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ChemInform Abstract: Iron-Catalyzed Cross-Coupling of Unactivated Secondary Alkyl Thio Ethers and Sulfones with Aryl Grignard Reagents.
Abstract
The first systematic investigation of unactivated aliphatic sulfur compounds as electrophiles in transition-metal-catalyzed cross-coupling are described. Initial studies focused on discerning the structural and electronic features of the organosulfur substrate that enable the challenging oxidative addition to the C(sp(3))-S bond. Through extensive optimization efforts, an Fe(acac)3-catalyzed cross-coupling of unactivated alkyl aryl thio ethers with aryl Grignard reagents was realized in which a nitrogen "directing group" on the S-aryl moiety of the thio ether served a critical role in facilitating the oxidative addition step. In addition, alkyl phenyl sulfones were found to be effective electrophiles in the Fe(acac)3-catalyzed cross-coupling with aryl Grignard reagents. For the latter class of electrophile, a thorough assessment of the various reaction parameters revealed a dramatic enhancement in reaction efficiency with an excess of TMEDA (8.0 equiv). The optimized reaction protocol was used to evaluate the scope of the method with respect to both the organomagnesium nucleophile and sulfone electrophile.
... [39,40] A very common methodology, which involves the use of nucleophilic substitution reactions (Scheme 1), is employed for the synthesis of a large number of catalytically relevant organosulfur compound (such as thioethers, pincer ligands, N-heterocyclic carbene and Schiff bases). [29,[41][42][43][44][45][46] This reaction leads to the introduction of thioether (CÀ SÀ C) functionality into the organic compound's framework by the reaction of an alkyl halide with a sulphur containing nucleophile (e. g. RSNa or ArSNa). ...
During the last two decades, organosulfur compounds have been used in the field of transition metal catalysis. Some of such compounds are known for their ability to withstand their exposure to air and moisture. These compounds are very important ligands. They may be obtained using simple and smooth modular synthetic protocols which include nucleophilic substitution reactions. The development of click chemistry represents a new era of innovation. It is a lighthouse of reliable and efficient reactions. In recent past, click chemistry has also been applied for the synthesis of such organosulfur ligands specifically suited for the dynamic field of transition metal catalysis. In order to synthesize novel compounds containing sulfur and triazole ring, click chemistry is an advantageous methodology over other approaches. This article covers the general features and uses of this methodology for the development of catalytically active organosulfur compounds. The significant advances in the design of transition metal catalytic systems utilizing such ligands, their use in the catalysis of many chemical transformations are also covered in this article. Effort has also been made to present a comparative overview of the performances of such catalysts vis‐à‐vis the catalysts designed commonly used ligands. Catalytic performances have been discussed thoroughly in order to identify the impact of ligand architecture on efficacy of the catalyst. Effect of reaction conditions (such as time, temperature etc.) and mechanistic aspects have also been rationalized.
... The C(aryl)À S bonds in aryl alkyl sulfides are usually preferentially cleaved, while the cleavage of the C(alkyl)À S bonds has been scarcely reported (Scheme 1C). [6] Site-selective cleavage of the CÀ S bonds in aryl alkyl sulfides remains a long-standing challenge. ...
The development of aryl alkyl sulfides as dichotomous electrophiles for site‐selective silylation via C−S bond cleavage has been achieved. Iron‐catalyzed selective cleavage of C(aryl)−S bonds can occur in the presence of β‐diketimine ligands, and the cleavage of C(alkyl)−S bonds can be achieved by t‐BuONa without the use of transition metals, resulting in the corresponding silylated products in moderate to excellent yields. Mechanistic studies suggest that Fe−Si species may undergo metathesis reactions during the cleavage of C(aryl)−S bonds, while silyl radicals are involved during the cleavage of C(alkyl)−S bonds.
... Prepared from (3-bromobutyl) benzene [23][24] stirred at room temperature for 1 h. The corresponding freshly distilled benzoyl chloride (44.3 mg, 0.32 mmol, 1.05 equiv) was then added, and the reaction mixture was stirred for 10 minutes, resulting in the precipitation of an orange solid. ...
Sulfur-containing compounds are increasingly important for designing pharmaceutical candidates that have accumulated broad research efforts toward developing effective methods to forge C-S bonds from various sulfuration agents. However, most established...
... drastically inhibited the reaction (25% conv., <2% 2), and 10% of the desulfonylated glycosyl-TEMPO adduct 45 was detected by GCMS analysis (Scheme 5a). This result suggests the in situ formation of a reactive glycosyl radical intermediate (via activation of 1 by a low-valent organoiron species [38,39] with concomitant formation of sulfinate [38], [50] ) which was captured by TEMPO in the reaction medium. ...
Stereoselective C‐glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, readily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome through transition‐metal catalysis remains challenging, and methods that leverage bench‐stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Herein, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C−C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles through distinct mechanisms and modes of activation. Diverse C‐aryl glycosides were secured with excellent selectivity, scope, and functional‐group compatibility, and reliable access to both α and β isomers was possible for key sugar residues.
... [8,9] Furthermore, the practical utility of TMEDA-assisted iron-catalyzed cross-coupling has also been demonstrated in several complex organic molecule syntheses. [10][11][12][13][14][15][16][17][18] While TMEDA represents one of the most practical and widely utilized additives in iron cross-coupling methodologies, the molecular-level role of TMEDA that facilitates effective catalysis remains unclear and debated in the literature. The most detailed studies combining organoiron synthesis, in situ iron speciation during catalysis, and organoiron reactivity toward electrophiles have focused on C(sp 2 )À C(sp 3 ) Kumada cross-couplings with TMEDA and mesityl (Mes) Grignard reagent. ...
Herein, we expand the current molecular‐level understanding of one of the most important and effective additives in iron‐catalyzed cross‐coupling reactions, N,N,N′,N′‐tetramethylethylenediamine (TMEDA). Focusing on relevant phenyl and ethyl Grignard reagents and slow nucleophile addition protocols commonly used in effective catalytic systems, TMEDA‐iron(II)‐aryl intermediates are identified via in situ spectroscopy, X‐ray crystallography, and detailed reaction studies to be a part of an iron(II)/(III)/(I) reaction cycle where radical recombination with FePhBr(TMEDA) (2Ph) results in selective product formation in high yield. These results differ from prior studies with mesityl Grignard reagent, where poor product selectivity and low catalytic performance can be attributed to homoleptic iron–ate species. Overall, this study represents a critical advance in how amine additives such as TMEDA can modulate selectivity and reactivity of organoiron species in cross‐coupling.
... Building on previous reports of cross coupling reactions of sulfones by Li, [35] Crudden, [36] and Denmark, [37] Baran and coworkers reported the nickel-catalyzed cross coupling of sulfones with aryl zinc reagents that proceeds in good yield with nonfluorinated, monofluorinated, and difluorinated sulfones by ar adical mechanism (Scheme 17). [34] Primary, secondary,a nd tertiary benzylic fluorides are all accessible, and the a-fluoro sulfones employed are readily accessible by several methods,i ncluding a-functionalization of simpler sulfones and Michael or Giese additions to vinyl sulfones. ...
Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.
... Further transformations based on sulfone unit [74][75][76] are also promising although several trials in our study was not successful. Actually, the sulfone unit in our products is a common moiety in pharmaceutically relevant compounds, 65,66,[77][78][79] which indicates the potential utility of our methodology in pharmaceutical synthesis. ...
Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N -heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E -selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to >99:1 e.r., >20:1 E / Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.
When γ,δ‐epoxy‐α,β‐unsaturated esters were treated with 3 equiv. of aliphatic Grignard reagents in the presence of 10 and 20 mol% FeCl2 and N,N,N’,N’‐tetramethylethylenediamine, regio‐ and stereoselective substitution of the epoxide moiety with the aliphatic Grignard reagent occurred, producing exclusively δ‐hydroxy‐γ‐alkyl‐α,β‐unsaturated esters. Similarly, γ,δ‐epoxy‐α,β,ϵ,ζ‐unsaturated esters and amides underwent transformation to the corresponding δ‐hydroxy‐γ‐alkyl‐α,β,ϵ,ζ‐unsaturated esters and amides as single isomers, respectively.
A long-standing issue about the correct identification of an important starting reagent, iron(III) hexafluoroacetylacetonate, Fe(hfac) 3 ( 1 ), has been resolved. The tris -chelated mononuclear complex was found to crystallize in two polymorph modifications which can be assigned as the low-temperature ( 1-L ) monoclinic P 2 1 / n and the high-temperature ( 1-H ) trigonal P \overline{3}. Low-temperature polymorph 1-L was found to transform to 1-H upon sublimation at 44 °C. Two modifications are clearly distinguished by powder X-ray diffraction (PXRD), single-crystal X-ray diffraction, differential scanning calorimetry (DSC), and melting-point measurements. On the other hand, the two forms share similar characteristics in direct analysis in real-time mass spectrometry (DART-MS), attenuated total reflection (ATR) spectroscopy, and some physical properties, such as color, volatility, sensitivity, and solubility. Analysis of the literature and some of our preliminary data strongly suggest that the appearance of two polymorph modifications for trivalent metal (both transition and main group) hexafluoroacetylacetonates is a common case for several largely used complexes not yet accounted for in the crystallographic databases.
As a recently developed redox‐neutral coupling reaction, transition‐metal‐catalyzed unimolecular fragment coupling (UFC) has been extensively investigated over the past decade. In comparison to conventional cross‐coupling reactions, cross‐electrophilic coupling (XEC) and cross‐dehydrogenative coupling (CDC) protocols eliminate the need for stoichiometric organometallic reagents, reductants, or oxidants. Additionally, it produces only minimal molecular by‐products for the formation of a series of C−C bonds and C−X bonds with high atom efficiency. This review presents a summary and classification of the research progress made over the past decade in this field. The research is classified into four main categories, decarbonylation, decarboxylation, desulfonylation, and deisocyanation, according to the type of small molecule that is liberated from the reaction system. This facilitates the implementation of more practical, straightforward, and expedient reaction operations. It is noteworthy that the reaction employs carbonyl compounds (aldehydes, ketones, carboxylic acid derivatives, etc.), sulfones, and amides, which are typically inexpensive and accessible, as reaction substrates. This groundbreaking synthetic approach has since yielded a plethora of outcomes and novel research avenues in related fields, while also offering benefits to other related fields.
Novel 2-substituted 1,3-bis[bis(3′,5′-di-tert-butylphenyl)phosphino]propanes (SciPROP-R; 1-R), as well as their iron complexes FeCl2(SciPROP-R) 2-R, are synthesized. Single-crystal X-ray analysis and solution-phase Fe K- and L-edge XAS of 2-R reveals that these complexes maintain tetrahedral geometry and hence paramagnetic high-spin properties both in the solid state and in the solution phase. 31P NMR results demonstrate that the superior coordination ability of SciPROP-TB (1-TB) is due to the bulky tert-butyl group at position 2 of the propane-1,3-diyl linker of the ligand. These novel iron-complexes catalyze Suzuki–Miyaura-type cross coupling under mild conditions. Notably, iron(II) chloride–1-TB complex (2-TB) exhibits excellent catalytic activity owing to the high coordination ability and electron-donating nature of 1-TB, being effective for chemoselective cross coupling between various alkyl chlorides and arylboron compounds.
Sulfone-tethered lactones/amides/amines display a diverse spectrum of biological activities, including anti-psychotic and anti-hypertensive. Sulfones are also widely present in functional materials and fragrances. We therefore reasoned that a regiodivergent and stereocontrolled strategy that merges the sulfone, lactone, and lactam motifs would likely lead to the discovery of new pharmacophores and functional materials. Here, we report mild conditions for the sulfonyllactonization of γ-lactam-tethered 5-aryl-4(E)-pentenoic acids. The annulation is highly modular, chemoselective, and diastereoselective. With respect to regioselectivity, trisubstituted alkenoic acids display a preference for 5-exo-trig cyclization whereas disubstituted alkenoic acids undergo exclusive 6-endo-trig cyclization. The lactam-fused sulfonyllactones bear angular quaternary as well as four contiguous stereocenters. The products are post-modifiable, especially through a newly developed Co-catalyzed reductive cross-coupling protocol.
The development of aryl alkyl sulfides as dichotomous electrophiles for site‐selective silylation via C−S bond cleavage has been achieved. Iron‐catalyzed selective cleavage of C(aryl)−S bonds can occur in the presence of β‐diketimine ligands, and the cleavage of C(alkyl)−S bonds can be achieved by t ‐BuONa without the use of transition metals, resulting in the corresponding silylated products in moderate to excellent yields. Mechanistic studies suggest that Fe−Si species may undergo metathesis reactions during the cleavage of C(aryl)−S bonds, while silyl radicals are involved during the cleavage of C(alkyl)−S bonds.
Stereoselective C‐glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, easily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome via transition metal catalysis remains challenging, and methods that leverage bench‐stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Here, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C−C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles via distinct mechanisms and modes of activation. Diverse C‐aryl glycosides were secured with excellent selectivity, scope, and functional group compatibility, and reliable access to both α and β isomers could be achieved for key sugar residues.
This review highlights the history and recent advances in dealkenylative functionalization. Through this deconstructive strategy, radical functionalizations occur under mild, robust conditions. The reactions described proceed with high efficiency, good stereoselectivity, tolerate many functional groups, and are completed within a matter of minutes. By cleaving the C(sp3)–C(sp2) bond of terpenes and terpenoid-derived precursors, rapid diversification of natural products is possible.
1 Introduction
2 Mechanism
3 History
4 Motivation to Pursue Dealkenylation
5 Dealkenylation in the Present
6 Conclusion
The readily available pyrimidinyl sulfones, in which the C–S bond is cleaved selectively, could serve as electrophiles in the Ni-catalyzed cross-coupling reactions to prepare 2,4-diarylated pyrimidines under mild conditions with a broad scope.
The exceptional versatility of sulfones has been extensively exploited in organic synthesis across several decades. Since the first demonstration in 2005 that sulfones can participate in Pd-catalysed Suzuki-Miyaura type reactions, tremendous advances in catalytic desulfitative functionalizations have opened a new area of research with burgeoning activity in recent years. This emerging field is displaying sulfone derivatives as a new class of substrates enabling catalytic C-C and C-X bond construction. In this review, we will discuss new facets of sulfone reactivity toward further expanding the flexibility of C-S bonds, with an emphasis on key mechanistic features. The inherent challenges confronting the development of these strategies will be presented, along with the potential application of this chemistry for the synthesis of natural products. Taken together, this knowledge should stimulate impactful improvements on the use of sulfones in catalytic desulfitative C-C and C-X bond formation. A main goal of this article is to bring this technology to the mainstream catalysis practice and to serve as inspiration for new perspectives in catalytic transformations.
Increasing saturation (Fsp3) remains a central strategy in the optimization of properties of molecules during drug discovery. Here, we describe a versatile and operationally simple one-pot procedure for accomplishing this...
A method for generating alkyl radicals using visible-light photoredox catalysis is described. This procedure was found to present an efficient means to access a diverse collection of 1°, 2°, and 3° alkyl radicals through the single-electron transfer of sulfones under mild reaction conditions. These alkyl radicals generated via the reductive desulfonylation of readily synthesized and stable alkylsulfones were engaged to forge C-C bonds. A detailed study was also carried out to shed light on the mechanism.
Organosulfone is a chemically-stable and versatile reagent in organic synthesis. The sulfonyl group is a strong electron-withdrawing substituent that permits the rapid functionalization of adjacent positions via deprotonation/alkylation, arylation, or conjugation addition reactions. However, after these reactions, removal of the sulfonyl group using highly reducing reagents is virtually the main choice. Therefore, the development of new methods to introduce various functional groups in the place of sulfonyl group will provide tremendous opportunities for straightforward synthesis of complex molecules. Recently our group has developed several new transformations of sulfone derivatives as reacting templates through α-functionalization followed by carbon-sulfonyl (C-SO2) bond activation. To activate C-SO2 bonds, we have established a new strategy focusing on the development of new catalysis/reagents and the design of sulfonyl groups. These methods could provide facile access to a variety of multiply-arylated structures such as di-, tri-, and tetraarylmethanes from stable and readily available reagents. In addition, the rapid preparation of α-fluorinated arylmethane derivatives by combination with selective α-fluorination of benzyl triflones was achieved, which opens up avenues for the development of unexplored biomolecules. Importantly, this work highlights the unique property of organosulfone to functionalize sp³ carbon centers in a modular manner.
Based on the idea of environmental friendliness, we first studied the hydrothiolation reactions of thiophenol with allylamine using a green catalyst-an external electric field (EEF). The hydrothiolation reactions could occur through Markovnikov addition (path M) and anti-Markovnikov addition (path AM) pathways. The calculation results demonstrated that when the EEF was oriented along F -X , F -Y , and F +Z directions, path M was accelerated. However, it is favorable for path AM only when the EEF is oriented along the +X and -Y-axes. In addition, the introduction of the EEF further increased and lowered the differences of the reaction barrier as the EEF was oriented along F -X , F -Y , and F +X directions. The solvent effects were also considered in this work. Hopefully, this unprecedented and green catalytic method for the hydrothiolation reactions of allylamine may provide guidance in the lab.
Transition metal catalyzed reactions that involve the activation of unactivated C–O bonds, such as those in alcohols, phenols, esters and ethers, are extensively reviewed. The development of suitable catalyst systems allows C–O bond activation to be applied to diverse transformations, including cross-coupling, C–heteroatom bond formation, C–H functionalization and annulation reactions. Key milestones in the related catalytic activation of C–S, C–N, C–Si and C–P bonds are also described.
Herein, we expand the current molecular‐level understanding of one of the most important and effective additives in iron‐catalyzed cross‐coupling reactions, N,N,N',N'‐tetramethylethylenediamine (TMEDA). Focusing on relevant phenyl and ethyl Grignard reagents and slow nucleophile addition protocols commonly used in effective catalytic systems, TMEDA‐iron(II)‐aryl intermediates are identified via in situ spectroscopy, X‐ray crystallography, and detailed reaction studies to be a part of an iron(II)/(III)/(I) reaction cycle where radical recombination FePhBr(TMEDA) (2Ph) results in selective product formation in high yield. These results differ from prior studies with mesityl Grignard reagent, where poor product selectivity and low catalytic performance can be attributed to homoleptic iron‐ate species. Overall, this study represents a critical advance in how amine additives such as TMEDA can modulate selectivity and reactivity of organoiron species in cross‐coupling.
Palladium-mediated cross-couplings are established as a core synthetic technology within the pharmaceutical industry for the assembly of biologically active molecules. Despite both their effectiveness and prevalence, the use of precious metals presents challenges from an environmental perspective. The ability of base metals such as Ni, Fe, and Cu to mediate carbon-carbon bond formations predates the discovery of the Pd-catalyzed methodologies though are far less established in terms of their broad scope and utility. The current chapter focuses on emerging developments in the use of non-precious metals in catalysis with potential applications in both research and development.
A metal and oxidant-free, practical and efficient method for the synthesis of highly versatile and synthetically useful ortho -trifluoromethanesulfonylated anilines from arylhydroxylamines and trifluoromethanesulfinic chloride was developed. This rapid transformation proceeded smoothly with good yields and excellent ortho -selectivity in the absence of any metals or ligands. Mechanistically, the reaction comprised a noncanonical O -trifluoro-methanesulfinylation of the arylhydroxylamine, and the subsequent [2, 3]-sigmatropic rearrangement to afford ortho -trifluoromethane-sulfonylated aniline derivatives. The practical application of this reaction was demonstrated by further conversion into a series of functional molecules under different reaction conditions.
A metal‐ and oxidant‐free, practical and efficient method for the synthesis of highly versatile and synthetically useful ortho‐trifluoromethanesulfonylated anilines from arylhydroxylamines and trifluoromethanesulfinic chloride was developed. This rapid transformation proceeded smoothly with good yields and excellent ortho‐selectivity in the absence of any metals or ligands. Mechanistically, the reaction comprised a noncanonical O‐trifluoromethanesulfinylation of the arylhydroxylamine, and the subsequent [2,3]‐sigmatropic rearrangement to afford ortho‐trifluoromethanesulfonylated aniline derivatives. The practical application of this reaction was demonstrated by further conversion into a series of functional molecules under different reaction conditions.
The reaction between aryl olefins and thiols in the presence of Oxone in toluene-water (9:1, v/v) affords β-hydroxy-2-arylethyl aryl sulfides smoothly by interception of the intermediary thiyl radicals with aryl...
A practical and direct method was developed for the production of versatile alkyl boronate esters via transition metal‐free borylation of primary and secondary alkyl sulfones. The key to the success of the strategy is the use of bis(neopentyl glycolato) diboron (B2neop2), with a stoichiometric amount of base as a promoter. The practicality and industrial potential of this protocol are highlighted by its wide functional group tolerance, the late‐stage modification of complex compounds, no need for further transesterification, and operational simplicity. Radical clock, radical trap experiments, and EPR studies were conducted which show that the borylation process involves radical intermediates.
We describe here a Ni-catalyzed Negishi coupling reaction to prepare 1,2-dialkyl enol ethers in a stereoconvergent fashion. This method employs readily available and bench-stable α-oxy-vinylsulfones as electrophiles. The C-sulfone bond in the α-oxy-vinylsulfone motif is cleaved chemoselectively in these reactions. The mild conditions are tolerant of a variety of functional groups on both partners, thus representing a general strategy for enol ether synthesis. This unique reactivity of α-oxy-vinylsulfones indicates their further application as electrophilic partners in cross-coupling reactions.
Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and p K a of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C–F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C–C bond formation (monofluoroalkylation) are inherently convergent and complexity-generating, they have studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition-metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.
In recent years, the use of organosulfones as a new class of cross-coupling partner in transition-metal catalyzed reactions has undergone significant advancement. In this personal account, our recent investigations into desulfonylative cross-coupling reactions of benzylic sulfone derivatives catalyzed by Pd, Ni, and Cu catalysis is described. Combined with the facile α-functionalizations of sulfones, our methods can be used to form valuable multiply-arylated structures such as di-, tri-, and, tetraarylmethanes from readily available substrates. The reactivity of sulfones can be increased by introducing electron-withdrawing substituents such as 3,5-bis(trifluoromethyl)phenyl and trifluoromethyl groups, which enable more challenging cross-coupling reactions. Reactive intermediates including Cu-carbene complexes were identified as key intermediates in sulfone activation, representing new types of C-SO2 bond activation processes. These results indicate sulfones are powerful functional groups, enabling new catalytic desulfonylative transformations.
The iron‐catalyzed alkyl–aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron‐catalyzed radical difluoroalkylation of arylborates with N‐heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N‐heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single‐electron‐transfer process, which enables both fluoroalkyl N‐heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N‐heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents.
The coordination of low-valent iron to the nitrogen atom of N-heteroaryl sulfones can overcome the reduction potential limitation in intermolecular electron-transfer processes, thus enabling sulfones with low reduction potentials to efficiently participate in radical cross-coupling.
Abstract
The iron-catalyzed alkyl–aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron-catalyzed radical difluoroalkylation of arylborates with N-heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N-heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single-electron-transfer process, which enables both fluoroalkyl N-heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N-heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents.
A new method for the generation of tertiary radicals thorugh single electron reduction of alkylsulfones promoted by Zn and 1,9-phenanthlorine has been developed. These radicals could be employed in the Giese rection, affording structually diverse quaternary products in good yields. With the high modularity and functional group compatibility of sulfones, the utility of this method was demonstrated by intramolecular and iterative reactions to give complex structures. The radical generation process was investigated by control experiments and theoretical calcutions.
A titanium(III)‐catalyzed desulfonylation gives access to functionalized alkyl nitrile building blocks from α‐sulfonyl nitriles, circumventing traditional base‐mediated α‐alkylation conditions and strong single electron donors. The reaction tolerates numerous functional groups including free alcohols, esters, amides, and it can be applied also to the α‐desulfonylation of ketones. In addition, a one‐pot desulfonylative alkylation is demonstrated. Preliminary mechanistic studies indicate a catalyst‐dependent mechanism involving a homolytic C−S cleavage.
A novel nickel-catalyzed reductive cross-coupling between aryl iodides and difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) enables C(sp2)-C(sp2) bond formation through selective C(sp2)-S bond cleavage, which demonstrates the new reactivity of 2-PySO2CF2H reagent. This method employs readily available nickel catalyst and sulfones as cross-electrophile coupling partners, providing facile access to biaryls under mild reaction conditions without pregeneration of arylmetal reagents.
While the global market for peptide/protein-based therapeutics is witnessing significant growth, the development of peptide drugs remains challenging due to their low oral bioavailability, poor membrane permeability, and reduced metabolic stability. However, a toolbox of chemical approaches has been explored for peptide modification to overcome these obstacles. In recent years, there has been a revival of interest in photoinduced radical thiol-ene chemistry as a powerful tool for the construction of therapeutic peptides.
In industries and academic laboratories, several late transition metal-catalyzed prerequisite reactions are widely performed during single and multistep synthesis. However, besides the desired products, these reactions lead to the generation of numerous chemical waste materials, by-products, hazardous gases, and other poisonous materials, which are discarded in the environment. This is partly responsible for the creation of global warming, resulting in climate adversities. Thus, the development of environmentally benign, cheap, easily accessible, and earth-abundant metal catalysts is desirable to minimize these issues. Certainly, iron is one of the most important metals belonging to this family. The field of iron catalysis has been explored in the last two-three decades out of its rich chemistry depending on its oxidation states and ligand cooperation. Moreover, this field has been enriched by the promising development of iron-catalyzed reactions namely, C–H bond activation, including organometallic C–H activation and C–H functionalization via outer-sphere pathway, cross-dehydrogenative couplings, insertion reactions, cross-coupling reactions, hydrogenations including hydrogen borrowing reactions, hydrosilylation and hydroboration, addition reactions and substitution reactions. Thus, herein an inclusive overview of these reaction have been well documented.
A transition-metal-free t-BuOK-mediated reductive C–P cross-coupling reaction of arylvinyl sulfides with diarylphosphine oxides through C–S bond cleavage has been developed. This protocol not only permits the synthesis of diaryl(2-arylethyl)phosphine oxides, but also achieves an unprecedented construction of a C–P bond through C–S bond cleavage and reduction of a C–C double bond in one pot.
Aryl chlorides are better substrates than the corresponding bromides or iodides in the presented cross-coupling with alkyl Grignard reagents that is catalyzed by iron salts (see scheme); even aryl tosylates are converted efficiently. This situation is attributed to a novel catalytic cycle, which probably involves iron complexes with formally negative oxidation states (probably Fe−II).
This first comprehensive book to cover this exciting field also deals with the biological aspects, such as enzymes with iron. Following an introduction, this handy reference and handbook goes on to deal with reductions, oxidations of C, H- and C=C bonds, oxidative allylic oxygenation and amination, the oxidation of heteroatoms, cross coupling reactions, aromatic and nucleophilic substitutions, addition to carbonyl compounds, and cyclisations as well as ring opening reactions. The chapters are clearly classified according to the reaction type, allowing readers to quickly locate the desired information.
In a set of volumes on sulphur-containing functionalgroups, the volume on the sulphonium group appeared in 1981 (in two parts). The present volume deals with sulphones and sulphoxides and further volumes, one on derivatives of sulphinic acids and another on derivatives of sulphenic acids, are now in the course of preperation, with a volume on sulphonic acid derivatives planned for the more distant future.
The rate constants kI and kOTs are determined for the reaction of methyl iodide and methyl tosylate with a number of transition-metal nucleophiles. The values of kI cover a span of 1011 in magnitude. The ratio kI/kOTs covers a range from 109 to 10-3, with some nucleophiles not reacting with methyl tosylate before undergoing decomposition. Unfortunately, except for Co(CN)53-, the ratio cannot be used as a guide to free-radical mechanisms. Except for Li2Cu2Me4, Li2AuMe2, and Li2PtMe4, log kI plotted against log kOTs gives a straight line, suggesting a common SN2 mechanism. The permethylated complexes are unique in having kI/kOTs less than unity.
Diethylbis(dipyridyl)iron (1) was isolated from a mixed catalyst system containing iron acetylacetonate, diethylaluminum monoethoxide, and dipyridyl. The structure of the ethyl-iron complex was established from elementary analysis, infrared spectroscopy, and chemical properties of the complex. Zero-valent iron-dipyridyl complexes, bis(dipyridyl)iron (2) and tris(dipyridyl)iron (3), were prepared by thermal decomposition of 1 at 50° in benzene, both in the absence and presence of excess dipyridyl. The isolated iron-dipyridyl complexes 1-3 showed the same catalytic behavior as the mixed catalyst system for butadiene oligomerization. The mechanism of butadiene cyclodimerization to cyclooctadiene and vinylcyclohexene by these iron-dipyridyl complexes was studied by using a deuterated monomer. Diethylbis(dipyridyl)iron was also active as a catalyst of acetylene and acrylonitrile polymerizations.
This account summarizes recent developments in the use of cheap, benign, and non-toxic iron salts as precatalysts for various cross coupling reactions. Although not yet nearly as mature as their palladium- or nickel -catalyzed counterparts, these transformations provide efficient and scalable solutions for many types of C-C-bond formations. Selected applications to the total synthesis of bioactive natural products illustrate the present state of the art.
Functional-group-compatible cross-coupling reaction of alkyl halides with arylzinc reagents takes place under iron catalysis in the presence of TMEDA, producing a variety of aromatic compounds in good to excellent yield. The pronounced effect of a magnesium salt was found to be the key to the promotion of the iron-catalyzed coupling reaction.
Heterocyclic sulfides and thiols react with Grignard reagents in the presence of NiCl2(Ph2PCH2CH2CH2PPh2) to afford the cross-coupling products in high yields. The reaction of 2,2′-dipyridyl disulfide with 3-phenylpropylmagnesium bromide is also described.
The iron complex acts as an efficient catalyst for the title reaction by a simple procedure without an additive and within short reaction time.
Nickel and palladium catalysts have been developed for the cross-coupling of many challenging secondary alkyl electrophiles. Recent progress in this area is reviewed with emphasis on the control of stereochemistry in the formation of tertiary stereocenters. Stereoconvergent methods are discussed and recent alternative stereospecific approaches are highlighted.
We report the first example of iron-catalyzed cross-coupling of α-halo-β,β-difluoroethylene-containing compounds with arylzinc reagents using TMEDA and dppp as coligands. The reaction affords a wide range of functional group tolerant gem-difluoromethylenated compounds in moderate to good yields. The facile dehalodefluorination of α-halo-β,β-difluoroethylene-containing compounds upon treatment of reductive metal reagents was mostly inhibited. Mechanistic studies indicated that the cross-coupling reaction could involve a single-electron-transfer process.
A facile method for the synthesis of aryl sulfides (29 examples) via a convenient C—S cross-coupling of aryl bromides and thiols is developed.
Alk-2-enesulfonyl chlorides 1-4 were synthesized by the BCl3-promoted ene reaction of alkenes with SO2. These sulfonyl chlorides were then used as electrophilic partners in iron-catalyzed desulfinylative cross-coupling reactions with different Grignard reagents (aromatic, aliphatic, and heteroaromatic). The reaction can be catalyzed with even 2 mol-% of the simple iron salt Fe(acac)(3). The regioselectivity of these allylations was studied by using sulfonyl chlorides 3 and 4 with aryl Grignard reagents. The scope of these allylations was further extended by the coupling of ester-substituted alk-2-enesulfonyl chloride 10 with aromatic Grignard reagents. Symmetrical products were synthesized by double C-C allylation with the use of 2-methylidenepropane-1,3-disulfonyl chloride (12). ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
A convenient synthesis of di- and trisubstituted olefins using the coupling of Grignard reagents with allylic sulphones in the presence of copper II acetylacetonate is reported. The influence of sulphone, Grignard reagent and solvent on the regio- and stereoselectivity is discussed.
Phenylmagnesiumbromid (II) reagiert mit Phenyl-?-styrylsulfid (I) in Gegenwart von Nickelchlorid-triphenylphosphin-Katalysator zum trans- Stilben (III) und Diphenyl (IV).
A new cross coupling reaction of vinylic sulphones with Grignard reagents catalyzed by nickel and iron complexes is described. This reaction is stereospecific: tri-substituted olefins of defined stereochemistry are obtained in good yield.
The lithium or magnesium derivatives of allyl, benzyl and alkyl sulphones are converted efficiently by a catalytic amount of nickel(II) acetylacetonate into symmetrical olefins in THF at 60°C. Thus, phytoene was obtained in a 74% yield from geranylgeranylsulphone.
Cupric salts, particularly triflates, convert α-sulphonyl carbanions into α-disulphones. Allylphenylsulphones couple preferentially in the 3-3′ mode.
Chlorophenyl alkyl sulfides are mono-arylated and -alkylated selectively with Grignard reagents, in the presence of Ni(PPh3)2Cl2, to give aryl- and alkyl-phenyl alkyl sulfides.
Synthetically useful procedures to effect selective conversion of C-S into C-C bonds have been developed by taking advantage of the sensitivity of reactions of Grignard reagents with aryl alkyl sulphides, catalyzed by low-valent nickel species, to steric effects. It is shown that the course of these reactions is influenced by the steric requirements of both the aryl and the alkyl moieties of the sulphides. Thus, selective mono-arylation and alkylation of easily available bis(alkylthio)benzenes can be effected in medium to high yields. This allows the introduction of two different aryl or alkyl groups into the benzene nucleus by sequential substitution of the two alkylthio functions.
The E-hydroxyalkylsulphone PhSO2CH2C(CH3)CHCH2OH is regioselectively and stereoselectively substituted by Grignard reagents in the presence of copper(II) acetylacetonate, giving E allylic alcohols in high yield. A recurrent synthesis of polyprenols and an efficient preparation of the African Monarch pheromone are described.
Displacement reactions of the sulphinate anion from sulfones by Grignard reagents with copper catalysis take place readily with allylic sulphones. The regio chemistry and stereochemistry of the reaction are discussed.
The stereo- and enantioselective synthesis of the yellow scale pheromone, (S)-(-)-3,9-dimethyl 6-(1-methylethyl) (E)-5,8-decadien 1-ol acetate, from 3-(R)+)-valerolactone and [(4-methyl 3-pentenyl) sulfonyl] benzene is described. The key step is the introduction of the isopropyl group by the stereoselective cross-coupling reaction of the dienesulfone with isopropylmagnesium chloride in the presence of FeCl3.
An original and regioselective method for the meta functionalisation of fluoro- and ethylbenzene is reported. This process involves a 2,5- disilylation of these substrates using trimethylchlorosilane in the presence of lithium in THF as the solvent. After aromatisation, monodesilylation in position 2- and electrophilic substitution of the trimethylsilyl group in position 5-, meta acetyl-, senecioyl-, benzoyl-, and iodo-fluorobenzenes and ethylbenzenes as well as the sodium salts of meta fluoro or meta ethylbenzenesulfonic acid and 3- aminosulfonylfluorobenzene were obtained in good yields.
Grignard reagents react with allyl sulphides, in the presence of catalytic amounts of copper(I) salts, giving alkenes. The corresponding sulphonium salts react more rapidly. Allyic rearrangement cannot be completely avoided.RésuméLes organomagnésiens réagissent sur les sulfures allyliques en présence de cuivre(I) pour engendrer des alcènes. Avec les sels de sulfonium allyliques la réaction est plus rapide. On forme ainsi des alcènes avec de bons rendements. La transposition allylique ne peut être totalement évitée.
The tris(4-phenyl-n-butyl)- and tris(4-phenyl-sec-butyl)chromium systems undergo stepwise fragmentation on warming. At low temperatures the products, in both cases, are the alkane and terminal olefin. At higher temperatures they are alkane, 1- and 2-alkene, respectively, and a chromium based isomerization catalyst. Both (4-phenyl-n-butyl)-and (4-phenyl-sec-butyl)chromium dichlorides undergo fragmentation to alkane and terminal olefin. We conclude that the two fundamental processes of homolysis and β-metal hydride elimination are involved in the fragmentation of alkylchromium compounds.
The title complexes have been prepared in moderate yields by reaction of α-sulfonyl carbanions with Cp(PPh3)NiCl; the crystal structure of two of these complexes shows that the nicle atom is linked to the α-carbon of the sulfonyl group and there is no interactioin between the metal and the SO2 moiety. When their solution in benzene are warmed to 90°C, these complexes very cleanly yield the corresponding α,β-unsaturated sulfone (E isomer). An efficient method of dehydrogenating secondary alkyl sulfones is reported.
The allylic substitution of stable enolates derived from diethyl malonate, ethyl cyanoacetate, ethyl benzylsulfonylacetate, bis(benzenesulfonyl)methane and sodium p-toluenesulfinate by a variety of allylic esters and sulfones have been investigated. Suitable ligands and reaction conditions have been found to ensure high yields, and in some cases considerable control of the regioselectivity of the reaction.RésuméOn a étudié la substitution allylique d'énolates stables provenant du malonate d'éthyle, du cyanoacétate d'éthyle, du benzène sulfonyl acétate d'éthyle, du bis(benzène sulfonyl)méthane et du p-toluène sulfinate de sodium par divers esters et sulfones allyliques. On a déterminé les ligands et les conditions de la réaction qui permettent d'obtenir des rendements élevés et, dans certains cas, un important contrôle de la régiosélectivité de la réaction.
Stable enolates such as diethyl malonate enolate can be smoothly substituted by allylic acetates (or sulfones) in the presence of nickel complexes. Sulfinate ions convert allylic acetates into sulfones.
A highly efficient, base-free, mild protocol for the palladium-catalyzed, copper-activated desulfitative couplings of vinyl and aryl β-nitrothioethers generates a wide variety of conjugated nitroorganics. Orthogonality to traditional Suzuki–Miyaura coupling is demonstrated, as well as synthetic utility, through reductive Cadogan cyclization, for the formation of indoles, carbazoles, and pyrroles.
A novel rhodium-catalyzed C–C bond formation was developed to construct biaryls through unreactive aryl C–S bond cleavage of thioethers with aryl boroxines. This protocol provided a supplemental method of traditional Suzuki–Miyaura coupling.
The Rh(I)-catalysed coupling of aryl and alkenyl boronic acids with simple aryl and alkenyl methyl sulfides is reported. The process employs bench-stable Rh(I) precatalysts incorporating small bite-angle chelating phosphine ligands (R2PCH2PR2, R = iPr, Cy), shows good functional group tolerance, and proceeds under mild reaction conditions. Importantly, aryl bromide activating groups are inert to the reaction conditions, allowing selective reaction at either a methyl sulfide or bromide activating group, depending on catalyst (metal) choice. The scope of the coupling reactions, their combination with Rh-catalysed hydroacylation reactions in cascade processes, together with preliminary mechanistic studies, are all documented.
Cross coupling of non-activated alkyl halides is a potentially transformative methodology in organic synthesis. Herein we review the recent development of nickel-catalyzed coupling of non-activated alkyl halides. The current understanding of the mechanism of these coupling reactions is highlighted. As the mechanism is ligand-dependant, the perspective is organized according to the types of ligands employed in the catalysis.
We report a novel strategy for the formal activation of sp3 C–O bonds under Ru catalysis. In this reaction, an O-alkylpyridine undergoes migratory rearrangement to its corresponding N-alkylpyridone via coordination of the Lewis basic N atom. This transformation represents the first general catalytic approach to O- to N-alkyl migration in N-containing heterocycles. Extension of this methodology to other heterocycles, including O-alkylpyridazines and O-alkylazoles, was achieved.
Nickel-catalysed coupling of arylmagnesium halides with aryl tert-butyl sulfones, and in particular with those bearing ortrto-substituents introduced by ortholithiation, gives ortho-substituted unsymmetrical biaryls.
Exposure of diaryl sulphides to tris(tri-n-butyl)phosphinonickel(0) is shown to lead to oxidative addition products, one of which has been characterized by n.m.r. spectral analysis and another by single-crystal X-ray analysis.
The reactions of alkenyl sulphides, benzenethiols, and aryl sulphides with methylmagnesium and arylmagnesium bromides, mediated by bis(triphenylphosphine)nickel dichloride, in benzene solution have been shown to lead to olefins (predominantly with retention of configuration), toluenes, and biphenyls in medium to high yields.
Primary allylic sulphides of benzothiazole-2-thiol react with butylmagnesium bromide in the presence of copper(I) iodide to yield, depending on the solvent, olefins with or without allylic rearrangement.
2-Methylprop-2-ene-, prop-2-ene-, 1-methylprop-2-ene-, and (E)-but-2-enesulfonyl chlorides have been used as electrophilic partners in desulfinylative palladium- catalyzed C–C coupling with Grignard reagents and sodium salts of dimethyl malonate and methyl acetoacetate. Neopentyl alk-2-ene sulfonates can also be used as electrophilic partners in desulfinylative allylic arylations and allylic alkylations. The regioselectivity of the allylic arylation and alkylation depends on the nature of the catalyst. With PdCl2(PhCN)2, (E)-crotyl derivatives are formed in high regioselectivity using either 1- methylprop-2-eneor (E)-but-2-enesulfonyl chloride.
A novel Fe–NHC catalytic system allows the alkyl–alkyl cross-coupling reaction of alkyl halides and alkylmagnesium reagents has been developed. To our knowledge, this is the first Fe-catalysed Kumada-type coupling for the formation of C(sp3)–C(sp3) bonds in the presence of functional groups. The process takes place under mild conditions, avoiding the formation of β-elimination products. Mechanistic studies suggest the intermediacy of Fe(I) complexes, formed by reduction with the Grignard reagent, as the active species.
Alkenyl aryl sulfoxides could be alkylated stereoselectively via their lithium salts to afford α-alkylated (E)-alkenyl sulfoxides. Reduction of the sulfoxides to the corresponding sulfides followed by nickel–phosphine complexes catalyzed coupling reaction with Grignard reagents gave trisubstituted olefins.
Ethyl (E)-3-methyl-2-heptenoate, 6, or ethyl (Z)-3-methyl-2-heptenoate, 8, was prepared in high yield with the perfect retention of configuration by the reaction of ethyl (E)-3-phenylthio-2-butenoate, 5, or (Z)-3-phenylthio-2-butenoate, 7, with n-butylmagnesium bromide and cuprous iodide, respectively.
The recent developments in cobalt catalysis are compiled in this review covering the years 2000 through 2007. Special focus is directed towards cobalt-catalysed ring-formation reactions as well as towards cobalt-catalysed (cross-) coupling reactions and synthetically useful applications thereof in the synthesis of acyclic compounds.
1 Introduction
2 Cobalt-Catalysed Cycloaddition Reactions
2.1 Cyclopropanation
2.2 Four-Membered-Ring Formation
2.3 Five-Membered-Ring Formation
2.4 Six-Membered-Ring Formation
2.5 Seven-Membered-Ring Formation
2.6 Eight-Membered-Ring Formation
2.7 Ten-Membered-Ring Formation
3 Cobalt-Catalysed Synthesis of Acyclic Compounds
3.1 Coupling Reactions between Alkenes and Alkynes
3.2 Cross-Coupling Reactions
3.3 Cobalt-Catalysed Coupling Reactions Using Grignard Reagents
3.4 Hydrocyanation, Hydrophosphination, Hydrosilylation and Hydrovinylation Reactions
3.5 Nucleophilic Substitution with Organocobalt Reagents
3.6 Cobalt-Catalysed Carbonylative Ring-Expansion and Ring-Opening Reactions
4 Miscellaneous
5 Conclusions and Outlook
In the presence of Fe(acac) 3, Grignard reagents react readily with alkenyl halides (X = I, Br or Cl) in a THF/NMP mixture to give the cross-coupling products in high yields with an excellent stereoselectivity (≤99.5%). The scope of the reaction is very broad since a vast array of functional groups are tolerated (esters, nitriles, aromatic or aliphatic halides and even ketones). The procedure reported herein is an interesting alternative to the classical Pd- or Ni-catalyzed reactions, especially for preparative organic chemistry.