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DMSO as a Reagent in the In Situ Generation of Isocyanates: A One Pot Method to Synthesize Unsymmetrical Ureas and Carbamates

Isocyanates are highly valued synthetic intermediates. Unfortunately, they are usually synthesized using toxic phosgene. Recently, the Rousseaux group published work demonstrating the in situ generation of various aryl isocyanates through reaction of DMSO, trifluoroacetic anhydride (TFAA), DBU, CO2, and an aryl amine.1 This method not only avoids using phosgene, it also eliminates the need to isolate and purify the isocyanate intermediate for subsequent reaction with either an amine or an alcohol to produce a urea or a carbamate, respectively. This one pot method also is noteworthy in that, in certain cases, purification simply requires a water wash. 

As shown in Scheme 1, DMSO plays a vital role in the generation of the isocyanate intermediate. DMSO reacts with TFAA to produce the trifluoroacetate sulfonium salt A. This salt acts as a dehydrating agent on the carbamate salt B to produce the isocyanate intermediate C. With the addition of an amine to the reaction mixture, a urea (compound 2) is generated; with the addition of an alcohol, a carbamate (compound 3) is the product. The intermediacy of the isocyanate was verified by IR monitoring of the reaction.

Scheme 1: One-pot pathway to ureas and carbamates

After optimization of the conditions, the scope of this reaction was tested with various amines (Scheme 2) and alcohols (Scheme 3).  Reaction with both primary and secondary amines universally resulted in excellent yields. Reaction with a variety of alcohols produced good to excellent yields.

Scheme 2: Synthesis of unsymmetrical ureas using this method

Scheme 3: Synthesis of carbamates using this method

To demonstrate the utility of this synthetic approach, these researchers synthesized the methyl carbamate of 4,4′-methylene diphenyl diisocyanate (MDI) (4a) and 2,4-toluene diisocyanate (TDI,) (4b). (These are important building blocks in the polymer industry.) With a brief reoptimization of the reaction conditions (changes in the proportions of the reactants), they were able to synthesize these difunctionalized compounds in excellent yields (Scheme 4).

Scheme 4: Important difunctionalized compounds synthesized by this method

In conclusion, this method provides a direct, one-pot route to unsymmetrical ureas and carbamates using DMSO, TFAA, CO2, DBU, and an aryl amine. All examples show high yield of the product. This method is straightforward and eliminates the need to use toxic phosgene in the synthesis of an isocyanate intermediate. It also does not require isolation of the isocyanate intermediate.

Debra D. Dolliver, Ph.D.

 

1 Ren, Y.; Rousseaux, S. A. L. J. Org. Chem. 2018, 83, 913.

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