Copper-ClickFerrophos-Complex-Catalyzed Enantioselective Reductive Aldol Reaction

Abstract

We have prepared several ClickFerrophos families and tested for the Cu(I)-catalyzed asymmetric reductive aldol reaction of ketones and aldehydes with an acrylic ester in the presence of phenylsilane. The Cu(I)-ClickFerrophos complex is efficient for the reaction of ketones with methyl acrylate to afford the erythro adducts both highly diastereo- and enantioselectively; the diastereomeric ratio of erythro/threo is improved when compared to the analogous Taniaphos.

Key words

aldol reactions - asymmetric catalysis - metallocenes - phosphorus - copper

References and Notes

• 1 For a review, see: Matsuda I. In Modern Rhodium-Catalyzed Organic Reactions   Evans PA. Wiley-VCH; Weinheim: 2005.  Chap. 6. p.111-128  
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• 4a Nishiyama H. Shiomi T. Tsuchiya Y. Matsuda I.
  J. Am. Chem. Soc.  2005,  127:  6972 
• 4b Ito J.-i. Shiomi T. Nishiyama H. Adv. Synth. Catal.  2006,  348:  1235 
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7

The use of other silanes such as dimethylphenylsilane, diethylmethylsilane, and triethoxysilane resulted in poor yields and selectivities under the same conditions.

8

Additives such as the triethylamine and tricyclohexyl phosphine did not affect the stereoselectivity.

9

Preparation of ( S , Rp )-5-(Diphenylphosphino)-1-{1-[2-(diphenylphosphino)ferrocenyl]ethyl}-1 H -1,2,3-triazole (CF2)
A 100 mL round-bottom flask containing a magnetic stirring bar was charged with 1-(1-azidoethyl)-2-bromoferrocene (400 mg, 1.20 mmol), trimethylsilylacetylene (180 µL, 1.32 mmol), t-BuOH (3.0 mL), and H₂O (3.0 mL). Sodium ascorbate (257 mg, 1.32 mmol) was added to the flask followed by CuSO₄˙7H₂O (162 mg, 0.65 mmol), and the resulting mixture was magnetically stirred for 24 h. The mixture was then extracted with CH₂Cl₂ (10 × 3 mL). The combined extracts were washed(brine), dried (MgSO₄), and the solvent was removed on a rotary evaporator to leave a yellow residue. The residue was treated overnight with a THF (5.0 mL) solution of TBAF (1.5 mmol) in THF at 50 ˚C. THF was removed by using a rotary evaporator and diluted with CH₂Cl₂ (20 mL) The solution was washed with H₂O, dried (MgSO₄), and the solvent was removed using a rotary evaporator. The residue was subjected to column chromatography on SiO₂ (hexane-EtOAc = 2:1 as eluent) to give the pure (S,Rp)-1-[1-(2-bromoferrocenyl)ethyl]-1H-1,2,3-triazole. Yellow solid; yield 140 mg, 0.40 mmol, 33%; mp 120-121 ˚C; [α]_D ^²5 +81 (c 0.36, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 2.04 (d, 3 H, J = 6.4 Hz), 4.26 (s, 5 H), 4.42 (s, 1 H), 4.53 (s, 1 H), 5.88 (q, 1 H, J = 6.9 Hz), 7.30 (s, 1 H), 7.56 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.0, 54.9, 64.9, 66.9, 71.1, 71.5, 79.1, 84.6, 121.7, 132.9.
In a 20 mL Schlenk tube containing a magnetic stirring bar were charged the triazole bromoferrocene prepared above (100 mg, 0.28 mmol) and dry THF (3.0 mL) under a slight pressure of nitrogen. The flask was cooled at -78 ˚C, and a hexane solution of n-BuLi (0.44 mL, 0.70 mmol, 1.6 M) was then added using a syringe through the septum with mag-netic stirring. After 10 min, Ph₂PCl (130 µL, 0.70 mmol) was injected into the mixture at -78 ˚C and stirred for 1 h. When the addition was completed, the mixture was allowed to warm to r.t. and then stirred for an additional 2 h. The reaction was quenched with sat. NH₄Cl, and the solution was then extracted with Et₂O (3 × 20 mL). The combined extracts were washed(brine), dried (Na₂SO₄), filtered, and the solvent was removed on a rotary evaporator to leave a yellow solid. The crude CF2 was purified by recrystal-lization from hexane-CH₂Cl₂. Yellow solid; yield, 130 mg, 0.20 mmol, 73%; mp 167-168 ˚C; [α]_D ^²5 +95 (c 0.34, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 1.61 (d, 3 H, J = 6.8 Hz), 3.81 (s, 1 H), 4.10 (s, 5 H), 4.45 (t, 1 H, J = 2.6 Hz), 4.90 (s, 1 H), 6.30 (m, 1 H), 6.60-7.60 (m, 21 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.6, 53.9 (dd, J = 9.2, 11.7), 69.8, 70.2, 70.8 (d, J = 3.7 Hz), 71.8 (d, J = 4.9 Hz), 75.3 (d, J = 10.2 Hz), 92.4 (d, J = 26.0 Hz), 127.0, 127.7 (d, J = 5.5 Hz), 127.9 (d, J = 8.1 Hz), 128.1 (d, J = 6.8 Hz), 128.3 (d, J = 7.2 Hz), 128.7, 128.8, 129.2, 129.8, 130.9 (d, J = 16.9 Hz), 132.4 (d, J = 18.6 Hz), 133.1 (d, J = 7.2 Hz), 133.3, 133.4, 133.5 (d, J = 7.9 Hz), 134.0, 134.1 (d, J = 21.5 Hz), 135.4 (d, J = 21.1 Hz), 137.1 (d, J = 8.5 Hz), 138.6, 139.1 (d, J = 9.6 Hz). ^³¹P NMR (121 MHz, CDCl₃): δ = -40.4 (d, J = 37.0 Hz), -24.5 (d, J = 37.0 Hz). HRMS: m/z calcd for C₃₈H₃₃FeN₃P₂ [M + H⁺]: 650.1577; found: 650.1573. The crystallographic data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. CCDC-717051.
Compound CF4 was similarly prepared by replacing Ph₂Cl with Cy₂PCl. Yellow solid; yield, 58%; mp 100-102 ˚C; [α]_D ^²5 +197 (c 0.24, CHCl₃). ^¹H NMR (300 MHz, CDCl₃):
δ = 0.90-2.10 (m, 47 H) including 2.04 (d, J = 7.0 Hz), 4.18 (s, 1 H), 4.26 (s, 5 H), 4.38 (s, 1 H), 6.12 (m, 1 H), 7.66 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 23.2, 53.9 (dd, J = 9.6, 12.0 Hz), 26.0-36.0 (several cyclohexyl signals), 69.0, 69.3, 69.6, 71.3 (d, J = 4.3 Hz), 79.3 (d, J = 24.6 Hz), 93.8 (d, J = 25.8 Hz), 131.7 (d, J = 24.3 Hz), 137.8 (d, J = 4.7). ^³¹P NMR (121 MHz, CDCl₃): δ = -33.0 (s), -19.3 (s). HRMS: m/z calcd for C₃₈H₅₇FeN₃P₂ [M + H⁺]: 674.3455; found: 674.3456. Compound CF3 was prepared by a similar preparative method for CF1 by replacing Ph₂PCl with Cy₂PCl according to a previous study. [6a] Yellow solid; mp 100-101 ˚C; [α]_D ^²5 +97 (c 0.31, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 0.90-2.30 (m, 47 H) including 2.04 (d, J = 6.9 Hz), 4.19 (s, 1 H), 4.29 (s, 5 H), 4.33 (s, 1 H), 6.17 (m, 1 H), 7.30-7.40 (m, 5 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 23.6 (dd, J = 3.2, 7.7 Hz), 26.0-36.0 (several cyclohexyl signals), 54.2, 68.5, 69.7, 71.2, 71.3, 78.4 (d, J = 25.3 Hz), 95.3 (d, J = 24.8), 127.9, 128.1, 128.4 (d, J = 30. 0 Hz), 129.3, 133.2, 151.6. ^³¹P NMR (121 MHz, CDCl₃): δ = -28.7 (s), -18.0 (s). HRMS: m/z calcd for C₄₄H₆₁FeN₃P₂ [M + H⁺]: 750.3768; found: 750.3767.

10

General Procedure for Cu/CF3-Mediated Reductive Aldol Reaction of Ketones 1 with Methyl Acrylate (2)
Under nitrogen, a 20 mL well-dried Schlenk tube equipped with a magnetic stirrer was charged with CuF(PPh₃)₃˙2MeOH (9.0 mg, 0.01 mmol), CF3 (7.5 mg, 0.01 mmol), and toluene (4.8 mL). The catalyst solution was stirred for 30 min at r.t., and phenylsilane (180 µL, 1.40 mmol) was then added at the same temperature. After cooling the solution at -50 ˚C, methyl acrylate (2, 110 µL, 1.20 mmol) and acetophenone (120 mg, 1.00 mmol) were simultaneously added to the solution. The mixture was stirred for 1 h at -50 ˚C, and then quenched by adding an aq NH₄F soln (5 mL). The aqueous layer was extracted by three portions of Et₂O (5 mL). The combined organic layers were then washed with brine (20 mL), dried over MgSO₄, filtered and concentrated by an evaporator. The residue was subjected to short SiO₂ column chromatography (hexane-EtOAc as the eluent) to give a diastereomeric mixture of the aldol adduct. The dr (erythro/threo) and ee values were determined by GC (CP CHIRASIL DEX CB 25 m) with reference to the literature.
erythro -Methyl 3-Hydroxy-2-methyl-3-phenylbutanoate (3a)
^¹H NMR (300 MHz, CDCl₃): δ = 1.32 (d, 3 H, J = 7.0 Hz), 1.46 (s, 3 H), 3.03 (q, 1 H, J = 7.0 Hz), 3.45 (s, 3 H), 4.02 (s, 1 H), 7.20-7.40 (m, 5 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 12.45, 26.6, 48.5, 51.6, 74.6, 124.6, 126.7, 128.1, 147.5, 177.1. GC Chirasil-Dex CB, 25 mm; isotherm 120 ˚C, t _R(major) = 18.5 min, t _R(minor) = 19.4 min. Other aldol products are fully characterized by spectroscopic analysis and the dr and ee values of products were determined by GC.