JACS: Boron and Lithium, Synthesis and Application of Chiral Secondary Alkyl Zinc Reagents
Enantiomerically enriched alkyl borates are a valuable building block in organic synthesis. They are typically chemically and conformationally stable and can be prepared by a variety of catalytic and non-catalytic methods. In addition, alkylboronic esters, upon stereospecific transformation, can be used to construct a range of non-racemic chiral compounds. However, alkylboronic esters are weakly nucleophilic reagents that are less reactive when involved in transmetalation compared to other organometallic compounds. Compared to alkylborates, organozinc reagents are more nucleophilic and conformationally stable, and in 2000, Knochel’s group (Angew. Chem., Int. Ed. 2000, 39, 4414.) reported for the first time that secondary alkylzinc reagents can be stereospecific-transmetalated with copper and palladium. transmetalation) with copper and palladium followed by coupling reactions with electrophilic reagents. Currently, although chemists have developed a series of effective strategies for the enantioselective synthesis of α-amino, α-boronyl, and cyclopropyl-substituted organozinc reagents, the synthesis of enantiomerically enriched secondary alkyl zinc compounds remains challenging. Download the Chemistry Plus App to your phone for greater convenience and more rewards.
In 1998, Knochel’s group (Synlett 1998, 1998, 1438.) reported that a secondary organoborane generated by the borohydration of an olefin could be stereospecifically transmetalated with diisopropylzinc, which led to the synthesis of an α-chiral organozinc reagent (Scheme 1a). in 2020, Knochel’s group (Angew. Chem., Int. Ed. 2020, 59, 320.) reported a stereospecific lithium-iodine exchange reaction followed by treatment with TMSCH2ZnCl-LiBr to generate the corresponding organozinc reagent (Scheme 1b). 2017, Ingleson’s group (Chem. Eur. J., 2017, 23, 15889.) reported the synthesis of α-chiral organozinc reagents (Scheme 1b). 2017, 23, 15889.) reported a strategy to generate diphenylzinc using PhB(pin)-t-BuLi adducts with zinc bromide (Scheme 1c). Recently, James P. Morken’s group at Boston College reported the synthesis of a series of chiral secondary alkyl zinc reagents using tBuLi to achieve activation of chiral secondary organoborate esters, which in turn can be subjected to stereo-retentive transmetallation reactions with zinc acetate or zinc chloride
First, the authors carried out a screening of the relevant reaction conditions using the borate derivative 1 as a model substrate (Table 1). When the chiral secondary organoborate ester was activated using tBuLi (1.0 eq.), followed by a stereospecific transmetalation reaction with Zn(OAc)2 (1.05 eq.), a chiral secondary alkyl zinc reagent could be generated. Subsequently, when [Pd-G3] (0.5 mol%) was used as a catalyst, CPhos (2.0 mol%) as a ligand, and LiCl (1.05 eq.) as an additive, the alkyl zinc reagent could be reacted with ArBr (1.20 eq.) in a mixed solvent of THF/toluene for 12 h at room temperature to afford the product 2 in 82% yield, with an er of 95:5 and an es of 98%.
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(Image credit: J. Am. Chem. Soc.)
Next, the authors investigated the reactivity and stereospecificity of B-to-Zn transmetallization by in situ 11B and 13C NMR (Figure 1). The results showed that the reaction was stereospecific when using zinc acetate or zinc chloride. Meanwhile, racemization may occur in the transmetallization of zinc to palladium. Moreover, the alkyl zinc complexes themselves are conformationally stable.
After obtaining the optimal reaction conditions described above, the authors extended the range of substrates for the electrophilic reagents (Figure 2). It was shown that a series of aryl halides, heteroaryl halides, as well as alkenyl halides, could be successfully reacted to obtain the
corresponding products 2-16 in yields of 40-78% with er of 91:9-96:4 and es of 91->98%.
Meanwhile, after the optimization of the reaction conditions, the organozinc reagent could first react with difluorocarbene, followed by further iodolysis to obtain difluoroiodomethyl derivatives (Figure 3). The results of substrate screening showed that a series of secondary organoborate esters, all of which could be successfully reacted to obtain phase
