Palladium‐Catalyzed Synthesis and Isolation of Functionalized Allylboronic Acids: Selective, Direct Allylboration of Ketones

• DOI: 10.1002/ange.201207951
• Publication Date: 2012-12-13T12:13:09Z
• Authors: Mihai Raducan; Rauful Alam; Kálmán J. Szabó
• Keywords: Borylation

Steht so nicht im Lehrbuch: Allylboronsäuren sind leicht ausgehend von Allylalkoholen erhältlich und reagieren ohne Zusatz Lewis-Säure-Katalysatoren bereitwillig selektiv mit Ketonen. Allyl boronates are very important reagents in advanced organic synthesis for the allylation of carbonyl compounds1 and cross-coupling2 reactions. A practically unrivalled property allylboronates is their highly regio- stereoselective addition to compounds afford homoallylic alcohols.1a–1d, 3 This high selectivity mainly based on two factors: 1) Allylboronates configurationally stable, unlike many allyl metal compounds4 (such as allyl-Grignard reagents, lithium or allylboranes) do not undergo metallotropic rearrangement E/Z isomerization at ambient conditions. 2) The six-membered ring transition state (TS) allylboration conformationally constrained, which leads a strong differentiation stereoselection process.3a, 5 Method development broadening number accessible functionalized one most challenges organoboron chemistry. In reactions with allylboronic esters, pinacolborate (allyl-Bpin) frequently applied source,1a–1d allyl-Bpins can be easily handled derivatives obtained by metal-catalyzed borylation precursors bis(pinacolato)diboron (B2pin2) boronate source.6 Problems synthetic applications arise from relatively low reactivity allyl-Bpin towards compounds. Although aldehydes react without catalysts, ketones not. There few attempts direct ester analogues reported literature. that have been successful require extreme conditions (for example, 8000 bar days), an unselective process;7 therefore, selective requires catalytic conditions.8 Some time ago we application diboronic acid 19 (now commercially available) source1e, 10 Pd-catalyzed allylic alcohols (3) obtain acids (4; Scheme 1).6c,6d However, owing instability, could isolated studied pure form. Therefore, potential remained unexploited. Synthesis isolation acids. We now substantially modified catalyst (2) reaction process, allowed these extremely useful (see Schemes 1 2, Table 1). outstanding utility demonstrated (uncatalyzed) under mild conditions, proceeds remarkably stereoselectivity 2). As previously noted,6c,6d fairly stable long they dissolved coordinating solvents. When solvents completely removed, rapid decomposition occurs. Careful experiments inert shown boroxine formation 4 (which observed 1H NMR) oxygen sensitivity (Scheme Formation boroxines organoboronic well known.1b, 11 case arylboronic corresponding usually still air stable. find any previous studies formed found all a–l become sensitive after drying, but kept glove box couple weeks extensive decomposition. thermal stability high. For heating e dry degassed THF 70 °C 18 h does lead borotropic rearrangement. After careful optimization, were able suitable wide range boronic aromatic (4 a–e) aliphatic f–l) substituents, including both acyclic a–g j–k) cyclic h–i, l) products. stereoselectivity. get perfect stereoselectivity, exception d, was 5:1 (E/Z) mixture. Notably, geraniol j nerol k underwent (Table 1, entries 11), double bond geometry remaining unchanged Boroxine upon drying. Entry Substrate Cat.[b] (mol %) Solvent[c] (molarity) t [h] Product Yield[d] [%] 2 (0.5) MeOH (1.0) 61[e] 0.2 80 (0.2) 71 DMSO/H2O 3:2 14 55 (2.0) 4:1 13 6 1[g] 51 7 (0.3) 50 8 3:1 68 9 b (5.0) 9:1 (0.4) 67 77[h] 79[h] 12 25 used different b. Catalyst a12 simply prepared dissolving PdCl2 aq. HCl, whereas available applied13 allylsilanes derivatives. less active, more than Catalysts phosphine ligands Pd2(dba)3 (dba=dibenzylideneacetone) ineffective Reactions neat 1–3, 5–7) proceeded rapidly loadings (0.2–0.5 mol %). sterically crowded substrates process slow, resulting reduction alcohols. cases, replaced mixture, always led slower reaction, suppressed undesired side DMSO also stabilizing forming Pd0 species, thus reducing rate deactivation Pd-catalyst. some unreactive combination (entries 12) optimize reduce by-products. concentration substrate factor. products protodeborylation when too molarity data Furthermore, precipitation initiated brine, yield product dependent ratio solvent water during purification stage. Geranyl neryl forced precipitate, therefore separated extraction into chloroform. Boronic l had similar solubility (MeOH DMSO) water. this (entry poor, even though selective. scalable; cinnamylboronic repeated gram (6 mmol) scale significant change To demonstrate acids, performed a–c These conducted either chloroform additives. mentioned above, other esters inefficient ketones. j–k reacted amazingly geranyl cleanly afforded epimeric f g acetophenone derivative c 6–7). Most room temperature, only ketone d required elevated temperature 4). expected, pinacolester (cinnamyl-Bpin) above using esters14 stannanes15 presence allylaluminum,16 titanocene17 selectivities same as, several cases lower than, b–d 2–4) resulted single diasteromer, analogous allylating methods, small amounts diastereomers reported. It concluded legendary inherited mechanism probably takes place through stereochemistry, stereochemistry f–g line via Type I TS 3). Allylboration Ketone Solvent Yield [%][b] 86 24 89 91 THF[c] 22 90 CHCl3[d] 96 94[e] 76[f] much higher toward (vs. derivatives) explained demanding nature B(OH)2 group relative Bpin group. Considering close COB contact TS5b stereoselectivity) steric demand groups attached boron atom essential success reaction. noticed strongly inhibited. That reason6d failure one-pot sequence MeOH). Solvents may coordinate empty pπ orbital compete An alternative explanation a–k prior 2), reactive itself. B/O 1:1, 1:2. Accordingly, receives electron density adjacent atoms boroxine. consequence, Lewis acidity derivative. summary, described synthetically method preparation method, source. first directly Our will hopefully open new routes natural synthesis,18 where interference paramount importance. typical Pd-catalyst (0.2–5 (2.4 added alcohol (2.0 appropriate stirred allotted filtration brine Ar; stirring h, precipitated solid filtered off. washed water, dried, stored Ar. 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