An Efficient Synthesis of α-Branched Enones

Abstract

A new method for preparing α-branched enones from carboxylic acid derivatives is reported. The procedure commenced by the reaction of N,O-dimethylamides with a masked acyl anion equivalent, followed by the addition of (trimethylsilyl-methyl)cerium dichloride to give intermediates that undergo Lewis acid mediated olefination to produce enol ethers that are then hydrolyzed to afford simple α-branched enones in high overall yields.

enones - Peterson olefination - titanium - acyl anion equivalents - homologation

References

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1c Mandai T. Takeshita M. Kawada M. Otera J. Chem. Lett.  1984,  1259 

1d Hegedus LS. Russel CE. J. Am. Chem. Soc.  1983,  105:  943 

1e Negishi E. Luo F.-T. J. Org. Chem.  1983,  48:  1560 

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3 Nahm S. Weinreb SM. Tetrahedron Lett.  1981,  22:  3815 

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5 Baldwin JE. Höfle GA. Lever OW. J. Am. Chem. Soc.  1974,  96:  7125 

6

All new compounds were purified (>95%) by flash chromatography or distillation and were characterized by ¹H NMR and ¹³C NMR, IR, and HRMS.

7 For example, see: Johnson CR. Tait BD. J. Org. Chem.  1987,  52:  281 

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9 For the previous synthesis and characterization of enones 4a, 4c, and 4d see: Siqueira-Filho EP. Rodrigues JAR. Moran PJS. Tetrahedron: Asymmetry  2001,  12:  847 

10 For the previous synthesis and characterization of enone 4e see: Cormier RA. Schreiber WL. Agosta WC. J. Am. Chem. Soc.  1973,  95:  4873 

11 For the previous synthesis and characterization of enone 4g see: Bates RW. Devi TR. Tetrahedron Lett.  1995,  36:  509 

12

Characterization data for new enones 4b, 4f, and 4h. Enone 4b: ¹H NMR (400 MHz, CDCl₃): δ = 7.34-6.86 (comp, 4 H), 6.04 (d, J = 1.2 Hz, 1 H), 5.65 (d, J = 1.2 Hz, 1 H), 3.76 (s, 3 H), 2.26 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.3, 156.8, 148.4, 130.5, 130.1, 128.0, 124. 0, 121.2, 111.0, 55.7, 27.4. MS (CI): m/z = 177 [M + H⁺]. IR (neat): 2939, 1698, 1600, 1491, 1243, 1170, 1026 cm^-1. Enone 4f: ¹H NMR (400 MHz, CDCl₃): δ = 5.65 (s, 1 H), 5.23 (s, 1 H), 2.23 (s, 3 H), 2.00-1.96 (comp, 3 H), 1.80 (d, J = 2.9 Hz, 6 H), 1.73-1.64 (comp, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 203.4, 159.1, 120.1, 40.9, 37.7, 37.0, 30.3, 28.8. MS (CI): m/z = 205 [M + H⁺]. IR (neat): 2906, 1676, 1265, 1135 cm^-1. Enone 4h: ¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.25 (comp, 5 H), 6.00 (s, 1 H), 5.77-5.76 (m, 1 H), 4.50 (s, 2 H), 3.48 (t, J = 6.5 Hz, 2 H), 2.33 (s, 3 H), 2.30-2.25 (comp, 2 H), 1.67-1.58 (comp, 2 H), 1.55-1.45 (comp, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.1, 149.2, 138.8, 128.6, 127.9, 127.7, 125.3, 73.1, 70.4, 30.5, 29.7, 26.2, 25.2. MS (CI): m/z = 233 [M + H⁺]. IR (neat): 2937, 2860, 1678, 1454, 1365, 1104 cm^-1.

13 Kauffmann T. König R. Pahde C. Tannert A. Tetrahedron Lett.  1981,  22:  5031 

14

The 4g produced from enantiomerically pure (>99% ee) proline had an enantiomeric ratio of >97:3; Chiralcel OD column, flowrate = 1.0 mL/min, gradient elution (1 to 3% i-PrOH/hexanes over 60 min).

15

Enone 4d was most conveniently purified by distillation at 90-93 °C (10 mm Hg).