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A direct oxidative alkylarylation reaction of N-arylacrylamides with simple alkanes for the synthesis of 3,3-disubstituted oxindoles under metal-free conditions was demonstrated. By using PhI(OAc)2 [(diacetoxy)iodobenzene] as an oxidant, a series of 3,3-disubstituted oxindoles bearing different aryl or alkyl substituents were generated in moderate to excellent chemical yields via a radical-initiated alkylation/cyclization process. The reported method features good functional group tolerance and wide substrate range, and provides an effective method for the preparation of various alkyl substituted 3,3-disubstituted oxindoles.

This review reports the synthesis of various bioactive macrocycles, involving ring-closing metathesis as a key step, developed since ca. 2000. These macrocycles exhibited biological activities such as antiviral, antifungal, antibacterial, and anticancer activities, and more. Thus, their syntheses and utilization are essential for both synthetic organic and medicinal chemists.

Triazole-based compounds possess a broad range of activity and can be synthesized using click chemistry. Many new chemotherapeutic agents have been developed in recent years by exploiting click chemistry and these are covered in this review.

The extensive range of uses of N-heterocycles as potent bioactive motifs has attracted researchers to expand newer methods for their efficient synthesis. Particularly, indoles are widely known for their prevalent pharmacological properties. Green chemistry provides various synthetic tools viz. alternative energy resources, nonconventional solvents, nano-catalysts, etc. Modern strategies of using ultrasound as an alternative energy resource in organic synthesis has led to the development of environment friendly and cost-effective techniques. The chemical and mechanical effects of ultrasound waves impart significant enhancement in both stoichiometric and catalytic reactions. The exclusive physicochemical properties of water offer widespread utility for carrying out organic reactions in this medium. The aim of this review article is to provide an inclusive summary of the combined use of ultrasound and aqueous media for the facile synthesis of biologically vital indole derivatives.1 Introduction2 Synthesis of Biologically Vital Indoles2.1 Spirocyclic Indoles2.2 Non-spiro 3-Substituted Indoles2.3 Miscellaneous Indole Syntheses3 Conclusions

The syntheses of five new 1-chloro-3-aryl-5-trichloromethyl-1λ4,2,4,6-thiatriazines, aryl = 4-R-C6H4- (R = CH3O, CH3, H, Cl and CF3), are reported with full characterization. Single-crystal X-ray diffraction structure determinations on all, as well as the 5-CF3 analogue which also has R = CF3, with models produced by Hirshfeld atom refinement, produced high-accuracy structures. All six exemplars form lateral dimers with short contacts that define a centrosymmetric {δ+S···Nδ−}2 motif, with interaction distances from 3.0473(9) to 3.422(3) Å, which do not vary in an expected manner with R. Normal population analysis charges computed by B3LYP-D3/6-311++G(d,p) DFT methods show small variations, and entirely as expected from the inductive effects of R. Gas-phase minimization of the dimers with M06-2X/aug-cc-pVDZ or B3LYP-D3/6-311++G(d,p) methods, with full counterpoise correction, replicate the experimental geometries for the 5-CF3, the 5-CCl3/CH3OC6H4 and the 5-CCl3/CH3C6H4 experimental structures, but diverge for other CCl3 exemplars. Interaction energies are more than double those computed for [(HC)2N2S]2. Using a geometry-optimized model with H in place of CX3, the interaction energy reduces to a very realistic –22 to –24 kJ/mol for just the {δ+S···Nδ−}2 motif, suggesting that CX3 interactions contribute 21% (CF3) to 37% (CCl3) of the total.

High-yielding and mild conditions are used to prepare of 1-bromo-2-alkyl- or 2-arylpent-4-en-2-ols/1-bromo-2-alkyl- or 2-arylpent-4-yn-2-ols from α-diazoketones. The reaction involves allylation/propargylation with successive bromide insertion using in situ generated allyltin bromide/or propargyltin bromide from activated tin metal and allyl/or propargyl bromide.

A modular and highly reliable click approach is applied for the expeditious synthesis of lactose- and galactose-coated calixarene-cored G1 and G2 generation glycodendrimers, respectively. The developed calixarene glycodendrimers have been characterized by using extensive spectral analysis including NMR (1H and 13C), MS, IR, and SEC data.

With the help of the photothermal effect of gold nanoparticles (AuNPs), the hydration of the arylacetylenes to synthesize carbonyl compounds is successfully achieved. The reaction proceeds smoothly for various substrates and the ketone products are obtained in good isolated yields up to 91%. The successful gram-scale and sunlight-exposure experiments illustrate the potential application of this method in the future organic syntheses.

A one-step chlorosulfonylation of acrylamides via a photocatalytic redox process is described. This reaction provides α-chlorosulfonylamides with a quaternary center with high regioselectivity via radical process. It is amenable to a broad range of substrates and the products are obtained in moderate to good yields.

Transition-metal-catalyzed C–H activation has emerged as a powerful strategy for molecular synthesis with unique levels of resource economy. Weak secondary dispersion interactions were found to play an essential role in these transformations in terms of kinetic efficacy and selectivity. This Account summarizes our group’s recent progress in the rationalization and quantification of London dispersion effects within the transition-metal-catalyzed C–H activation.1 Introduction2 Annulation Reactions3 Alkylation Reactions4 Arylation Reactions5 Olefination Reactions6 Oxygenation Reactions7 Conclusion

In this review we give an overview of the syntheses and photophysical properties of the new class of fluorescent dyes based on a [1,3]-dioxolo[4,5-f]benzodioxole core and their derivatives. Starting from commercially available reactants (e.g., sesamol, 1,2,4,5-tetrachlorobenzene) the core units can be prepared in a simple manner. Then, the benzene core can be derivatized via lithiation and their photophysical properties can be adjusted as desired. The obtained fluorophores have an absorption range of 403–520 nm and an emission range of 495–665 nm. This class of fluorescent dyes is also characterized by a long fluorescence lifetime, a high stability towards photobleaching, large Stokes shifts, and small size. Thus, the DBD dyes are optimally suited for optical sensing.1 Introduction2 Synthesis3 Properties4 Applications

This graphical review provides a concise overview of indole alkaloids and chemical reactions that have been reported to transform both these natural products and derivatives to rapidly access new molecular scaffolds. Select biologically active compounds from these synthetic efforts are reported herein.

Multicomponent reactions (MCRs) cover strategically employed chemical transformations that incorporate three or more reactants in one pot leading to a functionalized final product. Thus, it is an ideal tool to achieve high levels of complexity, diversity, yields of desired products, atom economy, and reduced reaction times. Sugars belong to the class of naturally occurring compounds with fascinating applications in the field of drug discovery due to the presence of various hydroxy groups and well-defined stereochemistry. However, their potential in MCRs has been realized only recently. This account describes recent advances in the synthesis of sugar-derived heterocycles synthesized by MCRs. We hope to encourage the synthetic and medicinal chemistry community to apply this powerful MCR chemistry to generate novel glycoconjugate challenges.1 Introduction2 Synthesis of Various Functionalized Sugar Compounds2.1 Passerini and Ugi Multicomponent Reactions2.2 Petasis Reaction2.3 Hantzsch Reaction2.4 Domino Ferrier–Povarov Reaction2.5 Marckwald Reaction2.6 Groebke–Blackburn–Bienaymé (GBB) Reaction2.7 Prins–Ritter Reaction2.8 Debus–Radziszewski Imidazole Synthesis Reaction2.9 Mannich Reaction2.10 A3-Coupling Reaction2.11 [3+2]-Cycloaddition Reactions2.12 Miscellaneous Reactions3 Conclusion

A metal- and base-free, robust, and convenient approach for the synthesis of isoxazoline derivatives is reported. This protocol involves 1,3-dipolar cycloaddition between in situ generated nitrile oxides from the corresponding aldoximes using [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser’s reagent) and maleimides, styrene and acrylonitrile. The described methodology is very attractive as it is operationally simple, has broad scope, and does not require any base, metal, or other additives.

The Vilsmeier–Haack reaction has historically been a topic of significant interest to organic chemists, and it continues to attract considerable attention. The reaction itself provides a facile route towards a large number of aromatic and heteroaromatic systems. The Vilsmeier–Haack reagent, generated from amides and halides, is found to be very important in organic synthesis. This account highlights recent developments in the synthetic utility of the Vilsmeier–Haack reagent.1 Introduction2 Formylation3 Formylation and Chlorination4 Formylation and Acetylation5 Chlorination6 ortho-Formylation7 Miscellaneous8 Conclusions

The incorporation of fluorinated substituents in cyclopentadienyl anions leads to distinct changes in the properties of the corresponding metal complexes, e.g., with regards to electrochemical properties or metal–ligand bonding energies. This review summarizes the synthetic challenges of the preparation and coordination of fluorinated cyclopentadienyl anions.1 Introduction2 Fluorinated Cyclopentadienyls3 Cyclopentadienyls with One CF3 Group4 Cyclopentadienyls with Four CF3 Groups5 Cyclopentadienyls with Five CF3 Groups6 Cyclopentadienyls with ‘Fluorous Ponytails’7 Cyclopentadienyls with C6F5 Groups8 Trends in Interaction Energies9 Conclusion

Use of sustainable energy sources in synthetic organic chemistry has become one of the most popular research topics due to environmental pollution and global warming. In this review, we discuss photocatalyst-free and transition-metal-free light-induced reactions for the construction of carbon–carbon (C–C) bonds. The reaction systems discussed here are C–C bond formation via carbene intermediates, radical intermediates, and miscellaneous reactions via cyclization.1 Introduction2 C–C Bond Formation via Carbene Intermediates3 C–C Bond Formation via Radical Intermediates4 Miscellaneous C–C Bond Formation via Cyclization5 Conclusion

(Hetero)aryl dehalogenation is a classical transformation usually performed using hydrogen gas and a metal supported on carbon, notably palladium (Pd/C). Though efficient, the need for a milder and operationally simple dehalogenation can arise. We found that the combination of Pd/C as catalyst and triethylsilane (TES) as hydrogen donor in THF resulted in a broadly applicable, easy to set up, and scalable debromination and deiodination. Optimization of the reaction showed that 1 mol% of Pd/C and 4 equiv of TES at room temperature were sufficient to obtain full conversion of most synthons of pharmaceutical interest in 4–24 h. The newly found conditions were applied to a large range of aromatic and heteroaromatic substrates, affording the desired targets in good to excellent yields with an exceptional functional group tolerance.

The synthesis of 1-(trifluoromethyl)alkenes through nickel-catalyzed alkylation/arylation of 1-chloro-3,3,3-trifluoroprop-1-ene (HCFO-1233zd) with alkyl/aryl zinc reagents and cobalt-catalyzed reductive cross-coupling between HCFO-1233zd and aryl bromides has been developed. These approaches feature broad substrate scope, high functional group tolerance, and the use of industrial feedstocks and low-cost nickel/cobalt catalysts, providing facile routes to access 1-(trifluoromethyl)alkenes. Diverse transformations of the resulting 1-(trifluoromethyl)alkenes demonstrated the synthetic utility of the current approaches.

The biogenesis-inspired synthesis of the structurally unique 15(14→11)abeo-steroid penicillitone starting from commercially available ergosterol is reported. Key to the strategy is an intramolecular vinylogous aldol reaction of a 14,15-secoergostane obtained from the previously reported 14,15-secosteroid platform. Since a similar intermediate has been employed to access the strophasterol class of natural products, this work points at a possible biosynthetic connection between penicillitone and the strophasterols.

The difluoroalkylation of unactivated alkenes with ethyl iododifluoroacetate via visible light-induced process has been developed. This transformation provides selective access to difluoroalkylated indole derivatives in good yields depending on the choice of base, solvent, as well as the loading of ethyl iododifluoroacetate.

Anilines selectively arylated at their ortho, meta or para positions are useful building blocks in synthesis and have found applications in many areas. The most straightforward method for their synthesis relies on the direct arylation of a C(sp2)–H bond of anilines, an attractive strategy avoiding the prefunctionalization of the starting anilines provided that such arylations proceed with high levels of regioselectivity. Such reactions are presented and discussed, in a comprehensive manner, in this review article, with an emphasis on the regioselectivity of the processes and factors governing both the reactivity and selectivity. 1 Introduction2 ortho-Arylation of Anilines2.1 Direct C(sp2)–H ortho-Arylation of Anilines2.2 Directed C(sp2)–H ortho-Arylation of Anilines3 meta-Arylation of Anilines4 para-Arylation of Anilines4.1 Direct C(sp2)–H para-Arylation of Anilines via Oxidative Radical Homodimerization4.2 Direct C(sp2)–H para-Arylation of Anilines via Transition-Metal Catalysis5 Conclusion and Outlook

Palladium-catalyzed cross-coupling of ortho-alkenyl bromobenzenes and α-aryl-α-diazoesters was realized. The reactions proceeded in moderate to excellent yields with broad substrate scope, providing a straightforward method for the synthesis of 1,1-disubstituted indenes. The reaction is thought to undergo a tandem alkenyl C–H activation/carbene insertion sequence, in which a C,C-pallada(II)cycle is the key intermediate.

This review describes the chemical composition of flaxseed (Linum usitatissimum) and its general health effects, as well as the currently available knowledge concerning its action on the female reproductive state, functions on the ovary and ovarian cells and reproductive hormones, as well as possible constituents and extra- and intracellular mediators mediating its effects on female reproductive processes. Flaxseed contains a number of biologically active molecules, which, acting through multiple signalling pathways, can determine numerous physiological, protective and therapeutic effects of flaxseed. The available publications demonstrate the action of flaxseed and its constituents on the female reproductive system – ovarian growth, follicle development, the resulting puberty and reproductive cycles, ovarian cell proliferation and apoptosis, oo- and embryogenesis, hormonal regulators of reproductive processes and their dysfunctions. These effects can be determined by flaxseed lignans, alpha-linolenic acid and their products. Their actions can be mediated by changes in general metabolism, metabolic and reproductive hormones, their binding proteins, receptors and several intracellular signalling pathways, including protein kinases, transcription factors regulating cell proliferation, apoptosis, angiogenesis and malignant transformation. Flaxseed and its active molecules are found potentially useful for improving farm animal reproductive efficiency and treatment of polycystic ovarian syndrome and ovarian cancer.

The evolution of methods for carbonyl allylation and crotylation of alcohol proelectrophiles culminating in the design of iodide-bound ruthenium-JOSIPHOS catalysts is prefaced by a brief historical perspective on asymmetric carbonyl allylation and its relevance to polyketide construction. Using gaseous allene or butadiene as precursors to allyl- or crotylruthenium nucleophiles, respectively, new capabilities for carbonyl allylation and crotylation have been unlocked, including stereo- and site-selective methods for the allylation and crotylation of 1,3-diols and related polyols.1 Introduction and Historical Perspective2 Ruthenium-Catalyzed Conversion of Lower Alcohols into Higher Alcohols3 Conclusion and Future Outlook

A convergent [4+2] stereoselective block glycosylation strategy has been developed for the synthesis of the hexasaccharide repeating unit of the capsular polysaccharide of Klebsiella K19 strain in very good yield. The p-methoxybenzyl (PMB) group was used as a temporary alkyl protecting group, which was removed by tuning the glycosylation conditions. A thioglycoside was used as a glycosyl acceptor in an orthogonal glycosylation reaction. A late-stage TEMPO-mediated selective oxidation of a primary hydroxyl group into carboxylic acid allowed incorporation of the d-glucuronic acid moiety in the hexasaccharide. A combination of N-iodosuccinimide (NIS) and perchloric acid supported over silica (HClO4–SiO2) was used as a thiophilic promoter for the activation of thioglycosides. HClO4–SiO2 was also used as a solid acid activator for a glycosyl trichloroacetimidate derivative.

We describe the efficient total syntheses of naturally occurring tripeptides acidiphilamides A–C and epi-acidiphilamides A–C, which were prepared from commercially available l-phenyl alanine using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) as peptide coupling reagent. The structures of the natural acidiphilamides A, B and C were characterized by NMR, MS and SOR data, which match those of natural products, whereas the structures of epi-acidiphilamides A, B and C were confirmed by 2D NMR studies.

A group of thirteen catalysts of type [Ru(Cp/Cp*)(P–P)(MeCN)]PF6, bearing cooperative or noncooperative bidentate phosphine ligands, were evaluated for the catalytic acceptorless dehydrogenation of indoline. The systematic comparison revealed that the optimal cooperative catalyst structure included a Cp ancillary ligand, and an N,N-disubstituted P,P-disubstituted 1,5-diaza-3,7-diphosphacyclooctane ligand, denoted as (PR 2NR′ 2). A cooperative complex bearing a PPh 2NPh 2 ligand exhibited about a twofold longer lifetime than a noncooperative analogue with (diphenylphosphino)ethane (dppe) as the supporting bisphosphine ligand. The cooperative catalyst effectively dehydrogenated a range of indoline substrates to give substituted indoles.

We report a concise and green total synthesis of 1,4-dideoxy-1,4-imino-l-arabinitol hydrochloride from naturally occurring d-xylose. The key step involves a stereospecific substitution of a hydroxy group, without prior derivatization, in which the only byproduct is water. This opens up a novel benign route to iminosugar derivatives with diverse biological activities.

The direct hydrogermylation of alkenes under Lewis acid catalysis is reported. The use of borane B(C6F5)3 as a catalyst allows for a mild, metal-free hydrogermylation of alkenes and concomitant reduction of ketones and aldehydes. Regardless of electronic biases, anti-Markovnikov hydrogermylation is observed in high yields. Moreover, the process is scalable and proceeds under mild conditions at room temperature.

This Graphical Review provides an overview of amide bond activation achieved by selective oxidative addition of the N–C(O) acyl bond to transition metals and nucleophilic acyl addition, resulting in acyl and decarbonylative coupling, together with key mechanistic details pertaining to amide bond distortion underlying this reactivity manifold.

A simple, eco-friendly and straightforward synthesis of hydrazones has been devised that is conducted in the presence of chitosan Hydrochloride (chitosan·HCl) as catalyst in aqueous-ethanol medium at room temperature. The current protocol offers metal-free synthesis, adaptability to large-scaleup, good yields, and quicker reaction time. All ten synthesized hydrazones also showed good antimycobacterial activity, with minimum inhibitory concentrations (MICs) ranging from 3.12 to 6.25 μg/mL. One of the products presented strong binding affinity against M. tuberculosis pantothenate synthetase (pdb id: 3IVX) with a Glide docking score of –8.803 kcal/mol. Molecular dynamics simulation analysis of its complex with 3IVX retained good stability over the simulation period of 20 ns.

In molecular design, large alkyl groups are used to introduce bulk and steric crowding of the catalytic center to improve catalytic efficiency and selectivity. The bulky groups are highly polarizable, increasing their ability to participate in stabilizing noncovalent interactions. The rationalization of noncovalent interaction trends is of both fundamental and practical interest as it provides new design concepts for catalysis and synthesis. Highly congested molecules always present challenges to chemists. Crowded benzene systems are an important class of compounds with well-established thermodynamic properties. The latter were used in this work to develop tools to quantify the degree of stabilization or destabilization in benzene systems crowded with bulky isopropyl and tert-butyl substituents. The basic idea was to quantify the delicate balance between repulsive and attractive interactions inherent in crowded benzene systems. The ensemble of experimental thermodynamic data and DFT-D3 calculations enabled the development of quantitative scales of the dispersion contributions and their understanding at the molecular level.

A novel, conceptually distinct synthesis of a key precursor to sacubitril, an antihypertensive drug, is presented. The well-demonstrated hetero-Diels–Alder addition of in situ generated nitrosoalkenes to electron-rich enol ethers was engaged to establish the required functionalities with controllable relative stereochemistry. An asymmetric variant of the enol ether enabled access to the target molecule in enantiopure form.

A heterogeneous CoOCN composite was synthesized via a one-pot reaction of [Co(NO3)2] and urea at 500 °C in a muffle furnace. The composite was fully characterized by FTIR, Raman, powder XRD, and XPS techniques. The catalyst was found to be efficient for the hydrations of aryl alkynes and nitriles under aerobic conditions. In addition, the catalyst exhibits high catalytic performance for the reduction of nitroarenes under inert gas-free conditions. This multitasking CoOCN composite was found to be highly suitable for all derivatives of nitrobenzene, alkynes, and nitriles because good to excellent yields were obtained. The catalyst was recovered quantitatively from the reaction mixture by simple filtration and consequently reused for seven consecutive cycles in all reactions without significant loss of catalytic activity. Hence, the synthesized CN-doped CoOCN composite worked as a multitasking catalyst for various value-added organic transformations, and it is highly economical and reusable for up to seven catalytic cycles without any activation, with even the last cycle producing reasonable yields of up to 48–50%.

A methodology for the oxidation of α-trifluoromethyl alcohols to the corresponding trifluoromethyl ketones is presented. A catalytic quantity of a nitroxide is used, and potassium persulfate serves as the terminal oxidant. The methodology proves effective for aromatic, heteroaromatic, and conjugated alcohol substrates. It can be extended to nonfluorinated secondary alcohols and, in this case, can be applied to a range of aromatic, heteroaromatic, and aliphatic alcohols.

Photoredox catalysis has revolutionized synthetic chemistry in recent decades. However, the field has traditionally used high-energy blue/ultraviolet light to activate chromophores. High-energy irradiation is associated with several drawbacks (e.g., activation of sensitive functional groups, undesired metal-ligand homolysis, background activation of molecules, and poor penetration), which has led researchers to develop alternative systems with lower energy deep red (DR) or near-infrared (NIR) light. This graphical review provides a concise overview of photophysical principles relevant to photoredox catalysis. Several applications that benefit from low-energy irradiation, such as large-scale batch reactions, photodynamic therapy, biological labeling, and multi-photon excitation are reviewed.

Three carvotacetones (1 – 3) isolated from Sphaeranthus africanus were screened in 60 cancer cell lines at the National Cancer Institute (NCI) within the Developmental Therapeutics Program (DTP). At the concentration of 10−5 M, compound 1 (3,5-diangeloyloxy-7-hydroxycarvotacetone) turned out to be the most active compound against ACHN and UO-31 renal cancer cell lines with growth percent values of − 100% (all cells dead). Compound 2 (3-angeloyloxy-5-[2″,3″-epoxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone) showed strong effects in SK-MEL-5 melanoma and ACHN renal cancer cells with inhibition values of 93% and 97%, respectively. Compound 3 (3-angeloyloxy-5-[3″-chloro-2″-hydroxy-2″-methylbutanoyloxy]-7-hydroxy-carvotacetone) exhibited a quite strong effect on renal cancer cells with a growth inhibitory effect of 96% against ACHN and UO-31 cells. When treated with five different concentrations of 1 (1 × 10−8, 1 × 10−7, 1 × 10−6, 1 × 10−5, and 1 × 10−4 M), HOP-92 cells were found to be most sensitive with GI50, TGI, and LC50 values of 0.17, 0.40, and 0.96 µM, respectively. When using the ApoTox-Glo triplex assay to evaluate the apoptosis inducing effects of seven carvotacetones isolated from S. africanus in CCRF-CEM cells, compounds 1 – 6 increased caspase-3/7 activity with 1, 2, and 4 (3-angeloyloxy-5,7-dihydroxycarvotacetone) exhibiting the highest activitiy, indicating induction of caspase-dependent apoptosis.

The first regioselective syntheses of 1,2-thiaselenane-4-amine (TSA4) and 1,2-thiaselenane-5-amine (TSA5) are developed. Both are redox motifs with high value in chemical biology that until now were hindered by tedious synthesis. An aziridine intermediate and a kinetically controlled S-acylation were leveraged for regioselective chalcogen installations. Short, fast sequences were optimised with just one or two chromatographic steps that cheaply deliver these motifs on scale for high throughput inhibitor screening, and thus provide a robust methodology for assembling other selenenyl sulfides.

Linearly fused retinoid derivatives have been synthesized via a straightforward pathway using a palladium-catalyzed reductive Heck cyclization strategy. The synthesis involved a four-step linear approach utilizing iodination, sulfonylation or benzylation or esterification, palladium-catalyzed Sonogashira cross-coupling and palladium-mediated reductive Heck cyclization.

Due to the increasing need for fluorine-containing drugs, the synthesis of organofluorine scaffolds has become a highly researched area of synthetic organic chemistry. The introduction of the trifluoromethyl group into the structure of an organic molecule has considerable potential and several advantages concerning the characteristics of the fluorinated pharmaceuticals. The incorporation of a CF3 group at multiple bonds containing a nitrogen heteroatom is a relatively new field and currently it is an expanding area of synthetic chemistry. This short review summarizes, for the first time, recent developments in trifluoromethylation reactions of isonitriles.1 Introduction2 Trifluoromethylation Reactions of Isonitriles2.1 Synthesis of Trifluoromethylated Phenanthridine Derivatives2.2 Synthesis of Trifluoromethylated Quinoline Derivatives2.3 Synthesis of Trifluoromethylated Isoquinoline Derivatives2.4 Synthesis of Trifluoromethylated Indole Derivatives2.5 Synthesis of Trifluoromethylated Pyridine Derivatives3 Summary and Outlook

In the pharmaceutical industry, boronic acid and esters play an important role in API-based synthesis. The most efficient way of preparing various active agents is palladium-catalyzed Suzuki–Miyaura borylation reactions. Herein, we report the formation of dimerization product [6,6′-biimidazo[1,2-a]pyridine]-2,2′-dicarboxamide derivatives 7a–j from 6-bromoimidazo[1,2-a]pyridine-2-carboxylate by employing the same conditions. A regioselective borylation of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (3) was examined for the formation of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate (4a) but it was found to be directed towards the dimerization product 5. The nitrogen-rich system was incorporated into potential anti-cancer and anti-TB agents through acid amine coupling reactions between acid 6 and various amines (dialkyl/cyclic sec./tert.) to form the final adducts 7. Five derived scaffolds were identified as moderately active in TB activity against the H37Rv strain, while two compounds were found to be particularly potent in NCI-60 anti-cancer screening in nine cancer panels.

A synthesis of novel bicyclic 1,3,5-triazinane-2,4-diones has been accomplished through base-promoted fragmentation followed by cyclization. Various saturated ring-fused bicyclic urazoles were prepared by two complementary methods: by the reaction of N,N′-bis(2-chloroethyl)urazoles with various nucleophiles or by using 4-substituted urazoles and dibromoalkanes. Treatment of these symmetrical urazole derivatives with LDA at –78 °C to 25 °C resulted in fragmentation of the N–N bond to form an imine that underwent intramolecular cyclization, resulting in moderate yields of nonsymmetric heterocycle derivatives with an asymmetric (racemic) center and various ring sizes. The utility of these transformations was extended to syntheses of a tricyclic system and bicyclic systems containing additional heteroatoms.

A diastereo- and enantioselective synthesis of diazobicyclic oxadiazines was developed through an organocatalytic cycloaddition reaction. Asymmetric catalytic [3+3]-cycloaddition of γ-hydroxy-α,β-unsaturated carbonyls with N,N′-cyclic azomethine imines, using a squaramide-based catalyst, provided biologically important enantioenriched diazobicyclic oxadiazines in good yields with moderate to high diastereo- and enantioselectivities (up to 10:1 dr and 79:21 er).

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of a thiolate of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt. The reactions allow facile and low-cost synthesis of valuable α,α-difluoro substituted aliphatic carboxylate esters under mild conditions, and demonstrate the dual-functional role of arenethiolates in photocatalysis as both a strong photoreductant in a redox cycle and a hydrogen-atom-transfer catalyst.

We report herein the tetraethylammonium bromide catalyzed intramolecular oxidative cyclization of O- or S-alkylated salicylic or thiosalicylic acid derivatives to access 4H-benzo[d][1,3]dioxin-4-ones or 4H-benzo[d][1,3]oxathiin-4-ones, respectively. The oxidative cyclization of salicylic acid derivatives proceeds through a radical pathway at 110 °C. In contrast, the cyclization of the thiosalicylic acids proceeds smoothly at room temperature via an ionic pathway. Notably, the overall reactions are fast, completed within short reaction times, furnishing the products in high yields and with smooth formation of quaternary carbon centers.