Regioselective Formal β-Allylation of Carbonyl Compounds Enabled by Cooperative Nickel and Photoredox Catalysis

The Tsuji–Trost reaction between carbonyl compounds and allylic precursors has been widely used in the synthesis of natural products and pharmaceutical compounds. As the α-C−H bond is far more acidic than the β-C−H bond, carbonyl compounds undergo highly regioselective allylation at the α-position and their β-allylation is therefore highly challenging. This innate α-reactivity conversely hampers diversity, especially if the corresponding β-allylation product is targeted. Herein, we present a formal intermolecular β-C−C bond formation reaction of a broad range of aldehydes and ketones with different allyl electrophiles through cooperative nickel and photoredox catalysis. β-Selectivity is achieved via initial transformation of the aldehydes and ketones to their corresponding silyl enol ethers. The overall transformation features mild conditions, excellent regioselectivity, wide functional group tolerance and high reaction efficiency. The introduced facile and regioselective β-allylation of carbonyl compounds proceeding through cooperative catalysis allows the preparation of valuable building blocks that are difficult to access from aldehydes and ketones using existing methodology.     

C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Gerüstumlagerung eines α,β -ungesättigten γ,δ-Epoxiketons bei der Birch-Reduktion: Strukturaufklärung mittels 13C-INADEQUATE-NMR-Spektroskopie

Skeleton Rearrangement of an α-β-Unsaturated γ,δ-Epoxyketone during Birch Reduction: Structure Elucidation by Means of ¹³C-INADEQUATE-NMR Spectroscopy When the γ-epoxide 2 of β-ionone is treated under standard Birch-reduction conditions, unexpectedly a 70% combined yield of regioisomeric octalones 4 and 5 is isolated. These products unquestionably result form cleavage of the central epoxide C?C bond. The structure of compounds 4 and 5 could be determined by means of ¹³C-INADEQUATE-NMR spectroscopy.     

Mechanism-inspired engineering of phenylalanine aminomutase for enhanced β-regioselective asymmetric amination of cinnamates

Turn to switch: A mutant of phenylalanine aminomutase was engineered that can catalyze the regioselective amination of cinnamate derivatives (see scheme, red) to, for example, β-amino acids. This regioselectivity, along with the X-ray crystal structures, suggests two distinct carboxylate binding modes differentiated by C(β)-C(ipso) bond rotation, which determines if β- (see scheme) or α-addition takes place.     

Effect of the N-terminal basic residue on facile Cα-C bond cleavages of aromatic-containing peptide radical cations

Fragmentation of radical cationic peptides [R(G)(n-2)X(G)(7-n)]˙(+) and [R(G)(m-2)XG]˙(+) (X = Phe or Tyr; m = 2-5; n = 2-7) leads selectively to a(n)(+) product ions through in situ C(α)-C peptide backbone cleavage at the aromatic amino acid residues. In contrast, substituting the arginine residue with a less-basic lysine residue, forming [K(G)(n-2)X(G)(7-n)]˙(+) (X = Phe or Tyr; n = 2-7) analogs, generates abundant b-y product ions; no site-selective C(α)-C peptide bond cleavage was observed. Studying the prototypical radical cationic tripeptides [RFG]˙(+) and [KFG]˙(+) using low-energy collision-induced dissociation and density functional theory, we have examined the influence of the basicity of the N-terminal amino acid residue on the competition between the isomerization and dissociation channels, particularly the selective C(α)-C bond cleavage viaβ-hydrogen atom migration. The dissociation barriers for the formation of a(2)(+) ions from [RFG]˙(+) and [KFG]˙(+)via their β-radical isomers are comparable (33.1 and 35.0 kcal mol(-1), respectively); the dissociation barrier for the charge-induced formation of the [b(2)- H]˙(+) radical cation from [RFG]˙(+)via its α-radical isomer (39.8 kcal mol(-1)) was considerably higher than that from [KFG]˙(+) (27.2 kcal mol(-1)). Thus, the basic arginine residue sequesters the mobile proton to promote the charge-remote selective C(α)-C bond cleavage by energetically hindering the competing charge-induced pathways.     

C1-C2 cleavage of C1-functionalized 8-oxabicyclo-[3.2.1]-oct-6-en-3-one. Stereoselective preparation of 4-substituted butenolides

Diastereoisomeric epimers at C1′ of 4-(1-methyl-2-oxo-butyl)-2-butenolide, and the corresponding saturated γ-lactones, were synthesized by hydrolysis of 1-methoxy-8-oxabicyclo[3.2.1] oct-6-en-3-one, under acidic conditions. These butenolides are interesting synthetic building blocks, precursors of biologically active natural products like insect pheromones. Their formation could be explained by a cleavage at the C1-C2 bond of the oxabicyclic precursor. On the basis of the experimental data we have proposed a mechanism of hydrolytic cleavage which is formally an intramolecular reverse Dieckmann process.     

Conformational Studies of Marine Polyhalogenated α-Chamigrenes Using Temperature-Dependent NMR Spectra. Cyclohexene-ring flipping and rigid-chair cyclohexane ring in the presence of equatorial halogen atoms at C(8) and C(9)

Temperature-dependent NMR spectra indicate that the α-chamigren-3-ones (?) -11 , (+) -12 , (+) -14 (?) -15 , (+) -16, 18 , and 19 bearing equatorial halogen atoms at C(8) and C(9) undergo slow conformational flipping of the envelope-shaped enone ring, while the cyclohexane ring is maintained in the chair conformation. The α-chamigren-3-ols (+) -20 and (+) -21 , obtained by hydride reduction of (+) -12 , behave similarly, with slow half-chair inversion of the cyclohexenol ring. In each case, both conformers are about equally populated and detectable by NMR, except in the case of (+) -15 , where repulsive interactions between Br? C(2) and H_eq?C(7) make the population of the conformer 15b with Me—C(5) faced to H_ax?C(10) so low that it escapes direct ¹H-NMR detection. The energy barriers to these conformational motions are viewed to arise mainly from repulsive interactions between Me—C(5) and the axial H-atoms at C(8) and C(10), while, contrary to previous beliefs, no twist-boat conformations of the cyclohexane ring intervene. Similar conclusions hold for the 4,5-epoxides of both (?) -6 and (+) -7 . Clean Jones oxidatio of (?) -2 to 17 , where the CH₂?C(5) bond is maintained, and acid dehydration-isomerization of the α-chamigrene (+) -21 to the β-chamigrene (+) -24 , reflect the special stability of β-chamigrenes, providing a reason for their frequent occurrence in nature.     

Directed synthesis of noncentrosymmetric molybdates using composition space analysis

A systematic investigation of the factors governing the reaction product composition, hydrogen bonding, and symmetry was conducted in the MoO3/3-aminoquinuclidine/H2O system. Composition space analysis was performed through 36 individual reactions under mild hydrothermal conditions using racemic 3-aminoquinuclidine. Single crystals of three new compounds, [C7H16N2][Mo3O10] x H2O, [C7H16N2]2[Mo8O26] x H2O, and [C7H16N2]2[Mo8O26] x 4 H2O, were grown. The relative phase stabilities for these products are dependent upon the reactant mole fractions in the initial reaction gel. This phase stability information was used to direct the synthesis of two new noncentrosymmetric compounds, using either (S)-(-)-3-aminoquinuclidine dihydrochloride or (R)-(+)-3-aminoquinuclidine dihydrochloride. [(R)-C7H16N2]2[Mo8O26] and [(S)-C7H16N2]2[Mo8O26] both crystallize in the noncentrosymmetric space group P2(1) (No. 4), which has the polar crystal class 2 (C2). The second-harmonic generation activities were measured on sieved powders. The structure-directing properties of the molybdate components in each compound were determined using bond valence sums. The structures of all five compounds were determined using single-crystal X-ray diffraction.     

High coordination chemically bound compounds of noble gases with hydrocarbons: Ng(CCH)4 and Ng(CCH)6, (Ng=Xe or Kr)

Ab initio calculations predict the existence of the compounds Ng(-C[triple bond]CH)4 and Ng(-C[triple bond]CH)6, where Ng=Xe or Kr. Presently known organic noble gas compounds have a coordination number of two at most. The Ng(-C[triple bond]CH)(4) molecules have D(4h) symmetry, and Ng(-C[triple bond]CH)(6) molecules have O(h) symmetry. The bonding in all these compounds is partly ionic and partly covalent, with significant contributions from both types of bonding. The relatively high vibrational frequencies and the substantial Ng-(C[triple bond]CH) binding energy in these species indicate that these compounds should be fairly stable, at least in cryogenic conditions. These compounds could be a very interesting addition to the range of known organic noble gas compounds. Suggestions are made on possible approaches to their preparation.     

Transformations of p-menthadienes under the action of potassium tert-butanolate in dimethyl sulfoxide

The products of the transformation of α- and γ-terpinenes, terpinolene, (+)-transisolimonene, and (+)-limonene under the action of potassium tert-butanolate in dimethyl sulfoxide contained — in addition to the α- and γ-terpinenes, isoterpinolene, p-mentha-3,8-diene and p-cymene found previously — terpinolene, α- and β-phellandrenes, p-mentha-2,4-diene (in a total amount of 1–3%), and polymers. Under these conditions, limonene is racemized. The primary products of the isomerization reaction have been identified. A supplementary scheme for the isomerization transformations of p-menthadienes is presented.     

Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(?) radical in the β-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.     

Synthetic Studies on Damascenones

The odor principle β-damascenone and its isomer α-damascenone have been prepared by treatment of the corresponding ethyl safranates with excess allyl lithium followed by alkoxide catalyzed isomerization of the resulting products with β, γ-unsaturated ketonic side chains. Addition of allyltriphenylphosphorane (preferably prepared from allyltriphenylphosphonium chloride) rather than the propenyl isomer to ethyl α-isopropylidene-acetoacetate produced ethyl α-safranate. This represents a new, potentially general method for the synthesis of functionalized cyclohexadienes.     

Functionalised oligoenes with unusual topologies: synthesis, electrochemistry and structural studies on redox-active

New [3]- and [4]-dendralenes bearing electron-donor 1,3-dithiole and ferrocene substituents have been synthesised. Compounds 8, 15 and 17 have been characterised by single-crystal X-ray diffraction. Two of the dithiole rings of 8 are conjugated (dihedral angle 9 degrees), while the third dithiole ring is almost orthogonal to this plane, and hence its pi-electron system is isolated. For the dendralene precursor molecule 15, the substituted cyclopentadienyl ring, two C=C bonds and fused dithiole and dithiine rings comprise an extended pi-conjugated system. In molecule 17 the potential conjugation path C(6)C(3) C(4)C(5)-C5Hs is distorted by an 8 degrees twist around the C(3)-C(4) bond and a 7 degrees twist around the C(5)-C(21) bond, and the delocalisation along the chain is insignificant. Solution electrochemical data demonstrate that the dendralenes are strong pi-electron donors, which give rise to dication, radical trication or tetracation species. Spectroelectrochemical studies on compounds 7 and 10 suggest that the radical species are situated within the linear 1,2-ethylenediylidene moieties and that a conformational change may occur at the dication redox stage. UV/Vis spectroscopic data are consistent with poor cross-conjugation in these systems.     

{(COD)Ru[RNC(H)-C(H)C(Ph)]2} (RMe, Et): The first structurally characterized mononuclear ruthenium complexes with enyl-imino ligands and their relevance in ruthenium catalyzed C-H activation reactions

The reaction of α,β-unsaturated imines with [(1,5-cyclooctadiene)-bis(2-methylallyl)-ruthenium(II)] leads to the formation of mononuclear ruthenium complexes of the general formula {(COD)Ru[RNC(H)-C(H)C(Ph)]₂}. In these complexes the imine ligands are deprotonated in β-position with respect to the imine double bond and coordinate as an enyl-imino ligand. In the case of R = Me, Et the corresponding compounds have been characterized by X-ray crystallography. The relevance of these complexes with respect to ruthenium catalyzed C-C coupling reactions of the same α,β-unsaturated imines is demonstrated by the structural analysis of another mononuclear ruthenium complex in which two imine ligands are reductively coupled (R = Cy). [(1,5-Cyclooctadiene)-bis(2-methylallyl)-ruthenium(II)] also turns out to be a highly effective precatalyst in the reaction of the respective imines with carbon monoxide and ethylene to produce heterocyclic compounds.     

5,10:8,9-Disecosteroids (= Steroklastanes): A new type of modified steroids

Thermolysis of steroidal 5α, 8α- peroxides of type 3a-d generates as major products the corresponding diseco compounds containing a 14-membered ring instead of the standard A-B-C-ring skeleton. Depending on the reaction conditions, either the primary products of type 9 or the α, β-unsaturated ketones of type 4 , formed by subsequent elimination of AcOH, are isolated. The latter, configurationally uniform compounds undergo epoxidation of the C(9)=C(10) bond followed by a Baeyer-Villiger oxidation to give, as final products, the 15-membered cyclic epoxyenol lactones of type 20 and 21 . The structures of the various products were determined by ¹H- and ¹³C-NMR spectroscopy. The conformations of the 14- and 15-membered rings were established by X-ray structure analyses of 7 and 21a . A reaction mechanism for the above transformations is discussed.     

β-Phenylseone α,β-Unsaturated Aldehydes,Efficient Three Carbon Homologating Agents. 1,3-Carbonyl Transposition

The easily obtained β-phenylseleno α,β-unsaturated aldehydes react with Grignard reagents and with n-butyllithium leading to the 1,2-addition products, which upon acidic hydrolysis in the presence of silica gel afford the selenium-free α,β-unsaturated carbonyl compounds with 1,3-carbonyl transposition.     

Co-oligomerization of ethylene and higher linear alpha olefins. I. Co-oligomerization with the sulfonated nickel ylide-based catalytic system

Co-oligomers of ethylene and a series of linear α-olefins (propylene, 1-butene, 1-hexene, 1-heptene, 1-octene, and 1-decene) were synthesized with a homogeneous catalyst consisting of sulfonated nickel ylide and diethylaluminum ethoxide at 90°C. GC analysis of the co-oligomerization products allowed complete structural identification of all reaction products, α-olefins with linear and branched chains, vinylidene olefins, and linear olefins with internal double bonds. The article describes the reaction scheme of ethylene–olefin co-oligomerization. The scheme includes chain initiation reactions (insertion of ethylene or an olefin into the Ni? H bond), chain propagation reactions, and chain termination reactions via β-hydride elimination. Primary and secondary inertions of α-olefins into the Ni? H bond in the initiation stage proceed with nearly equal probabilities. Higher olefins participate in the chain growth reactions (insertion into the Ni? C bond) also both in primary and secondary insertion modes. The primary insertion of an α-olefin molecule into the Ni? C bond produces the β-branched Ni? CH₂? CR₁R₂ group. This group is susceptible to β-hydride elimination with the formation of vinylidene olefins. However, the Ni? CH₂? CR₁R₂ groups can participate in further ethylene insertion reactions and thus form vinyl oligomerization products with branched alkyl groups. On the other hand, the secondary insertion of an α-olefin molecule into the Ni? C bond produces the α-branched Ni? CR₁R₂ bond which does not participate in further chain growth reactions and undergoes the β-hydride elimination reaction with the formation of linear reaction products with internal double bonds. Most co-oligomer molecules contain only one α-olefin fragment. However, the analysis of ethylene-propylene and ethylene-1-heptene co-oligomers allowed identification of products with two olefinic fragments which are also formed in the copolymerization reactions with small yields.     

DFT study of the fragmentation mechanism of uracil RNA base

The fragmentation process of the uracil RNA base has been investigated via DFT calculations in order to assign fragments to the ionisation mass spectrum obtained after dissociation induced by collision experiments. The analysis of the electronic distribution and geometry parameters of the cation allows selection of several bonds that may be cleaved and lead to the formation of various fragments. Differences are observed in the electronic behaviour of the bond breaking as well as the energy required for the cleavage. It is reported that N(3)-C(4) and N(1)-C(2) bonds are more easily cleaved than the C(5)-C(6) bond, since the corresponding energy barriers amount to ΔG = +1.627, +1.710, +5.459 eV, respectively, which makes the C(5)-C(6) bond cleavage almost prohibited. Among all possible formed fragments, the formation of the OCN(+) fragment for the peak at m/z = 42 Da is excluded because of an intermediate that was not observed experimentally and too a large free energy barrier. Based on the required free energy, it is observed that two fragment derivatives: C(2)H(4)N(+) and C(2)H(2)O˙(+) may be formed, with a small preference for C(2)H(4)N(+). This latter product is not formed through a retro Diels Alder reaction in contrast to C(2)H(2)O˙(+). The following sequence is proposed for the peak at 42 Da: C(2)H(4)N(+) (from N(1)-C(2), C(4)-C(5) cleavages) > C(2)H(2)O˙(+) (from N(3)-C(4), N(1)-C(2) and C(5)-C(6) cleavages) > C(2)H(4)N(+) (from N(1)-C(2), N(3)-C(4) and C(4)-C(5)) > C(2)H(2)O˙(+) (from C(5)-C(6), N(1)-C(2) and N(3)-C(4) cleavages) > NCO(+) (from N(1)-C(2), C(4)-C(5) and N(3)-C(4) cleavages). Finally the peak at 28 Da is assigned to CNH(2)(+) derivatives that can be formed through two different paths, the easiest one requiring 5.4 eV.     

Identification of the products of oxidation of quercetin by air oxygen at ambient temperature

Oxidation of quercetin by air oxygen takes place in water and aqueous ethanol solutions under mild conditions, namely in moderately-basic media (pH approximately 8-10) at ambient temperature and in the absence of any radical initiators, without enzymatic catalysis or irradiation of the reaction media by light. The principal reaction products are typical of other oxidative degradation processes of quercetin, namely 3,4-dihydroxy-benzoic (proto-catechuic) and 2,4,6-trihydroxybenzoic (phloroglucinic) acids, as well as the decarboxylation product of the latter--1,3,5-trihydroxybenzene (phloroglucinol). In accordance with the literature data, this process involves the cleavage of the gamma-pyrone fragment (ring C) of the quercetin molecule by oxygen, with primary formation of 4,6-dihydroxy-2-(3,4-dihydroxybenzoyloxy)benzoic acid (depside). However under such mild conditions the accepted mechanism of this reaction (oxidative decarbonylation with formation of carbon monoxide, CO) should be reconsidered as preferably an oxidative decarboxylation with formation of carbon dioxide, CO2. Direct head-space analysis of the gaseous components formed during quercetin oxidation in aqueous solution at ambient temperature indicates that the ratio of carbon dioxide/carbon monoxide in the gas phase after acidification of the reaction media is ca. 96:4%. Oxidation under these mild conditions is typical for other flavonols having OH groups at C3 (e.g., kaempferol), but it is completely suppressed if this hydroxyl group is substituted by a glycoside fragment (as in rutin), or a methyl substituent. An alternative oxidation mechanism involving the direct cleavage of the C2-C3 bond in the diketo-tautomer of quercetin is proposed.