Effect of halogens on the activity of halonitrobenzenes in reactions with carbanions

On the basis of competition experiments using a model VNS reaction of chloromethyl phenyl sulfone with halonitrobenzenes it was shown that halogen substituents activate electron-deficient nitroarenes for the addition of carbanions whereas they protect the positions they occupy against the addition.     

Vicarious Nucleophilic Substitution of Hydrogen and Formation of Aziridine Rings in Reactions of Benzonaphthyridines and their N-Oxides with Chloromethyl Phenyl Sulfone

 Treatment of benzonaphthyridines with chloromethyl phenyl sulfone in the presence of base led to the formation of aziridine rings annelated to the benzonaphthyridine skeleton, whereas their N-oxides underwent vicarious nucleophilic substitution of hydrogen (VNS), thus leading to the corresponding phenylsulfonylmethyl derivatives.     

Vicarious Nucleophilic Substitution of Hydrogen and Formation of Aziridine Rings in Reactions of Benzonaphthyridines and their N-Oxides with Chloromethyl Phenyl Sulfone

Summary.  Treatment of benzonaphthyridines with chloromethyl phenyl sulfone in the presence of base led to the formation of aziridine rings annelated to the benzonaphthyridine skeleton, whereas their N-oxides underwent vicarious nucleophilic substitution of hydrogen (VNS), thus leading to the corresponding phenylsulfonylmethyl derivatives. Received December 11, 2000. Accepted (revised) January 22, 2001     

Substituent effects on the electrophilic activity of nitroarenes in reactions with carbanions

The effect on electrophilic activity of substituents located para, ortho, and meta to the nitro group of nitrobenzenes was determined by using vicarious nucleophilic substitution of hydrogen (VNS) with the carbanion of chloromethyl phenyl sulfone (1) as the model process. Values for the relative activities of substituted nitroarenes are given relative to nitrobenzene, which was taken as the standard. This process was chosen as a model reaction because it meets key criteria, such as the wide range of substituents that can be present on the nitrobenzene ring, a low sensitivity to steric hindrance, and in particular the possibility of ensuring conditions in which the overall relative rates of reaction in competitive experiments are equal to the relative rates of nucleophilic addition. The values of relative rates of addition, which were taken to be a measure of electrophilic activity, were determined by competitive experiments in which pairs of nitroarenes competed for the VNS reaction with carbanion of 1. A comprehensive set of data for effects of substituents on the electrophilic activity of nitroarenes is presented for the first time.     

Reactions of nitroheteroarenes with carbanions: bridging aromatic, heteroaromatic, and vinylic electrophilicity

The relative rate constants for the vicarious nucleophilic substitution (VNS) of the anion of chloromethyl phenyl sulfone (1-) with a variety of nitroheteroarenes, for example, nitropyridines, nitropyrroles, nitroimidazoles, 2-nitrothiophene, and 4-nitropyrazole, have been determined by competition experiments. It was shown that nitropyridines are approximately four orders of magnitude more reactive than nitrobenzene. Among the five-membered heterocycles 2-nitrothiophene is the most active followed by nitroimidazoles and 4-nitropyrazole. Nitropyrroles are the least electrophilic nitroheteroarenes with reactivities comparable to nitrobenzene. Quantum chemically calculated methyl anion affinities (B3LYP/6-311G(d,p)//B3LYP/6-31G(d)) of the nitroarenes correlated only moderately with the partial relative rate constants. The correlation of these activities with the LUMO energies of nitroarenes is even worse. By measuring the second-order rate constants of the addition of 1- to nitroarenes and to diethyl arylidenemalonates 10, it was possible to link the electrophilic reactivities of nitroheteroarenes with the comprehensive electrophilicity scale based on the linear-free-energy-relationship log k(20 degrees C)=s(N+E).     

A three-component coupling process based on vicarious nucleophilic substitution (VNS(AR))-alkylation reactions: an approach to indoprofen and derivatives.

The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen reacts with a series of alkyl halides to generate the corresponding alpha-alkylated conventional VNS product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a range alpha-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component coupling reaction. Reactions of alpha-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16) with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones and esters bearing an alpha-aryl quaternary center. The VNS-alkylation protocol has been applied to the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four steps and 24% overall yield from nitrobenzene.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones

The sulfone functional group has a strong capacity to direct the asymmetric transfer hydrogenation (ATH) of ketones in the presence of [(arene)Ru(TsDPEN)H] complexes by adopting a position distal to the η⁶‐arene ring. This preference provides a means for the prediction of the sense of asymmetric reduction. The sulfone group also facilitates the formation of a range of reduction substrates, and its ready removal provides a route to enantiomerically enriched alcohols that would otherwise be extremely difficult to prepare by direct ATH of the corresponding ketones.     

Regioselectivity in SNH reactions of some 3-nitro-1,8-naphthyridines with chloromethyl phenyl sulfone

A number of 2-X-3-nitro-1,8-naphthyridines (X= H,D,OH,Cl,NH₂, OEt) react with the anion of chloromethyl phenyl sulfone exclusively into 2-X-3-nitro-4-(phenylsulfonylmethyl)-1,8-naphthyridines in high yield. The reaction is found by quantum chemical calculations to be controlled by the interactions of the HOMO of the nucleophile with the LUMO of the substrate, and not by charge.     

S<Subscript>N</Subscript><Superscript>H</Superscript> reactions of 3-fluoronitroarenes with chloromethyl sulfone as the method for the construction of 6-fluoro-3-sulfonylindoles

5-R-6-Fluoro-3-phenylsulfonylindoles were synthesized by the S_N ^H reaction of 3-fluoronitrobenzenes with chloromethyl phenyl sulfone in DMSO in the presence of KOH with subsequent reduction of the nitro group and intramolecular cyclization of imidates. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1980–1984, October, 2007.     

1H NMR Detection of σ-Adducts in S NH Reactions of Nitroquinolines with Chloromethyl Phenyl Sulfone

The intermediate -adducts of chloromethyl phenyl sulfone with 3-nitro-, 5-nitro-, 6-nitro-, 7-nitro- and 8-nitroquinoline are detected by ¹H NMR spectroscopy.     

Metalation of alkyl aryl sulfones: qualitative and quantitative product determination

The metalation of methyl phenyl sulfone (I) and methyl naphthyl sulfone (II) was investigated under a variety of conditions. The product species were determined qualitatively and quantitatively after characterization with some electrophilic agents. After the primary metalation at the methyl position, species of various metalation degrees were prsent simultaneously, including the 1,1,1-trimetalated derivatives. With high LiR/sulfone ratios, in addition to the products of the primary metalation, compounds arising from metalation of the aromatic ring were formed as well as those from reduction, cleavage, etc.     

Asymmetric synthesis of α,β-epoxysulfones via phase-transfer catalytic Darzens reaction

Described is the asymmetric synthesis of α,β-epoxysulfones by the catalytic phase-transfer Darzens reaction of chloromethyl phenyl sulfone with various aromatic aldehydes in the presence of the cinchona alkaloid-derived chiral phase-transfer catalysts bearing N-2,3,4-trifluorobenzyl moiety. The trans-(αR,βR)-epoxysulfones were obtained in good chemical yields (81-95%) with high enantioselectivities (up to 97% ee) in the presence of N-(2,3,4-trifluorobenzyl)quinidinium bromide.     

Quantum-chemical study of the regioselectivity in <Emphasis Type="Italic">S</Emphasis><Subscript>N</Subscript>H reactions of some 3-nitro-1,5-naphthyridines with chloromethyl phenyl sulfone

Quantum-chemical calculations of geometries and the heats of formation of the intermediate σ-adducts in the reaction of 3-nitro-1,5-naphthyridine and its 2-substituted derivatives with the carbanion of the chloromethyl phenyl sulfone have been investigated by the PM3 method. The calculations confirm the experimentally observed regioselectivity of the studied reactions. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1845–1849, December, 2005.     

Comparative study on the transition metal complexes of a novel thiacalix[4]arene derivative

A comparative study on Zn²⁺ and Cu²⁺ complexes of the novel compound 5,11,17,23-tetra-tert-butyl-25,27-bis{[4-(methoxycarbonyl)phenyl]methoxy}-2,8,14,20-tetrathiacalix[4]arene, that possesses potential as a core unit for the construction of molecular receptors, is presented using semiempirical AM1 calculation. The possible structures of each metal complex and their corresponding energetic data are compared with the parent 5,11,17,23-tetra-tert-butyl-2,8,14,20-tetrathiacalix[4]arene. The complexation ability of both thiacalix[4]arenes towards the two metal ions is discussed on the basis of binding energies. Both thiacalix[4]arene 1:1 complexes show higher complexation ability towards Cu²⁺. However, 5,11,17,23-tetra-tert-butyl-25,27-bis{[4-(methoxycarbonyl)phenyl]methoxy}-2,8,14,20-tetrathiacalix[4]arene presents lower complexation ability when compared with the 5,11,17,23-tetra-tert-butyl-2,8,14,20-tetrathiacalix[4]arene. The results of liquid–liquid extraction experiments of the thiacalix[4]arenes are in good agreement with the theoretical calculations.     

Cyclometalated complexes derived from calix[4]arene bisphosphites and their catalytic applications in cross-coupling reactions

Palladium and platinum dichloride complexes of a series of symmetrically and unsymmetrically substituted 25,26;27,28-dibridged p-tert-butyl-calix[4]arene bisphosphites in which two proximal phenolic oxygen atoms of p-tert-butyl- or p-H-calix[4]arene are connected to a P(OR) (R = substituted phenyl) moiety have been synthesized. The palladium dichloride complexes of calix[4]arene bisphosphites bearing sterically bulky aryl substituents undergo cyclometalation by C-C or C-H bond scission. An example of cycloplatinated complex is also reported. The complexes have been characterized by NMR spectroscopic and single crystal X-ray diffraction studies. During crystallization of the palladium dichloride complex of a symmetrically substituted calix[4]arene bisphosphite in dichloromethane, insertion of oxygen occurs into the Pd-P bond to give a P,O-coordinated palladium dichloride complex. The calix[4]arene framework in these bisphosphites and their metal complexes adopt distorted cone conformation; the cone conformation is more flattened in the metal complexes than in the free calix[4]arene bisphosphites. Some of these cyclometalated complexes proved to be active catalysts for Heck and Suzuki C-C cross-coupling reactions but, on an average, the yields are only modest.     

Chemically engineered papain as artificial formate dehydrogenase for NAD(P)H regeneration

Organometallic complexes of the general formula [(η(6)-arene)Ru(N?N)Cl](+) and [(η(5)-Cp*)Rh(N?N)Cl](+) where N?N is a 2,2'-dipyridylamine (DPA) derivative carrying a thiol-targeted maleimide group, 2,2'-bispyridyl (bpy), 1,10-phenanthroline (phen) or ethylenediamine (en) and arene is benzene, 2-chloro-N-[2-(phenyl)ethyl]acetamide or p-cymene were identified as catalysts for the stereoselective reduction of the enzyme cofactors NAD(P)(+) into NAD(P)H with formate as a hydride donor. A thorough comparison of their effectiveness towards NAD(+) (expressed as TOF) revealed that the Rh(III) complexes were much more potent catalysts than the Ru(II) complexes. Within the Ru(II) complex series, both the N?N and arene ligands forming the coordination sphere had a noticeable influence on the activity of the complexes. Covalent anchoring of the maleimide-functionalized Ru(II) and Rh(III) complexes to the cysteine endoproteinase papain yielded hybrid metalloproteins, some of them displaying formate dehydrogenase activity with potentially interesting kinetic parameters.     

The 1.4 and 248 nm radiation response of chemically amplified resists containing arylmethyl sulfone photoacid generators

The X-ray (1.4 nm) and deep UV (248 nm) radiation responses of chemically amplified photoresists incorporating arylmethyl sulfone photoacid generators were evaluated. The arylmethyl sulfones were primarily derivatives of benzyl phenyl sulfone, selected to reveal the importance of desulfonylation and internal abstraction with regard to the photochemical efficiency of acid generation. At 1.4 nm, benzyl phenyl sulfone gave a much more sensitive resist than dibenzyl sulfone, while the methyl derivatives of benzyl phenyl sulfone did not give much improvement over the parent compound. This suggests that desulfonylation is more important than internal abstraction for increased photochemical efficiency. At 248 nm, similar trends were observed, but with some modifications arising from the variation in extinction coefficient among the sulfones. Sensitivities at or below 20 mJ/cm² were obtained for both wavelength ranges.     

Identification of alkylarene chloromethylation products using gas-chromatographic retention indices

Gas-chromatographic retention indices on standard nonpolar polydimethylsiloxane stationary phases allow identification of products formed by known organic reactions even without using mass-spectrometric data. The efficiency of this approach was demonstrated by the example of identification of previously uncharacterized chloromethyl derivatives of alkylarenes, including structural isomers of compounds containing several chloromethyl groups, directly in reaction mixtures. Chromatographic analysis of such reaction mixtures allows identification of positional isomers of the starting alkylarenes even when they are present simultaneously. The retention indices were determined for the first time for more than 50 alkyl-(chloromethyl)arenes, by-products of chloromethylation, and chloromethyl derivatives of the simplest alkyl phenyl ketones.     

Molybdocalixarene structure control via rim deprotonation. synthesis, characterization, and crystal structures of calix[4]arene Mo(VI) monooxo complexes and calix[4]arene alkali metal/Mo(VI) dioxo complexes

We report a series of calix[4]arene Mo(VI) dioxo complexes M2RC4MoO2 (M = alkali metal, R = H or Bu(t)) that were fully characterized by NMR, X-ray, IR, UV/vis, and elemental analysis. Molybdocalix[4]arene structures can be controlled via lower rim deprotonation, groups at para positions of calix[4]arene, and alkali metal counterions. Mono deprotonation at the lower rim leads to calix[4]arene Mo(VI) monooxo complexes RC4MoO (R = H, Bu(t), or allyl), and full deprotonation gives rise to calix[4]arene Mo(VI) dioxo complexes. Structural studies indicate that HC4 Mo(VI) dioxo complexes easily form polymeric structures via cation-pi interaction and coordination between different calixarene units. However, Bu(t)C4 Mo(VI) dioxo complexes tend to form dimers or tetramers due to steric hindrance of the tert-butyl groups at para positions in calixarene. The structures of the reduced side products A and C were determined by X-ray diffraction studies. The mechanism of RC4MoO formation from the reaction of calixarene monoanions with MoO2Cl2 appears to include the addition of a calixarene -OH group across a Mo=O bond.