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The dual role of nitrogen bases is shown in the ARGET ATRP with ascorbic acid acetonide. High pKa bases lead to more ascorbate anion (faster polymerizations) but in presence of oxygen/water are detrimental to the catalyst (hydroxide formation).

An anomalous polystyrene gel was obtained during the copper-catalyzed “activators regenerated by electron transfer” “atom transfer radical polymerization” (ARGET ATRP) of styrene at 60–70 °C, using ascorbic acid/Na2CO3 as the reducing system and EtOAc/EtOH as the solvent mixture. The result is remarkable since no branching nor cross-linking reagents were added to the reaction mixture and their formation in situ was excluded. The anomalous PS branching, at the origin of the phenomenon, requires a generic bifunctional initiator and is mechanistically bound to termination reactions between bifunctional macroinitiators. As a matter of fact, the branching/cross-linking phenomenon loses intensity, or even disappears, under reaction conditions that cause the built-up of CuII or increase the chain polymerization rate. The temperature is also a critical variable since no branching was observed for temperatures higher than 90 °C. We believe that the route toward gelation starts with a controlled chain polymerization of styrene from the bifunctional initiator, soon integrated by a step-growth polymerization due to radical coupling of the terminal units. The progressive decrease in the number of chains and free radicals in the reaction mixture should make more and more probable the intramolecular coupling between the C−Cl ends of the remaining long and entangled chains, producing a polycatenane network. [Figure not available: see fulltext.]

“Activator regenerated by electron transfer” “atom transfer radical polymerization” (ARGET ATRP) process catalyzed by CuCl2/tris(2-pyridylmethyl)amine (TPMA) (1/1) in ethyl acetate/ethanol (EtOAc/EtOH) for the polymerization of styrene from ethyl 2,2-dichloropropanoate (EDCP) is described. The (re)generation of the activating CuI complex is accomplished by Na2CO3 without the addition of any explicit reducing agent. Differently from the analogous process operating in the presence of ascorbic acid/carbonate as the reducing system, branching is not present and control over polymerization is improved. The activation mechanism should follow a composite route, where both EtOH and TPMA contribute to the regeneration of the catalyst. The oxidation of TPMA is suggested by the absence of the ligand in the final reaction mixture and by the reduction of CuII even in t-BuOAc/t-BuOH, notwithstanding the very poor ability of t-BuOH as a reducing agent. Oxidative degradation of TPMA causes a progressive malfunctioning of the redox catalyst. Consequently, the polymerization rate, after a prompt start, becomes slower and slower, fixing conversions at around 50% (4.5 h). This means a gradual decrease of the free radical concentration, which develops unfavorable conditions for the reductive coupling (termination) between the bifunctional growing chains, preserving a controlled growth of the polymer.

A new copper(II) chloride/tris(2-piridylmethyl)amine (1/1) catalysed “Activators Regenerated by Electron Transfer” “Atom Transfer Radical Polymerisation” (ARGET ATRP) process for the polymerisation of styrene is described. The salient features of the method are the simultaneous use of ascorbic acid (reducing agent) and Na2CO3 (basic agent), the employment of a bifunctional initiator (ethyl 2,2-dichloropropionate) and the utilisation of a green solvent mixture composed of ethyl acetate and ethanol (AcOEt/EtOH). Na2CO3 plays a central role since not only preserves the ligand from protonation, but it can also activate the reducing agent. The quantity of monomer in the reaction mixture, the AcOEt/EtOH ratio and the load of ascorbic acid/carbonate are important factors for achieving a regular transformation. Working at 100 °C and with a metal load of only 0.025 mol%, an almost perfectly controlled telechelic polystyrene is produced, provided that conversion is kept below 50%. If conversion is higher, the control is gradually lost due superimposition of a step-growth process to the main chain polymerisation process. Two interesting phenomena, encountered during this study, are activation of the redox complex by using only Na2CO3 and gelation of polystyrene at 60 °C.

Atom transfer radical polymerization (ATRP) is one of the most powerful techniques to synthesize precisely tailored polymers and macrostructures. Activators regenerated by electron transfer (ARGET) ATRP was developed as a “green” strategy to decrease the load of the metal catalyst. However, ARGET ATRP usually uses not-so-green reducing agents (e.g. Sn2+) or expensive and industrially impractical procedures. For these reasons, we report an ARGET ATRP of styrene with various carbonates as reducing agents, both alone and paired with ascorbic acid (AA), using monofunctional initiators and Cl or Br as exchanging atoms. The solvent mixture is composed of the green combination of EtOAc and EtOH, even in the presence of modest amounts of H2O. Cyclic voltammetry was used to evaluate the effect of H2O on the catalyst, as well as the absence of AA. The system returned high yields and low dispersities with low amounts of catalyst (~60 ppm) and moderate reaction times. Excellent results were obtained only with the Cl-ATRP system. NMR spectroscopy and kinetic analyses proved the livingness of the final polymer chains.

The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG⧧ rotation varied between 20 kcal mol–1) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol–1) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical–polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature.\ud \ud

The cyclisation of N-allyl-N-substituteda- polychloroamides is efficiently obtained through a copper-catalysed activators regenerated by electron transfer–atom transfer radical cyclisation process, with a metal load of only 0.5 mol%. The redox catalyst is introduced in its inactive form as copper( II) chloride/[nitrogen ligand] complex, and continuously regenerated to the active copper(I) chloride/[ nitrogen ligand] species by ascorbic acid. To preserve the catalyst integrity, the hydrochloric acid, released after each regeneration cycle, has been quenched by carbonate. The choice of the solvent is critical, the best performance being observed in ethyl acetate-ethanol (3:1).

Copper mediated cyclization of activated 1-substituted enamides occurs via a 5-endo radical-polar crossover process. Trichloroacetyl derivatives can undergo further reactions post cyclization (elimination of HCl or dimerization potentially via copper carbenoid intermediates). Reaction of α-halo trienamides derived from β-ionone furnish either β- or γ-lactams via 4-exo or 5-exo cyclizations respectively depending upon the enamide tautomer undergoing reaction. For the less reactive dichloroacetamide derivative a competing regioselective methyl migration-aromatization prior to cyclization is observed.\ud \ud

Recently we found that a copper catalysed Ueno–Stork cyclization can be a very useful means for the expedient synthesis of dichloro-γ-lactones, but, to take advantage of this step, the method still lacks of an efficient and selective follow-up. This Letter describes our progress in that field, unveiling the use of a supported and recyclable Cr (VI) catalyst for the simultaneous deprotection and oxidation of cyclic dichloro hemiacetals.

The selective and efficient acetylation of the hemiacetal hydroxyl in the equilibrium mixture between RCl2C(OAll)OH and AllOH/RCl2CHO was achieved using the acylating system Ac2O/Et3N/dimethylaminopyridine (DMAP).

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The resulting optically active γ-nitroesters gave access to optically active β,β-disubstituted γ-aminoacids as well as α,α-disubstituted succinic acids, both being biologically relevant compounds.

3-Alkyl-3-chloro-4-chloromethyl-γ-lactones were synthesized in acceptable yields, exploiting the CuCl-N,N,N′,N″,N″-pentamethyldiethylenetriamine catalyzed atom transfer radical cyclization (ATRC) of O-allyl-2,2-dichlorohemiacetal acetates, starting materials easily prepared from 2,2-dichloroaldehydes. The oxidation of the intermediate dichloro-2-acetoxytetrahydrofurans was completed in a two-step, one-pot procedure: hydrolysis to γ-lactol and final oxidation to lactone with Jones' reagent.

An unreported 5-endo-trig atom-transfer radical cyclization of cyclic N-α-dichloroacyl-ketene-N,S-acetals, which evolves as a tandem radical-polar process, is described. The reaction, which is carried out in the presence of a Cu(I) complex catalyst (10 mol%) and an inorganic base (i.e., carbonate), can be exploited as the key step for a novel, short, and versatile synthesis of the 3,4-disubstituted maleic anhydride nucleus.

A new, five-step route to ( Z)-pulchellalactam, a CD45 protein tyrosine phosphatase inhibitor, is presented. Key steps are the copper(I) chloride-bipyridyl catalyzed atom-transfer radical cyclization- of an appropriate allyl α,α-dichloroacetate and the subsequent dehydrochlorination/prototropic rearrangement of the resulting dichlorolactone.

The natural fragrances (+)- trans whisky lactone 2 and (+)- trans cognac lactone 4 , together with a minor amount of their (−)- cis stereoisomers, were prepared in 50% and 42% overall yield, respectively, starting from racemic 1-hepten-3-ol (±)- 5 and 1-octen-3-ol (±)- 6 . The procedure involved first the enantioconvergent, lipase mediated transformation of the secondary allylic alcohols derived dichloroacetates (±)- 7 and (±)- 8 into the corresponding homochiral (+)- 7 and (+)- 8 , combined with their cyclization under a transition metal catalyzed atom transfer process.

The rearrangement of eight new Z -arylhydrazones of 3-benzoyl-5-phenylisoxazoles ( 3d – k ) into the relevant 2-aryl-4-phenacyl-2 H -1,2,3-triazoles ( 4d – k ) in dioxane/water solution at different proton concentrations has been quantitatively studied in a wide temperature range (293–333 K). The data collected together with some our previous ones on compounds 3a – c have allowed a deep study of the substituent effects on the course of the rearrangement, thus increasing our knowledge on the Boulton–Katritzky reactions in isoxazole derivatives and on the temperature effects on free energy relationships.

The rearrangement of a trichloro-pyrrolidin-2-one, prepared by the CuCl–TMEDA catalyzed atom transfer radical cyclization of N-alkyl-N-(3-chloro-2-propenyl)-2,2-dichloromyristamide, with n-propylamine or CH3ONa/CH3OH, is the key step of a new, short and inexpensive route to chaetomellic anhydride C and (±)-erythro-roccellic acid.

The copper(I) or ruthenium(II)-mediated radical cyclisation of halo-amides has been utilised to afford functionalised pyrrolidinones via 5-endo-trig or 5-exo-trig radical cyclisation pathways. This methodology has been applied to novel and concise syntheses of the anti-epileptic drug gabapentin and the biologically active natural product pulchellalactam.

α,β-Unsaturated hydrazones can be easily converted into N -allyl hydrazines by reaction with dimethylamine–borane/ p -toluenesulfonic acid under mild reaction conditions. The reduction works well for N ′-allylhydrazides but N ′-allyl- N , N -dimethylhydrazines are rapidly reoxidised by air and so need to be manipulated under an inert atmosphere prior to N ′-acylation. Competitive conjugate reduction can also be observed and the regioselectivity of the dimethylamine–borane attack is determined by steric and/or electronic factors. The procedure is also effective for the CN reduction of unconjugated hydrazones.

Cyclisation of a variety of halo-enamides with copper(I) or ruthenium(II) complexes has been investigated. The regioselectivity of the radical cyclisation, which can proceed via either a 4- exo or 5- endo pathway, to form β- or γ-lactam products respectively, is determined by the nature of the metal oxidant and the reaction conditions. Thus, whereas copper(I)/bipyridine reactions give predominantly γ-lactams, the use of copper(I)/TMEDA or dichlorotris(triphenylphosphine)ruthenium(II) affords mainly β-lactams.

An effective and environmentally benign preparation of 2,2-dichloroaldehydes has been achieved by chlorination of aldehydes with Cl 2 (g) in CH 2 Cl 2 , using 2,6-lutidine hydrochloride as recoverable catalyst. Remarkable qualities of the process are: easy work up, high purity products, HCl as the only ‘waste’ stream and inherent bias to the scale up.

A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-alpha-perchloroacyl-2-(Z)-alkyliden-1,3-thia-zinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol-ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study. (C) 2012 Elsevier Ltd. All rights reserved.

Methyl 2,2-dihalocarboxylates add easily to carbonyl compounds in fair to good yields through the intermediate formation of 2-haloester enolates; the reaction is promoted by zinc, following a “Barbier” type procedure.

The chemoselective N-acylation of 2-amino alcohols with methyl 2,2-dichloro carboxylates occurs smoothly and in excellent yields.

Methyl 2-Br-2-Cl-carboxylates afford 2-alkyl-2-Cl-4-Br-carboxylates in fair yields by reaction with terminal alkenes, under mild conditions, through a radical process promoted by CuBr/Fe0 in DMF/CH2C12.

The discovery that cycloalkanes can form thermomorphic systems with typical polar organic solvents has led to the development of less-polar electrolyte solutions. Their mixing and separation can be regulated reversibly at a moderate temperature range. The phase switching temperature can be controlled by changing the solvent compositions. While biphasic conditions are maintained below the phase switching temperature, conductive monophasic conditions as less-polar electrolyte solutions are obtained above the phase switching temperature. After the electrochemical transformations, biphasic conditions are reconstructed below the phase switching temperature, facilitating the separation of cycloalkane where hydrophobic products or designed hydrophobic platforms are selectively partitioned. Several polar organic solvents, including acetonitrile, methanol, and pyridine, can be used in this system according to the requirement of the reactions.

The preparation of -perchloroacyl chlorides, from reaction of the corresponding unfunctionalized acyl halides with chlorine, was efficiently achieved under base-catalysis, using a tetraalkylammonium chloride as catalyst. The process is solvent-free and the procedure is easy, inexpensive, and suitable for scale-up.

Methyl 2,2-dichloro or 2-bromo-2-chloro carboxylates were obtained in excellent yields by oxidation–chlorination of 2-(1-haloalkyl)-4-methyl-1,3-dioxolanes with trichloroisocyanuric acid.

The reaction rates for the rearrangement of eleven (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 3a-k into the relevant (2-aryl-5-phenyl-2H-1, 2,3-triazol-4-yl)ureas 4a-k in the presence of trichloroacetic acid or of piperidine have been determined in toluene at 313.1 K. The results have been related to the effect of the aryl substituent by using Hammett and/or Ingold-Yukawa-Tsuno correlations and have been compared with those previously collected in a protic polar solvent (dioxane/water) as well as with those on the analogous rearrangement of the corresponding (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole 1a-k in benzene. Some light can thus be shed on the general differences of chemical reactivity between protic polar (or dipolar aprotic) and apolar solvents.

A ‘green’ ARGET-ATRC, for the CuCl[PMDETA] catalysed cyclo -isomerization of N -allyl-α-polychloroamides to γ-lactams is described. The process works efficiently (yields 78–96%), uses a bio-solvent, as ethanol, and exploits the reducing feature of ascorbic acid to limit, at a low level (2–4%), the amount of catalyst. To preserve the efficacy of the catalytic cycle, addition of Na 2 CO 3 is essential, which quenches the HCl released during the CuCl[PMDETA] regeneration step. Profitable features of the process are: mild reaction temperatures (25–37 °C), relatively short reaction times (usually 5 h) and low solvent volumes (2 mmol of substrate/mL of ethanol). The method, upon stoichiometric adjustment, was also used for the synthesis of α,β-unsaturated-γ-lactams from N -(2-chloroallyl)-α-polychloroamides, via a tandem process involving an ATRC and a reductive [1,2]-elimination.

The preparation of 3-alkyl-4-(chloromethyl)-1-RSO 2 -1 H-pyrrol-2(5 H)-oneswas efficiently accomplished through a [1,2]-eliminationof γ-lactams derived from the copper(I)-catalysed ATRCof 2,2-dichloro- N-(2-chloroallyl)- N-RSO 2 -amides. The two reactionscan be integrated into a sequential one-pot process.

Chaetomellic anhydride A and an analog (with two additional carbons) were obtained, on a preparative scale, starting from amides derived from the acylation of 2-(2-propenylamino)pyridine with 2,2-dichloropalmitic or 2,2-dichlorostearic acid. An alternative approach, in which the methyl substituent of the target anhydride is introduced by the carboxylic acid reactant and the long aliphatic chain is added through the allylamino moiety, proved unviable.

The constants of ion-pair formation with 3-nitroaniline (3NO(2)A) for eight halogenoacetic acids (HAAs, 3a-h: TFA, TCA, TBA, DFA, DCA, DBA, MCA, and MBA), and five 2,2-dichloroalkanoic acids containing 3-8 carbon atoms (HAs, 5a-e: DCPA, DCBA, DCMBA, DCVA, and DCOA) have been determined in TOL at 298.1 K. The results obtained brought to evidence for HAAs the formation of ion-pairs with two different stoichiometries (base-acid, 1:1 or 1:2), while in contrast the HAs furnish only the 1:1 pairs. The different steric and electronic requirements of HAAs and HAs seem to be responsible for such an unlikely behavior. At the same time, the acid-catalyzed MRH of the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole (1) into (2,5-diphenyl-2H-1,2,3-triazol-4-yl)urea (2) in the presence of the five HAs above has been investigated in TOL at 313.1 K. Thus, in contrast with previous results in the presence of several HAAs, a unique pathway for the rearrangement has been observed, again pointing out the importance of the above effects on the initial acid/base interactions. Finally the acidic strength of TFA against seven nitroanilines (NA, 4a-g: 4NO(2)A, 3NO(2)A, 3Me4NO(2)A, 4Me3NO(2)A, 2Me3NO(2)A, 2NO(2)A, and 3,5diNO(2)A) characterized by a very different basicity has been measured in TOL at 298.1 K.

Atom transfer radical cyclization (ATRC) of N-alkyl N-allyl dichloroamides to γ-lactams, catalyzed by 'naked' CuCl, worked efficiently in DMF, whereas, when the same dichloroamides were N-sulfonylated, DMF needed to be replaced by acetonitrile. The outcome of the cycloisomerization with N-substituted N-allyl trichloroacetamides was less affected by solvent choice, although for an effective reaction to occur, the solvent had to dissolve the cuprous salt. Catalyst loading ranged between 5 and 20 mol%.

The preparation of the 3,4-dialkyl-substituted maleic anhydride nucleus, through the functional rearrangement of dichloro γ-lactams, allowed the comparison of various N-substituents in the functional rearrangement step. The 2-pyridyl group proved to be the most appropriate N-substituent for the hydrolysis of the 5-methoxy-1,5-dihydro-2H-pyrrol-2-one intermediate into the 5-hydroxy adduct, and for the hydrolysis of the maleimide nucleus into the maleic anhydride. The oxidation of the 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one into the corresponding maleimide was achieved with manganese(IV) oxide.

A key intermediate for the synthesis of Tyromycin A, a C-20 tetrachlorodicarboxylic acid, was produced in six steps starting with the dimerization of methyl 10-undecenoate which was obtained from a renewable resource, e.g. castor oil. The acyloin condensation product was then oxidized, transformed to the diene, followed by ozonization, chlorination and finally oxidation to the corresponding tetrachlorodicarboxylic acid.

2-Propylbenzo[d][1,3,2]dioxaborole and related derivatives are shown to initiate a range of radical reactions under mild conditions.

Enantioselective deacetylation of a-(±)-botryodiplodin acetate was successfully accomplished by means of lipase PS to afford (+)-botryodiplodin and a-(+)-botryodiplodin acetate with high enantiomeric excesses. Enzyme-mediated transesterification of the acetylated molecule with n-butanol, as well as its hydrolysis in several organic solvents, are also reported. The CD spectra of (+)-botryodiplodin and a-(+)-botryodiplodin acetate are also presented.

—(±)-Botryodiplodin and (±)-epi-botryodiplodin acetates were prepared in good yields following a practical four step route. The method, for the construction of the strategic tetrahydrofuran ring, hinged on an unprecedented halogen atom transfer Ueno–Stork cyclization of an O-allyl a,a-dihalohemiacetal acetate, catalyzed by the redox complex CuCl/N,N,N0,N00,N00-pentamethyldiethylenetriamine.

The reaction of N-substituted 4-methyl-2-pyrrolidinones or 4-diethoxyphosphoryl analogues, carrying at least two chlorine atoms between the C(3) and C(6) carbons, with alkaline methoxide in methanol afforded the corresponding 5-methoxylated 3-pyrrolin-2-ones, useful adducts for the preparation of agrochemicals or medicinal compounds.

The benzoylamino group was identified as a useful radical cyclization auxiliary that can be smoothly removed on hydro-de-halogenation of chlorinated N-substituted-pyrrolidin-2-ones with Raney-Ni. This methodology was successfully implemented in a new and appealing route to the anti-epileptic drug gabapentin.

Silybin, a natural occurring flavolignan isolated from the fruits of Silibum marianum, has been reported to exert antioxidant and free radical scavenging abilities. It was suggested to act also as an iron chelator. The complexation and protonation equilibria of the ferric complex of this compound have been studied by potentiometric, spectrophotometric and electrochemical techniques. The formation of the complex silybin-Ga(III) in anhydrous DMSO-d6 has been studied by 1H NMR spectroscopy. Mass spectrometry and infrared spectroscopy on silybin-Fe(III) complex confirm all data obtained by 1H NMR spectroscopy. The experimental results show that silybin binds Fe(III) even at acidic pH. Different ternary complexes were observed at increasing methoxide ion concentration and their stability constants have been calculated. The results show the possible role of silybin in relation to the chelation therapy of chronic iron overload, as occurs in the treatment of Cooley's anemia.

The Kharasch addition of methyl 2,2-dichlorocarboxylates or trichloro acetic acid derivatives to alkenes, affording the corresponding 1:1 adducts, is promoted by the iron filings/N,N-dimethylformamide system.

α-Halo aldehydes are regenerated in excellent yields from the corresponding dimethyl acetals by acetic anhydride-acetyl chloride-sodium acetate trihydrate in chloroform.

Thioethers are transformed by manganese(IV) oxide-trimethylchlorosilane in CH3OH in high yields to sulphoxides, exclusively.

α-Chloroacetals are obtained in almost quantitative yields, by treating acetals with MnO 2 -trimethylchlorosilane in CH 3 OH:CH 3 CN (1:1). The halogenation is explained by a ligand-transfer process on an enolether intermediate, mediated by a Mn(IV)-chloride species.