Current Organic Chemistry - Volume 13, Issue 17, 2009

Chemists are now moving away from volatile, environmentally harmful, and biologically incompatible organic solvents. With its low cost, ready availability, and capacity to remove environmentally unfriendly by-products, water and alternative biocompatible reaction media such as ionic liquids are obvious replacement. Recent advances in free radical chemistry in water have expanded the versatility and flexibility of homolytic bond formations in aqueous media and ionic liquids. This special Hot Topic issue highlights the substantial progress, which has been made in the last decade to “tame” the reactive free radical species in aqueous phase reaction and alternative media. The issue describes conventional radical reactions in organic and aqueous media and their applications. There are 2 review articles in the on radical reactions in broad range of free radical transformation in aqueous and alternative media, such as ionic liquids, solid phase, microwaves and supercritical CO2, in the issue collate the unique application and tutorial hints for designing the optimum free radical reaction. Article by Lykakis et al., describes the decatungstate W10O32 4- catalyzed photooxygenation of cumenes in the presence of molecular oxygen and triethylsilane representing an important potential for free radical reactions in synthesis. Article by Nanni et al., focuses on radical additions of thiols to alkenes and alkynes in ionic liquids, which is adding an extra dimension to the scope of free radical reactions in alternative media. Article by Grabovskiy et al., describes investigation both synthetic and mechanistic of 5-Hydroxy-6-methyluracil, an efficient scavenger of peroxyl radical in water. The article by Johnson and Chen et al. focuses on investigation of the broad range of free radical transformation in beta-cyclodextrin based molecular reactors and polyHIPEs as alternative reaction media. It shows that, armed with an elementary knowledge of kinetics and some common sense, it is possible to harness radicals into tremendously powerful tools for solving synthetic problems and broad range of applications. The issue is a valuable and informative entry for growth and development of green free radical chemistry in aqueous and alternative media.

Several organic radical transformations in aqueous media using organometallic chemistry are presented. Group XIV-elements, such as Si and Ge, and Sn-centered radicals make use of novel methodologies in water which employ both hydrophilic and lipophilic substrates without the requirements of surfactants. Different radical initiation techniques that account for effective initiation of the radical chain reactions in aqueous media are also described, such as the thermal decomposition of azo compounds, the direct photolysis (in the absence of an organic peroxide or other photolytic radical promoter) of silanes, dioxygen initiation techniques, and radical initiation in the absence of solvent, and in the presence of adventitious oxygen. Hydrometallation of multiple bonds with (Me3Si)3SiH and germane analogs in water are also described with the above mentioned initiating techniques, under solvent-free conditions, and performed in continuous flow microreactors. The use of other metal-centered radicals that promote synthetically useful organic transformations in water, such as Mg, Mn, and Zn, is presented. These transformations encompass simple organohalide reductions, and several types of carbon-carbon bond forming reactions, demonstrating the wide scope of organometallic radical chemistry in water for accomplishing organic transformations. Group XIII- centered radicals are also shown to be excellent mediators for organic radical reactions in water, such as Barbier-type alkylations and allylations of carbonyl compounds.

Recent advances in free radical chemistry have expanded the versatility and flexibility of carbon-carbon bond formation in water or aqueous media. This review highlights the substantial progress, which has been made in the last decade to shift the paradigm in free radical chemistry from conventional solvents to ionic liquids, microwaves, supercritical CO2 and fluorous solvents. This review focused on recent advances in several classes of widely useful free radical reactions in alternative media leading to the formation of C-C and C-H bonds. The review will also explore the recent advances in performing stereo-selective free radical reactions in an unconventional media. Stereospecific aspects and mechanistic details of the transformations will be addressed.

The radical addition of thiols to double and triple carbon-carbon bonds was examined in typical ionic liquids ([bmim][PF6], [bmim][Tf2N], and [bmim][BF4]) under different temperature/initiator conditions (i.e. 80-100 °C / AIBNVAZO ®, r.t. / triethylborane, r.t. / AIBN / UV radiation, r.t. / photoinitiator / UV radiation). All the addition products were usually obtained with high efficiencies and very good recyclability of the ionic liquid. In some cases, small but significant differences were noticed by changing the reaction medium from benzene to a ionic liquid. The possibility of applying this procedure to click-chemistry reactions with thiols/alkenes of biological interest is also discussed.

The reactivity of 5-hydroxy-6-methyluracil (HMU) towards peroxyl radicals generated from the aerobic thermal decomposition of 2,2'-azo-bis(2-amidinopropane)dihydrochloride (AAPH) has been investigated. The oxidation product of HMU is dihydro-5,5,6-trihydroxy-6-methylpyrimidin-2,4-dion-e (94%). The relative oxidation rate of HMU vs. quercetin by peroxyl radicals generated from AAPH has been measured as 0.20 ± 0.04 at 54.6°C, hence HMU is the effective scavenger of peroxyl radicals. The overall kinetic parameters and the efficiency of radical generation from AAPH in water solution at pH 7.0 (0.1 M phosphate buffer) have been determined using HMU in temperature range 26° - 84°C.

The decatungstate W10O32 4- catalyzed photooxygenation of cumenes in the presence of molecular oxygen and triethylsilane has been thoroughly studied. In all cases the corresponding tertiary hydroperoxides were formed as the major products. Based on stereoisotopic studies as well as on primary and β-secondary isotope effects, we provide strong evidence for a stepwise mechanism, in which a hydrogen atom abstraction occurs in the rate-determining step of the reaction. In addition, the oxidation of (S)-2-phenylbutane by decatungstate/Et3SiH catalytic system, shows the formation of the two enantiomeric alcohols, (R)-2-phenylbutan-2-ol and (S)-2-phenylbutan-2-ol, in equimolar amounts. This product racemization confirms further the presence of a stepwise mechanism and support the formation of a free carbon-centered radical intermediate.

In this communication we report C-C bond formation through reductive radical cyclization/termination and oxidative radical/ cyclization termination reactions inside β-cyclodextrin as a molecular reactors in aqueous media.

3,3'-Benzene-1,4-diylbis(1-phenylprop-2-enone) 3 reacted with 2-cyanoethanethioamide 4 to afford the corresponding 4,4'-benzene-1,4-diylbis(6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) 5. The synthetic potentiality of compound 5 was investigated in the present study via its reactions with several active-hydrogen containing compounds 6a-f aiming to synthesize 4,4'-(1,4-phenylene)bis(3-amino-6-phenylthieno[2,3-b]pyridine) derivatives 8a-h directly in case of 8d,e,f,h and via 2,2'-{1,4-Phenylenebis[(3-cyano-6-phenylpyridine-4,2- diyl)thio]} derivatives 7a-c,g in case of 8a-c,g. The structures of all the newly synthesized heterocyclic compounds were elucidated by considering the data of IR, 1 H NMR, mass spectra as well as that of elemental analyses. Anti-cancer activities for all the newly synthesized heterocyclic compounds were investigated.

A smooth and rapid one step synthesis of novel pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines 4a,b and 7, pyrido[2',3':3,4]pyrazolo[5,1-c]triazines10-12a,b, pyrido[3“,2“:4',5']thieno[3',2':4,5]pyrimido/triazino[1,6-a]benzimidazoles 15-20 in synthetically useful yields utilizing, 3-amino-4-phenyl-5-(saccharin-2-yl)-1H-pyrazolo[3,4-b]pyridine (3) were described. The structure assignment of the new compounds is based on chemical and spectroscopic evidence. Preliminary biological studies of some synthesized compounds showed promising antimicrobial activities.