstrated that alkoxides greatly stabilize zinc carbenoids for enantioselective cyclopropanations.[6] Furthermore, Herrmann et al. reported that methylzinc acetate can be efficiently used for the synthesis of methyltrioxorhenium (MTO), even on large scales. [7] Herein, we report the preparation of solid salt-stabilized functionalized aryl, heteroaryl, and benzylic zinc reagents of the general formula RZnOPiv·Mg(OPiv)(X)·2 LiCl (X = Cl, Br, or I; OPiv = pivalate; abbreviated RZnOPiv for clarity). These new zinc reagents are readily prepared by a one-pot synthesis in which the organic halide (RX; X = Cl, Br) is treated with magnesium turnings (2.5 equiv) [8] and the THFsoluble salt Zn(OPiv) 2 ·2 LiCl [9] (2; 1.5 equiv). Under these conditions, the formation of the zinc reagent is observed at 25 8C within 2 h.[10] The presence of Zn(OPiv) 2 ·2 LiCl (2) not only stabilizes the resulting zinc reagent, but also accelerates its formation dramatically. Whereas 4-bromo-1,2-dimethylbenzene (1 a) requires 2 h in the presence of Mg/ ZnCl 2 ·2 LiCl, [8] the insertion reaction is complete within 20 min when using the combination Mg/Zn(OPiv) 2 ·2 LiCl (2). After evaporation of the solvent, the corresponding solid organozinc pivalate 3 a is obtained in 77 % yield.[11] This rate acceleration is essential for tolerating sensitive functional groups. This route is widely applicable and after evaporation of the THF, the resulting solid arylzinc reagents are obtained in 57-84 % yield as easy to handle powders (Scheme 1). This is in contrast to regular zinc reagents which produce only highly viscous oils when the solvents are evaporated.By using this method we have prepared a range of arylzinc reagents bearing electron-donating substituents (3 a-f; FG = Me, OMe, SMe, OTIPS, TMS, OCONEt 2 ; 57-81 %) or electron-deficient substituents (3 g-j; FG = F, CF 3 , CO 2 Et, CN; 59-84 %; Scheme 1). Although the ester-and nitrilesubstituted zinc reagents 3 i and 3 j can be prepared in satisfactory yields (59-64 %) by direct insertion, an improvement has been achieved by using an I/Mg or Br/Mg exchange with iPrMgCl·LiCl followed by transmetalation with Zn(OPiv) 2 ·2 LiCl (2; 72-89 %). [12] Moreover, the solid zinc reagents of type 3 are stable under argon at room temperature for several months without significant loss of activity. Importantly, these zinc compounds can now be weighed in air (95 % of the active zinc specie...