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ChemInform Abstract: A Convenient Conversion of Terminal Alkenes into Homologous Unsaturated and Doubly Unsaturated Esters.
Abstract
Unsaturated and doubly unsaturated esters have been synthesized in two steps by the application of a radical xanthate transfer process of a simple methylsulfoxide starting material to a range of terminal alkenes. syn-Elimination of the sulfoxide gives α,β-unsaturated esters, which coupled with a xanthate elimination yields α,β,γ,δ-unsaturated esters.
... (7 of 18) e202300218 could be introduced, a phthalimido-protected methylamino unit as in 127; [27] a phosphonylketone as in 128; [28] a selectively protected ketoaldehyde as in 129; [29] a dithiane mono-oxide as in 130; [30] a difluoromethylsulfide as in 131; [31] chlorodifluoromethyl motif as in 132a, from which the xanthate can be reduced off using (Me3Si)3SiH and the chlorine eliminated from 132b by treatment with DBU to give finally difluorovinyl derivative 133; [32] a sulfoxide ester 134, which can be directly thermolyzed in refluxing toluene to give unsaturated methyl ester 135. [33] In this Scheme, and in the rest of this article, the diastereoisomeric ratio is approximately 1 : 1, unless indicated otherwise. ...
This review describes applications of radical reactions developed in the authors’ laboratory for the modification of carbohydrates. It focuses on tin‐free variation on the Barton‐McCombie deoxygenation; on reductive de‐iodination; on intermolecular radical additions of xanthates; on allylations and vinylations of xanthates and iodides, with emphasis on allylations using allylic alcohols activated as fluoropyridyl ethers; and, finally, on the synthesis of mercaptosugars.
... [24] Xanthate 36 allows the synthesis of indoline 37 possessing an unsaturated ester side-chain. [25] Both radical steps leading to adduct 23 t and indoline 27 t have to be conducted at slightly lower temperatures to avoid premature elimination of the sulfoxide group. The use of the more thermally robust methyls ulfoxide instead of the more commonp henylor tolyl-sulfoxide furtherh elps in managing the reactions equence. ...
Convergent routes to a variety of indolines, indoles, oxindoles, and their aza analogues involving radical additions of xanthates are described. Three approaches are summarized. The first is the least general and relies on the generation of aryl or heteroaryl radicals starting from diazonium salts. The second involves radical addition to N‐allylanilines followed by ring‐closure onto the aromatic core. A large variety of indolines and azaindolines can thus be obtained and, in many cases, converted into the corresponding indoles and azaindoles by various methods. The synthesis of novel fluoroazaindolines and fluoroazaindoles by a rare homolytic ipso‐substitution of fluorine atoms is particularly noteworthy. The last approach hinges on the direct modification of indoles by radical addition to the pyrrole subunit of the indole nucleus. Application of this methodology to the total synthesis of melatonin and the alkaloids mersicarpine, caulerpine, and the pentacyclic skeleton of tronocarpine is briefly discussed. Most of the compounds described herein would be difficult to obtain by more traditional routes.
... The data were in agreement with the literature. [19] (2E,4E)-Ethyl-5-(4-nitrophenyl)penta-2,4-dienoate (8 c): ...
An efficient Knoevenagel condensation reaction was used to construct a series of alfa-cyano-alfa,omega-diaryloligovinylenes which show prominent fluorescence emission in the solid state. When investigating the effect of conjugated length to the fluorescent properties, we found that the diene structure show superior solid-state luminescence by homologous structure-comparison. And the emission color could be adjusted by introducing donors or acceptors functional groups at the terminal aryl groups. We can realize the full-color emission in visible region by simply decorating different functional group in alfa-cyano-alfa,omega-diaryldivinylene moiety. The structure-property relationships were elucidated and some observations like substituted position effect were discussed. These series of compounds have potential applications as full-color solid emissive candidates in material science and their simple structure make them flexible to modify for further hybrid properties.
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... [8] In terms of formation of the C4ÀC4a bond, some recent representative examples include Pd 0 -catalysed cyclopropane CÀH activation, [25] Povarov reaction, [26] intramolecular Heck reaction, [27] Ni 0 -mediated reductive cross-coupling, [28] Bi IIIcatalysed Friedel-Crafts cyclisation, [29] domino reaction from benzyl azide and enamides, [30] and intramolecular radical cyclisation. [31] Although many of these methods involve a CÀH activation event in one of the coupling partners, [26a-c, 29-31] the synthesis of 1,2,3,4-tetrahydroquinolines by the direct coupling of two CÀH bonds remains a challenge. ...
CEH is identified as inexpensive and efficient catalyst for all approaches to the title heterocycles including double cyclizations [cf.
... [8] In terms of formation of the C4ÀC4a bond, some recent representative examples include Pd 0 -catalysed cyclopropane CÀH activation, [25] Povarov reaction, [26] intramolecular Heck reaction, [27] Ni 0 -mediated reductive cross-coupling, [28] Bi IIIcatalysed Friedel-Crafts cyclisation, [29] domino reaction from benzyl azide and enamides, [30] and intramolecular radical cyclisation. [31] Although many of these methods involve a CÀH activation event in one of the coupling partners, [26a-c, 29-31] the synthesis of 1,2,3,4-tetrahydroquinolines by the direct coupling of two CÀH bonds remains a challenge. ...
A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant. Copper(II) 2-ethylhexanoate: The synthesis of oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines from linear precursors by direct C-H, Ar-H coupling by using a single copper catalyst is reported (see scheme; DIPEA=diisopropylethylamine, EWG=electron-withdrawing group). The cyclisations are simple to perform, run open to the air, are moisture insensitive, and use an inexpensive catalyst.
An approach to trifluoroacetylation of aromatic conjugated esters successfully led to the efficient and selective introduction of trifluoroacetyl group to the electron‐deficient β‐ or δ‐carbon atom of ester under mild reaction conditions by magnesium‐promoted reduction, followed by deacetalization with trifluoroacetic acid in moderate to good yields. A variety of fluorinated keto esters derived from ethyl cinnamates and β, γ‐ or γ‐, δ‐unsaturated fluorinated keto esters from aromatic dienoesters with a longer conjugation system were synthesized through this simple methodology utilizing ethyl trifluoroacetate as a fluorine‐containing carbon source.
Concise preparations of elaborated polycyclic and heterocyclic systems present in natural products were obtained using the nosyl group as a functional protecting group not only to mask the reactivity of a sensitive moiety but also to provide a structure desired in the final target. The group is transferred to the substrate during deprotection through a novel extension of the Truce-Smiles rearrangement in tandem with a 1,4-addition. This strategy provides access to a ring system laden with valuable functionalities for subsequent manipulations and can serve as a versatile building block for the construction of more complex molecular architectures such as indoles in a manner compatible with the concepts of green chemistry and atom economy.
A one-pot Smiles rearrangement has been developed as a useful protocol for the straightforward synthesis of diverse N-aryl-nicotinamides. This method also provides chemoselective access toward diarylamines based on the different substitutions of the amide group. The potential application of the transformation is exemplified by the synthesis of an on-market succinate dehydrogenase inhibitor, boscalid. A substituent-mediated Smiles rearrangement to N-aryl-nicotinamides and diarylamines has been developed. In addition to the wide range of heterocyclic building blocks, the one-pot process also provides an efficient access to an on-market fungicide, boscalid.
Radical-initiated support: Xanthates were used as chemical reagents for the sidewall covalent functionalization of carbon nanotubes. The best grafting yields were obtained with stoichiometric ratios of xanthate and the radical initiator lauroyl peroxide. One grafted function was used as a tether for bimetallic cluster compounds, which were converted into very small (1-2 nm) supported nanoparticles upon heating.
The observations and reasoning leading to the discovery of the degenerative transfer of xanthates and related thiocarbonylthio derivatives are briefly described. A few synthetic applications are presented, and the consequences on the emergence of the RAFT and MADIX polymerization technologies as well as some mechanistic aspects are briefly discussed.
A new, mild, and environment friendly process for the reduction of S-alkyl-thionocarbonates, iodides and related compounds to the corresponding hydrocarbons at room temperature with good to excellent yields is described. This method uses a trialkylborane in excess (Et3B or Bu3B) and air.
The degenerative radical addition-transfer of xanthates onto alkenes allows the rapid assembly of richly functionalized structures. Various families of open-chain, cyclic, and polycyclic compounds can thus be readily accessed. Furthermore, the process can be extended to the synthesis or modification of aromatic and heteroaromatic derivatives by exploiting the possibility of using peroxides both as initiators and stoichiometric oxidants. The modification of existing polymers and the controlled synthesis of block polymers by what is now known as the RAFT/MADIX (reversible addition–fragmentation transfer/macromolecular design by interchange of xanthate) process is described briefly.
Thionocarbonates and xanthates of alcohols, bromides, iodides and isonitriles can be transfromed to the corresponding hydrocarbons with hypophosphorous acid or its salts in radical chain reactions.
Fluoride induced elimination of beta-xanthylsilanes, formed by the radical addition of xanthates to allylsilanes, leads to the formation of diversely substituted allyl derivatives.
The behaviour and synthetic scope of the C-2 centred radicals derived from 1,3-dithiane and 1,3-dithiane 1-oxide have been studied. Both radicals are available from the corresponding xanthates and have proved suitable substrates for the xanthate transfer reaction. However, the synthetic scope of the former is severely limited by the fact that it does not add to unactivated olefins. The latter on the other hand is a more promising radical precursor and undergoes smooth radical addition to a wide range of alkenes. Furthermore, subsequent transformations of some of the radical adducts confirm its utility as a synthetic equivalent of both the methyl and the formyl radical.
Armido Studer received his Diploma in 1991 and his PhD in 1995 from the ETH Zürich under the direction of Professor Dieter Seebach. He continued his scientific education as a Swiss National Science Foundation Postdoctoral Fellow at the University of Pittsburgh with Professor Dennis P. Curran, where he worked on fluorous phase chemistry. In 1996, he started his independent career at the ETH Zürich. In 2000, he was appointed as Associate Professor of Organic Chemistry at the Philipps-University in Marburg, Germany. His current research interests focus on the development of new synthetic methods in free radical chemistry.
The use of free radical reactions in organic synthesis has witnessed an extraordinary development in recent years. When properly conceived, radical processes often exhibit many of the properties desired by synthetic organic chemists, such as flexibility, mildness, and selectivity. Unfortunately, the number of synthetically useful radical-generating systems is still limited, and most applications have relied on tin hydride chemistry. Secondary O-alkyl-S-methyl xanthates, for example, eact with tributyltin hydride to give the corresponding alkane (the Barton-McCombie reaction). It was, however, found that the isomeric O-methyl-S-alkyl xanthates undergo cleavage of the weaker carbon–sulfur bond and that a chain reaction can be sustained without tin or other heavy metals. A variety of synthetically interesting free radicals can thus be produced and captured, the last propagating step being a reversible transfer of the xanthate group. S-Propargyl xanthates represent a special class. Their radical chemistry can be easily overshadowed by hitherto unknown but equally interesting nonradical behavior. Upon heating, a thermal [3,3] sigmatropic rearrangement occurs to give the allenyl isomer, which is in equilibrium with a novel betaine structure. This species is at the heart of a number of new transformations, including formal [3+2] cycloadditions, formation of esters with inversion in the case of secondary alcohols, conversion into 1,3-dithiol-2-ones, generation of cisoid dienes, carbon, carbon-carbon bond formation through reaction with acid chlorides etc. This account provides a brief description of this original radical and nonradical chemistry of xanthates, an old family of compounds that still harbors many mysteries.
Quenching the enolates of esters and ketones with dimethyl disulfide or diphenyl disulfide produces the corresponding α-sulfenylated products. The regio- and chemospecificity of these reactions are defined. Oxidation to the sulfoxide followed by thermolysis leads smoothly to the α,β-unsaturated systems. Temperatures for the elimination of the phenyl sulfoxides are normally around 50°C, whereas those for the methyl sulfoxides are normally around 110°C. In both cases, the presence of the carbonyl group significantly facilitates the elimination. Dipole-dipole effects account, in part, for this effect and rationalize the regioselectivity observed in cyclic cases. In some cases, the use of sulfenic acid traps, amines or trímethyl phosphite, is required for good yields. The synthesis of two bee pheromones demonstrates the utility of this approach for introduction of unsaturation. Conditions for mono- vs. disulfenylation are discussed. Use of the latter to effect conversion of an active methylene group into a carbonyl group is illustrated.
This review summarises recent work on the dithiocarbonyl group transfer reaction. Xanthates,
in particular, have proved to be extremely useful for both inter- and intra-molecular additions. The
broad applicability of the intermolecular addition to un-activated olefins opens tremendous opportunities
for synthesis, since various functional groups can be brought together under mild conditions and complex
structures can be rapidly assembled. The presence of the xanthate in the product is also apowerful
asset for further modifications, by both radical and non-radical pathways. Of special importance
is the access to highly substituted aromatic and heteroaromatic derivatives and the synthesis of block
polymers through acontrolled radical polymerisation mediated by various dithiocarbonyl agents
(RAFT and MADIX processes).
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Adducts from the radical addition of xanthates to ethyl vinyl sulfide readily undergo elimination of the xanthate group upon thermolysis to give vinylic and/or allylic sulfides, depending on the structure. In the case of α-xanthyl ketones, the adducts are converted into α-keto vinyl carbinols by rearrangement of the sulfoxides derived from the vinylic and allylic sulfides.
The fascinating story of olefin (or alkene) metathesis (eq
1) began almost five decades ago, when Anderson and
Merckling reported the first carbon-carbon double-bond
rearrangement reaction in the titanium-catalyzed polymerization of norbornene. Nine years later, Banks and Bailey reported “a new disproportionation reaction . . . in which olefins are converted to homologues of shorter and longer carbon chains...”. In 1967, Calderon and co-workers named this metal-catalyzed redistribution of carbon-carbon double bonds olefin metathesis, from the Greek word “μετάθεση”, which means change of position. These contributions have since served as the foundation for an amazing research field, and olefin metathesis currently represents a powerful transformation in chemical synthesis, attracting a vast amount of interest both in industry and academia.
A review has been reported that suggests that the application profile of the olefin metathesis catalysts can be controlled by a proper choice of a N-heterocyclic carbene ligand. Olefin metathesis has emerged as a powerful tool for the formation of C-C double bonds in organic synthesis. Since the metathesis process is neural and reversible, one can obtain a mixture of both substrates and products coexisting in a thermodynamical equilibrium. A spectacular progress in Ru-alkylidene catalyst design was achieved when N-heterocyclic carbenes (NHCs) were introduced as ancillary ligands. Stretching frequencies of NHC-containing carbonyl transition metal complexes were studied to quantify the electron density transfer from the NHC ligand to the metal. It is expected that the future development of new highly active catalysts with even better recyclability will help to overcome the crucial problem of ruthenium contamination in the pharmaceutical industry.
Among the many types of transition-metal-catalyzed C-C bond-forming reactions, olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Consequently, olefin metathesis is now widely considered as one of the most powerful synthetic tools in organic chemistry. Until recently the intermolecular variant of this reaction, cross-metathesis, had been neglected despite its potential. With the evolution of new catalysts, the selectivity, efficiency, and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. These advances, together with a better understanding of the mechanism and catalyst-substrate interactions, have brought us to a stage where more and more researchers are employing cross-metathesis reactions in multistep procedures and in the synthesis of natural products. The recent inclusion of alkynes and hindered bicyclic olefins as viable substrates for bimolecular metathesis coupling, the discovery of enantioselective cross-metathesis and cross-metathesis in water, and the successful marriage of metathesis and solid-phase organic synthesis has further widened the scope of this versatile reaction.
[reaction: see text] Reductive cleavage of the carbon-sulfur bond present in S-alkyl-thionocarbonates (xanthates) was achieved by high-yielding, tin-free radical reactions based on phosphorus reagents. The combination hypophosphorous acid/triethylamine/AIBN led to fast, efficient, and smooth formation of the alkane. Reduction with diethyl phosphite was sufficiently slow to permit sequential intermolecular addition of a 2-oxoalkyl xanthate onto an olefin followed by cleavage of the newly formed carbon-sulfur bond.
[reaction: see text] S-[1-(N-Acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (6), a readily available xanthate, adds efficiently to various functionalized olefins to give the corresponding adducts 8 via a radical chain reaction initiated by a small amount of lauroyl peroxide.
A two-step preparation of 2,3-trans disubstituted tetrahydrofuran derivatives is reported from S-alkyl dithiocarbonates. The study of the group transfer reaction from xanthates and alkenes afforded intermediate S-alkyl dithiocarbonates. From 2,3-dihydrofuran derivatives, the displacement of the resulting anomeric xanthates with various nucleophiles in the presence of Lewis acid allowed the formation of new carbon-carbon and carbon-heteroatom bonds. This strategy was illustrated by a two-step synthesis of a precursor of modified 2'-beta-C-branched nucleoside analogues.
Xanthates and related derivatives have proved to be extremely useful for both inter- and intramolecular radical additions. The broad applicability of the intermolecular addition to un-activated olefins opens tremendous opportunities for synthesis, since various functional groups can be brought together under mild conditions and complex structures can be rapidly assembled. The presence of the xanthate in the product is also a powerful asset for further modifications, by both radical and non-radical pathways. Of special importance is the access to highly substituted aromatic and heteroaromatic derivatives and the synthesis of block polymers through a controlled radical polymerisation mediated by various thiocarbonylthio group containing agents (RAFT and MADIX processes).
(Chemical Equation Presented) An open relationship: The triethylborane/O2-mediated addition of xanthates to vinyl epoxides and derivatives represents an efficient process to form carbon-carbon bonds. Complex structures can be rapidly assembled in a modular, convergent manner, under mild conditions, using readily available reagents (see scheme, Bn = benzyl). The formation of quaternary centers proved especially facile.
New routes to organofluorine derivatives based mostly on the powerful xanthate radical transfer technology are described. A special emphasis is placed on the synthesis of trifluoromethyl-substituted structures, including trifluromethyl ketones and fluorinated aromatic and heteroaromatic substances of interest to the pharmaceutical and agrochemical industries.
InRadicals in Organic Synthesis
- A Bstuder
- M Bossart