Computational Study-Led Organocatalyst Design:  A Novel, Highly Active Urea-Based Catalyst for Addition Reactions to Epoxides

Abstract

An in silico study examined the stabilities of hydrogen-bonded complexes between simple thiourea catalysts and three different electrophiles and identified a novel, highly active N-tosyl urea catalyst for the promotion of addition reactions to epoxide electrophiles. Synthesis and evaluation of 6 revealed it to be a powerful catalyst for the addition of 1,2-dimethylindole to styrene oxide under conditions in which simple N,N-bis-aryl ureas and thioureas (including 1) are inactive. Subsequent studies determined 6 to be compatible with a range of indole and epoxide substrates (including (E)-stilbene oxide) and found that relatively poor nucleophiles such as sterically and electronically deactivated anilines, thiophenol, and benzyl alcohol could be efficiently and regioselectively added to oxiranes under mild conditions.

The Design of Novel, Synthetically Useful (Thio)urea-Based Organocatalysts

“…43 To our delight, the N-tosylurea catalyst succeeded in accelerating the reaction where simple N,N¢-diaryl(thio)ureas failed completely (entries 1-7). 44 Of the other catalysts tested that are potentially capable of donating two hydrogen bonds to the substrate, only 47 and 48 proved marginally active (entries 8 and 9). In order to validate the convenient in silico design concept based on catalyst-substrate interactions (vide supra), we then needed to demonstrate that 44 was also capable of promoting the addition of other nucleophiles to oxirane electrophiles.…”

Computational prediction of small-molecule catalysts

“…But they are not as effective at activating epoxides. To tackle this problem, Stephen Connon, Isabel Rozas and their colleagues used computational methods to model the structures of analogues of thioureas and ureas in complex with epoxides19. On the basis of their results, they predicted that N -tosyl ureas would form stronger complexes with epoxides than would thioureas or ureas and therefore could catalyse epoxide ring-opening reactions.…”

“…Chemists designed an organocatalyst selective for the anti configuration (bottom) based on computational analysis of information from a proline-catalysed Mannich reaction16. b , The design of an epoxide-activating urea catalyst (bottom) came from the computational analysis of known thiourea catalysts (top) that activate carbonyl-containing compounds19. c , Rhodium-catalysed [5 + 2]-cycloaddition reactions of vinylcyclopropanes with allenes (not shown) or alkynes (top) are fast, but the analogous reactions with alkenes (centre) are slow.…”

Novel phenyl(thio)ureas bearing (thio)oxothiazoline group as potential BACE-1 inhibitors: synthesis and biological evaluation

“…Based on these remarks, two very simple ureas 4k and 4l were prepared and assayed as BACE-1 inhibitors. 1,3-Bis(3,5-Bis(trifluoromethyl)phenyl)urea, 4k is well known in the field of organocatalysis [42][43][44][45][46][47][48][49][50] . The two N-H are highly acidic and equivalent in 4k.…”