Divergent Elementoboration: 1,3‐Haloboration versus 1,1‐Carboboration of Propargyl Esters

Abstract This work showcases the 1,3‐haloboration reaction of alkynes in which boron and chlorine add to propargyl systems in a proposed sequential oxazoliumborate formation with subsequent ring‐opening and chloride migration. In addition, the functionalization of these propargyl esters with dimethyl groups in the propargylic position leads to stark differences in reactivity whereby a formal 1,1‐carboboration prevails to give the 2,2‐dichloro‐3,4‐dihydrodioxaborinine products as an intramolecular chelate. Density functional theory calculations are used to rationalize the distinct carboboration and haloboration pathways. Significantly, this method represents a metal‐free route to highly functionalized compounds in a single step to give structurally complex products.

Abstract: This work showcasest he 1,3-haloboration reaction of alkynesi nw hich borona nd chlorine add to propargyl systems in ap roposed sequential oxazoliumborate formation with subsequent ring-opening and chloride migration.I na ddition, the functionalization of these propargyl esters with dimethyl groups in the propargylic position leads to stark differences in reactivity whereby a formal 1,1-carboboration prevails to give the 2,2-dichloro-3,4-dihydrodioxaborinine products as an intramolecular chelate.D ensityf unctional theory calculations are used to rationalize the distinctc arboborationa nd haloboration pathways. Significantly, this method represents am etalfree route to highly functionalized compoundsi nasingle step to give structurally complex products.
Although as ignificant amount of research has focused on the sterically encumbered, strong Lewisa cid, B(C 6 F 5 ) 3 ,a sw ell as others of as imilar nature, [13] other commercially available boranes have seeminglyb een absent from recent studies. Hence, this work aims to reinvigorate the use of such boranes in ar ange of synthetically imperative transformations.
Herein, we show how subtle adaptations to the alkyne starting material can dramatically alter the reactivity with the borane reagent to give the stereoselective trans-product of a formal 1,3-haloboration, or alternatively ac omplex 1,1-carboboration mechanism to yield as table dichlorodihydrodioxaborinine heterocycle all in very good to excellent conversions. Importantly,t hese reagents are then well positioned to undergo further functionalization such as cross-couplings [14] or allylations. [15] Initial investigations of the commerciallya vailable PhBCl 2 used the model substrate 1a in a1 :1 stoichiometric ratio to yield as ingle product in near quantitative yields as observedu sing in situ multinuclear NMR spectroscopy.D etailed NMR spectroscopy (HSQC, HMBC) revealed the proposed structure of 3a,w hich interestinglyi st he product of af ormal 1,3-haloboration reaction. These encouragingi nitial results then led us to expandt he substrate scope to as eries of phenyl substituted propargyl esters ( Figure 1, Scheme 2). It was observed that in most cases the target haloboration product could be clearly identified with conversionsg reater than 95 % at ambient temperature with reactiont imes of 8h (3a), 18 h(3b,c), and 48 h( 3d).
Fortunately,t he storageo fasaturated CH 2 Cl 2 / hexane solution of 3c at À40 8Cp roduced ac rop of crystalss uitable for X-ray diffraction. The structure was unambiguously determinedt ob ei ndeed the product of af ormal 1,3-haloboration agreeing with spectroscopic analyses (Figure 2). Metricso ft he solid-state structure are as expected with the stereochemical conformation being determined as the trans product. Earlier work by Erker showcased the ability of vinylboranes to undergo photoinduced interconversion between the E/Z conformers upon exposure to UV light; [16] thus, it was hoped similarr eactivity could be observed here to yield the intramolecular chelate. However, no such speciesc ould be detected in the 11 BNMR post-irradiation, leaving the spectra identical to that of the non-irradiated product 3.
To gain some insight into the proposed mechanism,i sotopic labeling studies werep erformed. The terminal position of the alkyne was deuterated selectively using an amine appended resin (WA50) in accordance with the literature. [17] Tracking the reactionp rogress using both 1 Ha nd 2 HNMR spectroscopy whilst comparing the in situ data of the protic versus deuterated compounds shed light on the fate of the terminal alkynyl hydrogen atom and hence the reactionm echanism (see below,S cheme4). A 1 Hr esonancea td = 6.6 ppm is observed in 3a for the proton on the carbon adjacent to boron, whichi s evidently absent in 3a D (Figure 2). Additionally,f ollowing the Scheme2.Reactionbetween PhBCl 2 and 1 to give 1,3-haloboration products 3.V alues are given as in situ NMRc onversions. Solid-state structure of compound 3c,C:grey,H:white, N: blue, O: red, B: yellow-green, Cl:green.Thermal ellipsoidsshowna t5 0% probability (inset). HNMR spectra of the reactions using 1a and 1a D clearly shows the alkyne resonance at d = 2.5 ppm diminishing in intensity with the commensurate appearance of the previously identified new resonance at d = 6.6 ppm.
Furtherd erivatization of the starting materials to include methyl groups in the propargylic position was undertaken to yield compounds 2a-2c (Figure 1). Upon exposure of 2 to a stoichiometric amount of PhBCl 2 ,n ew resonances in the 1 H and 11 BNMR spectra were noted after 8hat 45 8C, which, interestingly, were not consistentw ith the 1,3-haloboration products 3 from reagents 1.I ndeed,abroad singlet resonance was observedi nt he 1 HNMR spectrum at ca. d = 3.8 ppm alongside as harp singlet resonance in the 11 BNMR spectrum at ca. d = 8ppm indicating the formation of ac helating dioxaborinine type structure as seen in Scheme 3. This was further expounded by means of the 13 CNMR spectra with the presence of a new sp 3 carbon adjacent to boron presenting ar esonancea t ca. d = 40 ppm versus 120 ppm for the adjacents p 2 carbon in 3.S toring 4a-c as as aturated CH 2 Cl 2 /hexane solution produced an umber of colorlessc rystals suitable for X-ray diffraction, whichi ndeed determined the moleculars tructure to be the product of af ormal1 ,1-carboboration reaction ( Figure 3). Of particular note is the regioselectivity of this reaction with the product predominating as the selective transfero ft he aryl group over the chloride fragment. [18] This migration pattern could be confirmed once again through detailed 2D NMR spectroscopy to affirmt he molecular connectivity revealed in the solid-state structure (see the Supporting Information).
When comparing the divergente lementoboration observed here, it is proposed that the inclusion of non-H groups in the propargylic position must play ac riticalr ole in which pathway is undertaken in this reaction.M echanistically we proposet hat an initial 1,2-trans-oxyboration step occurs to yield the zwitterionic dioxolium borate. [19] During the formationo ft his 5-membered dioxoliumi ntermediate (I,S cheme 4), when simple hydrogen atoms occupy the R 2 position, the formation of 3 is slightly more favorable compared to when methyl groups are included in the R 2 position. Conversely,i fmore bulky methyl groups are included, then the chloride migration pathway is less favored over 1,2-aryl group migration resulting in the generation the intramolecular chelate 4.T hese experimental findings are supported through in silico studies (see below and the Supporting Information). Additionally,w hen using compound 5,w hich features ac ombination of Ha nd Me in the propargyl position, am ore complex transformation is observed when monitoring the reaction coordinate over time. Analyzing Scheme3.ReactionbetweenP hBCl 2 and 2 to give 1,1-carboboration products 4.Y ieldsa re given as isolated yields. the in situ 1 Ha nd 11 BNMR spectra suggests that, after initial combination of PhBCl 2 with 5 in a1 :1.2r atio, the haloboration product 6 prevails, as observed by the characteristicb road singlet at d = 6.35 ppm alongside the formation of ar esonance at ca. d = 5.2 ppm for the proposed vinyl and methylenep rotons, respectively (see the Supporting Information). Over time, these resonances reduce in intensity giving way to an ew broad singlet at d = 3.36 ppm, consistent with the generation of the proton in the adjacent to the borane in the chelating structure 7.I na ddition, new resonances appear for the newly formed vinyl protonq uartet at d = 5.45 ppm, and the methyl doublet at d = 1.90 ppm. This assertion is bolstered when observing the in situ 11 BNMR spectra over time whereby the expected singlet at about d = 55.1 ppm formsa fter 1h at ambient temperature, which reduces in intensity over time yielding another singlet resonance at ca. d = 9.1 ppm, again indicating the reversible formationof6 en route to 7 (Scheme 5).
To shed light on the divergent reactivity realized in this work, DFT calculations were performed. The reactionp athways for haloboration (upper) and carboboration (lower) are displayed in Figure 4. Pleasingly,t he formation of products 3 and 4 proceeds in line with the proposed Scheme 4v ia the key dioxolium intermediate I.O nce the intermediate I is formed, chloridem igration is the transition state for the haloboration reactiona nd phenyl migration is the rate-determining transition state for the carboboration reaction.I ti sc lear from Figure 4, upon comparison of the pathways, that carboboration (R 2 = Me) is strongly thermodynamically preferred over haloboration (R 2 = H). Intriguingly,h owever, we found that the hypothetical carboboration product (see the Supporting Information, Ta ble S1)f or R 2 = Hi s> 30 kcal mol À1 more stable than the R 2 = Hh aloboration product obtained experimentally,r aising the question:w hy does the carboboration reactionn ot occur for R 2 = H?
After 1,2-trans-oxyboration and formation of the intermediate dioxolium intermediate I,t wo pathways are available: 1) chloride migration that resultsi nametastable haloboration product or 2) phenyl migration that yields the thermodynamically favored carboboration product. The carboboration reaction of 1a is disfavored for two reasons: first, followingt he kinetically favored pathway,c hloride migration occursy ielding the haloboration product and reversion back to the dioxolium I is strongly hindered by ah igh reverse barrier( DG gas = + 28.9 kcal mol À1 )f rom the product. Second, in order to yield the carboboration product from I,aprohibitively large barrier for phenyl migration (DE gas =+37.20 kcal mol À1 )m ust be overcome (see the Supporting Information, sections 3.2. 3 and 3.2.4). For comparison, the phenyl migration barrier for compounds 2a (R 2 = Me) is 9kcal mol À1 lower than for 1a (R 2 = H). Hence, for 1a (R 2 = H), the kinetically favored haloboration product is formed. Conversely,t he haloboration product of 2a Scheme4.Proposed mechanism for the divergent elementoborationo f1 and 2 using PhBCl 2 .
Intriguingly,i nl ine with the observed reversible behavioro f the mono-methylate 5 to form haloboration product 6 and then the carboboration product 7 (see Scheme 5), calculations show ar everse barrier from the product of DG gas =+25.8 kcal mol À1 ,w hich is intermediate between those found for R 2 = H and R 2 = Me and an intermediate barrier for phenylm igration of DE gas =+29.2 kcal mol À1 .H ence, according to mechanistic and energetic considerations, the mono-methylate should form am ore kinetically stable haloboration product than bimethylate and is therefore more likely to be isolable under comparable reactionc onditions, exactly in line with our findings. The phenyl migration barrier is lower for R 2 = Me, Ht han R 2 = H, so the carboboration product is more likely to be isolable, again in agreement with our observations in Scheme5. These findings show that 3 and 6 are more kinetically stable than the haloborated product of 2a (R 2 = Me), explaining why both 3 and 6 are observed. The relatively low barriers for phenylm igration to form 4 and 7 with the strongt hermodynamic driving force explain why the carboboration products occur for R 2 = Me and R 2 = Me, H. Overall, these calculations reveal ar emarkably subtle interplay of kinetic and thermodynamic factors that are acutely sensitive to the R 2 groups and which causeprofoundly different reaction products.
In summary,t his work has shown both the formal 1,1-carboboration as well as formal 1,3-haloboration of alkynes can occur through simple tuning of the alkyne starting material being used. All of these multi-step reactions proceed cleanly with high conversionsa nd yields being noted in ao ne-pot, atom efficient manner,g arnering synthetically useful and functionally diverse compounds for further reactivity.Indepth computational studies have helped elucidate the proposed mechanism that differentiates this divergentelementoboration.