Abstract:The Suzuki–Miyaura (SM) reaction is one of the most important methods for C−C bond formation in chemical synthesis. In this communication, we show for the first time that the low toxicity, inexpensive element zinc is able to catalyze SM reactions. The cross‐coupling of benzyl bromides with aryl borates is catalyzed by ZnBr2, in a process that is free from added ligand, and is compatible with a range of functionalized benzyl bromides and arylboronic acid pinacol esters. Initial mechanistic investigations indica… Show more
“…Interestingly, addition of 3.0 equivalent of LiBr to the reaction of compound 1a with Ph 2 Zn led to full conversion of the starting material and gave the coupled compound 3a in 78% yield with 95.5:4.5 e.r. These experimental results suggest that an anionic zincate [Ph 2 ZnBr] - might be involved in the reaction, consistent with the observation from Ingleson and co-workers 31 that mixing 2.0 equivalents of lithium aryl boronate with ZnBr 2 at room temperature generated an anionic [Ph x ZnBr y ] - ( x + y = 3).Fig. 3Control experiments.…”
Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph
2
ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph
2
ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr
2
was described.
“…Interestingly, addition of 3.0 equivalent of LiBr to the reaction of compound 1a with Ph 2 Zn led to full conversion of the starting material and gave the coupled compound 3a in 78% yield with 95.5:4.5 e.r. These experimental results suggest that an anionic zincate [Ph 2 ZnBr] - might be involved in the reaction, consistent with the observation from Ingleson and co-workers 31 that mixing 2.0 equivalents of lithium aryl boronate with ZnBr 2 at room temperature generated an anionic [Ph x ZnBr y ] - ( x + y = 3).Fig. 3Control experiments.…”
Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph
2
ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph
2
ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr
2
was described.
“…LiO t Bu reacted with the ArBpin reagent to form Li[ArB(pin)O t Bu], as determined by 11 B NMR 19 F NMR spectroscopy of the reaction of these two components alone. This borate was also the major form of the boron reagent in the catalytic system, as determined by the similarity of the 11 B NMR and 19 F NMR resonances of the catalytic reaction to those of the borate generated separately (Scheme c) . The lithium cation in this boronate complex is more loosely bound than that in LiO t Bu and can act as the Lewis acid to catalyze formation of MeI.…”
Section: Resultsmentioning
confidence: 93%
“…This borate was also the major form of the boron reagent in the catalytic system, as determined by the similarity of the 11 B NMR and 19 F NMR resonances of the catalytic reaction to those of the borate generated separately (Scheme 6c). 19 The lithium cation in this boronate complex is more loosely bound than that in LiO t Bu and can act as the Lewis acid to catalyze formation of MeI. Moreover, the alkoxide unit in this borate complex is much less nucleophilic than that in LiO t Bu and does not react with MeI.…”
A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C−H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C−H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether.
“…A mixture of equimolar of benzyl carbonate 1I and benzyl chloride 4A was reacted with phenylboronic acid 5a. When the reaction was conducted under conditions for esters, only carbonate 1I was consumed to form 6Ia; 9 4A remained unreacted. To the contrary, only chloride 4A was consumed under conditions for halides.…”
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