1. Enantiospecific Trifluoromethyl-Radical-Induced Three Component Coupling of Boronic Esters with Furans
Initially we investigated the proposed three-component coupling reaction using iodoniums and transition metal catalysts. As shown in Scheme 4, the main product we observed is the direct coupled product of furan and aryl group from iodonium, which indicates the direct transmetalation of furanyl from boronate complex to Pd(II) species is more preferential than desired SEAr process. We then tried some other electrophiles under transition metal free conditions to mediate this three-component coupling. Fortunately, these reactions work well and give the desired intermediates in good yields (Scheme 5).
We then focused on using trifluoromethyl-based electrophiles because this group has found widespread utility in pharmaceuticals, endowing molecules with more attractive levels of bioavailability and membrane permeability relative to the hydrocarbon-based parent compounds. Indeed, new methods to introduce the trifluoromethyl group have received considerable attention in recent years. We recognized the potential application of electrophilic trifluoromethylation in our proposed three-component coupling reaction, which would provide access to enantioenriched trifluoromethylated furans, a motif that has been incorporated into potential drug candidates targeting the treatment of postherpetic neuralgia (Scheme 6).
We found that in the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2-lithio furan and non-racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three-component coupling to give the corresponding 2,5-disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2-metallate rearrangement upon single-electron oxidation (Scheme 7). The proposed mechanism is shown in Scheme 8.
In addition to electrophilic trifluoromethylation reagents, we found that other electrophiles can also be applied in the three-component coupling reaction (Scheme 9). For example, the addition of the tropylium cation to a boronate complex led to an enantiospecific transformation into the desired 7-furanyl cycloheptatriene derivative, a member of a class of compounds that have recently found new applications in the generation of gold carbenes. Additionally, treatment of boronate complexes with 1,3-benzodithiolylium tetrafluoroborate gave the desired adducts in good yields.
2. Enantiospecific Alkynylation of Alkylboronic Esters
As shown below, we report the development of an alkynylation protocol that enables the enantiospecific transformation of structurally diverse secondary and tertiary pinacolboronic esters into terminal and internal alkynes.
Using the optimized conditions, we converted a variety of enantioenriched secondary boronic esters into their corresponding alkynyl derivatives (Scheme 11). The transformation occurred cleanly in the presence of cyclopropyl, alkene, azide, electron-rich aryl, silyl ether and tBu ester functional groups and showed essentially complete enantiospecific. The alkynylation protocol was also successfully applied to hindered boronic ester derived from menthol.
The alkynylation of tertiary boronic esters proved to be more challenging. Presumably, the increased steric hindrance close to the boron atom slows both vinyl boronate formation and subsequent electrophilic activation, thus allowing decomposition of the vinyllithium reagent and 1,2-migration of the vinyl boronate to become competitive. In an effort to slow these side reactions, we investigated the use of vinyl carbamate in place of vinyl bromide. Indeed treating a THF solution of vinyl carbamate and tertiary boronic esters with LDA (‒78 °C, 1 h) followed by I2/MeOH gave the 1,1-O-carbamoylalkylalkene in excellent conversion. The alkynes were obtained by treating the 1,1-O-carbamoylalkylalkene with tBuLi in high yields (Scheme 12). Other enantioenriched tertiary boronic esters including alkene-bearing, diaryl and non-benzylic substrates were converted into their alkyne derivatives in very good yield and with complete enantiospecificity. Additionally, sterically hindered secondary boronic esters, such as cyclopropyl substrate and cholesterol derivative, which gave low to moderate yields by using vinyl bromide as the reagent, were transformed into the corresponding alkyne derivatives in very good yield and enantio-/diastereospecificity by using the vinyl carbamate protocol. Pleasingly, double alkynylation of 1,2-bis(boronic ester) could also be achieved to give 1,2-diyne in high yield and high enantiospecificity.
