Cyclization of N-(3-Oxoalkyl)chloroacetamides Under Basic Conditions. Synthesis of cis-3,4-Epoxypiperidin-2-ones

It has been shown that N-(3-oxoalkyl)chloroacetamides (1) can be converted into cis-3,4-epoxypiridin-2-ones (2) upon treatment with t-BuOK in a t-BuOH-C6H6 solution due to a resulting intramolecular Darzens reaction. It has been found that under kinetically controlled reaction conditions (NaOH/C6H6), besides the intramolecular Darzens reaction an intramolecular alkylation takes place.


Results and Discussion
We have found that the treatment of compounds 1a-e with potassium t-butoxide in a t-butanol and benzene mixture at 0°C afforded the corresponding cis-3,4-epoxypiperidin-2-ones 2a-e in 10-71% yields (Table 1) as a result of an intramolecular Darzens reaction (Scheme 2). Besides the deprotonation of the α-carbamoyl position, the α-carbonyl position is deprotonated too and this causes, in the case of compounds 1c,d, the formation of α,β-unsaturated ketones as a result of an E 1 cb elimination that leads to decreased yields of the desired compounds 2c,d. This complication does not occur in the reactions of the alkyl substituted N-(3-oxoalkyl)chloroacetamides 1a,b,e under the same reaction conditions.
Use of a solvent mixture containing t-butanol provides a proton donating medium and as a result makes the deprotonation an equilibrium and therefore a thermodynamically controlled process. This kind of reaction conditions leads to formation of cis-3,4-epoxypiperidin-2-ones (2).

Conclusions
It has been shown that N-(3-oxoalkyl)chloroacetamides undergo an intramolecular cyclization under the influence of bases via both intramolecular alkylation and intramolecular Darzens reactions. Despite the moderate and sometimes low yields of products observed, nevertheless the cyclization of N-(3-oxoalkyl)chloroacetamides can be proposed as a potentially useful method for the synthesis of cis-3,4epoxypiperidin-2-ones because of the ready availability of the precursors.

Acknowledgments
We are grateful to the Russian Foundation for Basic Research (grant No 99-03-33013) and Russian Ministry of Education (grant No E00-5.0-282) for financial support of this work.

Reaction of N-(3-oxoalkyl)chloroacetamides 1a-e with t-BuOK in t-BuOH-benzene media.
A solution of t-BuOK, freshly prepared from potassium (0.055 g, 1.4 mmol) and t-BuOH (5 mL) was added dropwise over 2 hours to a stirred solution of compound 1a-e (1.4 mmol) in a mixture of benzene (5mL} and t-butanol (5 mL) at 0 °C. The reaction mixture was stirred for 6 hours at room temperature, poured into water (50 mL) and extracted with chloroform (3 x 15mL). The combined extracts were washed with water to pH~7, dried with MgSO 4 and concentrated in vacuo to give a residue which, after colomn chromatography on silica (eluent 3:1 CHCl 3 -EtOAc), afforded the products 2a-e.

Reaction of 2-chloro-N-(1,1-dimethyl-3-oxobutyl)acetamide 1b with sodium hydroxide in benzene.
Sodium hydroxide powder (0.25 g, 6.25 mmol) was added to a solution of compound 1b (1.00 g, 5.2 mmol) in benzene, the resulting mixture was boiled for 1-2 min and then diluted with a 5 % aqueous solution of acetic acid. The organic layer was separated and the aqueous one was extracted with chloroform (2 x 10 mL). The combined organic extracts were dried with MgSO 4 and the solvent was removed in vacuo. The residue was chromatographed on silica, eluting first with 1:1 CHCl 3 -EtOAc for the separation of 2b and then with i-PrOH for separation of 3b.