Schreiner's Thiourea Research Articles

Photochemical domino reaction driven C-H/S-H functionalization of bioactive molecules to access xanthene scaffolds.

A visible-light-induced C(sp2)-H functionalization of indoles by using Schreiner's thiourea as the organocatalyst has been reported. With the aid of a three-component domino reaction between 2-hydroxybenzaldehydes, cyclic-1,3-diketones, and a variety of indoles, the corresponding densely functionalized xanthene scaffolds were isolated in good to excellent yields. Apart from these, a broad range of other bioactive natural products including kojic acid, lawsone, and 4-hydroxycoumarin were also investigated instead of indoles for the present work. All the molecules participated in the photochemical reaction smoothly and provided the desired xanthenes in synthetically valuable yields. Therefore, the present energy-efficient catalytic strategy was also very successful in executing challenging carbon-sulfur bond formation reactions, demonstrating the synthetic potentiality of the work. Notably, this air-stable, transition metal-free approach with broad functional group tolerability provides an alternative to conventional methods.

Thiourea as oxyanion stabilizer for Iridium catalyzed, base free green synthesis of amines: Synthesis of cardiovascular drug ticlopidine

Thiourea can act as a hydrogen bond donor and as a Bronsted acid catalyst. In this manuscript, Schreiner's thiourea acts as an oxyanion stabilizer for addition of alcohol to [Ir] catalyst is described. Thiourea and [Ir] catalyzed alcohol amination without any base or strong acid is reported. The method was applied for the synthesis of cardiovascular drug ticlopidine.

Maleic Acid/Thiourea‐Catalyzed Dearomative ipso‐Friedel–Crafts Reaction of Indoles to Produce Functionalized Spiroindolenines

AbstractA dearomative spirocyclization of diazo‐functionalized indoles was developed under metal‐free conditions. Although the spiroindolenine architecture with a tertiary alkyl substituent at the 2‐position is a privileged scaffold of bioactive molecules, a general synthetic strategy has remained elusive. In this study, a dual catalyst system comprising maleic acid and Schreiner's thiourea was used to construct a spiroindolenine core that was inaccessible by rhodium or silver catalysis. Computational studies revealed a unique macrocyclic transition state consisting of the substrate, maleic acid, and thiourea cocatalyst, which lowered the activation energy of spirocyclization through multipoint mutual interactions.

Influence of Anion-Binding Schreiner's Thiourea on DMAP Salts: Synergistic Catalysis toward the Stereoselective Dehydrative Glycosylation from 2-Deoxyhemiacetals.

Amines are used as additives to facilitate or increase the host-guest chemistry between the thiourea and the anions of Bronsted acids. However, we here demonstrate, for the first time, the synergistic effect of the combination of DMAP/HCl/Schreiner's thiourea in catalyzing dehydrative glycosylation. The variations in the electronic effects of the cationic Bronsted acid part (the protonated DMAP) in the presence of chloride binding Schreiner's thiourea have been discussed using NMR and X-ray crystallographic techniques.

Computational Study on the Synergic Effect of Brønsted Acid and Hydrogen-Bonding Catalysis for the Dearomatization Reaction of Phenols with Diazo Functionality.

Catalytic dearomative transformations of phenol variants via an ipso-Friedel-Crafts reaction could provide a straightforward method for the rapid assembly of functionalized spiromolecules as versatile synthetic scaffolds. We previously reported a dearomative spirocyclization reaction by merging Brønsted acid and hydrogen-bonding catalysis. However, it was unclear how the reaction proceeded and how the synergic effect was triggered. Described herein are the computational studies used to elucidate the reaction mechanism. Such calculations indicated that the applied catalysts, maleic acid and Schreiner's thiourea, work cooperatively. The synergic effect enabled the chemoselectivity to interconvert between phenol dearomatization and O-H insertion, which is a major side reaction. This investigation also revealed that not only does the Schreiner's thiourea catalyst serve as a hydrogen bonding donor, but the sulfur atom in thiourea possesses a general base function. The dual functional support of the thiourea along with maleic acid would thus realize the chemoselective prioritization of dearomatization over the O-H insertion reaction under mild conditions.

Photochemical synthesis of acetals utilizing Schreiner's thiourea as the catalyst

Schreiner's thiourea activating aldehydes in photochemical reactions.

Photoacid-Catalyzed Friedel-Crafts Arylation of Carbonyls.

In this report, we demonstrate that visible-light-induced thiourea photoacids catalyze C-C bond-forming reactions. Upon photoirradiation, Schreiner's thiourea [(N,N'-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea] catalyzes the double Friedel-Crafts addition of indoles to aldehydes and isatins to form the corresponding triarylmethanes and 3,3'-diarylindolin-2-ones. This protocol is amenable to a wide range of aldehyde and isatin electrophiles, as well as a variety of electronically diverse indoles. Mechanistic studies show that light is required for reaction initiation.

Condition Screening for Sustainable Catalysis in Single-Electron Steps by Cyclic Voltammetry: Additives and Solvents.

Cyclic voltammetry-based screening method for Cp2 TiX-catalyzed reactions is extended to the screening of solvents other than tetrahydrofuran for bulk electrolysis of the catalyst and radical arylation. It was found that CH3 CN can be used as a solvent for both processes without additives. Furthermore, in tetrahydrofuran, squaramide L2 is more efficient than the previously reported supramolecular halide binder, Schreiner's thiourea L1. The results extend the usefulness of the proposed time and resource-efficient screening method for designing catalysis reactions in single-electron steps.

Why electrostatically enhanced thiourea is better than Schreiner's thiourea in both catalytic activity and regioselectivity?

Electrostatically enhanced thiourea is more active and efficient than Schreiner's thiourea in the ring-opening aminolysis of styrene oxide with aniline, and the underlying reasons were explored by DFT calculations.

A DFT Perspective on Diels–Alder Organocatalysts Based on Substituted Phosphoramides

Phosphoramides are an interesting alternative to the thiourea motif that has long been used in organocatalysis. In the R1N(H)‐P(O)(R3)‐N(H)R2 formulation, phosphoramides give the advantage of having a third variable substituent, R3, compared to the two available in thioureas, and the possibility of introducing chirality with an asymmetric phosphorus center. In this work, we present a systematic computational study on the catalytic properties of these underexplored compounds. These studies show the catalytic potential of a series of substituted phosphoramides in Diels–Alder reactions, including the asymmetric [4+2] cycloaddition of pro‐chiral substrates. The nature of the phosphorus‐bound R3 substituent has a significant impact both on catalytic activity and enantioselectivity. Remarkably, several of the phosphoramides studied are predicted to be more active than the Schreiner's thiourea organocatalyst.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

Quantification of Catalytic Activity for Electrostatically Enhanced Thioureas via Reaction Kinetics and UV-vis Spectroscopic Measurement.

Charged thiourea derivatives containing one and two methylated or octylated pyridinium ion centers and a tetraarylborate or triflate counteranion are reported. These novel catalysts are much more active in the Friedel-Crafts reactions of trans-β-nitroalkenes with N-methylindoles than the privileged N, N'-bis(3,5-bis(trifluoromethyl)phenyl)thiourea (i.e., Schreiner's thiourea) by up to 2-3 orders of magnitude. A previously reported UV-vis spectroscopic method by Kozlowski et al. was exploited to rationalize their reactivity order along with noncharged analogues. These results offer a new design strategy for organocatalysts by introducing positively charged centers without adding additional N-H, O-H, or S-H hydrogen bond donor sites.

Direct N-Glycofunctionalization of Amides with Glycosyl Trichloroacetimidate by Thiourea/Halogen Bond Donor Co-Catalysis.

Using a halogen bond (XB) donor and Schreiner's thiourea as cooperative catalysts, various amides, including the asparagine residues of several peptides, were directly coupled with glycosyl trichloroacetimidates to give unique N-acylorthoamides in good yields. Synthetic applications of N-acylorthoamides, including rearrangement to the corresponding β-N-glycoside, were also demonstrated.

Direct N‐Glycofunctionalization of Amides with Glycosyl Trichloroacetimidate by Thiourea/Halogen Bond Donor Co‐Catalysis

AbstractUsing a halogen bond (XB) donor and Schreiner's thiourea as cooperative catalysts, various amides, including the asparagine residues of several peptides, were directly coupled with glycosyl trichloroacetimidates to give unique N‐acylorthoamides in good yields. Synthetic applications of N‐acylorthoamides, including rearrangement to the corresponding β‐N‐glycoside, were also demonstrated.

A Case Study of Thiourea‐Assisted Iminium Formation by Hydroxyl Anion Binding: Kinetic, Spectroscopic and Computational Evidences

AbstractThe experimental and computational study of the mechanism of the iminium‐organocatalyzed formation of N‐hydroxypyrrolidines from nitrones, revealed up to three activation levels of the Schreiner's thiourea used as co‐catalyst, i.e: (i) formation of the iminium ion through hydroxyl anion recognition forming a stable ion pair; (ii) enolization of the nitrone through a H‐bond network and (iii) activation of the nitrone moiety towards the final ring closure. The computational model supports the mechanism and the catalytic cycle. This mechanistic rationale is supported by the lack of reactivity of preformed iminium ion with the nitrone in the absence of thiourea‐hydroxyl complex and the observed reactivity when a complex thiourea‐tetrabutylammonium hydroxide is added.magnified image

Schreiner's Thiourea Promoted [2+2] Cycloaddition of Captodative Azetidinones and Nitroolefins

Strained, captodative benzylideneazetidinones were demonstrated to function as potent reaction partners in thermal [2+2] cycloadditions with nitro alkenes. The relief of strain during the cycloaddition could be leveraged to secure kinetic and thermodynamic stability for the aminonitrocyclobutane ring. Accordingly, this mild and robust procedure could be used to simplify the synthesis of azaspiro[3.3]heptanes, a motif that serves as a rigid piperidine bioisostere.

A Concise One‐Pot Organo‐ and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3‐b]furan‐3‐ol: An Approach to the Synthesis of HIV Protease Inhibitors

AbstractA simple and efficient one‐pot synthesis of enantiopure hexahydrofuro[2,3‐b]furan‐3‐ol, a crucial component of HIV‐1 protease inhibitors, was developed. The one‐pot process involves an organocatalytic condensation followed by an enzymatic optical resolution. The condensation of 1,2‐dihydrofuran and glycolaldehyde was achieved using Schreiner's thiourea catalyst (1 mol‐%). A subsequent lipase‐catalyzed kinetic resolution gave the target alcohol with >99 % ee. To demonstrate the practicality of this method, Darunavir, an HIV‐1 protease inhibitor used to treat multi‐drug‐resistant HIV, was synthesized.

Electrostatically Enhanced Thioureas.

A new class of readily prepared thiourea catalysts with one or more positively charged centers and no new hydrogen-bonding sites are exploited in several bond-forming reactions and are orders of magnitude more reactive than Schreiner's thiourea. These findings provide the basis for a new strategy for activating hydrogen-bond catalysts.

ChemInform Abstract: N,N′‐Bis[3,5‐bis(trifluoromethyl)phenyl]thiourea: A Privileged Motif for Catalyst Development

AbstractReview: 64 refs.

N,N′-Bis[3,5-bis(trifluoromethyl)phenyl]thiourea: a privileged motif for catalyst development

Over the last decade, the use of (thio)urea derivatives as organocatalysts in organic chemistry has increased rapidly. One of the key features is their ability to activate substrates and subsequently stabilize partially developing negative charges (e.g., oxyanions) in the transition states employing explicit double hydrogen bonding. Among (thio)urea-based catalysts, N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea developed by Schreiner's group (abbreviated here as Schreiner's thiourea) has played a very important role in the development of H-bond organocatalysts. Nowadays it is used extensively in promoting organic transformations, and the 3,5-bis(trifluoromethyl)phenyl motif thereof is used ubiquitously in H-bond catalysts. This review summarizes the key developments of Schreiner's thiourea-mediated reactions with the aim to further expand the applications of (thio)urea-based catalysts.