Metal Chloride-Promoted Aldol Reaction of α-Dimethylsilylesters with Aldehydes, Ketones, and α-Enones

Abstract

In the presence of a catalytic amount of LiCl, α-dimethylsilylesters (α-DMS-esters) 1 smoothly reacted with various aldehydes at 30 °C to give aldols in good to high yields. On the other hand, the aldol reaction with ketones was effectively promoted by MgCl₂ rather than by LiCl. α-Enones also underwent the metal chloride-promoted addition of 1 at the carbonyl carbon or β-carbon.

aldehydes - aldol reactions - ketones - Michael additions - α-silylesters

References

1a Modern Aldol Reactions   Vol. 2:  Mahrwald R. Wiley-VCH; Weinheim Germany: 2004. 

1b Miura K. Hosomi A. In Main Group Metals in Organic Synthesis   Vol. 2:  Yamamoto H. Oshima K. Wiley-VCH; Weinheim Germany: 2004.  Chap. 10. p.409 

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Related works:

7a Miura K. Tamaki K. Nakagawa T. Hosomi A. Angew. Chem. Int. Ed.  2000,  39:  1958 

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For the fluoride ion-catalyzed aldol reaction of ethyl trimethylsilylacetate, see:

10a Nakamura E. Shimizu M. Kuwajima I. Tetrahedron Lett.  1976,  1699 

10b Nakamura E. Hashimoto K. Kuwajima I. Tetrahedron Lett.  1978,  2079 

α-DMS-esters 1 can be easily prepared from the corresponding esters by deprotonation with LiNi-Pr₂ followed by silylation with Me₂SiHCl. See:

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11c

Typical Procedure for the Preparation of α-DMS-esters 1
Under N₂ atmosphere, n-BuLi (1.61 M in hexane, 62 mL, 100 mmol) was added to a solution of i-Pr₂NH (14 mL, 100 mmol) in THF (100 mL) over 5 min at 0 °C. After 10 min, the mixture was cooled to -78 °C. Then, EtOAc (9.3 mL, 95 mmol) was added to the solution of LDA over 5 min. After 2 h, the reaction mixture was treated with chlorodimethyl-silane (12.2 mL, 110 mmol) and gradually warmed to r.t. over 12 h. The resultant mixture was diluted with dry pentane (50 mL) and filtered through Celite^®. After evaporation of the filtrate, the residual oil was diluted with dry pentane (50 mL) again, filtered through Celite^®, and evaporated. Purification of the crude product by distillation gave 1a (9.2 g, 63 mmol) in 66% yield.
Compound 1a: bp 58-60 °C (180 Torr). IR (neat): 1669 (C=O), 1253, 1205 cm^-1. ¹H NMR (CDCl₃): δ = 0.20 (d, J = 3.6 Hz, 6 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.96 (d, J = 3.3 Hz, 2 H), 4.06 (sept, d, J = 3.6, 3.3 Hz, 1 H), 4.10 (q, J = 6.9 Hz, 2 H). ¹³C NMR (CDCl₃): δ = -4.36 (CH₃ × 2), 14.09 (CH₃), 24.08 (CH₂), 59.91 (CH₂), 172.54 (C). Anal. Calcd for C₆H₁₄O₂Si (%): C, 49.53; H, 9.69. Found: C, 49.27; H, 9.65.

12

General Procedure for the Aldol Reaction of 1 with Aldehydes 2
Under the atmosphere, dry LiCl (5.5 mg, 0.13 mmol) was added to a two-necked, round-bottomed flask (10 mL), which was connected with a nitrogen balloon. After introduction of nitrogen, DMF (1.0 mL) was added to the flask. The mixture was warmed to 30 °C under stirring. After 10 min, 2 (0.50 mmol) and 1 (0.60 mmol) were added to the mixture. After being stirred for 5 h, the reaction mixture was treated with 2 M aq HCl (1 mL) for 5 min and neutralized with sat. aq NaHCO₃. The aqueous mixture was extracted with EtOAc (3 × 10 mL). The extract was dried over Na₂SO₄ and evaporated. The crude product was purified by silica gel column chromatography.

The Reformatsky reaction of ethyl bromoacetate with 5g shows much lower stereoselectivity toward equatorial attack. See:

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Recent reports on the Lewis acid-catalyzed reactions:

15a Ishihara K. Hanaki N. Funahashi M. Miyata M. Yamamoto H. Bull. Chem. Soc. Jpn.  1995,  68:  1721 

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Lewis base catalyzed reactions:

16a RajanBabu TV. J. Org. Chem.  1984,  49:  2083 

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Aldol reactions of α-enones:

17a Hanyuda K. Hirai K. Nakai T. Synlett  1997,  31 

17b Braun M. Mai B. Ridder D. Eur. J. Org. Chem.  2001,  3155 

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18 The bond dissociation energy of Si-Cl in Me₃SiCl (472 kJ/mol) is larger than that of Si-Br in Me₃SiBr (402 kJ/mol). See: Walsh R. In The Chemistry of Organic Silicon Compounds   Vol. 1:  Patai S. Rappoport Z. Wiley; Chichester UK: 1989.  Chap. 5. p.371 

19

As shown in Table [3] , the reaction of 1a with 8a proceeded efficiently irrespective of the metal chloride used. This observation may be due to higher coordinating ability (Lewis basicity) of α-enones, which allows carbonyl activation even with less Lewis acidic metal ions. For the coordinating ability of α-enones, see ref. 17a.