Electronic Effects in a Green Protocol for (Hetero)Aryl-S Coupling.

Aryl and heteroaryl iodides have been efficiently converted into the corresponding thioacetates in cyclopentyl methyl ether (CPME), a green solvent, under Cu catalysis. The chemoselectivity of the reaction is mainly controlled by electronic factors, enabling the conversion of both electron-rich and electron-deficient substrates into the corresponding thioacetates in good to excellent yields. The products can be easily deprotected to the corresponding thiolates to carry out additional synthetic transformations in situ. Surprisingly, despite CPME's relatively low dielectric constant, the reaction rate significantly increased when conducted under microwave irradiation conditions. This synthetic methodology exhibits a remarkable tolerance to functional groups, mild reaction conditions, and a wide substrate scope, utilizing a safe and inexpensive CuI pre-catalyst in the green solvent CPME. A non-aqueous workup allowing for the complete recovery of both catalyst and solvent makes this approach an environmentally sustainable protocol for C(sp2) sulfur functionalization. Additionally, the reaction shows selective cross-coupling with iodides in competition with chlorides and bromides, allowing its use in multistep syntheses. To demonstrate the potential of this methodology, it was applied to the high-yield synthesis of a photochromic dithienylethene, where a selective synthesis had not been reported before.

Selective noncovalent proteasome inhibiting activity of trifluoromethyl-containing gem-quaternary aziridines.

The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.

Leveraging the 3-Chloro-4-fluorophenyl Motif to Identify Inhibitors of Tyrosinase from Agaricus bisporus.

Tyrosinase (EC 1.14.18.1) is implicated in melanin production in various organisms. There is a growing body of evidence suggesting that the overproduction of melanin might be related to several skin pigmentation disorders as well as neurodegenerative processes in Parkinson's disease. Based on this consideration, the development of tyrosinase inhibitors represents a new challenge to identify new agents in pharmaceutical and cosmetic applications. With the goal of identifying tyrosinase inhibitors from a synthetic source, we employed a cheap and facile preliminary assay using tyrosinase from Agaricus bisporus (AbTYR). We have previously demonstrated that the 4-fluorobenzyl moiety might be effective in interactions with the catalytic site of AbTYR; moreover, the additional chlorine atom exerted beneficial effects in enhancing inhibitory activity. Therefore, we planned the synthesis of new small compounds in which we incorporated the 3-chloro-4-fluorophenyl fragment into distinct chemotypes that revealed the ability to establish profitable contact with the AbTYR catalytic site. Our results confirmed that the presence of this fragment is an important structural feature to improve the AbTYR inhibition in these new chemotypes as well. Furthermore, docking analysis supported the best activity of the selected studied compounds, possessing higher potency when compared with reference compounds.

Synthesis, computational investigation and biological evaluation of α,α-difluoromethyl ketones embodying pyrazole and isoxazole nuclei as COX inhibitors.

α,α-Difluoromethyl ketones (DFMKs) have emerged as currently investigated agents benefiting from the merging of chemico-physical features conferred by the constitutive elements (-CHF2 and carbonyl moietites). With a view to biological applications, the additional incorporation of heterocycles is a desirable property enabling the tuning of critical factors encompassing the pharmaco-dynamic and kinetic profiles. The underexplored assembling of α,α-difluoromethyl-heteroaromatic ketones is herein implemented via a conceptually intuitive Weinreb amide acylative transfer of a putative difluoromethyl-carbanion. To make the strategy productive, we adopted the commercially available TMSCHF2 pronucleophile - characterized by robust chemical stability and manipulability (bp 65 °C) - which upon Lewis-base mediated activation delivers the competent CHF2-nucleophile. The synthetic protocol was carried out on pyrazole- and isoxazole-based scaffolds, and a panel of heteroaryl-DFMKs was consequently developed as potential COX-inhibitors. In this sense, the bioisosterism deducted through docking studies between the widely expressed carboxylic group (in several clinically used COX inhibitors) and the -COCHF2 motif introduced herein supports this rationale. To confirm the docking results, all compounds were tested against both COX-1 and COX-2 enzyme isoforms showing activity in the micromolar range and a good selectivity index (SI). They were also evaluated for their biocompatibility using NIH/3T3 cells to which they did not show any significant toxicity.

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines.

The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer. However, to the best of our knowledge, aziridine derivatives showing inhibitory activity towards proteasome have never been described before. Herein we report a new class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays (two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together, these results are promising for developing more potent PIs.

Application of Biobased Solvents in Asymmetric Catalysis.

The necessity of more sustainable conditions that follow the twelve principles of Green Chemistry have pushed researchers to the development of novel reagents, catalysts and solvents for greener asymmetric methodologies. Solvents are in general a fundamental part for developing organic processes, as well as for the separation and purification of the reaction products. By this reason, in the last years, the application of the so-called green solvents has emerged as a useful alternative to the classical organic solvents. These solvents must present some properties, such as a low vapor pressure and toxicity, high boiling point and biodegradability, and must be obtained from renewable sources. In the present revision, the recent application of these biobased solvents in the synthesis of optically active compounds employing different catalytic methodologies, including biocatalysis, organocatalysis and metal catalysis, will be analyzed to provide a novel tool for carrying out more ecofriendly organic processes.

Direct and straightforward transfer of C1 functionalized synthons to phosphorous electrophiles for accessing gem-P-containing methanes.

The direct transfer of different α-substituted methyllithium reagents to chlorinated phosphorous electrophiles of diverse oxidation state (phosphates, phosphine oxides and phosphines) is proposed as an effective strategy to synthesize geminal P-containing methanes. The methodology relies on the efficient nucleophilic substitution conducted on the P-chlorine linkage. Uniformly high yields are observed regardless the specific nature of the carbanion employed: once established the conditions for generating the competent nucleophile (LiCH2Hal, LiCHHal2, LiCH2CN, LiCH2SeR etc.) the homologated compounds are obtained via a single operation. Some P-containing formal carbanions have been evaluated in transferring processes, including the carbonyl-difluoromethylation of the opioid agent Hydrocodone.

Taking advantage of lithium monohalocarbenoid intrinsic α-elimination in 2-MeTHF: controlled epoxide ring-opening en route to halohydrins.

The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding ß-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses.

The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.

Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four-Membered Sulfur-Containing Cycles.

A formal CH2 -CH2 homologation conducted with C1 carbenoids on a carbon electrophile for the obtainment of a four-membered cycle is reported. The logic proposes the consecutive delivery of two single nucleophilic CH2 units to an isothiocyanate-as competent electrophilic partner-resulting in the assembling of a rare imino-thietane cluster. The single synthetic operation procedure documents genuine chemocontrol, as indicated by the tolerance to various reactive elements decorating the starting materials. Significantly, the double homologation protocol is accomplished directly on a carbon electrophile, thus not requiring the installation of heteroatom-centered manifolds (e.g. boron).

Electrophilicity Scale of Activated Amides: 17 O†NMR and 15 N†NMR Chemical Shifts of Acyclic Twisted Amides in N-C(O) Cross-Coupling.

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to nN →π*C=O conjugation. In this study, we report electrophilicity scale by exploiting 17 O NMR and 15 N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.

Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-ß-Diketiminates and the Dual Role of LiCH2I.

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation-metalation-acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated ß-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH2Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.

Chemoselective reduction of isothiocyanates to thioformamides mediated by the Schwartz reagent.

Thioformamides are easily prepared - under full chemocontrol - through the partial reduction of isothiocyanates with the in situ generated Schwartz reagent. The high electrophilicity of the starting materials enables the straightforward addition of the hydride ion, thus constituting a reliable and high-yielding method for obtaining variously functionalized thioformamides. Sensitive chemical groups to the reduction conditions such as nitro, ester, alkene, azo, azide and keto groups do not interfere with the chemoselectivity of the process. Moreover, the stereochemical information embodied in the starting material is fully retained in the final products. The synthetic potential of the selected thioformamide template is also briefly discussed.

Telescoped, Divergent, Chemoselective C1 and C1-C1 Homologation of Imine Surrogates: Access to Quaternary Chloro- and Halomethyl-Trifluoromethyl Aziridines.

A conceptually novel, high-yielding, mono- or bis-homologation was realized with lithium halocarbenoids and enables the one-step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH2 Cl and LiCH2 F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.

α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations, and Structural X-ray Analysis.

Primary and secondary α-halomethyl diazoketones generated via Arndt-Eistert chemistry with minimum loading of diazomethane efficiently alkylate aromatic amines in the presence of calcium oxide to furnish the corresponding α-arylamino diazoketones under full chemocontrol. Such a simple inorganic acid scavenger fully neutralizes the hydrohalic acid formed during the nucleophilic displacement which otherwise would immediately react to produce the corresponding α-haloketone. The methodology can be further exploited in analogous acylation-type processes on secondary arylamino diazoketones. In depth spectroscopic (1H, 13C, and 15N NMR ) and crystallographic analyses document interesting structural features of these previously unknown diazo derivatives.

An unusual thionyl chloride-promoted C-C bond formation to obtain 4,4'-bipyrazolones.

Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a representative 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylate was confirmed by X-ray crystal structure analysis.

Exploiting a "Beast" in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy.

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

A greener and efficient access to substituted four- and six-membered sulfur-bearing heterocycles.

The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (log k'w) and calculated log P (clog P) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18 columns, which results in increased retention times.

Efficient Access to All-Carbon Quaternary and Tertiary α-Functionalized Homoallyl-type Aldehydes from Ketones.

ß,γ-Unsaturated aldehydes with all-carbon quaternary or tertiary α-centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C1 homologation, 2) Lewis acid mediated epoxide-aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a ß,γ-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents.

A synthesis of tetrasubstituted pyrazoles containing two, three or four pyridinyl substituents is described. Hence, the reaction of 1,3-dipyridinyl-1,3-propanediones with 2-hydrazinopyridine or phenylhydrazine, respectively, affords the corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd catalysts turned out to be the method of choice to obtain the desired tetrasubstituted pyrazoles. The formation of different unexpected reaction products is described. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a condensation product was confirmed by crystal structure analysis.