Nitrone and nitroso species are versatile compounds to react with alkenes or butadienes to access five- and six-membered nitroxy (NO) containing heterocycles, to offer further access to acyclic 1,3- and 1,4-amino alcohols after facile cleavage of the NO bonds. The N- and O-functionalizations of alkynes with nitrones or nitroso species have been explored less well than the corresponding alkene reactions. In recent decades, gold catalysts have enabled the electrophilic activation of alkynes with weak nucleophiles. This review summarizes recent progress to implement N- and O-functionalizations of alkynes with common NO containing species including nitrone, nitroso, nitro and other nitroxy derivatives. Reported reactions include the following three topics: (i) 1,2-difunctionalizations, (ii) cyclizations and (iii) cycloaddition or annulation reactions. The review is organized according to the types of nucleophiles, followed by reactions of the mentioned types. Enantioselective functionalizations of alkynes with these nitroxy nucleophiles are also included.

Recent Advances in Gold-Catalyzed N- and O-Functionalizations of Alkynes with Nitrones, Nitroso, Nitro and Nitroxy Species

[2,3]-Sigmatropic rearrangement processes of allylic ylides or their equivalents can be applied to a variety of different substrates and generate products of wide interest/applicability to organic synthesis. This review describes the development and applications of stereoselective [2,3]-rearrangement reactions in which a substoichiometric amount of a catalyst is used in either the formation of the reactive intermediate or the [2,3]-rearrangement step itself.

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Catalytic Stereoselective [2,3]-Rearrangement Reactions

The one-pot intramolecular double Michael reaction of compounds having two different α, β-unsaturated carbonyl groups to form polycyclic compounds can be carried out by three different methods: in the first the substrate is treated with lithium hexamethyldisilazide, in the second with chlorotrimethylsilane, triethylamine, and zinc chloride at an elevated temperature, and in the third with tert-butyldimethylsilyl trifluoromethanesulfonate and triethylamine. The reaction proceeds with complete regioselectivity and high stereoselectivity following a stepwise mechanism. Spiro-fused bicyclo[2.2.2]octane derivatives can be constructed with high stereoselectivity by the intromolecular double Michael reaction by using the first method. Enantiomerically pure atisine and the enantiomer of atisirene were synthesized stereoselectively by application of this methodology. The syntheses of steroids and angular triquinane-type sesquiterpenoids were possible with the second method. Heterocyclic compounds with a bridgehead nitrogen atom were obtained by the reaction of α, β-unsaturated amides following the second and third methods. The asymmetric synthesis of tylophorine with diastereofacial control was achieved by the intramolecular reaction according to the third method. The sulfur-mediated intramolecular double Michael reaction utilizing the third method produced trans-hydroindane derivatives. Furthermore, the intramolecular Michael-aldol reaction can be employed in synthesizing polycyclic systems with cyclobutane units by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine. The intermolecular double Michael reaction and related reactions will also be described.

Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction

Stereochemistry of the Base‐Promoted Michael Addition Reaction

The addition of stabilized nucleophiles to activated π-systems is one of the oldest and most useful constructive methods in organic synthesis, dating back more than a hundred years. In 1887 Michael, after whom the most well-known example of this reaction was named, published the first of a series of papers on this reaction describing the addition of the sodium salt of both diethyl malonate (1) and ethyl acetoacetate (2) to ethyl cinnamate (3) to give the products (4) and (5), respectively (equation 1).1 This Michael reaction, in which a carbanion stabilized by one or usually two electron-withdrawing groups adds to the β-carbon of an α,β-unsaturated carbonyl derivative, represents one of the earliest and most highly utilized methods for carbon–carbon bond formation. In that same 1887 paper,1a Michael also reported the synthesis of triethyl cyclopropane-1,1,2-tricarboxylate (9) from (1) and ethyl α-bromoacrylate (6) via the intermediates (7) and (8), a synthetic route to cyclopropanes used often today (Scheme 1). In 1894 he showed that an alkynic ester could also function as the electrophilic component in these reactions, e.g. (1) and (10a) or (10b) giving (11a) or (11b), respectively (equation 2).2 This reaction and its variants were in wide use around the turn of the century to prepare straight chain polycarboxylates, e.g. the reaction of (12) to give (13; equation 3) and cyclohexane-1,3-diones, e.g. (15; equation 4) (via Knoevenagel and Claisen condensations).3 The combination of Michael addition followed by intramolecular aldol condensation and decarboalkoxylation furnishes cyclohexenones, e.g. isophorone (17; equation 5), from enones such as mesityl oxide (16) and the salt of ethyl acetoacetate (2).4 This process of annulation was made much more general in the 1930s by Robinson and his coworkers,5 who showed that vinyl ketones and their derivatives, e.g. Mannich bases, could be used with simple ketone enolates to produce cyclohexenones of a wide variety, e.g. (20; equation 6), a process which has come to be known as the Robinson annulation.6

Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes

Cationic N-Heterocyclic Carbene Copper-Catalyzed [1,3]-Alkoxy Rearrangement of N-Alkoxyanilines

Multisubstituted ortho-anisidines were efficiently synthesized via cationic N-heterocyclic carbene-Cu-catalyzed domino rearrangement of N-methoxyanilines that possess an electron-donating functional group, such as an alkyl or an aryl group, at the ortho position. The reaction proceeded first through a [1,3]-rearrangement of the methoxy group to the ortho position bound to the electron-donating substituent, followed by a semipinacol type [1,2]-rearrangement of the electron-donating group from the ortho to the meta position. Mechanistic studies suggest that both rearrangement reactions are promoted by a cationic Cu catalyst.

Copper-Catalyzed Domino [1,3]/[1,2] Rearrangement for the Efficient Synthesis of Multisubstituted ortho-Anisidines.

Reaction of 2-cyclohexen-1-ones (3a-c) with tert-butyldimethylsilyl triflate and triethylamine gave selectively cross-conjugated dienol ethers (4a-c) except 3-methyl-2-cyclohexen-1-one (3d). Reaction of 6-(5-ethoxycarbonyl-3, 3-dimethyl-4-pentenyl-1)-2-cyclohexen-1-one (10) under the same reaction conditions gave rise to annelation affording to tricyclo [5.2.2.01, 5] undecenes (11) along with the throughconjugated dienol ether (12).

Reaction of conjugated enones with tert-butyldimethylsilyl triflate and intramolecular annelation

Intramolecular double Michael reaction of the α,β-unsaturated enone ester (5) using lithium hexamethyldisilazide produced the tricyclo[5.2.2.01,5] undecane derivative (4) in a highly stereoselective manner. The annulation of (5) was further investigated under various conditions. The tricyclic compound (4) was converted into the tetracyclo[7.3.1.04,12.05,13]tridecane derivative (31), the CDF part of Aconitum alkaloids, via a Wagner–Meerwein-type rearrangement.

Yasuhiro Ishida

Papers

Cationic N-Heterocyclic Carbene Copper-Catalyzed [1,3]-Alkoxy Rearrangement of N-Alkoxyanilines

Copper-Catalyzed Domino [1,3]/[1,2] Rearrangement for the Efficient Synthesis of Multisubstituted ortho-Anisidines.

Reaction of conjugated enones with tert-butyldimethylsilyl triflate and intramolecular annelation

Stereocontrolled synthesis of the CDF part of Aconitum alkaloids via intramolecular double Michael reaction

Cu-catalyzed skeletal rearrangement of O-propargylic electron-rich arylaldoximes into amidodienes.