Enantioselective Reduction of Benzofuranyl Aryl Ketones

Abstract

Enantioselective transfer hydrogenation of benzofuranyl aryl ketones proceeds with moderate to good enantioselectivity even when the aryl group is not sterically differentiated by ortho-substituents. The best results are obtained with substrates that are functionalised by electron-withdrawing aryl groups that contrast with the electron-rich benzofuran, which is consistent with [Ru-ArC-H]˙Ar π interactions acting as a control element. Enantioselective pressure hydrogenation gives lower enantioselectivity irrespective of electronic effects, unless the aryl group is ortho-substituted, in which case up to 86% ee can be realised.

Key words

asymmetric transfer hydrogenation - asymmetric hydrogenation - heterocyclic ketones - asymmetric catalysis - electronic control

References and Notes

• 1a The comprehensive handbook of homogeneous hydrogenation   Elsevier CJ. DeVries JNH. Wiley-VCH; Weinheim: 2006. 
• 1b Ikariya T. Blacker AJ. Acc. Chem. Res.  2007,  40:  1300 
• 1c Gladiali S. Alberico E. Chem. Soc. Rev.  2006,  35:  226 
• 1d Hashiguchi S. Fujii A. Takehara J. Ikariya T. Noyori R. J. Am. Chem. Soc.  1995,  117:  7562 
• 1e Ohhuma T. Ooka H. Ikariya T. Noyori R. J. Am. Chem. Soc.  1995,  117:  10417 
• 1f Takehara J. Hashiguchi S. Fujii A. Inoue S.-I. Ikariya T. Noyori R. Chem. Commun.  1996,  233 
• 1g Blacker AJ, and Mellor BJ. inventors;  WO9842643A1. 
• 1h Doucet H. Ohkuma T. Murata K. Yokozawa T. Kazawa M. Katayama E. England AF. Ikariya T. Noyori R. Angew. Chem. Int. Ed.  1998,  37:  1703 
• 2a Noyori R. Ohkuma T. Angew. Chem. Int. Ed.  2001,  40:  40 
• 2b Lennon IC. Casy G. Johnson NB. Chem. Today  2003,  63 
• 2c Lennon IC. Moran PH. Curr. Opin. Drug Discovery Dev.  2003,  6:  855 
• 2d Lennon IC. Ramsden JA. Org. Process Res. Dev.  2005,  9:  110 
• 2e Diaz-Venezuela MB. Phillips SD. France MB. Gunn ME. Clarke ML. Chem. Eur. J.  2009,  15:  1227 
• 2f Chen C.-Y. Reamer R. Chilenski JR. McWilliams CJ. Org. Lett.  2003,  5:  5039 
• 2g Ohkuma T. Koizumi M. Yoshida M. Noyori R. Org. Lett.  2000,  2:  1749 
• 2h Morris DJ. Hayes AM. Wills M. J. Org. Chem.  2006,  71:  7035 
• 3a Wu X. Vinci D. Ikariya T. Xiao J. Chem. Commun.  2005,  447 
• 3b Zaidlewicz M. Tafelska-Kaczmarek A. Prewysz-Kwinto A. Tetrahedron: Asymmetry  2005,  16:  3205 
• 4a Nichols DE. Hoffman AJ. Oberlender RA. Riggs RM. J. Med. Chem.  1986,  29:  302 
• 4b Cho C.-H. Neuenswander B. Lushington GH. Larock RC.
  J. Comb. Chem.  2008,  10:  941 ; and references therein
• 4c Nichols DE. Snyder SE. Oberlender R. Hohnson MP. Huang Z. J. Med. Chem.  1991,  34:  276 
• 4d Johansson G. Brisander N. Sundquist S. Hacksell U. Chirality  1998,  10:  813 
• 4e de Carvalho e Silveiria GP. Coelho F. Tetrahedron Lett.  2005,  46:  6477 
• 4f Sun L.-Q. Takaki K. Chen J. Bertenshaw S. Iben L. Mahle CD. Ryan E. Gao Q. Xu C. Bioorg. Med. Chem. Lett.  2005,  15:  1345 
• 4g Vinh TK. Lopez Delgado PO. Fernandez-Perez S. Walters HM. Smith HJ. Nichols PJ. Simons C. Bioorg. Med. Chem. Lett.  1999,  9:  2105 
• 5a Brandt P. Roth P. Andersson PG. J. Org. Chem.  2004,  69:  4885 
• 5b Ohhuma T. Koizumi M. Ikehira H. Yokozawa T. Noyori R. Org. Lett.  2000,  2:  659 
• 5c Sandoval CA. Qixun S. Liu S. Noyori R. Chem. Asian J.  2010,  4:  1221 
• 6 Maerten E. Agbossou-Niedercorn F. Castanet Y. Mortreux A. Tetrahedron  2008,  64:  8700 
• 7 Gill M. Tetrahedron  1984,  40:  621 
• 8 An almost identical R-configured alcohol to 13 (fluoro rather than chloro) gave opposite optical rotation to (S)-13, see: Botta M. Summa V. Corelli F. Di Pietro G. Lombardi P. Tetrahedron: Asymmetry  1996,  7:  1263 

9

The catalysts used were formed from either [RuCl₂(benzene)]₂, [RuCl₂(p-cymene)]₂ or [RhCl₂Cp*]₂ and (S,S)-Ts-DPEN or (1R,2S)-(+)-cis-1-amino-2-indanol. Using [RuCl₂(R)-BINAP(R,R)-DPEN], alcohol 16 was assigned as having R-configuration by Mosher analysis^6,8 on the mandelate ester (see the Supporting Information). A similar analysis was carried out on alcohol 15. The other alcohols, which show similar HPLC behaviour, are therefore proposed to have the (R)-configuration. Transfer hydrogenation reactions using [RuCl₂(benzene)]₂, [RuCl₂(p-cymene)]₂ or [RhCl₂Cp*]₂ combined with (S,S)-Ts-DPEN or (1R,2S)-(+)-cis-1-amino-2-indanol as catalyst, gave the opposite S-configured alcohols in each case.
2-(Trimethylsilyl)benzofuran:⁷ A solution of 2,3-benzo-furan (5.1 mL, 46 mmol) in anhydrous THF (50 mL) was cooled to -78 ˚C in a nitrogen atmosphere. n-BuLi (40 mL, 1.6 M in hexanes, 64 mmol) was then added slowly to the solution. After stirring at -78 ˚C for 1 h, chlorotri-methyl-silane (9.5 mL, 75 mmol) was added to the suspension. The mixture was then allowed to stir at -78 ˚C for 1 h, then at r.t. for a further 16 h. The reaction mixture was diluted with hexanes, filtered, and evacuated in vacuo to give a crude yellow oil (9.108 g). The crude product was purified by column chromatography (silica, hexane), to give a colourless oil (7.368 g, 39 mmol, 84%). ^¹H NMR (400 MHz, CDCl₃):
δ = 0.34 (s, 9 H, SiCH₃), 6.84 (s, 1 H, CHCSiMe₃), 7.13-7.29 (m, 2 H, 2 × ArH), 7.45-7.60 (s, 2 H, 2 × ArH); ^¹³C NMR (75 MHz, CDCl₃): δ = 0.1 [Si(CH₃)₃], 113.1 [CHC(SiMe₃)], 117.8 (ArCH), 122.8 (ArCH), 124.1 (ArCH), 126.1 (ArCH), 129.8 (ArC ipso-CH), 159.9 (CSiMe₃), 165.3 (ArC ipso-Oxygen); MS (ES+): m/z = 213.12 [M + Na]⁺.
Acylation of 2-(trimethylsilyl)benzofuran; General Procedure A: To a solution of an acid chloride (1.1 equiv) in anhydrous CH₂Cl₂ under a nitrogen atmosphere, trimethyl-silylbenzofuran (1.0 equiv) was added. The solution was stirred vigorously at r.t., whilst TiCl₄ (1.25 equiv) was added dropwise. The resulting suspension was stirred at r.t. for 48 h, followed by addition of water. The solution was extracted with Et₂O, dried, and concentrated in vaccuo to give the crude product. The crude product was purified by column chromatography (hexane-CH₂Cl₂).
Using general Procedure A: Using trimethylsilylbenzofuran (5.00 g, 26.3 mmol), 2-methoxy-benzoyl chloride (4.39 g, 28.5 mmol), and TiCl₄ (3.6 mL, 33.2 mmol) in CH₂Cl₂ (100 mL), ketone 10 was obtained as a pale-yellow oil (4.10 g, 17.4 mmol, 66%). ^¹H NMR (400 MHz, CDCl₃): δ = 2.43 (s, 3 H, CH₃), 7.26-7.33 (m, 4 H, 4 × ArH), 7.40-7.45 (m, 1 H, ArH), 7.46-7.51 (m, 1 H, ArH), 7.56 (m, 1 H, ArH), 7.62 (d, 1 H, ArH), 7.60-7.64 (m, 1 H, ArH), 7.66-7.69 (m, 1 H, ArH); ^¹³C NMR (75 MHz, CDCl₃): δ = 20.2 (CH₃), 113.2 (CHCC=O), 117.9 (ArCH), 123.9 (ArCH), 124.4 (ArCH), 125.7 (ArCH), 127.5 (ArC ipso-CH), 128.9 (ArCH), 129.0 (ArCH), 131.4 (ArCH), 131.7 (ArCH), 137.8 (ArC), 153.1 (OCC=O), 156.7 (ArC ipso-Oxygen), 187.4 (C=O); MS (ES+): m/z = 258.85 [M + Na]⁺; HRMS: m/z calcd. for C₁₆H₁₂O₂Na: 259.0735; found: 259.0732; IR: 3064, 1939, 1660, 1549,1445, 1328, 1219, 1186, 1114cm^-¹; Anal. Calcd for C₁₆H₁₂O₂: C, 81.34; H, 5.12. Found: C, 81.39; H, 5.05.
Transfer Hydrogenation; General Procedure B: Under a nitrogen atmosphere, the substrate, internal standard, 0.25 mol% metal complex, 0.5 mol% ligand and t-BuOK (1 M in t-BuOH) were transferred into a microwave vial and dissolved in anhydrous and degassed solvent (3 mL) and stirred for 2 min. The reaction was then heated and stirred for16 h. The vials were cooled and the crude reaction mixture was analysed by ^¹H NMR using tetraethylsilane as an internal standard to calculate the conversion into product. In some instances, the products were isolated using column chromatography, and the products were fully characterised.
Pressure Hydrogenation; General Procedure C: Under a nitrogen atmosphere, the substrate, internal standard, 0.25 mol% metal complex and 0.5 mol% ligand were transferred into a microwave vial and dissolved in anhydrous and degassed solvent (3 mL) and stirred for 2 min. The vials were then transferred to a steel autoclave and pressurised with H₂ gas. The reaction was then heated and stirred for 16 h. The autoclave was immersed in cold water and depressurised. The crude reaction mixture was then analysed by ^¹H NMR using tetraethylsilane as an internal standard to calculate the conversion into product.
( S )- o -Methylphenyl(benzofuran-2-yl)methanol (16): Using general procedure B with substrate (58.3 mg, 0.23 mmol), [RhCp*Cl₂]₂ (0.25 mol%), and aminoindanol (0.5 mol%), a yellow semi-solid was obtained (69 mg, 0.228 mmol, 99%, >99% conversion, 74% ee [determined by HPLC: OD-H (i-PrOH-hexane, 10:90; flow: 0.5 mL/min)]). Comparison of the HPLC behaviour of this compound to an analogous sample that had been treated with methoxyphenyl-acetic acid and analysed by NMR, showed this sample to have (S)-configuration. [α] _d ^²0 +28.2 (c = 2.2 g/100 mL, CHCl₃); ^¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 3 H, CH₃), 2.42 (br s, 1 H, OH), 6.07 (s, 1 H, CHOH), 6.34 (s, 1 H, ArH), 7.08-7.24 (m, 5 H, 5 × ArH), 7.35-7.45 (m, 2 H, 2 × ArH), 7.46-7.53 (m, 1 H, ArH); ^¹³C NMR (75 MHz, CDCl₃): δ = 19.1 (CH₃), 67.5 (CHOH), 104.6 (ArCH), 111.5 (CHCC=O), 121.3 (ArCH), 122.7 (ArCH), 124.5 (ArCH), 126.3 (ArCH), 128.4 (ArC ipso-CH), 128.7 (ArCH), 130.9 (ArCH), 136.0 (ArC), 138.7 (ArC), 156.0 (OCC=O), 159.2 (ArC ipso-oxygen); MS (ES+): m/z = 260.77 [M + Na]⁺.
For full experimental details, spectroscopic and analytical data, along with a discussion on the assignment of the configurations, see the Supporting Information.