From receptors in the nose to supramolecular biopolymers, nature shows a remarkable degree of specificity in the recognition of chiral molecules, resulting in the mirror image arrangements of the two forms eliciting quite different biological responses. It is thus critically important that during a chemical synthesis of chiral molecules only one of the two three-dimensional arrangements is created. Although certain classes of chiral molecules (for example secondary alcohols) are now easy to make selectively in the single mirror image form, one class-those containing quaternary stereogenic centres (a carbon atom with four different non-hydrogen substituents)-remains a great challenge. Here we present a general solution to this problem which takes easily obtainable secondary alcohols in their single mirror image form and in a two-step sequence converts them into tertiary alcohols (quaternary stereogenic centres). The overall process involves removing the hydrogen atom (attached to carbon) of the secondary alcohol and effectively replacing it with an alkyl, alkenyl or aryl group. Furthermore, starting from a single mirror image form of the secondary alcohol, either mirror image form of the tertiary alcohol can be made with high levels of stereocontrol. Thus, a broad range of tertiary alcohols can now be easily made by this method with very high levels of selectivity. We expect that this methodology could find widespread application, as the intermediate tertiary boronic esters can potentially be converted into a range of functional groups with retention of configuration.

Direct electrophilic borylation using Y(2)BCl (Y(2) = Cl(2) or o-catecholato) with equimolar AlCl(3) and a tertiary amine has been applied to a wide range of arenes and heteroarenes. In situ functionalization of the ArBCl(2) products is possible with TMS(2)MIDA, to afford bench-stable and easily isolable MIDA-boronates in moderate to good yields. According to a combined experimental and computational study, the borylation of activated arenes at 20 °C proceeds through an S(E)Ar mechanism with borenium cations, [Y(2)B(amine)](+), the key electrophiles. For catecholato-borocations, two amine dependent reaction pathways were identified: (i) With [CatB(NEt(3))](+), an additional base is necessary to accomplish rapid borylation by deprotonation of the borylated arenium cation (σ complex), which otherwise would rather decompose to the starting materials than liberate the free amine to effect deprotonation. Apart from amines, the additional base may also be the arene itself when it is sufficiently basic (e.g., N-Me-indole). (ii) When the amine component of the borocation is less nucleophilic (e.g., 2,6-lutidine), no additional base is required due to more facile amine dissociation from the boron center in the borylated arenium cation intermediate. Borenium cations do not borylate poorly activated arenes (e.g., toluene) even at high temperatures; instead, the key electrophile in this case involves the product from interaction of AlCl(3) with Y(2)BCl. When an extremely bulky amine is used, borylation again does not proceed via a borenium cation; instead, a number of mechanisms are feasible including via a boron electrophile generated by coordination of AlCl(3) to Y(2)BCl, or by initial (heteroarene)AlCl(3) adduct formation followed by deprotonation and transmetalation.

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Hydride abstraction from N,N′-bis(adamantyl)-1-hydrido-1,3,2-benzodiazaborole with catalytic [Ph 3 C][closo-CB 11 H 6 Br 6 ] resulted in a low yield of arene borylation and a major product derived from migration of both adamantyl groups to the arene backbone. In contrast, the related arylsubstituted diazaborole N,N′-(2,6-diisopropylphenyl)-1-bromo-1,3,2-diazaborole did not borylate benzene or toluene, being resistant to halide abstraction even with strong halide acceptors: e.g., [Et 3 Si][closo-CB 11 H 6 Br 6 ]. The reactivity disparity arises from greater steric shielding of the boron p z orbital in the 2,6-diisopropylphenyl-substituted diazaboroles. Boron electrophiles derived from 1-chloro-1,3,2-benzodithiaborole ((CatS 2 )BCl) are active for arene borylation, displaying reactivity between that of catecholato-and dichloro-boron electrophiles.[(CatS 2 )B(NEt 3 )][AlCl 4 ] is significantly less prone to nucleophile-induced transfer of halide from [AlCl 4 ]¯to boron compared to catecholato and dichloro borocations, enabling it to borylate arenes containing nucleophilic −NMe 2 moieties in high conversion (e.g., N,N,4-trimethylaniline and 1,8-bis(dimethylamino)naphthalene). Calculations indicate that the magnitude of positive charge at boron is a key factor in determining the propensity of chloride transfer from [AlCl 4 ]¯to boron on addition of a nucleophile.

Tertiary alkylamines are common motifs in many natural products and pharmaceuticals but access to them in enantiomerically enriched form can sometimes present a major challenge. A standard route to these compounds involves the addition of nucleophiles, for example, organometallic reagents [1] or cyanide [2] to ketimines, but other indirect methods have also been reported.[3] Whilst many of these methods have been successful in delivering high levels of stereocontrol, the level of selectivity is highly substratedependent.We recently reported a conceptually new method for the synthesis of tertiary alcohols that routinely delivered more than 98 % ee over a broad range of substrates (Scheme 1).[4] In this process, lithiation of secondary carbamates 1 followed by treatment with boronic esters and subsequent addition of MgBr 2 /MeOH gave the tertiary boronic esters 2, which were finally oxidized to tertiary alcohols in high ee. We reasoned that isolation of the intermediate tertiary boronic esters and subsequent amination could provide a new route to C-tertiary alkylamines in high ee. Whilst amination of primary and even secondary boronic esters had been reported, [5][6][7] the much more challenging tertiary boronic esters had not. We therefore embarked on this study and now report that C-tertiary alkylamines can indeed be obtained in more than 98 % ee using this methodology.Of the reported amination transformations, Mattesons direct conversion of a potassium trifluoroborate salt into an amine [7] turned out to be the most efficient and reliable, [8] and after some modification of the reaction conditions [9] this protocol was ultimately successful. Thus, a broad range of tertiary boronic esters were first converted into the corresponding trifluoroborates 3 and then treated with SiCl 4 and an alkyl azide (Table 1). Using this protocol with benzyl azide 4 a, the tertiary trifluoroborate 3 a was converted into the tertiary benzylamine 5 aa in 94 % yield and 99 % ee (entry 1). The methodology could be extended to other substituted benzylic and alkyl azides (entries 2, 3). In terms of the scope of the tertiary trifluoroborate, hindered alkyl groups (iPr, cHex; entries 4-6) and even diarylalkyl trifluoroborates (entries 7, 8) could all be employed, leading to C-tertiary alkyl amines with very high ee. The latter two examples are noteworthy as the diarylalkyl boron intermediates are especially prone to homolysis and radical recombination but no erosion in ee was observed.Some limitations of the methodology however, were uncovered. For example, the homoallylic trifluoroborate salt 6 only gave the tertiary amine 7 in 14 % yield together with ketone 8 in 75 % yield (Scheme 2, see Supporting Information for a mechanistic discussion on the origin of 8).The para-methoxy analogue of the trifluoroborate 3 f was also ineffective. Since both the meta-methoxy substrate 3 f and the para-methoxybenzylic secondary trifluoroborate salt [10] worked well, it showed that this limitation was specific to the tertiary, electron-rich diaryl trifl...