An Alternative Route to Protected Aldols: Cobalt-Catalyzed Hydroformyl­ation of Epoxides and in situ Protection of β-Hydroxyaldehydes by HC(OMe)₃

Abstract

A wide range of epoxides were efficiently converted to protected aldols by hydroformylation-acetalization using Co₂(CO)₈ as a catalyst in trimethyl orthoformate. The formylation of terminal epoxides was regioselective for the terminal position, and (S)-1-benzyloxy-2,3-epoxypropane was transformed into (R)-1-benzyl­oxy-4,4-dimethoxybutan-2-ol with retention of the configuration.

acetals - hydroformylations - epoxides - cobalt - aldols

References

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9

A typical procedure is as follows: A mixture of cyclohexene oxide (0.50 mL, 5.0 mmol), Co₂ (CO)₈ (43 mg, 0.125 mmol) and 5 (98 mg, 0.25 mmol) in trimethyl orthoformate (10 mL) was placed in a 20 mL Schlenk tube and degassed by freeze-thaw cycles. Then, the solution was transferred into a 50 mL autoclave. After carbon monoxide (40 atm) and hydrogen (40 atm) were pressurized, the resulting mixture was stirred at 90 °C for 21 h. The reaction mixture was cooled down to the ambient temperature, and the carbon monoxide and hydrogen pressure were slowly released. The volatile materials were evaporated and the resulting crude residue was treated with MeOH (10 mL) under refluxing overnight. The solvent was removed off by evaporation, and then the residue was purified by silica gel chromatography (hexane-EtOAc = 10:1) to give 3 in 70% yield. ¹H NMR (CDCl₃): δ = 4.28 (d, J = 6.9 Hz, 1 H), 4.12 (s, 1 H), 3.53-3.46 (m, 1 H), 3.45 (s, 3 H), 3.35 (s, 3 H), 2.04-1.97 (m, 1 H), 1.79-1.61 (m, 4 H), 1.25-1.12 (m, 3 H), 1.05-0.96 (m, 1 H). ¹³C NMR (CDCl₃): δ = 108.97, 71.22, 55.26, 52.32, 45.78, 34.24, 26.37, 24.99, 24.39. Anal. Calcd for C₉H₁₈O₃: C, 62.04; H, 10.41. Found: C, 61.86; H, 10.35.

10

The configuration was assigned by comparing the ¹H NMR signals of the diol given by reduction of 3 (60% yield) with those reported. [11]

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12 During the reaction, we observed more amount of gas absorption than the expected amount for the reaction with epoxide. This phenomenon is probably due to the reaction of HC(OMe)₃ with CO/H₂ to yield CH₃CH(OMe)₂, MeOH and HCO₂Me, see: Piacenti F. Cioni C. Pino P. Chem. Ind. (London)  1960,  1240 

13

Spectral data for new compounds. Compound 7a: ¹H NMR (CDCl₃): δ = 4.26 (d, J = 8.3 Hz, 1 H), 3.99-3.94 (m, 1 H), 3.42 (s, 3 H), 3.32 (s, 3 H), 2.68 (br s, 1 H), 2.10-2.03 (m, 1 H), 2.01-1.92 (m, 1 H), 1.88-1.81 (m, 1 H), 1.77-1.65 (m, 1 H), 1.63-1.53 (m, 1 H), 1.41-1.33 (m, 1 H). ¹³C NMR (CDCl₃): δ = 108.02, 75.59, 54.83, 51.56, 49.26, 33.49, 25.56, 21.27. Anal. Calcd for C₈H₁₆O₃: C, 59.97; H, 10.07. Found: C, 60.11; H, 9.85. Compound 7b: ¹H NMR (CDCl₃): δ = 4.33 (d, J = 5.5 Hz, 1 H), 3.89-3.82 (m, 1 H), 3.44 (s, 3 H), 3.37 (s, 3 H), 2.95 (d, J = 5.1 Hz, 1 H), 1.76-1.71 (m, 1 H), 1.59-1.50 (m, 1 H), 1.45-1.27 (m, 7 H), 0.97-0.90 (m, 6 H). ¹³C NMR (CDCl₃): δ = 108.32, 70.51, 56.16, 53.88, 44.91, 35.78, 27.05, 21.46, 19.75, 14.44, 14.13. Anal. Calcd for C₁₁H₂₄O₃: C, 64.67; H, 11.84. Found: C, 64.63; H, 11.94. Compound linear-7c: ¹H NMR (CDCl₃): δ = 4.29 (d, J = 6.0 Hz, 1 H), 3.70-3.64 (m, 1 H), 3.61-3.56 (m, 1 H), 3.45 (s, 3 H), 3.37 (s, 3 H), 2.85 (dd, J = 7.8, 4.1 Hz, 1 H), 1.87-1.81 (m, 1 H), 1.42-1.20 (m, 10 H), 0.88 (t, J = 6.9 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 108.89, 62.62, 55.85, 53.48, 42.73, 31.72, 29.56, 27.06, 26.61, 22.60, 14.05. Anal. Calcd for C₁₁H₂₄O₃: C, 64.67; H, 11.84. Found: C, 64.56; H, 11.92. Compound linear-7d: ¹H NMR (CDCl₃): δ = 4.61 (t, J = 5.5 Hz, 1 H), 4.05-3.99 (m, 1 H), 3.55 (qd, J _H-Cl = 11 Hz,
J _H-H = 6.0 Hz, 2 H), 3.39 (s, 3 H), 3.38 (s, 3 H), 3.07 (br s, 1 H), 1.93-1.84 (m, 2 H). ¹³C NMR (CDCl₃): δ = 103.16, 68.33, 53.87, 53.43, 49.34, 36.72. Anal. Calcd for C₆H₁₃O₃Cl: C, 42.74; H, 7.77. Found: C, 42.56; H, 7.88. Compound linear-7e: ¹H NMR (CDCl₃): δ = 7.37-7.27 (m, 5 H), 4.60 (t, J = 5.5 Hz, 1 H), 4.56 (s, 2 H), 4.02-3.95 (m, 1 H), 3.49-3.46 (m, 1 H), 3.43-3.40 (m, 1 H), 3.36 (s, 3 H), 3.36 (s, 3 H), 2.87 (s, 1 H), 1.81-1.78 (m, 2 H). ¹³C NMR (CDCl₃): δ = 138.00, 128.41, 127.70, 103.17, 74.09, 73.32, 67.33, 53.51, 53.32, 36.23. Anal. Calcd for C₁₃H₂₀O₄: C, 64.98; H, 8.39. Found: C, 64.80; H, 8.35. [α]_D ²⁶ for linear-(R)-7e = 1.7° (c 3.0, CHCl₃).

14

No racemization was confirmed by HPLC analysis (DAICEL CHIRALCEL OD-H, Hexane-i-PrOH = 95:5). The absolute configuration was determined based on the optical rotation of 2-hydroxy-1,4-butanediol which was prepared from linear-(R)-7e in 4 steps.

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