Ethoxycarbonyl Isothiocyanate1


[16182-04-0]  · C4H5NO2S  · Ethoxycarbonyl Isothiocyanate  · (MW 131.49)

(highly reactive isothiocyanate for condensation and cyclization reactions to form thioamides, thioureas, and heterocycles1)

Physical Data: bp 44-46 °C/10 mm Hg; d 1.160 g cm-3.

Solubility: freely miscible in most organic solvents.

Form Supplied in: colorless to pale brown liquid.

Purification: distillation in vacuo.

Handling, Storage, and Precautions: exceedingly pungent odor, irritating to eyes and nose; store at 0 °C; slowly decomposed by water; reacts exothermically with alcohols and amines. This reagents should only be handled in a fume hood.

Thiourea Synthesis.

Ethoxycarbonyl isothiocyanate reacts with stoichiometric amounts of ammonia, primary, and secondary amines to afford the expected thioureas in high yield (eq 1).1

Synthesis of Thioamides.

Friedel-Crafts thioacylation of aromatics with ethoxycarbonyl isocyanate mediated by Aluminum Chloride gives moderate to good yields of arylthioamides or N-ethoxycarbonylthioamides, dependent on reaction conditions (eq 2).2

The thioamides synthesized by the reaction of cyclic or acyclic enamines with ethoxycarbonyl isothiocyanate can be isolated or carried on further to 4-thiouracils upon treatment with an additional primary amine (eq 3).3,4

Synthesis of Heterocycles.

Ethoxycarbonyl isothiocyanate is sufficiently reactive for functionalization of urea nitrogens. Treatment of N,N-disubstituted ureas with ethoxycarbonyl isothiocyanate followed by base-catalyzed ring closure and S-methylation provides a convenient synthesis of 1,3,5-triazine-2,4-diones (eq 4).5

Ethoxycarbonyl isothiocyanate was used as a key starting point in a convenient and multigram synthesis of 1,2,4-oxadiazolidine-3,5-dione (eq 5), a bioisostere for the carboxylic acid group.6

The synthesis of 5-amino-1,2,3-thiadiazoles can be achieved through [3 + 2] cycloaddition of ethoxycarbonyl isothiocyanate with diazo ketones (eq 6).7

The reaction of 2-alkylamino8 and 2-alkylhydrazino9 aza-heterocycles with ethoxycarbonyl isothiocyanate has been used to generate interesting mesoionic species.

1. Esmail, R.; Kurzer, F. S 1975, 301.
2. Papadopoulos, E. P. JOC 1976, 41, 962.
3. Lamon, R. W. JHC 1968, 5, 837.
4. Takahata, H.; Nakajima, T.; Yamazaki, T. S 1984, 703.
5. Sanemitsu, Y. S 1985, 429.
6. Renaut, P.; Thomas, D.; Bellamy, F. D. S 1991, 265.
7. Burger, K.; Rudolph, M.; Neuhauser, H.; Gold, M. S 1992, 1150.
8. Coburn, R. A.; Bhooshan, B. JOC 1973, 38, 3868.
9. Marley, H.; McCullough, K. J.; Preston, P. N.; Wright, S. H. B. CC 1988, 506.

Frank J. Villani, Jr.

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA

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