Alkynes as Synthetic Equivalents of Ketones and Aldehydes: A Hidden Entry into Carbonyl Chemistry

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: acetals; aldehydes; alkynes; carbonyl compounds; catalysis; condensations; cyclizations; electronic structure; ketones; nucleophilic addition; rearrangements.

Scheme 1

Markovnikov (top) and anti-Markovnikov (bottom) hydration of alkynes converts them into either ketones or aldehydes, respectively.

Scheme 2

Synthetic equivalency of alkynes and carbonyl compounds.

Scheme 3

Thermodynamics of enol and enamine formation from an alkyne and a ketone.

Scheme 4

Each alkyne opens not one but two doors into carbonyl chemistry.

Scheme 5

Synthesis of α-arylphenones and α,α-diarylketones through directed catalytic alkyne arylations.

Scheme 6

Comparison of alkynes and carbonyls as precursors for vinyl ethers.

Scheme 7

Comparison of alkynes and ketones in intramolecular spiro-ketalizations.

Scheme 8

Utimoto’s Au-catalized acetal formation from alkyne starting materials.

Scheme 9

Dudley’s intramolecular bishydroxylation of alkynes.

Scheme 10

Gold catalyzed bis-alkoxylation of alkynes in the synthesis of spiroketals by Forsyth and coworkers.

Scheme 11

Thermodynamics of hemiacetal/vinyl ether transformation can be unfavorable.

Scheme 12

Top: Two patterns (C-enolexo and C-enolendo) for exo-tet cyclizations. Bottom: Although cyclizations of enolates can occur at either the carbon or oxygen, this process is controlled by stereoelectronic factors (see discussion in text).

Scheme 13

Approaches to selective exo-dig and endo-dig cyclizations can be accomplished by using either a classic anionic or a Lewis acid-mediated (the so-called “Electrophile-Promoted Nucleophilic Closure (EPNC) processes) pathways with different stereoelectronic requirements.

Scheme 14

Potential energy surfaces for selected exo-dig and endo-dig anionic cyclizations of N- (blue dashed, italic) and O- (violet dashed, non-italics) anions with terminal alkynes.

Scheme 15

Two approaches to regioselective alkyne/carbonyl transformations.

Scheme 16

Base promoted 5-exo-dig cyclizations of primary and secondary alcohols onto terminal triple bonds.

Scheme 17

The solvent dependent cyclizations of oxygen anions with three sp²-atoms in the linking chain.

Scheme 18

Top: The cyclization of o-carboxy acetylenes, formed via cuprate addition, prefers the 5-exo-dig pathway. Bottom: Regioselective 6-endo-dig cyclizations of acetylenic carboxylates at five-membered rings.

Scheme 19

Control of N-nucleophilic closures by changing alkyne electronics.

Scheme 20

Diverging mechanistic pathways in reactions of peri-substituted acetylenyl-9,10-anthraquinones and guanidine.

Scheme 21

Reductive dimerization of ethynyl anthraquinones.

Scheme 22

“The LUMO Umpolung”: coordination of a Lewis acid at the alkyne changes the LUMO symmetry and deactivates a destabilizing secondary orbital interaction that disfavors endo-dig cyclizations.

Scheme 23

The formal “all-endo” metal-assisted cyclization cascade is initiated by a 5-endo-dig closure followed by two 6-endo-dig closures.

Scheme 24

Cycloisomerizations of terminal alkynols under Ru-catalysis.

Scheme 25

Two possible stabilization patterns for the Petasis-Ferrier rearrangement.

Scheme 26

Au-catalyzed versions of the Petasis-Ferrier reaction. Top: cation stabilization by an endocyclic donor assists transformation of homopropargylic esters and amides into heterocyclic products. Bottom: cation stabilization by an exocyclic donor assists transformation of ortho-alkynyl benzyl methyl ethers into naphthalenes.

Scheme 27

1,2-shifts in the Baeyer-Villiger and aza-Baeyer-Villiger reactions.

Scheme 28

Alkyne “disassembly” via carbonyl cascades leading to nitrogen insertion between alkyne carbons. Note that the fragmentation−recyclization sequence is analogous to the Petasis−Ferrier rearrangement whereas the [1,2]-shift can be considered as an aza-analogue of the Baeyer-Villiger reaction.

Scheme 29

Synthesis of cyclic enones from dicarbonyls and diynes.

Scheme 30

Use of alkynes as enolate equivalents in the formal aldol condensations with aldehydes (“alkyne-carbonyl metathesis”).

Scheme 31

Suggested mechanism of the alkyne-carbonyl “aldol condensations”.

Scheme 32

Au-catalyzed hydrative cyclizations of diynes.

Scheme 33

Ruthenium catalyzed hydrative cyclization of diynes.

Scheme 34

Use of alkyne high energy and cross-over to the “carbonyl reaction field” for the full disassembly of triple bond.

Scheme 35

Complete scission of the triple bond in keto alkynes mediated by the retro-Mannich reaction.

Scheme 36

Variations of retro-Mannich-mediated alkyne fragmentations with the 2nd nucleophilic attack being intermolecular.

Scheme 37

Reaction of α-alkynylketones with aminoalcohols.

Scheme 38

Reaction of α-ketoacetylenes with pseudoephedrine.

Scheme 39

C≡C bond scission in 1- and 2-phenylethynyl-9,10-anthraquinones.

Scheme 40

Expanded alkyne fragmentation reactions to compounds containing varied functionalities.

Scheme 41

Alkyne fragmentation reactions in pyridine containing substrates.

Scheme 42

Retrosynthetic equivalency of alkynes and methyl group (top) and protected carboxylic acids (bottom).

Scheme 43

Reaction of CF₃-ynones with amino alcohols.

Scheme 44

Retrosynthetic analysis of two potential routes to metal-carbenes from alkynes and ketones.

Scheme 45

α-Oxo gold carbenes via Au-catalyzed alkyne oxidation.

Scheme 46

Palladium and Gold catalyzed cycloisomerizations of 1-ethynyl-2-propenyl acetates to 2-cyclopentenones.

Scheme 47

Insertion of cyclobutene ring between two carbonyl carbons via pericyclic chemistry of alkynes.