Al Postigo

Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents

Electrophilic trifluoromethylation reactions have been the latest approach to achieve the fluoroalkylation of compounds with newly-discovered reagents, such as the Tognis (1-trifluoromethyl-1,2-benziodoxol-3-(1 H)-one), Umemotos (S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate), Yagupolskiis (S-(trifluoromethyldiarylsulfonium salts), Shreeves (S-(trifluoromethyl)dibenzothiophenium triflate), and Shibatas (trifluoromethylsulfoximine salts) reagents. All these reagents produce an electrophilic trifluoromethylating (CF3 (+) ) species that undergoes reaction with nucleophiles. In addition, these latter reactive species (i.e. CF3 (+) ) can undergo electron-transfer (ET) processes affording CF3 (⋅) radicals that expand the scope to substrates other than conventional nucleophiles that can undergo reaction. In this Review, we shall discuss the trifluoromethylation reactions of diverse families of organic substrates of biological interest as a means to comparing the reagents scope and best reaction conditions. Some, though not all, of these reactions require the assistance of metal or organometallic catalysts. Some require additives and catalysts to promote the fluoroalkylation reaction, but invariably all are initiated and carried out by electrophilic trifluoromethylating species.

Radiation chemical studies of methionine in aqueous solution: understanding the role of molecular oxygen.

The oxidation of methionine is an important reaction in the biological milieu. Despite a few decades of intense studies, several fundamental aspects remain to be defined. We have investigated in detail the gamma-radiolysis of free methionine in the absence and presence of molecular oxygen followed by product characterization and quantification. The primary site of attack by HO(*) radicals and H(*) atoms is the sulfur atom of methionine. We have disclosed that HO(*) radicals do not oxidize methionine to the corresponding sulfoxide in either the presence or the absence of oxygen; the oxidizing species is H(2)O(2) derived either from the radiolysis of water or from the disproportionation of the byproduct O(2)(*-). 3-Methylthiopropionaldehyde is the major product of HO(*) radical attack in the presence of molecular oxygen. Together with the direct oxidation at sulfur as the major product, the potential of H(*) atoms is also proven to be highly specific for sulfur atom attack under anoxic and aerobic conditions. The major products derived from the H(*) atoms attack are found to be alpha-aminobutyric acid or homoserine, in the absence or presence of oxygen, respectively. All together, these results help clarify the fate of methionine related to a biological environment and offer a molecular basis for envisaging other possible pathways of in vivo degradation as well as other markers.

Difluoromethylation Reactions of Organic Compounds

The relevance of the -CF2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF2 H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2 H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF2 H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF2 -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF2 -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF2 H or CF2 Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

Synthetically useful carbon–carbon and carbon–sulphur bond construction mediated by carbon- and sulphur-centred radicals in water and aqueous media

This account is focused on carbon–carbon, and carbon–sulphur bond-forming reactions through the use of carbon- and sulphur-centred radicals in water, respectively. It intends to show the scope and applications of these types of radicals with a synthetic goal, thus helping the radical synthetic chemist to grasp the fundamental aspects of the syntheses of a wide array of organic compounds through radical methods in environmentally friendly media. This account excludes the syntheses of organic substrates with the aid of organometallic/metal-centred radicals such as other Group IV-radicals and transition-metal radicals, and the important class of radical reductions currently accomplished in water using different metallic reducing species. The array of substrates synthesized through the present method encompasses intermolecular and intramolecular radical carbon–carbon bond formation reactions in water, and radical carbon–sulphur bond formation reactions. Among the radical carbon–carbon bond formation reactions, special attention is devoted to atom-transfer radical reactions, radical addition reactions to olefins, radical addition to carbon–nitrogen double bonds, the carboaminohydroxylation of alkenes, and the analogues of Knovonoegel reactions, the synthesis of functionalized enol ethers, thr carboazidation and azidation, and ynol formation, and radical cyclization reactions in water.

Perfluoroalkylation reactions of (hetero)arenes

Perfluoroalkylation reactions of arenes have not been the subject of intense study as has been the case for the trifluoromethylation reactions of aromatics. However, the new synthetic methods proposed for achieving homolytic aromatic substitution reactions with perfluoroalkyl moieties have begun to claim a relevant role in functionalization reactions, as revealed by the interesting properties of arenes with large perfluoroalkyl chains. Methods for achieving Ar–Rf bonding reactions can be classified into thermal and photochemical, which can in turn make use of transition metals or be non-metal catalyzed. Reactions are mainly radical in nature. Radical methods for introducing Rf moieties into arenes have resulted as being the most popular and versatile options available to synthetic chemists.

Recent Advances on Radical Nucleophilic Substitution Reactions

The radical nucleophilic substitution mechanism or SRN1 is a chain process, in which radicals and radical anions are intermediates. This process has been extensively used to effect substitution on a wide variety of substrates. The SRN1 reaction has been studied from both mechanistic and synthetic standpoints. The SRN1 mechanism requires an initiation step. Spontaneous electron transfer (ET) from the nucleophile to the substrate has been observed in a few systems; light stimulation, electrodes, alkali metals or inorganic salt-mediation is used otherwise. There are systems that are totally inert or undergo rather slow substitutions by classical polar mechanisms. Their lack of reactivity is usually due to strain (cycloalkyl and polycycloalkyl halides), steric (cycloalkyl, polycycloalkyl and neopentyl halides), or electronic factors (unactivated aromatic, vinyl halides and perfluoroalkyl halides). For these families of compounds, the nucleophilic substitution can be accomplished by the SRN1 mechanism. Conversely, there is a class of substrates, for which substitution can be achieved through both polar and ET mechanisms; however, the ET pathway is favored in some systems (i.e.: alkyl halides with EWG). We propose to undertake a compilation and critical review on SRN1 reactions dealing with substitutions on aromatic substrates, cycloalkyl, bridgehead, neopentyl, vinyl halides, perfluoroalkyl iodides, aliphatic substrates with EWG in the _ position and N,N-Dialkyl-p-toluenesulfonamides. With this aim in mind, we expect to cover recent SRN1 substitutions, with an emphasis on the scope of the process in terms of synthetic capability and target applications.

Organic Synthesis in Water Mediated By Silyl Radicals

Fil: Barata Vallejo, Sebastian. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Quimica Organica; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

Photoinduced Electron Transfer-Mediated Substitutions in Aqueous Media

This account intends to cover recent literature on photoinduced substitution reactions in water or aqueous media with synthetic utility. Synthetically-useful electron-transfer substitution reactions performed in aqueous media are noteworthy and not much developed. These reactions performed either through radicals or radical ion intermediates generated photochemically in aqueous environment will prove convenient and alternative sustainable options at hand for the organic synthetic chemist. Metal-mediated photoinduced electron transfer reactions will not be dealt with in this account, as have been the subject of recent review articles, as is the case of radical perfluoroalkyla- tion substitution reactions in aqueous media which have been recently summarized.

Mechanistic studies on the reactions of trimethylsilanide and trimethylstannylide ions with haloarenes in hexamethylphosphoramide

Abstract The large positive ρ values obtained from Me 3 M − ions reacting with appropriately-substituted chloroarenes (4.1±0.1, and 2.94±0.02 for M=Sn and Si, respectively) can be accounted for the presence of a strong negative charge in the transition state of the substitution reaction. These ρ values for Me 3 Sn − and Me 3 Si − nucleophilic attack on ArX provide evidence for the overall larger selectivity of the former, compared with the more reactive, and less selective Me 3 Si − ions. When 1-allyloxy-2-halobenzenes (X=Cl, I) are allowed to react with Me 3 Sn − ions in HMPA, an ipso substitution product 6 is obtained, in addition to stannylated products on the allylic moiety. This reaction proceeds by a HME process, as opposed to the same reaction carried out in liquid ammonia, where (2,3-dihydro-benzofuran-3-ylmethyl)-trimethylstannane ( 4 ) is furnished in high yield through an S RN 1 mechanism. Reaction of Me 3 Si − ions with 1-allyloxy-2-iodobenzene in HMPA, affords only the ipso -substituted product, namely 2-(allyloxy-phenyl)-trimethylsilane ( 11 ), through the intermediacy of a hypervalent silicon species.

Transition metal- and organophotocatalyst-free perfluoroalkylation reaction of amino(hetero)aromatics initiated by the complex [(TMEDA)I·I3] and visible light

Radical initiation for the perfluoroalkylation reaction of amino(hetero)aromatics has been accomplished employing the complex [(TMEDA)I·I3] and visible light. This methodology circumvents the use of metal(organo)catalysts and biologically-relevant substrates are easily substituted with RF moieties employing a mild and environmentally benign radical strategy starting from readily-available perfluoroalkyl iodides RFI.