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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EMTECS (Electrophile-Mediated Three-Component Enantiospecific Cross-Couplings)

Teaser

Summary

The Suzuki-Miyaura cross-coupling of boronic acids and esters with sp2 electrophiles is one of the most powerful Câ€“C bond forming reactions in organic synthesis. It has found widespread application across the areas of pharmaceutical, agrochemical, and materials science. The importance and impact of this transformation was recognised in 2010 with the Nobel Prize in Chemistry (Scheme 1). Despite its broad utility, the scope of the reaction is narrow with respect to sp3 substituted boronic esters. Except for a few specific and isolated examples, secondary and tertiary boronic esters do not react well with sp2 electrophiles, which limits the application of this reaction in asymmetric synthesis. However, due to the potential power of such transformations, there has been increasing interest in finding alternative strategies that enable stereospecific sp3â€“sp2 cross-couplings.

Recently, the host group developed a metal-free, stereospecific cross-coupling reaction of chiral alkyl boronates with electron-rich aromatics, promoted by the use of electrophilic oxidants (Scheme 2). We plan to substantially extend this cross-coupling chemistry through the application of a range of different electrophiles that will not only mediate the cross-coupling process, but also remain in the final product, creating multiple carbonâ€“carbon bonds stereospecifically (Scheme 3). Through the use of this strategy, we expect to prepare doubly functionalised enantiopure aromatic compounds in a very efficient three-component coupling process that utilises readily accessible enantiopure alkyl boronic esters, electron-rich aromatics and various electrophiles.

Work performed

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 (â€’78 Â°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-carbamoylal

Final results

We developed an enantiospecific trifluoromethyl-radical-induced three component coupling of boronic esters with furans. We believe this method would provide a readily access to enantioenriched trifluoromethylated furans, a motif that has been incorporated into potential drug candidates targeting the treatment of postherpetic neuralgia.

We also found that enantioenriched secondary and tertiary boronic esters can be alkynylated in good yield and with high levels of enantiospecificity by using a protocol involving a Zweifel-type olefination followed by a 1,2-elimination reaction. Owing to the variety of functional groups into which alkynes can be transformed, we believe that this protocol significantly contribute to the realization of a future where most organic molecules could be prepared from boronic ester building blocks and will find wide applications in the area of organic synthesis and pharmaceutical industry.