UC Santa Cruz

Grignard reagents react with one equivalent of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane, HBpin) at ambient temperatures in tetrahydrofuran (THF) to afford the corresponding pinacol boronate esters. Initially formed trialkoxy alkyl borohydride intermediate quickly eliminates hydridomagnesium bromide (HMgBr) and affords the product boronate ester in very good yields. Hydridomagnesium bromide, in turn, disproportionates to a 1:1 mixture of magnesium hydride (MgH2) and magnesium bromide (MgBr2) on addition of pentane to the reaction mixture. This reaction can also be carried out under Barbier conditions where the neat HBpin is added to the flask prior to the in situ formation of Grignard reagent from the corresponding organic halide and magnesium metal. Pinacolboronate ester synthesis under Barbier conditions does not give Wurtz coupling side products from reactive halides, such as benzylic and allylic halides. Both di- and trihaloaryl species as well as dihalo heteroaryl species can also be used to produce the corresponding arylboronate esters under Barbier conditions with HBpin. The reaction between HBpin and various Grignard reagents is an efficient, mild, and general method for the synthesis of pinacolboronate esters.

Diisopropylaminoborane (BH2-N(iPr)2) is prepared by reacting lithium diisopropylaminoborohydride (iPr-LAB) with trimethylsilyl chloride (TMSCl). Aliphatic, aromatic, and heteroaromatic (diisopropylamino)boranes are readily synthesized at ambient temperature (0 °C) in 1 hour by the reaction of Grignard reagents with BH2-N(iPr)2. Two contending reaction pathways have tentatively been identified. In one pathway, HMgBr acts as the leaving group from the initially formed bromomagnesium organo(diisopropylamino)borohydride, affording the product organodiisopropylaminoborane (RBH-N(iPr)2). The increased sterics and the diminished Lewis acidity of RBH-N(iPr)2 prevents it from further reacting with Grignard reagents. In the second pathway, the product may be formed by a hydride transfer from bromomagnesium organo(diisopropylamino)borohydride to the starting material BH2-N(iPr)2. It was found that only 1.2 equivalents of BH2-N(iPr)2 was required for greater than 95% conversion to the organo(diisopropylamino)borane. Simple acid hydrolysis of the product organo(diisopropylamino)borane leads to the corresponding boronic acid in good to excellent yield.

Functionalized arylzinc halides can be prepared by the direct insertion of zinc to functionalized arylzinc halides (ArZnX) mediated by lithium chloride (LiCl) in THF under refluxing conditions. LiCl is hypothesized to increase reactivity of the Zn surface through solvation of surface-bound ArZnX species, exposing a larger surface area of reactive Zn metal. The corresponding ArZnX species is capable of forming arylpinacolboronate esters from HBpin in low yields. HBpin is incompatible with LiCl in THF, as the Li+ ion is suspected to strongly coordinate to the oxygen atoms of Bpin and weaken the B-O bonds. Functionalized arylzinc iodides can also be prepared under catalytic conditions using cobalt bromide (CoBr2) and Zn dust activated by TMSCl and 1,2-dibromoethane in acetonitrile. Subsequent reaction with HBpin is capable of forming the corresponding boronate ester in low yields. The complication with using HBpin is the coordination and side reactions that occur between HBpin and acetonitrile. The use of other solvents, such as THF, is not compatible with CoBr2. The reaction also leads to reduction of the ArZnX as well as homocoupling to form Ar-Ar species. While producing lower yields of boronate esters, this presents a proof of concept for the possible use of other boron sources with these systems.

Iodine also reacts with pinacolborane at ambient reaction conditions in THF to form the iodoalkoxy borate species (4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (IboxBpin). One equivalent of iodine and HBpin react to form IBpin, which then interacts with 4-, 5-, or 6-membered cyclic ethers by cleavage of one ether bond to form the corresponding iodoalkoxy pinacolborate. Treatment with aryl Grignard reagent reacts with one of iodoalkoxy pinacolborate in THF to form the corresponding aryl pinacolboronate ester while reforming and liberating THF as a leaving group.