Intramolecular Stetter Reaction Research Articles

A Simple Tool to Benchmark Reactivity in Asymmetric Catalysis

AbstractHerein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.

Catalytic role of the enol ether intermediate in the intramolecular Stetter reaction: a computational perspective.

The intramolecular Stetter reaction catalyzed by a carbene is investigated by density functional theory (DFT) calculations and kinetic simulations. Catalyst 1 first reacts with aldehyde 2 to give the primary adduct (PA). The PA undergoes the intramolecular oxa-Michael reaction to irreversibly generate enol ether intermediate 9. The conversion of the enol ether to the Breslow intermediate (BI) requires the assistance of a base such as the PA. The next step involves formation of a carbon-carbon bond through the Michael addition, and expulsion of the catalyst generates the Stetter product 7. Calculations show that the catalytic cycle is composed of two irreversible processes: the first one involves the exergonic formation of the enol ether intermediate, while the second one is the conversion of the enol ether to the final product. Kinetic simulations using initial concentrations of [1]0 = 0.005 M and [2]0 = 0.025 M demonstrate that under a steady-state condition, 35% of the catalyst rests on the state of the enol ether (0.0018 M). The catalyst resting state therefore consists of the unbound form (the free catalyst) and its bound form (the enol ether species). According to variable time normalization analysis, the reaction exhibits a second-order dependence (first order in catalyst and first order in substrate), which agrees with experiments. The oxa-Michael reaction to form the enol ether is identified to be turnover limiting in the intramolecular Stetter reaction, which rationalizes the observed electronic effect of the Michael acceptor on the reactivity, as well as the measured isotope effect with respect to the aldehydic proton/deuteron. The base that participates in the BI formation has a significant effect on the build-up of the resting state 9 and the active catalyst concentration. In addition, the thermodynamic stability of the enol ether is found to depend on the tether length between the aromatic aldehyde and the Michael acceptor, as well as the chemical nature of the carbene catalyst. The favorability for the oxa-Michael reaction is therefore suggested to govern the reactivity of the intramolecular Stetter transformation.

Installation of an organocatalyst into a protein scaffold creates an artificial Stetterase.

Using a protein scaffold covalently functionalised with a thiamine-inspired N-heterocyclic carbene (NHC), we created an artificial Stetterase (ArtiSt) which catalyses a stereoselective, intramolecular Stetter reaction. We demonstrate that ArtiSt functions under ambient conditions with low catalyst loading. Furthermore, activity can be increased >20 fold by altering the protein scaffold.

Remote Electronic Tuning of Chiral N-Heterocyclic Carbenes.

Our recent efforts to develop novel N-Heterocyclic carbene (NHC)-catalyzed asymmetric reactions are described. During our investigation for development of the acylation reactions via acylazoliums generated by the reactions of NHCs and α-oxidized aldehydes, we have observed significant effects of substitution at a remote site of the carbene carbon of NHCs. In addition, we also observed a significant enhancement of the enantioselectivity by the addition of carboxylate anions. From this observation, we proposed a novel working hypothesis involving a formation of a complex of the substrate and additive to reinforce the recognition of the catalyst for enhancement of the catalytic performance of the asymmetric N-heterocyclic carbene system. By applying this concept, we achieved the kinetic resolutions of both cyclic and acyclic alcohols in excellent enantioselectivities. The effects of the remote substitution were also observed in intramolecular Stetter reaction and intermolecular benzoin reaction. In these reactions, the comparison of the catalytic performance of the NHCs bearing variable remote substitutions provided insights into the reaction mechanism because the remote substitution tuned the electronic nature of NHCs without affecting the steric and electrostatic factors around the reaction site. We also developed an intramolecular benzoin condensation involving two aldehydes, which is challenging to realize. Using the substrates bearing proper protecting groups, we succeeded in the stereo divergent synthesis of a variety of inososes, which are important intermediates for the synthesis of biologically active cyclitols.

Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products.

The remote electronic effects of chiral N-heterocyclic carbene catalysts on the asymmetric intramolecular Stetter reaction are investigated. The reaction rate and enantioselectivity were markedly influenced by a substituent at a remote position of the catalyst. The absolute configurations of the products are revised on the basis of X-ray diffraction. Density-functional theory calculations rationalize the improvement of the enantioselectivity using an electron-deficient catalyst.

Sequential One-Pot Carbene-Catalyzed Intramolecular Stetter Reaction and Acid-Mediated Condensation: Access to Heteroatom Analogues of π-Extended Polyaromatic Hydrocarbons.

In this Letter, we disclose a simple and effective method to access a variety of phenanthro[9,10-b]furan and 1H-dibenzo[e,g]indole derivatives based on the design of a carbene-catalyzed intramolecular Stetter reaction followed by a Paal-Knorr reaction in one-pot. These compounds are a class of π-extended polycyclic aromatic hydrocarbon (PAH) derivatives containing an oxygen/nitrogen atom. The practical utility of the developed transformation was demonstrated on the gram scales and postsynthetic transformations thereof.

Asymmetric Total Syntheses of (+)-5-epi-Schisansphenin B and the Proposed Structure of (+)-15-Hydroxyacora-4(14),8-diene.

The asymmetric total syntheses of (+)-5-epi-schisansphenin B and the proposed structure of (+)-15-hydroxyacora-4(14),8-diene have been accomplished from 1,3-cyclopentadione (10) in eight synthetic steps. The enantioselective palladium-catalyzed redox-relay Heck alkenylation, the intramolecular Stetter reaction, and the regioselective Tiffeneau-Demjanov-type ring expansion were the pivotal steps in these syntheses.

Cover Feature: Kinetic and Structure‐Activity Studies of the Triazolium Ion‐ Catalyzed Intramolecular Stetter Reaction (26/2021)

The Cover Feature shows collaborative work from the O'Donoghue and Smith groups that describes mechanistic studies of the popular NHC-catalyzed intramolecular Stetter reaction process. A word-cloud approach was used to create a visual representation of the manuscript through using and scaling the most popular and relevant words from the publication, superimposed on the chemical catalytic cycle, conveying crucial information at a glance in a visual manner. More information can be found in the Communication by A. Smith et al.

Kinetic and Structure‐Activity Studies of the Triazolium Ion‐ Catalyzed Intramolecular Stetter Reaction

AbstractMechanistic studies of the triazolium ion‐catalyzed intramolecular Stetter reaction using initial rates analysis in NEt3/NEt3 ⋅ HCl buffered methanol showed the reaction to be first‐order in catalyst and zero‐order in aldehyde over a broad range of aldehyde concentrations. The observed reaction rate is higher for catalysts bearing N‐aryl substituents with electron‐withdrawing groups. A concurrent, NHC‐independent substrate isomerization was also observed and found to demonstrate a first‐order dependence on aldehyde concentration. The reported data are consistent with deprotonation to form the Breslow intermediate being turnover‐limiting in this process.

N‐Heterocyclic Carbene (NHC)‐Catalyzed Intramolecular Stetter Reaction to Access Dibenzo‐fused Seven‐membered Heterocycles

AbstractHerein, we have delineated an NHC‐catalyzed transformation to access dibenzo‐fused seven‐membered heterocyclic compounds via intramolecular Stetter reaction under ambient conditions. A range of dibenzo[b,f]oxepine and dibenzo[b,f]thiepine derivatives have been generated in very good to excellent yields. The 1,4‐dicarbonyl functionality of a representative derivative has undergone further heterocyclization via Paal‐Knorr reaction.

NHC-Mediated Synthesis of Tricyclic Spirocarbocycles via an Intramolecular Stetter Reaction of Cyclic Enal-Enones.

A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-1,4-diketones in 31-72% yields. The ring size of the spiro compounds can be easily controlled using different cyclic enals and enones or by altering the length of the carbon tether.

Construction of Spirofused Tricyclic Frameworks by NHC-Catalyzed Intramolecular Stetter Reaction of a Benzaldehyde Tether with a Cyclic Enone.

Various benzaldehyde tethers with a cyclic enone were prepared from commercially available 2-hydroxybenzaldehydes via a three-step sequence involving triflate formation, Sonogashira cross-coupling, and regioselective hydrogenation. These substrates were then exposed to an N-heterocyclic carbene, whereupon intramolecular Stetter reaction proceeded smoothly to give various spirofused tricyclic 1,4-diketones in 30-87% yields. Furaldehyde and nicotinaldehyde derivatives also participated in the reaction under the Stetter conditions.

Sequential Assembly of Morita-Baylis-Hillman Carbonates and Activated ortho-Vinylbenzaldehydes To Construct Chiral Methanobenzo[7]annulenone Frameworks.

The α-regioselective asymmetric [3 + 2] annulation reaction of Morita-Baylis-Hillman carbonates from isatins and activated ortho-vinylbenzaldehyses was developed by the catalysis of a chiral tertiary amine. The sequential N-heterocyclic carbene-mediated intramolecular Stetter reaction was conducted to finally furnish the bridged 5,8-methanobenzo[7]annulen-9-one architectures incorporating a spirooxindole motif with excellent stereoselectivity.

NHC-Catalyzed Organocatalytic Asymmetric Approach to 2,2-Disubstituted Benzofuran-3(2H)-ones Containing Fully Substituted Quaternary Stereogenic Center

A highly efficient and enantioselective approach to the synthesis of functionalized benzofuran-3(2H)-ones is presented. It proceeds via an intramolecular Stetter reaction using β,β-disubstituted Michael acceptors in the construction of five-membered rings with fully-substituted quaternary stereogenic centers and is promoted by terpene-derived triazolium salts. As a result, a series of chiral 2,2-disubstituted benzofuran-3(2H)-one derivatives with linear, branched, and cyclic aliphatic substitutions on the quaternary stereogenic center were obtained in high yields and with excellent enantioselectivities of up to 99% ee.

Synthesis of (−)-Verbenone-derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction

Two novel chiral verbenone-derived triazolium salts have been synthesized from readily available (−)-verbenone and found to be efficient for the enantioselective intramolecular Stetter reaction. The approach, based on the intramolecular annulation between acyl anion equivalents and Michael acceptors, benefits from broad substrate scope, high chemical and stereochemical efficiency, and operational simplicity. Mono-, and disubstituded chromanone derivatives have been obtained in excellent yields and in a highly stereochemical manner.

Synthesis of 2-Aryl Naphthoquinones by the Cross-Dehydrogenative Coupling Involving an NHC-Catalyzed endo-Stetter Reaction.

An N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction proceeding via the endo-fashion was the key step for the transition-metal-free and mild cross-dehydrogenative coupling of 2-cinnamoyl benzaldehydes allowing for the synthesis of 2-aryl naphthoquinones. In this transformation, the carbene generated from the triazolium salt using Na2CO3 catalyzes the intramolecular Stetter reaction, which was followed by air oxidation to reinstall the C-C double bond.

Synthesis of γ,γ-Disubstituted Butenolides through a Doubly Vinylogous Organocatalytic Cycloaddition.

A novel organocatalytic approach to γ,γ-disubstituted butenolides is described. It is based on a fully site-selective functionalization of 5-alkylidenefuran-2(5H)-ones via trienamine-mediated [4+2]-cycloaddition with α,β,γ,δ-diunsaturated aldehydes. The developed methodology proceeds with excellent stereocontrol and constitutes a unique example of trienamine chemistry with vinylogous dienophiles. Importantly, the reaction has very broad scope and allows for the introduction of substituents also in the α- or the β-position of the butenolide ring. Usefulness of the products obtained has been confirmed in the intramolecular Stetter reaction leading to polycyclic product.

Total synthesis and structural revision of (±)-nidemone.

Total synthesis of the revised structure of (±)-nidemone has been accomplished from 6-bromo-2-hydroxybenzaldehyde (5) in either six or eight synthetic steps in 6% and 10% overall yield, respectively, without using any protecting group. The revised structure of nidemone was confirmed by single-crystal X-ray diffraction analysis. Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in the synthesis.

Total Synthesis of the Proposed Structure of (±)-Nidemone.

Total synthesis of the proposed structure of (±)-nidemone has been accomplished either from 2-hydroxy-6-methoxybenzaldehyde (7) or 2-bromo-6-methoxybenzaldehyde (8) in 10 and 13 synthetic steps, respectively. Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in the synthesis.

Immobilization of Privileged Triazolium Carbene Catalyst for Batch and Flow Stereoselective Umpolung Processes

A strategy for the immobilization of the valuable triazolium carbene Rovis catalyst onto polystyrene and silica supports is presented. Initially, the catalyst activity and recyclability were tested under batch conditions in the model stereoselective intramolecular Stetter reaction leading to optically active chromanones. Good results in terms of yield (95%) and enantioselectivity (ee 81–95%) were detected for the polystyrene-supported catalyst (10 mol %), while poorer results were collected for the silica-supported analogue. Also, continuous-flow experiments were performed by fabricating the corresponding polystyrene monolithic microreactors (pressure-resistant stainless-steel columns) to prove the benefits of the heterogeneous catalysis and the flow regime observing a high stability of the catalytic bed (48 h) with unaltered conversion efficiency and stereoselectivity.