Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)−H] Functionalization of Ynones

A new approach for the cyclopenta[b]annulation of heteroarenes through metal‐free and directing‐group‐free γ′[C(sp³)?H] functionalization and intramolecular hydroalkylation of ynones has been developed. In an unprecedented event, nucleophilic addition of an organophosphine to the designed ynones triggers γ′[C(sp³)?H] functionalization, leading to the formation of heteroaryl‐based ortho‐quinodimethane (oQDM) intermediates that undergo carbocyclization to provide cyclopentannulated heteroarenes in good yields and excellent stereoselectivities. Deuterium‐labeling experiments substantiated the proposed reaction mechanism as well as the speculated epimerization.     

1,3‐O‐Transposition or Trisubstituted Z‐Enol Ester? A Comparative Study of Reactions of Ynones

Ynones are useful substrates for transition‐metal‐mediated synthesis. The Au^I‐catalyzed 1,3‐O‐transposition is an important reaction of ynones. Recently, an efficient Cu^I‐catalyzed synthesis of trisubstituted Z‐enol esters via interrupting the traditional 1,3‐O‐transposition reaction of ynones was reported by Zhu's group. Herein, density functional theory studies disclosed that the hydrogen bond formed by carboxylic acid plays an important role for the reactivity and selectivity in this novel reaction. A qualitative rule was also found to explain the substituent effect in the ynone substrate, and this is consistent with experiments. The Au^I‐catalyst and Cu^I‐catalyst were further compared to interpret the essential cause of why the Au^I‐catalyst prefers the 1,3‐O‐transpostion reaction. These conclusions might be helpful for the rational design of reactions of ynones.     

Zinc‐Catalyzed Dehydrogenative Cross‐Coupling of Terminal Alkynes with Aldehydes: Access to Ynones

Because of the lack of redox ability, zinc has seldom been used as a catalyst in dehydrogenative cross‐coupling reactions. Herein, a novel zinc‐catalyzed dehydrogenative C(sp²)? H/C(sp)? H cross‐coupling of terminal alkynes with aldehydes was developed, and provides a simple way to access ynones from readily available materials under mild reaction conditions. Good reaction selectivity can be achieved with a 1:1 ratio of terminal alkyne and aldehyde. Various terminal alkynes and aldehydes are suitable in this transformation.     

Palladium‐ and Solvent‐Free Synthesis of Ynones by Copper(I)‐Catalyzed Acylation of Terminal Alkynes with Acyl Chlorides under Aerobic Conditions

Air‐stable Cu^I/cryptand‐22 complex was found to be a highly active catalyst for the solvent‐free cross‐coupling reaction of terminal alkynes with different acyl chlorides in the presence of Et₃N as base to give the corresponding ynones in quantitative yields.     

Theory of the Formation and Decomposition of N‐Heterocyclic Aminooxycarbenes through Metal‐Assisted [2+3]‐Dipolar Cycloaddition/Retro‐Cycloaddition

The theoretical background of the formation of N‐heterocyclic oxadiazoline carbenes through a metal‐assisted [2+3]‐dipolar cycloaddition (CA) reaction of nitrones R¹CH?N(R²)O to isocyanides C?NR and the decomposition of these carbenes to imines R¹CH?NR² and isocyanates O?C?NR is discussed. Furthermore, the reaction mechanisms and factors that govern these processes are analyzed in detail. In the absence of a metal, oxadiazoline carbenes should not be accessible due to the high activation energy of their formation and their low thermodynamic stability. The most efficient promotors that could assist the synthesis of these species should be “carbenophilic” metals that form a strong bond with the oxadiazoline heterocycle, but without significant involvement of π‐back donation, namely, Au^I, Au^III, Pt^II, Pt^IV, Re^V, and Pd^II metal centers. These metals, on the one hand, significantly facilitate the coupling of nitrones with isocyanides and, on the other hand, stabilize the derived carbene heterocycles toward decomposition. The energy of the LUMO_CNR and the charge on the N atom of the C?N group are principal factors that control the cycloaddition of nitrones to isocyanides. The alkyl‐substituted nitrones and isocyanides are predicted to be more active in the CA reaction than the aryl‐substituted species, and the N,N,C‐alkyloxadiazolines are more stable toward decomposition relative to the aryl derivatives.     

Selective Carbonyl−C(sp3) Bond Cleavage To Construct Ynamides,Ynoates, and Ynones by Photoredox Catalysis

Carbon–carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl−C(sp³) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl‐radical‐enabled carbonyl−C(sp³) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β‐carbonyl alkoxyl radical generation from β‐carbonyl alcohols, including alcohols with high redox potential ( >2.2 V vs. SCE in MeCN). β‐Amide, β‐ester, and β‐ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio‐ and chemoselectivity under mild reaction conditions.     

Selective Carbonyl−C(sp3) Bond Cleavage To Construct Ynamides,Ynoates, and Ynones by Photoredox Catalysis

Carbon–carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl−C(sp³) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl‐radical‐enabled carbonyl−C(sp³) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β‐carbonyl alkoxyl radical generation from β‐carbonyl alcohols, including alcohols with high redox potential ( >2.2 V vs. SCE in MeCN). β‐Amide, β‐ester, and β‐ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio‐ and chemoselectivity under mild reaction conditions.     

Mass spectrometric study of conjugated bifunctional acetylenes: 2—Ynals and ynones

This study is based on results obtained by new techniques for observing metastable ions which make it possible to determine the fragmentation paths of conjugated ynals and ynones. For the ynals, the most interesting fragment is the [M–28]⁺˙ ion. For the ynones, when a McLafferty rearrangement is feasible, the ion arising therefrom is more abundant than the [M? CO]^+. ion. However, this elimination of a neutral CO molecule is quite important for the true acetylene ketones.     

Inorganic‐Base‐Mediated Hydroamination of Alkenyl Oximes for the Synthesis of Cyclic Nitrones

A method based on hydroamination mediated by inorganic base was developed for the synthesis of cyclic nitrones from alkenyl oximes. DFT calculations of the reaction pathway suggested that this hydroamination could proceed through an unprecedented nucleophilic amination of the unactivated alkene by the oxime nitrogen atom. The transition state of this reaction is stabilized by an ionic interaction between a metal cation such as K⁺ and the oxime oxygen and negatively charged alkene moiety.     

Enantioselective synthesis of homocarbocyclic-2′-oxo-3′-azanucleosides

The enantioselective synthesis of homocarbocyclic-2′oxo-3′-azanucleosides has been performed by cycloaddition reaction of the N-glycosyl nitrones with allyl nucleobases. The use of nitrones originated from two different carbohydrates, the N-ribosyl nitrone and the N-mannosyl nitrone, proceeded in a stereocontrolled and predictable manner with a good degree of enantioselectivity, so allowing an easy entry to both enantiomers.     

Dérivés C-glycosyliques. VII. Synthèse et réactions de nitrones dérivées de sucres. Communication préliminaire

The syntheses of three types of sugar nitrones (aldonitrone, ketonitrone and α-β unsaturated aldonitrone) are described. On 1,3-dipolar cycloaddition with phenylacetylene, the aldonitrone gave two Δ₄-isoxazolines epimeric at the new asymetric carbon, while the same reaction on the ketonitrone led to a spiro-Δ₄-isoxazoline. The reaction of these nitrones with carbon nucleophiles like phenylethynylmagnesium bromide constitutes a novel chain-extension reaction in carbohydrate chemistry.     

Spin Trapping of Radical Intermediates Generated by the Oxidation of Substituted 4‐Methylphenols

A series of substituted 4‐methylphenols 1 and 2 was oxidized with PbO₂ in the presence of nitroso compounds 3 – 10 . The formation of adducts of benzyl radicals with the nitroso spin traps in the reaction mixture was established, suggesting the abstraction of an H‐atom from the methyl substituent of 1 or 2 . In the consecutive steps, the adducts underwent a further rearrangement to the corresponding nitrones. When the starting phenol contained bulky ^tBu groups in ortho‐position (see 2,6‐di(tert‐butyl)‐4‐methylphenol ( 1a )), the stable 2,6‐di(tert‐butyl)‐4R‐phenoxy radicals (R=? CH?N⁺(O^?)? X) were detected as the final radical products. The indirect evidence of nitrones in the reaction mixture was performed in one case by the reaction with a RO radicals.     

Alkene‐Directed N‐Attack Chemoselectivity in the Gold‐Catalyzed [2+2+1]‐Annulations of 1,6‐Enynes with N‐Hydroxyanilines

Kinetically unstable nitrones are generated from gold‐catalyzed reactions of 1,6‐enynes with N‐hydroxyanilines, and subsequently trapped by tethered alkenes to furnish [2+2+1]‐annulations. Our experimental data reveal that such nitrones arise from atypical N‐attack chemoselectivity that is triggered by tethered alkenes to facilitate the key protodeauration reaction.     

Highly efficient transition metal-free coupling of acid chlorides with terminal alkynes in [bmim]Br: A rapid route to access ynones using MgCl2

A simple, mild, highly efficient and transition metal-free protocol for synthesis of ynones in an ionic liquid is described. In this approach, the coupling reaction of different acid chlorides with terminal alkynes was efficiently carried out using 0.05 mol% MgCl₂ in the presence of triethylamine in [bmim]Br at room temperature to afford the corresponding ynones in good to excellent yields. This method is highly efficient for various acid chlorides and alkynes including aliphatic, aromatic, and heteroaromatic substrates bearing different functional groups. The influence of some parameters in this reaction including type of ionic liquid, base and catalyst has been discussed.     

Enantioselective Synthesis of Tertiary Propargylic Alcohols under N‐Heterocyclic Carbene Catalysis

A straightforward procedure to carry out the enantioselective benzoin reaction between aldehydes and ynones by employing a chiral N‐heterocyclic carbene (NHC) as catalyst was developed. Under the optimized reaction conditions, these ynones undergo a clean and selective 1,2‐addition with the catalytically generated Breslow intermediate, not observing any byproduct arising from competitive Stetter‐type reactivity. This procedure allows the preparation of tertiary alkynyl carbinols as highly enantioenriched materials, which have the remarkable potential to be used as chiral building blocks in organic synthesis.     

H-N HMBC as a valuable tool for the identification and characterization of nitrones

¹H-¹⁵N HMBC has been evaluated as an efficient and high-speed method to determine ¹⁵N chemical shifts for nitrones, which can be used to identify aromatic nitrones and to extract structural information by comparison with reference data. Substituent effects have been measured on C and N aryl groups separately, showing up the influence of electronic effects on C-aryl groups rather than N-aryl groups on the ¹⁵N chemical shifts. Steric effects are remarkable in the case of C-aryl-N-alkyl nitrones. Depending on N or C substitution, chemical shift changes in such an additive way that it is possible to predict chemical shifts for unknown nitrones.     

Synthesis of substituted 2-(thiophen-2-yl)-1<Emphasis Type="Italic">H</Emphasis>-imidazol-1-ols

Substituted 2-(thiophen-2-yl)-1H-imidazol-1-ols were synthesized by cyclization of the corresponding α-thienyl nitrones in alkaline medium. α-Thienyl nitrones were obtained by reaction of N-(1-hydroxyimine-1-R-propan-2-yl)hydroxylamines with thiophene-2-carbaldehyde in methanol. At boiling α-thienyl nitrones in methanol in the presence of sodium methylate 5-aryl(hetaryl)-2-(thiophen-2-yl)-1H-imidazol-1-ols are formed chemoselectively.     

Dehydrogenative TEMPO‐Mediated Formation of Unstable Nitrones: Easy Access to N‐Carbamoyl Isoxazolines

N‐carbamoyl nitrones represent an important class of reagents for the synthesis of a variety of natural and biologically active compounds. These compounds are generally converted into valuable 4‐isoxazolines upon cyclization reaction with dipolarophiles. However, these types of N‐protected nitrones are highly unstable, which limits their synthesis, storage and practical use, enforcing alternative lengthy or elaborated synthetic routes. In this work, a 2,2,6,6‐tetramethylpiperidin‐1‐oxyl (TEMPO)‐mediated formal “dehydrogenation” of N‐protected benzyl‐, allyl‐ and alkyl‐substituted hydroxylamines followed by in situ trapping of the generated unstable nitrones into N‐carbamoyl 4‐isoxazolines is presented. A plausible mechanism is also proposed, in which the dipolarophile shows an important assistant role in the generation of the active nitrone intermediate. This simple protocol avoids the problematic isolation of N‐carbamoyl protected nitrones, providing new synthetic possibilities in isoxazoline chemistry.     

Catalytic Enantioselective Quick Route to Aldol‐Tethered 1,6‐ and 1,7‐Enynes from ω‐Unsaturated Aldehydes

An effective asymmetric route to functionalized 1,6‐ and 1,7‐enynes has been developed based on a direct cross‐aldol reaction between ω‐unsaturated aldehydes and propargylic aldehydes (α,β‐ynals) promoted by combined α,α‐dialkylprolinol ether/Brønsted acid catalysis. This synergistic activation strategy is key to accessing the corresponding aldol adducts with high stereoselectivity, both enantio‐ and diastereoselectivity. The aldol reaction also proceeds well with propargylic ketones (α,β‐ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson–Khand conditions.     

Radical‐Induced Metal‐Free Alkynylation of Aldehydes by Direct CH Activation

A direct C(sp²)?H alkynylation of aldehyde C(O)?H bonds with hypervalent iodine alkynylation reagents provides ynones under metal‐free conditions. In this method, 1‐[(triisopropylsilyl)ethynyl]‐1,2‐benziodoxol‐3(1H)‐one (TIPS‐EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and α,β‐unsaturated aldehydes.