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Reductive Α-Borylation of Α,Β-Unsaturated Esters Using NHC Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Reductive a-borylation of a,b-unsaturated esters using NHC–BH3 activated by I2 as a metal-free Cite this: Chem. Sci.,2019,10,1434 a † All publication charges for this article route to -boryl esters have been paid for by the Royal Society of Chemistry James E. Radcliffe, Valerio Fasano, Ralph W. Adams, Peiran You and Michael J. Ingleson * Useful a-boryl esters can be synthesized in one step from a,b-unsaturated esters using just a simple to access NHC–BH3 (NHC ¼ N-heterocyclic carbene) and catalytic I2. The scope of this reductive a-borylation methodology is excellent and includes a range of alkyl, aryl substituted and cyclic and acyclic a,b-unsaturated esters. Mechanistic studies involving reductive borylation of a cyclic a,b-unsaturated ester with NHC–BD3/I2 indicated that concerted hydroboration of the alkene moiety in the a,b-unsaturated ester proceeds instead of a stepwise process involving initial 1,4-hydroboration; this is in contrast to the recently reported reductive a-silylation. The BH2(NHC) unit can be transformed into Creative Commons Attribution 3.0 Unported Licence. electrophilic BX2(NHC) moieties (X ¼ halide) and the ester moiety can be reduced to the alcohol with the borane unit remaining intact to form b-boryl alcohols. The use of a chiral auxiliary, 8-phenylmenthyl Received 27th September 2018 ester, also enables effective stereo-control of the newly formed C–B bond. Combined two Accepted 17th November 2018 step ester reduction/borane oxidation forms diols, including excellent e.e. (97%) for the formation of DOI: 10.1039/c8sc04305a S-3-phenylpropane-1,2-diol. This work represents a simple transition metal free route to form bench rsc.li/chemical-science stable a-boryl esters from inexpensive starting materials. Introduction multi-step nature and oxidising conditions indicate that there is This article is licensed under a a need for other routes. This is particularly the case if the new Organoboranes are ubiquitous in synthetic chemistry due to the a-boryl carbonyls use boron protecting groups complementary wide range of C–Y(Y¼ C, N, O, etc.) bond forming reactions that to MIDA (in terms of stability/reagent compatibility). can be carried out using these species.1,2 To this end, the Open Access Article. Published on 19 November 2018. Downloaded 9/30/2021 5:56:39 PM. discovery of new C–B bond forming reactions remains of importance and topical interest. The ability to form a-boryl carbonyl compounds is desirable as they are functionality rich amphoteric molecules that contain nucleophilic organoborane and electrophilic carbonyl moieties. Until recently, these compounds were largely overlooked in synthetic endeavours due to their instability with respect to formation of the O-boron enolate isomer. However, this has started to change in the last decade due to the quaternized at B stabilization approach which has enabled access to stable (with regard to C / O boryl migration) a-boryl-carbonyls thereby facilitating a range of subsequent transformations.3,4 MIDA-protected (MIDA ¼ N- methyliminodiacetate) a-boryl carbonyls are the most explored to date and are accessed by a hydroboration–oxidation- rearrangement procedure (Scheme 1a).3,4 While notable, the School of Chemistry, University of Manchester, Manchester, M13 9PL, UK. E-mail: [email protected] † Electronic supplementary information (ESI) available: Full synthetic methods and characterization details (.PDF), computational details (.xyz) and crystallographic data (.cif). CCDC 1864774–1864779. For ESI and crystallographic data in CIF or Scheme 1 Previous main routes to quaternized a-boryl carbonyls and other electronic format see DOI: 10.1039/c8sc04305a this work. 1434 | Chem. Sci.,2019,10,1434–1441 This journal is © The Royal Society of Chemistry 2019 View Article Online Edge Article Chemical Science In notable previous work, the use of base-stabilized boranes that on appropriate activation NHC–boranes can react with p a 18 and -diazo carbonyls enabled catalysed formation of alterna- nucleophiles in an analogous manner to silanes/B(C6F5)3. a – tive (to MIDA) quaternized at boron -boryl carbonyls (Scheme Therefore we hypothesised that NHC BH3, upon activation, will 5,6 – a b 1b). In this area Curran et al. pioneered the use of NHC BH3 react with , -unsaturated esters to generate NHC-stabilized (NHC ¼ N-heterocyclic carbene) compounds to afford a-boryl a-boryl esters (Scheme 1d). Herein, we demonstrate that 7,8 carbonyls under transition metal or I2 catalysis. Base stabi- a wide range of a,b-unsaturated esters undergo highly selective lised a-BH2-carbonyl products are bench stable and stable to reductive a-borylation using a simple NHC–BH3 compound and 5,6 strong bases/nucleophiles, and thus are complementary to catalytic I2 as an activator. This represents a facile, metal free MIDA-boronates which while being bench/acid stable are route to bench stable a-boryl-esters (including quaternary sensitive to strong bases.9 In comparison, a-Bpin esters and organoborane and diastereoselective examples) that are amides (produced via a novel Cu catalyzed 1,4-hydroboration/ amenable to further functionalisation, for example to afford isomerization process) are not bench stable and are highly enantiopure diols. sensitive to protodeboronation due to their non-quaternized at 10 a B nature. Base stabilised organoboranes, including -BH2- Results and discussion esters, can be utilised in a range of functional group trans- formations including the Suzuki–Miyaura reaction on appro- This work commenced with the assessment of the relative priate activation.5–11 However, the current synthetic approaches stability of the O- and C-boron bound isomers derived from a to base stabilised -BH2 carbonyls generally require diazo reductive borylation of a,b-unsaturated carbonyls using NHC– a compounds (of which extremely limited examples are BH3. Notably, previous work calculated that -boryl esters are commercially available), precluding the formation of quater- thermodynamically favored compared to the O-boron enolate nary a-boryl carbonyls, while their more hazardous nature isomer when the boron moiety is B(diol), whereas when it is provides an additional drawback. Very recently, Zhu and co- BMe2 the two isomers are effectively isoenergetic (DG < a À1 Creative Commons Attribution 3.0 Unported Licence. workers demonstrated that -boryl carbonyls also can be 1 kcal mol ). The BMe2 analogue is more Lewis acidic at boron accessed by gold-catalysed oxidative coupling of terminal and thus also had a low energy barrier to interconversion alkynes with Lewis base–borane adducts (Scheme 1c), while between the O- and C-boron bound isomers.19 Reductive bor- a 12 notable this is limited to forming primary -boryl carbonyls. ylation will require electrophilic NHC–BH2Y(Y¼ I, NTf2 etc.) Therefore the formation of a wide range of bench stable a-boryl- species, which will possibly form NHC–BHY(R) on reaction with a b – carbonyl derivatives in one-pot from simple starting materials , -unsaturated esters before hydride transfer from NHC BH3 without using transition metal catalysis was an unsolved occurs.20,21 Thus it was feasible that there would be a low barrier problem before this work. to interconversion between O- and C-BH2(NHC) bound isomers An attractive route to a-boryl carbonyls that is the focus of mediated by NHC–BHY(R). In this case the relative stability of This article is licensed under a this work is 3,4-hydroboration of a,b-unsaturated carbonyls, the two isomers would dramatically affect the product distri- where the boryl group is selectively added at the 3 position, bution. Calculations therefore were carried out at the M06-2X/6- a termed reductive -borylation (Scheme 1d). While the reductive 311G(d,p) level with a CH2Cl2 solvation model (polarizable b-borylation of a,b-unsaturated carbonyl species has been re- continuum model, PCM). The a,b-unsaturated carbonyls Open Access Article. Published on 19 November 2018. Downloaded 9/30/2021 5:56:39 PM. ported,13,14 we are aware of no previous examples of selective analyzed were butenal, pentenone, 2,2-dimethylhexenone, N,N- reductive a-borylation of substrates such as cinnamates and dimethyl buteneamide and methyl crotonate (Scheme 3). The – crotonates. It should be noted that NHC BH3 can reductively NHC–borane adduct used was IMe–BH3 (IMe ¼ 1,3-dimethyl- borylate strong Michael acceptors (Mayr E values > À18); imidazol-2-ylidene), as it is the smallest and most readily 12 however, the direct reaction between NHC–BH3 and a,b-unsat- accessed NHC–borane. For the ketones and aldehydes it was urated carbonyl derivatives that are weaker Michael acceptors found that the O-boron enolates were favored over the a-boryl does not proceed (ethyl cinnamate has an E value of À24.5 for carbonyl isomers. In contrast, it was found that for the ester and example, Scheme 2).15 Furthermore, the catalysed hydro- amide substrates, the a-boryl carbonyl products were more À boration of a,b-unsaturated carbonyl compounds using stable (by 12.1 and 7.8 kcal mol 1, respectively). Based upon common boranes (e.g. CatBH and PinBH) proceeds via 1,4- these ndings we investigated the borylation of unsaturated 16 hydroboration. Recently, the Chang group reported the esters and amides using NHC–BH3/activator. reductive a-silylation of a,b-unsaturated carbonyls, using 17 silanes/B(C6F5)3. Previous work from some of us has indicated Scheme 2 Previous work on reductive borylation of Michael accep- Scheme 3 Calculated relative energies of O- and C-BH2(IMe) bound tors using NHC–BH3. isomers. This journal is © The Royal Society of Chemistry 2019 Chem. Sci.,2019,10,1434–1441 | 1435 View Article Online Chemical Science Edge Article For reaction optimisation IMe–BH3 and I2 were selected due to their low cost (or simple synthesis), ease of handling (IMe– BH3 is bench stable) and facile reactivity to give electrophilic – 7,20,21 – IMe BH2I.
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