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Alkynes As Synthetic Equivalents of Ketones and Aldehydes: a Hidden Entry Into Carbonyl Chemistry

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Alkynes As Synthetic Equivalents of Ketones and Aldehydes: a Hidden Entry Into Carbonyl Chemistry molecules 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 Molecules 2019, 24, 1036; doi:10.3390/molecules24061036 www.mdpi.com/journal/molecules Molecules 2019, 24, 1036 2 of 36 Molecules 2019, 24, x FOR PEER REVIEW 2 of 35 whilethe othe ther one other is formally one is formally reduced, reduced, hydration hydration is obviously is obviously not a redox not process, a redox and process, water andis neither water an is oxidantneither annor oxidant a reductant. nor a reductant. 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 fromformal a formal point pointof view, of view, it can it canalso also give give access access to tocarbonyl carbonyl derivatives derivatives if if the intermediate vinylvinyl anion anion is is trapped trapped by by a reaction a reaction with with a heteroatomic a heteroatomic electrophile electrophile or an oxidantor 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 an It is additional worth noting oxidant. that reactions It is worth of alkynes noting with that heteroatomic reactions electrophilesof 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. Molecules 2019, 24, 1036 3 of 36 Molecules 2019, 24, x FOR PEER REVIEW 3 of 35 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− 20alkynes 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. Molecules 2019, 24, 1036 4 of 36 Molecules 2019, 24, x FOR PEER REVIEW 4 of 35 Scheme 3. Thermodynamics of enol and enamine formation from an alkyne and aa ketone.ketone. 1.2. Low Polarization
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