Organocatalytic Synthesis of α-Trifluoromethyl Allylboronic Acids by Enantioselective 1,2-Borotropic Migration

Chiral α-substituted allylboronic acids were synthesized by asymmetric homologation of alkenylboronic acids using CF3/TMS-diazomethanes in the presence of BINOL catalyst and ethanol. The chiral α-substituted allylboronic acids were reacted with aldehydes or oxidized to alcohols in situ with a high degree of chirality transfer. The oxygen-sensitive allylboronic acids can be purified via their isolated diaminonaphthalene (DanH)-protected derivatives. The highly reactive purified allylboronic acids reacted in a self-catalyzed reaction at room temperature with ketones, imines, and indoles to give congested trifluoromethylated homoallylic alcohols/amines with up to three contiguous stereocenters.

C hiral allylboronic acids 1 are ideal reagents for asymmetric synthesis because of their high reactivity in self-catalyzed allylboration reactions that occur with high stereochemical fidelity. However, the synthesis of chiral allylboronic acids has been an unmet challenge in organic synthesis. Our experience with Pdcatalyzed synthesis of (achiral) allylboronic acids 2 ( Figure 1a) and conclusions based on related mechanistic studies 3 suggested that a metal-free approach would be rewarding for effective control of the stereoselectivity. We hypothesized that the synthesis of chiral allylboronic acids may be devised by using an organocatalytic homologation strategy. The first methods for asymmetric homologation of organoboron compounds were reported by the Matteson group. 4,5 Aggarwal and co-workers 6 applied a useful lithiation−borylation method (Figure 1b) for the synthesis of chiral allyl-Bpin species, 7 including an example of an α-trifluoromethyl allylboronate derivative. 8 This method is based on stoichiometric formation of chiral lithium carbenoid intermediates, and therefore, it is not suitable for the direct synthesis of allylboronic acids. The Ley 9−11 and Wang 12 groups ( Figure 1c) reported a homologation method based on diazo carbenoid reagents. This method was suitable for the synthesis of (achiral) allylboronic acids, which were used in one-pot allylborations 9,11 or converted to their Bpin derivatives. 12 A similar approach was employed by Molander and co-workers ( Figure  1c) for the synthesis of benzylboronic acids from trifluoromethyl diazomethane. 13,14 Arnold and co-workers presented a method for the synthesis of chiral α-CF 3 alkyl-and benzylboron compounds by directed evolution of enzymes. 15,16 Fluorinated organoboronates are useful reagents for selective synthesis of organofluorines. 13−21 The CF 3 motif very often occurs 22−24 in pharmaceuticals and agrochemical products (Figure 1d). 25−29 Here we present a new methodology for the synthesis of chiral α-CF 3 allylboronic acids (Figure 1e). Our concept ( Figure 2) is based on reacting alkenylboroxine 2, trifluor-omethyl diazomethane 3, catalytic amounts of BINOL (4), 30−36 and stoichiometric amounts of EtOH. Alkenylboroxine 2 readily reacts with diazo compound 3. 9−11 However, this reaction results in racemic product, such as rac-1-OR. The racemic background reaction can be avoided by addition of EtOH to the reaction mixture, which forms unreactive alkylboronic esters 2-OEt, which are weaker Lewis acids 37 than the corresponding boroxines 2. 30,31 Because of the dynamic covalent bonding 38 ability of boron, BINOL 4 undergoes transesterification with 2-OEt to form chiral alkenyl boronate A. Exchange of the alkyl group to an aromatic moiety leads to a substantial increase in the Lewis acidity of boron, 37 and therefore, A and 3 form ate complex B in the stereoinduction step of the process (see Figure S3). Then the alkenyl group undergoes stereoselective 1,2-migration 10,39 to afford C. Subsequently, ethanolysis of C gives product 1-OEt.
The optimal conditions for the homologation involved using 2a with an excess of 3, 20 mol % 4 and 2 equiv of EtOH (Table 1, entry 1). The oxygen-sensitive allylboronic ester 1a-OEt was protected with diaminonaphthalene (DanH) 40 to give 5a with 98% ee in 69% yield. When the reaction was repeated with 10 mol % catalyst 4, the yield was substantially lowered (12%), but the enantioselectivity was practically unchanged (96% ee) (entry 2). Replacement of iodo-BINOL 4 with bromo-BINOL (entry 3) led to decreases in the yield (9%) and the enantioselectivity (88% ee). Interestingly, increasing the loading of bromo-BINOL (entry 4) to 30 mol % led to a high yield (73%) and selectivity (94% ee). When bulky γsubstituents were employed in the BINOL catalyst (entry 5), both the yield and selectivity strongly declined. Application of the parent BINOL as the catalyst gave a low yield (4%) and relatively low selectivity (72% ee). When a commercially available alkenylboronic acid was used as the substrate (entry 7), the reaction proceeded in poor yield (18%) but with excellent selectivity (97% ee). When EtOH was replaced by i PrOH (entry 8), the yield dropped (44%) but the selectivity was still high (96% ee). In the absence of EtOH (entry 9), a complex reaction mixture was obtained, from which 5a was isolated in 4% yield with 47% ee. The poor enantioselectivity can be rationalized by the racemic background reaction (2 + 3 → rac-1-OR in Figure 2). The complex reaction mixture is a consequence of the poor stability of 1 and its boroxine in the absence of EtOH. Simple aliphatic alcohols esterify the boronic acids/boroxines and thus protect them from decomposition under the reaction conditions of the borylation ( Figure  1a). 2,32,41 When both EtOH and the BINOL catalyst were omitted (entry 10), a complex reaction mixture was obtained again. Without molecular sieves (entry 11), the yield was poor, probably because the slow formation of chiral alkenyl-BINOLtype intermediate A (Figure 2). At room temperature, changing dichloromethane (DCM) to toluene leads to lowering the yield and a slight decrease of the ee (entries 12 −13).
Under the optimal conditions, alkyl-substituted alkenylboronic acids 2a−c reacted readily to give the corresponding α-CF 3 allylboronic acid esters 1(a-c)-OEt and Bdan derivatives 5a−c ( Figure 3a). Aryl-substituted alkenylboronic acids (2d− g) reacted somewhat slower than the aliphatic ones. Cinnamyl derivative 5d was formed in 54% yield (93% ee) when 20 mol % catalyst was used. However, with 20 mol % catalyst, 5e formed only in 26% yield (89% ee). Therefore, the catalyst loading was increased to 30 mol % to obtain acceptable yields of 5e−g (50−70%). The absolute configuration of crystalline 5e was determined to be S by X-ray diffraction. On the basis of the structural similarities of the substrates and the reaction conditions, we assumed that the absolute configuration of the other species (5a−d, 5f, and 5g) was the same. The reactions can be easily scaled up. For example, the synthesis of 5a on 1 and 2 mmol scales occurred with 98 and 96% ee in 78 and 68% yield, respectively.
The transient allylboron compounds 1-OEt reacted with aldehyde 6a in situ (Figure 1b). The enantioselectivity for the formation of 7a−d varied between 90 and 98% ee. In addition, only one of the four possible diastereomers was formed in each case. We did not detect any Z isomer of 7a−e in the crude product of the reaction. Usually, α-substituted allylboron  compounds with bulky protecting groups (e.g., pinacol or 9-BBN) react with poor E/Z selectivity in allylboration reactions. 42,43 These selectivity issues can often be solved by application of additives, but in the presented processes, poor E/Z selectivity was avoided by the small size of the B(OEt) 2 group. Notably, small molecules with alkenyl-CF 3 motifs 44−48 are very important drugs, such as in anticancer agents, 25 pesticides, 26 and herbicides 27 (Figure 1d). Formation of 7e from 1f proceeded with 75% ee. The relatively low enantioselectivity is a consequence of the fact that 1f-OEt is formed with lower selectivity (86% ee, 5f) than other allylboronic acids. The yields are in the range of 41−60% based on alkenylboronic acid monomers after a two-step process. Another useful reaction is the stereoselective in situ oxidation of the chiral allylboron compounds to the corresponding α-CF 3 allylic alcohols 8a−c (Figure 3c), which were obtained in 50−78% yield with 90−99% ee. The corresponding trifluoroethanol motif 49,50 occurs for example in antitumor agent Z 28 and the monoamine oxidase inhibitor befloxatone (Figure 1d). 29 The asymmetric homologation concept can also be extended to the synthesis of chiral α-silyl allylboronic acids, such as 1h-OEt (Figure 3d). In this reaction, 3 was replaced with TMSdiazomethane. Dan protection of 1h-OEt failed, and therefore, we isolated pinane derivative 9. The homologation affording 9 proceeded with high selectivity (99:1 d.r., corresponding to 98% ee for 1h-OEt) in 51% yield. In situ allylboration of 6a gave homoallylic alcohol 10 with high selectivity.
We were able to obtain purified oxygen-sensitive allylboronic acids such as 1a and 1d by hydrolysis of the corresponding isolated Dan-protected products (5a and 5d) ( Table 2). The increased reactivity of the purified products unleashed the outstanding synthetic potential of chiral allylboronic acids. As we reported previously, in the presence of molecular sieves (or other drying agents), pure allylboronic acids form very reactive allylboroxines. 2,30,31,37 Purified 1a in the presence of molecular sieves reacted with 6a in just 10 min to afford 7a ( Table 2, entry 1). Notably, the enantioselectivities with purified and in situ-formed 1a were identical. This was also confirmed by the reaction of cinnamyl analogue 1d with 6a (entry 2). Allylboration of 6b with in situ-generated 1a-OEt failed to give 7f (Figure 3b). However, purified 1a in the presence of molecular sieves gave 1a-boroxine (see the Supporting Information), which reacted with 6b to afford 7f (entry 3) with excellent selectivity (98% ee) in 67% yield. The purification (1a-OEt → 5a → 1a sequence) is essential to obtain 7f, as demonstrated by a control experiment (entry 4). When 2 equiv of EtOH was added to 1a prior to addition of 6b, formation of 7f was not observed. Likewise, 1a-Bpin did not react with 6b under the reaction conditions applied for 1a (entry 5). Aliphatic ketones (6c−e) also reacted smoothly with allylboronic acids. Cyclohexanones 6c and 6d gave the corresponding products 7g and 7h with 91−97% ee in 50− 72% yield (entries 6 and 7). The reaction of racemic methyl cyclohexanone 6d with 1d is spectacular, as in this reaction the major enantiomer (97% ee) 7h was formed with three contiguous stereocenters in a single reaction step. Acyclic aliphatic ketone 6e reacted in high yield (72%) but with only 82% ee, affording densely functionalized tertiary homoallyl alcohol 7i. The synthetic utility of purified chiral allylboronic acids was further demonstrated by allylboration of indoles 11,31,51,52 6f and 6g with 1d to afford 7j and 7k with high selectivities (entries 9 and 10). From skatole 6g, the Ealkenyl-CF 3 product 7k with three adjacent stereocenters was formed with 89% ee. Isoquinoline derivative 31,53 6h reacted with purified 1d to afford 7m with 93% ee in 54% yield. Allylboration of 6i 54,55 with 1a gave α-amino acid derivative 7n with 98% ee in 72% yield.
In summary, we have presented a new methodology for the catalytic synthesis of chiral α-CF 3 or α-SiMe 3 allylboronic acids using stabilized diazomethane derivatives. The basic concept of stereoselective 1,2-borotropic migration can certainly be extended to nonstabilized diazoalkanes as well by solving the issues of electrophilic side reactions (e.g., protonation of the diazoalkanes) competing with the formation of the ate complex Journal of the American Chemical Society pubs.acs.org/JACS Communication (B). The enantioenriched α-CF 3 and α-SiMe 3 allylboronic acids readily undergo in situ allylboration with aldehydes or can be converted to the corresponding allylic alcohols with high levels of chirality transfer. The purified chiral allylboronic acids are very reactive and highly stereoselective reagents in the allylation of aldehydes, ketones, imines, and indoles. Very promising application areas for these types of allylboronic acids are in drug design ( Figure 1d) and natural product synthesis. 56 Table 2. Showcase for Application of Purified α-CF 3 Allylboronic Acids in Stereoselective Synthesis a a Unless otherwise stated, 5 (0.1 mmol) was hydrolyzed with 3 N H 2 SO 4 in DME, and then 1 was extracted with toluene under Ar. b Isolated yields. c1 H NMR spectra of 1a and 1d are given in the Supporting Information. d Using 2 equiv of EtOH without molecular sieves. e 1a-Bpin and 6b were stirred at 40°C without molecular sieves.
Journal of the American Chemical Society pubs.acs.org/JACS Communication