Sulfonium Ylides Research Articles

Sequential Formal [4+1]‐Cycloaddition, C−H Functionalization and Suzuki–Miyaura Cross‐Coupling for the Synthesis of Trisubstituted Isoxazolines

AbstractSuzuki–Miyaura cross‐coupling reaction of 3‐bromomethyl isoxazolines with arylboronic acids was suggested as final C−C bond forming step in convenient diastereoselective route to trisubstituted isoxazolines. The required bromides were readily available from nitroalkenes and sulfonium ylides through an efficient sequence of formal [4+1]‐cycloaddition and C−H functionalization of intermediate isoxazoline N‐oxides. The synthetic utility of the obtained isoxazolines was demonstrated by their conversion into valuable products such as hydroxy ketone, pyrrolidinone, etc.

Sulfur-Mediated Reactions through Sulfonium Salts and Ylides

AbstractThis Account discusses several new reaction methods developed in our group that utilize sulfur-mediated reactions through sulfonium salts and ylides, highlighting the interplay of rational design and serendipity. Our initial goal was to convert aliphatic C–H bonds into C–C bonds site-selectively, and without the use of transition-metal catalysts. While a proof-of-concept has been achieved, this target is far from being ideally realized. The unexpected discovery of an anti-Markovnikov rearrangement and subsequent studies on difunctionalization of alkynes were much more straightforward, and eventually led to the new possibility of asymmetric N–H insertion of sulfonium ylides through Brønsted acid catalysis.1 Introduction2 Allylic/Propargylic C–H Functionalization3 Anti-Markovnikov Rearrangement4 Difunctionalization of Alkynes5 Asymmetric N–H Insertion of Sulfonium Ylides6 Conclusion

Ruthenium-Catalyzed Chemoselective N-H Bond Insertion Reactions of 2-Pyridones/7-Azaindoles with Sulfoxonium Ylides.

A ruthenium-catalyzed highly chemoselective N-alkylation of 2-pyridones has been developed, affording N-alkylated 2-pyridone derivatives in good yields and excellent N-selectivity. The key to achieve this unprecedented N-H rather than O-H insertion reaction is the use of CpRu(PPh3)2Cl as the catalyst and sulfoxonium ylides as the alkylation reagents. Moreover, this protocol is also amenable to 7-azaindoles by slightly varying the reaction conditions. Furthermore, sulfonium ylides are also suitable alkylation reagents, providing the N-alkylated 2-pyridones in good selectivity.

Synthesis of α,β-unsaturated epoxy ketones utilizing a bifunctional sulfonium/phosphonium ylide.

Herein, a new protocol for rapid synthesis of α,β-unsaturated epoxy ketones utilizing a bifunctional sulfonium/phosphonium ylide is described. This approach comprises two sequential chemoselective reactions between sulfonium and phosphonium ylides and two distinct aldehydes, which allows for the rapid construction of a variety of unsymmetric α,β-unsaturated epoxy ketones. This methodology allows the rapid construction of the core reactive functionality of a family of lipid peroxidation products, the epoxyketooctadecenoic acids, but can be further broadly utilized as a useful synthon for the synthesis of natural products, particularly those derived from oxidized fatty acids. Accordingly, a protocol utilizing this approach to synthesize the epoxyketooctadecenoic acid family of molecules is described.

A cascade deprotonation/intramolecular aldol reaction of α-carbonyl sulfonium ylides with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes to access thieno[2,3-b]indoles and benzothiophenes.

The first catalyst-free cascade deprotonation/intramolecular aldol reaction of α-carbonyl sulfonium ylides with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes was developed. A series of thieno[2,3-b]indoles and benzothiophenes were smoothly obtained in high to excellent yields. The salient features of the protocol include catalyst-free conditions, an environment-friendly solvent, broad substrate scope, and large-scale synthesis.

Diastereoselective sulfur ylide rearrangements from gold catalyzed oxidation of ynamides

The [2,3]-sigmatropic rearrangement of sulfonium ylides bearing substituted allyl groups creates two contiguous stereocentres. Low diastereoselectivity is typically observed from commonly used α-diazocarboxylic ester precursors. High diastereoselectivity was previously revealed in a gold-catalyzed multicomponent route into allyl sulfonium ylides by reaction of ynamide, oxidant and allyl sulfides. The effect of substrate modifications on the diastereoselectivity have been studied, with N -phenyl methanesulfonamide derived ynamides proving the most effective. This report includes an enhanced experimental procedure, and a demonstration that the gold-catalyzed process remains highly effective at −78 °C.

C2-Selective C-H Methylation of Heterocyclic N-Oxides with Sulfonium Ylides.

A redox-neutral C2-selective methylation of heterocyclic N-oxides with sulfonium ylides is described herein. This report presents unprecedented findings for the utility of sulfonium ylides as the methylation source of N-heterocycles beyond the Corey-Chaykovsky reaction. Intriguingly, pyrrolidine plays a significant role in minimizing the reductive C2-methylation process. This method is characterized by its mild conditions, simplicity, and excellent site selectivity. The applicability of the developed protocol is showcased by the late-stage methylation and sequential transformations of complex drug molecules.

Cu(I)/Chiral Bisoxazoline-Catalyzed Enantioselective Sommelet-Hauser Rearrangement of Sulfonium Ylides.

Catalytic asymmetric thia-Sommelet-Hauser rearrangement of sulfonium ylides remains a great challenge due to its multistep reaction mechanism involving metal carbene formation, proton transfer, and [2,3]-sigmatropic rearrangement. In particular, the key problem of such reactions is the differentiation of the enantiotopic lone pair electrons of sulfur, which generates the sulfonium ylide intermediate bearing chirality on the sulfur atom. With a modified chiral bisoxazoline ligand, we developed a Cu(I)-catalyzed asymmetric thia-Sommelet-Hauser rearrangement with good to excellent enantioselectivities. Mechanistic studies provide insights into the details of the reaction mechanism.

Computational insight into the mechanism and origin of high regioselectivity in the ring-opening cyclization of spirocyclopropanes with stabilized sulfonium ylides by the DFT.

Chromanes with high bioactivity play an important role in nature, and cyclization reactions of cyclopropanes with sulfonium ylides to form chromane skeletons have attracted great attention of scientists. The mechanism as well as origins of regioselectivity and stereoselectivity for the ring-opening/cyclization reactions between cyclohexane-1,3-dione-2-spirocyclopropanes and stabilized sulfonium ylides in CH2Cl2 were investigated by using the density functional theory (DFT) M06-2X/6-311+G(d,p)//M06-2X/6-31G(d,p) method combined with the SMD model. The calculated results revealed that the reaction process involved two key steps: the ring-opening step and the cyclization step, with the former being the rate-determining and stereoselectivity-determining step. The regioselectivity of the ring-opening step of spirocyclopropane indicated that the tertiary carbon was more preferential than the secondary one when sulfonium ylide attacked spirocyclopropane. The theoretical results confirmed that the stereoselectivity of the reaction to form the trans-isomer product is more favorable than the cis-isomer, and the calculated trans/cis ratio is in accordance with the experiment. Moreover, the conceptual density functional theory reactivity indices suggest that the electronic effect controls the regioselectivity. What is more, the stereoselectivity analyzed by weak non-covalent interaction also shows the importance of electronic effect. Graphical Abstract.

Gold-Catalyzed Sigmatropic Rearrangement Reactions via Carbene Transfer Reactions.

Sigmatropic rearrangements are an important fundamental toolbox in organic synthesis to access complex molecular fragments. Yet, the rearrangement reactions of onium ylides via gold catalyzed carbene transfer reactions are relatively unexplored. Herein, we describe a gold-catalyzed sigmatropic rearrangement of sulfonium and selenium ylides (39 examples, up to 99% yield). Furthermore, we report on the limitations of sigmatropic rearrangement reactions of aryl allyl anilines, which deliver exclusively C-H functionalized products.

Monofluoromethyl‐Substituted Sulfonium Ylides: Preparation, Structure‐Reactivity Study and Substrate Scope†

Summary of main observation and conclusionStructure‐reactivity study of a family of electrophilic monofluoromethylating reagents based on sulfonium ylide skeleton with different steric hindrance and electron‐withdrawing properties was described. These studies led us to discover two highly reactive reagents 3 with a cyclic malonate backbone and 6 with an electron‐poor 1,1,1,5,5,5‐hexafluoropentane‐2,4‐dione backbone. The high reactivity of reagent 6 allowed to highly selectively access either C‐monofluoromethylated or O‐monofluoromethylated β‐ketoesters in high yields by the use of different bases. In addition, reactions of reagent 3 with a variety of nucleophiles including phenols, carboxylic acids, thiophenols or heteroaryl nucleophiles occurred in full conversion within 10 min at room temperature and the scopes for these reactions were reported in detail.

Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of α-Tertiary Amino Ketones from Sulfonium Ylides.

Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones, which is particularly useful for the less accessible acyclic α-tertiary cases. By a protonation-amination sequence, our approach represents a rare asymmetric H-heteroatom bond insertion by α-carbonyl sulfonium ylides, an attractive surrogate of diazocarbonyls. The mild intermolecular C-N bond formation was catalyzed by chiral phosphoric acids with excellent efficiency and enantioselectivity. The products are precursors to other important chiral amine derivatives, including drug molecules and chiral ligands. The enantioselectivity was controlled by dynamic kinetic resolution in the amination step, rather than the initial protonation. This process opens up a new platform for the development of other related insertion reactions.

Regioselective Difunctionalization of 2,6-Difluorophenols Triggered by Sigmatropic Dearomatization.

Regioselective difunctionalization of 2,6-difluorophenols with aryl sulfoxides and nucleophiles has been accomplished. The reaction is composed of (1) Pummerer-based [3,3] sigmatropic dearomatization to generate 2,4-cyclohexadienone, (2) Michael addition of a nucleophile, and (3) liberation of HF for rearomatization. Besides the [3,3] rearrangement, [2,3] sigmatropic rearrangement from sulfonium ylide generated from alkyl sulfoxide promotes the dearomatization, resulting in installation of α-sulfanylalkyl group.

Cover Picture: Hemin Catalyzed Dealkylative Intercepted [2, 3]‐Sigmatropic Rearrangement Reactions of Sulfonium Ylides with 2, 2, 2‐Trifluorodiazoethane (Adv. Synth. Catal. 10/2020)

Cover Picture: Hemin Catalyzed Dealkylative Intercepted [2, 3]‐Sigmatropic Rearrangement Reactions of Sulfonium Ylides with 2, 2, 2‐Trifluorodiazoethane (Adv. Synth. Catal. 10/2020)

Hemin Catalyzed Dealkylative Intercepted [2, 3]‐Sigmatropic Rearrangement Reactions of Sulfonium Ylides with 2, 2, 2‐Trifluorodiazoethane

AbstractA dealkylative intercepted [2, 3]‐sigmatropic rearrangement reaction of allylic sulfides with 2, 2, 2‐trifluorodiazoethane (CF3CHN2) is reported, the commercially available and biocompatible catalyst hemin was found to efficiently catalyze this transformation across a diverse set of allylic sulfides with in situ generated CF3CHN2, providing excellent yields (up to 99%) under mild condition without inert gas protection. In addition, CF3CHN2 exhibited unique reactivity toward this process compared with other frequently used diazo reagents. This work expands the range of carbene‐mediated transformations catalyzed by hemin and introduces a concise and general strategy for exploiting new possibility of reactions concerning organosulfides.magnified image

Towards the Preparation of Stable Cyclic Amino(ylide)Carbenes.

Cyclic amino(ylide)carbenes (CAYCs) are the ylide-substituted analogues of N-heterocyclic Carbenes (NHCs). Due to the stronger π donation of the ylide compared to an amino moiety they are stronger donors and thus are desirable ligands for catalysis. However, no stable CAYC has been reported until today. Here, we describe experimental and computational studies on the synthesis and stability of CAYCs based on pyrroles with trialkyl onium groups. Attempts to isolate two CAYCs with trialkyl phosphonium and sulfonium ylides resulted in the deprotonation of the alkyl groups instead of the formation of the desired CAYCs. In case of the PCy3-substituted system, the corresponding ylide was isolated, while deprotonation of the SMe2-functionalized compound led to the formation of ethene and the thioether. Detailed computational studies on various trialkyl onium groups showed that both the α- and β-deprotonated compounds were energetically favored over the free carbene. The most stable candidates were revealed to be α-hydrogen-free adamantyl-substituted onium groups, for which β-deprotonation is less favorable at the bridgehead position. Overall, the calculations showed that the isolation of CAYCs should be possible, but careful design is required to exclude decomposition pathways such as deprotonations at the onium group.

Photochemical Doyle-Kirmse Reaction: A Route to Allenes.

This Letter describes the metal-free, blue-light-induced [2,3]-sigmatropic rearrangement of sulfonium ylides generated from donor/acceptor diazoalkanes and propargyl sulfides. The reaction furnishes highly functionalized allenes from a broad range of starting materials in decent yield. Mechanistic experiments supported by the literature data suggest singlet carbenes as intermediates in this reaction.

Synthesis of Epoxides from Alkyl Bromides and Alcohols with in Situ Generation of Dimethyl Sulfonium Ylide in DMSO Oxidations.

Direct conversion of the readily available alkyl bromides and alcohols to value-added epoxides using dimethyl sulfoxide (DMSO) under mild reaction conditions has been developed. Benzyl and allyl bromides, and activated and unactivated alcohols all proceeded smoothly to give epoxides in high to excellent yield. Dimethyl sulfide, generated by DMSO oxidations, was in situ elaborated to form the substituted dimethyl sulfonium ylide species that participates in the Corey-Chaykovsky epoxidation in a domino and one-pot fashion, respectively.

Iridium-Catalyzed B-H Bond Insertion Reactions Using Sulfoxonium Ylides as Carbene Precursors toward α-Boryl Carbonyls.

An iridium-catalyzed B-H bond insertion reaction between borane adducts and sulfoxonium ylides to afford α-boryl carbonyls has been developed. The starting materials are safe and readily available. In addition, analogues of sulfoxonium ylides, such as sulfonium salts and sulfonium ylides could also be amenable to the reaction.

Retro‐Corey‐Chaykovsky Epoxidation: Converting Geminal Disubstituted Epoxides to Ketones

AbstractCorey‐Chaykovsky epoxidation has been widely applied in the conversion of aldehydes and ketones to epoxides with sulfonium and sulfoxonium ylides. The reverse transformation is realized for conversion of geminal disubstituted epoxides to ketones in the presence of DABCO in refluxing mesitylene. The method is a weak basic transformation from epoxides to ketones with loss of a methylene group and can be applied as an alternative strategy of the acid‐catalyzed Meinwald rearrangement or oxidation for conversion of epoxides to carbonyl compounds.