ETHYL 3-OXO CYCLOBUATNE CARBOXYLATE

To methylene chloride (100 mL) at -78° C. was added oxalyl chloride (1.79 mL, 21.2 mmol), followed by dimethyl sulfoxide (2.51 mL, 35.3 mmol). triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with iN HC1. Organic layer was separated off and the aq.phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCO3 solution followed by water (50 mL) and dried over Na2SO4. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. ‘HNMR (400 MHz, CDC13): ö 4.20 (q, J= 7.1 Hz, 2H), 3.44-3.37 (m, 2H), 3.31 -3.17 (m, 3H, ), 1.28 (t, J= 7.1 Hz, 3H).Step 1 : ethyl 3-oxocyclobutane-l-carboxylate: triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC0triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC0triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCC solution followed by water (50 mL) and dried over Natriethyl orthoacetate (21.31 g, 0.13 1 mol) was added to a solution of 3-oxocyclobutane-1-carboxylic acid (5.0 g, 0.043 mol) intoluene (100 mL) and the reaction mixture was refluxed for 6 h. The reaction mixture wasquenched with a IN HCI solution and the layers were separated off. The organic layer waswashed with saturated NaHCO3 solution (2 x 50 mL), brine (2 x 50 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to get the product (5.3 g, 85percent) as a yellow liquid. ‘H NMR (400 MHz, CDC13): ö 4.23-4.17 (q, J 7.0 Hz, 2H), 3.44-3.37 (m, 2H), 3.32-3.16 (m, 3H), 1.30-1.26 (t, J 7.0 Hz, 3H).1A. 3-Oxo-cyclobutanecarboxylic acid ethyl ester A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCOA solution of 3-oxo-cyclobutanecarboxylic acid (0.5 g, 4.38 mmol), triethylorthoacetate (2.4 mL, 13.1 mmol) and toluene (10 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI. The organic phase was separated, washed with a saturated NaHC0Ethyl 3 -oxocyclobutanecarboxylate [00217] To a -78 °C solution of 3-oxocyclobutanecarboxylic acid (2.0 g, 17.5 mmol) in EtOH (20 mL) was bubbled HC1 gas for 3 min. The solution was then warmed to rt and stirred at rt for 18 h. Volatiles were concentrated in vacuo and the residue was chromatographed (S1O2; 10percent EtOAc:hexanes) to afford the title compound (2.15 g, 82percent yield) as a clear oil. A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI (120 mL). The organic phase was separated, washed with a saturated NaHCOMaintaining an inert atmosphere, 3-oxocyclobutanecarboxylic acid (200 mg, 1.75 mmol) was dissolved in dry tetrahydrofuran (7.0 mL) and, after cooling the system in an ice-water bath, dimethylformamide (1 drop) and oxalyl chloride (276 L, 3.51 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, while a change from colorless to yellow was observed. Then, the solvent was evaporated under reduced pressure and the residue re-dissolved in ethanol (7 mL) and stirred for 1 h. The course of the reaction could be followed by TLC analysis (20percent EtOAc/hexane). Finally, the solvent was evaporated and keto ester 1m was obtained with 82percent yield after purification by column chromatography on silica gel (20-30percent EtOAc/hexane).

Molecular Weight:142.15
XLogP3:-0.1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:142.062994177
Monoisotopic Mass:142.062994177
Topological Polar Surface Area:43.4
Heavy Atom Count:10
Complexity:154
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes