Simple Tools for α-Oxygenation of Aldehydes and Ketones

The α-hydroxycarbonyl moiety is an important structural motif in organic synthesis and is present in a substantial number of natural products. A variety of methods have been developed to prepare this functionality including α-oxygenation of enolates with electrophilic oxidizing agents as well as dihydroxylation or epoxidation of enol ethers.1 Recently, aminooxylation of aldehydes 2 and ketones3 has been demonstrated using nitrosobenzene. However, this latter protocol requires a large excess of the carbonyl compound in tandem with syringe pump techniques which diminishes from the usefulness of the transformation.

Nicholas Tomkinson of Cardiff University (UK) recently reported several practical reagents for preparation of N-tert-butyl-O-benzoylhydroxylamine hydrochloride (669407) is a bench stable reagent for α-functionalization of a variety of aldehydes under mild conditions (Scheme 1). The reaction can be performed in open air and in the presence of moisture. Benzoylation occurs in high yield at both secondary and tertiary centers as demonstrated by the reactions of this reagent with isovaleraldehyde and cyclohexanecarboxaldehye (Figure 1).

 N-tert-butyl-O-benzoylhydroxylamine hydrochloride

Scheme 1

cyclohexanecarboxaldehye

Figure 1

While this reagent is only useful on aldehyde substrates, a similar bench stable reagent can be applied towards the α-oxygenation of ketones. Treatment of cyclohexanone with N-methyl-O-benzoylhydroxylamine hydrochloride (669393) in water provides the benzoyl-protected alcohol in excellent yield, presumably through a pericyclic rearrangement of an intermediate iminium ion (Scheme 2). A previous synthesis of this molecule from cyclohexanone by House required a laborious five-step procedure.5

pericyclic rearrangement of an intermediate iminium ion

Scheme 2

Both acyclic and cyclic ketones undergo oxidation at mild temperatures to afford protected alcohols in good to excellent yield (Scheme 3, Figure 2). The reagent is tolerant of existing functionality (e.g. sulfonamides, free hydroxyl groups, and unsaturation), and in the case of non-symmetrical ketones, oxidation occurs regiospecifically at the more substituted carbon. In addition to water and DMSO, THF and CHCl3 can also be used as solvents with similar yields.

acyclic and cyclic ketones undergo oxidation

Scheme 3

acyclic and cyclic ketones undergo oxidation

Figure 2

Our company is delighted to add these new α-benzoylation tools to our growing arsenal of oxidation reagents.

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References

1.
Chen B, Zhou P, Davis FA, Ciganek E. 2003. ?-Hydroxylation of Enolates and Silyl Enol Ethers.1-356. http://dx.doi.org/10.1002/0471264180.or062.01
2.
Brown SP, Brochu MP, Sinz CJ, MacMillan DWC. 2003. The Direct and Enantioselective Organocatalytic ?-Oxidation of Aldehydes. J. Am. Chem. Soc.. 125(36):10808-10809. http://dx.doi.org/10.1021/ja037096s
3.
Zhong G. 2003. A Facile and Rapid Route to Highly Enantiopure 1,2-Diols by Novel Catalytic Asymmetric?-Aminoxylation of Aldehydes. Angew. Chem. Int. Ed.. 42(35):4247-4250. http://dx.doi.org/10.1002/anie.200352097
4.
Hayashi Y, Yamaguchi J, Hibino K, Shoji M. 2003. Direct proline catalyzed asymmetric ?-aminooxylation of aldehydes. Tetrahedron Letters. 44(45):8293-8296. http://dx.doi.org/10.1016/j.tetlet.2003.09.057
5.
Bøgevig A, Sundén H, Córdova A. 2004. Direct Catalytic Enantioselective?-Aminoxylation of Ketones: A Stereoselective Synthesis of?-Hydroxy and?,??-Dihydroxy Ketones. Angew. Chem. Int. Ed.. 43(9):1109-1112. http://dx.doi.org/10.1002/anie.200353018
6.
Hayashi Y, Yamaguchi J, Sumiya T, Shoji M. 2004. Direct Proline-Catalyzed Asymmetric?-Aminoxylation of Ketones. Angew. Chem. Int. Ed.. 43(9):1112-1115. http://dx.doi.org/10.1002/anie.200353085
7.
Córdova A, Sundén H, Bøgevig A, Johansson M, Himo F. 2004. The Direct Catalytic Asymmetric?-Aminooxylation Reaction: Development of Stereoselective Routes to 1,2-Diols and 1,2-Amino Alcohols and Density Functional Calculations. Chem. Eur. J.. 10(15):3673-3684. http://dx.doi.org/10.1002/chem.200400137
8.
Beshara CS, Hall A, Jenkins RL, Jones TC, Parry RT, Thomas SP, Tomkinson NCO. A simple method for the ?-oxygenation of aldehydes. Chem. Commun..(11):1478-1480. http://dx.doi.org/10.1039/b418101h
9.
Beshara CS, Hall A, Jenkins RL, Jones KL, Jones TC, Killeen NM, Taylor PH, Thomas SP, Tomkinson NCO. 2005. A General Method for the ?-Acyloxylation of Carbonyl Compounds. Org. Lett.. 7(25):5729-5732. http://dx.doi.org/10.1021/ol052474e
10.
House HO, Richey FA. 1969. Use of ketoxime derivatives to prepare .alpha.-acetoxy ketones. J. Org. Chem.. 34(5):1430-1439. http://dx.doi.org/10.1021/jo01257a050

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