Nature of the intermediates in gold(I)-catalyzed cyclizations of 1,5-enynes

The carbene or carbocationic nature of the intermediates in the gold-catalyzed cycloisomerization of 1,5-enynes can be revealed, depending on the ligands on the gold catalysts. Gold complexes with highly electron-donating ligands promote reactions that proceed via intermediates with carbene-like character, leading to products with a bicyclo[3.1.0]hexene skeleton. The intermediate cyclopropyl endo-gold carbenes formed in this cyclization have been trapped, for the first time, to give biscyclopropane derivatives in a reaction that proceeds in a concerted fashion, according to DFT calculations.     

Gold(I)-catalyzed intramolecular cyclopropanation of dienynes

Gold(I) complexes are the most active catalysts for the biscyclopropanation of dienynes to form tetracyclic compounds. PtII and ZnII are also able to promote the biscyclopropanation, although less efficiently. The configurations obtained in all cases with the use of gold(I) catalysts can be explained by the pathway proceeding through anti cyclopropyl gold carbenes. Similar intermediates are most probably involved in reactions catalyzed by RuII and PtII. Two different cyclopropanation pathways have been found; they depend on the structures of the cyclopropyl gold carbenes (anti or syn) and the relative arrangements of the metal carbenes and the alkenes.     

N-heterocyclic carbene catalyzed domino cyclization of propargylic alcohols and benzoyl isocyanates

N-Hetereocyclic carbenes (NHCs) were found to be efficient catalysts for the cyclization of propargylic alcohols and isocyanates. Domino cyclization reactions were carried out using isopropyl-substituted imidazolium salt as a precatalyst, and a wide range of substituted oxazolidinones were obtained in high yields.     

Gold(I)-catalyzed intermolecular addition of carbon nucleophiles to 1,5- and 1,6-enynes

Gold(I)-catalyzed addition of carbon nucleophiles to 1,6-enynes gives two different type of products by reaction at the cyclopropane or at the carbene carbons of the intermediate cyclopropyl gold carbenes. The 5-exo-dig cyclization is followed by most 1,6-enynes, although those bearing internal alkynes and alkenes react by the 6-endo-dig pathway. The cyclopropane versus carbene site-selectivity can be controlled in some cases by the ligand on the gold catalyst. In addition to electron-rich arenes and heteroarenes, allylsilanes and 1,3-dicarbonyl compounds can be used as the nucleophiles. In the reaction of 1,5-enynes with carbon nucleophiles, the 5-endo-dig pathway is preferred.     

Cyclization of 1,6-enynes catalyzed by gold nanoparticles supported on TiO2: significant changes in selectivity and mechanism, as compared to homogeneous Au-catalysis

Gold nanoparticles supported on TiO(2) (1.2 mol %) catalyze, for the first time under heterogeneous conditions, the cycloisomerization of a series of 1,6-enynes in high yields. In several cases, the product selectivity differs significantly as compared to homogeneous Au(I)-catalysis. Based on product analysis and stereoisotopic studies it is proposed that the major or exclusive pathway involves a 5-exo cyclization mode to form stereoselectively gold cyclopropyl carbenes that undergo a single cleavage pathway, in contrast to homogeneous Au-catalysis where the double cleavage pathway operates substantially.     

Copper-Catalyzed Azide–Ynamide Cyclization to Generate α-Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N-Heterocycles

Here an efficient copper-catalyzed cascade cyclization of azide-ynamides via α-imino copper carbene intermediates is reported, representing the first generation of α-imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N-heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX-Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.     

Intramolecular reactions of alkynes with furans and electron rich arenes catalyzed by PtCl2: the role of platinum carbenes as intermediates

5-(2-Furyl)-1-alkynes react, with PtCl(2) as catalyst, to give phenols. On the basis of DFT calculations, a cyclopropyl platinacarbene complex was found as the key intermediate in the process. The cyclopropane and dihydrofuran rings of this intermediate open to form a carbonyl compound, which reacts with the platinum carbene to form an oxepin, which is in equilibrium with an arene oxide. When the reaction is carried out in the presence of water, dicarbonyl compounds are obtained, which support the proposed mechanism. Other cyclizations of alkynes with furans or electron-rich arenes give products of apparent Friedel-Crafts-type reactions, although these processes could also proceed by pathways involving the formation of cyclopropyl platinum carbenes.     

Copper‐Catalyzed Azide–Ynamide Cyclization to Generate α‐Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N‐Heterocycles

Here an efficient copper‐catalyzed cascade cyclization of azide‐ynamides via α‐imino copper carbene intermediates is reported, representing the first generation of α‐imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N‐heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX‐Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.     

Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo‐Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl‐cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three‐membered ring of vinyl‐cyclopropyl ketones to allow the formal homo‐Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non‐electron‐rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo‐Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.     

[8+2] and [8+3] Cyclization Reactions of Alkenyl Carbenes and 8‐Azaheptafulvenes: Direct Access to Tetrahydro‐1‐azaazulene and Cyclohepta[b]pyridinone Derivatives

The reactivity of Fischer alkenyl carbenes toward 8‐azaheptafulvenes is examined. Alkenyl carbenes react with 8‐azaheptafulvenes with complete regio‐ and stereoselectivity through formal [8+3] and [8+2] heterocyclization reactions, which show an unprecedented dependence on the C_β substituent at the alkenyl carbene complex. Thus, the formal [8+3] heterocyclization reaction is completely favored in carbene complexes that bear a coordinating moiety to give tetrahydrocyclohepta[b]pyridin‐2‐ones. Otherwise, alkenyl carbenes that lack appropriate coordinating groups undergo a formal [8+2] cyclization with 8‐azaheptafulvenes to give compounds that bear a tetrahydroazaazulene structure. A likely mechanism for these reactions would follow well‐established models and would involve a 1,4‐addition/cyclization in the case of the [8+2] cyclization or a 1,2‐addition/[1,2] shift–metal‐promoted cyclization for the [8+3] reaction. The presence of a coordinating moiety in the carbene would favor the [1,2] metal shift through transition‐state stabilization to lead to the [8+3] product. All these processes provide an entry into the tetrahydroazaazulene and cycloheptapyridone frameworks present in the structure of biologically active molecules.     

Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes Generated from Sulfoxonium Ylides

Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Brønsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium–carbene complex, followed by N−H or C−H functionalization of an aniline or enamine, respectively, and a final acid‐catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.     

Gold(I)-catalysed arylation of 1,6-enynes: different site reactivity of cyclopropyl gold carbenes

Gold(I)-catalysed addition of electron-rich arenes and heteroarenes to 1,6-enynes gives two different types of products by reaction of the intermediate cyclopropyl gold carbenes at the cyclopropane or at the carbene.     

Divergent synthesis of fully substituted isoxazoles and spiro-fused pyrazolin-5-ones from cyclopropyl oximes

Efficient and divergent synthesis of fully substituted isoxazoles and spiro-fused pyrazolin-5-ones is developed from cyclopropyl oximes based on selection of reaction conditions. Under Appel conditions (PPh₃/CBr₄), substituted isoxazoles were synthesized from cyclopropyl oximes via a ring-opening and intramolecular cyclization process, whereas by treatment of cyclopropyl oximes with p-toluenesulfonyl chloride in the presence of potassium hydroxide, spiro-fused pyrazolin-5-ones were obtained via tandem ketoxime tosylation and intramolecular cyclization.     

Copper‐Catalyzed Asymmetric Annulation Reactions of Carbenes with 2‐Iminyl‐ or 2‐Acyl‐Substituted Phenols: Convenient Access to Enantioenriched 2,3‐Dihydrobenzofurans

We have developed a method for the highly diastereo‐ and enantioselective construction of 2,3‐dihydrobenzofurans bearing tetrasubstituted carbon stereocenters by means of annulation reactions between carbenes and 2‐iminyl‐ or 2‐acyl‐substituted phenols through catalysis by readily accessible copper(I)/bisoxazoline catalysts under mild conditions. These reactions feature a unique mechanism in which the copper catalyst serves a dual function: first it reacts with the diazo compound to generate a metal carbene, and second, upon formation of an oxonium ylide, it acts as a Lewis acid to activate the imine or ketone for diastereo‐ and enantioselective cyclization.     

Thermal C2-C6 cyclization of enyne-allenes. Experimental evidence for a stepwise mechanism and for an unusual thermal silyl shift

Enyne-allenes 4a-c bearing various cyclopropyl systems as radical clock reporter groups at the allene terminus have been synthesized and subjected to thermal C2-C6 cyclization. The ratio of ene versus formal Diels-Alder products could be rationalized on the basis of steric effects. Only the thermolysis of 4c, equipped with the fast diphenylcyclopropylcarbinyl radical clock, afforded a 1,3-butadienyl benzofulvene clearly formed via cyclopropyl ring opening. This finding provides unambiguous evidence for a stepwise mechanism of the C2-C6 cyclization making it possible to suggest a lifetime for the intermediate diradical of >1x10(-10) s (at 170 degrees C). An interesting corollary was the isolation of an unexpected silyl shift product in the thermolysis of all three enyne-allenes that allows explanation of the loss of the TIPS group in some of the Diels-Alder products. For a full understanding of the mechanism, silyl and hydrogen shift processes were interrogated using DFT.     

Phenanthrene-fused azo-ene-ynes: synthesis of dibenzo[f,h]cinnoline and dibenzo[e,g]isoindazole derivatives

The cyclization reactions of a phenanthreno-fused azo-ene-yne compound have been studied both experimentally and computationally. Experimental results show that this system is prone to dimerization, more so than previously studied naphthalene- and benzene-based analogues. Calculations reveal that pyrazoles and arene-fused pyrazoles strongly stabilize carbenes in the 5-position through "coarctate conjugation", suggesting a stationary concentration of the carbenes/carbenoids during cyclization that is high enough for dimerization.     

Experimental and computational exploration of indolizinyl carbene generation. A route to biindolizines

In previous work, (E)-2-enynyl pyridines were reported to yield indolizinyl singlet carbenes through base-catalyzed E/Z isomerization followed by a 5-exo-dig pseudocoarctate cyclization. We report herein that in the presence of ethyl acrylate these carbenes undergo stereoselective cis-cyclopropanation due mainly to electrostatic interactions in the transition state. The scope of this carbene generation scheme has been further explored through the preparation of a symmetric bis(pyridylenyl)alkyne which spontaneously furnished the biindolizine core in a one-pot reaction. Computational characterization of this transformation suggests a highly asynchronous double cyclization.     

Beta-trimethylsilyl cyclopropylcarbenes

Thermal decomposition of the in situ generated lithium salt of the tosylhydrazone derivative of cyclopropyl trimethylsilylmethyl ketone gave 1-cyclopropyl-1-trimethylsilylethylene, a product of exclusive silyl migration. Thermal decomposition of the sodium salts of tosylhydrazone derivatives of 1-trimethylsilylcyclopropyl alkyl ketones also gave methylenecyclopropane products derived from trimethylsilyl migration. These reactions were interpreted in terms of rapid trimethylsilyl migration to carbene-like centers that compete effectively with ring expansion processes of cyclopropylcarbenes. Computational studies (B3LYP/6-31G) suggest that cyclopropyl stabilization of carbenes is more effective than beta-trimethylsilyl stabilization. However, beta-trimethylsilyl stabilized conformations are easily attained, and these conformations can lead to silyl migrations. There are two minimum energy conformations of methyl-1-trimethylsilylcyclopropylcarbene, 27, and the rotational barrier to interconversion of these conformations (5.4 kcal/mol) is substantially lower than in the parent cyclopropylcarbene (15 kcal/mol). The onset of a stabilizing interaction in the transition state between the carbene vacant orbital with the adjacent Si-C sigma-orbital is proposed. Computational studies also show a very small (2.0 kcal/mol) barrier for trimethylsilyl migration in trimethylsilylmethyl cyclopropylcarbene, 11.     

Single and Consecutive Cyclization Reactions of Alkynyl Carbene Complexes and 8‐Azaheptafulvenes: Direct Access to Polycyclic Pyrrole and Indole Derivatives

The reactivity of alkynyl and enynyl Fischer carbene complexes towards 8‐azaheptafulvenes is examined. Alkynyl carbenes 1 a – f undergo regioselective [8+2] heterocyclization with 8‐aryl‐8‐azaheptafulvenes 2 a , b providing cycloheptapyrroles 3 and 4 with metal carbene or ester functionality at C3. Moreover, consecutive cyclization reactions are involved when enynyl carbenes are used. Thus, the cyclopenta[b]pyrrole framework 7 is formed by the consecutive [8+2] cyclization and cyclopentannulation reactions. The initially formed cyclopentannulation adduct can be intercepted through a Diels–Alder reaction with classic dienophiles to afford increasing structural complexity (compounds 8 and 9 ). More importantly, the construction of the indole skeleton is accomplished with a high degree of substitution and functionalization (compounds 11 – 15 ) by a one‐pot sequence that involves [8+2] cyclization, R? NC or CO insertion, and ring closure.     

Non-stabilized transition metal carbenes as intermediates in intramolecular reactions of alkynes with alkenes

In this tutorial review we summarize the two major pathways followed in the reaction of alkenes with alkynes catalysed by electrophilic transition metals. If the metal coordinates simultaneously to the alkyne and the alkene, an oxidative cyclometallation can ensue to give a metallacyclopentene, which usually evolves by [small beta]-hydrogen elimination to give Alder-ene cycloisomerisation derivatives. On the other hand, coordination of the metal to the alkyne promotes the attack of the alkene to give metal cyclopropyl carbenes.