Urea derivatives are highly active catalysts for the base-mediated generation of terminal epoxides from aldehydes and trimethylsulfonium iodide

Abstract

N,N -Diarylureas have been shown to efficiently catalyse sulfonium ylide-mediated aldehyde epoxidation reactions for the first time. These processes are of broad scope and can be coupled with a subsequent Cu(II) ion-catalysed Meinwald rearrangement to give an efficient and convenient protocol for aldehyde homologation without intermediate purification.Epoxides are among the most versatile and useful synthetic building blocks available to the organic chemist. One of the most straightforward non-oxidative methods for the synthesis of these compounds is the Corey-Chaykovsky (CC) reaction involving the base-mediated addition of sulf(ox)onium ylides to aldehydes. 1The mechanism of this reaction involves the addition of the ylide 1 (formed from the deprotonation of the corresponding sulfonium salt by the dimsyl ion 1b,d or the reaction of a sulfide with a Simmons-Smith reagent 2 ) to the carbonyl electrophile 2 to form the zwitterionic intermediate 3, which undergoes ring closure to afford the oxirane product 4 (Scheme 1). This reaction has received considerable attention and significant progress towards the development of general asymmetric variants of the process using chiral (often in situ formed) sulfonium ylides has been made.3 While smooth, enantioselective alkylidene transfer from ylides to aldehydes has been demonstrated, 4 the corresponding methylene transfer to form terminal epoxides is characterised by (super)stoichiometric sulfide loadings and moderate yields/enantioselectivity; 5 with the most successful protocols involving a metal-mediated Simmons-Smith type carbenoid transfer. 5e,fScheme 1 Mechanism of CC reaction.Since it seems clear that the hitherto most common strategy involving the use of chiral sulfonium ions is unlikely to lead to highly enantioselective methylene transfer protocols, we became interested in developing an organocatalytic strategy based on the use of hydrogen bonding 6 to activate the aldehyde towards nucleophilic attack by the ylide, the idea being that if a catalyst capable of aldehyde activation under simple CC reaction conditions could be identified, it could be later modified to do the same in a face selective manner. In addition, such a strategy would not require the tedious multistep synthesis of enantiopure sulfide catalysts.We were also intrigued by the lack of activity of the readily available and inexpensive 7 trimethylsulfonium iodide in CC reactionsfor example this salt has been shown to be unreactive under convenient biphasic conditions (aq. NaOH-CH 2 Cl 2 , rt) and has been reported to give appreciable product yields only on heating in the presence of a phase transfer catalyst 5b-d,8 -conditions not conducive to either hydrogen-bond mediated catalysis or arguably hydrogen-bond directed asymmetric induction either. Likewise, solid-liquid two-phase systems have been developed (NaOH or KOH(s)/MeCN), 9-13 however heating is involved and the formation of cinnamonitrile can also be problematic.14, 15 We therefore considered the ability to promote efficient CC reactions bet...

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

“…Reasoning, therefore, that (thio)urea derivatives could stabilise the developing negative charge on the oxygen heteroatom in the rate-determining 34 addition step (see 26, Scheme 5) transition state of the CoreyChaykovsky reaction, we set out to evaluate the influence of a range of (thio)urea catalysts in the synthesis of styrene oxide from benzaldehyde under biphasic conditions. 35 Selected results from this study are outlined in Table 3: in the absence of catalyst, no reaction was detected after 24 hours. While urea and thiourea were inactive, N,N¢-diaryl analogues with electron-deficient aromatic substituents promoted the reaction at 5 mol% levels.…”

“…To examine the validity of this hypothesis we evaluated the (thio)ureas shown in Table 5 as catalysts of the hitherto unknown organocatalytic reduction of benzil (34) to benzoin (35) in conjunction with catalytic amounts of Nbenzylnicotinamide (BNA) as the hydride donor in the presence of sodium dithionite. A range of control experiments where one of the two catalytic reaction components was removed demonstrated that significant levels of reduction occurred only when the BNA (which is reduced in situ by the dithionite) and the (thio)urea catalyst were present together (Table 5, entries 1-7).…”

Synthesis and NMR Binding Studies towards Rational Design of a Series of Electron‐Withdrawing Diamide Receptors/Organocatalysts

“…This receptor might exist in the syn – syn conformation due to intramolecular interactions between acidic aromatic C–H groups and the sulfur atom as observed for some thiourea molecules 13. Finally, a bifunctional hybrid amide/ N ‐acylsulfonamide 7 was prepared incorporating both increased hydrogen bond donating properties and also the possibility to deprotonate the sulfonyl N–H; a potentially useful feature where proton transfer may occur and/or where activation of an electrophile plays a key role in the catalytic cycle 17,18. In this paper, we report the synthesis, comparative anion binding properties, X‐ray structure of 5 and preliminary catalytic and kinetic results in the Baylis–Hillman reaction 19…”

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.…”