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conia ene reaction wikipedia jump to content main menu main menu move to sidebar hide navigation main page contents current events random article about wikipedia contact us contribute help learn to edit community portal recent changes upload file special pages search search appearance donate create account log in personal tools donate create account log in contents move to sidebar hide top 1 history and mechanism 2 advancements 3 activation modes toggle activation modes subsection 3 1 enolate activation 3 2 alkyne activation 3 3 ene yne activation 3 4 one metal dual activation 3 5 two metal dual activation 4 applications in total synthesis 5 references toggle the table of contents conia ene reaction 1 language español edit links article talk english read edit view history tools tools move to sidebar hide actions read edit view history general what links here related changes upload file permanent link page information cite this page get shortened url switch to legacy parser print export download as pdf printable version in other projects wikimedia commons wikidata item appearance move to sidebar hide from wikipedia the free encyclopedia chemical reaction conia ene reaction named after jean marie conia reaction type group transfer identifiers organic chemistry portal conia ene reaction in organic chemistry the conia ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene giving a cyclic product with a new carbon carbon bond as initially reported by j m conia and p le perchec the conia ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component 1 like other pericyclic reactions the original conia ene reaction required high temperatures to proceed limiting its wider application however subsequent improvements particularly in metal catalysis have led to significant expansion of reaction scope consequently various forms of the conia ene reaction have been employed in the synthesis of complex molecules and natural products history and mechanism edit in the late 1960s the laboratory of chemist jean marie conia investigated small carbocyclic molecules specifically as products of ene type reactions with carbonyls 2 these efforts culminated in a 1975 review paper titled the thermal cyclisation of unsaturated carbonyl compounds 1 in its original manifestation the conia ene reaction comprised the intramolecular cyclization of ε ζ unsaturated ketones or aldehydes to functionalized cyclopentanes upon intense heating 1 3 the proposed mechanism invoked a six membered ene reaction like transition state in which the enol tautomer reacts concertedly with the pendant alkene the same conditions were found to give six and nine membered rings with the appropriate substrates although with lower yields and diastereoselectivity in the case of γ δ and δ ε unsaturated ketones equilibrium favored the linear product over the cyclopropane or cyclobutane alkynyl ketones were also found to cyclize under thermal conditions giving a mixture of the conjugated and skipped cyclic enones two key drawbacks prevented wider implementation of the initial conia ene reaction first molecules with additional functional groups were often incompatible with the high temperatures required for conversion second regio and diastereoselectivity depended entirely on the substrate offering little to no control over the orientation of the product advancements edit in the decades after the discovery of the conia ene reaction several improvements allowed for milder reaction conditions and greater control of product stereo and regiochemistry for example the carbonyl component formerly a ketone or aldehyde became a substituted β ketoester or malonate ester such carbonyls enolize much more readily yielding better access to the desired enol tautomer 4 additionally the alkene component was replaced with an alkyne which not only gave better cyclization in accordance with baldwin s rules but also furnished a product containing an alkene that served as a useful handle for further transformations 5 finally recent efforts have featured metal mediated and metal catalyzed conia ene reactions that can be rendered asymmetric using chiral ligands 6 activation modes edit these advancements have produced five main types of conia ene reactions characterized by the operative activation mode namely enolate alkyne or ene yne activation and one or two metal dual activation note that though the mechanisms of conia ene variants differ from the initial ene like cyclization they are still considered conia ene or conia ene type reactions 6 in addition due to the complexity of some conia ene reaction systems the true mechanism may lay somewhere between several different activation modes enolate activation edit enolate activation is the simplest conia ene activation mode in this mode the carbonyl starting material is treated with a strong base such as nbuli nah or tbuok to form a metal stabilized enolate which then attacks the tethered alkyne and transfers the metal cation an early example of enolate activation was reported by taguchi and coworkers in 1999 7 the authors found that in the presence of catalytic base alkynyl substituted malonate esters undergo facile cyclization to the corresponding cyclopentanes high yields were also obtained with substituted cyanoacetate sulfonylacetate and phosphonoacetate analogs alkyne activation edit in conia ene reactions proceeding via alkyne activation a suitable late transition metal au ag pt pd coordinates to the alkyne and increases its electrophilicity thus the enol tautomer of the carbonyl can attack more readily toste et al pioneered two of the first examples of alkyne activation in 2004 8 using a cationic au i complex the authors formed a wide variety of cyclized products from linear β ketoester starting materials notably the reactions are run under mild conditions and give high diastereoselectivity moreover by shortening the alkyne tether from three carbons to two substituted cyclopentenes can also be accessed 9 ene yne activation edit in ene yne activation the least common of the five modes a single metal species coordinates with the enol alkene and the tethered alkyne simultaneously activating both moieties for reaction nickel cobalt and rhenium complexes have all been employed in this manner 6 a representative example was reported by malacria et al in 1994 in which an alkynyl substituted β ketoester was treated with cyclopentadienyl cobalt complex and irradiation to give disubstituted methylene cyclopentane 10 one metal dual activation edit to effect dual activation by a single metal the same metal species that activates the enolate also interacts with the alkyne though the precise mechanisms are poorly understood and likely vary from case to case metals such as in zn fe and cu are proposed to operate via this mode 6 one reaction system thought to proceed via one metal dual activation is that developed by shaw et al in 2014 using a catalytic fe iii salen complex shaw and coworkers were able to access chiral cyclopentanes from an array of alkynyl tethered β ketoesters and analogs thereof 11 the reaction tolerated a wide range of ketones phenyl homoallyl cyclopropyl 2 furyl etc esters ethyl tert butyl etc and ester analogs nitro phosphono cyano sulfonyl etc two metal dual activation edit two metal dual activation represents the combination of the enolate activation mode and the alkyne activation mode into a single reaction system generally a hard oxophilic metal k na ag activates the enolate oxygen while a soft carbophilic metal pd cu mo coordinates with the alkyne in some instances however the precise role of each metal is unclear 6 for example in a 2005 study toste et al found that treatment of an alkynyl tethered β ketoester with a pd ii phosphine complex and yb otf 3 effected asymmetric cyclization to the corresponding cyclopentane 12 it is proposed that a pd enolate adds into a yb activated alkyne though there is also precedent for pd activation of alkynes 13 applications in total synthesis edit following their development of au catalyzed conia ene reactions toste and coworkers employed such a transformation toward the alkaloid natural product lycopladine a 14 starting from chiral cyclohexenone 1 a series of enone functionalizations gave silyl enol ether 2 as the conia ene precursor to effect cyclization 2 was treated with catalytic aucl pph 3 and agbf 4 to furnish vinyl iodide 3 in high yield as a single diastereomer the remainder of the molecule was completed in three steps to give lycopladine a in eight steps and 17 overall yield in 2012 carreira et al synthesized racemic gomerone c a halogenated terpene isolated from the red algae laurencia majuscula and employed au catalyzed conia ene cyclization as the penultimate step 15 having obtained silyl enol ether 7 in 11 steps from bicycle 6 itself the product of a diels alder cycloaddition between siloxydiene 4 and enone 5 the authors subject 7 to 50 mol echavarren s catalyst to deliver tricycle 8 in 65 yield this compound is then elaborated to gomerone c by chlorination of the exo methylene in 2020 yang and coworkers employed a diastereoselective conia ene reaction during their asymmetric synthesis of waihoensene a structurally dense terpenoid from podocarpus totara var waihoensis first synthesized by the lee group in 2017 16 vinylogous ester 9 was first functionalized in six steps to chiral conia ene precursor 10 subsequent treatment of 10 with tbuok in dmso gave bicycle 11 in 83 yield as a single diastereomer this compound then required eight additional transformations to reach waihoensene in 15 steps and 4 overall yield references edit 1 2 3 conia j m le perchec p 1975 the thermal cyclisation of unsaturated carbonyl compounds synthesis 1 1 1 19 doi 10 1055 s 1975 23652 s2cid 94889581 conia j m 1968 syntheses of cyclopropylcarbonyl compounds angew chem int ed 7 8 570 575 doi 10 1002 anie 196805701 conia ene reaction organic chemistry portal matthews w s bares j e bartmess j e bordwell f g cornforth f j drucker g e margolin z mccallum r j mccollum g j vanier n r 1975 equilibrium acidities of carbon acids vi establishment of an absolute scale of acidities in sulfoxide solution j am chem soc 97 24 7006 7014 doi 10 1021 ja00857a010 baldwin j e 1976 rules for ring closure j chem soc chem commun 18 18 734 736 doi 10 1039 c39760000734 1 2 3 4 5 hack d blümel m chauhan p philipps a r enders d 2015 catalytic conia ene and related reactions chem soc rev 44 17 6059 6093 doi 10 1039 c5cs00097a pmid 26031492 kitagawa o suzuki t fujiwara h fujita m taguchi t 1999 alkaline metallic reagent catalyzed hydrocarbocyclization reaction of various active methine compounds having an unactivated 4 alkynyl or allenyl group tetrahedron lett 40 24 4585 4527 doi 10 1016 s0040 4039 99 00797 2 kennedy smith j j staben s t toste f d 2004 gold i catalyzed conia ene reaction of β ketoesters with alkynes j am chem soc 126 13 4526 4527 doi 10 1021 ja049487s pmid 15070364 staben s t kennedy smith j j toste f d 2004 gold i catalyzed 5 endo dig carbocyclization of acetylenic dicarbonyl compounds angew chem int ed 43 40 5350 5352 doi 10 1002 anie 200460844 pmid 15468061 stammler r malacria m 1994 new cobalt catalyzed cycloisomerization of β ketoester ε acetylenic synlett 1 92 doi 10 1055 s 1994 22751 s2cid 94650335 shaw s white j d 2014 a new iron iii salen catalyst for enantioselective conia ene carbocyclization j am chem soc 136 39 13578 13581 bibcode 2014jachs 13613578s doi 10 1021 ja507853f pmid 25213211 corkey b k toste f d 2005 catalytic enantioselective conia ene reaction j am chem soc 127 49 17168 17169 bibcode 2005jachs 12717168c doi 10 1021 ja055059q pmid 16332048 streuff j white d e virgil s c stoltz b m 2010 a palladium catalyzed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocenters nat chem 2 3 192 196 bibcode 2010natch 2 192s doi 10 1038 nchem 518 pmc 2917108 pmid 20697457 staben s t kennedy smith j j huang d corkey b k lalonde r l toste f d 2006 gold i catalyzed cyclizations of silyl enol ethers applications to the synthesis of lycopladine a angew chem int ed 45 36 5991 5994 doi 10 1002 anie 200602035 pmid 16888820 huwyler n carreira e m 2012 total synthesis and stereochemical revision of the chlorinated sesquiterpene gomerone c angew chem int ed 51 52 13066 13069 doi 10 1002 anie 201207203 pmid 23161813 qu y wang z zhang z zhang w huang j yang z 2020 asymmetric total synthesis of waihoensene j am chem soc 142 14 6511 6515 bibcode 2020jachs 142 6511q doi 10 1021 jacs 0c02143 pmid 32203659 s2cid 263581627 retrieved from https en wikipedia org w index php title conia ene_reaction oldid 1361635185 categories organic reactions reaction mechanisms hidden categories articles with short description short description matches wikidata this page was last edited on 29 june 2026 at 04 59 utc page was 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