Efficient C−B Bond Formation Promoted by N-Heterocyclic Carbenes: Synthesis of Tertiary and Quaternary B-Substituted Carbons through Metal-Free Catalytic Boron Conjugate Additions to Cyclic and Acyclic α,β-Unsaturated Carbonyls

Abstract

Metal-free, nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic α,β-unsaturated carbonyls. Reactions are readily catalyzed by 2.5-10 mol % of a simple N-heterocyclic carbene (NHC). A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. Transformations deliver β-boryl carbonyls bearing tertiary as well as quaternary B-substituted carbons in up to >98% yield. Preliminary studies indicate that, although related Cu-NHC-catalyzed reactions are equally efficient, the metal-free variant is more functional group tolerant; in contrast to the Cu-catalyzed reactions, the metal-free processes proceed readily in the presence of a terminal alkyne and do not promote concomitant diboration of an aldehyde. Representative functionalization of the resulting boron enolates demonstrates the strong influence of the Lewis acidic B of the β-boronate.Development of metal-free catalytic processes is critical to advancement of modern chemical synthesis; such protocols are valuable even in cases where a metal-catalyzed variant is available. The two reaction classes often proceed by mechanistically distinct pathways and can give rise to complementary reactivity and selectivity patterns. It is thus noteworthy that C-B bond formation has remained exclusively in the domain of metal-based catalysis. 1 Pt-, 2 Rh-, 3 Ni-4 and Cu-catalyzed 5 conjugate additions of diborons 6 with unsaturated esters have been disclosed; these transformations are largely or entirely limited to reactions of acyclic substrates E-mail: E-mail: amir.hoveyda@bc.edu. (with achiral and chiral catalysts, respectively). In only three cases is the formation of quaternary B-substituted carbons reported (all with acyclic enones). 4 Herein, we introduce a method for efficient C-B bond formation through transformations that are catalyzed by 2.5-10 mol % of a readily available N-heterocyclic carbene (NHC). Cyclic and acyclic α,β-unsaturated ketones or esters serve as substrates; β-boryl carbonyls with tertiary or quaternary B-substituted carbons are obtained in up to >98% yield. We illustrate that boron conjugate addition under metal-free conditions delivers reactivity and site-selectivity levels not attainable through the use of a Cu-catalyzed variant. 5 NIH Public AccessThe present investigations are based on the principle that a nucleophilic NHC 7 might associate with a Lewis acidic boron of commercially available bis(pinacolato)diboron (1) (Scheme 1). 8 The resulting electronic reorganization 9,10 could lead to activation of the B-B bond, promoting reaction with an appropriate electrophilic site through the general pathway in Scheme 1.To initiate our studies, we subjected cyclohexenone and bis(pinacolato)diboron (1) to a premixed solution of commercially available imidazolinium salt 2 and NaOt-Bu (10 mol % of each) in THF at 22 °C. As shown in entry 1 of Table 1, 66% conversion to the desire...

Metal‐Free Catalytic Boration at the β‐Position of α,β‐Unsaturated Compounds: A Challenging Asymmetric Induction

“…This field has recently been elegantly reviewed by Oestreich and co-workers, [6] and the authors conclude that asymmetric metal-free approaches to conjugate borylation might be the next pioneering step forwards. Hoveyda and coworkers recently reported an efficient metal-free b-boration of cyclic and acyclic a,b-unsaturated carbonyl groups promoted by N-heterocyclic carbenes (NHCs).[7] Mechanistic studies revealed that 10 mol % of carbene alone can activate the diboron reagent, bis(pinacolato)diboron (B 2 pin 2 ), by nucleophilic attack at one of the boron atoms (Scheme 1).After 1,4-addition of the reagent to the substrate the carbene is regenerated, this making the reaction catalytic.Attempts by Hoveyda and co-workers [7] to promote the bboration of 2-cyclohexen-1-one with PPh 3 and PCy 3 as nucleophilic reagents in the absence of a metal were unsuccessful. However, an early example by Hosomi and co-workers [8] showed that PBu 3 could induce slight conversion of benzylideneacetophenone into the b-borated ketone in the absence of the catalyst precursor CuOTf (Scheme 2).…”

“…Hoveyda and coworkers recently reported an efficient metal-free b-boration of cyclic and acyclic a,b-unsaturated carbonyl groups promoted by N-heterocyclic carbenes (NHCs). [7] Mechanistic studies revealed that 10 mol % of carbene alone can activate the diboron reagent, bis(pinacolato)diboron (B 2 pin 2 ), by nucleophilic attack at one of the boron atoms (Scheme 1).…”

Komplexe von N‐heterocyclischen Carbenen mit Boranen: Synthese und Reaktionen

“…[82] Mit Blick auf organokatalytische Reaktionen beobachteten Hoveyda und Mitarbeiter, dass das 1,4-Addukt 109 als einziges Diastereomer gebildet wurde, wenn das Enon 107 mit Bis(pinacolato)dibor (108) und einem in situ erzeugten NHC reagierte (Schema 23). [83] Der NHC-Diboran-Komplex 110 wurde hierbei als Intermediat im Katalysezyklus vorgeschlagen.…”

Title Pages

“…Multicomponent reactions have now been extended to reactions involving five, six or even eight components by the introduction of orthogonal functional groups 39 . Some random highlights deserving a mention include: a site-selective glycosylation of hydroxyketones at the ketone or the alcohol via hydrosilylation 40 ; a transition metal-free reductive C−C coupling of tosylhydrazones and aromatic or aliphatic boronic acids 41 ; N-heterocyclic carbene-catalyzed 1,4-addition-α-hydroxyalkylation of α,β-ethylenecarbonyl compounds with bis(pinacolato)diborane 42 ; a catalytic Wittig synthesis starting from bromides and aldehydes with regeneration of the [cyclic] phosphine using diphenylsilane 43 ; a biocatalytic equivalent of Friedel-Crafts allyl-, benzyl-or propargyl-ation using S-adenosyl-L-methionine and methyltransferases 44 ; and a synthesis of 2-functionalized pyrimidines/quinazolines from cyanic acid derivatives and enacylamines/anilides, providing a route to C2-and C4-substituted compounds 45 . To conclude, it is notable that it is now possible to predict new molecular targets for known drugs computationally 46 ; this involves systematically defining each target by its ligands then looking for chemical similarities with the drugs.…”