Abstract  Incidents involving the release of chemical agents can pose significant risks to public health. In such an event, emergency decontamination of affected casualties may need to be undertaken to reduce injury and possible loss of life. To ensure these methods are effective, human volunteer trials (HVTs) of decontamination protocols, using simulant contaminants, have been conducted. Simulants must be used to mimic the physicochemical properties of more harmful chemicals, while remaining non-toxic at the dose applied. This review focuses on studies that employed chemical warfare agent simulants in decontamination contexts, to identify those simulants most suitable for use in HVTs of emergency decontamination. Twenty-two simulants were identified, of which 17 were determined unsuitable for use in HVTs. The remaining simulants (n = 5) were further scrutinized for potential suitability according to toxicity, physicochemical properties and similarities to their equivalent toxic counterparts. Three suitable simulants, for use in HVTs were identified; methyl salicylate (simulant for sulphur mustard), diethyl malonate (simulant for soman) and malathion (simulant for VX or toxic industrial chemicals). All have been safely used in previous HVTs, and have a range of physicochemical properties that would allow useful inference to more toxic chemicals when employed in future studies of emergency decontamination systems.

Abstract  A new malonate possessing two pyrene moieties was synthesized as a fluoroionophore, and its structure and fluorescence spectroscopic properties were investigated. When excited at 344 nm in acetonitrile/chloroform (9:1, v/v), the synthesized bispyrenyl malonate has the fluorescence of intramolecular excimer (λem = 467 nm) emissions and not a pyrene monomer emission (λem = 394 nm). A large absolute fluorescence quantum yield was obtained in the solid state (ΦPL = 0.65) rather than in solution (ΦPL = 0.13). X-ray crystallography analysis clarified the molecular structure and alignment of the bispyrenyl malonate in the crystal phase, elucidating its fluorescence spectroscopic properties. Such analysis also suggests there are intramolecular C-H···π interactions and intermolecular π···π interactions between the pyrenyl rings. Interestingly, the synthesized bispyrenyl malonate exhibits excellent fluorescence sensing for the Cu2+ ion. Remarkable fluorescence intensity enhancement was only observed with the addition of the Cu2+ ion.

Abstract  Two novel carbohydrate-derived pyridyl (PYOX)- and cyclopropyl (CYBOX)-substituted oxazoline ligands were prepared from d-glucosamine hydrochloride and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-d-glucopyranose hydrochloride in two steps, respectively. The sugar-annulated PYOX ligand formed a stable metal complex with Pd(II), which was fully characterized by NMR spectroscopy and X-ray crystallography. NMR and X-ray analysis revealed a change of the conformation in the sugar moiety upon complexation with the palladium(II) species. Both glycosylated ligands resulted in high asymmetric induction (up to 98% ee) upon application as chiral ligands in the Pd-catalyzed allylic alkylation of rac-1,3-diphenylallyl acetate with dimethyl malonate (Tsuji-Trost reaction). Both ligands provided mainly the (R)-enantiomer of the alkylation product.

Abstract  A transition-metal-free decarboxylation coupling process for the preparation of α-amino acid esters, which succeeded in merging hydrolysis/decarboxylation/nucleophilic substitution, is well described. This strategy uses commercially available inexpensive starting materials, catalysts and oxidants and has a wide substrate scope and operational simplicity.

Abstract  A novel strategy of initiating an organocatalysed dynamic kinetic resolution (dr up to 99 : 1 and er up to 94 : 6) for the synthesis of chiral trans-2,5-dialkylcyclohexanones by an asymmetric conjugate addition of dimethyl malonate on to 6-substituted cyclohexenones is reported.

Abstract  Fragmental topology-activity landscapes (FRAGTAL), a new concept for encoding molecular descriptors for fragonomics into the framework of the molecular database records is presented in this paper. Thus, a structural repository containing biological activity data was searched in a substructure mode by a series of molecular fragments constructed in an incremental or decremental manner. The resulted series of database hits annotated with their activities construct FRAGTAL descriptors encoding a frequency of the certain fragments among active compounds and/or their activities. Actually, this method might be interpreted as a simplified adaptation of the frequent subgraph mining (FSM) method. The FRAGTAL method reconstructs the way in which medicinal chemists are used to designing a prospective drug structure intuitively. A representative example of the practical application of FRAGTAL within the ChemDB Anti-HIV/OI/TB database for disclosing new fragments for HIV-1 integrase inhibition is discussed. In particular, FRAGTAL method identifies ethyl malonate amide (EMA) as the diketo acid (DKA) related arrangement. Since new molecular constructs based on the EMA fragment are still a matter of future investigations we referred to this as anthe DKA offspring.

Abstract  The domino three-component coupling reaction of arynes with DMF and active methylenes or methines was studied as a highly efficient method for preparing heterocycles. Coumarin derivative 5 was formed when diethyl malonate (2) or α-bromomalonate (3) were used as a C2-unit. In contrast, dihydrobenzofurans 7a and 7b were obtained by using α-chloroenolates generated from α-chloromalonates 4a and 4b and Et2Zn. The benzofuran 15a could be obtained by using ethyl iodoacetate (14) as a C1-unit. The one-pot conversion of dihydrobenzofurans 7a, 7b and 8a into benzofurans 15a and 15b was also studied. The direct synthesis of benzofuran 15b was achieved by using the active methine 18 having ketone and ester groups.

Abstract  In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea organocatalysts 7-9 have been prepared in five steps starting from (+)-camphor. In addition, borneol-derived bifunctional thiourea organocatalysts 19/19' have been prepared in three steps from (1S)-(+)-camphorquinone. Novel organocatalysts 7-9, 19/19' have been evaluated in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene with low to moderate enantioselectivities (20%-60% ee). Configuration of all novel compounds has been meticulously determined using nuclear magnetic resonance (NMR) techniques.

Abstract  Active methylene compounds such as acetone, butanone, cyclopentanone, nitromethane, malononitrile, ethyl 2-cyanoacetate, diethyl malonate, and ethyl acetylacetate react with the C3 position of N-confused porphyrin in the presence of L-proline in refluxing THF-EtOH affording a variety of N-confused porphyrin derivatives in moderate yield. L-Proline catalyzes the reaction facilitating the formation of the carbanion derived from an active methylene compound simultaneously delivering protons to the N-confused porphyrin. Both processes are key factors of this reaction.

Abstract  The mechanism of Michael addition reactions of 1,3-dicarbonyl compounds to cyclic enones catalyzed by bifunctional Ru catalysts bearing N-sulfonylated (R,R)-DPEN ligands (DPEN = (R,R)-1,2-diphenylethylenediamine) was studied by NMR and DFT computational analyses. NMR investigation of the stoichiometric reactions of chiral amido Ru complexes, Ru(N-sulfonylated dpen)(η(6)-arene) 1a-c, with dimethyl malonate 2 and β-keto ester 3 revealed that at decreased temperatures deprotonation proceeds in a stereoselective manner to provide amine complexes. The reaction with malonic ester 2 provided exclusively C-bound amino Ru complexes 6a,c, while the reaction of β-keto ester 3 gave an equilibrium mixture of rapidly interconverting C- and O-bound complexes. The structures of C-bound Ru complex 6c and O-bound Ru complex 9c were determined by single crystal X-ray analysis. A computational study showed that the enatioselective C-C bond formation proceeds through intermediate formation of chelating ion pairs that coordinate a molecule of enone via the Ru metal center producing a highly organized environment for the C-C bond formation, yielding selectively only one enantiomer of the product. Systematic study of a series of the catalyst-substrate combinations revealed that the experimentally observed sense of enantioselection was consistently explained by computational analysis. The tendency of increasing ee with the bulk of the coordinated arene in Ru complex is reproduced computationally by changes in the difference of either ZPPE-corrected energies or Gibbs free energies for S- and R-pathways.

Abstract  ABSTRACT: Depending on the reaction conditions, different aluminium dialkylmalonate derivatives were obtained by reaction of aluminium alkoxides Al(OR)3 (R = Et, iPr, tBu) with dialkylmalonates, viz. Al(malonate)3 (malonate = dimethyl, diethyl, di-iso-propyl and di-tert-butyl malonate), Al2(OiPr)4(malonate)2 (malonate = di-iso-propyl and di-tert-butyl malonate), Al2(OiPr)2(di-iso-propylmalonate)4 and Al3(OH)(OEt)3(diethylmalonate)5. All compounds were characterized by NMR spectroscopy, and single crystal structure analyses are reported for each type of compound. An Al2(OiPr)2(dialkylmalonate)4 derivative was only obtained by disproportionation of Al2(OiPr)4(di-iso-propylmalonate)2, but not by reaction of Al(OiPr)3 with dialkylmalonates in the corresponding molar ratio. Reactions of Al(OtBu)3 only resulted in Al(malonate)3 derivatives, but no transesterification was observed, contrary to the reaction of Al(OiPr)3 with dimethyl or diethyl malonate.

GRAPHICAL ABSTRACT:

Abstract  Reaction of aryl nitriles with potassium ethyl malonate in the presence of zinc chloride and a catalytic amount of Hünig's base provided beta-amino acrylates in moderate to good yield. Compared to the classical Blaise reaction, this reaction is safer (endothermic), devoid of lacrimatory reagent, and is possible with 0.5-1.0 equiv of zinc chloride.

Abstract  [structure: see text]. A new series of amphiphilic G1-G3 dendrons containing purely aliphatic hydrocarbon dendritic surface sectors and one or two carboxylic acid group(s) at the focal point was synthesized in good yields. The key branching steps involve diallylation reactions of diethyl malonate or Meldrum's acid. These dendrons are highly soluble in hexane despite having highly polar carboxylic acid groups at the focal point.

Abstract  Threefold symmetrical chiral podands may simplify the stereochemistry of key catalytic intermediates for cases in which they only act as bidentate ligands. This applies to systems in which chemical exchange between the different kappa2-coordinated forms takes place and in which the non-coordinated sidearm may play a direct or indirect role at some earlier or later stage in the catalytic cycle. Palladium(II)-catalysed allylic substitutions provide appropriate test reactions along these lines. A series of neutral dichloropalladium(II) complexes, [PdCl2(iPr-trisox)] (1a), [PdCl2(Ph-trisox)] (1b), [PdCl2(Bn-trisox)] (1c) and [PdCl2(Ind-trisox)] (1d) (trisox=1,1,1-tris(oxazolinyl)ethane) were synthesised by reaction of the respective trisox derivative with [PdCl2(PhCN)2] and characterised inter alia by 15N NMR spectroscopy. Direct detection of the heteronuclei without isotope enrichment and with "normal" sample concentrations was achieved with the aid of a cryogenically cooled NMR probe on a 600 MHz NMR spectrometer. Whereas the 15N nuclei of the coordinated oxazoline rings resonate at delta=160-167 ppm and appear as two singlets due to their diastereotopicity, the signal assigned to the dangling oxazoline "arm" is observed at delta=238-240 ppm. Variable-temperature NMR studies along with a systematic series of magnetisation transfer experiments established exchange between ligating and non-ligating oxazoline rings. Reaction of [Pd(allyl)(cod)]BF4 (cod=cyclooctadiene) with Ph-trisox in CH(2)Cl(2) gave the corresponding allyl complex 2, for which fast exchange between the three oxazoline heterocycles as well as between the exo and endo diastereomers was observed along with a very slow eta3-eta1-eta3 process of the allyl fragment (magnetisation transfer). Palladium(0) complexes were prepared by reaction of trisox derivatives or sidearm-functionalised BOX (BOX=bis(oxazolinyl)dimethylmethane) ligands with [Pd(nbd)(alkene)] (nbd=norbornadiene, alkene=maleic anhydride or tetracyanoethylene). X-ray diffraction studies of the iPr-trisox and Ph-trisox complexes (3a and 3b) established Y-shaped trigonal planar coordination geometries with the trisox ligand coordinated in a bidentate fashion, whilst the pi-coordinated maleic anhydride ligand adopts one of the two possible diastereotopic orientations. As the catalytic test reaction, the allylic alkylation of 1,3-diphenylprop-2-enyl acetate substrate with dimethyl malonate as nucleophile (in the presence of N,O-bis(trimethylsilyl)acetamide) was investigated for the trisox derivatives, their BOX analogues, and a series of less symmetric "sidearm" functionalised bisoxazolines. The trisoxazoline-based catalysts generally induce a better enantioselectivity compared to their bisoxazoline analogues and display significant reduction of the induction period as well as rate enhancement.

Abstract  [reaction: see text] The arylation of ethyl acetoacetate, ethyl benzoyl acetate, and diethyl malonate under the catalysis of CuI/L-proline in DMSO proceeds smoothly at 40-50 degrees C in the presence of Cs2CO3 to provide the 2-aryl-1,3-dicarbonyl compounds in good yields. Both aryl iodides and aryl bromides are compatible with these reaction conditions.

Abstract  [reaction: see text]. A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. When ethyl acetoacetate was used as a nucleophile, bridged bicyclic products were obtained in good yields. The regiochemistry of conjugate addition was dependent on the quinone monoacetal substitution.

Abstract  [reaction: see text] The title alkaloid was synthesized in racemic form from 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (7) by a regioselective diallylation reaction followed by double ring-closing olefin metathesis and exhaustive reduction. Tetraoxobispidine 7 was itself prepared in three simple operations from dimethyl malonate. The entire sequence to alpha-isosparteine was conducted on a multigram scale and proceeded without recourse to chromatography.

Abstract  A four-step synthesis of the title compound starting from methyl acrylate, ethylenediamine, and dimethyl malonate is reported. The synthesis can be run on a multigram scale and is operationally simple. The use of protecting groups is avoided by utilizing the trioxocyclam as the key coupling intermediate.

Abstract  A butenolide-containing sugar available from the aldol condensation of methyl 4,6-O-benzylidene-alpha-D-glucopyranosid-2-ulose with diethyl malonate is autoxidized at the C-3 position into the corresponding alpha,beta-unsaturated gamma-lactone sugar by air, which subsequently undergoes 1,4-conjugate (Michael) addition of hydroxide ion (or water) leading to a C-branched-chain glucopyranosidulose. The autoxidations are also performed in weakly basic, neutral and weakly acidic medium, respectively.

Abstract  Solvent-free reactions of C(60) with active methylene compounds, either with or without carbon tetrabromide (CBr(4)), in the presence of a base under high-speed vibration milling (HSVM) conditions were investigated. The reaction of C(60) with diethyl bromomalonate was conducted under HSVM conditions in the presence of piperidine, triethylamine or Na(2)CO(3) to afford cyclopropane derivative. In the presence of CBr(4), methanofullerenes, and could be obtained by the direct reaction of C(60) with diethyl malonate, dimethyl malonate, ethyl acetoacetate and ethyl cyanoacetate, respectively, with the aid of 1,8-diazabicyclo[5,4,0]undec-7-ene, piperidine, triethylamine or Na(2)CO(3). More interestingly, 1,4-bisadducts and were produced by the reaction of C(60) with diethyl malonate and dimethyl malonate in the presence of piperidine, triethylamine or Na(2)CO(3) under HSVM conditions. On the other hand, dihydrofuran-fused C(60) derivatives, and were obtained from the reaction of C(60) with ethyl acetoacetate, 2,4-pentanedione and 5,5-dimethyl-1,3-cyclohexanedione with the aid of a base. Under the same conditions, less activated aryl methyl ketones such as 2-acetylpyridine, 2-acetylpyrazine and acetophenone provided monocarbonylated methanofullerene derivatives, and. Except for the Bingel reactions, all other reactions under the HSVM conditions are considered to proceed according to a single-electron-transfer mechanism.

Abstract  The branched building plays a pivotal part in the study of Dendrimers. In order to synthesized Dendrimers more effectively, we designed and synthesized four new branched building blocks via 2-4 steps starting from diethyl malonate and pentaerythritol. Their structures were confirmed by IR and 1HNMR etc. They compare favourably with previous branched building blocks as regards to steric hindrance and branched effect.

Abstract  Treatment of 5,10,15,20-tetraarylporphyrins (1) with perfluoroalkyl iodides (2) in the presence of Na(2)S(2)O(4)/NaHCO(3) in DMSO-CH(2)Cl(2) at 30-40 degrees C for several hours gives the corresponding 2-perfluoroalkylporphyrins (3). Nucleophilic attack on 3 with dimethyl malonate, diethyl malonate, malonitrile, or cyano acetate (Nu) anion results in the formation of (E)-3-Nu-2-perfuoroalkyl(methylenyl)chlorins. Electrophilic substitution on 3 with NBS or NO(2) affords regioselectively the corresponding 12(or 13)-bromo- and 12,13-dibromo- or nitroporphyrins.

Abstract  [reaction: see text] Rhodium-catalyzed asymmetric allylic alkylation of 1-substituted 2-propenyl acetates with dimethyl malonate proceeded with high enantioselectivity in the presence of cesium carbonate as a base and a rhodium catalyst generated from Rh(dpm)(C(2)H(4))(2) (dpm = dipivaloylmethanato) and a chiral phosphino-oxazoline whose basic skeleton is axially chiral binaphthyl to give branch alkylation products in greater than 90% ee.

Abstract  The azazirconacyclopentene-substituted phosphines 3 and 4 have been found to activate the C-H bonds of acetylenic systems, such as methylpropiolate, diphenylphosphinoacetylene and phenylacetylene, or of methylene compounds, such as malonitrile and diethylmalonate, to give complexes 5a-c, 6a and 6b. C-H bond activation also takes place with vinylacetate. Similar reactions with amines, alcohols, enolisable ketones, phenols, phosphonates, thiols and a second-generation SH-terminated dendrimer lead through X-H bond activation (X = N, O, P, S) to new complexes 8a-c, 9, 12 a,b, 13, 14a-c, 15, 16a and 16b. The azazirconacyclopentene-substituted amine 20 reacts to form analogous complexes. Zr-X bonds of these complexes (X = C, N, O, S) can be cleaved with diphenylchlorophosphine to give P-X phosphorus derivatives in high yield.