Ethyl-2-(4-chlorophenyl)cyclopropanecarboxylate
A mixture of 4-chlorostyrene (10.1 ml, 96 mmol) and rhodium acetate dimer (1 g, 4.5 mmol) in toluene (50 ml) was heated to 85° C. before adding ethyl diazoacetate (11.3 mls, 94 mmol) over 30 mins and the whole then heated at 80° C. for a further 1 h before concentration in vacuo. The residue was then purified by column chromatography using 1:2 DCM:pentane as eluant to give the title product as a colourless oil (7.8 g, 37%); Rf 1:2 (DCM:pentane) 0.35;
1HNMR (400 MHz, CDCl3) δ 1.15-1.3 (m, 4H), 1.5-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.4-3.55 (m, 1H), 4.2 (q, 2H), 6.95 (d, 2H), 7.20-7.28 (m, 2H); and LRMS: m/z, M+NH4+242.
trans-2-(4-Chlorophenyl)cyclopropanecarboxylic acid
The product from preparation 73 (7.8 g, 37 mmol) was dissolved in EtOH (75 mls) at room temperature under nitrogen and sodium methoxide (8.1 g, 150 mmol) was added portionwise over 15 mins. After the addition was complete, the mixture was then refluxed for 18 h. The reaction mixture was concentrated in vacuo, and the resulting residue diluted with DCM and water (150 mls, 2:1 mixture). The organic layer was removed, and the aqueous layer re-extracted with DCM (2×50 mls). The combined organic extracts were dried over MgSO4 and evaporated to provide the trans ester (4.96 g, 62%). Acidification of the aqueous layer with concentrated HCl to pH 1 resulted in a white precipitate, which was filtered and dried under vacuum to provide the hydrolysis product (the corresponding acid) as a white powder (1 .95 g, 27%). Dissolution of the ester in MeOH (50 mls), water (50 mls) and LiOH (1.34 g, 32 mmol) gave a clear solution which was heated at ca. 70° C. overnight. The reaction mixture was cooled, concentrated in vacuo, and acidified with concentrated HCl to pH 1. The resulting white precipitate was extracted with EtOAc (3×50 mls) and the combined organic extracts were dried over MgSO4 and evaporated to dryness, to provide the acid (4 g, 96%). This acid was combined with the hydrolysed product from the previous step to give a total of 5.95 g;
1HNMR (400 MHz, CDCl3) δ 1.3-1.4 (m, 1H), 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.5-2.6 (m, 1H), 7.00 (d, 2H), 7.26 (d, 2H); LRMS: m/z, M-H 195.
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