[556-61-6] · C2H3NS · Methyl Isothiocyanate · (MW 73.13)
(thiocarbamoylates NH, OH, SH, and organometallic compounds; used for preparation of a variety of heterocycles; derivatizes amino acids and peptides)
Alternate Name: MITC.
Physical Data: mp 31 °C; bp 117 °C; d 1.07 g cm-3.
Solubility: sol chlorinated, aromatic, hydrocarbon, ethereal solvents; reacts violently with H2O, basic and protic solvents.
Form Supplied in: white to pale orange solid; commercially available.
Handling, Storage, and Precautions: Warning: Toxic! Lachrymator! Irritant! Extremely flammable! Use only in a fume hood. Wear protective gloves and preferably a NIOSH-approved respirator. All transfers and reactions should be carried out under anhydrous conditions. Store in a cool dry place, taking care to avoid contamination with protic, basic, or organometallic materials, as these may induce (exothermic) polymerization.
Methyl isothiocyanate often differs from Methyl Isocyanate in reactivity, due to its lower overall electrophilicity and the high nucleophilicity of the S atom.2 Thus, while reaction of oxiranes with methyl isocyanate has often been reported, the same is not true for MITC, and requires a catalyst.3 Alkyl, aryl, primary, and secondary amines require no catalyst for serviceable reaction rates, and yield N,N´-disubstituted thioureas, which often display useful biological activity.4 Alcohols react slowly with MITC (days);5 the use of alkanolate salts increases the rate markedly.6 The nucleophilicity of the S atom in alkenylthiocarbamates may be attenuated to allow the preparation of 1,2-amino alcohols (from the oxazolidinones, see eq 1).6
Thiols react sluggishly (days, weeks), but often completely with MITC.7 Use of catalytic silylated thiol greatly increases the rate.8 Organometallic compounds9 and enolates10 react with MITC to provide C-thiocarbamoylated products, usually with high yields. Electron-rich aromatics will undergo extremely para-selective Friedel-Crafts acylation with MITC in high yield.11
Although not used as widely for heterocycle preparation as is methyl isocyanate, MITC provides access to a considerable variety of products. Hydrazino ketones, amino ketones, and aminoimidazoles afford (triazolo)imidazole derivatives.12 Amidines give triazines,13 amidrazones yield thiadiazoles,14 and diazomethane derivatives afford thiotriazoles.15 Hydroxychalcones provide 1,3-benzoxazine-2-thiones16 and arylpropynamides yield thiazolidin-4-ones17 upon treatment with MITC. Finally, cyanothioamides and enolizable ketones give 1,3-thiazoles18 and pyrimidinedithiones,19 respectively (see eq 2).
Phenyl isothiocyanate is generally interchangeable with MITC in the above reactions, but it seems uniquely able to undergo a Diels-Alder type reaction with 2-azadienes (see eq 3).20
MITC converts nearly all amino acids into 2-thioxo-4-oxoimidazolidines. These derivatives are readily differentiated by TLC, GC, and circular dichroism analyses, which is of use for protein analysis.21 Peptides may be modified for enhancement of activity and/or augmentation of bioavailability by reaction of side chain NH, OH, or SH groups with MITC.22
Erik P. Johnson
Ciba-Geigy Corporation, Summit, NJ, USA