Amine Catalysis for the Organocatalytic Diboration of Challenging Alkenes.

The generation of in situ sp2 -sp3 diboron adducts has revolutionised the synthesis of organoboranes. Organocatalytic diboration reactions have represented a milestone in terms of unpredictable reactivity of these adducts. However, current methodologies have limitations in terms of substrate scope, selectivity and functional group tolerance. Here a new methodology based on the use of simple amines as catalyst is reported. This methodology provides a completely selective transformation overcoming current substrate scope and functional/protecting group limitations. Mechanistic studies have been included in this report.

Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds.

The stereospecific cross-coupling of secondary boronic esters with sp(2) electrophiles (Suzuki-Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel-Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C-C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp(2))-C(sp(3)) and an adjacent C-B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Enantiospecific sp(2)-sp(3) coupling of secondary and tertiary boronic esters.

The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Metal-free borylative ring-opening of vinyl epoxides and aziridines.

A rational approach towards the borylative ring-opening of vinylepoxides and vinylaziridines, by the in situ formed MeO(-)→bis(pinacolato)diboron adduct, has been developed. The enhanced nucleophilic character of the Bpin (sp(2)) moiety from the reagent favours the SN2' conjugated B addition with the concomitant opening of the epoxide and aziridine rings. The reaction proceeds with total chemoselectivity towards the polyfunctionalised (-OH or -NHTs) allyl boronate. Theoretical calculations have determined the transition states that come from the reaction of the vinylic substrates with the activated MeO(-)→bis(pinacolato)diboron adduct, and a plausible mechanism for the organocatalytic borylative ring opening reaction has been suggested.

Essential role of phosphines in organocatalytic ß-boration reaction.

The use of phosphines to assist the organocatalytic ß-boration reaction of α,ß-unsaturated carbonyl compounds has been demonstrated with a selected number of substrates. The new method eludes the use of Brönsted bases to promote the catalytic active species and PR(3) becomes essential to interact with the substrate resulting in the formation of a zwitterionic phosphonium enolate. This species can further deprotonate MeOH when B(2)pin(2) is present forming eventually the ion pair [α-(H),ß-(PR(3))-ketone](+)[B(2)pin(2)·MeO](-) that is responsible for the catalysis.

Asymmetric organocatalytic diboration of alkenes.

The use of chiral alcohols to form the Lewis acid-base *RO(-)→ bis(pinacolato)diboron adduct, in situ, provides an opportunity to induce asymmetry in the organocatalytic diboration of alkenes and complements the well established transition metal-mediated enantioselective diboration.

Activation of diboron reagents with Brønsted bases and alcohols: an experimental and theoretical perspective of the organocatalytic boron conjugate addition reaction.

Bases play an important role in organocatalytic boron conjugate addition reactions. The sole use of MeOH and a base can efficiently transform acyclic and cyclic activated olefins into the corresponding ß-borated products in the presence of diboron reagents. Inorganic and organic bases deprotonate MeOH in the presence of diboron reagents. It is concluded, on the basis of theoretical calculations, NMR spectroscopic data, and ESI-MS experiments, that the methoxide anion forms a Lewis acid-base adduct with the diboron reagent. The sp(2) B atom of the methoxide-diboron adduct gains a strongly nucleophilic character, and attacks the electron-deficient olefin. The methanol protonates the intermediate, generating the product and another methoxide anion. This appears to be the simplest method to activate diboron reagents and make them suitable for incorporation into target organic molecules.

A new context for palladium mediated B-addition reaction: an open door to consecutive functionalization.

Palladium metal-catalyzed boron addition to unsaturated carbon-carbon bonds provides an efficient and convenient route for the preparation of organoboranes, which are versatile intermediates for organic synthesis. Palladium complexes are responsible for the exclusive catalytic performance and eventually allow access to selectively functionalized molecules by catalytic consecutive tandem sequences. The final objective is to find suitable palladium complexes that make it possible to perform a one-pot sequential reaction (B-addition/functionalization) by means of a multifaceted palladium catalyst. Mechanistic insights into the concatenated reactions through B chemistry are required if one wants to understand the experimental results.

Tandem beta-boration/arylation of alpha,beta-unsaturated carbonyl compounds by using a single palladium complex to catalyse both steps.

Diphenyl(3-methyl-2-indolyl)phosphine (C(9)H(8)NPPh(2), 1) gives stable dimeric palladium(II) complexes that contain the phosphine in P,N-bridging coordination mode. On treating 1 with [Pd(O(2)CCH(3))(2)], the new complexes [Pd(mu-C(9)H(7)NPPh(2))(NCCH(3))](2) (2) or [Pd(mu-C(9)H(7)NPPh(2))(mu-O(2)CCH(3))](2) (3) were isolated, depending on the solvent used, acetonitrile or toluene, respectively. Further reaction of 3 with the ammonium salt of 1 led to the substitution of one carboxylate ligand to afford [Pd(mu-C(9)H(7)NPPh(2))(3)(mu-O(2)CCH(3))] (4), in which the bimetallic unit is bonded by three C(9)H(7)NPPh(2)(-) moieties and one carboxylate group. Using this methodology, [Pd(2)(mu-C(6)H(4)PPh(2))(2)(mu-C(9)H(7)NPPh(2))(mu-O(2)CCX(3))] (X=H (7); X=F (8)) were synthesised from the ortho-metalated compounds [Pd(C(6)H(4)PPh(2))(mu-O(2)CCX(3))](2) (X=H (5); X=F (6)). Complexes 3, 4, 7, and 8 have been found to be active in the catalytic beta-boration of alpha,beta-unsaturated esters and ketones under mild reaction conditions. Hindrance of the carbonyl moiety has an influence on the reaction rate, but quantitative conversion was achieved in many cases. More remarkably, when aryl bromides were added to the reaction media, complex 7 induced a highly successful consecutive beta-boration/cross-coupling reaction with dimethyl acrylamide as the substrate (99% conversion, 89% isolated yield).

The selective catalytic formation of beta-boryl aldehydes through a base-free approach.

(NHC)Cu(I) complexes are key in a new strategy to selectively add a boron unit at the beta-position of alpha,beta-unsaturated aldehydes in the absence of a base.

Asymmetric induction on beta-boration of alpha,beta-unsaturated compounds: an inexpensive approach.

Transition metal complexes mediate beta-boration of alpha,beta-unsaturated carbonyl compounds highlighting the advantages of using inexpensive catalytic systems, (Cu, Ni), both in the catalytic activity and selectivity. The new C(beta)-B bond can be accomplished in a stereoselective manner by modifying the metal complex with chiral ligands. Alternative mechanistic studies support the enantioselectivity observed, and large-scale applications of this reaction are currently being developed.