Stereotactic transformation of alkyl borates achieved by direct transmetalation of boron to zinc
Enantiomerically enriched alkylboronic esters are useful building blocks in organic synthesis, as they are typically chemically and conformationally stable and can be prepared by a variety of catalytic and non-catalytic methods. In addition, alkylboronic esters undergo stereospecific transformations, allowing them to be used in the construction of a wide range of nonracemic chiral compounds. Despite these attractive features, alkylboronic esters are weakly nucleophilic compounds and therefore less active in the transmetallation process than other organometallic compounds. Organozinc reagents are more nucleophilic than alkylboronic esters, but they remain conformationally stable.The pioneering studies of Knochel and co-workers demonstrated that secondary alkylzinc reagents can undergo stereospecific translocation to copper and palladium, followed by coupling to electrophilic reagents. Although efficient methods have been reported to synthesize α-amino, α-boronyl, and cyclopropyl organozinc reagents, the preparation of simple enantiomerically rich secondary alkyl zinc compounds remains challenging.
Knochel reported that secondary organoboranes generated by the hydrogenation of olefins could undergo stereospecific transmetallation reactions with diisopropyl zinc, thus providing a route to the synthesis of α-chiral organozinc reagents (Scheme 1a). In subsequent studies, it was found that secondary organoborates could be converted to dimethylborane derivatives by treatment with methylmagnesium chloride; this was then reacted with (iPr)2Zn to produce organozinc compounds. Unfortunately, the latter process occurs with significant isomerization of the carbon stereocenter, probably as a result of the presence of metal halides in the reaction mixture. More recently, Knochel reported stereospecific lithium-iodine exchange followed by treatment with TMSCH2ZnCl-LiBr to produce the corresponding organozinc reagents (Scheme 1b). They also demonstrated that the organozinc reagents thus produced could be used in stereospecific Negishi cross-coupling reactions. In order to extend the range of transformations of organoboron compounds, some scientists have considered the direct translocation reaction of alkyl-activated alkylboronic esters with zinc salts. In a study of the zinc-catalyzed Suzuki-Miyaura reaction (Scheme 1c), Ingleson investigated the associated trans-metalation reaction. They found that the reaction of PhB(Pin)-t-BuLi adducts with zinc bromide rapidly produced diphenylzinc. Recently, Prof. Morken’s group from Boston College published an efficient, rapid, and stereospecific transmetallation reaction to prepare organozinc reagents from readily available pinacol-derived alkyl borates.
More recently, the authors have developed several copper-catalyzed stereospecific transformations of organoborate esters, which are thought to proceed by a simple boron to copper translocation followed by coupling to an electrophile, a process whose success relies on the activation of the otherwise inactive alkylborate ester by alkyl lithium. It was of interest to determine whether similar borate activation might be obtained in other transmetallation processes. Although there is precedent in Falck for s-BuLi-activated primary borate esters, preliminary experiments with Pd-catalyzed Suzuki-Miyaura cross-coupling of secondary borate esters 1 with t-BuLi activation failed to provide the target product (Table 1, entry 1). On the other hand, it was found that the tert-butyllithium-activated borate ester could be effectively consumed by treatment with zinc salts (NMR conversion of 70-98%, reaction time of 12 h) and the corresponding organozinc reagent might be generated. Subsequent addition of palladium catalyst 15 and aryl halides as electrophilic reagents provided the Negishi cross-coupling product in 46-82% yield. Notably, the enantiospecificity of the reaction depended on the identity of the zinc salt and the reaction time: zinc trifluoride and zinc acetate provided high stereospecificity (Table 1, entries 5 and 6), whereas the reaction with zinc mevalonate provided high specificity only when the easy metallization was carried out within a short reaction time (compare entries 7 and 8)
The racemization in the above coupling may occur at any stage of the multistep sequence. To directly explore the stereospecificity of the boron to zinc exchange step, the authors investigated the transmetallation of the isotopically labeled organoboronates 3-syn and 3-anti using in situ NMR spectroscopy (Fig. 1).11B NMR was first used to understand the conditions affecting the transmetallation of 3-syn (Fig. 1a-c). Addition of tert-butyl lithium (δ 35 ppm) to tetrahydrofuran gave a clean boron “salt” complex (δ 10.4 ppm) (Fig. 1a). Subsequent addition of zinc acetate (Fig. 1b) led to depletion of the boronate complex, as determined by a resonance reduction of 10.4 ppm, and the formation of tBuB(Pin) (δ 35.9 ppm) and a compound consistent with a three-coordinated borate ester (δ 55.8 ppm). Heating the reaction mixture to 60°C for 4 h (Fig. 1c) led to the complete conversion of the borate complex and possibly the borate ester to t-BuB(Pin) and presumably the corresponding organozinc metal exchange product.
To determine the stereospecificity of the transmetallation reaction, the above reaction sequences were analyzed by in situ 13C NMR spectroscopy (Fig. 1d-f). As shown in Fig. 1d, the stereoisomeric ratios of the reaction intermediates were readily measured by 13C NMR of integrally labeled carbons, and this ratio reflects the stereospecificity of each transformation as well as the conformational stability of each intermediate. Analysis of the reaction sequence indicated that the organoborate ester (Fig. 1d) could be freely isomerized into the derived borate complex (Fig. 1e), however, the subsequent addition of zinc acetate provided a mixture exhibiting several resonances (not shown), presumably because the alkyl zinc reagent is not homogeneous and is likely oligomeric. Addition of DMSO (50% v/v) to this solution resulted in a homogeneous mixture and a sharper spectrum (Fig. 1f). Although some minor resonances can be observed at the end of the sequence, the resonance corresponding to the 4-syn can be specified by its preparation independently of the 3-syn, and the data indicate a high stereospecificity of the whole process. As shown in Fig. 1g, reactions using zinc acetate or zinc chloride were observed to be stereospecific, suggesting that the racemization observed in Table 1 (i.e., entry 2) likely occurs during zinc-to-palladium exchange. Furthermore, the observations in Figure 1 indicate that the alkyl zinc species itself is conformationally stable, even when held at 60 °C for several hours
After determining good conditions for boron to zinc transition metals, the application of the method was investigated. Available reactions include transition metal-free alkenylation and arylation using alkenyl or aryl lithium reagents. In addition, direct stereospecific Suzuki-Miyaura cross-coupling between non-activated aliphatic secondary organoboron reagents and aryl halides was reported by Biscoe and Sigman (trifluoroborate) and Burke and colleagues. Despite these advances, the scope of these processes is currently being explored primarily through spatially unimpeded alkylboron species (typically α-methyl substituted) and non-heterocyclic aromatic or olefinic coupling partners. To complement these existing approaches, enantiomer-rich organozinc reagents prepared by boron to zinc translocation were examined as coupling partners for stereospecific Negishi cross-coupling reactions (Fig. 2). Fifteen effective coupling reactions were observed using Buchwald’s Pd-G3 complexes bound to CPhos.
Racemic organozinc reagents are known to react with diflocarbine and provide a variety of useful fluorine-containing compounds.2 Because of the ability to obtain enantiomerically rich organozinc compounds prepared as above, it was of interest to determine whether diflocarbine might be inserted in a stereospecific manner. As shown in Figure 3, by modifying the conditions developed by Dilman and coworkers, it was found that organozinc acetate and chloride intermediates reacted with in situ-generated diflocarbine to produce difluoromethyl zinc intermediates.
Liu had already established the trifluoromethylation reaction of primary alkyl zinc and cyclohexyl zinc reagents to give stable PYCu(III)(CF3)3 by translocation/reduction elimination.In this article, the process proceeded smoothly and provided enantiomerically-containing CF3-rich products (Fig. 4). Despite the poor solubility of the feedstock in this system, the best results were obtained by using non-polar hexane as the solvent for the trifluoromethylation reaction.
Several experiments were performed to gain insight into the mechanism of boron to zinc transmetallation. The transient 11B NMR resonance of 55 ppm observed during transmetallation with zinc (OAc)2 (Fig. 1b), based on comparisons with known compounds, could be intervening borate esters, acyloxyboranes, or related compounds. One possible pathway is the dissociation of the pinacol oxygen atom from the boron when the zinc salt is added. Such a process finds precedent in Aggarwal’s study and may provide ring-opening boronic acid esters or derived tethered compounds (i.e., A-C, Fig. 5).
To explore the mediating role of species such as A-C, we examined related structures. In one experiment, pinacol was deprotonated with one equivalent of n-BuLi and then treated with zinc (OPiv)2 (Fig. 6a). The putative ligand-exchange complex was then treated with dicyclohexylborane, and gas release was then observed with the immediate formation of a compound that exhibited an 11B NMR resonance at 55 ppm (suggested as D). Over time, the 55 ppm resonance weakened and a 35 ppm signal appeared, indicating the ability of the initial species to undergo translocation. Interestingly, a 10 ppm signal appeared during the reaction, corresponding to a tetra-coordinated boron complex (E or related). In another experiment (Fig. 6b), Et2B (OPiv) was prepared; it was rapidly consumed at a resonance of 55 ppm (62% conversion at 30 min) and was replaced by a resonance of 35 ppm upon treatment with lithium pinacol and zinc pivalate. Although this experiment suggests that acyloxyboranes may be involved in metal translocation, we note that the 11B NMR resonance of this species is much sharper than that observed in Fig. 1. In summary, these experiments suggest that three-coordinated borates are possible intermediates in the transmetallation process, but they do not rigorously determine whether these species themselves are involved in transmetallation or whether they are noncyclic precursors of reactive tetra-coordinated borates.
In summary, the authors report a stereospecific boron to zinc translocation and show that organozinc compounds can undergo useful stereospecific transformations. Preliminary mechanistic studies suggest that the stereospecific transfer of alkyl to zinc occurs on tetra-coordinated borate complexes. The authors expect that this approach can be used to prepare enantiomerically enriched organozinc reagents and to expand the range of applications for alkyl borates.
