Regio- and diastereoselective functionalization of (−)-cytisine

(−)-N-Benzyl cytisine has been stereoselectively substituted in moderate to high yields on its carbon 6 (Csp³ α to the pyridone nitrogen). The reaction involved the in situ trapping of the carbanion formed by reaction of lithium diisopropyl amide (LDA) and its reaction with electrophiles (alkyl, allyl, benzyl halides, non-enolizable aldehydes, and Weinreb amide). In the absence of an electrophile or with its addition after the formation of the carbanion, a dimeric structure was isolated (yield: 42%) resulting from the 1,4-addition of the carbanion on the pyridone ring of another cytisine molecule. Deprotection of the benzyl group (Olofson's reagent) allowed the formation of 6-substituted derivatives of the natural product, cytisine, a potent agonist of nicotinic receptors of subtype α₄β₂.     

Rearrangements of the carbanions derived from allyl benzyl thioether

The metalation of allyl benzyl thioether involves the benzylic or the allylic hydrogens. The benzylic carbanion undergoes a rapid[2,3] sigmatropic shift whereas the allylic carbanion gives rise to various rearrangements, among them migration of the allylic unit to the para position with allylic inversion. The temperature dependence of the ratio of products arising from the benzylic carbanion vs those from the allylic carbanion shows that the allylic-to-benzylic carbanion transformation occurs only under special conditions: (a) with slow addition of the base; (b) with thioether in excess relative to the base, and (c) on raising the temperature of the reaction medium from ?78° to ?15°. In the last instance, the proton transfer is intramolecular as shown with labeled thioethers. The extent of the different rearrangements depends on the temperature and solvent. A choice of mechanism cannot be made at this time for the para migration 5→9a. A leaving group effect on the reaction regioselectivity of the carbanion from allyl methyl thioether with benzyl halides has been noticed. The presence of dibenzyl indicates that, in addition to S_N2 reactions, some electron transfer process is occurring.     

Estimating carbon—mercury bond ionisation constants from PMR spectra of methylmercury compounds

Analysis of J(¹⁹⁹HgCH₃) spin coupling constants in PMR spectra of CH₃HgX (where X is a carbanion) shows that the affinity of various X groups for the methylmercury cation is linearly dependent on the acidity of the respective CH-acids XH.     

Reactions of transition metal carbonyl anions with 2-(1-bromoalkylidene)thiazolidin-4-ones: halogenophilic attack or deprotonation

Bromophilic attack by the transition metal carbonyl anion, [Re(CO)₅]Na (pK_a = 21.1), on 2-(1-bromoalkylidene)thiazolidin-4-ones is significantly faster than abstraction of an acidic lactam hydrogen (pK_a ∼17-18), when the generated carbanion is stabilized by an α-CN or α-PhCO group. The bromophilic reaction of 2-(1-bromoalkylidene)thiazolidin-4-one, having an α-CN electron-withdrawing group, resulted in formation of a new metallacyclic anionic complex. With less reactive vinyl bromides, containing an α-CONHPh or α-CO₂Et group, only deprotonation is observed. The role of the metal carbonyl anion is highlighted by a comparison with the 9-methylfluorenide carbanion (pK_a of 9-methylfluorene is 22.3), which reacts exclusively via a deprotonation pathway.     

Hybrid-Density Functional Theory Study and Natural Bond Orbital Interpretation of the Conformational Behavior of 1,3-Dioxanyl, 1,3-Dithianyl,and 1,3-Diselenanyl Carbanions

Abstract

The effective factors on the conformational properties of 1,3-dioxanyl (1), -dithianyl (2), and -diselenanyl (3) carbanions have been investigated by means of the hybrid-density functional theory (DFT) (B3LYP/6-311+G**)-based method and natural bond orbital (NBO) interpretation. The results obtained showed that the axial conformation (i.e., the axial H atom attached to C₂) of carbanion 1 is more stable than its equatorial conformation. Contrary to the carbanion 1, the equatorial conformations of carbanions 2 and 3 are more stable than their corresponding axial conformations. The instability of the axial conformations of carbanions 1–3 increases from carbanion 1 to carbanion 2 but decreases from carbanion 2 to carbanion 3. The NBO analysis showed that the anomeric effect (AE) associated with the electron delocalization increases from carbanion 1 to carbanion 2, but decreases from carbanion 2 to carbanion 3. The calculated total dipole moment values of the axial conformations of carbanions 1–3 are greater than those of their corresponding equatorial conformations, but the calculated total dipole moment difference values between the axial and equatorial conformations decreases from carbanion 1 to carbanion 3. Consequently, the AE associated with the electron delocalization, but not the total dipole moment changes (i.e., Δμ_ax–eq), thus explaining the total energy differences between the axial and equatorial conformations of carbanions 1–3. The correlations between the AE, dipole moments, ΔG_ax–eq, structural parameters, and conformational behaviors of carbanions 1–3 have been investigated.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Synthesis of some substituted 5,6,11,12-tetrahydro-dibenzo[a,e]cyclooctene derivatives through the intermediacy of tricarbonyl(η-arene)chromium complexes

5,6,11,12-Tetrahydrodibenzo[a,e]cyclooctene derivatives with α- and β-substituents are readily accessible from [Cr(CO)₃(5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene)] 2 via a two-step sequence, which involves addition of a nucleophile and oxidation of the intermediate anionic cyclohexadienyl complex. Nucleophiles used included LiCMe₂CN (A), LiCH₂CN (B), and (C). The results show that the primary carbanion LiCH₂CN and the S-stabilized carbanion give mixtures of α- and β-substituted products and in both cases α-isomers were major, whereas the opposite regioselectivity was obtained with the tertiary carbanion LiCMe₂CN.     

Electrochemical disk generation and ring identification of carbanions from organomercurials in acetonitrile

A rotating disk-ring electrode was used for study of a series of organomercury compounds R₂Hg, where R = CN, CF(NO₂)₂, C₆F₅, PhCC, p-NO₂C₆H₄OCC, PhSCH₂CC, PhCOCH₂, CH₂CN, CCl₂CCl, 2-phenyl-o-carboranyl. Reduction of these compounds at a Pt-disk in acetonitrile is a two-electron process and results in generation of the carbanion R^?. The carbanions generated at the disk interact with the solvent during their convective diffusion to the ring electrode where there may be oxidized. The main reaction in solution, shown using chromatography-mass spectrometry techniques, is acid-base interaction of carbanions with the solvent acetonitrile, which acts as a Brönsted acid. Reaching the ring, the carbanions may be oxidized at anodic potentials of the ring; oxidation potentials depend significantly on carbanion structure (e.g.+0.28 V (vs. SCE), for PhCC^? and +2.20 V for CN^?. It is shown that PK_a value of the carbanions do not correlate with the oxidation potentials, however, a linear correlation is observed between pK_a values and a special parameter called the efficiency coefficient.     

Boron trifluoride etherate-assisted ring opening of ethylene oxide by a chiral organolithium: enantioselective synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine

A practical synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine in high enantiomeric purity is described. The synthesis involves BF₃·Et₂O-assisted ring opening of ethylene oxide by a homochiral carbanion (R)-3, which is derived from sparteine-mediated asymmetric deprotonative lithiation of 1-Boc-pyrrolidine.     

gem-Difluoromethylation of α- and γ-ketoesters: preparation of gem-difluorinated α-hydroxyesters and γ-butyrolactones

PhSCF₂SiMe₃ has been demonstrated as difluoromethyl carbanion synthon (⁻CF₂H). It reacts chemoselectively with α- and γ-ketoesters at the keto group in the presence of a catalytic amount of TBAF in THF to give the corresponding α-hydroxy ester adducts as well as γ-gem-difluorophenylsulfanylmethylated-γ-butyrolactones in good yields. Reductive cleavage of the phenylsulfanyl group of these products employing Bu₃SnH/AIBN gives the corresponding gem-difluoromethylated α-hydroxyesters and γ-butyrolactones in good yields.     

Reactivite des carbanions benzyliques : VI. Structure et reactivite du trimethylsilyl-9 dihydro-9,10 anthracene; preparation des bis(trimethylsilyl)-9,9 et trimethylsilyl-9 alkyl-9 dihydro-9,10 anthracenes

The structure of 9-trimethylsilyl-9,10-dihydroanthracene (Me₃SiDHA) has been studied by NMR; the coupling constants of the three 9,10 protons do not change at between 25 and 90°C (ABM spectrum; J_AB }- 18.2; J_AM ? 1.2; J_BM ? 0.3 Hz in toluene-d₈), indicating that the Me₃Si group prefers the quasi axial position. In the presence of BuLi in THF, Me₃SiDHA reacts with Me₃SiCl to yield three new products: 9,9-bis(trimethylsilyl)-9,10-dihydroanthracene (IId) (major), (9,10-dihydroanthracen-9-yl)dimethylsilyl(trimethylsilyl)methane (V) and (9-trimethylsilyl-9,10-dihydroanthracen-9-yl)dimethylsilyl(trimethylsilyl)-methane (VI) together with the known 9,10-bis(trimethylsilyl)-9,10-dihydroanthracene (cis and trans). The carbanion of Me₃SiDHA can also be alkylated (alkyl  Me, Et, i-Pr) to the new 9,9-disubstituted derivatives: 9-Me₃Si-9-alkyl-DHA.The formation of the carbanion of Me₃SiDHA has been investigated and reveals a competition in the abstraction by the base of H₉ and H₁₀; the latter is less crowded but the 9-carbanion is stabilized by the vicinity of the silicon atom. The carbanion obtained from Me₃SiDHA reacts exclusively at C(9) with D₂O. A study of the alkylation of 9-trimethylsilyl-9-deuterio-9,10-dihydroanthracene shows that the generation of the 10-carbanion is followed by a 1,4 hydrogen rearrangement which yields the 9-carbanion. The mechanism is discussed and the roles of Me₃Si and t-Bu are compared in the DHA series.     

First SNAr reaction using TDAE-initiated carbanions in quinazoline series

We report herein the first example of a S_NAr reaction using TDAE-initiated carbanions in quinazoline series. The o-nitrobenzyl carbanion, formed by the action of TDAE on o-nitrobenzyl chloride, reacts with 4-chloro-2-trihalomethylquinazolines 4 and 5 via a S_NAr mechanism. This enabled a new series of 4-benzyl-2-trihaloquinazoline derivatives to be synthesized in good yields under mild reaction conditions offering promising prospects for pharmacomodulation.     

α,α-Difluoro-α-phenylsulfanylmethyl carbanion equivalent: a novel gem-difluoromethylenation of carbonyl compounds

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃) has been demonstrated as an α,α-difluoro-α-phenylsulfanylmethyl carbanion equivalent. gem-Difluorophenylsulfanylmethylation of carbonyl compounds has been successfully achieved by using PhSCF₂SiMe₃ in the presence of TBAF in THF. The adducts have been converted to the corresponding gem-difluoroalkenes by a novel pyrolytic and/or FVP elimination of the β-hydroxy-α-phenylsufinyl derivatives under reduced pressure.     

Halogens in γ-position enhance the acidity of alkyl aryl sulfones and alkane nitriles

On the basis of measuring the rates of base-catalyzed deuterium exchange the pK_a values of a series of 3-halopropyl aryl sulfones and 4-halobutyronitriles were estimated. It was shown that halogen substituents, although separated from the carbanionic site, exert a substantial carbanion stabilizing effect. These effects were rationalized by DFT calculations.     

Role of base in palladium-catalyzed arylation of carbanions

The arylation reaction of carbanions, derived from certain sulfones, cyanoacetic ester and malononitrile, with aryl bromides (using the catalytic system of Pd₂dba₃/3L, L=PPh₃, PtBu₃) as well as the reaction of the carbanions with one equivalent of 4-CF₃C₆H₄ Pd(PPh₃)₂Br has been studied. These reactions proceed smoothly provided that the base stronger than the initial carbanion is present in the reaction mixture. In the absence of the above type of base the reactions do not proceed at all. Taking that into account we have proposed a novel mechanism of palladium-catalyzed arylation of CH-acids. The main feature of this mechanism is the accelaration of the reductive elimination due to the deprotonation of the intermediate ArPdL₂CHXY. The correlation between the carbanion reactivity and the pK_a values for related CH-acids as well as the ligand effect are discussed in the framework of the proposed mechanism.     

Formation et réactivité de carbanions α phosphoramides. Mise en évidence d'une nouvelle réaction d'élimination

The reactivity of (diethoxy)-N-methyl-N-benzyl phosphoramide (I) and bis(dinethylamino)-N-methyl-N-benzylphosphoramide (II) when treated with strong bases (RLi, R₂NLi) is very different: (I) gives a novel elimination, whereas (II) under the same experimental conditions gives a stable carbanion whose reactivity has been investigated.     

A Quantum Chemical Study of the Acidity of Acetylene and 1,2-Dihydrobuckminsterfullerene Derivatives

DFT PBE0/cc-pVDZ method and the polarizable continuum model were used to determine pK _a values for buckminsterfullerene-acetylene hybrids C₆₀HCCH, C₆₀HCN, tert-butylacetylene, and propyne relative to tert-BuC₆₀H in a vacuum, carbon disulfide, tetrahydrofuran, and dimethyl sulfoxide. The energies of the СH-acid molecule and the carbanion (fulleride- or acetylide anion) were calculated using the same number of Gaussian orbitals. The surfaces of cavities formed by molecules and anions in a solvent are composed of spheres encompassing both atomic nuclei and lone electron pairs. An additional sphere excludes the solvent from the inner cavity of the fullerene.     

Mechanistic investigation and DFT calculation of the new reaction between S-methylisothiosemicarbazide and methyl acetoacetate

A study on the synthesis and mechanistical aspects of formation of 3-methyl-5-oxo-3-pyrazolin-1-carboxamide (MOPC) starting from S-methylisothiosemicarbazide hydrogen iodide and methyl acetoacetate was performed. In the alkaline aqueous solution, the intermediate methyl acetoacetate S-methylisothiosemicarbazone undergoes substitution of CH₃S^? anion by hydroxide anion, cyclization, carbanion formation, and elimination of methanol, thus yielding corresponding Na-enolate salt of pyrazol-5-one derivative. The structure of the compound obtained after protonation of the formed enolate salt was determined by means of spectroscopic techniques and single-crystal X-ray diffraction analysis. The mechanism of conversion of methyl acetoacetate S-methylisothiosemicarbazone into MOPC was investigated by means of the B3LYP functional, and it was found that the reaction is thermodynamically controlled.     

Oxidative nucleophilic substitution of hydrogen in nitroarenes with phenylacetic acid derivatives

Oxidative nucleophilic substitution of hydrogen (ONSH) in nitroarenes with carbanion of isopropyl phenyl acetate gives various products depending on the conditions and oxidant. The reaction carried out in liquid ammonia and KMnO₄ oxidant gives iso-propyl α-hydroxy-α-nitroarylphenylacetates formed via hydroxylation of the initial ONSH products. In some cases additionally dimeric, trimeric and tetrameric products are formed. In THF and Bu₄N⁺MnO₄⁻ or DDQ oxidants simple ONSH products are formed whereas oxidation by dimethyl dioxirane (DMD) gave iso-propyl hydroxyaryl phenyl acetates. The dimeric and trimeric products are apparently formed via coupling of nitrobenzylic radicals generated in course of oxidation with nitrobenzylic carbanions of the ONSH products.     

Synthesis of well-defined star block copolymers using 1,1-diphenylethylene chemistry

We described the use of 1,1 diphenylethylene derivatives in the synthesis of well-defined star block copolymers. Classical end-capping of polystyryl carbanion with −CH₂CH₂OTBDMSi derivative gives a heterobifunctional macroinitiator leading to ABC star block copolymers through successive anionic and ring opening polymerizations (ROP) or anionic and atom transfer radical (ATRP) polymerizations. An unexpected reaction between polystyryl carbanion and −CH₂OTBDMSi derivative, strongly depending on the medium polarity, opens an easy way to either A₂B or A₃B star block copolymers.     

1H NMR and kinetics studies of the reaction of 4-methyl, 4-bromo and 3-trifluoromethyl benzyltriflones with aromatic nitro-compounds

Rate measurements are reported for the reactions in methanol of carbanions derived from benzyltriflones, 2a–c, with 4-nitrobenzofurazan derivatives, 4a and 4b, to give anionic σ-adducts. ¹H NMR studies in DMSO-d₆ of the reaction of benzyltriflones, 2, and 4-nitrobenzofurazan, 4a, in the presence of triethylamine are consistent with products formed by the elimination of trifluoromethyl sulfinic acid from σ-adducts initially formed by carbanion attack at the 5-position of 4a. Evidence for the high steric requirements of the benzyltriflone anions come from the low value of β; the slope of the linear plot of values of log k₅ versus pK_a.