Anodic coupling of carboxylic acids to electron-rich double bonds: A surprising non-Kolbe pathway to lactones

Summary Carboxylic acids have been electro-oxidatively coupled to electron-rich olefins to form lactones. Kolbe decarboxylation does not appear to be a significant competing pathway. Experimental results indicate that oxidation occurs at the olefin and that the reaction proceeds through a radical cation intermediate.


Cyclic Voltammetry Experiments
A solution of the substrate (0.025 M) and tetraethylammonium tosylate (0.1 M) in the necessary solvent (noted in the text) was prepared. Cyclic voltammetry was performed with a sweep rate of 50 mV/s, with the sweep beginning in the positive direction. The half-wave oxidation potentials (E p/2 ) were measured from the resulting oxidation curve.

Substrate Synthesis and Characterization
OH O S S 6-(1,3-dithian-2-ylidene)heptanoic acid, 14c 2-(Trimethylsilyl)-1,3-dithiane (1.467g, 7.629 mmol, 2 equivalents) was dissolved in tetrahydrofuran (10 mL) under inert atmosphere, cooled to -78 • C, and treated with n-butyllithium (1.6 M in hexanes, 4.77 mL, 7.629 mmol, 2 equivalents). The resulting solution was stirred at -78 • C for 30 minutes, then at room temperature for 30 minutes. The solution was then cooled back to -78 • C and treated with 6-oxoheptanoic acid (0.6070g, 3.789 mmol, 1 equivalent, dissolved in 10 mL of tetrahydrofuran). After 15 minutes, cold bath was removed and the reaction was allowed to warm to room temperature as it stirred overnight. The reaction was quenched the following morning with 3 M aqueous hydrochloric acid to a pH of approximately 6. Ether was added, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed through silica gel with hexanes and ethyl acetate to give the desired product (67%) as a colorless oil. IR

S S
The title compound was prepared according to the same procedure for the synthesis of S-2, using ethyl 5-oxohexanoate instead of ethyl levulinate. Following that procedure, the title compound was prepared in a 75% yield.
IR (neat, cm −1 ) 1710, 1436, 1301. To a suspension of (methoxymethyl)triphenylphosphonium chloride (3.693 g, 10.77 mmol, 2.5 eq) in THF (15 mL) was added sodium bis(trimethylsilyl) amide (1.0 M in tetrahydrofuran, 10.8 mL, 2.5 eq) at 0 • C under argon atmosphere. The resulting solution was stirred at 0 • C for 30 min. Levulinic acid (0.5 g, 4.306 mmol, 1 eq) was then added via 1 mL tetrahydrofuran. The resulting suspension was allowed to stir overnight and warm to room temperature. After 22 hours, water was added and the Aqueous layer was washed with ether three times. The aqueous layer was then acidified with hydrochloric acid (3 M, aq) to a pH of 5. The aqueous layer was then extracted three times with diethyl ether. The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo, and chromatographed through silica gel with a mixture of hexanes and ethyl acetate to give the product as a colorless oil and a 2:1 mixture of isomers. (0.2434 g, 39% To a solution of (3-carboxypropyl)triphenylphosphonium bromide (1.1 g, 2.5 mmol, 1.2 eq.) in tetrahydrofuran (10 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 5.0 ml, 5.0 mmol, 2.4 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. P-anisaldehyde (0.25 ml, 2.0 mmol, 1 eq.) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 1 M aqueous hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (1:1 to 5:1 ether:hexanes) to give 0.31 g of product (73%) as a white solid. IR

HO O OMe
(4E)-5-(2-methoxyphenyl)pent-4-enoic acid, 19e To a solution of (3-carboxypropyl)triphenylphosphonium bromide (2.0 g, 4.8 mmol, 1.1 eq.) in tetrahydrofuran (20 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 9.5 ml, 9.5 mmol, 2.2 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. A solution of o-anisaldehyde (0.60 g, 4.4 mmol, 1 eq.) in tetrahydrofuran (2 ml) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 1 M aqueous hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.55 g of product (60%) as a white solid.
IR (neat, cm −1 ) 3034, 2341, 2360, 1706, 1596. To a solution of (3-carboxypropyl)triphenylphosphonium bromide (2.1 g, 4.9 mmol, 1.2 eq.) in tetrahydrofuran (20 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 9.7 ml, 9.7 mmol, 2.4 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. A solution of 2,4dimethoxybenzaldehyde (0.73 g, 4.0 mmol, 1 eq.) in tetrahydrofuran (3 ml) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 1 M aqueous hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (3:1 ether:hexanes) to give 0.67 g of product (70%) as a white solid.
IR (neat, cm −1 ) 3024, 2356, 1694. To a solution of (5-carboxypentyl)triphenylphosphonium bromide (0.58 g, 1.3 mmol, 1.2 eq.) in tetrahydrofuran (6 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 2.5 ml, 2.5 mmol, 2.3 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. M -anisaldehyde (0.13 ml, 1.1 mmol, 1 eq.) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.23 g of product (92%) as a colorless oil.

7-(2-methoxyphenyl)hept-6-enoic acid, 19f
To a solution of (5-carboxypentyl)triphenylphosphonium bromide (0.57 g, 1.2 mmol, 1.2 eq.) in tetrahydrofuran (6 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 2.5 ml, 2.5 mmol, 2.5 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. A solution of o-anisaldehyde (0.14 g, 1.0 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to rt overnight. Water and ether were added. The water layer was separated and acidified with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.20 g of product (82%) as a colorless oil.

HO O OMe
OMe 7-(2,4-dimethoxyphenyl)hept-6-enoic acid, 19j To a solution of (5-carboxypentyl)triphenylphosphonium bromide (0.57 g, 1.2 mmol, 1.1 eq.) in tetrahydrofuran (6 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 2.5 ml, 2.5 mmol, 2.4 eq.) at 0 • C. The solution was stirred for 30 min, then cooled to -78 • C. A solution of 2,4-dimethoxybenzaldehyde (0.175 g, 1.05 mmol, 1 eq.) in tetrahydrofuran (2 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.220 g of product (79%) To a suspension of (5-carboxypentyl)triphenylphosphonium bromide (4.228 g, 9.245 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 18.5 mL, 18.5 mmol, 2 eq.) at 0 • C. The solution was stirred for 30 min at 0 • C. A solution of benzaldehyde (0.94 mL, 9.245 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidified with 3 M hydrochloric acid to pH = 1, then extracted three times with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel with a mixture of hexanes and ethyl acetate to give 1.242 g of product (66%) as a colorless oil and a 2:1 mixture of isomers.
The spectral data catalogued below matches that which has been previously reported for this compound To a suspension of (5-carboxypentyl)triphenylphosphonium bromide (3.968 g, 8.676 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.4 mL, 17.4 mmol, 2 eq.) at 0 • C. The solution was stirred for 30 min at 0 • C. A solution of p-anisaldehyde (1.05 mL, 8.676 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The aqueous layer was washed three times with ether. The water layer was then acidified with 3 M hydrochloric acid to pH = 1 and extracted three times with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel with a mixture of hexanes and ethyl acetate to give 1.317 g of product (65%) as a light brown solid and