An Efficient Protocol for the Oxidative Hydrolysis of Ketone SAMP Hydrazones Employing SeO₂ and H₂O₂ under Buffered (pH 7) Conditions

Abstract

An effective oxidative protocol for the liberation of ketones from SAMP hydrazones employing peroxyselenous acid under aqueous buffered conditions (pH 7) has been developed. The procedure proceeds without epimerization of adjacent stereocenters or dehydration, in representative SAMP alkylation and aldol reaction adducts, respectively.

Key words

SAMP - oxidative cleavage - aldol reactions - ketones - SeO₂

References and Notes

• 1 Enders D. Eichenauer H. Angew. Chem., Int. Ed. Engl.  1976,  15:  549 
• 2 Job A. Janeck CF. Bettray W. Peter R. Enders D. Tetrahedron  2002,  58:  2253 ; and references therein
• 3 Enders D. Wortmann L. Peters R. Acc. Chem. Res.  2000,  33:  157 
• 4 Enders D. Plant A. Synlett  1994,  1054 
• 5 Said SB. Skarzewski J. Mlochowski J. Synthesis  1989,  223 
• 6 Stupp SI. Son S. Li LS. Lin HC. Keser M. J. Am. Chem. Soc.  1995,  117:  5212 
• 7 Eichenauer H. Friedrich E. Lutz W. Enders D. Angew. Chem., Int. Ed. Engl.  1978,  17:  206 
• 11 Enders D. Bockstiegel B. Synthesis  1989,  493 

8

General Procedure for the Synthesis of Hydrazones
A mixture of SAMP (0.04 mmol), ketone (0.04 mmol), and PTSA (0.004 mmol) was heated at reflux in cyclohexane
(1 mL) overnight. The mixture was then cooled to r.t., neutralized with sat. NaHCO₃ (3 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography to provide the desired hydrazone (70-98%).

9

General Procedure for the Synthesis of Ketones 7-15 and 22-24
To a r.t. solution of hydrazone (0.18 mmol) and SeO₂ (0.14 mmol) in MeOH (2.3 mL) was added pH 7 phosphate buffer (0.066 mL) followed by 30% H₂O₂ (0.066 mL). After completion of the hydrolysis reaction, sat. NaHCO₃ (3 mL) was added, and the aqueous layers were extracted with pentane (3 × 3 mL). The combined organic layers were combined, dried over Na₂SO₄, and concentrated. The residue was purified via flash chromatography to provide the corresponding ketone in 68-96% yield.

10

General Procedure for the Synthesis of Alkylated SAMP Hydrazones 19-21
To a solution of the corresponding hydrazone (0.26 mmol) in THF (2 mL) at -78 ˚C was added t-BuLi (1.6 M in pentane, 0.39 mmol). The mixture was kept at this temperature for 2 h before cooling to -100 ˚C. (S)-(+)-1-Iodo-2-methylbutane (0.52 mmol) was then added via syringe, the solution stirred at -100 ˚C for 0.5 h, and then at -78 ˚C for 2 h. The reaction was quenched with sat. NH₄Cl (3 mL). The aqueous layers were extracted with Et₂O (3 × 5 mL), and the combined organic layers were dried over Na₂SO₄, concentrated, and the residue was purified by flash chromatography to furnish the alkylated hydrazone in 90-96% yield.

12

General Procedure for the Synthesis of SAMP Aldol Products 25-27
To a solution of hydrazone (0.18 mmol) in THF (1.2 mL) at -78 ˚C was added t-BuLi (1.6 M in pentane, 0.18 mmol). The mixture was maintained at this temperature for 2 h before cooling to -100 ˚C. Benzaldehyde (0.36 mmol) was then added via syringe, the solution stirred at -100 ˚C for 0.5 h, and then at -78 ˚C for 2 h. The reaction was quenched with sat. NH₄Cl (3 mL), the aqueous layer extracted with Et₂O (3 × 5 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography to furnish aldol products in 68-96% yield

13

General Procedure for the Synthesis of β-Hydroxy Ketones 28-30
To a r.t. solution of the corresponding hydrazone (0.03 mmol) and SeO₂ (0.045 mmol) in MeOH (0.45 mL) was added pH 7 phosphate buffer (0.15 mL) followed by 30% H₂O₂ (0.015 mL). After completion, sat. NaHCO₃ (2 mL) was added to the mixture, and the aqueous layers were extracted with EtOAc (2 × 3 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (SiO₂ deactivated with 18% H₂O) to provide β-hydroxy ketones (65-81%).