Synthesis of trithiocarbonate raft agents and intermediates thereof

Preparation of Bis(Dodecylsulfanylthiocarbonyl) Disulfide

A 2000 mL 4-neck round bottom flask (fitted with mechanical stirrer, septum, thermocouple well, and reflux condenser with N 2 bubbler) was charged with heptane (1000 mL) and a solution of potassium t-butoxide in tetrahydrofuran (174.4 g, containing 34.7 g potassium t-butoxide, 0.31 mol). The resulting solution was cooled to ca. 5° C. and reacted with dodecanethiol (60.6 g, 0.30 mol, Sigma-Aldrich Co., Milwaukee, Wis.). The resulting white slurry was stirred for 30 min at 5-10° C. and then reacted with carbon disulfide (23.5 g, 0.31 mol) over a 20 min period. The mixture was stirred at 5° C. for 10 min, allowed to warm to 20-23° C. and stirred for 4 h. The resulting yellow slurry was reacted in portions with iodine (40.0 g, 0.158 mol) over a 40 min period at 16-18° C. The mixture was stirred at room temperature for 15 h. Distilled water was added, and the separated organic phase was washed with a solution of sodium chloride and sodium thiosulfate, then with sodium chloride solution. The organic layer was dried and the solvent was evaporated to provide 84.2 g (98%) of yellow solid. 1 H NMR (CDCl 3 ): 3.28 (t, J=7.4, a=97.75), 2.92 (minor triplet a=2.1), 2.66 (very minor triplet, a=0.52), 1.68 (apparent quintet, a=102.0), 1.43 to 1.17 (remaining CH 2 signals, a=914), 0.87 (t, J=7.0, a=153.1).

Preparation of 4-Cyano-4-(dodecylsulfanythiocarbonyl)sulfanyl Pentanoic Acid

A 2 liter, 3-neck flask fitted with reflux condenser, solids addition port, thermowell, and stir bar was charged with bis(dodecylsulfanylthiocarbonyl) disulfide (84.1 g, 151.6 mmol) and 760 mL ethyl acetate. The resulting solution was heated to gentle reflux and reacted with 4,4′-azobis(4-cyanopentanoic acid) (72.1 g, 257 mmol) (Wako Chemicals USA, Inc., Richmond, Va.) over 3.75 h. The reaction mixture was heated for an additional 16 h.

Ethyl acetate was removed under reduced pressure and the product was allowed to crystallize from heptane. The solid was filtered, washed with water, and dried to provide 110.0 g (91%). 1 H NMR (CDCl 3 ): 3.31 (t, a=2.00), 2.72 to 2.61 (m) and 2.58 to 2.34 (AB pattern with additional coupling, combined a=3.96), 1.87 (s, a=2.94), 1.68 (m, a=2.02), 1.42 to 1.20 (overlapping CH 2 signals, a=18.62), 0.87 (t, a=3.07), bd acid peak at ca. 10.0. Purity>99%. 13 C NMR (CDCl 3 ): 216.91 (C═S), 177.52 (CO 2 H), 118.96 (CN), 46.38, 37.24, 33.65, 32.01, 29.72 (overlapping signals), 29.68, 29.64, 29.52, 29.43, 29.17, 29.03, 27.79, 24.97, 22.78, 20.12, 14.20.

Preparation of Methyl 4-Cyano-4-(dodecylsulfanythiocarbonyl)sulfanyl Pentanoate

A solution of 4-cyano-4-(dodecylsulfanythiocarbonyl)sulfanyl pentanoic acid (C 12 H 25 SC(S)SC(Me)(CN)CH 2 CH 2 CO 2 H, 64.8 g, 160.5 mmol) in THF (195 mL) at 5-10° C. was treated with diazabicyclo[5.4.0]undec-7-ene (26.9 g, 176.6 mmol). The mixture was stirred for 5 min, then treated with methyl iodide (25.9 g, 182 mmol), and the resulting mixture was stirred for 18 hr.

The reaction mixture was diluted with heptane, filtered, and the solid was rinsed with heptane. The filtrate was washed successively with dilute sodium chloride, 1N hydrochloric acid, dilute sodium bicarbonate solution, and water. The dried organic phase was evaporated to give 64.13 g (96%) of amber oil.

1 H NMR: (CDCl 3 ): 3.70 (s, a=3.00), 3.31 (t, a=2.04), 2.66 to 2.56 (m, a=2.05) and 2.54 to 2.33 (AB pattern with additional coupling, a=2.05), 1.86 (s, a=3.02), 1.68 (m, a=2.27), 1.42 to 1.20 (overlapping CH 2 groups, a=19.24), 0.87 (t, a=3.28).

Preparation of Methoxymethyl Ester

A mixture of 4-cyano-4-(dodecylsulfanythiocarbonyl)sulfanyl pentanoic acid (1.21 g, 3.0 mmol), THF (10 mL), and freshly ground potassium carbonate (0.42 g, 3 mmol) was treated with chloromethyl methyl ether (0.25 mL, 3.1 mmol, Sigma-Aldrich Co., Milwaukee, Wis.). The mixture was heated at 40° C. and stirred for 18 h. The mixture was filtered and solid was washed with ethyl acetate. Evaporation provided 1.31 g viscous oil. 1 H NMR (CDCl 3 ): 5.24 (s, a=2.01), 3.47 (s, a=3.01), 3.31 (t, a=2.00), 2.70 to 2.61 (m, a=2.15), 2.56 to 2.34 (AB pattern with additional couplings, a=2.07), 1.87 (s, a=2.85), 1.68 (m, a=2.17), 1.38 (m) and 1.32 to 1.2 (overlapping CH 2 's, a=21.1), 0.87 (t, a=3.50). Consistent with desired ester; purity estimate=95%.

Comparative Example A

Attempted Synthesis of Bis(dodecylsulfanylthiocarbonyl) Disulfide

A 1000 mL 4-neck round bottom flask (fitted with mechanical stirrer, septum, thermocouple well, and condenser with N 2 inlet) was charged with a solution of potassium t-butoxide (17.2 g, 0.153 mol) in tetrahydrofuran (200 mL). The solution was cooled to ca. 5° C. and treated with dodecanethiol (30.3 g, 0.15 mol). The reaction mixture was stirred for 30 min at 5-10° C. The thick slurry was treated with carbon disulfide (11.8 g, 0.154 mol) over a ca. 30 min period. The mixture became yellow. The mixture was stirred at ca. 0° C. for 1 h and then was allowed to warm to room temperature. The resulting yellow solution was treated in portions with iodine prills (19.0 g, 0.075 mol) over a 20 min period, keeping the temperature controlled below 28-30° C. When iodine addition was complete, the mixture was stirred for 1.5 h. Ethyl acetate (300 mL) was added, and the mixture was treated with water (50 mL) and then with sodium thiosulfate solution (50 mL) and stirred vigorously. The organic layer was washed twice with sodium chloride solution, dried over Na 2 SO 4 , and evaporated to give only 31.6 g of almost colorless solid. 1 H NMR featured a major downfield CH 2 S signal at 2.67, and only traces of other triplet signals in the 3.4 to 2.8 range. The mass spectrum exhibited parent ion with m/e=402.335, consistent with C 24 H 50 S 2 , bis(dodecyl) disulfide.