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Akkattu T. Biju - One of the best experts on this subject based on the ideXlab platform.
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Transition-Metal-Free Thioamination of Arynes Using Sulfenamides
2019Co-Authors: Rahul N. Gaykar, Subrata Bhattacharjee, Akkattu T. BijuAbstract:The insertion of Arynes into the S–N σ-bond of sulfenamides allowing the synthesis of o-sulfanylaniline derivatives with reasonable functional group compatibility is presented. The Aryne generated from 2-(trimethylsilyl)aryl triflates using CsF in DME was the key for the success of this transition-metal-free thioamination reaction, which involves new C–N and C–S bond formations in a single step under mild conditions. Moreover, the synthetic potential of this method was demonstrated by the synthesis of the antidepressant drug vortioxetine
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Synthesis of Functionalized β-Keto Arylthioethers by the Aryne Induced [2,3] Stevens Rearrangement of Allylthioethers.
The Journal of organic chemistry, 2017Co-Authors: Manikandan Thangaraj, Tony Roy, Rahul N. Gaykar, Akkattu T. BijuAbstract:A mild and transition-metal-free synthesis of β-keto arylthioethers has been developed by the Aryne triggered [2,3] Stevens rearrangement of allylthioethers. The key sulfur ylide intermediate for the rearrangement was formed by the S-arylation of allylthioethers with Arynes generated from 2-(trimethylsilyl)aryl triflates using CsF. Later, the reaction products are converted into valuable heterocycles in two steps.
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Synthesis of Functionalized β‑Keto Arylthioethers by the Aryne Induced [2,3] Stevens Rearrangement of Allylthioethers
2017Co-Authors: Manikandan Thangaraj, Tony Roy, Rahul N. Gaykar, Akkattu T. BijuAbstract:A mild and transition-metal-free synthesis of β-keto arylthioethers has been developed by the Aryne triggered [2,3] Stevens rearrangement of allylthioethers. The key sulfur ylide intermediate for the rearrangement was formed by the S-arylation of allylthioethers with Arynes generated from 2-(trimethylsilyl)aryl triflates using CsF. Later, the reaction products are converted into valuable heterocycles in two steps
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employing Arynes in diels alder reactions and transition metal free multicomponent coupling and arylation reactions
Accounts of Chemical Research, 2016Co-Authors: Sachin Suresh Bhojgude, Anup Bhunia, Akkattu T. BijuAbstract:ConspectusArynes are highly reactive intermediates having several applications in organic synthesis for the construction of various ortho-disubstituted arenes. Traditionally, Arynes are generated in solution from haloarenes under strongly basic conditions. However, the scopes of many of the Aryne reactions are limited because of the harsh conditions used for their generation. The renaissance of interest in Aryne chemistry is mainly due to the mild conditions for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. This Account is focused on the Diels–Alder reaction of Arynes and their transition-metal-free application in multicomponent couplings as well as arylation reactions.The Diels–Alder reaction of Arynes is a powerful tool for constructing benzo-fused carbocycles and heterocycles. In 2012, we developed an efficient, broad-scope, and scalable Diels–Alder reaction of pentafulvenes with Arynes affording benzonorbornadiene derivatives. Subsequently, we accomplish...
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employing carboxylic acids in Aryne multicomponent coupling triggered by aziridines azetidines
Organic chemistry frontiers, 2016Co-Authors: Tony Roy, Sachin Suresh Bhojgude, Manikandan Thangaraj, Trinadh Kaicharla, Bikash Garai, Akkattu T. BijuAbstract:The transition-metal-free Aryne multicomponent coupling (MCC) involving carboxylic acids initiated by aziridines/azetidines has been reported. The use of aziridines as nucleophiles afforded N-aryl β-amino alcohol derivatives and the application of azetidines as nucleophilic triggers furnished N-aryl γ-amino alcohol derivatives in moderate to good yields. These reactions proceed under mild conditions and result in the formation of a new carbon–nitrogen bond and a new carbon–oxygen bond. The utility of carboxylic acids in Aryne MCCs has been demonstrated, and the synthetic potential of phenols as acid surrogates in the present Aryne MCCs has been realized.
Mark Lautens - One of the best experts on this subject based on the ideXlab platform.
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Development of an Intramolecular Aryne Ene Reaction and Application to the Formal Synthesis of (±)-Crinine
2016Co-Authors: David A Candito, Dennis Dobrovolsky, Mark LautensAbstract:A general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular Aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction, with exclusive migration of the trans-allylic-H taking place. Furthermore, the electronic nature of the Aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggests a concerted asynchronous transition state, resembling a nucleophilic attack on the Aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine
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development of an intramolecular Aryne ene reaction and application to the formal synthesis of crinine
Journal of the American Chemical Society, 2012Co-Authors: David A Candito, Dennis Dobrovolsky, Mark LautensAbstract:A general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular Aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction, with exclusive migration of the trans-allylic-H taking place. Furthermore, the electronic nature of the Aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggests a concerted asynchronous transition state, resembling a nucleophilic attack on the Aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine.
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Intramolecular Aryne-ene reaction: Synthetic and mechanistic studies
Journal of the American Chemical Society, 2011Co-Authors: David A Candito, Jane Panteleev, Mark LautensAbstract:Although the chemistry of Arynes is well developed, some challenges still remain. The ene reaction of Arynes has not gained widespread use in synthesis as a result of poor yields and selectivity. A general, high yielding and selective intramolecular Aryne-ene reaction is described providing various benzofused carbo- and heterocycles. Mechanistic data is presented, and a rationale for the resulting stereochemistry is discussed.
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synthesis of dihydronaphthalenes via Aryne diels alder reactions scope and diastereoselectivity
Journal of the American Chemical Society, 2005Co-Authors: Chris Dockendorff, Stefan Sahli, Madeline Olsen, Ludovic Milhau, Mark LautensAbstract:Novel Aryne Diels−Alder reactions with functionalized acyclic dienes are reported. These give useful cis-substituted dihydronaphthalene building blocks in good yield which are not easily accessible via other means, as demonstrated in the synthesis of sertraline. The first asymmetric Aryne cycloaddition with an acyclic diene is also reported, giving excellent diastereoselectivities with Oppolzer's sultam as a chiral auxiliary.
Jiarong Shi - One of the best experts on this subject based on the ideXlab platform.
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Domino Aryne Annulation via a Nucleophilic–Ene Process
2018Co-Authors: Jiarong Shi, Dachuan Qiu, Liang Tan, Xiaohua LuoAbstract:1,2-Benzdiyne equivalents possess the unique property that they can react with two arynophiles through iteratively generated 1,2- and 2,3-Aryne intermediates. Upon rational modification on the second leaving group of these Aryne precursors, a domino Aryne annulation approach was developed through a nucleophilic–ene reaction sequence. Various benzo-fused N-heterocyclic frameworks were achievable under transition metal-free conditions with a broad substrate scope
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diamination of domino Aryne precursor with sulfonamides
ChemInform, 2016Co-Authors: Dachuan Qiu, Xiao Yue, Jiarong ShiAbstract:The reaction of a domino Aryne precursor with sulfonamides efficiently afforded both 1,3-diaminobenzenes and trisubstituted 1,3-diaminobenzenes by simply varying the reaction conditions. Mechanistic study supports the sequential formation of two transient Aryne intermediates involved in the reaction.
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Aryne 1 2 3 trifunctionalization with aryl allyl sulfoxides
Journal of the American Chemical Society, 2016Co-Authors: Dachuan Qiu, Junli Wang, Jiarong ShiAbstract:An Aryne 1,2,3-trisubstitution with aryl allyl sulfoxides is accomplished, featuring an incorporation of C–S, C–O, and C–C bonds on the consecutive positions of a benzene ring. The reaction condition is mild with broad substrate scope. Preliminary mechanistic study suggests a cascade formal [2 + 2] reaction of Aryne with S═O bond, an allyl S → O migration, and a Claisen rearrangement.
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vicinal diamination of arenes with domino Aryne precursors
Organic Letters, 2016Co-Authors: Dachuan Qiu, Jiarong ShiAbstract:Vicinal diamination of domino Aryne precursors was achieved with sulfamides. The reaction proceeds through a two-Aryne pathway, accepting two N-nucleophiles at the 1,2-positions of an arene ring. Symmetrical and unsymmetrical diaminobenzenes were readily obtained.
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Selective Aryne Formation via Grob Fragmentation from the [2+2] Cycloadducts of 3‑TriflyloxyArynes
2016Co-Authors: Jiarong Shi, Dachuan QiuAbstract:A chemoselective ring-opening protocol of the formal [2+2] cycloadducts of 3-triflyloxyArynes was developed to generate 2,3-Aryne intermediate via Grob fragmentation. A variety of 1,3-di- and 1,2,3-trisubstituted arenes could be readily accessed through this [2+2] cycloaddition-2,3-Aryne formation sequence. The regioselectivity in these transformations originates from the steric repulsion of the aliphatic chain
Michael F Greaney - One of the best experts on this subject based on the ideXlab platform.
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the hexadehydro diels alder reaction a new chapter in Aryne chemistry
ChemInform, 2014Co-Authors: Catherine M Holden, Michael F GreaneyAbstract:Arynes continue to stimulate new reactions and theoretical insight in aromatic chemistry. This has been driven in recent years by the exceptional versatility of 2-(trimethylsilyl)phenyl triflate (1) as a precursor to ortho-benzyne.[1] Such compounds react under mild conditions and have enabled a substantial development of Aryne chemistry both in terms of classical transformations (nucleophilic addition, pericyclic reactions) and in opening up new areas, such as σ-insertion reactions and transition-metal-catalyzed processes. As with all methods for the generation of ortho-benzyne to date, compound 1 requires the removal of two adjacent groups from a pre-existing arene. Recent work from the groups of Hoye and Lee has utilized a completely different approach to ortho-Arynes, which proceeds through the intramolecular cycloaddition of triynes 3 (Scheme 1).[2, 3] This transformation, which was termed a hexadehydro-Diels–Alder (HDDA) reaction by Hoye in analogy to other dehydropericyclic reactions, is perhaps surprising at first glance because of the infrequently depicted Aryne resonance structure 4, which immediately arises from the [4+2] cycloaddition. The trapping of an ortho-benzyne intermediate generated in this fashion can then be accomplished by a variety of inter- and intramolecular transformations, affording new approaches to valuable benzenoid compounds. Scheme 1 Generation of ortho-Aryne intermediates from the established triflate precursor 1 (a) and through the hexadehydro-Diels–Alder (HDDA) reaction (b–d). OTf=trifluoromethanesulfonate, TMS=trimethylsilyl. The origin of the HDDA reaction lies in two independent reports from the groups of Johnson and Ueda in 1997.[4] Johnson and co-workers subjected the simple hydrocarbon 1,3,8-nonatriyne (6) to flash vacuum pyrolysis and were able to isolate indane and indene in a combined yield of 95 % (Scheme 1 c).[4a] The most likely mechanism appeared to be a [4+2] cycloaddition to form an Aryne, followed by reduction under the pyrolytic conditions. Deuterium labeling studies support this mechanism, ruling out a possible 1,2-shift/Bergman cyclization pathway. DFT calculations for the cycloaddition of acetylene with butadiyne gave the surprising result that the formation of benzyne through an HDDA reaction would be highly exothermic (−52 kcal mol−1) and accompanied by a large free energy of activation (37 kcal mol−1).[4c] The Ueda group observed that tetraynes such as 9 could cyclize to 5H-fluorenol derivatives at room temperature, with the intermediacy of an ortho-benzyne species being established by intra- and intermolecular trapping experiments (to give 10, for example).[4b] Ueda and co-workers then continued to investigate the scope of the HDDA reaction and established intramolecular trapping reactions with oxygen, sulfur, and nitrogen nucleophiles. Applications were demonstrated in the areas of helical polyene synthesis and in studies on the DNA-cleaving properties of the ortho-Aryne generated in this fashion.[5] The similarities to the Bergman and Myers–Saito cycloaromatization reactions are evident, and cleavage of the DNA strands, analogous to the en–diyne para-benzyne processes, was observed by the Ueda group using simple oxidative triggering of the HDDA reaction.[5a,d] Despite these impressive antecedents,[6] the potential of the HDDA approach to ortho-benzyne motifs was not widely appreciated until Hoye and co-workers published substantial extensions of this method in 2012.[2] They unexpectedly observed cycloaromatization of the oxidation product of tetrayne 11, which afforded benzenoid 12 through ortho-Aryne formation and trapping through a retro-Brook rearrangement of the silyl ether (Scheme 2 a). The substrate scope of this transformation is remarkably broad, as the reagent-free conditions were found to be suitable for a range of base-sensitive functional groups that would challenge conventional methods for Aryne formation (e.g., silyl groups, which are problematic for reagent 1, and esters, which are incompatible with metal–halogen exchange). Activation of the diynophile by electron-withdrawing groups was established, and ring-size effects and a wide variety of inter- and intramolecular trapping steps were studied. Successful HDDA and Diels–Alder trapping reactions were observed using CHCl3 as a solvent, which is an excellent hydrogen atom donor, pointing to a lack of radical character in the cyclization. DFT calculations for the HDDA cyclisation of 13 revealed a reaction profile that was quantitatively similar to that calculated by Johnson in earlier work and predicted the formation of the Aryne intermediate to be exothermic by a substantial 51 kcal mol−1. Scheme 2 HDDA cycloaromatization reactions, described by the groups of Hoye and Lee. TBS=tert-butyldimethylsilyl, Ts=para-toluenesulfonyl. Following this report, Lee and co-workers discovered an HDDA system based on the silver-catalyzed cycloaromatization of tetraynes 16.[3] The Aryne-trapping event was a striking C(sp3)–H activation to form polycyclic products such as 18; the silver catalyst is thought to form a metal-stabilized Aryne 17 (an “isoindolyne”),[7] which is capable of alkane C–H activation (Scheme 2 b). The reaction was exemplified on a variety of secondary alkane C–H bonds and poly-yne structures; gem-dimethyl substitution on the developing carbocycle 18 was observed to facilitate the reaction. Mechanistic investigations pointed towards a concerted addition of the C–H bond across the Aryne intermediate, a reaction with little precedent in carbocyclizations. For unsymmetric tetraynes, where regioisomeric arenes may be formed, moving the tethering NTs group to create a diynamide effectively activated this moiety to undergo an HDDA reaction. Since these initial reports, the Hoye and Lee groups have rapidly developed a host of reaction motifs that showcase both the unique reactivity of Arynes and the potential of the HDDA reaction in arene synthesis.[8, 9] Lee et al. have demonstrated that AgF, AgCF3, and AgSCF3 can all mediate HDDA reactions with incorporation of the respective fluorine-containing counterions to yield motifs that are valued in medicinal chemistry and agrochemistry.[9b] Such intermolecular trapping processes raise the prospect of regioisomeric products, a long-standing challenge in Aryne addition chemistry. Excellent regioselectivities were observed for the fluorination reaction (fluorine incorporated ortho to the R2 group; Scheme 2 b); however, the addition of the SCF3 and CF3 groups tended to produce mixtures. The factors that control intermolecular trapping in the HDDA reaction have been the focus of a recent study by the Lee group, who have delineated the electronic and steric control elements that are in operation for a range of nitrogen- and oxygen-based nucleophiles.[9c] Furthermore, both the Hoye and Lee groups have demonstrated Alder–ene chemistry as a trapping event, with the Hoye group achieving impressive HDDA/aromatic ene/Alder–ene cascade sequences (Scheme 3 a).[8b, 9a] The use of an external enophile enabled the capture of the product of the first ene reaction, isotoluene 24, which consecutively generated three rings in the absence of any external reagents and without the formation of any by-products (product 25). Scheme 3 Alder–ene and alkane-desaturation trapping processes in the HDDA reaction. The Hoye group have reported a particularly eye-catching example of HDDA chemistry, which involves alkane desaturation (Scheme 3 b).[8a] Alkane desaturation is known to occur during a number of biological processes, but there is no general synthetic equivalent. In the presence of a range of cycloalkanes, an HDDA reaction led to the production of cycloalkenes through a concerted process; excellent yields were obtained for cyclooctane, -heptane, and -pentane donors. Interestingly, cyclohexane was a poor substrate for this reaction. DFT calculations suggest that the near-planar, concerted transition state of the reaction favors 2 H donors that have a higher degree of eclipsed low-energy conformations. Tetrahydrofuran (THF) was also shown to be an effective donor, which is a significant result in the wider context of Aryne chemistry, as this solvent is frequently used with other ortho-benzyne precursors such as 1. It is noteworthy that the HDDA cyclization enabled mechanistic insight into Aryne reactivity that might be difficult to achieve using conventional precursors, where Aryne generation is often rate-limiting, and additional reagents can obscure the analysis of subsequent steps. In summary, the HDDA reaction offers a unique approach to ortho-Arynes; all atoms of the starting triyne are conserved in the product, and diverse functional groups may be installed by strategic design of the trapping steps. These transformations offer exciting potential for the synthesis of complex benzenoids of the type found in natural products and functional materials, with some exceptional examples of atom-economic cascade processes having already been demonstrated. Allied with new mechanistic insights into the trapping steps, these reactions open up significant new areas of study and application for the continually fascinating field of Aryne chemistry.
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continuous flow synthesis of trimethylsilylphenyl perfluorosulfonate benzyne precursors
Organic Letters, 2014Co-Authors: Boris Michel, Michael F GreaneyAbstract:2-(Trimethylsilyl)phenyl perfluorosulfonated Aryne precursors may now be accessed using flow chemistry, enabling the fast preparation of pure compounds with no requirement for low temperature lithiation or column chromatography. The process has been adapted to novel nonaflate precursors, utilizing the cheaper and more user-friendly nonaflyl fluoride reagent. The resultant nonaflates are shown to successfully participate in a range of Aryne reaction classes.
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use of 2 bromophenylboronic esters as benzyne precursors in the pd catalyzed synthesis of triphenylenes
Organic Letters, 2014Co-Authors: Joseantonio Garcialopez, Michael F GreaneyAbstract:ortho-Substituted aryl boronates are introduced as Aryne precursors for transition-metal-catalyzed transformations. On treatment with (t)BuOK and Pd(0), metal-bound Aryne intermediates are formed that undergo effective trimerization to form useful triphenylene compounds. For meta-substituted Arynes, the 3:1 product ratio in favor of non-C3 symmetric material is indicative of a benzyne mechanism.
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generation of benzyne from benzoic acid using c h activation
Chemical Communications, 2010Co-Authors: Alastair A Cant, Lee Roberts, Michael F GreaneyAbstract:ortho C–H activation of benzoic acids with Pd(II) generates an oxapalladacycle that can decarboxylate to produce a palladium-associated Aryne. The Arynes then undergo [2+2+2] trimerisation to afford triphenylenes.
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the benzyne aza claisen reaction
Angewandte Chemie, 2009Co-Authors: Alastair A Cant, Guillaume H V Bertrand, Jaclyn L Henderson, Lee Roberts, Michael F GreaneyAbstract:Adding an Aryne to a tertiary allylamine affords o-allylaniline products of an aza-Claisen rearrangement. The Aryne simultaneously provides the pi component for the rearrangement and the quaternization event that lowers the activation energy for the sigmatropic shift. The reaction was applied to the synthesis of medium-ring benzannulated amines (see scheme).
Dmitry S Kopchuk - One of the best experts on this subject based on the ideXlab platform.
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studies on the interactions of 5 r 3 2 pyridyl 1 2 4 triazines with Arynes inverse demand aza diels alder reaction versus Aryne mediated domino process
Organic and Biomolecular Chemistry, 2018Co-Authors: Dmitry S Kopchuk, I L Nikonov, Albert F Khasanov, Kousik Giri, Sougata Santra, Igor S Kovalev, Emiliya V Nosova, Sravya GundalaAbstract:The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted Aryne intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels–Alder products or 1,2,4-triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5 position of the 1,2,4-triazine core or in the Aryne moiety. The structures of the key products were confirmed based on X-ray data. Based on the density functional theoretical (DFT) studies of the Diels–Alder transition state geometries, the influence of the nature of Arynes on the direction of the 1,2,4-triazine transformation has been proposed.
