A more sustainable isothiocyanate synthesis by amine catalyzed sulfurization of isocyanides with elemental sulfur

Abstract

Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its derivatives, or CS₂. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides, elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was optimized in terms of sustainability, especially considering benign solvents such as Cyrene™ or γ-butyrolactone (GBL) under moderate heating (40 °C). Purification by column chromatography was further optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989 were achieved and the versatility of this straightforward procedure was shown by converting 20 different isocyanides under catalytic conditions, while obtaining moderate to high yields (34-95%).

Scheme 1. Overview of reported synthesis protocols towards isothiocyanates.

Scheme 2. Possible mechanistic pathway of the MCR between isocyanide (black), elemental sulfur (purple) and an amine (blue), whereby the amine acts as reactant as well as catalyst to form polysulfur chains A. Applying primary or secondary amines leads to thioureas, while tertiary amines lead to isothiocyanates B.

Scheme 3. Herein synthesized ITCs 3a–3t using the new procedure in a 2.5 mmol scale using elemental sulfur (1.12 eq. of sulfur atoms). If the isocyanide was a liquid at 40 °C, 2 mol% DBU and 417 μL solvent was used, if it was a solid, 5 mol% DBU and 1.25 mL solvent were used. For each compound, the yield and the reaction time are displayed. The first line corresponds to the reaction using Cyrene™ as solvent, the second line using GBL. The third line displays the reaction in Cyrene™ in a 15.5 mmol scale. GC-purities were in general >95% (see ESI†). (a) GC-purity was not determined (n.d.); (b) pressure vial was used; (c) GC-purity of the starting material 1i was 80% and of ITC 3i 83%; (d) 2.31 mmol isocyanide 1k was used; (e) 5 mol% DBU was used; (f) 2.00 mmol isocyanide 1t was used; (g) starting material was not/less soluble.

Scheme 4. Synthesis of polythioureas P1–3 with 1,5-diaminopentane 4 (green) and herein synthesized ITCs 3c, 3d and 3h (black).