Optimization of Ring‐Closing Metathesis: Inert Gas Sparging and Microwave Irradiation

A systematic study of a ring‐closing metathesis towards a tetrasubstituted double bond as part of a seven‐membered ring in a 5.7.5‐tricyclic guaianolide system is described. By combining two techniques, namely sparging an inert gas through the solution together with dielectric heating via microwave irradiation a high‐yielding ring‐closing metathesis reaction in this particularly challenging case was achieved. The results obtained compare favorably with conventional heating conditions or with microwave irradiation in a closed system. The key aspects seem to be that rapid microwave irradiation diminishes catalyst decay by allowing the required high reaction temperature to be reached quickly and homogeneously and thereby providing enough energy for a successful metathesis reaction, while inert gas sparging is purging off evolving ethylene to shift the equilibrium to the product.     

New Synthetic Approach to a [1.1.6] Metapara Cyclophane Derivative via Suzuki–Miyaura Cross‐Coupling and Ring‐Closing Metathesis

The synthesis of a [1.1.6] metapara cyclophane derivative, 1,5(1,4),3(1,3)‐tribenzenacycloundecaphan‐8‐ene‐6,11‐dione, has been achieved via the Suzuki–Miyaura cross‐coupling of α,α′‐dibromo‐m‐xylene with an arylboronic acid derivative followed by an allylation and ring‐closing metathesis reaction sequence.     

New Indenylidene‐Schiff Base‐Ruthenium Complexes for Cross‐Metathesis and Ring‐Closing Metathesis

We here report on the stability and catalytic activity of new indenylidene‐Schiff base‐ruthenium complexes 3a – f through representative cross‐metathesis (CM) and ring‐closing metathesis (RCM) reactions. Excellent activity of the new complexes was found for the two selected RCM reactions; prominent conversion was obtained compared to the commercial Hoveyda–Grubbs catalyst 2 . Moreover, excellent results were obtained for a standard CM reaction. Higher conversions were achieved with one of the indenylidene catalysts compared with Hoveyda–Grubbs catalyst. Unexpectedly, an isomerization reaction was observed during the CM reaction of allylbenzene. To the best of our knowledge, isomerization reactions in this model CM reaction in closed systems have never been described using first generation catalysts, including the Hoveyda–Grubbs catalyst. The first model CM reactions as well as the RCM reactions have been monitored using ¹H NMR. The course of the CM reaction of 3‐phenylprop‐1‐ene ( 8 ) and cis‐1,4‐diacetoxybut‐2‐ene ( 9 ) was monitored by GC. The isomerization reaction was studied by means of GC‐mass spectrometry and in situ IR spectroscopy. All catalysts were structurally characterized by means of ¹H, ¹³C, and ³¹P NMR spectroscopy.     

Stereo‐Controlled Asymmetric Bioreduction of α,β‐Dehydroamino Acid Derivatives

α,β‐Dehydroamino acid derivatives proved to be a novel substrate class for ene‐reductases from the ‘old yellow enzyme’ (OYE) family. Whereas N‐acylamino substituents were tolerated in the α‐position, β‐analogues were generally unreactive. For aspartic acid derivatives, the stereochemical outcome of the bioreduction using OYE3 could be controlled by variation of the N‐acyl protective group to furnish the corresponding (S)‐ or (R)‐amino acid derivatives. This switch of stereopreference was explained by a change in the substrate binding, by exchange of the activating ester group, which was proven by ²H‐labelling experiments.     

Ligand‐Free Nickel‐Catalysed 1,4‐Addition of Arylboronic Acids to α,β‐Unsaturated Carbonyl Compounds

A simple and efficient ligand‐free nickel‐based catalytic system has been developed for the 1,4‐addition of arylboronic acids to α,β‐unsaturated carbonyl compounds. With catalyst loadings of 1–2 mol%, a series of 1,4‐adducts from chalcones and cinnamates was obtained in moderate to excellent yields within 5–30 min under a nitrogen atmosphere and microwave irradiation. The 1,4‐addition of arylboronic acids to acrylates is less efficient.

     

One‐Pot Olefin Isomerization/Aliphatic Enamine Ring‐Closing Metathesis/Oxidation/1,3‐Dipolar Cycloaddition for the Synthesis of Isoindolo[1,2‐a]isoquinolines

N‐Alkyl‐N‐(2‐vinylbenzyl)prop‐2‐en‐1‐amine derivatives undergo a one‐pot olefin isomerization/aliphatic enamine ring‐closing metathesis (RCM)/oxidation/1,3‐dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh₃)₃, a second generation Hoveyda–Grubbs catalyst, and a 1,3‐dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2‐a]isoquinolines with a π‐conjugated four‐ring system, through three unique ruthenium‐catalyzed transformations.

     

Synthesis of Pyrrolizidine,Indolizidine, and Quinolizidine Derivatives Using Ruthenium‐Catalyzed Ring‐Opening Metathesis and Ring‐Closing Metathesis of Cycloalkene‐ynes

Ring‐opening metathesis and ring‐closing metathesis (ROM‐RCM) of a cyclopentene‐yne having an ester moiety was demonstrated using first‐ and second‐generation Grubbs’ catalysts. When the reaction of cycloalkene‐yne was carried out in the presence of 5 mol % of a ruthenium carbene complex under an ethylene atmosphere at room temperature, ROM‐RCM proceeded smoothly to give a pyrrolidine derivative in good yield, which could be converted to a pyrrolizidine derivative. Furthermore, ROM‐RCM of azabicyclo[2.2.1]heptene‐ynes using the second‐generation Grubbs’ catalyst was investigated. When an azabicycloheptene derivative was exposed to a catalytic amount of a ruthenium carbene complex, pyrrolizidine and indolizidine derivatives were obtained in good yields. The distribution of these products depends on the substituents on the alkyne. When azabicyclo[2.2.1]heptene‐ynes bearing large substituents on the alkyne were treated with ruthenium catalyst 1b , a pyrrolizidine derivative was obtained as the major product. ROM‐RCM of azabicyclo[2.2.2]octene‐ynes with 1b afforded quinolizidine derivative 20 , although the yield was moderate.     

Iridium‐Catalyzed Asymmetric Allylic Etherification and Ring‐Closing Metathesis Reaction for Enantioselective Synthesis of Chromene and 2,5‐Dihydrobenzo[b]oxepine Derivatives

Iridium‐catalyzed asymmetric etherifications of allylic carbonates with 2‐vinylphenols and 2‐allylphenols were realized. With a catalyst generated from 2 mol% of [Ir(cod)Cl]₂ (cod=cycloocta‐1,5‐diene) and 4 mol% of the phosphoramidite ligand L2 , the etherification products were obtained in excellent ees and then subjected to the ring‐closing metathesis reaction providing an efficient synthesis of enantioenriched 2H‐chromene and 2,5‐dihydrobenzo[b]oxepine derivatives.     

Mesocellular Foam‐Supported Catalysts: Enhanced Activity and Recyclability for Ring‐Closing Metathesis

Although ring‐closing metathesis (RCM) has been one of the most powerful methodologies for creating cyclic compounds, the pharmaceutical industry has not yet widely adopted this process commercially due to the high costs and leaching problems of homogeneous ruthenium catalysts. To circumvent these problems, we have immobilized the second‐generation Hoveyda–Grubbs catalyst effectively onto siliceous mesocellular foam (MCF). The open and interconnected pores of MCF facilitated ligand immobilization and substrate diffusion. We have observed that the ligand and metal loadings significantly affected the catalytic activity and recyclability. Enhanced recyclability by suppression of ruthenium leaching was achieved by using excess immobilized ligands. The resulting novel heterogenized catalysts demonstrated excellent activity and reusability for the RCM of various types of substrates.     

Organocatalytic Asymmetric Synthesis of Protected α,β‐Diamino Acids

In the presence of the readily available quinine‐derived catalyst 4d , highly diastereo‐ and enantioselective Mannich reactions of tosyl‐protected imines and α‐isothiocyanato imides proceeded to afford the protected α,β‐diamino acids, useful building blocks for natural products and biologically active compounds, in good to excellent yields.     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.     

Base‐Catalyzed Condensation of 2‐Hydroxybenzaldehydes with α,β‐Unsaturated Aldehydes – Scope and Limitations

The base‐catalyzed condensation of α,β‐unsaturated carbonyl compounds with 2‐hydroxybenzaldehydes yielding tetrahydroxanthones and dihydrobenzopyrans has been investigated. A novel access to highly functionalized dihydrobenzopyrans via a mild generation of the dienol of senecialdehyde and subsequent conjugated aldol reaction has been reported.     

Platinum‐Catalyzed Divergent Reactivity of α‐Hydroxyallenes: Synthesis of Dihydrofurans and α,β‐Unsaturated Ketones

α‐Allenols were catalytically transformed into dihydrofurans in the presence of platinum dichloride. Notably, using platinum dichloride along with silver triflate as the catalytic system, α,β‐unsaturated ketones were obtained. Therefore, the role of the silver salt may not just consist in the activation of the platinum precatalyst.

     

Regio‐ and Enantioselective Copper‐Catalyzed 1,4‐Conjugate Addition of Trimethylaluminium to Linear α,β,γ,δ‐Unsaturated Alkyl Ketones

A regio‐ and enantioselective copper‐catalyzed 1,4‐conjugate addition of trimethylaluminium to linear δ‐aryl‐substituted α,β,γ,δ‐unsaturated alkyl ketones was developed. A series of γ,δ‐unsaturated alkyl ketones were obtained in good yields with high regio‐ and enantioselectivity (up to 88% ee and 96:4 dr). Expansion of the reaction scope to substrates containing aromatic heterocycles also afforded good yields and enantioselectivities (up to 91% ee) with very high regioselectivities, exclusively providing the single 1,4‐products.

     

Ferrocene Redox Controlled Reversible Immobilization of Ruthenium Carbene in Ionic Liquid: A Versatile Catalyst for Ring‐Closing Metathesis

A ferrocene‐tagged ruthenium carbene 15 that can be reversibly immobilized in an ionic liquid (IL) via the controlled oxidation and reduction of a ferrocene tag was prepared. This offers a new strategy which uses redox chemistry to control immobilization and to recycle both the catalyst and the IL. In this experiment, 11 recycles were performed for the ring‐closing metathesis (RCM) of a substrate using 16 as the catalyst in an ionic liquid (IL). More importantly, after the reaction was completed, the ruthenium catalyst was easily separated from the supporting IL by just adding decamethylferrocene (DMFc) to reduce the cationic ferrocene and then extracting it with benzene. Thus, this recycle system offers an easy way to recycle both the ruthenium catalyst and the IL.     

Ring Size‐Selective Ring‐Closing Olefin Metathesis: Taking Advantage of the Deleterious Effect of Ethylene Gas

The deleterious effect of ethylene gas on the ring‐closing olefin metathesis (RCM) for the formation of 5‐ to 8‐membered rings was investigated. Significant rate differences caused by ethylene gas were observed among the different ring‐size formation reactions. Nevertheless, the rate differences can be advantageously utilized for chemoselective RCM.     

Bicyclic O,P Ligands for Catalytic Asymmetric 1,4‐Addition to α,β‐Unsaturated Ketones

A new class of bicyclic O,P ligands has been prepared and evaluated in the 1,4‐addition to α,β‐unsaturated ketones. The best results with the bicyclic ligand were obtained using a lower catalyst loading than what has been reported with similar ligands when adding a Grignard reagent to 2‐cyclohexenone.     

Non‐Enzymatic Geometry‐Selective Acylation of Tri‐ and Tetrasubstituted α,α′‐Alkenediols

A highly geometry‐selective organocatalytic acylation of tri‐ and tetra‐substituted 2‐alkylidene‐1,3‐propanediols has been developed. The highly E‐selective acylation of various tetrasubstituted 2‐alkylidene‐1,3‐propanediols was achieved in 96 to >99% selectivity for the first time by a non‐enzymatic protocol.     

Influence of isomer ratio and ring substituents in decomposition activation energies of α,α,α′,α′‐tetrasubstituted dibenzyls

Diethyl‐2,3‐dicyano‐2,3‐di‐(X‐substituted phenyl) succinates (X = p‐OCH₃, p‐CH₃, p‐Cl, H, p‐NO₂) can initiate the free‐radical polymerization of styrene. The decomposition rate constant and activation energy were measured by means of a dilatometer, and the results showed that they were strongly dependent on the ratio of meso‐ and dl‐isomers in the polysubstituted dibenzyl compounds and the properties of the ring substituents. On the other hand, it was found that the polystyrenes, which were obtained by initiation with hydrogen, had a much larger average molecular weight than that with p‐OCH₃ and p‐CH₃. The experimental phenomena were correlated with the structure of the radical resulting from hydrogen. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 81: 2964–2971, 2001     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.