Methylene Insertion Research Articles

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

Zinc Carbenoid-Promoted Methylene Insertion in Saturated Heterocycles: Mechanistic Insights and Reactivity Profiles

AbstractThe ring expansion of saturated heterocycles through methylene insertion into N–O bonds using a zinc carbenoid is described. This transformation is applied to 1,2-oxazetidines and 1,2-oxazolidines, while N-tosylated 1,2-oxazinane affords a ring-opened product. Density functional theory calculations suggest a stepwise reaction mechanism of the ring expansion and elucidate the origins of the different reactivities observed.

Methylene Insertion into Nitrogen-Heteroatom Single Bonds of 1,2-Azoles via a Zinc Carbenoid: An Alternative Tool for Skeletal Editing.

The nitrogen-heteroatom single bonds of 1,2-azoles and isoxazolines underwent methylene insertion in the presence of CH2 I2 (6 equiv.) and diethylzinc (3 equiv.) to produce a wide variety of the ring-expanded six-membered heterocycles. Density functional theory calculations suggest that the methylene insertion proceeds via cleavage of nitrogen-heteroatom single bonds followed by ring closure.

Catalytic Methylene Insertion between Amines and Terminal Alkynes via C–N Bond Cleavage of N,N-Dimethylacetamide: A Unique Route to Propargylic Amines

A copper-based system allows for the methylene insertion between an amine and a milder nucleophile, including a terminal alkyne counterpart, via C-N bond cleavage of N,N-dimethylacetamide. The method gives an expedient access to propargylic amines in good to excellent yields. A wide-ranging substrate scope and late-stage functionalization of complex molecules make the protocol practically valuable.

Lewis Acid Catalysed Asymmetric One-Carbon Ring-Expansion of Prochiral Cyclobutanones

AbstractEnantioselective methylene insertion into prochiral cyclobutanones is described providing access to chiral β-substituted cyclopentanones as important structural motif in synthesis and natural products. Commercially available trimethylsilyl as well as other silyl diazomethanes act as one-carbon synthon and scandium triflate is found to be a potent Lewis acid catalyst. By using bis(oxazoline) ligands, enantioinduction is achieved for a number of β-substituted cyclopentanones including examples bearing all-carbon quaternary stereocentres.

Reactivity of the TpRu(HN=CPh2)(PPh3)−Azido complex and Insertion of Methylene into the Tp B−H Bond

• We report [3+2] cycloaddition reactions of alkyne with the ruthenium azido complex. • The stable triazolato and tetrazolato products obtained in all cases were N (2)-bound. • We report that during protonation of ruthenium azido complex, methylene insertion accidentally took place, to yield unusual boron-methylated product. • Their structures are elucidated by IR, NMR and X-ray crystallography. Herein, we report on the reactivity of an Ru(II) azido complex allowing the facile synthesis of further interesting complexes. Starting from the parent chlorido complex (HN=CPh 2 )[Ru]−Cl { 1 , [Ru] = Tp(PPh 3 )Ru; Tp = HB(pz) 3 , pz = pyrazolyl)} the title complex (HN=CPh 2 )[Ru]−N 3 ( 2 ) was obtained upon reaction with NaN 3 . The N (2)-bound 4,5-bis-(methoxycarbonyl)-1,2,3-triazolato complex (HN=CPh 2 )[Ru]−{N 3 C 2 (CO 2 Me) 2 } ( 3 ) was obtained from reaction of 2 with dimethyl acetylene dicarboxylate (DMAD). Protonation of 3 with HCl afforded the N -coordinated triazolato complex {HN 3 C 2 (CO 2 Me) 2 }[Ru]−Cl ( 4 ). Reaction of CS 2 with 2 produced the thiocyanato complex (HN=CPh 2 )[Ru]−NCS ( 5 ). The Ru tetrazolato complex (HN=CPh 2 )[Ru]−N 4 C[C(CN)=C(CN) 2 ] ( 6 ) was prepared from 2 and tetracyanoethylene (TCNE). The reaction of 2 with HX gave the 17-electron Ru(III) complexes (Cl)[Ru]−X ( 7a , X = Cl ; 7b , X = Br) and the Ru(II) complexes containing the methyl tris(pyrazolyl)borate ligand Me Tp(PPh 3 )(HN=CPh 2 )Ru−X ( 8a , X = Cl ; 8b , X = Br), as a result of an unusual methylene insertion into the B−H bond of the Tp ligand with the CH 2 Cl 2 solvent as the assumed source for the methylene. The structures of 4, 5, 7a, 7b and 8b had been determined by X-ray diffraction analysis.

Formal Methylene Insertion into the C–H Bond of α-Carbonyl Aldonitrones with Dimethylsulfoxonium Methylide

Abstract A methylene group was introduced into the C–H bond of α-carbonyl aldonitrones by reaction with dimethylsulfoxonium methylide, producing one-carbon homologated C-methyl ketonitrones. This formal methylene insertion was applied to one-pot synthesis of quaternary C3-methyl isoxazolidines via successive 1,3-dipolar cycloaddition with alkenes bearing an electron withdrawing group.

You Only React Twice: Synthesis of 2-Iminothietanes by Twofold Methylene Insertion to Isothiocyanates

You Only React Twice: Synthesis of 2-Iminothietanes by Twofold Methylene Insertion to Isothiocyanates

Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four‐Membered Sulfur‐Containing Cycles

AbstractA formal CH2−CH2homologation conducted with C1 carbenoids on a carbon electrophile for the obtainment of a four‐membered cycle is reported. The logic proposes the consecutive delivery of two single nucleophilic CH2units to an isothiocyanate—as competent electrophilic partner—resulting in the assembling of a rare imino‐thietane cluster. The single synthetic operation procedure documents genuine chemocontrol, as indicated by the tolerance to various reactive elements decorating the starting materials. Significantly, the double homologation protocol is accomplished directly on a carbon electrophile, thus not requiring the installation of heteroatom‐centered manifolds (e.g. boron).

Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four-Membered Sulfur-Containing Cycles.

A formal CH2−CH2 homologation conducted with C1 carbenoids on a carbon electrophile for the obtainment of a four‐membered cycle is reported. The logic proposes the consecutive delivery of two single nucleophilic CH2 units to an isothiocyanate—as competent electrophilic partner—resulting in the assembling of a rare imino‐thietane cluster. The single synthetic operation procedure documents genuine chemocontrol, as indicated by the tolerance to various reactive elements decorating the starting materials. Significantly, the double homologation protocol is accomplished directly on a carbon electrophile, thus not requiring the installation of heteroatom‐centered manifolds (e.g. boron).

Reactivity and mechanism in reactions of methylene halides with cycloneophylplatinum(II) complexes: Oxidative addition and methylene insertion

ABSTRACT The reactions of methylene halides, CH2X2, with cycloneophylplatinum(II) complexes [Pt(CH2CMe2C6H4)(NN)], NN = 4,4’-di-t-butyl-2,2’-bipyridine or 3,4,7,8-tetramethyl-1,10-phenanthroline, gave either the product of cis oxidative addition [PtX(CH2X)(CH2CMe2C6H4)(NN)] or of cis oxidation with methylene insertion [PtX2(CH2CMe2C6H4CH2)(NN)]. By monitoring the reactions by NMR spectroscopy, it was shown that the major route to the methylene insertion product was by rearrangement of the initial product of oxidative addition. When X = I and NN = 4,4’-di-t-butyl-2,2’-bipyridine, the products of trans oxidative addition and methylene insertion were also detected in solution at intermediate stages of reaction. The methylene insertion step was strongly retarded in the presence of free halide, indicating that reaction occurred by way of a cationic intermediate formed by halide dissociation from [PtX(CH2X)(CH2CMe2C6H4)(NN)]. The chemistry gives useful insight into the possible mechanisms operating in catalytic chemistry involving methylene halides as methylene insertion reagents.

Hypervalent iodine mediated synthesis of imidazo[1,2-a]pyridine ethers: consecutive methylene linkage and insertion of ethylene glycol

Hypervalent iodine mediated selective synthesis of imidazo[1,2-a]pyridine ethers using ethylene glycol as a methoxy ethanol source as well as solvent under metal-free conditions is described.

Confinements on growth sites of Fischer-Tropsch synthesis, manifesting in hydrocarbon-chain branching – Nature of growth site and growth-reaction

Confinements on growth sites are recognized as essential principle of Fischer-Tropsch synthesis. Chain branching is sensitive against chain size. Similarities between FT-growth-sites and homogeneous pincer-complex catalysts are realized.In house developed methods for time resolved investigation of activity and selectivity are applied. An advanced ASF-model is defined, and on this basis probabilities of branching are calculated from experimental product distributions. Chain-length dependence in branching is quantified as branching pattern. Confinements on branching are studied for iron- and cobalt catalyst at varied CO partial pressure and during catalyst restructuring.With cobalt, FT-growth sites are observed as of dynamic nature, CO being involved. With iron, growth sites are stable, even during catalyst carbiding. The basic parameter to constitute a FT-growth site, be it on iron or cobalt, are specific confinements, regardless of differences in chemical or structural nature. Results and discussion of this work are aiming at disclosing the miracle of “gasoline synthesis from CO + H2 at normal pressure”, invented by Franz Fischer and Hans Tropsch, as the methylene insertion on homogeneous-complex-alike sites on the catalyst surface.

α-Alkoxyalkyl Triphenylphosphonium Salts: Synthesis and Reactions

Following numerous applications of Wittig reaction now functionalized phosphonium salts are gaining attention due to their characteristic properties and diverse reactivity. This review is focused on α-alkoxyalkyl triphenylphosphonium salts: an important class of functionalized phosphonium salts. Alkoxymethyltriphenylphosphonium salts are majorly employed in the carbon homologation of carbonyl compounds and preparation of enol ethers. Their methylene insertion strategy is extensively demonstrated in the total synthesis of a wide range of natural products and other important organic molecules. Similarly enol ethers prepared thereof are important precursors for different organic transformations like Diels-Alder reaction, Claisen rearrangement, Coupling reactions, Olefin metathesis and Nazarov cyclization. Reactivity of these α-alkoxyalkylphosphonium salts have also been studied in the nucleophilic substitution reactions. A distinctive application of this class of phosphonium salts was recently reported in the phenylation of carbonyl compounds under very mild conditions. Synthesis of structurally diverse alkoxymethyltriphenylphosphonium salts with variation in alkoxy groups as well as counter anions are reported in literature. Here we present a detailed account of different synthetic methodologies for the preparation of this unique class of quaternary phosphonium salts and their applications in organic synthesis.

Ring-size controlled dimerization of synthetic zinc chlorophyll derivatives possessing a 1-azacycloalkyl group through mutual coordination of amino moiety to central zinc atom

Zinc methyl 3-devinyl-pyropheophorbides-a bearing a (1-azacycloalkyl)methyl group at the 3-position were prepared by chemically modifying naturally occurring chlorophyll-a. The azacyclobutylated molecules closely dimerized through double coordination of the 31-nitrogen atom to the central zinc atom in 1%(v/v) dichloromethane and hexane to give red-shifted visible absorption and reverse S-shaped circular dichroism (CD) bands. The azacyclopentyl analog formed similarly π–π interacted and A-ring overlapped dimers with relatively weakened and lengthened Zn–N bonds to show less split excitonic bands, and its cofacial and anti-parallel supramolecule giving S-shaped CD bands was inversely twisted by the insertion of a methylene group in the 1-azacycloalkyl moiety. One more methylene insertion as in the azacyclohexyl derivative induced a least coordination ability and no more dimerization, so the compound with the most sterically crowded 31-N was monomeric in the less polar organic solvent. Steric factor at around the 31-nitrogen atom controlled the dimerization and affected the supramolecular structure with excitonically coupling visible absorption and CD bands.

Phenyliodine(III) Diacetate/I2 -Mediated Domino Approach for Pyrrolo[1,4]Thiazines and 1,4-Thiazines by a One-Pot Morin Rearrangement of N,S-Acetals.

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.

Stereochemistry of oxidative addition reactions of cycloneophyl complexes of Platinum(II): A methylene insertion reaction from dichloromethane

Unusual features are observed in studies of oxidative addition to cycloneophylplatinum(II) complexes [Pt(CH2CMe2C6H4)(NN)], 2, NN = 3,4,7,8-tetramethyl-1,10-phenanthroline (phen*) or 3, NN = 4,4′-di-t-butyl-2,2′-bipyridine (bubipy). The oxidative addition of 4-nitrobenzyl bromide to 2 or of HgCl2 to 3 occurs with cis stereochemistry to give [PtBr(CH2-4-C6H4NO2)(CH2CMe2C6H4)(phen*)] or [PtCl(HgCl)(CH2CMe2C6H4)(bubipy)], whereas similar reactions with dimethylplatinum(II) complexes occur with trans stereochemistry. The reaction of 2 with CH2Cl2 occurs, with formal insertion of methylene into the arylplatinum bond, to give [PtCl2(CH2CMe2C6H4CH2)(phen*)], the first time such a reaction has been observed with the reagent CH2Cl2. Hydrogen peroxide reacts with 2 to give oxidative addition with trans stereochemistry to give [Pt(OH)2(CH2CMe2C6H4)(phen*)] and reaction with chlorinated solvent then gives [PtCl(OH)(CH2CMe2C6H4)(phen*)]. Depending on the reaction conditions, the peroxyacid m-ClC6H4CO3H reacts with 2 to give [Pt(OH2)2(CH2CMe2C6H4)(phen*)](m-ClC6H4CO2)2, [{Pt(OH2)2(CH2CMe2C6H4)(phen*)}.{Pt(OH)(OH2)(CH2CMe2C6H4)(phen*)}](m-ClC6H4CO2)3, or [PtCl{OOC(=O)C6H4Cl-m}(CH2CMe2C6H4)(phen*)]. Computational studies indicate that the stereochemistry of oxidative addition may be determined by kinetic or thermodynamic factors in different cases, and that the unique CH2 insertion reaction with CH2Cl2 occurs by a radical mechanism. X-ray structure determinations are reported for eight of the platinum(IV) complexes.

Methylene insertion into an Fe2S2 cluster: formation of a thiolate-bridged diiron complex containing an Fe-CH2-S moiety.

Reduction of a thiolate-bridged FeIIFeIII complex leads to the cleavage of an Fe-S bond by the insertion of the methylene unit from CH2Cl2 to give a neutral FeIIFeIII complex with a novel Fe-CH2-S fragment. The structural and electrochemical differences of the alkylated and the non-alkylated Fe2S2 complexes are also examined.

Cs2CO3-promoted methylene insertion into disulfide bonds using acetone as a methylene source.

An efficient halogen-free Cs2CO3-promoted methylene insertion into disulfide bonds has been achieved using acetone as a methylene source under mild conditions. This method provides a convenient and practical route to dithioacetals in up to 96% yield with good functional group compatibility.

Oxidative cyclisation and methylene insertion in 1,3-indandione derivatives .The mechanistic studies

Dimethyl sulphoxide activated by acetic-anhydride introduces methylthiomethyl group into phenols,oxidises certain medicinally useful secondary alcohols to their corresponding ketones and brings about oxidative rearrangements in different substrates.It converts 4-hydroxy coumarins and dicoumarols,under varying conditions,to a variety of products of both pharmaceutical and mechanistic interest.
 When1,3-indandione (1) was interacted with this versatile reagent at water bath temperature,it afforded an ylide (2) and an oxidative cyclisation product (3).However,its interaction with Ar –CH = (CN)R,leads to the formation of a mechanistically interesting compound,indeno[1,2-b]-4H pyran(4). 
 DMSO alone has been used as a reagent and yields a number of products of mechanistic interest with different substrates.When 1,3-indandione (1) was refluxed with DMSO alone at elevated temperature,it results the formation of poly(methylene-bis) 1,3-indandione(5) involving methylene group insertion between different 1,3-indandione moieties.Methylene insertion has also been observed when 1,3-indandione (1) was condensed with formaldehyde in presence of alkali carbonates or primary amines to yield (6)and(7) respectively.