Michael Initiated Ring Closure Research Articles

Unveiling the beauty of cyclopropane formation: a comprehensive survey of enantioselective Michael initiated ring closure (MIRC) reactions

This review presents a comprehensive overview of the synthesis of cyclopropanes using enantioselective Michael Initiated Ring Closure (MIRC) reactions.

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles.

Herein, we present the first ever use of 3-isopropylidene oxindoles as electrophiles in vinylogous Michael initiated ring closure reaction (MIRC). Among the various alkylidene oxindoles used in enantioselective spirocyclization reactions, isopropylidene oxindoles are the least explored to date. The competing reactivity of isopropylidene oxindoles (electrophilicity vs nucleophilicity) in the presence of a chiral organocatalyst is controlled by the logical selection of a more reactive nucleophile. The methodology produces a library of densely substituted highly enantioenriched spirocyclopropyl oxindoles with excellent yield and stereoselectivities. Moreover, the first enantioselective synthesis of HIV-1 NNRT inhibitor indicates the importance of our synthesized spiro-cyclopropyl oxindole core.

Cesium Carbonate-Promoted Reaction of Nitro-Substituted Donor-Acceptor Cyclopropanes with Salicylaldehydes in Water: Access to Chromane Derivatives.

Nitro-substituted donor-acceptor cyclopropanes react with salicylaldehydes in the presence of cesium carbonate in water to give new chromane derivatives. The reaction takes place through in situ formation of allene intermediates from the cyclopropanes and subsequent Michael-initiated ring closure of the intermediates with salicylaldehydes.

Asymmetric Synthesis of Spiro-3,3'-cyclopropyl Oxindoles via Vinylogous Michael Initiated Ring Closure Reaction.

A novel organocatalytic cascade approach for the synthesis of spiro-cyclopropyl oxindole derivatives has been developed. The methodology is based on asymmetric vinylogous Michael addition of 4-nitroisoxazole derivatives to N-Boc isatylidene malonates followed by intramolecular alkylation. Its remarkable stereocontrol, wide substrate scope, and scalability highlight this new developed strategy. Moreover, this work represents the first example of vinylogous Michael initiated ring closure (MIRC) reaction for the synthesis of chiral 3,3'-cyclopropyl oxindole.

The Chemistry of Cyclopropanes and New Insights into Organocatalyzed Asymmetric Cyclopropanation

AbstractCyclopropane structure has been the object of interest in multiple investigations due to its prevalence in different natural products. In addition, this structure has a particular reactivity, specifically the 1,1‐cyclopropanedicarboxylate compounds, which act as acceptor‐donor cyclopropanes. Its reactivity could be compared with that of an α,β‐unsaturated carbonyl, which undergoes conjugate addition reaction and depending on the nature of the nucleophile this can lead to a cycloaddition reaction. Therefore, cyclopropane can be transformed into several useful structures in organic synthesis. Different methods have been described to achieve cyclopropanes such as, Simmons‐Smith reaction, decomposition of diazoalkanes and Michael‐Initiated ring closure (MIRC). Due to the absence of metals, this last method has been applied to the asymmetric organocatalytic synthesis of cyclopropanes, where the substrates activation is through the imine‐enamine intermediates formation or by hydrogen bonds. The asymmetric reaction consists of a domino reaction composed of a conjugate addition reaction and a cyclization reaction via intramolecular nucleophilic substitution. In this review, different asymmetric organocatalytic syntheses of the last two decades until 2021 are presented. With the intention to facilitate the reading of the review, an example of each paper was selected with the optimal reaction conditions and with the best organocatalyst producing the best yield and high stereoselectivity.

Enantioselective Cyclopropanation of 2‐Cyano‐3‐arylacrylates Using Carbohydrate‐Based Crown Ethers

AbstractEnantioenriched, highly functionalized cyclopropane derivatives were prepared by a simple and green approach using monosaccharide‐based chiral crown ethers as phase transfer catalysts. The Michael‐initiated ring closure (MIRC) reactions of diethyl bromomalonate with 2‐cyano‐3‐phenylacrylate took place with complete diastereoselectivity in the presence of chiral lariat ethers derived from carbohydrates and enantioselectivity up to 87 % ee was achieved. Among the catalysts tested, the monoaza‐15‐crown‐5 lariat ether having a methyl β‐d‐glucopyranoside unit and a 2‐(3,4‐dimethoxyphenyl)ethyl group on the nitrogen generated the highest asymmetric induction (87 % ee). In the reactions of analogous 2‐cyano‐3‐arylacrylates, enantioselectivity was in the range of 8–91 % ee.

Synthesis of Cyclopropenes and Fluorinated Cyclopropanes via Michael Initiated Ring Closure of Alkyl Triflones.

A facile synthesis of cyclopropenes and fluorinated cyclopropanes from readily available alkyl triflones was developed. The reaction, regardless of electronic effect, gave products in good to excellent yields and moderate diastereoselectivity. The mechanism may involve tandem Michael addition of triflones/intramolecular nucleophilic cyclization (elimination of -SO2 CF3 )/elimination of fluoride.

Base-promoted highly efficient synthesis of nitrile-substituted cyclopropanes via Michael-initiated ring closure.

A convenient and efficient annulation reaction has been developed for the general synthesis of dinitrile-substituted cyclopropanes in moderate to excellent yields. A variety of 2-arylacetonitriles and α-bromoennitriles were compatible under the standard conditions. The reaction was achieved through tandem Michael-type addition followed by intramolecular cyclization. The preliminary application of this method was confirmed by the synthesis of the 2,4-dioxo-3-azabicyclo[3.1.0]hexane scaffold.

Copper acetate catalysed C-C bond formation en route to the synthesis of spiro indanedione cyclopropylpyrazolones.

This article reports the synthesis of spiro compounds based on an indanedione-cyclopropane-pyrazolone framework. The reaction relied upon the Michael-initiated ring closure strategy and was carried out under Cu(OAc)2 catalysis, assisted by an oxygen atmosphere and the base Et3N. The final compounds were obtained as an inseparable mixture in most cases with modest to good yields using diverse substrates. Among the two plausible routes, computational studies indicated the feasibility of a route which involves a four-membered Cu containing intermediate. Given the generic nature of the developed method, it may be utilised to synthesise other analogous spiro systems.

Stereoselective synthesis and investigation of mechanism of trifluoromethylated cyclopropylphosphonate

Herein, we would like to present a one-pot stereoselective synthesis of a trisubstituted trifluoromethylated cyclopropylphosphonate derivative. The title compound was obtained using a Michael initiated ring closure protocol. NMR studies, as well as DFT calculations, confirmed preference of the reaction for the formation of only one isomer. This new building block can be used as a potential tool for development of a novel class of drugs.

Asymmetric Synthesis of Fluoro, Fluoromethyl, Difluoromethyl, and Trifluoromethylcyclopropanes.

Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,β-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.

Organocatalytic, Organic Oxidant Promoted, Enamine C−H Oxidation/Cyclopropanation Reaction

AbstractHerein, we demonstrate that organic, single‐electron oxidant in the presence of diarylprolinol silylether type catalyst serves as a tool for the transformation of electron‐rich enamines to iminium ions. These iminium ions take part in a subsequent Michael‐initiated ring‐closure (MIRC) reaction with in situ present nucleophile giving rise to overall cyclopropanation reaction of saturated aldehydes. Stereodefined cyclopropanes are obtained in high yields and selectivities. This one‐pot transformation represents the additional example of saturated aldehydes being used in the coupled one‐pot processes.magnified image

Carbohydrate-Based Azacrown Ethers in Asymmetric Syntheses

Carbohydrate-based crown ethers represent a special group of chiral phase transfer catalysts. Several derivatives of these macrocycles have been synthesized in our research group. Among these compounds, monoaza-15-crown-5 lariat ethers proved to be effective phase transfer and enantioselective catalysts in certain reactions. Those chiral azacrown ethers incorporating various carbohydrate moieties in the macrocyclic structure are reviewed, which generated asymmetric induction in reactions, such as Michael addition, epoxidation of enones, Darzens condensation and Michael-initiated ring-closure (MIRC) reaction. Effects on the catalytic activity of the structural changes are the focus.

Epoxides of d-fructose and l-sorbose: A convenient class of “click” functionality for the synthesis of a rare family of amino- and thio-sugars

The strained epoxide ring of oxirane-derived furanoside and pyranoside of d-fructose are regioselectively opened by various primary and secondary amines as well as azide to yield C4-alkylamino-C4-deoxy and the corresponding azido derivatives. The epoxide ring of a furanoside derived from l-sorbose, a C-5 epimer of d-fructose also afforded C4-amino and C4-azido analogues. All three epoxides generated piperazine linked disaccharides. These epoxides are also easily opened by p-tolylthiol to access thiosugars. One such thiosugar was converted to vinylsulfone-modified fructofuranoside and subjected to nucleophillic addition. A suitably designed vinyl sulfone-modified fructofuranoside having a leaving group at C-6, act as an efficient substrate for MIRC (Michael Initiated Ring Closure) reactions to construct cyclopropane skeleton in d-fructose. The strategy is general in nature and provides an easy access to cyclopropanated sugar derivatives. Thus, the easily accessible “spring loaded” epoxides of d-fructose and l-sorbose have been used as pivotal starting point for the synthesis of hitherto unknown modified carbohydrates.

3-Nitroacrylates as promising substrates for the construction of carbo- and heterocyclic structures

The review analyzes and summarizes methods for the synthesis of carbo- and heterocycles based on alkyl 3-nitroacrylates that were described over the past decade. The scope of the review includes cycloaddition reactions and tandem processes, in particular Michael-initiated ring closure (MIRC) reactions, giving functionalized carbo- and heterocycles, mainly five- and six-membered derivatives.

Asymmetric cyclopropanation reactions catalyzed by carbohydrate-based crown ethers

Optically active cyclopropane derivatives were prepared by a novel, simple and green approach in high enantioselectivities using monosaccharide-based chiral crown ethers as phase transfer catalysts. The crown ethers having d-glucopyranoside, d-mannopyranoside and d-altropyranoside units proved to be efficient catalyst in a few asymmetric phase transfer cyclopropanation reactions. The Michael-initiated ring closure (MIRC) reactions of diethyl bromomalonate with chalcones took place with complete diastereoselectivity and up to 99% ee. Using benzylidenemalononitrile, 2-arylidenemalononitriles, 2-benzylidene-1,3-indandione, substituted 2-benzylidene-1,3-indandiones, 2-arylidene-1,3-indandiones and 2-benzylidene-1,3-diphenyl-1,3-propanediones enantioselectivities up to 92%, 99%, 54% 93%, 89% and 72%, respectively, were achieved, in the presence of chiral lariat ethers derived from different monosaccharides. The absolute configuration of a cyclopropane diester product was determined by a combined CD spectroscopic and theoretical study.

One-Pot, Three-Component Condensation Reaction for the Synthesis of Novel Chromeno[3,2-f]Quinoline Derivatives

A one-potsynthesis of novel chromeno[3,2- f]quinoline derivatives has been achieved with good yields through Michael Initiated Ring Closure by employing a three-component condensation of an aromatic aldehyde, 5,5-dimethylcyclohexane-1,3-dione and 6-hydroxyquinoline in the presence of a catalytic amount of Et3N in ethanol under reflux conditions. The salient features of this protocol are a simple reaction procedure, good yields, avoidance of an aqueous work-up and simple purification by recrystallisation.

Formal [2+1] Annulation (Spiro‐Cyclopropanation) Reaction between Sulfur Ylides Derived from Baylis‐Hillman Bromides and Arylidene Indane‐1,3‐Dione

AbstractThe sulfonium salts derived from the Baylis‐Hillman bromides have been successfully employed for the selective cycloproporanation of arylidene indane‐1,3‐diones to synthesize densely substituted spiro‐cyclopropanes in good to excellent yields (upto 94 %). Products were obtained mostly in 1:1 diastereomeric ratio and were isolated in pure form. Diastereoselectivity has been improved by using suitably substituted starting materials. In this case a formal [2+1] annulation reaction competes over a probable [3+2] cycloaddition reaction. The reaction proceeds through a Michael initiated ring closure process of S‐ylides to the activated olefins for the formation of structurally strained spiro‐cyclopropanes.

An efficient catalyst-free synthesis of novel chromeno[4,3-b]quinolones through Michael initiated ring closure (MIRC) reaction with in situ generated 3-(arylmethylene)chroman-2,4-diones

A catalyst-free multicomponent reaction capable of affording a wide range of eighteen novel chromeno[4,3-b]quinolone derivatives (6a–6r) via one-pot two-step domino protocol, in ethylene glycol is reported. Catalyst-free conditions along with green solvent system make the process eco-friendly as well as economical. High yields of the products were obtained in short reaction times by forming three new bonds and one stereocenter in a single operation. The salient features of the present protocol are short reaction times, eco-friendly solvents, high yields and easy work-up procedure. SYNOPSIS A catalyst-free multicomponent reaction capable of affording a wide range of novel chromeno[4,3-b]quinolone derivatives via one-pot two-step domino protocol, in ethylene glycol is reported. Catalyst-free conditions along with green solvent system make the process eco-friendly and economical.

N,N′‐Dioxide–Lanthanum(III)‐Catalyzed Asymmetric Cyclopropanation of 2‐Cyano‐3‐arylacrylates with 2‐Bromomalonates

AbstractAn efficient N,N′‐dioxide–lanthanum(III) complex catalytic system has been developed for the diastereo‐ and enantioselective Michael‐initiated ring‐closure (MIRC) reaction of 2‐cyano‐3‐arylacrylates with 2‐bromomalonates. Various chiral cyclopropanes with multiple substitutions were obtained in high yields (up to 93%) with excellent dr (>95:5 dr) and good ee values (up to 91% ee). The catalytic system also worked for the tandem halogenation/asymmetric MIRC reaction of α,β‐unsaturated nitriles, malonates and NBS. Besides, a possible catalytic model has been proposed to explain the origin of the stereoselectivity.magnified image