Reductive Ring-opening Reaction Research Articles

Homologation of Alkenyl Carbonyls via a Cyclopropanation/Light-Mediated Selective C-C Cleavage Strategy.

We report herein our studies on the direct photoactivation of carbonyl cyclopropanes to give biradical intermediates, leading to selective cleavage of the more substituted carbon-carbon bond. Depending on the substrate structure, extended alkenes were isolated or directly reacted in a photo-Nazarov process to give bicyclic products. Based on these results, a unified reductive ring-opening reaction was developed by using diphenyl disulfide as a HAT reagent. By performing a sequential cyclopropanation/selective ring opening reaction, we achieved a CH2 insertion into the α,β bond of both acyclic and cyclic unsaturated carbonyl compounds. Our protocol provides a further tool for the modification of the carbon framework of organic compounds, complementing the recent progress in "skeletal editing".

Nickel-catalysed highly regioselective synthesis of β-acyl naphthalenes under reductive conditions.

Over the past decade, significant progress has been made in the direct C-H acylation of naphthalenes, occurring at the α or β-positions to yield valuable ketones through Friedel-Crafts acylation or transition-metal-catalysed carbonylative coupling reactions. Nevertheless, highly regioselective acylation of naphthalenes remains a formidable challenge. Herein, we developed a nickel-catalysed reductive ring-opening reaction of 7-oxabenzonorbornadienes with acyl chlorides as the electrophilic coupling partner, providing a new method for the exclusive preparation of β-acyl naphthalenes.

Photocatalytic dicarboxylation of strained C[sbnd]C bonds with CO2via consecutive visible-light-induced electron transfer

Dicarboxylic acids have a wide range of applications in the polymer industry to construct valuable materials. Photocatalysis has recently emerged as an efficient and sustainable strategy to generate dicarboxylic acids. However, photocatalytic dicarboxylation with CO2 is mainly limited to unsaturated bonds, and the dicarboxylation of CC single bonds still remains a challenge. Herein, we report a photocatalytic dicarboxylation of CC single bonds in strained rings with CO2 units via consecutive photo-induced electron transfer (ConPET). It is also the first photocatalytic reductive ring-opening reaction of cyclobutanes. Notably, this transition-metal-free protocol exhibits good functional group tolerance, broad substrate scope, facile scalability, and easy product derivatizations. Moreover, diacids can easily be derivatized to main-chain liquid crystalline polyesters.

Photocatalytic Carboxylation of C-N Bonds in Cyclic Amines with CO2 by Consecutive Visible-Light-Induced Electron Transfer.

Visible-light photocatalytic carboxylation with CO2 is highly important. However, it still remains challenging for reluctant substrates with low reduction potentials. Herein, we report a novel photocatalytic carboxylation of C-N bonds in cyclic amines with CO2 via consecutive photo-induced electron transfer (ConPET). It is also the first photocatalytic reductive ring-opening reaction of azetidines, pyrrolidines and piperidines. This strategy is practical to transform a variety of easily available cyclic amines to valuable β-, γ-, δ- and ϵ-amino acids in moderate-to-excellent yields. Moreover, the method also features mild and transition-metal-free conditions, high selectivity, good functional-group tolerance, facile scalability and product derivations. Mechanistic studies indicate that the ConPET might be the key to generating highly reactive photocatalysts, which enable the reductive activation of cyclic amines to generate carbon radicals and carbanions as the key intermediates.

Cobalt-catalyzed ring expansion/ring opening of oxetanes using phosphine oxides as promoters under hydroformylation conditions

Phosphine oxides, especially tricyclohexylphosphine oxide (P7), promote the cobalt catalyzed carbonylative ring expansion and reductive ring opening reaction of oxetanes under syngas atmosphere. Depending on the substrate structure and the stability of the carbocation intermediate either γ-lactones or primary alcohols are obtained in moderate to excellent yields. Syngas proved to play a crucial role for the catalyst activity and its stability in this process. Green solvents with high sustainability rankings, such as dimethyl carbonate (DMC), can be used in replacement of traditional solvents. The optimized conditions for both procedures were substrate (1 mmol), Co2(CO)8 (2 mol%), DMC (2 mL), 100 °C, gas phase – CO/H2 (1:1) 40 atm, 24 h resulting in the yields of 56–94% in the ring expansion, and 65–94% in the ring opening of oxetanes.

Flavin-enabled reductive and oxidative epoxide ring opening reactions

Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis.

Mechanism of Pd/C-catalyzed hydrogenation of furfural under hydrothermal conditions

Catalytic hydrogenation of furfural under hydrothermal conditions is of great importance and has recently attracted huge attention as an approach to obtaining a wide range of valuable chemicals from a renewable source. However, the data concerning the reaction mechanism of aqueous-phase furfural hydrogenation are very scarce, and it is still not clear which reactions lead to various carbonyl compounds, such as cyclopentanone, 4-oxopentanal, 5-hydroxy-2-pentanone. Herein, we present the results of an experimental study of the mechanism of reactions occurring in the furfural hydrogenation under hydrothermal conditions over the 1% Pd/CNTs catalyst. The following approaches have been used to study the reaction mechanism: hydrogenation of key intermediates formed upon the furfural conversion, and isotopic labeling experiments using D2O as a tracer in hydrogenation of furfural, which provides direct evidence of the occurring reactions. It was found that the furfural hydrogenation process is realized through four pathways including various reductive and acid-catalyzed furan ring opening reactions. The methods and approaches used in the present work, as well as the results obtained, can be useful in studying the mechanism of aqueous-phase hydrogenation of a wide range of oxygen-containing substrates in the presence of catalysts of different compositions.

Asymmetric Transfer Hydrogenation of Heterobicyclic Alkenes with Water as Hydrogen Source.

The asymmetric transfer hydrogenation of heterobicyclic alkenes was accomplished by using water as the sole hydrogen source. The transformation was co-catalyzed by Pd(OAc)2/Zn(OTf)2 dual catalyst with metallic zinc as reducing agent. Various azabenzonorbornadienes and oxabenzonorbornadienes were transformed to the corresponding chiral 1,2-dihydronaphthalenes by the asymmetric reductive ring-opening reactions with good to excellent enantioselectivities.

Additive-Free Three-Component Synthesis of Spiro-isoxazolidine-oxindoles Employing Trifluorodiazoethane.

An efficient three-component protocol for the synthesis of trifluoromethylated spiro-isoxazolidine-oxindoles has been developed. This approach employs the 1,3-dipolar cycloaddition of trifluoromethyl nitrone, generated in situ from trifluorodiazoethane and nitrosoarene, with phenacylideneoxindoles. A range of phenacyclideneoxindoles and nitrosoarenes can be subjected to this reaction to generate the spiro-isoxazolidine-oxindole derivatives. The reductive ring-opening reaction of isoxazolidines carried out to demonstrate the synthetic potential of our strategy resulted in an interesting rearrangement to yield pyrroloquinoline derivatives.

Formation and reductive ring opening reactions of indolyl bicyclic-isoxazolidines-II:7 access to novel natural product analogs

Attempted reductive cleavage of indolyl-bicyclic-isoxazolidines (4a,b; R=benzyl, phenyl) with ammonium formate, methanol-THF solvents, at ambient temperature, in the presence of Pd/C lead to facile synthesis of indolyl-α-hydroxy-γ-lactams (5a–b), derived from reductive cleavage of the NO bond of bicyclic-isoxazolidines, followed by intramolecular recyclization. On the other hand, reaction of 4c (R=ethyl) under identical conditions follows a different course affording 6, an analogue of naturally occurring marine alkaloid, aplysinopsin. A mechanistic rationale of observed reactivity behavior, supported by DFT calculations, is provided.

Formation and reductive ring opening reactions of indolyl-isoxazolidines: access to novel natural product analogs and precursors

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (2) with variedly substituted dipolarophiles were carried out to obtain syn- C4 and C5 substituted indolyl-isoxazolidines 6a–c and 7a–f, respectively. Reduction of obtained isoxazolidines, by employing various reducing agents, causes cleavage of the N–O bond, which is accompanied by concomitant cleavage of C–N bond leading to the formation of a library of novel indole based natural product analogs and precursors.

1,3-Dipolar cycloaddition reactions of phthalic anhydrides with an azomethine ylide

A series of phthalic anhydrides underwent a 1,3-dipolar cycloaddition reaction with N-benzylazomethine ylide to produce unstable spiro(isobenzofuran-1,5′-oxazolidin)-3-ones, which underwent a subsequent reductive ring-opening reaction to afford 1(3H)-isobenzofuranones.

Highly efficient and clean synthesis of 1-amino-2-acetylanthraquinone by copper-catalyzed reductive cleavage of isoxazole motif

A clean and highly efficient synthesis of 1-amino-2-acetylanthraquinone via reductive isoxazole ring cleavage of 3-methylanthra[1,2- c ]isoxazole-6,11-dione catalyzed by trace copper using hydrazine hydrate as a clean reducing agent and water as a green reaction medium under mild reaction conditions was investigated. Various transition-metal catalysts were screened for the reductive ring-opening reaction, and Cu(NO 3 ) 2 was shown to be an excellent catalyst. A conversion of 97.2% and 1-amino-2-acetylanthraquinone selectivity greater than 95% were obtained in the presence of 2.6 mol% Cu(NO 3 ) 2 (turnover number 38) with 1.3 equiv. of hydrazine hydrate for 2 h in water. The structure of the product was confirmed by 1 H nuclear magnetic resonance spectroscopy and mass spectrometry; the main byproduct was hydroxyl-substituted 1-amino-2-acetylanthraquinone. A possible reaction mechanism for the copper-catalyzed ring cleavage of 3-methylanthra[1,2- c ]isoxazole-6,11-dione with hydrazine hydrate was proposed. A trace-copper-catalyzed reductive isoxazole-ring-cleavage strategy for clean and highly efficient production of 1-amino-2-acetylanthraquinone under mild reaction conditions was presented.

Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines.

A rapid and simple procedure was devised for the synthesis of multifunctionalized cyclic β-amino esters and γ-amino alcohols via the 1,3-dipolar cycloaddition of nitrile oxides to β-aminocyclopentenecarboxylates. The opening of the isoxazoline reductive ring to the corresponding highly functionalized 2-aminocyclopentanecarboxylates occurred stereoselectively with good yields.

ChemInform Abstract: Synthesis of Tri‐ or Tetrasubstituted Pyrimidine Derivatives Through the [5 + 1] Annulation of Enamidines with either N,N‐Dimethylformamide Dialkyl Acetals or Orthoesters and Their Application in a Ring Transformation of Pyrimidines to Pyrido[2,3‐d]pyrimidin‐5‐one Derivatives.

The [5+1] annulation of enamidines, which were prepared from functionalized silanes, organolithium compounds and two nitriles, with N,N-dimethylformamide dialkyl acetals as the C1 unit is described, leading to the synthesis of tri- and tetrasubstituted pyrimidine derivatives under catalyst- and solvent-free reaction conditions. Furthermore, the [5+1] annulation of enamidines by using orthoesters as the C1 unit is described, in which catalytic amounts of ZnBr(2) catalyze the annulation to produce polysubstituted pyrimidines under toluene or xylene reflux conditions. Moreover, the combination of a reductive ring-opening reaction with [Mo(CO)(6)] and a subsequent intramolecular cyclization with tBuOK effectively causes a skeletal transformation from the pyrimidines containing an isoxazolyl and an ethoxy substituent to form pyrido[2,3-d]pyrimidin-5-one frameworks in excellent yield.

Synthesis of (−)-benzolactam-V8 by application of asymmetric aziridination

(−)-Benzolactam-V8, an artificially-designed cyclic dipeptide with strong tumor-promoter activity, was synthesized from benzyl ( S)- N-(2-formylphenyl)- N-methylvalinate by application of guanidinium ylide-participated asymmetric aziridination followed by the reductive ring-opening reaction of 3-arylaziridine-2-carboxylate formed.

Synthesis of Tri‐ or Tetrasubstituted Pyrimidine Derivatives through the [5+1] Annulation of Enamidines with either N,N‐Dimethylformamide Dialkyl Acetals or Orthoesters and Their Application in a Ring Transformation of Pyrimidines to Pyrido[2,3‐d]pyrimidin‐5‐one Derivatives

The [5+1] annulation of enamidines, which were prepared from functionalized silanes, organolithium compounds and two nitriles, with N,N-dimethylformamide dialkyl acetals as the C1 unit is described, leading to the synthesis of tri- and tetrasubstituted pyrimidine derivatives under catalyst- and solvent-free reaction conditions. Furthermore, the [5+1] annulation of enamidines by using orthoesters as the C1 unit is described, in which catalytic amounts of ZnBr(2) catalyze the annulation to produce polysubstituted pyrimidines under toluene or xylene reflux conditions. Moreover, the combination of a reductive ring-opening reaction with [Mo(CO)(6)] and a subsequent intramolecular cyclization with tBuOK effectively causes a skeletal transformation from the pyrimidines containing an isoxazolyl and an ethoxy substituent to form pyrido[2,3-d]pyrimidin-5-one frameworks in excellent yield.

Formal Total Synthesis of (+)-Lysergic Acid via Zinc(II)-Mediated Regioselective Ring-Opening Reduction of 2-Alkynyl-3-indolyloxirane

Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH(3)CN as the key step. With Zn(OTf)(2) as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.

Solvent‐ and Temperature‐Dependent Functionalisation of Enantioenriched Aziridines

A highly stereo- and regioselective functionalisation of chiral non-racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1 a,b, two differently configured chiral aziridinyllithiums could be generated (trans-1 a,b-Li in toluene and cis-1 a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1 c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1 c-ortho-Li at -78 °C and α-lithiated aziridine 1 c-α-Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and α-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1 a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α-lithiated aziridine (1 c-α-Li) has been generated at 0 °C. In addition, ortho-hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.

ChemInform Abstract: Synthesis and Reactivity of Enantiomerically Pure 2-Fluoromethyl-2-(1′-p-tolylsulfinyl)alkyl Oxiranes.

This paper presents an efficient procedure for preparing enantio- and diastereomerically pure 2-fluoromethyl-2-(1′-p-tolylsulfinyl)alkyl oxiranes, designed as versatile chirons to be transformed to a series of synthetically useful and biologically relevant compounds. In particular, (2S)-2-fluoromethyl-2-(1′-p-tolylsulfinyl)alkyl oxiranes, prepared by the reaction between (RS)-α-alkyl-β-keto-γ-fluoro sulfoxides and diazomethane, can be efficiently obtained in diastereomerically pure state via formation, purification and re-cyclization of the corresponding bromohydrins. Synthetic value of these oxiranes was demonstrated by their transformation to various sulfur-free synthetically and biologically interesting compounds via the reductive desulfurization, Pummerer, ring-opening and syn-elimination reactions. The presence of the methyl in α-position to the sulfoxide group in the starting compounds was found to interfere with a normal course of the Pummerer rearrangement giving rise to the corresponding vinyl sulfides in low chemical yield. By contrast the thermal syn-elimination reaction of the p-tolyl sulfoxide group provided an efficient entry to the sulfur-free vinyl derivatives.