Reactivity of 1,3-enyne MIDA boronates: exploration of novel 1,2-alkyne shift via gem-difluorination

The discovery of a new class of heteroatom-rich boron-containing molecules (BCMs) and iterative cross-coupling (ICC) partners created a toolbox for future drug developments using organoboron compounds. Herein, we report the potential utility of 1,3-enyne MIDA boronates to access diverse gem-difluoro MIDA boronates via novel 1,2-alkyne shift. This unique reactivity of 1,3-enyne MIDA boronates offers facile access to previously challenging β-difluorinated alkyl borons. Furthermore, we demonstrated the synthesis of various novel furan-based BCMs via 5-endo-dig cyclization and iterative coupling partners via copper-catalyzed hydroboration and platinum-catalyzed diboration reaction.


Introduction
Over the last two decades, organoboron compounds have received huge attention from medicinal chemists due to the revolutionary discovery of bortezomib, named Velcade. 1This ground-breaking invention has motivated synthetic chemists to develop a new path to achieve novel heteroatom-rich boroncontaining molecules (BCMs) (Scheme 1a). 2 Indeed, some of the valuable BCMs are difficult to access from the corresponding boronic acid or pinacol esters due to their instability under reaction conditions, which highlights the importance of the MIDA (N-methyliminodiacetic acid) as a protecting group for boron. 3There has been an ongoing interest in synthesizing sp 3 and heteroatom-rich boron-containing molecules via the functionalization of vinyl MIDA boronates. 4Among the various types of heteroatom-rich BCMs, organouorine compounds are extensively utilized in pharmaceuticals, agrochemicals, and materials science, which triggers the chemists to nd a better way to synthesize a novel boron-based uorinated architecture. 5er the subversive discovery of catalytic gem-diuorination of alkene surrogates, 6 some interesting gem-diuorination reactions of vinyl MIDA boronates 7 have been reported over the years (Scheme 1b).The electronic structures of the vinyl MIDA boronates have played an important role in the gem-diuorination using a hypervalent iodine platform. 7The Wang group stated that the 1,2-aryl 7a and 1,2-hydrogen 7b shis have been shown to be the selective initiator for the regioselective gem-diuorination of aryl and aliphatic vinyl MIDA boronates (trans or cis), whereas, for the 1,1-alkyl vinyl MIDA boronates, the Szabó group pointed out that the 1,2-boryl shi 7c was predominant over the 1,2-hydrogen shi (Scheme 1b).While we were preparing the revised version of our manuscript, the Gilmour group reported gem-diuorination of the 1,3-enyne system by introducing novel 1,2-alkyne shi (Scheme 1c). 8However, a similar reactivity using 1,3-enyne MIDA boronates remains undiscovered.First of all, there will be two different pi-systems where the activation can take place.Also, there will be three possibilities for the diuorination of 1,3-enyne MIDA boronates via activating the vinyl boronate ester.It can go via 1,2-alkyne, 1,2-boryl, or 1,2-alkyl shis when we treat with a stoichiometric amount of hypervalent iodine as an oxidant and Py$HF as a uorine source (Scheme 2a).Gratifyingly, we are delighted to introduce the novel 1,2-alkyne shi of 1,3-enyne MIDA boronates during the gem-diuorination, using the stoichiometric hypervalent iodine and Py$HF (Scheme 2a).
Over the years a large number of MIDA-based skeletons have been explored by researchers across the globe for their application in the synthesis of heteroatom-rich boron-containing molecules (BCMs). 4,9However, the reactivity of conjugated MIDA-based boron compounds remains mostly unexplored, which hampers the utility of MIDA-based compounds in organic synthesis.Among the various conjugated MIDA boronates, 1,3-enyne MIDA boronates are one of the most diversifying boron moieties, as it has two types of p-system along with one stable C-B bond, which can be selectively activated to access previously unknown diverse uorinated and heteroatomrich BCMs and conjugated MIDA based iterative coupling partners, which have not been studied before.
Moreover, we have also explored a 5-endo-dig cyclisation of 1,2-boryl alcohol to access novel halofuran-based BCMs (Scheme 2b).Finally, a previously unknown copper catalysed hydroboration and platinum catalyzed diboration of 1,3-diene MIDA-boronate were achieved to synthesize new building blocks for iterative coupling (Scheme 2b).We have not found any previous literature, where copper catalysed hydroboration was reported using vinyl or alkynyl MIDA-boronates.

Results and discussion
Our investigations began with the synthesis of 1,3-enyne MIDA boronates.We hypothesized that the synthesis of 1,3-enyne MIDA boronates can be achieved via the boron-Wittig reaction between propargylic aldehydes or ketones with lithiated geminal boronic esters.Fortunately, we have successfully optimized and explored the stereospecic synthesis of di, tri-, and tetrasubstituted 1,3-enyne boronates using the boron-Wittig reaction followed by the transesterication strategy (detailed optimization and substrate scope of 1,3-enyne MIDA boronates via the boron-Wittig reaction 4a-4s, 5a-5o, and 6a-6i can be found in the ESI pages 2-4 †).Now, our aim is to apply them for the stereoselective and regioselective synthesis of heteroatomrich boron-containing molecules (BCMs) and iterative coupling partners.First, we set our focus on the synthesis of uorine-containing BCMs via selective olen activation.We are interested in determining the reactivity of our 1,3-enyne MIDA boronates in light of the recent literature on gem-diuorination.We hypothesized that the gem-diuorination on 1,3-enyne MIDA boronates might end up with three regioselective products (via 1,2-alkyne, 1,2-alkyl, and 1,2-boryl migrations). 7However, we are surprised to observe the formation of a single gem-diuorinated product under Wang's conditions 7a using PIDA/HF-Py.To test our hypothesis, we employed our 1,3-enyne MIDA boronates 4i using Wang's conditions 7a and observed the formation of 7i (52% yield) without any other regioisomers (Table 1, entry 1).The geometry of 7i emphasized that the product is formed by the regioselective 1,2-alkyne migration.By the systematic screening of the oxidants, the optimised yield of the 1,2-alkyne migration product 7i (59%) was examined.It was discovered that two equivalents of PIDA were required to achieve the optimal yield (Table 1, entry 5).With the optimized conditions in hand, we next explored the scope of the reaction (Scheme 3).We have screened both aliphatic and aromatic 1,3enyne MIDA boronates with good yield and excellent regioselectivity (7a-7g).To check the electronic behaviour of the alkyne moiety, we screened both electron donation (7b) and withdrawing groups (7c, 7d, and 7f) and found that such type of 1,2alkyne shi is more facile in the case of electron withdrawing cores.In the case of strongly electron-rich systems (like 5c and 5m, see ESI page 3 †) the reactions were messy, which might be due to the strong affinity of the alkyne moiety as well as the alkene moiety towards the active catalyst.Similarly, the electronically diverse heteroaryl 1,3-enyne MIDA boronates (7n, 7m) have also not been tolerated under the optimized reaction conditions, which could be due to the same reactivity issue as strongly electron rich systems.To get a clear idea about the migration tendency of alkyne, alkyl, and boryl moieties, we screened both the di-and tri-substituted 1,3-enyne MIDA boronates and observed that the migration tendency of alkyne is higher than that of the alkyl or boryl moiety.To justify our result, we have proposed a novel vinyl carbocation C induced 1,2-alkyne migration mechanism based on the result and literature precedent (Scheme 4). 7First, the intermediate B is delivered by a regioselective vicinal uoroiodination that is sparked by the reaction of the 1,3-enyne double bond and (diuoroiodo) benzene, which was generated in situ from PIDA and Py$HF.Then, the vinyl carbocation species C is formed as a result of the intramolecular nucleophilic attack of the alkyne moiety on the C-I bond.The second regioselective uoride attack results in the ring-opening of C, which is accompanied by the homotopic 1,2-alkyne migration, furnishing a b-diuorinated alkyl boron compound.The higher electrophilicity of the carbon atom linked to a uorine atom could be the cause of this selectivity.This report may be the second of its kind because the 1,2-alkyne migration is still uncommon. 10ext, we explore the potential of 1,2-boryl alcohol (8) by introducing the 5-endo-dig cyclisation strategy. 11Here, we are very much excited to synthesize novel furan based BCMs, from the corresponding 1,2-boryl alcohol (8) by the Lewis acid-catalyzed cyclization and halocyclization (Scheme 5). 12To achieve our goal, we rst attempted the Upjohn dihydroxylation on 1,3-enyne  MIDA boronates.1d,13 The optimized conditions revealed that this dihydroxylation is fully concentration-dependent and the best yield (60%) came out using a 0.1 molar solvent system in a ratio of 18 : 1 : 1 (acetone: t BuOH : H 2 O).Now, we turned our attention to exploring the electrophilic 5-endo-dig cyclization of 1,2-boryl alcohol 8 using iodine and phenyl selenium chloride as an electrophilic source. 12Most importantly, using this strategy we easily accessed borylated halo-and selenofurans (9 and 11), which will further participate in various types of metal-catalyzed coupling reactions.The integrity of the halofuran was conrmed by the X-ray data (9b).Next, we further carried out Lewis acid catalyzed 5-endo-dig cyclization using 10% w/w AgNO 3 -SiO 2 and synthesized C-2 boryl substituted furans (10) with high yield. 12Importantly, this conversion was quantitative and we could not nd any by-product except an equivalent amount of water.With the optimized conditions in hand, we demonstrated the scope of the AgNO 3 -SiO 2 catalyzed 5-endo-dig cyclization with aromatic and aliphatic 1,3-enyne MIDA boronates, which is summarized in Scheme 5.The iodofuran product (9a) can be further derivatized to novel BCMs by employing Heck coupling (9aa), Sonaghashira coupling (9ab), Suzuki coupling (9ac), and [4 + 2] cycloaddition reaction (9ad).Interestingly, we were also able to introduce 5-endodig annulation of 1,3-enyne MIDA boronates by lowering the reaction temperature and synthesizing 2-vinyl 3-iodobenzofuran BCMs (12) with high yield and excellent stereoselectivity.Aer the selective activation of the alkene group, we are interested in activating the alkyne group of 1,3-enyne MIDA boronates for the synthesis of polyborylated-alkenes, which is the ultimate hope for the novel iterative cross-coupling partners. 15Over the last two decades several copper-catalyzed hydroboration and carboboration of 1,3-enyne systems have been known for the synthesis of diverse borylated compounds. 16owever, we have not found any copper catalysed transformations known with either vinyl or alkynyl MIDA-boronates, which could be due to the possible elimination of the MIDA ligand.Based on the previous literature, 16d the regioisomeric preference of hydroboration of 1,3-enyne was totally controlled by the ligand catalysis.As our synthesized 1,3-enyne B(MIDA) compounds are sufficiently crowded over the double bond, we suspect that 1,3-dienylboronates 13a or 13a 0 (via 3,4 or 4,3hydroboration) will be our hydroboration products.Aer this initial understanding, we started our optimization using 5a as a model substrate with B 2 (pin) 2 as a hydroboration coupling partner (Scheme 6).In entry 1, when we employed the Ito hydroboration 16d conditions (5 mol% CuCl, 6 mol% KO t Bu, 6 mol% PPh 3 , THF/MeOH), we ended up with the mixture of 3,4and 4,3-hydroboration products (13a : = 55 : 45) with poor yield.Interestingly, we have not found any 2,1-hydroboration product 13a 00 .Next, we tuned the ligand environment for a better regioselective outcome of 3,4-hydroboration product 13a (for detailed optimization, see ESI pages 6 and 7 †).We screened several monodentate and bidentate ligands, out of them paraanisyl phosphine gave the best (13a : = 75 : 25) regioselective outcome.The lower yield in entries 1 and 2 (Scheme 6) is due to the deprotection of the MIDA protecting group in the presence of 2 equivalents of MeOH solvent. 17To improve the yield, we carried out the reaction using only THF solvent (1 M) and got the expected product in good yield (70%) with the same regioselectivity ratio (entry 3). 18We did not nd any improvement in stereoselectivity by varying other solvent combinations.At this point, we decided to play with solvent concentration. 19The thorough optimization of the solvent concentration revealed that the 3,4-hydroboration is highly regioselective in 0.02 M solvent concentration.Having the optimized conditions in hand, we explored the scope of this hydroboration and found that aryl and heteroaryl 1,3-enyne MIDA boronates were working ne with good yield and diastereoselectivity (13a-13c).Interestingly, when we tested the scope of the aliphatic system (5h), no hydroboration product (13d) was obtained.
this diboration, we screened several polar and non-polar solvents, out of them, THF provided the best yield at 100 °C.We examined the scope of this diboration with aliphatic and aromatic 1,3-enyne MIDA boronates with high yield and diastereoselectivity (14a-14f).The structure of this tri-borylated olen was further conrmed by the X-ray (14d).We have not found a single example, where 1,3-enyne MIDA boronate compounds were successfully employed for the Pt(0)-catalyzed diboration. 21t last, we also extended the scope of the selective olen activation of 1,3-enyne MIDA boronates by applying the epoxidation strategy using m-CPBA, established by the Yudin and Burke group (Scheme 7). 22For the disubstituted 1,3enyne MIDA boronates, we observed only the epoxidation products (15a and 15b) but in the case of tri-substituted 1,3enyne MIDA boronates, we ended up with amphoteric previously unknown quaternary a-boryl aldehydes (16a-16d).In general, the oxiranyl MIDA boronates need to be treated with a Lewis acid for the formation of a-boryl aldehydes. 22owever, we observed one-step access to corresponding quaternary a-boryl aldehydes from the 1,3-enyne MIDA boronates without Lewis acid.We suspect that the difference in reactivity in the case of tri-substituted 1,3-enyne MIDA boronates vs. the di-substituted one is due to the stability of the quaternary propargylic carbocation (E), which can be formed in the presence of 3-chloro benzoic acid, a by-product from the m-CPBA reaction.

Conclusions
In summary, we have explored the novel reactivity of 1,3-enyne MIDA boronates by applying selective olen and alkyne activation strategies.By taking advantage of the unique 1,2-alkyne shi of 1,3-enyne MIDA boronates, a novel gem-diuorinated BCM has been synthesized via the vinyl carbocation intermediate.Notably, the success of this reaction is due to the alkene activation over the alkyne activation.Interestingly, a series of novel furan based BCMs have been synthesized by introducing the electrophilic and Lewis acidic catalyzed 5-endo-dig cyclization.To our delight, we found out the reason for the reactivity difference of substituted and unsubstituted propargyl oxirane MIDA boronates in the case of epoxidation.Finally, we have developed a new series of iterative cross-coupling partners by utilizing the concept of hydroboration and diboration techniques.

Scheme 1 Scheme 2
Scheme 1 Previous work and our state of the art.

Table 1
Optimization of gem-difluorination