Cross‐Coupling of α‐Carbonyl Sulfoxonium Ylides with C−H Bonds

The functionalization of carbon–hydrogen bonds in non‐nucleophilic substrates using α‐carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross‐coupling reactions of sulfoxonium ylides with C(sp²)−H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C−H activation, migratory insertion of the ylide into the carbon–metal bond, and protodemetalation, the last step being turnover‐limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium‐catalyzed dehydrative cyclization.     

An efficient method to prepare sulfoxonium ylides and their reactivity studies using copper powder and Sc(III) as catalysts: Molecular and electronic structure analysis

Sulfoxonium ylides are the viable alternatives for diazo compounds as carbene precursors. Unlike diazo compounds, these are bench-stable and crystalline solids. However, the existing methods for the synthesis of sulfoxonium ylides have disadvantages related to the yields, substrate scope, and usage of expensive catalysts. Therefore, it is necessary to develop efficient and competitive protocols for the preparation of sulfoxonium ylides. In this study, we developed an economically affordable protocol for the synthesis of sulfoxonium ylides from diazo compounds using copper powder as a catalyst. This protocol leads to the efficient multigram-scale synthesis of a wide range of sulfoxonium ylides in good yields. Further, we demonstrated scandium triflate–catalyzed carbene insertion into the N−H bond from sulfoxonium ylide. A variety of anilines and sulfoxonium ylides with various functional groups reacted well and produced the corresponding α-amino esters in good yields. All the synthesized compounds were characterized using various standard spectroscopic and analytical techniques. We also used computational methods to understand the electronic structure of all the sulfoxonium ylides using geometry optimization, frequency calculation, molecular orbital and natural bond orbital analysis, and energy decomposition analysis. Our computational results revealed that the interaction between carbene and dimethyl sulfoxide is covalent in nature and stable enough to handle in the absence of any catalyst.     

Enantioselective S−H Insertion Reactions of α-Carbonyl Sulfoxonium Ylides

The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S−H insertion reactions of aryl thiols and α-carbonyl sulfoxonium ylides.     

Co(III), Rh(III) & Ir(III)-Catalyzed Direct C−H Alkylation/Alkenylation/Arylation with Carbene Precursors

Metal carbenes play a pivotal role in transition-metal-catalyzed synthetic transfer reactions. The metal carbene is generated either from a diazo compound through facile extrusion of N₂ with a metal catalyst or in situ generated from other sources like triazoles, pyriodotriazoles, sulfoxonium ylides and iodonium-ylide. On the other hand, Co(III), Rh(III) & Ir(III)-catalyzed C−H functionalizations have been well established as a key synthetic step to enable the construction of various synthetic transformations. Interestingly, in recent years, merging of these two concepts C−H activation and carbene migratory insertion gained much attention, in particular group 9 metal-catalyzed arene C−H functionalizations with carbene precursors via carbene migratory insertion. In this review, we summarize recent advances in Co(III), Rh(III) & Ir(III)-catalyzed direct C−H alkylation/alkenylation/arylation with carbene precursors and also discuss key synthetic intermediates within the catalytic cycles.     

Insights into the Activation Mode of α-Carbonyl Sulfoxonium Ylides in Rhodium-Catalyzed C−H Activation: A Theoretical Study

A computational study has been performed to investigate the mechanism of Rh^III-catalyzed C−H bond activation using sulfoxonium ylides as a carbene precursor. The stepwise and concerted activation modes for sulfoxonium ylides were investigated. Detailed theoretical results showed that the favored stepwise pathway involves C−H bond activation, carbonization, carbene insertion, and protonation. The free energy profiles for dialkylation of 2-phenylpyridine were also calculated to account for the low yield of this reaction. Furthermore, the substituent effect was elucidated by comparing the energy barriers for the protonation of meta- and para-substituted sulfoxonium ylides calculated by density functional theory.     

Chemospecific Cyclizations of α‐Carbonyl Sulfoxonium Ylides on Aryls and Heteroaryls

The functionalization of aryl and heteroaryls using α‐carbonyl sulfoxonium ylides without the help of a directing group has remained so far a neglected area, despite the advantageous safety profile of sulfoxonium ylides. Described herein are the cyclizations of α‐carbonyl sulfoxonium ylides onto benzenes, benzofurans and N‐p‐toluenesulfonyl indoles in the presence of a base in HFIP, whereas pyrroles and N‐methyl indoles undergo cyclization in the presence of an iridium catalyst. Significantly, these two sets of conditions are chemospecific for each groups of substrates.     

Enantioselective Synthesis of 1,2-Benzothiazine 1-Imines via RuII/Chiral Carboxylic Acid-Catalyzed C−H Alkylation/Cyclization

Sulfondiimines are diaza-analogues of sulfones with a chiral sulfur center. Compared to sulfones and sulfoximines, their synthesis and transformations have so far been studied to a lesser extent. Here, we report the enantioselective synthesis of 1,2-benzothiazine 1-imines, i.e., cyclic sulfondiimine derivatives from sulfondiimines and sulfoxonium ylides via C−H alkylation/cyclization reactions. The combination of [Ru(p-cymene)Cl₂]₂ and a newly developed chiral spiro carboxylic acid is key to achieving high enantioselectivity.     

Direct synthesis of benzoxazinones via Cp*Co(III)-catalyzed C–H activation and annulation of sulfoxonium ylides with dioxazolones

A highly novel and direct synthesis of benzoxazinones was developed via Cp*Co(III)-catalyzed C–H activation and [3 + 3] annulation between sulfoxonium ylides and dioxazolones. The reaction is conducted under base-free conditions and tolerates various functional groups. Starting from diverse readily available sulfoxonium ylides and dioxazolones, a variety of benzoxazinones could be synthesized in one step in 32%-75% yields.     

亚砜叶立德在C—H键活化反应中的应用研究进展

过渡金属催化的导向C—H键活化反应具有反应效率高、选择性好、原子经济等优点,特别是卡宾前体参与的C—H活化反应已经发展为一种新颖的构筑碳碳键的合成策略.相比于传统的重氮化合物等卡宾前体,亚砜叶立德作为一种新型的卡宾前体,具有易于制备、性质稳定、操作安全等诸多优点,被广泛应用于C—H活化反应,可以便捷地转化成各种酰甲基化...     

Rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.     

Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

The first example of enantioselective S?H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S?H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.     

Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides

Described here is the first organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C–N bond formation is rate-determining.

An organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides has been developed to provide efficient access to α-amino esters without involving a metal carbenoid intermediate.     

Insights into the Activation Mode of α‐Carbonyl Sulfoxonium Ylides in Rhodium‐Catalyzed C−H Activation: A Theoretical Study

A computational study has been performed to investigate the mechanism of Rh^III‐catalyzed C−H bond activation using sulfoxonium ylides as a carbene precursor. The stepwise and concerted activation modes for sulfoxonium ylides were investigated. Detailed theoretical results showed that the favored stepwise pathway involves C−H bond activation, carbonization, carbene insertion, and protonation. The free energy profiles for dialkylation of 2‐phenylpyridine were also calculated to account for the low yield of this reaction. Furthermore, the substituent effect was elucidated by comparing the energy barriers for the protonation of meta‐ and para‐substituted sulfoxonium ylides calculated by density functional theory.     

Acid-catalyzed synthesis of imidazole derivatives via N-phenylbenzimidamides and sulfoxonium ylides cyclization

A straightforward method to synthesize imidazole derivatives from amidines and sulfoxonium ylides catalyzed by acids is reported in this study. Specifically, catalyzed by trifluoroacetic acid in DCE solvents can improve synthesis efficiency under metal-free conditions. A series of imidazole scaffolds were produced in good to excellent yields.     

Sulfilimines as Versatile Nitrene Transfer Reagents: Facile Access to Diverse Aza‐Heterocycles

We herein report the unprecedented synthesis of diverse biologically important aza‐heterocycles by employing sulfilimines as nitrene transfer reagents. This class of sulfur‐based aza‐ylides had not been successfully used for gold nitrene transfer before. This work contains an efficient generation of α‐imino gold carbenes by N?S cleavage of sulfilimines. These gold carbenes undergo C?H insertion, cyclopropanation, and nucleophilic attack to form indoles (44 examples), 3‐azabicyclo[3.1.0]hexan‐2‐imines (24 examples), and imidazoles (3 examples). Our study represents a unique gold‐catalyzed reaction between alkynes and sulfur ylides, and also includes the first aza‐heterocycle synthesis that proceeds by intermolecular nitrene transfer followed by cyclopropanation of the α‐imino gold carbenes. Moreover, an unexpected synthesis of 4‐acylquinolines (3 examples) from 2‐acylphenyl sulfilimines and propargylic silyl ether derivatives by a 1,2‐hydride shift onto the α‐imino gold carbene and a subsequent Mukaiyama aldol cyclization was discovered.     

Asymmetric synthesis of anti-homopropargylic alcohols from aldehydes and chiral sulfonimidoyl substituted bis(allyl)titanium complexes through generation and elimination of novel chiral alkylidenecarbene (dimethylamino)sulfoxonium ylides

A new method for the asymmetric synthesis of anti-configured homopropargylic alcohols 1 is described, which features the addition of chiral sulfonimidoyl substituted bis(allyl)titanium complexes 3 to aldehydes, the methylation of sulfonimidoyl substituted homoallylic alcohols 2 at the N-atom, and the elimination of alkenyl (dimethylamino)sulfoxonium salts 7 with LiN(H)tBu. The reaction of isopropyl, cyclohexyl, and methyl substituted allylic titanium complexes 3a-c with benzaldehyde, p-bromobenzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, (E)-3-phenylpropenal, and phenylpropynal afforded with high regio- and diastereoselectivities the anti-configured sulfonimidoyl substituted homoallylic alcohols 2a-j, respectively. Only one allylic unit of the titanium complexes 3a-c was transferred in the case of unsaturated aldehydes, and the starting allylic sulfoximines 2a-g were recovered in approximately 50% yield. The methylation of the silyl protected alkenyl sulfoximines 6a-j with Me(3)OBF(4) gave in practically quantitative yields the (dimethylamino)sulfoxonium salts 7a-j, respectively. Salts 7a-e, 7g, 7h, and 7j delivered upon treatment with 2 equiv of LiN(H)tBu the enantio- and diastereomerically pure saturated and unsaturated alkynes 9a-e, 9g, 9h, and 9j, respectively, in high yields. Besides the alkynes the sulfinamide 8 (96% ee) was isolated. Aminosulfoxonium salts 9f and 9i, which carry a CC triple bond, also suffered an elimination under these conditions but did not yield the corresponding diynes. Elimination of salts 7a-e, 7g, 7h, and 7j proceeds most likely through deprotonation at the alpha-position with formation of the novel alkylidenecarbene aminosulfoxonium ylides 19a-e, 19g, 19h, and 19j, respectively. The ylides 19a-e, 19g, 19h, and 19j presumably eliminate sulfinamide 8 with generation of the chiral nonracemic (beta-siloxyalkylidene)carbenes 20a-e, 20g, 20h, and 20j, which suffer a 1,2-H-shift with formation of alkynes 9. Support for the formation of the putative alkylidenecarbenes 20 as intermediates comes from the elimination of the beta-methyl substituted aminosulfoxonium salt 24, which delivered the enantio- and diastereomerically pure 2,3-dihydrofuran derivative 28 upon treatment with LiN(H)tBu in high yield. Here, the putative (beta-siloxyalkylidene)carbene 26 suffers a 1,5-O,Si bond insertion rather than a 1,2-Me shift. Methylation of the alkenyl sulfoximine 6a at the alpha-position with formation of 13 was achieved through deprotonation of the former with formation of the alpha-lithioalkenyl sulfoximine 11a and its treatment MeI. Reaction of the alpha-methylated alkenyl aminosulfoxonium salt 14a with LiNiPr(2) at low temperatures gave the enantio- and diastereomerically pure anti-configured homoallenylic alcohol derivative 15, while reaction of the salt with LiNiPr(2) or LiN(H)tBu at higher temperatures afforded the enantio- and diastereomerically pure nonterminal homopropargylic alcohol derivative 17. Deprotonation of the alkenyl (dimethylamino)sulfoxonium salts 7a and 7b with nBuLi afforded the novel alkylidenecarbene aminosulfoxonium ylides 19a and 19b, respectively, which upon treatment with MeI yielded the methylated aminosulfoxonium salts 14a and 14b, respectively.     

Rh(III)-catalyzed [4 + 1]-annulation of azobenzenes with α- carbonyl sulfoxonium ylides toward 3-acyl-(2H)-indazoles

A Rh(III)-catalyzed [4?+?1]-annulation of azobenzenes with α- carbonyl sulfoxonium ylides was developed to access 2H-indazoles in moderate to excellent yields with good functional group compatibilities. It proceeded with the sequential insertion of the Rh(III) carbene to the C?H bond and cyclization steps, where sulfoxonium ylides served as efficient and stable carbene precursor.     

Decomposition of diazoketones in organic sulfides and sulfoxides: Cyclopropane formation from diazoketones via sulfonium ylides

The catalytic decomposition of diazoketones in the presence of organic sulfides and sulfoxides, gives sulfonium and sulfoxonium ylides as the primary reaction products, the final products isolated depending upon the relative nucleophilicity of the sulfides compared to that of the corresponding ylides, and on the stability of the ylides. The mechanism, scope and limitations of a new method of cyclopropane formation from diazoketones are discussed. Some circumstantial evidence supporting a concerted process for Wolff rearrangement is presented.     

Rhodium(III)-catalyzed intermolecular cyclization of anilines with sulfoxonium ylides toward indoles

C2-substituted indoles were efficiently prepared with excellent regio-selectivity from N-phenylpyridin-2-amines and sulfoxonium ylides via cascade reaction of C-H alkylation/nucleophilic cyclization.     

Distal Allylic/Benzylic C−H Functionalization of Silyl Ethers Using Donor/Acceptor Rhodium(II) Carbenes

Regio- and stereoselective distal allylic/benzylic C−H functionalization of allyl and benzyl silyl ethers was achieved using rhodium(II) carbenes derived from N-sulfonyltriazoles and aryldiazoacetates as carbene precursors. The bulky rhodium carbenes led to highly site-selective functionalization of less activated allylic and benzylic C−H bonds even in the presence of electronically preferred C−H bonds located α to oxygen. The dirhodium catalyst Rh₂(S-NTTL)₄ is the most effective chiral catalyst for triazole-derived carbene transformations, whereas Rh₂(S-TPPTTL)₄ works best for carbenes derived from aryldiazoacetates. The reactions afford a variety of δ-functionalized allyl silyl ethers with high diastereo- and enantioselectivity. The utility of the present method was demonstrated by its application to the synthesis of a 3,4-disubstituted l -proline scaffold.