(1-Phenyl-1-tosyl)methyl isocyanide

Preparation

A 1-L, three-necked, roundbottomed flask fitted with an overhead stirrer, a 100 mL addition funnel, and a temperature probe was charged with THF (200 mL) and 1615 (27.6 g, 94.8 mmol). Phosphoryl chloride (17.7 mL, 190 mmol) was added and the resulting solution was stirred for 5 min at 25 C. After cooling the solution to 0 C, triethylamine (79.3 mL, 569 mmol) was added slowly over 30¨C45 min while keeping the internal reaction temperature below 10 C. After the addition of triethylamine was complete, the reaction mixture was warmed to 5¨C10 C and maintained at this temperature for 30¨C45 min. Ethyl acetate (140 mL) and water (140 mL) were added sequentially to the reaction mixture, stirring was continued for 5 min, and then the mixture was transferred to a separatory funnel and the aqueous layer was removed. The organic layer was washed with water (2á140 mL), saturated sodium hydrogen carbonate solution (140 mL), and brine (70 mL). The organic layer was transferred to a 500-mL, round-bottomed flask and concentrated on a rotary evaporator. The residue was diluted with 1-propanol (140 mL) and this solution was concentrated on a rotary evaporator to half of its original volume. The residue was cooled to 5¨C10 C for 30 min and the beige solid that crystallized was collected by filtration through a Buchner funnel. The filter cake was rinsed with 1-propanol (2á75 mL). The beige solid was dried in vacuo for 3¨C4 h to give 18.1¨C19.7 g (70¨C 76%) of a-tosylbenzyl isocyanide 1616.
Structurally analogous to TosMIC 1600 is PhosMIC 1617, which has a phosphonate residue instead of a sulfonate residue. Some representatives have been described by Bartlett.

Synthesis

General procedure for the synthesis of 1-((isocyano(phenyl)methyl)sulfonyl)-4-methylbenzene from N-(phenyl(p-toluenesulfonyl)methyl)formamide: N-(α-toluenesulfonylbenzyl)formamide (16.73 g, 57.8 mmol) and anhydrous THF (120 mL) were added to a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer. Phosphoryl chloride (10.78 mL, 116.0 mmol) was added slowly via syringe and the resulting reaction solution was stirred at 25 °C for 5 min. Subsequently, the reaction system was cooled to about 0 °C in an ice/salt bath and triethylamine (48.4 mL, 347.0 mmol) was slowly added through a dropping funnel over 45 min while the reaction temperature was controlled below 10 °C. After the addition of triethylamine, the reaction was continued with stirring at 5-10 °C (ice bath) for 45 min. After completion of the reaction, ethyl acetate (85 mL) and water (85 mL) were added to the system, stirred for 5 min and then transferred to a separatory funnel to separate and discard the aqueous layer. The organic phase was washed sequentially with water (2 x 85 mL), saturated sodium bicarbonate solution (85 mL), and brine (50 mL), and subsequently concentrated under reduced pressure to a slurry residue. The residue was diluted with n-propanol (85 mL) and concentrated to one-half of the original volume, cooled to 0 °C and kept at 0 °C for 15 min to promote crystallization. The resulting solid was collected by filtration through a Brinell funnel, washed with cold n-propanol (2 x 50 mL) and finally dried under vacuum to give α-toluenesulfonylbenzyl isocyanide (7.47 g, 48% yield) as a beige solid.1H NMR (200 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.2 Hz), 7.30-7.52 (m, 5H), and 5.61 (s, 1H), 2.47 (s, 3H).

References

[1] Patent: WO2018/53588, 2018, A1. Location in patent: Paragraph 00101
[2] Tetrahedron Letters, 1996, vol. 37, # 45, p. 8113 - 8116
[3] Patent: WO2005/80380, 2005, A1. Location in patent: Page/Page column 28-29
[4] Patent: WO2004/14900, 2004, A1. Location in patent: Page 27
[5] Organic Syntheses, 2000, vol. 77, p. 198 - 198