Alkynes As Synthetic Equivalents of Ketones and Aldehydes: a Hidden Entry Into Carbonyl Chemistry
Review Alkynes as Synthetic Equivalents of Ketones and Aldehydes: A Hidden Entry into Carbonyl Chemistry
Igor V. Alabugin 1,* , Edgar Gonzalez-Rodriguez 1, Rahul Kisan Kawade 1, Aleksandr A. Stepanov 2,3 and Sergei F. Vasilevsky 2,3
1 Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA; [email protected] (E.G.-R.); [email protected] (R.K.K.) 2 Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; [email protected] (A.A.S.); [email protected] (S.F.V.) 3 Novosibirsk State University, 2, Pirogova Str., 630090 Novosibirsk, Russia * Correspondence: [email protected]
Received: 18 February 2019; Accepted: 11 March 2019; Published: 15 March 2019
Abstract: The high energy packed in alkyne functional group makes alkyne reactions highly thermodynamically favorable and generally irreversible. Furthermore, the presence of two orthogonal π-bonds that can be manipulated separately enables flexible synthetic cascades stemming from alkynes. Behind these “obvious” traits, there are other more subtle, often concealed aspects of this functional group’s appeal. This review is focused on yet another interesting but underappreciated alkyne feature: the fact that the CC alkyne unit has the same oxidation state as the -CH2C(O)- unit of a typical carbonyl compound. Thus, “classic carbonyl chemistry” can be accessed through alkynes, and new transformations can be engineered by unmasking the hidden carbonyl nature of alkynes. The goal of this review is to illustrate the advantages of using alkynes as an entry point to carbonyl reactions while highlighting reports from the literature where, sometimes without full appreciation, the concept of using alkynes as a hidden entry into carbonyl chemistry has been applied.
Keywords: alkynes; carbonyl compounds; ketones; aldehydes; condensations; cyclizations; catalysis; nucleophilic addition; acetals; rearrangements; electronic structure
1. Introduction Alkynes, one of the most familiar “textbook” functionalities, are highly versatile and useful, as illustrated by their widespread application in different fields of chemistry, biology and materials science [1,2]. However, despite being familiar, alkynes display a number of interesting and underappreciated electronic features. For example, alkynes’ high energy [3] confers them an edge by making alkyne synthetic transformations highly thermodynamically favorable, and generally irreversible. Likewise, the presence of two orthogonal π-bonds that can be manipulated separately supports flexible synthetic strategies that render alkynes valuable for the design of efficient cascade transformations [4]. Furthermore, hidden behind these “obvious” traits are other more subtle aspects of this functional group’s appeal. For example, alkynes can be considered as super-stabilized 1,2-dicarbenes [4,5], as well as a perfect atom-economical, carbon-rich building unit for the preparation of extended polyaromatics [3,6–23]. This review will focus on yet another interesting alkyne feature, i.e., the fact that the -C≡C- alkyne unit has the same oxidation state as the -CH2C(O)- unit of a typical carbonyl compound. This equivalency is readily illustrated by the fact that alkynes are converted to carbonyl compounds via hydration (Scheme1). Although in this process one of the alkyne carbons is formally oxidized
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Scheme 1. Markovnikov (top) and anti-Markovnikovanti-Markovnikov (bottom) hydration of alkynes converts them into either ketones or aldehydes, respectively.respectively.
Thus, “classic carbonyl chemistry” can be accessed through alkynes, and new alkyne cascade transformations can be engineered by unmasking the hidden carbonyl nature of alkynes. The goal of this review is to illustrate the advantagesadvantages ofof usingusing alkynesalkynes asas anan entryentry pointpoint toto carbonylcarbonyl reactions.reactions. The connection between alkynes and carbonyl compounds is generally mediated by formation of bonds between alkyne carbons and heteroatoms. In a similar similar fashion fashion to to water water addition addition to to alkynes, alkynes, additions of of other other nucleophiles nucleophiles do do not not change change the the overall overall oxidation oxidation state state of the of thefunctional functional group. group. For example,For example, the addition the addition of O- or of N O--centered or N-centered nucleophiles nucleophiles transforms transforms an alkyne an into alkyne enol into and enolenamine and derivativesenamine derivatives respectively. respectively. Although Although the addition the additionof C-centered of C-centered nucleophiles nucleophiles to alkynes to alkynesis an overall is an reductionoverall reduction from a from formal a formal point point of view, of view, it can it can also also give give access access to to carbonyl carbonyl derivatives derivatives if if the intermediate vinyl vinyl anion anion is is trapped trapped by by a reaction a reaction with with a heteroatomic a heteroatomic electrophile electrophile or an oxidant or an oxidant [24,25]. Alternatively,[24,25]. Alternatively, the “preoxidized” the “preoxidized” alkynes (ynols alkynes [26 ]( orynols ynamine [26] or derivatives ynamine derivatives [27]) can enter [27] the) can carbonyl enter thereaction carbonyl part ofreaction the reaction part of hypersurface the reaction after hypersurface reaction with after a C-nucleophile reaction with directly, a C-nucleophile without a directly, need for withoutan additional a need oxidant. for anIt is additional worth noting oxidant. that reactions It is worth of alkynes noting with that heteroatomic reactions electrophiles of alkyneslead with to productsheteroatomic with electrophiles higher oxidation lead to states products (e.g., α with-dicarbonyls) higher oxidation but we will states not discuss(e.g., α- suchdicarbonyls) transformations but we willin the not present discuss review. such transformations in the present review. Given that the same intermediates (e.g., enols and enamines) can be accessed starting from a carbonyl co compound,mpound, the alkyne and the carbonyl functionalities are conceptually equivalent as two possible entry points to the many useful processes where such reactive intermediates are involved (Scheme2 2).). FromFrom this,this, oneone cancan visualizevisualize howhow alkynesalkynes andand carbonylscarbonyls lielie onon thethe samesame potentialpotential energyenergy surface as the two energy minima connected via a multitude of routes –including–including those that traverse enols and enamines. However, of course, there are differences between the two functionalities as well, and this is where it gets interesting. Due to these differences, each starting material (alkyne vs. carbonyl) possess their own advantages and disadvantages. Let’s discuss them from a conceptual perspective.
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SchemeScheme 2.2. SyntheticSynthetic equivalencyequivalency ofof alkynesalkynes andand carbonylcarbonyl compounds.compounds.
1.1. TheHowever, High Energy of course, of Alkynes there Can are be differe Used tonces Drive between Difficult the Transformations two functionalities as well, and this is whereIn it general gets interesting. terms, the Due high to energythese differences, stored in alkyneseach starting [3] can material be a strong (alkyne advantage vs. carbonyl) in reaction possess design.their own To advantages illustrate the and vastly disadvantages. different amount Let’s discuss of energy them stored from a in conceptual alkynes relative perspective. to carbonyls, it is instructive to compare the thermodynamic parameters for the transformation of an alkyne and1.1. The a carbonyl High Energy compound of Alkynes to Ca theirn be corresponding Used to Drive Difficult enol (Scheme Transformations3). Whereas. the reactions of the modelIn alkyne general (2-butyne) terms, the are high highly energy favorable stored (~ in−20 alkynes kcal/mol!), [3] can the be analogous a strong reactionsadvantage of in the reaction model ketonedesign. (2-butanone) To illustrate arethe 6–10vastly kcal/mol different uphill. amount These of energy differences stored clearly in alkynes show therelati energeticve to carbonyls, advantage it ofis instructive accessingenols to compare and enamines the thermodynamic from alkynes. parameters No thermodynamic for the transformation penalty needs of anto alkyne be paid and in a suchcarbonyl transformations. compound to their corresponding enol (Scheme 3). Whereas the reactions of the model alkyne (2-butyne) are highly favorable (~−20 kcal/mol!), the analogous reactions of the model ketone (2-butanone) are 6–10 kcal/mol uphill. These differences clearly show the energetic advantage of accessing enols and enamines from alkynes. No thermodynamic penalty needs to be paid in such transformations.
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Scheme 3. Thermodynamics of enol and enamine formation from an alkyne and aa ketone.ketone.
1.2. Low Polarization of Alkynes Endows Them withwith FlexibleFlexible SelectivitySelectivity Another keykey featurefeature that that gives gives alkynes alkynes more more versatility versatility than than their their carbonyl carbonyl equivalents equivalents arise fromarise thefrom fact the that fact a non-symmetricthat a non-symmetric alkyne alkyne can yield can two yield distinct two distinct carbonyl carbonyl compounds. compounds. For example, For example, terminal alkynesterminal can alkynes be synthetic can be equivalents synthetic equivalents of either ketones of either or aldehydes ketones dependingor aldehydes on dependingthe “Markovnikov on the vs.“Markovnikov anti-Markovnikov” vs. anti- [Markovnikov”28,29] regiochemistry [28,29] ofregiochemistry their addition of reactions. their addition It is through reaction thiss. It“divergent is through selectivity”this “divergent that selectivity” the alkyne, that like the Schrodinger’s alkyne, like cat,Schrodinger’s displays its cat, intrinsic displays duality—each its intrinsic duality of the alkyne—each carbonsof the alkyne has the carbo potentialns has tothe be potential either oxidized to be either or reduced oxidized in or the reduced process in of the nucleophilic process of addition. nucleophilic It is theaddition. nucleophile It is the that nucleophile chooses betweenthat chooses the twobetween potentialities. the two potentialities. In short, each In alkyne short, openseach alkyne not one opens but twonot one doors but into two carbonyl doors into chemistry carbonyl (Scheme chemistry4). (Scheme 4).
Scheme 4. Each alkyne opens not one but two doors into carbonyl chemistry.
Of course, the lack of polarizationpolarization has a flipflip sideside asas well.well. BecauseBecause the carbonyl group is highly polar,polar, aldehydesaldehydes andand ketonesketones are are “pre-activated” “pre-activated” for for reaction reaction with with nucleophiles nucleophiles and and their their selectivity selectivity is “pre-programmed”.is “pre-programmed”. The The alkyne alkyne moiety moiety is less is polarized less polarized and generally and generally needs an needsadditional an additional activation stepactivation to interact step withto interact a nucleophile. with a nucleophile. Although the Although need for preactivationthe need for maypreactivation look like amaydisadvantage look like, ita alsodisadvantage, offers an opportunityit also offersfor thean designopportunity of catalytic for the processes design with of catalyticpotential advantagesprocesses with for the potential control ofadvantages selectivity. for the control of selectivity. Let us illustrate the divergent selectivity that can arise from regioselective control of nucleophilic addition to alkynes by using an elegant example reported by Park and coworkers [30]. This work
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Let us illustrate the divergent selectivity that can arise from regioselective control of nucleophilic Molecules 2019, 24, x FOR PEER REVIEW 5 of 35 addition to alkynes by using an elegant example reported by Park and coworkers [30]. This work discloses an elegant way to control the regiochemical outcomeoutcome ofof alkynealkyne derivatization. Here, the useuse of aminesamines asas directingdirecting groupsgroups facilitatedfacilitated thethe palladium-catalyzedpalladium-catalyzed arylation of alkynes and, through thethe choicechoice ofof substituentssubstituents onon thethe amine,amine, dictateddictated whichwhich ofof thethe twotwo regioisomericregioisomeric aminopalladationaminopalladation intermediatesintermediates is preferred.preferred. The finalfinal reductivereductive eliminationelimination stepstep completescompletes thethe regioselectiveregioselective alkynealkyne α aminoarylation sequence. sequence. Finally, Finally, hydrolysis hydrolysis of the of resulting the resulting enamine enamine yields either yields the eith-arylphenoneer the α- α α orarylphenone, -diarylketone, or α,α-diarylketone, depending on depending the amine on choice the amine (Scheme choice5). (Scheme 5).
Scheme 5. 5. SynthesisSynthesis of α of-arylphenoneα-arylphenoness and andα,α-diarylketoneα,α-diarylketoness through through directed directed catalytic catalytic alkyne alkynearylations. arylations.
This example clearly highlights that an alkyne starting material has the potential to givegive twotwo distinct isomers as products, and that the selectivity can be tuned on demand to provide either of the twotwo products. products. Such Such diverging diverging one-step one-step reactivity reactivity would would be impossible be impossible from a single from carbonyl a single precursor. carbonyl precursor.In the following sections, we will show other approaches to the control of regioselectivity for nucleophilicIn the following additions sections, to alkynes. we For will example, show other theuse approaches of alkynes to as the cyclization control of precursors regioselectivity also gives for annucleophilic opportunity additions to control to alkynes. the regioselectivity For example, of the addition use of by alkynes using as the cyclization stereoelectronic precursors preferences also gives for cyclean opportun formationity to [31 control]. Sometimes, the regioselectivity these preferences of addition can even by overrideusing the important stereoelectronic factors preferences such as alkyne for polarizationcycle formation as will [31] be. Sometimes, illustrated these by the preferences “anti-Michael” can even additions override provided important in Section factors 3.2such. as alkyne polarization as will be illustrated by the “anti-Michael” additions provided in Section 3.2. 2. Alkynes in Ketal Formation 2. AlkynesIn addition in Ketal to the Formati high energyon content and the potential for tunable divergent selectivity, the use of alkynesIn addition as carbonyl to the surrogates high energy has other content advantages. and the potential For example, for tunable the alkyne divergent functionality selectivity, is relatively the use π kineticallyof alkynes inert as carbonyl (i.e., the surrogates alkyne -bonds has other are strong) advantages. and, in For the absence example, of the strongly alkyne donor functionality or acceptor is substituents,relatively kinetically has no inert intrinsic (i.e., polarity.the alkyne The π-bonds chemical are inertnessstrong) and, of in alkynes the absence under of various strongly reaction donor or acceptor substituents, has no intrinsic polarity. The chemical inertness of alkynes under various reaction conditions accounts for their broad tolerance in transformations that would be problematic for other functionalities, such as carbonyls. Of course, chemical inertness can be both a blessing and a curse but, in the case of alkynes, a breakthrough that greatly facilitated their application in chemical
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synthesis came with the development of alkyne-selective (“alkynophilic”) π-acidic metal catalysts
Molecules[32–37].2019 Such, 24 ,selective 1036 catalysts (especially, the cationic Au-species) allowed chemists to “unlock”6 of 36 alkyne reactivity on demand with a large degree of control. To illustrate this advantage, let’s take the textbook reactions of O-nucleophiles with carbonyl groups. These reactions have found widespread conditionsapplications accounts ranging for from their a simple broad protecting tolerance in group transformations installation thatto the would late stage be problematic functionalization for other in functionalities,the preparation such of complex as carbonyls. molecular Of course, architectures. chemical One inertness of the canproblems be both inhere a blessingnt to this and approach a curse but, is inthat the the case chemo of alkynes,- and regioselective a breakthrough reactions that greatly at the carbonyl facilitated moiety their applicationcan be difficult in chemical in the presence synthesis of cameseveral with carbonyls the development [38]. The ability of alkyne-selective to use an alkyne (“alkynophilic”) selectively as a πcarbonyl-acidic metal equivalent catalysts even [32 in– 37the]. Suchpresence selective of carbonyl catalysts groups (especially, allows for the selective cationic functional Au-species) group allowed manipulations. chemists to Moreover, “unlock” the alkyne use reactivityof non-carbonyl on demand precursors, with e.g. a large, alkynes, degree can of provide control. elegant To illustrate synthetic this strategies advantage, where let’s the take alkyne the textbookmoiety serves reactions as a protecting of O-nucleophiles group for with a carbonyl. carbonyl Because groups. the These alkynes reactions are less have po foundlar and widespread inherently applicationsless electrophilic ranging than from carbonyls, a simple their protecting use expands group installationthe range of to possible the late stage reaction functionalization conditions and in theprovides preparation additional of complex flexibility molecular in the reaction architectures. design. One of the problems inherent to this approach is that theComparison chemo- and of regioselectivealkynes and carbonyls reactions as at starting the carbonyl materials moiety for can the be synthesis difficult of in enol the presenceethers and of severalketals is carbonyls given in Scheme [38]. The 6. abilityIn the toabsence use an of alkyne structural selectively restraints as a(e.g., carbonyl a non equivalent-enolizable evenpart inof the presencemolecule), of a carbonyltypical carbonyl groups allowsprecursor for can selective form two functional enolates group (endo manipulations.- and exo-isomers), Moreover, each of the which use ofcan non-carbonyl undergo an exo precursors,-tet-cyclization e.g., alkynes, by displacing can provide a leaving elegant group synthetic at a suitable strategies position. where The theselectivity alkyne moietyhere is servescontrolled as a by protecting the relative group abundance for a carbonyl. of the Because two enolates the alkynes and their are lessrelative polar reactivity and inherently in the lessrespective electrophilic cyclization than steps. carbonyls, Although their such use expandsprocesses the can range be controlled of possible and reaction used efficiently, conditions such and providescontrol is additionalnot always flexibility trivial. On in the the other reaction hand, design. homogeneous Au-catalysis gives direct access to vinyl ethersComparison through hydroalkoxylation of alkynes and carbonyls of alkyne/catalyst as starting compl materialsex [39 for–41] the. The synthesis process ofis enolcatalytic, ethers atom and- ketalseconomical is given and in scalable. Scheme 6. In the absence of structural restraints (e.g., a non-enolizable part of the molecule),In the apresence typical carbonyl of suitable precursor π-acidic can catalysts, form two the enolates vinyl ethers (endo- obtained and exo-isomers), from alkynes each can of also which be canfurther undergo converted an exo-tet-cyclization into ketals. This by powerful displacing technique a leaving groupprovides at a an suitable atom position. economical The and selectivity redox hereneutral is controlledapproach in by late the stage relative spiroketalization. abundance of Although the two enolates intramolecular and their ketalization relative reactivity of carbonyls in the is respectivemore favorable cyclization thermodynamically steps. Although than such its intermolecular processes can beversion controlled (Scheme and 7 usedvs. Scheme efficiently, 3), use such of controlalkynes iscomes not always with additional trivial. On synthetic the other flexibility hand, homogeneousas illustrated in Au-catalysis Scheme 7. gives direct access to vinyl ethers through hydroalkoxylation of alkyne/catalyst complex [39–41]. The process is catalytic, atom-economical and scalable.
Scheme 6. Comparison of alkynes and carbonyls as precursors for vinyl ethers.
In the presence of suitable π-acidic catalysts, the vinyl ethers obtained from alkynes can also be further converted into ketals. This powerful technique provides an atom economical and redox neutral approach in late stage spiroketalization. Although intramolecular ketalization of carbonyls is more Molecules 2019, 24, 1036 7 of 36 favorable thermodynamically than its intermolecular version (Scheme7 vs. Scheme3), use of alkynes comesMolecules with 20192019,, additional 2424,, xx FORFOR PEERPEER synthetic REVIEWREVIEW flexibility as illustrated in Scheme7. 77 ofof 3535
SchemeScheme 7.7. Comparison of alkynes andand ketonesketones inin intramolecularintramolecular spiro-ketalizations.spiro--ketalizations.
BothBoth inter-inter -- andand intramolecular intramolecular alkoxylations alkoxylations of of alkynes alkynes have have been been reported reported using using various various alkynophilicalkynophilic metalmetal salts.salts. In 1991, Utimoto [42] [[42]42] andand coworkerscoworkers showed that alkynesalkynes can bebe directlydirectlytly convertedconverted intointo acetalsacetals oror ketalsketals usingusing NaAuClNaAuCl444.. TheyThey havehave successfullysuccessfully converted converted terminal terminal acetylenes acetylenes intointo dimethyl dimethyl dimethyl acetals acetals acetals in in in excellent excellent excellent yields yields yields in refluxing in in refluxing refluxing methanol methanol methanol (Scheme (Scheme (Scheme8a). However, 8a). 8a). However, However, Au (III) Au Auis quickly (III) (III) is is reducedquickly reduced into the inactiveinto the metallicinactive gold.metallic Shortly gold. thereafter, Shortlytly thereafter,thereafter, Teles [43] andTeles coworkers [43][43] and coworkers found that found a new + classthatthat aa of newnew cationic classclass [L-Au]ofof cationiccationiccomplexes [L[L--Au]++ complexescomplexes (where L is (where(where phosphine, LL isis phosphine,phosphine, phosphite phosphitephosphite or arsine) oror serve arsine)arsine) as excellent serveserve asas catalystsexcellentexcellent forcatalystscatalysts the addition forfor thethe of additionaddition alcohols ofof to alcoholsalcohols alkynes toto (Scheme alkynesalkynes8 b).(Scheme(Scheme These 8b).8b). catalysts TheseThese achieve catalystscatalysts total achieveachieve turnover tottotal 5 numbersturnovturnoverer ofnumbersnumbers up to 10 ofof moles upup toto of10105 product5 moles of per product mole of per catalyst, mole andof catalyst, they are and neither they water are neither nor air water sensitive. nor However,air sensitive. the However, reaction has the a reaction drawback, has as a drawback, it uses concentrated as it uses concentrated solutions of strong solutions acids. of strong acids.
SchemeScheme 8.8. Utimoto’s Au Au-catalized--catalizedcatalized acetalacetal formationformation fromfrom alkynealkyne startingstarting materials.materials.
TheThe advantages advantages discussed discussed above above are are displayed displayed in in many many examples, examples, including including those those from from the the TrostTrost [[44][44]44],,, FurstnerFurstner [[45][45]45],,, DudleyDudleyDudley [[46][46]46],,, andandand ForsythForsythForsyth groupsgroupsgroups [[47]47[47]]... ForFor example,example, inin 2010,2010, DudleyDudley andand coworkerscoworkers reportedreported tt thehe synthesis synthesis of of cephalosporolidecephalosporolide cephalosporolide H, H, an an anti anti-inflammatory--inflammatoryinflammatory agentagent agent containingcontaining containing aa 5,55,5 a 5,5spiroketalspiroketal spiroketal system system system [46][46] [46.. A A]. Akey key key spiroketal spiroketal spiroketal-forming--formingforming system system system step step step in in in the the the synthetic synthetic synthetic route route route towards towards this this this naturalnatural productproduct waswas accomplishedaccomplished throughthrough anan Au(I)Au(I) catalyzedcatalyzed hydroxylationhydroxylation ofof anan alkynealkyne precursor (Scheme((Scheme9 9,,, top). top).top). This report clearly illustrates the advantage of the alkyne functionality over the carbonyl group, as alkyne activation is achieved through the selection of suitable π--acidic metal catalysts and further finefine--tunedtuned byby choochoosingsing thethe rightright ligandsligands toto completecomplete thethe coordinationcoordination spheresphere ofof thethe catalyticcatalytic metal.metal. For example, the Au(I) catalyzed cyclization of alkyne A in MeOH gives rise to a 1:1 mixture of epimericepimeric 5,55,5 spiroketalsspiroketals BB andand C.C. ThisThis mixturemixture cancan bebe isomerizedisomerized intointo aa singlsinglee diastereomerdiastereomer (in(in 86%86% yield) with ZnCl22,, aa LewisLewis acidacid thatthat isis capablecapable ofof chelationchelation withwith thethe pendantpendant hydroxyhydroxy groupgroup andand thethe spiroketalspiroketal oxygenoxygen ofof thethe adjoiningadjoining ring.ring. Alternatively,Alternatively, alkynealkyne AA cancan bebe convertedconverted selectivelyselectively intointo tthe epimericepimeric 5,55,5--spiroketalspiroketal CC byby uusingsing Pd(CHPd(CH33CN)22Cl22 as the catalyst.
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HO nC7H15 nC7H15 1) AuCl O O O MeOH, rt O O O 2) ZnCl , MgO HO 2 CH H3C 3 B CH OTBS nC H CH2Cl2, rt 3 7 15 cephalosporolide H H3C 69% overall yield OH >20:1 dr O O A Molecules 2019, 24, x FOR PEER REVIEW TBSO 8 of 35 PMP Pd(CH CN) Cl O 3 2 2 nC7H15 CH3CN, rt O O O O O nC7H15 HO HO nC7H15 nC7H15 1) AuCl CH O O O H3C 3 C MeOH, rt O 42% overallO yield epi-cephalosporolideO H 2) ZnCl , MgO HO 2 CH9:1 dr H3C 3 B CH OTBS nC H CH2Cl2, rt H C 3 7 15 cephalosporolide H 3 Scheme 9.9. Dudley’s intramolecular 69% bishydroxylation overall yield of alkynes. OH >20:1 dr O O ThisSimilarly, reportA Forsyth clearly illustrates and coworkers the advantage recognised of the that alkyne highly functionality oxygenated over spiro the-ring carbonyl systems group, of TBSO as alkynePMP activation is achieved throughPd(CH CN) theCl selection of suitable π-acidic metalO catalysts and further azaspiracid marine toxins can be accessed3 2 2 through bis-hydroalkoxylationnC7H15 of an alkyne precursor CH3CN, rt O fine-tuned(Scheme 10). by choosing the right ligands to complete theO coordinationO sphere of theO catalyticO nC H metal. HO 7 15 For example, the Au(I) catalyzed cyclization of alkyneCH A in MeOH gives rise to a 1:1 mixture of H3C 3 C epimeric 5,5 spiroketals B and C. This mixture can42% be isomerizedoverall yield into a singleepi-cephalosporolide diastereomerH (in 86% yield) with ZnCl2, a Lewis acid that is capable of chelation9:1 dr with the pendant hydroxy group and the spiroketal oxygen of theScheme adjoining 9. Dudley’s ring. intramolecular Alternatively, bishydroxylation alkyne A can be of converted alkynes. selectively into the epimeric 5,5-spiroketal C by using Pd(CH3CN)2Cl2 as the catalyst. Similarly, Forsyth and coworkers recognised that highly oxygenated spiro-ringspiro-ring systems of azaspiracid marine toxins can be accessed through bis-hydroalkoxylationbis-hydroalkoxylation of an alkyne precursor (Scheme 1010).).
Scheme 10. Gold catalyzed bis-alkoxylation of alkynes in the synthesis of spiroketals by Forsyth and coworkers.
The oxadispiroketal A-D ring system of this natural product was assembled by Au-catalyzed 6- exo-dig cyclization of an internal alcohol onto the alkyne [47]. Ring size and strain of the product determine the regioselectivity of the initial attack of the hydroxy group on the alkyne–Au (I) complex. The resulting enol ether product consequently undergoes PPTS catalyzed spiro B-ring formation in a 75% yield under thermodynamically controlled reaction conditions. The authors also suggest that the use of an alkyne as a surrogate for a ketone reduces the possibility of alkene isomerization. Scheme 10. GoldGold catalyzed catalyzed bis bis-alkoxylation-alkoxylation of ofalkynes alkynes in the in the synthesis synthesis of spiroketals of spiroketals by Forsyth by Forsyth and andcoworkers coworkers.. 3. Vinyl Ether Generation from Alkynes TheIn this oxadispiroketal section, we will A A-D- Dshow ring ring howsystem system the of connection of this this n naturalatural between product product alkynes was was assembled assembledand enol byderivatives by Au Au-catalyzed-catalyzed can be6- 6-exo-digexploitedexo-dig cyclization for cyclization the preparation of of an an internal internal of heterocycles. alcohol alcohol onto onto From the the alkynea alkyne practical [47] [47 point.]. Ring Ring of size size view, and and the strain strain use ofof of carbonylthe product vs. determinealkyne precursors the regioselectivity as starting materials of the initial for attack a one- ofstep the synthesis hydroxy hydroxy ofgroup group vinyl on on ethers the the alkyne alkyne–Au is complementary.–Au (I) (I) complex. complex. The resultingIt is important enol ether to note product at this consequently point that carbonyls undergoes are, PPTSof course, catalyzed versatile spiro synthetic B-ring formation precursors in as a well.75% yield For under example, thermodynamically although carbonyls controlled are intrinsically reaction conditions. electrophilic, The authors they can also be suggest converted that into the use of an alkyne as a surrogate for a ketone reduces the possibility of alkene isomerization.
3. Vinyl Ether Generation from Alkynes In this section, we will show how the connection between alkynes and enol derivatives can be exploited for the preparation of heterocycles. From a practical point of view, the use of carbonyl vs. alkyne precursors as starting materials for a one-step synthesis of vinyl ethers is complementary. It is important to note at this point that carbonyls are, of course, versatile synthetic precursors as well. For example, although carbonyls are intrinsically electrophilic, they can be converted into
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The resulting enol ether product consequently undergoes PPTS catalyzed spiro B-ring formation in a 75% yield under thermodynamically controlled reaction conditions. The authors also suggest that the use of an alkyne as a surrogate for a ketone reduces the possibility of alkene isomerization.
3. Vinyl Ether Generation from Alkynes In this section, we will show how the connection between alkynes and enol derivatives can be exploited for the preparation of heterocycles. From a practical point of view, the use of carbonyl vs. alkyne precursors as starting materials for a one-step synthesis of vinyl ethers is complementary. It is important to note at this point that carbonyls are, of course, versatile synthetic precursors Molecules 2019, 24, x FOR PEER REVIEW 9 of 35 as well. For example, although carbonyls are intrinsically electrophilic, they can be converted into nucleophiles via via enolization. enolization. In their In their parent parent electrophilic electrophilic form, carbonyls form, carbonyls can react with can O-nucleophiles react with O- withnucleophiles the formation with the of hemiacetals, formation of a processhemiacetals, that, asa process any sugar that, chemist as any can sugar testify, chemist is quite can favorable testify, inis itsquite intramolecular favorable in version.its intramolecular The hemiacetals version. can The be, hemiacetals in principle, can converted be, in principle, into vinyl converted ethers but into this processvinyl ethers is not but always this process thermodynamically is not always favorablethermodynamically (Scheme 11 favorable). (Scheme 11).
SchemeScheme 11.11. ThermodynamicsThermodynamics ofof hemiacetal/vinylhemiacetal/vinyl ether transformation can be unfavorable.
Alternatively, cyclic vinylvinyl ethersethers cancan bebe formedformed directlydirectly whenwhen nucleophilicnucleophilic carbonyl-derivedcarbonyl-derived functionalities (i.e. (i.e.,, enols or enolates) attack an electrophilic carbon with a suitable leaving group. group. Such processes are well-knownwell-known but, as we will discuss below, they are quite complex from the stereoelectronic perspective.perspective. When alkynes are used as the the starting starting material, material, they are generally generally activated towards the intramolecular nucleophilic nucleophilic attack attack (often (often as as a π a-complexπ-complex with with a suitable a suitable Lewis Lewis acid). acid). As w Ase will we show will showbelow, below, this activation this activation is important is important from from both both the the kinetic kinetic (decreasing (decreasing the the addition addition barrier) barrier) and thermodynamic (stabilizing the cyclization product) points of view. Furthermore, such coordination can facilitate synthetic access to the less favorablefavorable “endo-dig”“endo-dig” version of alkyne cyclizations via the so-calledso-called “LUMO Umpolung”Umpolung” (vide(vide infra)infra) [[48,49]48,49].. Rules for enolate cyclizations are relatively complex becausebecause twotwo orbital arrays need to be aligned in thethe cycle-closingcycle-closing bond forming step [[50,51]50,51].. The enolateenolate C=C bond can be exocyclic to the newly formed ring in the so-calledso-called “enolexo” closures or, alternatively, thethe enolateenolate can be endocyclicendocyclic to the new ringring inin thethe “enolendo”“enolendo” closures. closures. Furthermore, Furthermore, the the enolate enolate closure closure can can occur occur at at either either the the carbon carbon or oxygenor oxygen (Scheme (Scheme 12). 12 Baldwin’s). Baldwin’s rules rules for enolatesfor enolates suggested suggested that that 3- and 3- 4-(enolendo)-and 4-(enolendo) closures- closures for both for exo-tetboth exo and-tetexo-trig and exo modes-trig modes are unfavorable are unfavorable cyclization cyclization modes, modes, while while 5- and 5-6-(enolendo)- and 6-(enolendo) and-3- and to 7-(enolexo)-3- to 7-(enolexo) were- were classified classified as favorable. as favorable. Even Even now, now, not all not cyclization all cyclization modes modes for the for enolates the enolates have beenhave systematicallybeen systematically explored. explored.
Molecules 2019, 24, x FOR PEER REVIEW 9 of 35
nucleophiles via enolization. In their parent electrophilic form, carbonyls can react with O- nucleophiles with the formation of hemiacetals, a process that, as any sugar chemist can testify, is quite favorable in its intramolecular version. The hemiacetals can be, in principle, converted into vinyl ethers but this process is not always thermodynamically favorable (Scheme 11).
Scheme 11. Thermodynamics of hemiacetal/vinyl ether transformation can be unfavorable.
Alternatively, cyclic vinyl ethers can be formed directly when nucleophilic carbonyl-derived functionalities (i.e., enols or enolates) attack an electrophilic carbon with a suitable leaving group. Such processes are well-known but, as we will discuss below, they are quite complex from the stereoelectronic perspective. When alkynes are used as the starting material, they are generally activated towards the intramolecular nucleophilic attack (often as a π-complex with a suitable Lewis acid). As we will show below, this activation is important from both the kinetic (decreasing the addition barrier) and thermodynamic (stabilizing the cyclization product) points of view. Furthermore, such coordination can facilitate synthetic access to the less favorable “endo-dig” version of alkyne cyclizations via the so-called “LUMO Umpolung” (vide infra) [48,49]. Rules for enolate cyclizations are relatively complex because two orbital arrays need to be aligned in the cycle-closing bond forming step [50,51]. The enolate C=C bond can be exocyclic to the newly formed ring in the so-called “enolexo” closures or, alternatively, the enolate can be endocyclic to the new ring in the “enolendo” closures. Furthermore, the enolate closure can occur at either the carbon or oxygen (Scheme 12). Baldwin’s rules for enolates suggested that 3- and 4-(enolendo)- closures for both exo-tet and exo-trig modes are unfavorable cyclization modes, while 5- and 6-(enolendo)- and Molecules3- to 7-(enolexo)2019, 24, 1036- were classified as favorable. Even now, not all cyclization modes for the enolates10 of 36 have been systematically explored.
Molecules 2019, 24, x FOR PEER REVIEW 10 of 35
Scheme 12. Top: Two patterns (C-enolexo(C-enolexo and C-enolendo)C-enolendo) for exo-tetexo-tet cyclizations. Bottom: A Althoughlthough cyclizations of enolates can occur at either the carbon or oxygen, this process is controlled by stereoelectronic factorsfactors (see(see discussiondiscussion inin text).text).
Rules forfor alkynealkyne cyclizations cyclizations (often (often referred referred to asto “theas “the dig-cyclizations”) dig-cyclizations”) are lessare complexless complex but more but tunable.more tunable. For anionic For nucleophiles, anionic nucleophiles, exo-cyclizations exo-cyclizations are preferred are in preferred the absence in of the large absence thermodynamic of large orthermodynamic electronic bias [ or52 ]. electronic This preference bias originates[52]. This from preference the stereoelectronic originates preferences from the stereoelectronicfor nucleophilic attackpreferences at the for alkyne nucleophilicπ*-orbital. attack Coordination at the alkyne of the π* alkyne-orbital. to aCoordinati Lewis acidon leads of the to thealkyne removal to a Lewis of the orbitalacid leads symmetry to the removal restrictions of the (via orbital “LUMO symmetry Umpolung” restrictions [48], Scheme (via “LUMO 13) and Umpolung” allows for both[48], exo-digScheme and13) and endo-dig allows processes for both exo to proceed-dig and without endo-dig stereolectronic processes to proceed penalty. without stereolectronic penalty.
Scheme 13. Approaches to selective exo exo-dig-dig and endo-digendo-dig cyclizations can be accomplished by using either a classic anionic or a LewisLewis acid-mediatedacid-mediated (the(the so-calledso-called “Electrophile-Promoted“Electrophile-Promoted Nucleophilic Closure (EPNC) processes)processes) pathwayspathways withwith differentdifferent stereoelectronicstereoelectronic requirements.requirements.
3.1. Anionic Cyclizations without Alkyne Preactivation 3.1. Anionic Cyclizations without Alkyne Preactivation For the intramolecular attack of negatively charged nucleophiles at alkynes, the general For the intramolecular attack of negatively charged nucleophiles at alkynes, the general stereoelectronic factors favor exo cyclizations [52]. Under kinetic control, the exo preference is clear stereoelectronic factors favor exo cyclizations [52]. Under kinetic control, the exo preference is clear when the the two two possible possible cyclic cyclic products products have have rings rings of similar of similar size and size strain and (i.e., strain either (i.e., both either are both strained are forstrained the 3-exo/4-endo for the 3-exo/4 pair-endo or both pair are or relativelyboth are relatively strain-free strain -the 5-exo/6-endo-free -the 5-exo/6 pair).-endo A peculiar pair). A exception peculiar isexception the case is of the 4-exo case and of 5-endo-dig4-exo and 5 anionic-endo-dig closures anionic where closures the two where barriers the two are barriers quite similar are quite (Scheme similar 14, middle)(Scheme [53 14]., This middle) seemingly [53]. irregular This seemingly trend originates irregular from trend the interplay originates of from stereoelectronic the interplay factors of withstereoelectronic thermodynamic factors contributions with thermodynamic to the activation contributions barrier [to54 ,the55]. activation Because the barrier exo-product [54,55]. Because is much morethe exo strained-product than is much the endo-product more strained in than the 4-exo/5-endo the endo-product pair, in the the endo-cyclization 4-exo/5-endo pair, is much the endo more- exothermiccyclization is and much the exo/endomore exothermic kinetic competitionand the exo/endo becomes kinetic relatively competition close (Scheme becomes 14 relatively). close (Scheme 14).
Molecules 2019, 24, 1036 11 of 36 Molecules 2019, 24, x FOR PEER REVIEW 11 of 35
Scheme 14.14. PotentialPotential energy energy surfaces surfaces for for selected selected exo-dig exo-dig and and endo-dig endo- anionicdig anionic cyclizations cyclizations of N- of (blue N- dashed,(blue dashed,italic) italic and O) and- (violet O- (violet dashed, dashed, non-italics) non-italics anions) anions with terminal with terminal alkynes. alkynes.
Note, however, that that cyclizations cyclizations of of the the NN- -and and OO-centered-centered anions anions onto onto an an alkyne alkyne transform transform a aheteroheteroatomatom-centered-centered anion anion into into a acarbcarbanion.anion. The The energy energy cost cost due due to to this this unfavorable change is substantial. As As the the result, result, formation formation of small of small cycles, cycles, especially especially from alkoxide from alkoxideanions is often anions endergonic is often andendergonic reversible and (Scheme reversible 14). (EvenScheme for the 14). kinetically Even for favorable the kinetically 5-exo/6-endo-dig favorable 5 cyclizations,-exo/6-endo-dig the formationcyclizations, of the these formation relatively of large these cycles relatively formed large from cycles the parent formed anionic from the oxygen parent systems anionic is closeoxygen to beingsystems thermoneutral. is close to being We will thermoneutral. show in one We of the will following show in sections one of thehow following this feature sections can be how used this for introductionfeature can be of used elements for introduction of thermodynamic of elements control of thermodynamic in these cyclizations. control in these cyclizations.
3.2. Use of Stereoelectronic Exo-PreferenceExo-Preference for OverridingOverriding AlkyneAlkyne PolarizationsPolarizations. In this section, section, we we will will illustrate illustrate some some of of the the features features for for alkyne alkyne cyclizations, cyclizations, mostly mostly using using O- Onucleophiles.-nucleophiles. The The key key preference preference is isthat that for for the the exo exo-cyclizations.-cyclizations. Sometimes, Sometimes, this stereoelectronic stereoelectronic preference is is strong strong enough enough to to cause cause additions additions that that go against go against alkyne alkyne polarization polarization such as such the as“anti the- “anti-Michael”Michael” intramolecular intramolecular additions additions to alkynyl to alkynyl ketones ketones (Scheme (Scheme 15). 15).
Scheme 15.15. Two approachesapproaches toto regioselectiveregioselective alkyne/carbonylalkyne/carbonyl transformations.
Base-catalyzedBase-catalyzed cyclizations cyclizations of of aliphatic aliphatic alcohols alcohols exclusively exclusively follow follow the 5-exo-path the 5-exo-path where where the cyclic the vinylcyclic anion vinyl is anion trapped is trapped by protonation, by protonation, thus activating thus activating another acyclic another alcohol. acyclic When alcohol. a secondary When a secondary allylic alcohol [56] is used as opposed to a primary alcohol [57,58], the process becomes more sluggish and gem-dimethyl groups are required (Scheme 16). Addition of an anion-stabilizing
Molecules 2019, 24, 1036 12 of 36
Molecules 2019,, 24,, xx FORFOR PEERPEER REVIEWREVIEW 12 of 35 allylic alcohol [56] is used as opposed to a primary alcohol [57,58], the process becomes more sluggish groupand gem at-dimethyl the terminal groups carbon are renders required 5- (Schemeexo-dig cyclizations16). Addition of ofoxygen an anion-stabilizing nucleophiles more group efficient at the [59,60]terminal.. carbon renders 5-exo-dig cyclizations of oxygen nucleophiles more efficient [59,60].
SchemeScheme 16 16... Base promoted 5 5-exo-dig-exo-dig cyclizations of primary and secondary alcohols onto terminal tripletriple bonds.bonds.
InIn those those cases, cases, where where the the exo exo-- and endo endo-cyclizations-cyclizations are are intrinsically intrinsically cl close,ose, reaction reaction conditions, conditions, suchsuch as the choice of solvent solvent can be be used used to to control control regioselectivity. regioselectivity. For example, Miranda and and coworkerscoworkers [61] [61] found found that that the “anti“anti-Michael”-Michael” exo exo-dig-dig product product is is formed (79% yield) when the cyclizationcyclization is is carried carried out out in in a a protic protic sol solventvent like ethanol (Scheme 17).17). In In this this interesting interesting example, example, the the stereoelectronicsstereoelectronics of of cyclization go go against alkyne polarization in in determining the regioselectivity of alkynealkyne reaction. reaction. On On the the other other hand, hand, when when using using acetone acetone as as the the solvent, solvent, the the selectivity selectivity ch changesanges to to favor favor thethe endo endo-dig-dig product. product. These These solvent solvent effects effects suggest suggest that that the the 5 5-exo-exo cyclization cyclization is is kinetically kinetically favorable andand gives gives the product as long as the cyclized carbanion is rapidly trapped by protonation, whereas inin anan aproticaprotic solvent solvent likelike acetone, acetone, thth thee initially formed 5 5-exo-dig-exo-dig vinyl vinyl anion anion has has sufficient sufficient time to rearrangerearrange into the more s stabletable 6 6-endo-dig-endo-dig product.
SchemeScheme 17 17... TheThe solvent solvent dependent dependent cyclizations cyclizations of oxygen of oxygen anions anions with three with sp three22-atoms sp2 -atomsin the linking in the chain.linking chain.
3.3.3.3. Use Use of of Strain Strain Effects Effects to to Favor Favor 6 6-endo-endo Selectivity CastroCastro and co co-workers-workers showed that the condensation of o--halobenzoichalobenzoic acids with substituted coppercopper acetylides acetylides in in DMF DMF or or pyridine pyridine leads, leads, in inmost most cases, cases, to 5 to-membered 5-membered lactones. lactones. Only Only in the in case the ofcase N- ofpropylacetylideN-propylacetylide has hassome some of the of the 6-endo 6-endo-product-product been been observed observed (Scheme (Scheme 18, 18 , phthalide phthalide to isocoumarinisocoumarin ratioratio ratio 2:1)2:1) 2:1) [62,63] [62,63 ] The The analogous analogous cyclization cyclization of of O-Oethynylbenzoic-ethynylbenzoic acid acid also also yielded yielded the the γ- lactonelactoneγ-lactone productproduct product ofof of55-exo 5-exo-dig-dig closure closure [64] [64.. ]. Interestingly, the 5-exo-dig preference observed for the benzoic acid derivatives can be completely overruled when a more strained five-membered heterocyclic core is used. A variety of N- containing heterocycles, shown in Scheme 18, exhibit complete 6-endo-dig selectivity [64–67].. TheseThese observations are consistent with the role of strain on the competition between closely matched radical cyclization [55,68]..
Molecules 2019, 24, 1036 13 of 36 Molecules 2019, 24, x FOR PEER REVIEW 13 of 35
R R I R Cu R OH O + O heat, DMF OH O O O Molecules 2019, 24, x FOR PEER REVIEW O Product ratio 13 of 35 R = n-Pr 2 : 1 R R HO I O R Me HO O Cu R Me I O Me O O + CuOH R O Cu nBu O heat, DMFMe N OH O heat, DMF heat, DMF X N MeO N R O O N O X N I Product ratio N nBu H H MeR = n-Pr R = Ph 66% yield 2 : 1 X = CO Et R = n-C6H11 67% yield 2 56% yield HO Me O HO Me O I O Me O Cu R O Cu nBu Scheme 18. 18. Top:Top: TheThe cyclization cyclizationMe of oN of-carboxy o-carboxy acetylenes, acetylenes, formed formed via cuprate via cuprate addition, addition,O prefers prefers the 5- heat, DMF heat, DMF X exothe- 5-exo-digdig pathway.N pathway.Me Bottom:Bottom: RegioselectiveRegioselectiveN 6-endoR - 6-endo-digdig cyclizations cyclizations of acetylenic of acetylenic carboxylates carboxylates at five- N X N I N nBu memberedat five-membered rings. rings. H H Me R = Ph 66% yield X = CO Et R = n-C6H11 67% yield 2 56% yield 3.4. ControllingInterestingly, Regioselectivity the 5-exo-dig Using preference Elements observed of Thermodynamic for the benzoic Control acid derivatives can be completely overruledScheme when 18. Top: a more The cyclization strained five-membered of o-carboxy acetylenes, heterocyclic formed core via is cuprate used. Aaddition, variety prefers of N-containing the 5- Vasilevsky and Alabugin analyzed competing cyclization pathways in the cyclization of N- heterocycles,exo-dig pathway. shown in Bottom: Scheme Regioselective 18, exhibit complete 6-endo-dig 6-endo-dig cyclizations selectivity of acetylenic [64–67 ].carboxylates These observations at five- are centered nucleophiles (Scheme 19) [69]. The Ph group steers the cyclization down the 5-exo path by consistentmembered with rings. the role of strain on the competition between closely matched radical cyclization [55,68]. providing benzylic stabilization to the anionic center in the product. On the other hand, the competition3.4. Controlling between Regioselectivity the 5-exo Using and 6 Elements-endo-dig of closures Thermodynamic in alkyl Controlsubstituted acetylenes remains tight. The activation barriers for the two cyclizations are within 1 kcal/mol from each other. However, the Vasilevsky and Alabugin analyzed competing cyclization pathways in the cyclization of 5-exoVasilevsky-dig cyclization and Alabuginis predicted analyzed to be endothermic competing and cyclization readily pathwaysreversible in solution, the cyclization whereas of theN- N-centered nucleophiles (Scheme 19)[69]. The Ph group steers the cyclization down the 5-exo path 6centered-endo-dig nucleophiles closure is ~10 (Scheme kcal/mole 19) [69]exothermic.. The Ph group steers the cyclization down the 5-exo path by byproviding providing benzylic benzylic stabilization stabilization to to the the anionic anionic center center in in the the product. product. On On the the other other hand, thethe competition between the 5 5-exo-exo and 6 6-endo-dig-endo-dig closures in alkyl substituted substituted acetylenes acetylenes remains remains tight. tight. The activation barriers for the two cyclizationscyclizations areare withinwithin 11 kcal/molkcal/mol from from each other. However, the 5-exo-dig5-exo-dig cyclization is predicted to be endothermic and readily reversible in solution, whereas the 6-endo-dig6-endo-dig closure is ~10 kcal/mole exothermic. exothermic.
Scheme 19. Control of N-nucleophilic closures by changing alkyne electronics.
These anionic cyclizations have a weak thermodynamic driving force because the transformation of a relatively stable nitrogen anion into a carbanionic center is inherently unfavorable. Formation of the final products is negotiated through tautomerization into a more stable anion via protonScheme shifts. 19 19. A. Controlring expansion of N--nucleophilicnucleophilic process closures is also pos by changing sible for the alkyne 5-exo electronics.-products. Vasilevsky, Alabugin and coworkers sought a deeper understanding of the exo/endo interplay in cyclizationsThese anionic anionic of alkynes cyclizations cyclizations by using have the have a weak system a thermodynamic weak shown thermodynamic in Scheme driving 20 [70] force driving. The because polyfunctional force the transformation because internal the nucleophileoftransformation a relatively corresponds stable of a nitrogen relatively a hemiamina anion stable intol derived a nitrogen carbanionic from anion addition center into is of inherently a guanidine carbanionic unfavorable. to the center carbonyl is Formation inherently moiety of peritheunfavorable. final-substituted products Formation acetylenic is negotiated of the anthraquinones. final through products tautomerization is The negotiated presence through into of several a more tautomerization nucleophilic stable anion intoand via protona electrophilic more stabl shifts.e Acentersanion ring via expansion accounts proton shifts. for process the A multichannelring is also expansion possible mode process for the of 5-exo-products. theis also observed possible reactivity. for the 5 -exo Several-products. reaction cascades originateVasilevsky, from alternative AlabuginAlabugin andandcyclization coworkerscoworkers modes soughtsought proceeding aa deeperdeeper via understandingunderstanding N-6-endo-dig ofof-, thetheN-6 exo/endoexo/endo-exo-dig- interplayand O-5- exoin cyclizations- cyclizationsdig attacks. ofThe of alkynes alkynesratio of by these by using using products the thesystem systemis sensitive shown shown into theScheme in nature Scheme 20 of[70] alkyne20. The[ 70 ].substitution,polyfunctional The polyfunctional i.e., internal donor Arinternalnucleophile groups nucleophile favor corresponds the formation corresponds a hemiamina of 6 a- hemiaminalexol -deriveddig products from derived addition[71] from whereas of addition guanidine the acceptor of guanidine to the p- carbonylnitrophenyl to the moiety carbonyl group of directsmoietyperi-substituted theof peri-substituted reaction acetylenic towards anthraquinones. acetylenic the heterocyclic anthraquinones. The amides presence via The of t he presenceseveral 5-exo nucleophilic-dig of several step. The nucleophilic and 5 - electrophilicexo-product and undergoescenters accounts a subsequent for the transformation multichannel modewhich ofis formally the observed equivalent reactivity. to the Several full cleavage reaction of the cascad triplese originate from alternative cyclization modes proceeding via N-6-endo-dig-, N-6-exo-dig- and O-5- exo-dig attacks. The ratio of these products is sensitive to the nature of alkyne substitution, i.e., donor Ar groups favor the formation of 6-exo-dig products [71] whereas the acceptor p-nitrophenyl group directs the reaction towards the heterocyclic amides via the 5-exo-dig step. The 5-exo-product undergoes a subsequent transformation which is formally equivalent to the full cleavage of the triple
Molecules 2019, 24, 1036 14 of 36 electrophilic centers accounts for the multichannel mode of the observed reactivity. Several reaction cascades originate from alternative cyclization modes proceeding via N-6-endo-dig-, N-6-exo-dig- and O-5-exo-dig attacks. The ratio of these products is sensitive to the nature of alkyne substitution, i.e., donor Ar groups favor the formation of 6-exo-dig products [71] whereas the acceptor p-nitrophenyl Molecules 2019, 24, x FOR PEER REVIEW 14 of 35 groupMolecules directs 2019, 24 the, x FOR reaction PEER REVIEW towards the heterocyclic amides via the 5-exo-dig step. The 5-exo-product14 of 35 undergoes a subsequent transformation which is formally equivalent to the full cleavage of the triple bond and insertion of a nitrogen atom between the two acetylenic carbons (to be discussed in Section bond and insertion of a nitrogen atom between the two acetylenic carbons (to be discussed in Section5). 5).
Scheme 20. 20.Diverging Diverging mechanistic mechanistic pathways pathways in reactions in reactions of peri-substituted of peri-substituted acetylenyl-9,10- acetylenyl-9,10- anthraquinones and guanidine.
A particularly interesting process observed in these systems is reductive dimerization of such quinones into tetracene diones asas displayed in SchemeScheme 21[ [72]72].. The mechanism mechanism for this transformation transformation is still unclear.unclear.
Scheme 21. Reductive dimerization of ethynyl anthraquinones.
3.5. Electrophile-Promoted Nucleophilic Cyclizations (EPNC)—Rendering Endo-Cyclizations Possible through “LUMO Umpolung” Coordination of an external Lewis acid to an alkyne increases alkyne electrophilicity rendering it a willing partner in many useful synthetic transformations [33]. Simultaneously, this coordination changes the nature of alkyne frontier molecular orbitals (FMOs). We named such change “LUMO Umpolung” because the LUMO of the complex resembles the HOMO of the starting alkyne [30]. This
Molecules 2019, 24, 1036 15 of 36
3.5. Electrophile-Promoted Nucleophilic Cyclizations (EPNC)—Rendering Endo-Cyclizations Possible through “LUMO Umpolung” Coordination of an external Lewis acid to an alkyne increases alkyne electrophilicity rendering it a willing partner in many useful synthetic transformations [33]. Simultaneously, this coordination changes the nature of alkyne frontier molecular orbitals (FMOs). We named such change “LUMO MoleculesMolecules 20192019,, 2424,, xx FORFOR PEERPEER REVIEWREVIEW 1515 ofof 3535 Umpolung” because the LUMO of the complex resembles the HOMO of the starting alkyne [30]. changeThischange change in in the the in orbitalthe orbital orbital symmetry symmetry symmetry renders renders renders both both both exo exo exo-dig--digdig and and and endo endo endo-dig--digdig cyclizations cyclizations cyclizations possible possible possible in in in this this cyclizationcyclization family family (El (Electrophile-Promoted(Electrophileectrophile--PromotedPromoted Nucleophilic Nucleophilic ClosureClosure (EPNC)(EPNC) processes;processes; SchemeScheme 222222)[)) [73][73]73]...
SchemeScheme 22.22. 22. “The“The“The LUMOLUMO LUMO Umpolung”:Umpolung”: Umpolung”: coordinationcoordination coordination ofof aa Lewis ofLewis a Lewis acidacid atat acid thethe atalkynealkyne the alkynechangeschanges changes thethe LUMOLUMO the symmetryLUMOsymmetry symmetry and and deactivates deactivates and deactivates a a destabilizing destabilizing a destabilizing secondary secondary secondary orbital orbital interaction interaction orbital interaction that that disfavors disfavors that disfavorsendoendo--digdig cyclizations.endo-digcyclizations. cyclizations.
OnceOnce formed, formed, formed, the the the vinyl vinyl vinyl ethers ethers ethers can can can be used be be used used for the for for subsequent the the subsequent subsequent C-C bond C C--CC formations bond bond formations formations if the substrate if if the the substratehassubstrate additional has has additional additionalappropriately appropriately appropriately activated electrophilic activated activated electrophilic electrophilic units. In particular, units. units. Inthis In particular, particular, cyclization t this modehis cyclization cyclization has been modeshownmode has has to be been been effective shown shown in to to initiating be be effective effective an all in in endo-selective init initiatingiating an an cascade, all all endo endo which--selectiveselective fuses cascade, cascade, a polycyclic which which aromatic fusesfuses a a polycyclicbackbonepolycyclic to aromaticaromatic the electron-rich backbonebackbone furan toto thethe subunit electronelectron [74--richrich–76 ], furanfuran as shown subunitsubunit in Scheme [74[74––76]76] ,23, asas. Theshownshown mechanism inin SSchemecheme of 23 the23.. TheThe 2nd mechanismandmechanism 3rd ring ofof formation thethe 2nd2nd isandand so far3rd3rd unclear ringring formationformation and may eitherisis soso farfar include unclearunclear sequential andand maymay activation eithereither includeinclude of the two sequentialsequential alkynes activatiasactivati electrophiliconon ofof thethe Au-complexes twotwo alkynesalkynes asas or electrophilicelectrophilic an Au-catalyzed AuAu--complexescomplexes Bergman oror cyclization anan AuAu--catalyzedcatalyzed [77] followed BergmanBergman by couplingcyclizationcyclization of [77]the[77] benzofuran followedfollowed byby and couplingcoupling dehydronapthalene ofof thethe benzofuranbenzofuran subunits. andand dehydronapthalenedehydronapthalene subunits.subunits.
SchemeScheme 23. 23. TheThe formal formal “all “all“all-endo”--endo”endo” metal metalmetal-assisted--assistedassisted cyclization cyclization cascade cascade is is initiated initiated by by a a 55-endo-dig 5--endoendo--digdig closureclosure followed followed by by two 6 6-endo-dig6--endoendo--digdig closures. closures.
3.6.3.6. EndoEndo--CascadeCascade throughthrough VinylideneVinylidene IntermediatesIntermediates CaiCai etet al.al. illustratedillustrated thatthat thethe cyclizationcyclization selectivityselectivity cancan bebe shiftedshifted reliablyreliably inin favorfavor ofof thethe endoendo-- digdig cyclizations cyclizations by by changing changing the the reaction reaction mechanism mechanism [78][78].. The The 5, 5, 6, 6, 7, 7, and and 8 8--endoendo--digdig cycloisomerizationscycloisomerizations ofof terminalterminal alkynolsalkynols areare possiblepossible underunder RuRu--catalycatalysissis duedue toto thethe formationformation andand trappingtrapping ofof thethe RuRu--vinylidenevinylidene intermediate.intermediate. ThroughThrough thisthis robustrobust protocol,protocol, thethe preparationpreparation ofof “non“non-- branched”branched” cycliccyclic ethersethers ofof differentdifferent sizesize isis achievableachievable inin aa modularmodular andand efficientefficient wayway ((SchemeScheme 2424).).
Molecules 2019, 24, 1036 16 of 36
3.6. Endo-Cascade through Vinylidene Intermediates Cai et al. illustrated that the cyclization selectivity can be shifted reliably in favor of the endo-dig cyclizations by changing the reaction mechanism [78]. The 5, 6, 7, and 8-endo-dig cycloisomerizations of terminal alkynols are possible under Ru-catalysis due to the formation and trapping of the Ru-vinylidene intermediate. Through this robust protocol, the preparation of “non-branched” cyclic ethers of different size is achievable in a modular and efficient way (Scheme 24). Molecules 2019, 24, x FOR PEER REVIEW 16 of 35
Scheme 24. CycloisomerizatiCycloisomerizationsons of terminal alkynols under Ru Ru-catalysis.-catalysis.
The next section showsshows howhow enolenol ethers ethers prepared prepared from from alkynes alkynes can can be be involved involved into into additional additional in insitu situ transformations transformations that that add add synthetic synthetic value value to theto the product. product.
4. Petasis Petasis-Ferrier-Ferrier Rearrangement The connection connection between betwe alkynesen alkynes and carbonyls and carbonyls is also illustrated is also by illustrated Petasis-Ferrier by rearrangementPetasis-Ferrier (PFR).rearrangement PFR is a valuable(PFR). PFR process is a valuable that utilizes process the dualthat (O-utilizes vs. C-) the reactivity dual (O- ofvs. enolates C-) reactivity for the of controlled enolates forformation the controlled of C-C formation bonds via of an C isomerization-C bonds via an [79 isomerization–81,83–85]. In [79 classic–84]. In version classicof vers theion PFR, of the a cyclic PFR, vinyla cyclic ethers vinyl undergoes ethers undergoes an acid-catalyzed an acid-catalyzed ring opening ring opening via the C-Ovia the bond C-O scission bond scission (the reverse (the reverse of enol Oof-cyclization enol O-cyclization with a cationic with a cationic electrophile). electrophile). Such scission Such scission forms an forms enol, an concomitantly enol, concomitantly with a cationic with a cationiccenter. The center. latter The serves latter as anserves electrophile as an electrophile that can, in that the lastcan, step in the of thelast PFR step cascade, of the PFR recapture cascade, the recaptureenol at the theC-terminus enol at the of theC-terminus latter. This of C-Cthe bondlatter. formation This C-C viabond a recyclization formation via step a recyclization furnishes the step new furnishescyclic product the new Scheme cyclic 25 product. The cationic Scheme intermediate 25. The cationic usually intermediate has to be stabilized usually has (typically to be s bytabilized a lone pair(typically of an adjacent by a lone heteroatom) pair of an in adjacent order for heteroatom) the C-O scission in order process forto the be Cthermodynamically-O scission process feasible. to be Thethermodynamically Au-catalyzed versions feasible. of The PFR Au utilize-catalyzed homopropargylic versions of derivativesPFR utilize as homopropargylic carbonyl precursors derivatives [86–93]. as carbonyl precursors [85–92].
Scheme 25. Two possible stabilization patterns for the Petasis-Ferrier rearrangement.
The Au-catalyzed PFR cascades developed by the groups of Rhee [85,86] and Zhang [87,88] are initiated as the enol ether formed via an O-nucleophilic attack at an activated alkyne/Au(I) π-complex (Scheme 26, top). The fragmentation of the vinyl ether intermediate is typically assisted by the
Molecules 2019, 24, x FOR PEER REVIEW 16 of 35
Scheme 24. Cycloisomerizations of terminal alkynols under Ru-catalysis.
The next section shows how enol ethers prepared from alkynes can be involved into additional in situ transformations that add synthetic value to the product.
4. Petasis-Ferrier Rearrangement The connection between alkynes and carbonyls is also illustrated by Petasis-Ferrier rearrangement (PFR). PFR is a valuable process that utilizes the dual (O- vs. C-) reactivity of enolates for the controlled formation of C-C bonds via an isomerization [79–84]. In classic version of the PFR, a cyclic vinyl ethers undergoes an acid-catalyzed ring opening via the C-O bond scission (the reverse of enol O-cyclization with a cationic electrophile). Such scission forms an enol, concomitantly with a cationic center. The latter serves as an electrophile that can, in the last step of the PFR cascade, recapture the enol at the C-terminus of the latter. This C-C bond formation via a recyclization step furnishes the new cyclic product Scheme 25. The cationic intermediate usually has to be stabilized (typically by a lone pair of an adjacent heteroatom) in order for the C-O scission process to be thermodynamicallyMolecules 2019, 24, 1036 feasible. The Au-catalyzed versions of PFR utilize homopropargylic derivatives17 of 36 as carbonyl precursors [85–92].
SchemeScheme 25. 25. TwoTwo possible stabilization patterns for the Petasis Petasis-Ferrier-Ferrier rearrangement.
The Au Au-catalyzed-catalyzed PFR cascades developed by the groups of Rhee [85,86] [86,87] and Zhang [87,88] [88,89] are π initiatedMolecules 2019 as the , 24, enol x FOR ether PEER formed REVIEW via an an OO--nucleophilicnucleophilic attack at an activated alkyne/Au alkyne/Au(I)(I) π--complexcomplex17 of 35 (Scheme 26 26,, top). top) The. The fragmentation fragmentation of the of vinyl the vinyl ether ether intermediate intermediate is typically is typically assisted assisted by the presence by the presenceof an endocyclic of an endocyclic heteroatom heteroatom donor. Such donor. reactions Such were reactions successfully were used successfully for the preparation used for the of preparationbiologically of active biologically heterocycles. active Subsequently,heterocycles. Subseq Pati anduently, Alabugin Pati and reported Alabugin that, reported when an that, aromatic when anring aromatic can be usedring ascan an be endocyclic used as an donor endocyclic with the donor assistance with the of aassistance properly positionedof a properly exocyclic positioned aryl exocyclicdonor, the aryl Au-catalyzed donor, the PFR Au can-catalyzed be utilized PFR for can synthesis be utilized of carbocyclic for synthesis aromatic of carbocyclic systems (Scheme aromatic 26, systemsbottom) (Scheme [94]. 26, bottom) [93].
Scheme 26. AuAu-catalyzed-catalyzed versions of the Petasis-FerrierPetasis-Ferrier reaction. Top: Top: cation cation stabilization by an endocyclic donor assists transformation of homopropargylic esters and amides into heterocyclic products. Bottom: cation cation stabilization by a ann exocyclic donor assists transformation of ortho-alkynyl-alkynyl benzyl methyl ethers into naphthalenes.
Overall, the mildmild andand efficientefficient Au-catalyzedAu-catalyzed Petasis-Ferrier/aromatization Petasis-Ferrier/aromatization sequence converts alkynes into into activated activated enol enol ethers. ethers. Alkoxy Alkoxy substitution substitution in the pr inoducts the productscan be used can for be subsequent used for syntheticsubsequent transformations, synthetic transformations, such as such the as highly the highly regioselective regioselective oxidative oxidative dimerization dimerization into tetranaphthyls [[93]94]..
5. The “Oxidant-Free Nitrogen Baeyer-Villiger Rearrangement” In this section, we will show a cascade transformation of an alkyne that involves two “carbonyl reactions”, the Petasis-Ferrier reaction and an “aza Baeyer-Villiger (BV) rearrangement”. The Baeyer- Villiger reaction provides an important synthetic connection between ketones and esters [94–99]. More than a century after its discovery, this transformation still continues to provide a valuable connection between these key organic functional groups. The key step in the mechanism of Baeyer-Villiger (BV) rearrangement involves a 1,2-alkyl shift in a tetrahedral intermediate formed by the addition of a peroxyacid to the carbonyl group of an ester (i.e., the Criegee intermediate) [100]. This reaction is assisted, by exchange of a weak O-O bond [101] into a more stable C-O bond and two stereoelectronic effects [102–105]. The key participants include the p-type lone pair of O1, the breaking C2-Rm bond and the O3-O4 acceptor (Scheme 27). The “primary stereoelectronic effect” requires antiperiplanarity of the breaking O-O bond and the migrating C-Rm bond. The “secondary effect” is switched on when the lone pair of the O1H group aligns with the breaking C-Rm bond [106,107].
Molecules 2019, 24, 1036 18 of 36
5. The “Oxidant-Free Nitrogen Baeyer-Villiger Rearrangement” In this section, we will show a cascade transformation of an alkyne that involves two “carbonyl reactions”, the Petasis-Ferrier reaction and an “aza Baeyer-Villiger (BV) rearrangement”. The Baeyer-Villiger reaction provides an important synthetic connection between ketones and esters [95–100]. More than a century after its discovery, this transformation still continues to provide a valuable connection between these key organic functional groups. The key step in the mechanism of Baeyer-Villiger (BV) rearrangement involves a 1,2-alkyl shift in a tetrahedral intermediate formed by the addition of a peroxyacid to the carbonyl group of an ester (i.e., the Criegee intermediate) [101]. This reaction is assisted, by exchange of a weak O-O bond [102] into a more stable C-O bond and two stereoelectronic effects [103–106]. The key participants include the p-type lone pair of O1, the breaking C2-Rm bond and the O3-O4 acceptor (Scheme 27). The “primary stereoelectronic effect” requires antiperiplanarity of the breaking O-O bond and the migrating C-Rm bond. The “secondary effect” is switched on when the lone pair of the O1H group aligns with the MoleculesMoleculesbreaking 20192019 C-R,, 2424m,, xxbond FORFOR PEERPEER [107 REVIEW,REVIEW108]. 1818 ofof 3535
SchemeSchemeScheme 27.27. 27. 1,21,21,2-shifts--shiftsshifts inin in thethe the BaeyerBaeyer Baeyer-Villiger--VilligerVilliger and and azaaza aza-Baeyer-Villiger--BaeyerBaeyer--VilligerVilliger reactions. reactions.
AnAn azaaza aza-version--versionversion ofof of thethe BVBV reactionreaction wouldwould would openopen open aa a directdirect direct syntheticsynthetic synthetic pathpath path fromfrom from ketonesketones ketones toto to amides.amides. amides. ThisThis processprocess wouldwould requirerequire thethe 1,21,2 1,2-shift--shiftshift toto breakbreak thethe NN N-X--XX bondbond betweenbetween between nitrogennitrogen nitrogen andand aa a leavingleaving leaving groupgroup group X.X. As As far far far as as as we we we know, know, know, there there there is no is is example nono example example of such of of reaction such such reaction reaction that starts that that directly starts starts directly directlyfrom a carbonyl from from a a precursorcarbonyl carbonyl precursorprecursorand proceeds andand via proceedsproceeds a hemiaminal viavia aa hemiaminalhemiaminal intermediate intermediateintermediate [109]. However, [108][108] use.. However,However, of an alkyne useuse starting ofof anan alkyne alkyne material startingstarting led to materialmaterialthe discovery ledled toto of thethe an discoverydiscovery aza-BV reaction ofof anan azaaza in--BV aBV cascade reactionreaction where inin aa cascadecascade this process wherewhere is coupledthisthis processprocess with isis a coupledcoupled Petasis-Ferrier wwithith aa PetasisPetasisreaction--FerrierFerrier [70,72 ,110 reaction reaction,111]. The[70,72,109,110][70,72,109,110] outcome of.. this The The cascade outcome outcome is quite of of this this remarkable—this cascade cascade is is quite quite sequence remarkable remarkable of reactions——thisthis sequencesequenceinserts a nitrogen of of reactions reactions atom inserts inserts between a a thenitrogen nitrogen two alkyne atom atom carbons between between (Scheme the the two two 28 alkyne alkyne). The overall carbons carbons transformation (Scheme(Scheme 28) 28).. leads The The overalloverallto the formation transformation transformation of six new leads leads bonds to to the the at the formation formation two alkyne of of sixsix carbons newnew bondswith bonds complete at at the the two two disassembly alkyne alkyne carbons carbons of the alkyne with with completecompletemoiety. Note disassemblydisassembly that this cascade ofof thethe alkynealkyne alkyne moiety.moiety. transformation NoteNote thatthat is thisthis mediated cascadecascade by alkynealkyne classic transformationtransformation carbonyl chemistry, isis mediatedmediated i.e., the bybyfragmentation classic classic carbonyl carbonyl−recyclization chemistry, chemistry, sequence i.e., i.e., is the the similar fragmentation−recyclization fragmentation−recyclization the Petasis−Ferrier rearrangement sequence sequence and is is the similar similar [1,2]-shift the the Petasis−FerrierPetasis−Ferrierconverting the rearr cyclicrearrangementangement heminal into andand lactamthethe [1,2][1,2] is--shiftshift the aza-analogue convertingconverting thethe of cycliccyclic the Baeyer-Villiger heminalheminal intointo lactamlactam oxidation isis thethe (except azaaza-- analogueanaloguethat it is done ofof thethe without BaeyerBaeyer- any-VilligerVilliger oxidants!). oxidationoxidation (except(except thatthat itit isis donedone withoutwithout anyany oxidants!).oxidants!).
SchemeScheme 28.28. 28. AlkyneAlkyneAlkyne “disassembly”“disassembly” “disassembly” viavia carbonylviacarbonyl carbonyl cascadescascades cascades leadingleading leading toto nitrogennitrogen to nitrogen insertioinsertio insertionnn betweenbetween between alkynealkyne carbons.carbons.alkyne carbons. Note Note that that the theNote fragmentation−recyclization fragmentation−recyclization that the fragmentation− recyclization sequence sequence is is analogous analogous sequence to to is the the analogous Petasis−Ferrier Petasis−Ferrier to the rearrangementrearrangementPetasis−Ferrier whereaswhereas rearrangement thethe [1,2][1,2] whereas--shiftshift cancan the bebe [1,2]-shift consideredconsidered can asas be anan considered azaaza--analogueanalogue as an ofof aza-analoguethethe BaeyerBaeyer--VilligerVilliger of the reaction.reaction.Baeyer-Villiger reaction.
LikeLike thethe BV,BV, thethe “aza“aza--BV”BV” involvesinvolves aa 1,21,2--carboncarbon shiftshift atat thethe carboncarbon atomatom substitutedsubstituted withwith twotwo heteroatomsheteroatoms (hemiaminal(hemiaminal ratherrather thanthan hemiacetal).hemiacetal). InIn bothboth processes,processes, thethe CC--CC bondbond scissionscission isis assistedassisted byby thethe C=OC=O bondbond formationformation andand scissionscission ofof aa bondbond atat thethe heteroatomheteroatom thatthat acceptsaccepts thethe migratingmigrating ggroup.roup. InIn thethe classicclassic BV,BV, thethe breakingbreaking bondbond isis thethe OO--OO bondbond whereaswhereas inin thethe presentpresent versionversion ofof thethe azaaza--BV,BV, thethe breakingbreaking bondbond isis thethe NN--LGLG bond,bond, wherewhere LGLG isis aa CC--centeredcentered leavingleaving group.group.
6.6. AlkynesAlkynes asas CarbonylCarbonyl SurrogateSurrogatess inin thethe SynthesisSynthesis ofof AldolAldol ProductsProducts InIn the the previousprevious sections, sections, we we have have shown shown the the utility utility of of alkynes alkynes in in “heterocyclizations” “heterocyclizations” via via reactionsreactions withwith heteroatomicheteroatomic nucleophiles.nucleophiles. InIn thisthis section,section, wewe willwill illustrateillustrate thethe valuevalue ofof alkynesalkynes fforor thethe CCCC bondbond formationformation inin “carbocyclizations”.“carbocyclizations”. TheThe aldolaldol condensationcondensation isis oneone ofof thethe classicclassic syntheticsynthetic transformationstransformations thatthat takestakes advantageadvantage ofof thethe dualdual abilityability ofof thethe carbonylcarbonyl functionalityfunctionality toto serveserve asas aa sourcesource ofof bothboth thethe electrophileelectrophile (carbonyl)(carbonyl) andand nucleophilenucleophile (enol/enolate)(enol/enolate) partnerspartners forfor thethe CC--CC bondbond formationformation.. HoweverHowever,, ththeseese transformationstransformations oftenoften dependdepend onon chemochemo--selectiveselective formationformation ofof anan enolateenolate fromfrom oneone carbonylcarbonyl precursorprecursor inin thethe presencepresence ofof ananotherother [111,112][111,112].. TheThe challengechallenge arisesarises mainlymainly becausebecause ofof thethe differentdifferent possiblepossible enolateenolate formationsformations,, anan issueissue thatthat isis inherentinherent toto thethe aldolaldol condensation,condensation, withwith symmetricsymmetric ketonesketones beingbeing thethe exception.exception. ExploitingExploiting alkynesalkynes asas hiddenhidden carbonylcarbonyl precursorsprecursors allowsallows forfor
Molecules 2019, 24, 1036 19 of 36
Like the BV, the “aza-BV” involves a 1,2-carbon shift at the carbon atom substituted with two heteroatoms (hemiaminal rather than hemiacetal). In both processes, the C-C bond scission is assisted by the C=O bond formation and scission of a bond at the heteroatom that accepts the migrating group. In the classic BV, the breaking bond is the O-O bond whereas in the present version of the aza-BV, the breaking bond is the N-LG bond, where LG is a C-centered leaving group.
6. Alkynes as Carbonyl Surrogates in the Synthesis of Aldol Products In the previous sections, we have shown the utility of alkynes in “heterocyclizations” via reactions with heteroatomic nucleophiles. In this section, we will illustrate the value of alkynes for the CC bond formation in “carbocyclizations”. The aldol condensation is one of the classic synthetic transformations that takes advantage of the dual ability of the carbonyl functionality to serve as a source of both the electrophileMolecules 2019, (carbonyl) 24, x FOR PEER and REVIEW nucleophile (enol/enolate) partners for the C-C bond formation. However,19 of 35 these transformations often depend on chemo-selective formation of an enolate from one carbonyl precursorthe use of in each the presence of the alkyne of another carbons [112 in,113 each]. The of challengethe alkyne arises units mainly as either because a nucleophilic of the different or an possibleelectrophilic enolate partner formations, depending an issue on the that activation is inherent method to the aldol (Scheme condensation, 4). with symmetric ketones beingTo the understand exception. the Exploiting advantages alkynes of alkyne as hidden as a carbonyl better carbonyl precursors surrogate, allows we for havethe use compared of each ofthermodynamics the alkyne carbons for the in eachsynthesis of the of alkyne cyclic enones units as as either depicted a nucleophilic in Scheme or29. an The electrophilic calculations partner shows dependingthat transformations on the activation of both method model (Scheme alkynes4). octa-2,6-diyne and octa-1,6-diyne into 1-(2-methyl- cyclopentTo understand-1-en-1-yl)ethanone the advantages are highly of alkyne exergonic as a better (−56.7 carbonyl Kcal/mole surrogate, and we − have59.7 compared kcal/mole, thermodynamicsrespectively). However, for the accessing synthesis the of same cyclic enone enones from as the depicted carbonyl in Schemeprecurs or,29 .octane The- calculations2,7-dione, is showsuphill by that 2.6 kcal/mole. transformations These comparisons of both model clearly alkynes illustrate octa-2,6-diyne that one can utilize and alkynes octa-1,6-diyne stored energy into 1-(2-methyl-cyclopent-1-en-1-yl)ethanoneefficiently in the synthesis of aldol products. are highly exergonic (−56.7 Kcal/mole and −59.7 kcal/mole, respectively).For the preparation However, accessingof non-symmetric the same enones, enone from one thehas carbonylto match precursor,precisely the octane-2,7-dione, electrophilic and is uphillnucleophilic by 2.6 kcal/mole.components These by the comparisons design of starting clearly illustrate materials. that In onealkynes, can utilize this match alkynes can stored be done energy via efficientlycatalyst design, in the so synthesis each of ofalkynes aldol products.can be either the E+ or Nu− partner.
SchemeScheme 29.29. SynthesisSynthesis ofof cycliccyclic enonesenones fromfrom dicarbonylsdicarbonyls andand diynes.diynes.
ForAcid the-catalyzed preparation reactions of non-symmetric of alkynes and enones, aldehydes one hasallow to matchto use preciselyalkynes as the enolate electrophilic equivalents and nucleophilicin aldol condensations components (Scheme by the 30 design). of starting materials. In alkynes, this match can be done via catalyst design, so each of alkynes can be either the E+ or Nu− partner. Acid-catalyzed reactions of alkynes and aldehydes allow to use alkynes as enolate equivalents in aldol condensations (Scheme 30).
Scheme 30. Use of alkynes as enolate equivalents in the formal aldol condensations with aldehydes (“alkyne-carbonyl metathesis”).
Molecules 2019, 24, x FOR PEER REVIEW 19 of 35 the use of each of the alkyne carbons in each of the alkyne units as either a nucleophilic or an electrophilic partner depending on the activation method (Scheme 4). To understand the advantages of alkyne as a better carbonyl surrogate, we have compared thermodynamics for the synthesis of cyclic enones as depicted in Scheme 29. The calculations shows that transformations of both model alkynes octa-2,6-diyne and octa-1,6-diyne into 1-(2-methyl- cyclopent-1-en-1-yl)ethanone are highly exergonic (−56.7 Kcal/mole and −59.7 kcal/mole, respectively). However, accessing the same enone from the carbonyl precursor, octane-2,7-dione, is uphill by 2.6 kcal/mole. These comparisons clearly illustrate that one can utilize alkynes stored energy efficiently in the synthesis of aldol products. For the preparation of non-symmetric enones, one has to match precisely the electrophilic and nucleophilic components by the design of starting materials. In alkynes, this match can be done via catalyst design, so each of alkynes can be either the E+ or Nu− partner.
Scheme 29. Synthesis of cyclic enones from dicarbonyls and diynes.
MoleculesAcid2019-catalyzed, 24, 1036 reactions of alkynes and aldehydes allow to use alkynes as enolate equivalents20 of 36 in aldol condensations (Scheme 30).
Scheme 30. Use of alkynes as enolate equivalents in the formal aldol condensations with aldehydes Molecules(“alkyne-carbonyl(“alkyne 2019, 24-carbonyl, x FOR PEER metathesis”).metathesis”) REVIEW . 20 of 35
Several intra- intra- and and intermolecular intermolecular versions versions of this of alkyne-aldehyde this alkyne-aldehyde coupling coupling successfully successfully provided providedtrisubstituted trisubstituted enones in theenones presence in the of presence Lewis and of BrønstedLewis and acids Brønsted (AgSbF acids6, BF 3(AgSbF(OEt2),6 or, BF HBF3(OEt4)[2114), or]. ThisHBF4 reaction) [113]. This proceeds reaction in higher proceeds yields in under higherthe yields catalytic under activation the catalytic by AgSbF activation6. Intermolecular by AgSbF6. Intermolecularcoupling proceeds coupling stereoselectively proceeds stereoselectively with the formation with of the a singleformation geometrical of a single isomer. geometrical The suggested isomer. Themechanism suggested of themechanism alkyne-carbonyl of the alkyne reaction-carbonyl involves reaction complexation involves of complexation Ag(I) with either of Ag(I) the alkyne with either or the thecarbonyl alkyne oxygen or the that carbonyl facilitates oxygen a formal that “2facilitates + 2” cycloaddition a formal “2 that + 2” leads cycloaddition to the formation that leads of unstable to the formationoxete intermediate. of unstable As shownoxete intermediate. in Scheme 31 ,As This shown strained in heterocycleScheme 31, can This undergo strained a cycloreversionheterocycle can to undergoconjugated a cycloreversion enone. to conjugated enone.
Scheme 31. Suggested mechanism of the alkyne alkyne-carbonyl-carbonyl “aldol condensations” condensations”..
Subsequent research greatly expanded synthetic utility of these reactions to include ketones and nonnon-activated-activated alkynes alkynes [114 [115––117]117,.119 Considering]. Considering the mechanism, the mechanism, one can one classify can classify this process this process as a formal as a alkyneformal- alkyne-carbonylcarbonyl “metathesis” “metathesis” where the where carbonyl the carbonyl double doublebond is bond“transferred” is “transferred” to one of to the one alkyne of the carbonsalkynecarbons [118–121] [120. This–123 process]. This was process suggested was suggested to serve as to “a serve completely as “a completely atom economical atom economical alternative toalternative the use toof the stabilized use of stabilized Wittig reagents Wittig reagents in carbo innyl carbonyl olefination” olefination” [113]. [One114]. can One also can consider also consider this processthis process as another as another example example where where alkyne alkyne behaves behaves as a as1,2 a-dicarbene 1,2-dicarbene equivalent. equivalent. Due to the alkyne/carbonyl alkyne/carbonyl equivalency, equivalency, one one can can initiate similar intramolecular cascades by starting from a diyne rather than a ynone or an ynal. An example of this chemistry is provided by Au-catalyzedAu-catalyzed hydrative cyclizations of diynes (Scheme(Scheme 3232)[) [122]124]..
Scheme 32. Au-catalyzed hydrative cyclizations of diynes.
Molecules 2019, 24, x FOR PEER REVIEW 20 of 35
Several intra- and intermolecular versions of this alkyne-aldehyde coupling successfully provided trisubstituted enones in the presence of Lewis and Brønsted acids (AgSbF6, BF3(OEt2), or HBF4) [113]. This reaction proceeds in higher yields under the catalytic activation by AgSbF6. Intermolecular coupling proceeds stereoselectively with the formation of a single geometrical isomer. The suggested mechanism of the alkyne-carbonyl reaction involves complexation of Ag(I) with either the alkyne or the carbonyl oxygen that facilitates a formal “2 + 2” cycloaddition that leads to the formation of unstable oxete intermediate. As shown in Scheme 31, This strained heterocycle can undergo a cycloreversion to conjugated enone.
Scheme 31. Suggested mechanism of the alkyne-carbonyl “aldol condensations”.
Subsequent research greatly expanded synthetic utility of these reactions to include ketones and non-activated alkynes [114–117]. Considering the mechanism, one can classify this process as a formal alkyne-carbonyl “metathesis” where the carbonyl double bond is “transferred” to one of the alkyne carbons [118–121]. This process was suggested to serve as “a completely atom economical alternative to the use of stabilized Wittig reagents in carbonyl olefination” [113]. One can also consider this process as another example where alkyne behaves as a 1,2-dicarbene equivalent. Due to the alkyne/carbonyl equivalency, one can initiate similar intramolecular cascades by startingMolecules 2019from, 24 a, 1036diyne rather than a ynone or an ynal. An example of this chemistry is provided21 of by 36 Au-catalyzed hydrative cyclizations of diynes (Scheme 32) [122].
Scheme 32. AuAu-catalyzed-catalyzed hydrative cyclizations of diynes.diynes.
The proposed mechanism for this transformation includes transformation of one of the alkynes into an enol ether (the nucleophilic component) and conversion of the other alkyne into an electrophile via a π-complex with the catalyst. After cyclization, the resulting ketal is transformed into the corresponding ketone by hydrolysis. Furthermore, one can make the enone products of formal aldol condensations from alkynes by bypassing the polar path for the CC bond formation altogether. Trost and coworkers illustrated this possibility in ruthenium-catalyzed synthesis of cyclic enones from diyne precursors (Scheme 33). In this process, water was used as the reagent for unmasking the hidden carbonyl after the CC bond formation [125]. The initial step involves formation of “metallacyclopentadiene” intermediate which then undergoes regioselective H2O attack at less hindered site giving desired product. A complete chemoselectivity was observed for significantly bulkier groups affording single regioisomer. In this reaction the use of Ru-catalyst allows one to use the dicarbene character of alkynes. In the initial stage, the C=C moiety is formed by coupling the internal alkyne carbons and leaving the external carbons as two metal carbenoids (show this conceptually). The difference of this design is that the alkyne-carbonyl conversion is done at the final step of reaction (rather than by nucleophilic attack at the alkyne) by the hydration step that releases the Ru-catalyst and furnishes the C(O) and CH2 groups from the two C=Ru moieties. Molecules 2019, 24, x FOR PEER REVIEW 21 of 35
The proposed mechanism for this transformation includes transformation of one of the alkynes into an enol ether (the nucleophilic component) and conversion of the other alkyne into an electrophile via a π-complex with the catalyst. After cyclization, the resulting ketal is transformed into the corresponding ketone by hydrolysis. Furthermore, one can make the enone products of formal aldol condensations from alkynes by bypassing the polar path for the CC bond formation altogether. Trost and coworkers illustrated this possibility in ruthenium-catalyzed synthesis of cyclic enones from diyne precursors (Scheme 33). In this process, water was used as the reagent for unmasking the hidden carbonyl after the CC bond formation [123]. The initial step involves formation of “metallacyclopentadiene” intermediate which then undergoes regioselective H2O attack at less hindered site giving desired product. A complete chemoselectivity was observed for significantly bulkier groups affording single regioisomer. In this reaction the use of Ru-catalyst allows one to use the dicarbene character of alkynes. In the initial stage, the C=C moiety is formed by coupling the internal alkyne carbons and leaving the external carbons as two metal carbenoids (show this conceptually). The difference of this design is that the alkyne-carbonyl conversion is done at the final step of reaction (rather than by nucleophilic Moleculesattack at2019 the, 24 alkyne), 1036 by the hydration step that releases the Ru-catalyst and furnishes the C(O)22 ofand 36 CH2 groups from the two C=Ru moieties.
Scheme 33.33. Ruthenium catalyzed hydrativehydrative cyclizationcyclization ofof diynes.diynes.
AlkynesAlkynes inin Retro-AldolRetro-Aldol andand Retro-MannichRetro-Mannich FragmentationsFragmentations AsAs alkynes are higher higher in in energy energy than than carbonyls, carbonyls, alkynes alkynes can can be beconverted converted back back to carbonyls to carbonyls via viaaddition/isomerization addition/isomerization (Scheme (Scheme 34). 34 In). Inaddition addition to to the the simple simple hydrolysis, hydrolysis, more more interesting interesting transformationstransformations involveinvolve conversionconversion ofof substitutedsubstituted alkynesalkynes toto thethe productsproducts ofof reactionsreactions thatthat wouldwould bebe endergonicendergonic ifif startedstarted fromfrom aa carbonylcarbonyl precursor.precursor. ForFor example,example, in thosethose casescases wherewhere aldolaldol oror similarsimilar condensation/additioncondensation/addition product product is is less less stable than its carbonyl precursors,precursors, accessingaccessing suchsuch productsproducts fromMoleculesfrom thethe 2019 alkynealkyne, 24, x sideFORside PEER leadsleads REVIEW toto theirtheir furtherfurther reactionreaction viavia aa retro-additionretro-addition (i.e.,(i.e., fragmentation)fragmentation) mode.mode.22 of 35
Scheme 34. Use of alkyne high energy and cross cross-over-over to the “carbonyl reaction field” field” for the full disassembly of triple bond.bond.
Recently, severalseveral examples of such reactions which proceed via the retro-Mannichretro-Mannich route were described by by Vasilevsky, Vasilevsky, Alabugin Alabugin and and coworkers coworkers [124] [126.]. These These reactions reactions can can be beused used for forcleaving cleaving the thetriple triple bonds bonds under under relatively relatively mild mild conditions. conditions. For For example, example, the the full full alkyne alkyne fragmentation fragmentation can can be induced in the reaction of ethylene diamine with diarylketoacetylenes. This process leads to the formation of acetophenones and 2-substituted imidazolines (Scheme 35).
Scheme 35. Complete scission of the triple bond in keto alkynes mediated by the retro-Mannich reaction.
In these transformations, controlling the regiochemistry of the ketone formation is crucial for the success. Alkynes with acceptor substituents undergo Michael addition producing a relatively stable enamino ketone that can be isolated. However, at higher temperatures this intermediate undergoes a stereoelectronically favorable [49,125] 5-exo-trig cyclization followed by efficient retro-Mannich fragmentation. The fragmentation is assisted by a stereoelectronically optimal interaction [126] of the breaking C-C bond with lone pair of one of the nitrogen atoms. It is important to note that in order to keep the overall reaction as a “redox neutral” process, the final fate of the two alkyne carbons has to be opposite. While one of the carbons ends as part a methyl group (reduced relative to alkyne), the other one ends up as C1 of a dihydroimidazole (oxidized relative to alkyne; Scheme 36).
Molecules 2019, 24, x FOR PEER REVIEW 22 of 35
Scheme 34. Use of alkyne high energy and cross-over to the “carbonyl reaction field” for the full disassembly of triple bond.
MoleculesRecently,2019, 24 ,several 1036 examples of such reactions which proceed via the retro-Mannich route23 were of 36 described by Vasilevsky, Alabugin and coworkers [124]. These reactions can be used for cleaving the triple bonds under relatively mild conditions. For example, the full alkyne fragmentation can be inducedbe induced in inthe the reaction reaction of ofethylene ethylene diamine diamine with with diarylketoacetylenes diarylketoacetylenes.. This This process process leads leads to to the formation of acetophenones and 2-substituted2-substituted imidazolines (Scheme(Scheme 35).).
Scheme 35. 35. CompleteComplete scission scission of the of triple the bond triple in keto bond alkynes in keto mediated alkynes by mediated the retro-Mannich by the reaction.retro-Mannich reaction.
In these transformations, controlling the regiochemistry ofof the ketone formation is crucial for the success. Alkynes Alkynes with with acceptor substituents undergo Michael addition producing a relatively stable enamino ketone that can be isolated. However, at higher temperaturestemperatures this intermediate undergoes a stereoelectronically favorable [49,125] [49,127] 5-exo-trig5-exo-trig cyclization followed by efficientefficient retro-Mannichretro-Mannich fragmentation. The fragmentation is assisted by a a stereoelectronically stereoelectronically optimal interaction [126] [128] of the breaking C-CC-C bond with lone pair of one of the nitrogen atoms.atoms. It is important to note that in order to keep the overall reaction as a “redox neutral” process, the finalfinal fate of the two alkyne carbons has to be opposite. While one of the carbons ends as part a met methylhyl group (reduced relative to alkyne), the other one ends up as C1 of a dihydroimidazoledihydroimidazole (oxidized Moleculesrelative 2019 to alkyne;alkyne, 24, x FOR; Scheme PEER REVIEW 36). 23 of 35
Scheme 36. Variations of retro-Mannich-mediatedretro-Mannich-mediated alkyne fragmentations with the 2nd nucleophilic attack being intermolecular.
Reactions of α-alkynylketones with other type of binucleophiles, aminoalcohols, proceed in a more complex manner [127]. The effects of electronic and steric factors were investigated by choosing substrates containing donor (p-methoxyphenyl) and acceptor (phenyl and p-nitrophenyl) substituents. The choice of nucleophiles was expanded to include 2-aminoethanol, 2-(methyl- amino)ethanol and the more sterically hindered 2-(methylamino)-1-phenylpropan-1-ol. Intermolecular addition to α-ketoacetylenes lead to corresponding enamines (Scheme 37, bottom).
Scheme 37. Reaction of α-alkynylketones with aminoalcohols.
The subsequent intramolecular Michael addition step is sensitive to the nature of the amine. The introduction of additional methyl and phenyl substituents in ethanolamine dramatically changes the direction of the process. In the reaction of α-ketoacetylenes with more sterically hindered partners, the transformation of the initial adduct to the products of the full triple bond cleavage required more stringent conditions (Scheme 37, top). The suggested pathway of this cascade includes addition of a water molecule to the enamine and then, through 6-membered transition state (TS) and by stereoelectronic assistance of the exocyclic nitrogen leading to the final C-C cleavage -formation of amides and the common methyl aryl ketones. The fragmentation step is likely to be assisted by intermolecular proton transfer to the developing negative charge at the carbonyl oxygen from the properly positioned N-H bond within the six- membered transition state TS (Scheme 38).
Molecules 2019, 24, x FOR PEER REVIEW 23 of 35
MoleculesScheme2019, 2436., 1036 Variations of retro-Mannich-mediated alkyne fragmentations with the 2nd nucleophilic24 of 36 attack being intermolecular.
Reactions of α-alkynylketones-alkynylketones with other type of binucleophiles,binucleophiles, aminoalcohols, proceed in a more complex manner [[127]129].. The effects of electronic and steric factors were investigated by choosing substrates containing containing donor donor (p-methoxyphenyl) (p-methoxyphenyl) and acceptor and acceptor (phenyl and (phenylp-nitrophenyl) and p-nitrophenyl) substituents. Thesubstituents. choice of The nucleophiles choice of was nucleophiles expanded was to include expanded 2-aminoethanol, to include 2-aminoethanol, 2-(methyl-amino)ethanol 2-(methyl- andamino)ethanol the more sterically and the hindered more 2-(methylamino)-1-phenylpropan-1-ol. sterically hindered 2-(methylamino) Intermolecular-1-phenylpropan addition-1-ol. toIntermolecularα-ketoacetylenes addition lead to to α corresponding-ketoacetylenes enamines lead to corr (Schemeesponding 37, bottom). enamines (Scheme 37, bottom).
Scheme 37 37.. Reaction of α--alkynylketonesalkynylketones with aminoalcohols.
The subsequent subsequent intramolecular intramolecular Michael Michael addition addition step step is sensitive is sensitive to the to thenature nature of the of amine. the amine. The Theintroduction introduction of additional of additional methyl methyl and phenyl and phenyl substituents substituents in ethanolamine in ethanolamine dramatically dramatically changes changes the thedirection direction of the of theprocess. process. In Inthe the reaction reaction of ofα-αketoacetylenes-ketoacetylenes with with more more sterically sterically hindered hindered partners, partners, the transformation of the initial adduct to the products of the full triple bond cleavage required m moreore stringent conditions (Scheme 3737,, top).top). The suggested pathway of this cascade includes addition of a water molecule to the enamine and then, through 6 6-membered-membered transition state (TS) and by stereoelectronic assistance of the exocyclic nitrogen leading leading to to the the final final C-C C-C cleavage cleavage -formation -formation of amides of amides and the and common the common methyl aryl methyl ketones. aryl ketones.The fragmentation The fragmentation step is likely step to is be likely assisted to beby assisted intermolecular by intermolecular proton transfer proton to the transfer developing to the developingnegative charge negative at the charge carbonyl at the carbonyloxygen from oxygen the from properly the properly positioned positioned N-H bon N-Hd bond within within the six the- six-memberedMoleculesmembered 2019 transition, 24, transitionx FOR PEER statestate REVIEW TS (Scheme TS (Scheme 38). 38 ). 24 of 35
Scheme 38.38. Reaction of α--ketoacetylenesketoacetylenes with pseudoephedrine.
Both 1 1-- and and 2 2-phenylethynyl-9,10-anthraquinones,-phenylethynyl-9,10-anthraquinones, the the vinylogs vinylogs of ofα-ketoacetylenesα-ketoacetylenes in which in which the thecarbonyl carbonyl group group is removed is removed further further away awayfrom the from triple the bond triple can bond also can be alsoinvolved be involved into full intoscission full scissionof the C of≡C the bond. C≡ C However, bond. However, conditions conditions are harsher are harsher than in than the in case the of case α-acetylenic of α-acetylenic ketones. ketones. The Thefragmentation fragmentation proceeds proceeds most most effectively effectively in refl in refluxinguxing pyridine pyridine with with the the 50 50-fold-fold excess excess of of the nucleophile (Scheme 3939))[ [128]130]..
Scheme 39. C≡C bond scission in 1- and 2-phenylethynyl-9,10-anthraquinones.
More important is the possibility of expanding the alkyne fragmentation reactions to compounds with other functional groups, also positioned away from the alkyne moiety by the example of family of nitro-substituted diaryl alkynes with different positions of the acceptor NO2- group (Scheme 40) [129].
Scheme 40. Expanded alkyne fragmentation reactions to compounds containing varied functionalities.
Thus, presence of a para nitro group is sufficient for the triple bond scission in the reaction with 1,2-diaminoethane, leading to the fragmentation products: 1-methyl-4-nitrobenzene (68%) and 2- phenylimidazoline (61%). Electron-deficiency of the alkyne moiety is more important than alkyne polarization. For example, 1,2-bis(4-nitrophenyl)ethyne, a symmetric alkyne with two acceptor groups, reacts faster (1 h), yielding 51% p-nitrotoluene and 55% imidazoline. This chemistry can be expanded to alkynes with electron-deficient heterocycle substituents such as the pyridine moiety (Scheme 41). For example, 4-pyridinyl alkyne was fully transformed in the two fragmentation products, 2-phenyl-4,5-dihydroimidazole and 4-methylpyridine (picoline).
Molecules 2019, 24, x FOR PEER REVIEW 24 of 35 Molecules 2019, 24, x FOR PEER REVIEW 24 of 35
Scheme 38. Reaction of α-ketoacetylenes with pseudoephedrine. Scheme 38. Reaction of α-ketoacetylenes with pseudoephedrine. Both 1- and 2-phenylethynyl-9,10-anthraquinones, the vinylogs of α-ketoacetylenes in which the carbonylBoth group 1- and is 2 -removedphenylethynyl further-9,10 away-anthraquinones, from the triple the bond vinylogs can also of αbe-ketoacetylenes involved into infull which scission the ofcarbonyl the C≡ groupC bond. is removed However, further conditions away arefrom harsher the triple than bond in thecan casealso ofbe αinvolved-acetylenic into ketones. full scission The fragmentationof the C≡C bond. proceeds However, most conditions effectively are in harsher refluxing than pyridine in the case with of the α- acetylenic 50-fold excess ketones. of The the nucleophileMoleculesfragmentation2019, (Scheme24, 1036 proceeds 39) [128] most. effectively in refluxing pyridine with the 50-fold excess of25 of the 36 nucleophile (Scheme 39) [128].
Scheme 39. C≡C bond scission in 1- and 2-phenylethynyl-9,10-anthraquinones. SchemeScheme 39.39. CC≡≡CC bond bond scission scission in in 1 1-- and and 2 2-phenylethynyl-9,10-anthraquinones.-phenylethynyl-9,10-anthraquinones. More important is the possibility of expanding the alkyne fragmentation reactions to compoundsMore important important with other is the is functional thepossibility possibility groups, of expanding of also expanding positioned the alkyne the away fragmentation alkyne from fragmentation the reactions alkyne moiety to reactions compounds by the to withexamplecompounds other of functional family with oofther groups,nitro functional-substituted also positioned groups, diaryl away also alkynes positioned from with the alkynedifferent away moiety from positions by the the alkyne of example the moietyacceptor of family by NO the of2- groupnitro-substitutedexample (Scheme of family 40) diaryl [129]of nitro alkynes. -substituted with different diaryl positionsalkynes with of the different acceptor positions NO2-group of the (Scheme acceptor 40)[ NO1312].- group (Scheme 40) [129].
Scheme 40. 40.Expanded Expanded alkyne alkyne fragmentation fragmentation reactions reactions to compounds to c containingompounds varied containing functionalities. varied functionalities.Scheme 40. Expanded alkyne fragmentation reactions to compounds containing varied Thus,functionalities. presence of a para nitro group is sufficient for the triple bond scission in the reaction withThus, 1,2-diaminoethane, presence of a para leading nitro to group the fragmentation is sufficient for products: the triple 1-methyl-4-nitrobenzene bond scission in the reaction (68%) with and 1,22-phenylimidazoline-diaminoethane,Thus, presence leadingof (61%). a para Electron-deficiencyto nitro the group fragmentation is sufficient of products: the for alkyne the triple 1 moiety-methyl bond is-4 more-scissionnitrobenzene important in the (68%)reaction than alkyneand with 2- polarization.phenylimidazoline1,2-diaminoethane, For example, (61%). leading 1,2-bis(4-nitrophenyl)ethyne,Electron to the - fragmentationdeficiency of the products: alkyne a symmetric moiety 1-methyl alkyne is- 4more-nitrobenzene with important two acceptor (68%) than groups,alkyne and 2- polarization.reactsphenylimidazoline faster (1 For h), yielding example, (61%). 51%Electron 1,2-pbis(4-nitrotoluene-deficiency-nitrophenyl)ethyne, andof the 55% alkyne imidazoline. a symmetricmoiety is more alkyne important with two than acceptor alkyne groups,polarization.This reacts chemistry Forfaster example, can(1 h be), yielding expanded 1,2-bis(4 51%- tonitrophenyl)ethyne, alkynesp-nitrotoluene with electron-deficient and a55% symmetric imidazoline. heterocycle alkyne with substituents two acceptor such asgroups, theThis pyridine reacts chemistry faster moiety can (1 (Schemeh be), yieldingexpanded 41). 51% For to example,alkynesp-nitrotoluene with 4-pyridinyl electron and 55% alkyne-deficient imidazoline. was heterocycle fully transformed substituents in the such two asfragmentationMolecules theThis pyridine 2019 chemistry, 24, products,x moietyFOR canPEER (Schemebe 2-phenyl-4,5-dihydroimidazole REVIEW expanded 41). Forto alkynes example, with 4- electronpyridinyl and 4-methylpyridine-deficient alkyne washeterocycle fully (picoline). transformed substituents25 in suchof the 35 twoas the fragmentation pyridine moiety products, (Scheme 2-phenyl 41). For-4,5 example,-dihydroim 4-idazolepyridinyl and alkyne 4-methylpyridine was fully transformed (picoline). in the two fragmentation products, 2-phenyl-4,5-dihydroimidazole and 4-methylpyridine (picoline).
Scheme 41. Alkyne fragmentation reactions in pyridine containing substrates.
In summary, reaction of electron-deficient electron-deficient alkynes with ethylene diamine is a general transformation that can involve notnot onlyonly αα-acetylenic-acetylenic ketonesketones butbut otherother suitablysuitably activatedactivated alkynes.alkynes. From a synthetic perspective, the combination of Sonogashira cross cross-coupling-coupling and fragmentation presented in in this this work work opens opens the door the for door two for potentially two potentially useful synthetic useful transformations: synthetic transformations: introduction ofintroduction methyl groups of meth toyl electron-deficient groups to electron aryl-deficient halides aryl or triflateshalides or or triflates introduction or introduction of masked of carboxyl masked (imidazoline)carboxyl (imidazoline) into donor into aryl donor halides aryl or triflates. halides These or triflates. transformations These transformations suggest retrosynthetic suggest equivalencyretrosynthetic of equivalency alkynes and of one-carbon alkynes and synthons, one-carbon in thesynthons, most reduced in the most and oxidizedreduced and forms oxidized of the latterforms (Schemeof the latter 42). (Scheme 42).
Scheme 42. Retrosynthetic equivalency of alkynes and methyl group (top) and protected carboxylic acids (bottom).
It is also interesting that reaction of the β-ethanolamines with CF3-ynones follows a different path where the C(sp3)-C(sp) bond of the enone is broken (Scheme 43) [129,130].
Scheme 43. Reaction of CF3-ynones with amino alcohols.
This interesting example demonstrates the role of the nature of the acyl group in the direction of the aza-Michael-addition of β-aminoethanols to α-alkynyl ketones. Reaction of CF3-ynones with
MoleculesMolecules 20192019,, 2424,, xx FORFOR PEERPEER REVIEWREVIEW 2525 ofof 3535
SchemeScheme 41.41. AlkyneAlkyne fragmentationfragmentation reactionsreactions inin pyridinepyridine containingcontaining substrates.substrates.
InIn summary, summary, reaction reaction of of electron electron--deficientdeficient alkynes alkynes with with ethylene ethylene diamine diamine is is a a general general transformationtransformation thatthat cancan involveinvolve notnot onlyonly αα--acetyleacetylenicnic ketonesketones butbut otherother suitablysuitably activatedactivated alkynes.alkynes. FromFrom aa syntheticsynthetic perspective,perspective, thethe combinationcombination ofof SonogashiraSonogashira crosscross--couplingcoupling andand fragmentationfragmentation presentedpresented in in this this work work opens opens the the door door for for two two potentially potentially useful useful synthetic synthetic transformations: transformations: introductionintroduction ofof methmethylyl groupsgroups toto electronelectron--deficientdeficient arylaryl halideshalides oror triflatestriflates oror introductionintroduction ofof maskedmasked carboxylcarboxyl (imidazoline) (imidazoline) into into donor donor aryl aryl halides halides or or triflates. triflates. These These transformations transformations suggest suggest retrosyntheticMoleculesretrosynthetic2019, 24 ,equivalencyequivalency 1036 ofof alkynesalkynes andand oneone--carboncarbon synthons,synthons, inin thethe mostmost reducereducedd andand oxidizedoxidized26 of 36 formsforms ofof thethe latterlatter (Scheme(Scheme 42).42).
SchemeScheme 42.42. RetrosyntheticRetrosynthetic equivalency equivalency of of alkynes alkynes and and methyl methyl group group (top) (top) and and protected protected carboxylic carboxylic acidsacids (bottom) (bottom).(bottom)..
ItIt isisis alsoalsoalso interesting interestinginteresting that thatthat reaction reactionreaction of ofof the thetheβ-ethanolamines ββ--ethanolaminesethanolamines with withwith CF3 CF-ynonesCF33--ynonesynones follows followsfollows a different aa differediffere pathntnt 3 pathwherepath wherewhere the C(sp thethe C(spC(sp)-C(sp)33))--C(sp)C(sp) bond bondbond of the ofof enone thethe enoneenone is broken isis brokenbroken (Scheme (Scheme(Scheme 43)[131 43)43), 132 [129,130][129,130]]. ..
SchemeScheme 43.4343.. ReactionReaction of of CF CF33---ynonesynonesynones withwith aminoamino alcoholsalcohols alcohols...
ThisThis interestinginteresting exampleexample example demonstratesdemonstrates demonstrates thethe the rolerole role ofof of thethe the naturenature nature ofof of thethe the acylacyl acyl groupgroup group inin inthethe the directiondirection direction ofof β α theofthe the aza aza aza-Michael-addition--MichaelMichael--additionaddition of of of β β--aminoethanolsaminoethanols-aminoethanols to to to α α--alkynylalkynyl-alkynyl ketones. ketones. ketones. Reaction Reaction Reaction of of CF CF33---ynonesynonesynones with with amino alcohols transform ketoacetylenes into two carbonyl compounds -trifluoroacetylated amides and methylarylketones.
7. Alkynes in the Synthesis of α-oxo Gold Carbenes In this section, we give an example of an oxidative alkyne transformation that leads to a carbonyl derivative with an additional useful functionality. The versatility of metal carbenes makes them useful intermediates for synthetically challenging transformations. A common approach to alpha-oxo metal carbenes is the metal catalyzed decomposition of diazo-carbonyl compounds that can be synthesized from carbonyl precursors containing an active alpha methylene group [133,134]. Despite its synthetic utility, these highly energetic diazo-intermediates are potentially explosive and hazardous. Under the right conditions, alkynes allow for another approach towards α-oxo carbenoids that obviates the need of diazo-derivatives (Scheme 44). This transformation is not surprising since, as mentioned in previous sections, alkynes can be considered as super-stabilized 1,2-dicarbenes. In the presence of a suitable oxidant and a catalyst their oxidation yields α-oxo-gold carbenes in an operationally easy and environmentally benign fashion [135,136]. Both intermolecular and intramolecular oxidation methods of alkyne for transformation to oxo-gold carbene have been developed [137]. Molecules 2019, 24, x FOR PEER REVIEW 26 of 35 Molecules 2019, 24, x FOR PEER REVIEW 26 of 35 amino alcohols transform ketoacetylenes into two carbonyl compounds -trifluoroacetylated amides aminoand methylarylketones. alcohols transform ketoacetylenes into two carbonyl compounds -trifluoroacetylated amides and methylarylketones. 7. Alkynes in the Synthesis of α-oxo Gold Carbenes 7. Alkynes in the Synthesis of α-oxo Gold Carbenes In this section, we give an example of an oxidative alkyne transformation that leads to a carbonyl derivativeIn this withsection, an we additional give an example useful functionality of an oxidative. The alkyne versatility transformation of metal that carbenes leads to makes a carbonyl them derivativeuseful intermediates with an additional for synthetically useful functionalitychallenging .transformations. The versatility ofA common metal carbenes approach makes to alpha them- usefuloxo metal intermediates carbenes is for the synthetically metal catalyzed challenging decomposition transformations. of diazo-carbonyl A common compounds approach that to canalpha be- oxosynthesized metal carbenes from carbonyl is the metal precursors catalyzed containing decomposition an active of alpha diazo methylene-carbonyl groupcompounds [131,132] that. Despite can be synthesizedits synthetic from utility, carbonyl these precursors highly energetic containing diazo an active-intermediates alpha methylene are potentially group [131,132] explosive. Despite and itshazardous. synthetic Under utility, the right these conditions, highly energetic alkynes allow diazo -forintermediates another approach are potentially towards α -oxo explosive carbenoids and hazardous.that obviates Under the need the right of diazo conditions,-derivatives alkynes (Scheme allow 44for). anotherThis transformation approach towar is notds α surprising-oxo carbenoids since, thatas mentioned obviates the in previousneed of diazo sections,-derivatives alkynes (canScheme be considered 44). This transformation as super-stabilized is not 1,2 surprising-dicarbenes. since, In asthe mentioned presence ofin aprevious suitable sections,oxidant andalkynes a catalyst can be theirconsidered oxidation as super yields-stabilized α-oxo-gold 1,2 -carbenesdicarbenes. in anIn theoperationally presence of easy a suitable and environmentallyoxidant and a catalyst benign their fashion oxidation [133,134] yields. α Both-oxo -gold intermolecular carbenes in and an operationallyintramolecular easy oxidation and environmentallymethods of alkyne benign for transformation fashion [133,134] to oxo. Both-gold intermolecular carbene have been and Moleculesintramoleculardeveloped2019 [135], 24, 1036 oxidation. methods of alkyne for transformation to oxo-gold carbene have27 been of 36 developed [135].
Scheme 44. Retrosynthetic analysis of two potential routes to metal-carbenes from alkynes and Schemeketones. 44. 44. RetrosyntheticRetrosynthetic analysis analysis of two of two potential potential routes routes to metal-carbenes to metal-carbenes from alkynes from alkynes and ketones. and ketones. Among many reports, Zhang and coworkers reported one of the early examples of accessing gold Among carbenes many from reports, alkynes usingZhang an and external coworkers organic reported oxidant one [[136]138 of].. In the particular, particular, early examples a mild ofapproach accessing to αgold-oxo-oxo carbenes carbenes from involves alkynes Au-catalyzedAu using-catalyzed an external intermolecular organic oxidant oxidation [136] of . terminaltInerminal particular, alkynes a mild where approach pyridine to Nα--oxides-oxooxides carbenes act act as as theinvolves the oxidant oxidant Au (Scheme-catalyzed (Scheme 45). intermolecular It45 was). It proposed was proposed oxidation that after that of the terminal after initial the addition alkynes initial of where additionO-nucleophile pyridine of O- toNnucleophile-oxides Au-activated act to as Au alkyne the-activated oxidant of homopropargyl alkyne(Scheme of 45 homopropargyl). alcohol, It was proposedexpulsion alcohol thatof, pyridine expulsion after the and ofinitial back pyridine addition donation and of from back O- goldnucleophiledonation [139 ]from yields to gold Au the-activated [137] desired yields α alkyne-oxo the golddes of ired homopropargyl carbene α-oxo intermediates. gold carbene alcohol intermediates., The expulsion Au-carbene of The pyridine can Au then-carbene and undergo back can andonationthen insertion undergo from reaction angold insertion [137] with yields reaction the pendantthe des withired OH the α group, pendant-oxo gold yielding OH carbene group, dihydrofuran-3-ones intermediates. yielding dihydrofuran The Au in- goodcarbene-3-ones yields. can in Mesylthengood undergoyields. alcohol M anesyl is used insertion alcohol as an isreactionadditive used as with an in orderadditive the pendant to removein order OHthe to group, remove basic pyridine yielding the basic sidedihydrofuran pyridine product side that-3 -productones could in poisongoodthat couldyields. the Au-catalyst.poison Mesyl alcohol the Au Formation -iscatalyst. used as ofFormationanα additive-oxo gold of in α carbeneorder-oxo togold remove was carbene further the basic was supported furtherpyridine by supported side isolation product by of mesylatethatisolation could of as poisonmesylate an insertion the as Auan product. insertion-catalyst. produc Formationt. of α-oxo gold carbene was further supported by isolation of mesylate as an insertion product.
Scheme 45. α--OxoOxo gold carbenes via Au Au-catalyzed-catalyzed alkyne oxidation.oxidation. Scheme 45. α-Oxo gold carbenes via Au-catalyzed alkyne oxidation. 8. Alkynes as Carbonyls in the Rautenstrauch Rearrangement
An example that showcases how the utilization of alkynes can expand well established carbonyl chemistry (e.g., the Nazarov reaction) is the Rautenstrauch rearrangement. The Rautenstrauch rearrangement, a Pd-catalyzed variant of the Nazarov cyclization [140] was initially reported as a way to facilitate the transformation of 1-ethynyl-2-propenyl acetates to the corresponding 2-cyclopentenones (Scheme 46, left) [141]. Of crucial importance for this transformation is the presence of the acetate group in the starting enyne. First, it is the synergy between the roles of the acetate group and the alkyne moiety that allows for the “unmasking” of the alkyne as a carbonyl equivalent -for this unmasking to happen, the acetate has to undergo a 1,2 migration from its original position (the propargyl position) forming a cyclic intermediate. The latter is believed to give access to palladacarbene species from which a Nazarov-type cyclization onto the metal center is possible. Molecules 2019, 24, x FOR PEER REVIEW 27 of 35
8. Alkynes as Carbonyls in the Rautenstrauch Rearrangement An example that showcases how the utilization of alkynes can expand well established carbonyl chemistry (e.g., the Nazarov reaction) is the Rautenstrauch rearrangement. The Rautenstrauch rearrangement, a Pd-catalyzed variant of the Nazarov cyclization [138] was initially reported as a way to facilitate the transformation of 1-ethynyl-2-propenyl acetates to the corresponding 2- cyclopentenones (Scheme 46, left) [139]. Of crucial importance for this transformation is the presence of the acetate group in the starting enyne. First, it is the synergy between the roles of the acetate group and the alkyne moiety that allows for the “unmasking” of the alkyne as a carbonyl equivalent -for this unmasking to happen, the acetate has to undergo a 1,2 migration from its original position (the propargyl position) forming a cyclic intermediate. The latter is believed to give access to palladacarbene species from which a Nazarov-type cyclization onto the metal center is possible. Although the Ratenstrauch rearrangement offers an efficient route to disubstituted cyclopentenones, its biggest limitation is that only achiral cyclopentenones substituted at the 2 and 3 positions can be prepared through this method. The loss of chiral information from optically active starting materials has been proposed as experimental evidence that the metallocarbene-intermediate mechanism is operational [140–144]. These limitations were later overcome by the Toste group who developed an Au-catalyzed variant of the Rautenstrauch reaction. In this transformation, the substitution pattern of the accessible cyclopentanone products was expanded to the 3, 4, and 5 positions [145]. Furthermore, their approach allowed for the transfer of chiral information from the starting eneyne to the cyclopentanone (Scheme 46, right). This interesting result gave suggested that, under the gold catalysis, a different mechanism bypassing the metallocarbene may be operational. In order to explain the reaction’s stereoselectivity, it was proposed that C-C bond formation needs to happen prior to C-O scission on the stereogenic center, and that the transformation could pass Moleculesthrough2019 a transition, 24, 1036 state where the breaking C-O bond is orthogonal to the plane of the olefin during28 of 36 the Nazarov-type step.
Scheme 46. 46. PalladiumPalladium and and Gold Gold catalyzed catalyzed cycloisomerizations cycloisomerizations of 1- ofethynyl 1-ethynyl-2-propenyl-2-propenyl acetates acetates to 2- tocyclopentenones. 2-cyclopentenones.
9. ConvertingAlthough Alkynes the Ratenstrauch to Carbonyls rearrangement Via Pericyclic Reactions offers an efficient route to disubstituted cyclopentenones, its biggest limitation is that only achiral cyclopentenones substituted at the 2 and 3 Anionic oxy-Cope rearrangement of bis-alkynes produced by reaction of acetylides with benzil positions can be prepared through this method. The loss of chiral information from optically active proceeds below room temperature and continues via electrocyclic ring closure [146]. Computational starting materials has been proposed as experimental evidence that the metallocarbene-intermediate studies confirm significant barrier decrease for the rearrangement where the central C-C bond is mechanism is operational [142–146]. These limitations were later overcome by the Toste group who developed an Au-catalyzed variant of the Rautenstrauch reaction. In this transformation, the substitution pattern of the accessible cyclopentanone products was expanded to the 3, 4, and 5 positions [147]. Furthermore, their approach allowed for the transfer of chiral information from the starting eneyne to the cyclopentanone (Scheme 46, right). This interesting result gave suggested that, under the gold catalysis, a different mechanism bypassing the metallocarbene may be operational. In order to explain the reaction’s stereoselectivity, it was proposed that C-C bond formation needs to happen prior to C-O scission on the stereogenic center, and that the transformation could pass through a transition state where the breaking C-O bond is orthogonal to the plane of the olefin during the Nazarov-type step.
9. Converting Alkynes to Carbonyls Via Pericyclic Reactions Anionic oxy-Cope rearrangement of bis-alkynes produced by reaction of acetylides with benzil proceeds below room temperature and continues via electrocyclic ring closure [148]. Computational studies confirm significant barrier decrease for the rearrangement where the central C-C bond is weakened by the oxyanionic radical stabilizing groups. This cascade offers another entry point into carbonyl chemistry from bis-propargylic bis-alkynes. Because of the presence of two hydroxyl groups at the central bond of the bis-acetylenes, these compounds can be considered as a latent dicarbonyl functionality that is revealed by the oxy-Cope process in its bis-enolized state. As a result, one can couple the pericyclic step with typical carbonyl chemistry, such as intramolecular aldol condensations (Scheme 47). Molecules 2019, 24, x FOR PEER REVIEW 28 of 35 weakened by the oxyanionic radical stabilizing groups. This cascade offers another entry point into carbonyl chemistry from bis-propargylic bis-alkynes. Because of the presence of two hydroxyl groups at the central bond of the bis-acetylenes, these compounds can be considered as a latent dicarbonyl functionality that is revealed by the oxy-Cope processMolecules in2019 its, 24 bis, 1036-enolized state. As a result, one can couple the pericyclic step with typical carbonyl29 of 36 chemistry, such as intramolecular aldol condensations (Scheme 47).
SchemeScheme 47. 47. InsertionInsertion of of cyclobutene cyclobutene ring ring between between two two carbonyl carbonyl carbons carbons via via pericyclic pericyclic chemistry chemistry of alkynes.of alkynes.
10.10. Conclusions Conclusions WithWith broad broad strokes, strokes, we we have have illustrated illustrated a a few few opportunities opportunities that that arise arise from from the the synthetic synthetic equivalencyequivalency of of carbonyl carbonyl compounds compounds and and alkynes. alkynes. Considering Considering the large the largebody bodyof the ofpublished the published work, thework, over theview overview is certainly is certainly not comprehensive, not comprehensive, but we but hope we hopethat it that will it willserve serve as a ashelpful a helpful reminder reminder of thisof this useful useful connection connection between between two two of ofthe the most most common common and and important important functional functional groups groups of of organic organic chemistry.chemistry. Such Such connections connections should should not not be be overlooked overlooked in the search for efficient efficient synthetic strategies.strategies.
Funding:Funding: ThisThis research research was was funded funded by by the the National National Science Science Foundation Foundation ( (grantgrant number number:: CHE CHE-1800329).-1800329).
AcknowledgmentsAcknowledgments:: I.A.I.V.A. and andR.K. R.K.K.are grateful are grateful to the National to the NationalScience Foundation Science Foundation (CHE-1800329) (CHE-1800329) for support forof thissupport research. of this E.G. research.-R. is thankful E.G.-R. for is thankfulthe support for provided the support by providedCONACYT by and CONACYT to Joel M. and Smith to Joel for M. valuable Smith for valuable discussions. discussions. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflicts of interest. References and Notes References 1. Chernick, E.T.; Tykwinski, R.R. Carbon-rich nanostructures: The conversion of acetylenes into materials. 1. Chernick, E.T.; Tykwinski, R.R. Carbon-rich nanostructures: The conversion of acetylenes into materials. J. J. Phys. Org. Chem. 2013, 26, 742–749. [CrossRef] Phys. Org. Chem. 2013, 26, 742–749, doi:10.1002/poc.3160. 2. Diederich, F.; Stang, P.J.; Tykwinski, R.R. Acetylene Chemistry: Chemistry, Biology and Material Science; 2. Diederich, F.; Stang, P.J.; Tykwinski, R.R. Acetylene Chemistry: Chemistry, Biology and Material Science; Wiley- Wiley-VCH: Weinheim, Germany, 2005. VCH: Weinheim, Germany, 2005. 3. Alabugin, I.V.; Gonzalez-Rodriguez, E. Alkyne Origami: Folding Oligoalkynes into Polyaromatics. 3. Alabugin, I.V.; Gonzalez-Rodriguez, E. Alkyne Origami: Folding Oligoalkynes into Polyaromatics. Acc. Acc. Chem. Res. 2018, 51, 1206–1219. [CrossRef][PubMed] Chem. Res. 2018, 51, 1206–1219, doi:10.1021/acs.accounts.8b00026. 4. Alabugin, I.V.; Gold, B. “Two Functional Groups in One Package”: Using Both Alkyne π-Bonds in Cascade 4. Alabugin, I.V.; Gold, B. “Two Functional Groups in One Package”: Using Both Alkyne π-Bonds in Cascade Transformations. J. Org. Chem. 2013, 78, 7777–7784. [CrossRef][PubMed] Transformations. J. Org. Chem. 2013, 78, 7777–7784, doi:10.1021/jo401091w. 5. Zeidan, T.; Kovalenko, S.V.; Manoharan, M.; Clark, R.J.; Ghiviriga, I.; Alabugin, I.V. Triplet acetylenes 5. Zeidan, T.; Kovalenko, S.V.; Manoharan, M.; Clark, R.J.; Ghiviriga, I.; Alabugin, I.V. Triplet acetylenes as as Synthetic Equivalents of 1,2-Dicarbenes. Phantom n,π* State Controls Reactivity in Triplet Synthetic Equivalents of 1,2-Dicarbenes. Phantom n,π* State Controls Reactivity in Triplet Photocycloaddition. J. Am. Chem. Soc. 2005, 127, 4270–4285. [CrossRef][PubMed] Photocycloaddition. J. Am. Chem. Soc. 2005, 127, 4270–4285, doi:10.1021/ja043803l. 6. Senese, A.D.; Chalifoux, W.A. Nanographene and Graphene Nanoribbon Synthesis via Alkyne 6. Senese, A.D.; Chalifoux, W.A. Nanographene and Graphene Nanoribbon Synthesis via Alkyne Benzannulations. Molecules 2019, 24, 118. [CrossRef][PubMed] 7. Benzannulations.Hein, S.J.; Lehnherr, Molecules D.; Arslan, 2019 H.;, 24 Uribe-Romo,, 118, doi:10.3390/molecules24010118. F.J.; Dichtel, W.R. Alkyne Benzannulation Reactions for the Synthesis of Novel Aromatic Architectures. Acc. Chem. Res. 2017, 50, 2776–2788. [CrossRef][PubMed] 8. Trost, B.M.; Li, C.J. (Eds.) Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations; Wiley-VCH: Weinheim, Germany, 2014. 9. Scott, L.T.; Hashemi, M.M.; Meyer, D.T.; Warren, H.B. Corannulene. A convenient new synthesis. J. Am. Chem. Soc. 1991, 113, 7082–7084. [CrossRef] Molecules 2019, 24, 1036 30 of 36
10. Jordan, R.S.; Wang, Y.; McCurdy, R.D.; Yeung, M.T.; Marsh, K.L.; Khan, S.I.; Kaner, R.B.; Rubin, Y. Synthesis of Graphene Nanoribbons via the Topochemical Polymerization and Subsequent Aromatization of a Diacetylene Precursor. Chem 2016, 1, 78–90. [CrossRef] 11. Jordan, R.S.; Li, Y.L.; Lin, C.-W.; McCurdy, R.D.; Lin, J.B.; Brosmer, J.L.; Marsh, K.L.; Khan, S.I.; Houk, K.N.; Kaner, R.B. Synthesis of N = 8 Armchair Graphene Nanoribbons from Four Distinct Polydiacetylenes. J. Am. Chem. Soc. 2017, 139, 15878–15890. [CrossRef] 12. Goldfinger, M.B.; Swager, T.M. Fused Polycyclic Aromatics via Electrophile-Induced Cyclization Reactions: Application to the Synthesis of Graphite Ribbons. J. Am. Chem. Soc. 1994, 116, 7895–7896. [CrossRef] 13. Goldfinger, M.B.; Crawford, K.B.; Swager, T.M. Synthesis of Ethynyl-Substituted Quinquephenyls and Conversion to Extended Fused-Ring Structures. J. Org. Chem. 1998, 63, 1676–1686. [CrossRef] 14. Feng, X.; Pisula, W.; Müllen, K. From Helical to Staggered Stacking of Zigzag Nanographenes. J. Am. Chem. Soc. 2007, 129, 14116–14117. [CrossRef] 15. Mukherjee, A.; Pati, K.; Liu, R.-S. A Convenient Synthesis of Tetrabenzo-[de,hi,mn,qr]naphthacene from Readily Available 1,2-Di(phenanthren4-yl)ethyne. J. Org. Chem. 2009, 74, 6311–6314. [CrossRef] 16. Mohamed, R.K.; Mondal, S.; Guerrera, J.V.; Eaton, T.M.; Albrecht-Schmitt, T.E.; Shatruk, M.; Alabugin, I.V. Alkynes as Linchpins for the Additive Annulation of Biphenyls: Convergent Construction of Functionalized Fused Helicenes. Angew. Chem. Int. Ed. 2016, 55, 12054–12058. [CrossRef] 17. Tsvetkov, N.P.; Gonzalez-Rodriguez, E.; Hughes, A.; dos Passos Gomes, G.; White, F.D.; Kuriakose, F.; Alabugin, I.V. Radical Alkyne Peri-annulations for Synthesis of Functionalized Phenalenes, Benzanthrenes, and Olympicene. Angew. Chem. Int. Ed. 2018, 57, 3651–3655. [CrossRef] 18. Mohamed, R.; Mondal, S.; Gold, B.; Evoniuk, C.J.; Banerjee, T.; Hanson, K.; Alabugin, I.V. Alkenes as Alkyne Equivalents in Radical Cascades Terminated by Fragmentations: Overcoming Stereoelectronic Restrictions on Ring Expansions for the Preparation of Expanded Polyaromatics. J. Am. Chem. Soc. 2015, 137, 6335–6349. [CrossRef] 19. Yang, W.; Monteiro, J.H.S.K.; de Bettencourt-Dias, A.; Catalano, V.J.; Chalifoux, W.A. Pyrenes, Peropyrenes, and Teropyrenes: Synthesis, Structures, and Photophysical Properties. Angew. Chem. Int. Ed. 2016, 55, 10427–10430. [CrossRef] 20. Yang, W.; Longhi, G.; Abbate, S.; Lucotti, A.; Tommasini, M.; Villani, C.; Catalano, V.J.; Lykhin, A.O.; Varganov, S.A.; Chalifoux, W.A. Chiral Peropyrene: Synthesis, Structure, and Properties. J. Am. Chem. Soc. 2017, 139, 13102–13109. [CrossRef] 21. Yang, W.; Bam, R.; Catalano, V.J.; Chalifoux, W.A. Highly Regioselective Domino Benzannulation Reaction of Buta-1,3-diynes to Construct Irregular Nanographenes. Angew. Chem. Int. Ed. 2018, 57, 14773–14777. [CrossRef] 22. Ozaki, K.; Murai, K.; Matsuoka, W.; Kawasumi, K.; Ito, H.; Itami, K. One-Step Annulative π-Extension of Alkynes with Dibenzosiloles or Dibenzogermoles by Palladium/o-chloranil Catalysis. Angew. Chem. Int. Ed. 2017, 56, 1361–1364. [CrossRef] 23. Ito, H.; Ozaki, K.; Itami, K. Annulative π-Extension (APEX): Rapid Access to Fused Arenes, Heteroarenes, and Nanographenes. Angew. Chem. Int. Ed. 2017, 56, 11144–11164. [CrossRef] 24. Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das, P.J. All-Carbon Quaternary Stereogenic Centers in Acyclic Systems through the Creation of Several C–C Bonds per Chemical Step. J. Am. Chem. Soc. 2014, 136, 2682–2694. [CrossRef] 25. Das, J.P.; Chechik, H.; Marek, I. A unique approach to aldol products for the creation of all-carbon quaternary stereocentres. Nat. Chem. 2009, 1, 128–132. [CrossRef] 26. Umezu, S.; Gomes, G.; Yoshinaga, T.; Sakae, M.; Matsumoto, K.; Iwata, T.; Alabugin, I.V.; Shindo, M. Regioselective One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes to Ynolates. Angew. Chem. Int. Ed. 2016, 56, 1298–1302. [CrossRef] 27. DeKorver, K.A.; Li, H.; Lohse, A.G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R.P. Ynamides: A Modern Functional Group for the New Millennium. Chem. Rev. 2010, 110, 5064–5106. [CrossRef] 28. Beletskaya, I.P.; Nenajdenko, V.G. Towards the 150th anniversary of the Markovnikov’s rule. Angew. Chem. 2018.[CrossRef] 29. Beletskaya, I.P.; Ananikov, V.P. Transition-Metal-Catalyzed C−S, C−Se, and C−Te Bond Formation via Cross-Coupling and Atom-Economic Addition Reactions. Chem. Rev. 2011, 111, 1596–1636. [CrossRef] Molecules 2019, 24, 1036 31 of 36
30. Park, J.-W.; Kang, B.; Dong, V.M. Catalytic Alkyne Arylation Using Traceless Directing Groups. Angew. Chem. Int. Ed. 2018, 57, 13598–13602. [CrossRef] 31. Gilmore, K.; Alabugin, I.V. Cyclizations of Alkynes: Revisiting Baldwin’s Rules for Ring Closure. Chem. Rev. 2011, 111, 6513–6556. [CrossRef] 32. Hashmi, A.S.K. Gold-Catalyzed Organic Reactions. Chem. Rev. 2007, 10, 3180–3211. [CrossRef] 33. Dorel, R.; Echavarren, A.M. Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity. Chem. Rev. 2015, 115, 9028–9072. [CrossRef] 34. Arcadi, A. Alternative Synthetic Methods Through New Developments in Catalysis by Gold. Chem. Rev. 2008, 108, 3266–3325. [CrossRef] 35. Gorin, D.J.; Sherry, B.D.; Toste, F.D. Ligand Effects in Homogeneous Au Catalysis. Chem. Rev. 2008, 108, 3351–3378. [CrossRef] 36. Fürstner, A. Gold and platinum catalysis-a convenient tool for generating molecular complexity. Chem. Soc. Rev. 2009, 38, 3208–3221. [CrossRef] 37. Dudnik, A.; Chernyak, N.; Gevorgyan, V. Copper-, Silver-, and Gold Catalyzed Migratory Cycloisomerization Leading to Heterocyclic Five-Membered Rings. Aldrichim. Acta 2010, 43, 37–46. [CrossRef] 38. Perron, F.; Albizati, K.F. Chemistry of spiroketals. Chem. Rev. 1989, 89, 1617–1661. [CrossRef] 39. Teles, J.H. Hydration and Hydroalkoxylation of CC Multiple Bonds, in Modern Gold Catalyzed Synthesis; Hashmi, A.S.K., Toste, F.D., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2012; pp. 201–235. 40. Goodwin, J.A.; Aponick, A. Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes. Chem. Commun. 2015, 51, 8730–8741. [CrossRef] 41. Antoniotti, S.; Genin, E.; Michelet, V.; Genêt, J.-P. Highly efficient access to strained bicyclic ketals via gold-catalyzed cycloisomerization of bis-homopropargylic diols. J. Am. Chem. Soc. 2005, 127, 9976–9977. [CrossRef] 42. Fukuda, Y.; Utimoto, K. Effective transformation of unactivated alkynes into ketones or acetals with a gold(III) catalyst. J. Org. Chem. 1991, 56, 3729–3731. [CrossRef] 43. Teles, J.H.; Brode, S.; Chabanas, M. Cationic gold(I) complexes: Highly efficient catalysts for the addition of alcohols to alkynes. Angew. Chem. Int. Ed. 1998, 37, 1415–1418. [CrossRef] 44. Trost, B.M.; O’Boyle, B.M.; Hund, D. Total Synthesis and Stereochemical Assignment of (−)-Ushikulide, A. J. Am. Chem. Soc. 2009, 131, 15061–15074. [CrossRef] 45. Benson, S.; Collin, M.-P.; Arlt, A.; Gabor, B.; Goddard, R.; Fürstner, A. Second-generation total synthesis of Spirastrellolide F methyl ester: The alkyne route. Angew. Chem. Int. Ed. 2011, 50, 8739–8744. [CrossRef] [PubMed] 46. Tlais, S.F.; Dudley, G.B. Stereocontrol of 5,5-spiroketals in the synthesis of Cephalosporolide H epimers. Org. Lett. 2010, 12, 4698–4701. [CrossRef][PubMed] 47. Li, Y.; Zhou, F.; Forsyth, C.J. Gold(I)-catalyzed bis-spiroketalization: Synthesis of the trioxadispiroketal-containing A–D rings of Azaspiracid. Angew. Chem. Int. Ed. 2007, 46, 279–282. [CrossRef][PubMed] 48. Alabugin, I.V.; Gilmore, K. Finding the right path: Baldwin “Rules for Ring Closure” and stereoelectronic control of cyclizations. (Invited “Viewpoint”). Chem. Commun. 2013, 49, 11246–11250. [CrossRef][PubMed] 49. Gilmore, K.; Mohamed, R.K.; Alabugin, I.V. The Baldwin Rules: Revised and Extended. WIREs Comput. Mol. Sci. 2016, 6, 487–514. [CrossRef] 50. Baldwin, J.E.; Kruse, L.I. Rules for ring closure. Stereoelectronic control in the endocyclic alkylation of ketone enolates. J. Chem. Soc. Chem. Commun. 1977, 233–235. [CrossRef] 51. Baldwin, J.E.; Lusch, M.J. Rules for ring closure: Application to intramolecular aldol condensations in polyketonic substrates. Tetrahedron 1982, 38, 2939–2947. [CrossRef] 52. Alabugin, I.V.; Gilmore, K.; Manoharan, M. Rules for Anionic and Radical Ring Closure of Alkynes. J. Am. Chem. Soc. 2011, 133, 12608–12623. [CrossRef] 53. Gilmore, K.; Manoharan, M.; Wu, J.; Schleyer, P.v.R.; Alabugin, I.V. Aromatic Transition States in Non-Pericyclic Reactions: Anionic 5-Endo Cyclizations are Aborted Sigmatropic Shifts. J. Amer. Chem. Soc. 2012, 134, 10584–10594. [CrossRef] Molecules 2019, 24, 1036 32 of 36
54. Alabugin, I.V.; Manoharan, M.; Breiner, B.; Lewis, F. Control of Kinetics and Thermodynamics of [1,5]-Shifts by Aromaticity: A View Through the Prism of Marcus Theory. J. Am. Chem. Soc. 2003, 125, 9329–9342. [CrossRef][PubMed] 55. Alabugin, I.V.; Manoharan, M. Thermodynamic and Strain Effects in the Competition Between 5-Exo-dig and 6-Endo-Dig Cyclizations of Vinyl and Aryl Radicals. J. Am. Chem. Soc. 2005, 127, 12583–12594. [CrossRef] 56. Marvell, E.N.; Titterington, D. A novel synthesis of 4-cycloheptenones. Tetrahedron Lett. 1980, 21, 2123–2124. [CrossRef] 57. Eglinton, G.; Jones, E.R.H.; Whiting, M.C. Researches on acetylenic compounds. Part XXXVIII. A new method for the introduction of the acetylenic linkage. J. Chem. Soc. 1952, 2873–2882. [CrossRef] 58. Paul, R.; Tchelitcheff, S. Derivatives of 4-pentyn-1-ol. C. R. Acad. Sci. 1950, 230, 1872–1873. 59. Padwa, A.; Krumpe, K.E.; Weingarten, M.D. An Unusual Example of a 6-Endo-Dig Addition to an Unactivated Carbon-Carbon Triple Bond. J. Org. Chem. 1995, 60, 5595–5603. [CrossRef] 60. Trost, B.M.; Runge, T.A. Palladium-catalyzed 1,3-oxygen-to-carbon alkyl shifts. A cyclopentanone synthesis. J. Am. Chem. Soc. 1981, 103, 7559–7572. [CrossRef] 61. García, H.; Iborra, S.; Primo, J.; Miranda, M.A. 6-Endo-Dig vs. 5-Exo-Dig ring closure in o-hydroxyaryl phenylethynyl ketones. A new approach to the synthesis of flavones and aurones. J. Org. Chem. 1986, 51, 4432–4436. [CrossRef] 62. Castro, C.E.; Gaughan, E.G.; Owsley, D.C. Indoles, Benzofurans, Phthalides, and Tolanes via Copper(I) Acetylides. J. Org. Chem. 1968, 31, 4071–4078. [CrossRef] 63. Castro, C.E.; Havlin, R.; Honwad, V.K.; Malte, A.; Moje, S. Copper(I) substitutions. Scope and mechanism of cuprous acetylide substitutions. J. Am. Chem. Soc. 1969, 91, 6464–6470. [CrossRef] 64. Shvartsberg, M.S.; Vasilevsky, S.F.; Anisimova, T.V.; Gerasimov, V.A. Cyclization of acetylenylpyrazolecarboxylic acids. Russ. Chem. Bull. 1981, 30, 1071–1076. [CrossRef] 65. Vasilevsky, S.F.; Rubinshtein, E.M.; Shvartsberg, M.S. Condensation of N-methyl-4-iodopyra zolecarboxylic acids with copper acetylides. Russ. Chem. Bull. 1978, 30, 1021–1023. [CrossRef] 66. Vasilevsky, S.F.; Gerasimov, V.A.; Shvartsberg, M.S. Condensation of iodo-N-methylpyrazole-4-carboxylic acids with copper acetylides. Russ. Chem. Bull. 1981, 30, 683–685. [CrossRef] 67. Prikhodko, T.A.; Kurilenko, V.M.; Vasilevsky, S.F.; Shvartsberg, M.S. Synthesis and certain properties of acetylenylindoles. Russ. Chem. Bull. 1990, 39, 120–127. [CrossRef] 68. Vasilevsky, S.F.; Gold, B.; Mikhailovskaya, T.F.; Alabugin, I.V. Strain Control in Nucleophilic Cyclizations: Reversal of exo-Selectivity in Cyclizations of Hydrazides of Acetylenyl Carboxylic Acids by Annealing to a Pyrazole Scaffold. J. Phys. Org. Chem. 2012, 25, 998–1005. [CrossRef] 69. Vasilevsky, S.F.; Mikhailovskaya, T.F.; Mamatyuk, V.I.; Bogdanchikov, G.A.; Manoharan, M.; Alabugin, I.V. Tuning Selectivity of Anionic Cyclizations: Competition between 5-Exo- and 6-Endo-dig Closures of Hydrazides of o-Acetylenyl Benzoic Acids and Based-catalyzed Fragmentation/Recyclization of the Initial 5-Exo-Dig Products. J. Org. Chem. 2009, 74, 8106–8117. [CrossRef][PubMed] 70. Vasilevsky, S.F.; Baranov, D.S.; Mamatyuk, V.I.; Gatilov, Y.V.; Alabugin, I.V. An Unexpected Rearrangement which Disassembles Alkyne Moiety Through Formal Nitrogen Atom Insertion between Two Acetylenic Carbons and Related Cascade Transformations: New Approach to Sampagine Derivatives and Polycyclic Aromatic Amides. J. Org. Chem. 2009, 74, 6143–6150. [CrossRef] 71. Baranov, D.S.; Vasilevsky, S.F. Reaction of guanidine with peri-substituted (R-ethynyl)-9,10-anthraquinones bearing electron-donating substituents. Russ. Chem. Bull. 2010, 59, 1031–1034. [CrossRef] 72. Vasilevsky, S.F.; Baranov, D.S.; Mamatyuk, V.I.; Fadeev, D.S.; Gatilov, Y.V.; Stepanov, A.A.; Vasilieva, N.V.; Alabugin, I.V. Conformational Flexibility of Fused Tetracenedione Propellers Obtained from One-Pot Reductive Dimerization of Acetylenic Quinones. J. Org. Chem. 2015, 80, 1618–1631. [CrossRef] 73. Godoi, B.; Schumacher, R.F.; Zeni, G. Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes Containing Heteroatom. Chem. Rev. 2011, 111, 2937–2980. [CrossRef] 74. Byers, P.M.; Rashid, J.I.; Mohamed, R.K.; Alabugin, I.V. Polyaromatic Ribbon/Benzofuran Fusion via Consecutive Endo Cyclizations of Enediynes. Org. Lett. 2012, 14, 6032–6035. [CrossRef][PubMed] 75. Hirano, K.; Inaba, Y.; Takahashi, N.; Shimano, M.; Oishi, S.; Fujii, N.; Ohno, H. Direct Synthesis of Fused Indoles by Gold-Catalyzed Cascade Cyclization of Diynes. J. Org. Chem. 2011, 76, 1212–1227. [CrossRef] [PubMed] Molecules 2019, 24, 1036 33 of 36
76. Asiri, A.M.; Hashmi, A.S.K. Gold-catalysed reactions of diynes. Chem. Soc. Rev. 2016, 45, 4471–4503. [CrossRef][PubMed] 77. Gomes, G.P.; Alabugin, I.V. Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization. J. Am. Chem. Soc. 2017, 139, 3406–3416. [CrossRef][PubMed] 78. Cai, T.; Yang, Y.; Li, W.-W.; Qin, W.-B.; Wen, T.-B. Efficient endo Cycloisomerization of Terminal Alkynols Catalyzed by a New Ruthenium Complex with 8-(Diphenylphosphino)quinoline Ligand and Mechanistic Investigation. Chem. Eur. J. 2018, 24, 1606–1618. [CrossRef] 79. Ferrier, R.J. Unsaturated carbohydrates. Part 21. A carbocyclic ring closure of a hex-5-enopyranoside derivative. J. Chem. Soc. Perkin Trans. 1 1979, 1455–1458. [CrossRef] 80. Petasis, N.A.; Lu, S.-P. STEREOCONTROLLED SYNTHESIS OF SUBSTITUTED TETRAHYDROPYRANS FROM 1,3-DIOXAN-4-ONES. Tetrahedron Lett. 1996, 37, 141–144. [CrossRef] 81. Smith III, A.B.; Fox, R.J.; Razler, T.M. Evolution of the Petasis−Ferrier Union/Rearrangement Tactic: Construction of Architecturally Complex Natural Products Possessing the Ubiquitous cis-2,6-Substituted Tetrahydropyran Structural Element. Acc. Chem. Res. 2008, 41, 675–687. [CrossRef] 82. For selected applications of the Petasis–Ferrier rearrangement in the total synthesis of natural products, see: 83. Smith, A.B., III; Bosanac, T.; Basu, K. Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing Metathesis. J. Am. Chem. Soc. 2009, 131, 2348–2358. [CrossRef] 84. Smith, A.B., III; Simov, V. Total Synthesis of the Marine Natural Product (−)-Clavosolide, A. A Showcase for the Petasis—Ferrier Union/Rearrangement Tactic. Org. Lett. 2006, 8, 3315–3318. [CrossRef] 85. Smith III, A.B.; Mesaros, E.F.; Meyer, E.A. Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a Petasis−Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strategy. J. Am. Chem. Soc. 2006, 128, 5292–5299. [CrossRef] 86. Bae, H.J.; Jeong, W.; Lee, J.H.; Rhee, Y.H. Gold(I)-Catalyzed Access to Tetrahydropyran-4-ones from 4 (Alkoxyalkyl)oxy-1-butynes: Formal Catalytic Petasis–Ferrier Rearrangement. Chem. Eur. J. 2011, 17, 1433–1436. [CrossRef] 87. Kim, C.; Bae, H.J.; Lee, J.H.; Jeong, W.; Kim, H.; Sampath, V.; Rhee, Y.H. Formal Alkyne Aza-Prins Cyclization: Gold(I)-Catalyzed Cycloisomerization of Mixed N,O-Acetals Generated from Homopropargylic Amines to Highly Substituted Piperidines. J. Am. Chem. Soc. 2009, 131, 14660–14661. [CrossRef] 88. Cui, L.; Li, C.; Zhang, L. A Modular, Efficient, and Stereoselective Synthesis of Substituted Piperidin-4-ols. Angew. Chem. Int. Ed. 2010, 49, 9178–9181. [CrossRef] 89. Liu, L.; Zhang, L. Access to Electron-Rich Arene-Fused Hexahydroquinolizinones through a Gold-Catalysis-Initiated Cascade Process. Angew. Chem. Int. Ed. 2012, 51, 7301–7304. [CrossRef] 90. Sze, E.M.L.; Rao, W.; Koh, M.J.; Chan, P.W.H. Gold-Catalyzed Tandem Intramolecular Heterocyclization/Petasis–Ferrier Rearrangement of 2-(Prop-2-ynyloxy)benzaldehydes as an Expedient Route to Benzo[b]oxepin-3(2 H)-ones. Chem. Eur. J. 2011, 17, 1437–1441. [CrossRef] 91. Gade, A.B.; Patil, N.T. Gold(I)-Catalyzed Hydroaminaloxylation and Petasis–Ferrier Rearrangement Cascade of Aminaloalkynes. Org. Lett. 2016, 18, 1844–1847. [CrossRef] 92. Aaseng, J.E.; Iqbal, N.; Sperger, C.A.; Fiksdahl, A. 3-Fluorotetrahydropyran-4-one derivatives from homopropargyl acetal. J. Fluorine Chem. 2014, 161, 142–148. [CrossRef] 93. Jiang, G.J.; Wang, Y.; Yu, X.Z. DFT Study on the Mechanism and Stereochemistry of the Petasis–Ferrier Rearrangements. J. Org. Chem. 2013, 78, 6947–6955. [CrossRef] 94. Pati, K.; Alabugin, I.V. Synthesis of Substituted Biaryls Through Gold-Catalyzed Petasis-Ferrier Rearrangement of Propargyl Ethers. Eur. J. Org. Chem. 2014, 19, 3986–3990. [CrossRef] 95. Hassall, C.H. Baeyer-Villiger Oxidation of Aldehydes and Ketones. In Organic Reactions; John Wiley & Sons, Inc.: New York, NY, USA, 1957; Volume 9. [CrossRef] 96. Renz, M.; Meunier, B. 100 Years of Baeyer–Villiger Oxidations. Eur. J. Org. Chem. 1999, 737–750. [CrossRef] 97. Strukul, G. Transition Metal Catalysis in the Baeyer–Villiger Oxidation of Ketones. Angew. Chem. Int. Ed. 1998, 37, 1198–1209. [CrossRef] 98. Yaremenko, I.A.; Vil’, V.A.; Demchuk, D.V.; Terent’ev, A.O. Rearrangements of organic peroxides and related processes. Beilstein J. Org. Chem. 2016, 12, 1647–1748. [CrossRef] Molecules 2019, 24, 1036 34 of 36
99. Ten Brink, G.J.; Arends, I.W.C.E.; Sheldon, R.A. The Baeyer−Villiger Reaction: New Developments toward Greener Procedures. Chem. Rev. 2004, 104, 4105–4124. [CrossRef] 100. Rioz-Martínez, A.; Cuetos, A.; Rodríguez, C.; de Gonzalo, G.; Lavandera, I.; Fraaije, M.W.; Gotor, V. Dynamic Kinetic Resolution of α-Substituted β-Ketoesters Catalyzed by Baeyer–Villiger Monooxygenases: Access to Enantiopure α-Hydroxy Esters. Angew. Chem. Int. Ed. 2011, 50, 8387–8390. [CrossRef] 101. Criegee, R. Die Umlagerung der Dekalin-peroxydester als Folge von kationischem Sauerstoff. Justus Liebigs Ann. Chem. 1948, 560, 127–135. [CrossRef] 102. Gomes, G.d.P.; Vil, V.; Terent’ev, A.; Alabugin, I.V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 6783–6791. [CrossRef] 103. Crudden, C.M.; Chen, A.C.; Calhoun, L.A. A Demonstration of the Primary Stereoelectronic Effect in the Baeyer–Villiger Oxidation of α-Fluorocyclohexanones. Angew. Chem. Int. Ed. 2000, 39, 2851–2855. [CrossRef] 104. Chandrasekhar, S.; Roy, C.D. Conformationally restricted Criegee intermediates: Evidence for formation and stereoelectronically controlled fragmentation. J. Chem. Soc. Perkin Trans. 2 1994, 2141–2143. [CrossRef] 105. Alabugin, I.V.; Gomes, G.d.P.; Miguel, A.A. Hyperconjugation. WIREs Comput. Mol. Sci. 2018, e1389. [CrossRef] 106. Vil’, V.A.; Gomes, G.d.P.; Bityukov, O.V.; Lyssenko, K.A.; Nikishin, G.I.; Alabugin, I.V.; Terent’ev, A.O. Interrupted Baeyer–Villiger Rearrangement: Building A Stereoelectronic Trap for the Criegee Intermediate. Angew. Chem. Int. Ed. 2018, 57, 3372–3376. [CrossRef] 107. Noyori, R.; Sato, T.; Kobayashi, H. Remote substituent effects in the Baeyer-Villiger oxidation. I. through-bond γ substituent effect on the regioselectivity. Tetrahedron Lett. 1980, 21, 2569–2572. [CrossRef] 108. Noyori, R.; Kobayashi, H.; Sato, T. Remote substituent effects in the Baeyer-Villiger oxidation. II. regioselection based on the hydroxyl group orientation in the tetrahedral intermediate. Tetrahedron Lett. 1980, 21, 2573–2576. [CrossRef] 109. Of course, substituent migrations from an sp2-hybridized carbon (usually, a carbonyl) to a nitrogen with a good leaving group are known as the part of Curtius, Schmidt, and Lossen rearrangements. 110. Baranov, D.; Gold, B.; Vasilevsky, S.; Alabugin, I.V. Divergent Cyclizations of 1-R-Ethynyl-9,10-anthraquinones: Use of Thiourea as a “S2-” Equivalent in an “Anchor-Relay” Addition Mediated by Formal C-H Activation. J. Org. Chem. 2013, 78, 2074–2082. [CrossRef] 111. Baranov, D.S.; Vasilevsky, S.F.; Gold, B.; Alabugin, I.V. Urea as a Solvent and Reagent for the Addition/Cyclization/Fragmentation Cascades Leading to 2-R-7H-dibenzo[de,h]quinolin-7- one Analogues of Aporphinoid Alkaloids. RSC Adv. 2011, 1, 1745–1750. [CrossRef] 112. Heathcock, C.H. The Aldol Reactions. In Comprehensive Organic Synthesis; Trost, B.M., Fleming, I., Heathcock, C.H., Eds.; Pergamon: Oxford, UK, 1991; Volume 2, pp. 99–181. 113. Palomo, C.; Oiarbide, M.; García, J.M. The Aldol Addition Reaction: An Old Transformation at Constant Rebirth. Chem. Eur. J. 2002, 8, 36–44. [CrossRef] 114. Rhee, J.U.; Krische, M.J. Alkynes as Synthetic Equivalents to Stabilized Wittig Reagents: Intra- and Intermolecular Carbonyl Olefinations Catalyzed by Ag(I), BF3, and HBF4. Org. Lett. 2005, 7, 2493–2495. [CrossRef] 115. Jin, T.; Yang, F.; Liu, C.; Yamamoto, Y. TfOH-catalyzed intramolecular alkyne–ketone metathesis leading to highly substituted five-membered cyclic enones. Chem. Commun. 2009, 3533–3535. [CrossRef] 116. Kurtz, K.C.M.; Hsung, P.R.; Zhang, Y. A Ring-Closing Yne-Carbonyl Metathesis of Ynamides. Org. Lett. 2006, 8, 231–234. [CrossRef] 117. Balog, A.; Geib, S.J.; Curran, D.P. Additive and Medium Effects on Lewis Acid-Promoted Cationic.pi.-Cyclizations of Alkenyl- and Alkynylcyclopentane-1,3-diones. J. Org. Chem. 1995, 60, 345–352. [CrossRef] 118. For a detailed review that outlines many mechanistic scenarios, see: 119. Yamamoto, Y.; Gridnev, I.D.; Patil, N.T.; Jin, T. Alkyne activation with Brønsted acids, iodine, or gold complexes, and its fate leading to synthetic application. Chem. Commun. 2009, 5075–5087. [CrossRef] 120. Curini, M.; Epifano, F.; Maltese, F.; Rosati, O. Ytterbium Triflate Promoted Coupling Reaction Between Aryl Alkynes and Aldehydes. Synlett 2003, 552–554. [CrossRef] 121. Saito, A.; Umakoshi, M.; Yagyu, N.; Hanazawa, Y. Novel One-Pot Approach to Synthesis of Indanones through Sb(V)-Catalyzed Reaction of Phenylalkynes with Aldehydes. Org. Lett. 2008, 10, 1783–1785. [CrossRef] Molecules 2019, 24, 1036 35 of 36
122. Viswanathan, G.S.; Lee, C.-J. A highly stereoselective, novel coupling reaction between alkynes and aldehydes. Tetrahedron Lett. 2002, 43, 1613–1615. [CrossRef] 123. González-Rodríguez, C.; Escalante, L.; Varela, J.A.; Castedo, L.; Saá, C. Brønsted Acid-Promoted Intramolecular Carbocyclization of Alkynals Leading to Cyclic Enones. Org. Lett. 2009, 11, 1531–1533. [CrossRef] 124. Sperger, C.; Fiksdahl, A. Gold-Catalyzed Cyclizations of 1,6-Diynes. Org. Lett. 2009, 11, 2449–2452. [CrossRef] 125. Trost, B.M.; Rudd, M.T. A Mechanistic Dichotomy in Ruthenium-Catalyzed Propargyl Alcohol Reactivity: A Novel Hydrative Diyne Cyclization. J. Am. Chem. Soc. 2003, 125, 11516–11517. [CrossRef] 126. Roy, S.; Davydova, M.P.; Pal, R.; Gilmore, K.; Tolstikov, G.A.; Vasilevsky, S.F.; Alabugin, I.V. Dissecting Alkynes: Full Cleavage of Polarized C≡C Moiety via Sequential Bis-Michael Addition/Retro-Mannich Cascade. J. Org. Chem. 2011, 76, 7482. [CrossRef] 127. Baldwin, J.E. Rules for ring closure. J. Chem. Soc. Chem. Commun. 1976, 734–736. [CrossRef] 128. Alabugin, I.V. Stereoelectronic Effects: A Bridge between Structure and Reactivity; John Wiley & Sons, Ltd.: Chichester, UK, 2016. [CrossRef] 129. Vasilevsky, S.F.; Davydova, M.P.; Mamatyuk, V.I.; Pleshkova, N.V.; Fadeev, D.S.; Alabugin, I.V. Reaction of a,b-alkynylketones with b-amino alcohols: Pseudoephedrine assisted cleavage of triple bond via formal internal redox process. Mendeleev Commun. 2015, 25, 377–379. [CrossRef] 130. Vasilevsky, S.F.; Davydova, M.P.; Mamatyuk, V.I.; Tsvetkov, N.; Hughes, A.; Baranov, D.S.; Alabugin, I.V. Full Cleavage of C≡C Bond in Electron-Deficient Acetylenes via Reaction with Ethylenediamine. Aust. J. Chem. 2017, 70, 421–429. [CrossRef] 131. Davydova, M.P.; Vasilevsky, S.F.; Nenajdenko, V.G. Reaction of trifluoroacetyl acetylenes with β-amino alcohols. Synthesis of enaminoketones and unusual fragmentation. J. Fluorine Chem. 2016, 190, 61–67. [CrossRef] 132. Druzhinin, S.V.; Balenkova, E.S.; Nenajdenko, V.G. Recent advances in the chemistry of α,β-unsaturated trifluoromethylketones. Tetrahedron 2007, 63, 7753–7808. [CrossRef] 133. Doyle, M.P.; McKervey, M.A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley: New York, NY, USA, 1998. 134. Barluenga, J.; Rodríguez, F.; Fañanás, F.J.; Flórez, J. Metal Carbenes in Organic Synthesis. In Topics in Organometallic Chemistry; Dötz, K.H., Ed.; Springer: Berlin, Germany, 2004; Volume 13, pp. 59–122. [CrossRef] 135. Blanco Jaimes, M.C.; Hashmi, A.S.K. Gold-Catalyzed Oxygen- Atom Transfer to Alkynes. In Modern Gold Catalyzed Synthesis; Hashmi, A.S.K., Toste, F.D., Eds.; Wiley-VCH: Weinheim, Germany, 2012; pp. 273–296. 136. Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L. Au-Catalysed oxidative cyclisation. Chem. Soc. Rev. 2016, 45, 4448–4458. [CrossRef] 137. Zhang, L. A non-diazo approach to α-oxo gold carbenes via gold-catalyzed alkyne oxidation. Acc. Chem. Res. 2014, 47, 877–888. [CrossRef][PubMed] 138. Ye, L.; Cui, L.; Zhang, G.; Zhang, L. Alkynes as Equivalents of α-Diazo Ketones in Generating α-Oxo Metal Carbenes: A Gold-Catalyzed Expedient Synthesis of Dihydrofuran-3-ones. J. Am. Chem. Soc. 2010, 132, 3258–3259. [CrossRef][PubMed] 139. Benitez, D.; Shapiro, N.D.; Tkatchouk, E.; Wang, Y.; Goddard, W.A., III; Toste, F.D. A Bonding Model for Gold(I) Carbene Complexes. Nat. Chem. 2009, 1, 482–486. [CrossRef][PubMed] 140. Santelli-Rouvier, E.J.; Santelli, M. The Nazarov Cyclisation. Synthesis 1983, 6, 429–442. [CrossRef] 141. Rautenstrauch, V. 2-Cyclopentenones from 1-ethynyl-2-propenyl acetates. J. Org. Chem. 1984, 49, 950–952. [CrossRef] 142. Mainetti, E.; Mouries, V.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J. The Effect of a Hydroxy Protecting Group on the PtCl2-Catalyzed Cyclization of Dienynes—A Novel, Efficient, and Selective Synthesis of Carbocycles. Angew. Chem. Int. Ed. 2002, 41, 2132–2135. [CrossRef] 143. Miki, K.; Ohe, K.; Uemura, S. Ruthenium-Catalyzed Cyclopropanation of Alkenes Using Propargylic Carboxylates as Precursors of Vinylcarbenoids. J. Org. Chem. 2003, 68, 8505–8513. [CrossRef] 144. Nevado, C.; Cardenas, D.J.; Echavarren, A.M. Reaction of Enol Ethers with Alkynes Catalyzed by Transition Metals: 5exo-dig versus 6endo-dig Cyclizations via Cyclopropyl Platinum or Gold Carbene Complexes. Chem. Eur. J. 2003, 9, 2627–2635. [CrossRef][PubMed] 145. Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. Platinum- and Gold-Catalyzed Cycloisomerization Reactions of Hydroxylated Enynes. J. Am. Chem. Soc. 2004, 126, 8654–8655. [CrossRef] Molecules 2019, 24, 1036 36 of 36
146. Harrak, Y.; Blasykowski, C.; Fensterbank, L.; Malacria, M. PtCl2-Catalyzed Cycloisomerizations of 5-En-1-yn-3-ol Systems. J. Am. Chem. Soc. 2004, 126, 8656–8657. [CrossRef][PubMed] 147. Shi, X.; Gorin, D.J.; Toste, F.D. Synthesis of 2-Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch Rearrangement. J. Am. Chem. Soc. 2005, 127, 5802–5803. [CrossRef][PubMed] 148. Pal, R.; Clark, R.J.; Manoharan, M.; Alabugin, I.V. Fast Oxy-Cope Rearrangements of Bis-alkynes: Competition with Central C−C Bond Fragmentation and Incorporation in Tunable Cascades Diverging from a Common Bis-allenic Intermediate. J. Org. Chem. 2010, 75, 8689–8692. [CrossRef]
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