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p-Toluenesulfonylmethyl isocyanide is a synthetic reagent used in the synthesis of triplet drugs with the 1,3,5-trioxazatriquinane skeleton, pyrroles, oxazoles and in imidazoles. It serves as an isonitrile component in a diastereoselective Passerini reaction. Furthermore, it is used in the Van Leusen reaction to convert aldehydes to nitriles.
Successive alkylation with different alkyl groups, followed by acid hydrolysis, leads to unsymmetrical ketones: Tetrahedron Lett., 4229 (1977). Similarly, dialkylation with ɑω-dihalides gives cyclobutanones: Synthesis, 325 (1980), or larger-ring ketones: Tetrahedron Lett., 22, 4193 (1981). Reaction of monoalkylated TosMIC with ɑω-dihalides is a useful route to 1,5- or 1,6-diketones: Rec. Trav. Chim., 104, 50 (1985):
In the presence of base (e.g. KO-t-Bu) in an aprotic solvent, e.g. DME, ketones are cyanated to give the homologous nitriles; see, e.g.: Org. Synth. Coll., 6, 41 (1988). Hindered ketones can be cyanated in DMSO: J. Org. Chem., 42, 3114 (1977). Aldehydes condense with TosMIC at -50o, followed by hydrolysis in refluxing methanol: Synth. Commun., 10, 399 (1980).
In contrast, aldehydes with K2CO3 in refluxing methanol lead to high yields of 5-substituted oxazoles: Tetrahedron Lett., 2369 (1972); with acid chlorides, the corresponding 4-tosyl oxazoles are obtained. For asymmetric induction in the oxazole synthesis by use of π-arylaldehyde-chromium tricarbonyl complexes, see: Tetrahedron: Asymmetry, 3, 287 (1992).
Other applications in heterocyclic synthesis include the synthesis of:
Imidazoles by reaction with imidoyl chlorides: Tetrahedron Lett., 2373 (1972). Thiazoles by reaction with CS2 under phase-transfer conditions: Synthesis, 501 (1977). 1,2,4-Triazoles by reaction with diazonium salts, and pyrroles by reaction with Michael acceptors: Tetrahedron Lett., 5337 (1972). Pyrroles are also formed by reaction with aldehydes followed by either ethyl cyanoacetate to give 3-cyanopyrroles: J. Org. Chem., 57, 2245 (1992), or nitromethane to give 3-nitropyrroles: Tetrahedron, 47, 4639 (1991); Synthesis, 871 (1996). The same products are also obtained by reaction of TosMIC with nitroalkenes, from Henry reaction of the aldehydes with nitromethane:
For a brief feature on uses of the reagent in synthesis, see: Synlett, 363 (2005).
Bano, H.; Yousuf, S. Crystal structure of p-toluenesulfonylmethyl isocyanide. Acta Crystallogr. Sect. A 2015, 71 (6), 0412-0412.
Murale, D. P.; Hong, S. C.; Yun, J.; Yoon, C. N.; Lee, J. S. Rational design of a photo-crosslinking BODIPY for in situ protein labeling. Chem. Commun. 2015, 51 (30), 6643-6646.
Hazard Statements: H301-H311-H331-H334
Toxic if swallowed. Toxic in contact with skin. Toxic if inhaled. May cause allergy or asthma symptoms or breathing difficulties if inhaled.
Precautionary Statements: P261-P264b-P270-P271-P280-P285-P301+P310-P302+P352-P304+P340-P311-P312-P330-P361-P363-P501c
Avoid breathing dust/fume/gas/mist/vapours/spray. Wash face, hands and any exposed skin thoroughly after handling Do not eat, drink or smoke when using this product. Use only outdoors or in a well-ventilated area. Wear protective gloves/protective clothing/eye protection/face protection. In case of inadequate ventilation wear respiratory protection. IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. IF ON SKIN: Wash with plenty of soap and water. IF INHALED: Remove to fresh air and keep at rest in a position comfortable for breathing. Call a POISON CENTER or doctor/physician. Call a POISON CENTER or doctor/physician if you feel unwell. Rinse mouth. Remove/Take off immediately all contaminated clothing. Wash contaminated clothing before reuse. Dispose of contents/ container to an approved waste disposal plant