Diarylmethanols by Catalyzed Asymmetric Aryl Transfer Reactions onto Aldehydes Using Boronic Acids as Aryl Source

Abstract

Using a planar-chiral ferrocene as catalyst and combinations of functionalized aldehydes and substituted arylboronic acids as starting materials, asymmetric aryl transfer reactions give access to structurally diverse, optically active diarylmethanols in high yields and enantioselectivities.Keywords: arylboronic acids; C À C bond formation; diarylmethanols; enantioselective catalysis; organozinc reagents Diarylmethanols 3 with defined stereochemistry at the hydroxy-bearing carbon are important intermediates for the synthesis of numerous compounds with high biological and/or physiological activity.[1] For example, neobenodine and orphenandrine show anticholinergic as well as anthihistaminic properties.[2] Recently, diarylmethanols have been used in the synthesis of pharmaceuticals containing asymmetrical 1,1'-diarylalkyl subunits.[3] The most common routes towards diarylmethanols are either enantioselective reductions of prochiral benzophenone derivatives [4] or asymmetric carbon-carbon bond formations starting from aromatic aldehydes and appropriate organometallic compounds. [5,6] Despite the fact that the latter strategy has attracted considerable attention due to its enormous synthetic potential, the so far evaluated substrate range appears rather limited. Thus mostly, aryl transfer reactions onto (unsubstituted) benzaldehyde (Scheme 1, Ar 2 = Ph) or phenyl-to-aldehyde transfers have been studied leading to arylphenylmethanols. The synthesis of diarylmethanols with two differently substituted aryl groups via zinc reagents has, to the best of our knowledge, never been in the focus of an intensive study. [7] In 2002, we described a general approach for aryl transfer reactions to aromatic aldehydes involving arylzinc species formed in situ from arylboronic acids 1 and diethylzinc. Ferrrocene 4 served as catalyst (Scheme 1). [8] Noteworthy is the fact that with a single catalyst both enantiomers of 3 became accessible by choosing the appropriate combination of arylboronic acid 1 and aldehyde 2. Also in this case, only arylphenylmethanols were prepared.Wondering about the flexibility of this method and with the goal to investigate the applicability of the approach in the preparation of more functionalized molecules, we have now studied the catalytic synthesis of 1,1'-disubstituted diarylmethanols (e.g., products with aryls other than phenyl). This involved structural variations of both the arylboronic acids 1 as well as the aldehydes 2. The results are summarized in Table 1.To our delight we found that most diarylmethanols 3 were formed in good yields and high enantioselectivities (Figure 1). For example, 4-chlorophenyl-2'-methylphenylmethanol (3a) was obtained with 91 % ee in 71 % yield (Table 1, entry 1). In the catalysis starting from 2-bromobenzaldehyde (2c) and 3-methoxyphenylboronic acid (1c) diarylmethanol ent-3b was formed with 88 % ee in 66 % yield (entry 3). Using the "reverse combination" of substrates, the enantiomeric product 3b was obtained by aryl transfer from 2-bromophenylboronic acid (1b) ...

Practical Implications of Boron‐to‐Zinc Transmetalation for the Catalytic Asymmetric Arylation of Aldehydes

“…In apparent contradiction to this prediction, however, standard experimental procedures for transmetalation normally involve heating a mixture of boroxine or boronic acid and a large excess of diethylzinc for extended periods of time (typically 12 h at 60 8C). [5,6] These problems can be partially overcome by using triaryl boroxines, although several hours are still necessary for the transfer the aryl moieties from boron to zinc, [7] which is a drawback of this methodology for practical applications.…”

“…A variety of aryl boron species have been used for this purpose, [5][6][7] as well as several other reagents. [8,9] In fact, a catalytic enantioselective aldehyde arylation involving a triaryl boroxine [10] as the ultimate source of the aryl group has recently found an industrial application.…”

Enhancement of the Catalytic Activity of Chiral H8‐BINOL Titanium Complexes by Introduction of Sterically Demanding Groups at the 3‐Position

“…www.chemeurj.org except for the phenylation of m-anisaldehyde to give compound 2k,the former exhibited higher enantioselectivity. [13a, 17] To gain insightinto our catalyst complexes, structural studies were carried out for titanium complexes derived from DPP-H 8 -BINOL (1d)b ys olid-state X-ray analysisa nd solution-phase VT-NMR spectroscopy.T reatment of ligand 1d with Ti(OiPr) 4 (2 equiv) in toluene at room temperaturef ollowed by removal of the solvent and iPrOH in vacuo and subsequent recrystallization from toluene/Et 2 Og ave the bis-titanium intramolecular aggregate complex 1d-IA as singlec rystals for the X-ray analysis. [13] For ac omplex with al igand/Tir atio of 1:1, formation of am ononuclear complex M with tetracoordinate Ti IV was proved in the solid state by X-ray crystallography for the BINOL derivative 3c bearing sterically demanding tert-butyl dimethylsilyl (TBS) groups at the 3-and 3'-positions.…”

“…[1][2][3][4][5][6][7][8][9] The enantio-enriched diaryl-,a ryl-heteroaryl-, and diheteroarylmethanols produced by this reactiona re important structural motifs and precursors in the synthesis of pharmaceutically important molecules. [1][2][3][4][5][6][7][8][9] The enantio-enriched diaryl-,a ryl-heteroaryl-, and diheteroarylmethanols produced by this reactiona re important structural motifs and precursors in the synthesis of pharmaceutically important molecules.…”

Catalytic enantioselective arylations: boron to zinc exchange as a powerful tool for the generation of transferable aryl groups

“…17 Bolm and co-workers also succeeded in expanding their methodology to investigate the synthesis of diarylmethanols with two differently substituted aryl groups (Figure 2). 18 The authors found that most diarylmethanols were performed in good yields and high enantioselectivities. For example, 4-chlorophenyl-2'-methylphenylmethanol was obtained in 71% yield and 91% ee.…”