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Chitosan exhibits moderate antimicrobial properties. Here, we enhanced the antimicrobial properties of chitosan through alkylation and chlorination and evaluated the effect of alkylation on chitosan's hydrophobicity, bacterial attachment, chlorination, biocidal property, and stability. First, chitosan films were prepared through casting and were then immersed in a hexanal solution of different concentrations. The aldehyde groups of hexanal reacted with the amino group in chitosan through a Schiff base reaction. Next, the hexanal-modified chitosan films were soaked in 10 % bleach to form N-halamine. The results demonstrated that the surface became more hydrophobic, and chitosan films with increased hexanal-grafting concentrations exhibited less bacterial attachment. However, the degree of chlorination decreased as the degree of alkylation increased, further reducing the diameter of the zone of inhibition. Nevertheless, all chlorinated samples could kill ~5 log of Staphylococcus aureus and Escherichia coli within 30 min. Unlike previous results for chlorinated chitosan, in this study, alkylation before chlorination enhanced antibacterial properties and bactericidal ability and decelerated the degradation of chlorinated samples. The results of a systematic evaluation indicated that a hexanal-grafting concentration of approximately 80 mM maintains the equilibrium of the various properties of chitosan. Alkylated and chlorinated chitosan has considerable potential application as mask filter layers.

A metallaphotoredox-catalyzed strategy for the selective and divergent aminocarbonylation of alkynes with amines and 1 atm of CO is reported. This synergistic protocol not only enables the Markovnikov-selective hydroaminocarbonylation of alkynes to afford α,β-unsaturated amides, but also facilitates a sequential four-component hydroaminocarbonylation/radical alkylation in the presence of tertiary and secondary alkyl boronate esters, which allows for straightforward conversion of alkynes into corresponding amides. Preliminary mechanistic studies disclose that a photoinduced oxidative insertion of aniline and CO into nickel followed by a migratory insertion of (carbamoyl)nickel species could be involved.

Organophosphonium salts containing C(sp3 )-+ P bonds are among the most utilized reagents in organic synthesis for constructing C-C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C-H and C(sp3 )-+ P bond functionalizations. In the present study, C-H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp3 )-+ PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.

The photo-/electrocatalytic functionalization of quinoxalin-2(1H)-ones has emerged as a promising and powerful approach for post-synthetic modification of quinoxalin-2(1H)-ones. This review provides an overview of recent developments in photo-/electrocatalytic functionalization of quinoxalin-2(1H)-ones including arylation, alkylation, fluoroalkylation, amination, phosphorylation, acylation, alkoxylation, thiolation, silylation, and annulation. The reaction scope and the related mechanism are also well discussed.

In this paper, a simple and clean process for the alkylation and arylation of nitrogen-containing heterocycles is reported. The reactions were conducted using the Q-tube® as a non-conventional technology, in water as a green solvent, at overboiling temperature. The developed strategy was used to improve two steps in the total synthesis of caffeine, as reported by Narayan, and then extended to the preparation of N-decorated xanthines. Finally, piperidine, methyl piperazine, and isatine were proven to be suitable substrates for the protocol proposed herein.

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a catalytic enantioselective dehydrative lactonization of allylic alcohols using a novel Pd(II)-catalyst containing the imidazole-based P,N -ligand ( S )-StackPhos is reported. The high-yielding reactions are operationally simple to perform with enantioselectivities up to 99% ee. This strategy facilitates the replacement of a poor leaving group with what would ostensibly be a better leaving group in the product avoiding complications arising from racemization by equilibration.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the β-amino ester derivative.

We describe cooperative bimetallic catalysis that enables regio-/stereodivergent asymmetric α-allylations of aldimine esters. By employing Et

We report a method for direct enantioselective alkylation of 3-alkynoic and 2,3-alkendioic acids that form quaternary stereogenic centers, and application of this method to the total enantioselective synthesis of a complex alkaloid (+)-goniomitine. The methods were effective in the alkylation of both 3-alkynoic acids, 2,3-alkendioic acids substrates with a broad range of heterocyclic and functionalized alkyl group substituents. Accompanying crystallographic studies provide mechanistic insight into the structure of well-defined chiral aggregates, highlighting cation-π interactions between lithium and alkyne groups.

Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this strategy also provides a simple and powerful platform for stereodivergent synthesis, whereby all the possible stereoisomers of products bearing two stereocenters can be easily prepared from the same set of starting materials. In this Minireview, the development of stereodivergent allylic substitution, propargylic substitution, hydrofunctionalization, and annulation based on bimetallic catalysis has been summarized. It is expected that more bimetallic catalytic systems will be developed and applied for the stereodivergent synthesis of valuable molecules.

Alkyl constitutes one of the most widely used groups in organic synthesis. Here, the development of a series of thianthrenium salts, which act as reliable alkylation reagents, are ready to engage in copper-catalyzed Sonogashira reaction to build C(sp 3 )-C(sp) bonds under mild photoinduced conditions. Diverse alkyl thianthrenium salts, methyl and disubstituted thianthrenium salts are employed with great functional breadth, since sensitive Cl, Br and I are compatible and challenging to achieve by conventional approaches. The generality of the developed alkyl reagents has also been demonstrated in copper-catalyzed Kumada reactions.

The reaction of propargyl difluorides R 1 CF 2 C≡CR 2 with alkylzincs R 3 ZnCl giving axially chiral fluorinated allenes R 1 FC=C=CR 2 R 3 with high enantioselectivity (up to 99% ee) was found to be catalyzed by a chiral diene/rhodium complex. A key step in the catalytic cycle is selective elimination of one of the enantiotopic fluorides at b-position of an alkenyl-Rh intermediate which is generated by regioselective addition of R 3 -Rh onto the triple bond of the starting difluorides.

Site-selective chemical modification of protein side chain has probed enormous opportunities in the fundamental understanding of cellular biology and therapeutic applications. Primarily, in the field of biopharmaceuticals, the formulation of bioconjugates has been found to have more potential than an individual constituent. In this regard, Lysine and Cysteine are the most widely used endogenous amino acid for these purposes. Recently, the aromatic side chain residues (Trp, Tyr, and His) that are low abundant in protein have gained more attention in therapeutic applications due to their advantages of chemical reactivity and specificity. This review discusses the site-selective bioconjugation methods for aromatic side chains (Trp, Tyr and His) and highlights the developed strategies in the last three years, along with their applications. Also, the review highlights the prevalent methods published earlier. We have examined that metal-catalyzed and photocatalytic reactions are gaining more attention for bioconjugation, though their practical operation is under development. The review has been summarized with the future perspective of protein and peptide conjugations contemplating therapeutic applications and challenges.

The N-alkylation reaction of N-benzoyl 5-(aminomethyl)tetrazole (5-AMT) with benzyl bromide was carried out in the presence of K2CO3 as a base. Two separable regioisomers were obtained, thus their purification led to determine the proportion of each of them, and their structures were attributed essentially based on 1H and 13C NMR spectroscopy in addition to the elemental analysis and MS data. In order to confirm the results obtained at the synthesis level, a computational study was carried out by application of density functional theory (DFT) using the Becke three-parameter hybrid exchange functional and the Lee-Yang-Parr correlation functional (B3LYP).

We report herein comprehensive investigations of alkylation/sulfur exchange reactions of sulfur-containing substrates including nucleosides such as s2U, m5s2U, s4U, s2A and s2T-incorporated DNA enable by comprehensive screenings of the reagents (2a-2h). It has been proven that iodoacetamide (2a) displays the most promising feasibility toward sulfur-containing substrates including s2T, s2U, m5s2U, s4U and s2A. In sharp contrast, the alkylation process with S-benzyl methanethiosulfonate (BMTS, 2h) displays the best application potential only for s4U. Based on these results, the fluorescent labeling of s2T-incorporated DNA and m5s2U-modified RNA has been achieved.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1942044 .

A Ni-catalyzed reductive cross-coupling of heteroaryl imines with C(sp³) electrophiles for the preparation of heterobenzylic amines is reported. This umpolung-type alkylation proceeds under mild conditions, avoids the pre-generation of organometallic reagents, and exhibits good functional group tolerance. Mechanistic studies are consistent with the imine substrate acting as a redox-active ligand upon coordination to a low-valent Ni center. The resulting bis(2-imino)heterocycle·Ni complexes can engage in alkylation reactions with a variety of C(sp³) electrophiles, giving heterobenzylic amine products in good yields.

Herein, we developed secondary-alcohol-selective C-H alkylation of 1,3-butane diol by combining an acridinium photoredox catalyst and a thiophosphoric acid hydrogen atom transfer (HAT) catalyst. The use of non-coordinating solvent such as dichloromethane (DCM) improved secondary α-alkoxy C-H selectivity by lowering bond dissociation energy (BDE) through intramolecular hydrogen bonding.

The rapid exploration of sp

Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the pro-gramming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus pro-gramming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring.

Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (-)-berkeleyone A and its five congeners ((-)-preaustinoids A, A1, B, B1, and B2) in 12-15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)3 -mediated sequential Krapcho dealkoxycarbonylation/carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α-ketol, α-hydroxyl-β-diketone, etc.) responsible for the biomimetic diversification of (-)-berkeleyone A into its five preaustinoid congeners.

The first total synthesis of marine anti-cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α -position alkylation of Wieland-Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6-tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6-fused core structure of dysiherbol A, respectively. A late-stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

The iron-catalyzed alkyl-aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron-catalyzed radical difluoroalkylation of arylborates with N-heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N-heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single-electron-transfer process, which enables both fluoroalkyl N-heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N-heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents.

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l -proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N -alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O -acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

Sulfur mustard (SM) is a chemical warfare agent which use is banned under international law and that has been used recently in Northern Iraq and Syria by the so-called Islamic State. SM induces the alkylation of endogenous proteins like albumin and hemoglobin thus forming covalent adducts that are targeted by bioanalytical methods for the verification of systemic poisoning. We herein report a novel biomarker, namely creatine kinase (CK) B-type, suitable as a local biomarker for SM exposure on the skin. Human and rat skin were proven to contain CK B-type by Western blot analysis. Following exposure to SM ex vivo, the CK-adduct was extracted from homogenates by immunomagnetic separation and proteolyzed afterwards. The cysteine residue Cys282 was found to be alkylated by the SM-specific hydroxyethylthioethyl (HETE)-moiety detected as the biomarker tetrapeptide TC(-HETE)PS. A selective and sensitive micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HRMS) method was developed to monitor local CK-adducts in an in vivo study with rats percutaneously exposed to SM. CK-adduct formation was compared to already established DNA- and systemic albumin biomarkers. CK- and DNA-adducts were successfully detected in biopsies of exposed rat skin as well as albumin-adducts in plasma. Relative biomarker concentrations make the CK-adduct highly appropriate as a local dermal biomarker. In summary, CK or rather Cys282 in CK B-type was identified as a new, additional dermal target of local SM exposures. To our knowledge, it is also the first time that HETE-albumin adducts, and HETE-DNA adducts were monitored simultaneously in an in vivo animal study.

Arsenosugars are a group of arsenic-containing ribosides that are found predominantly in marine algae but also in terrestrial organisms. It has been proposed that arsenosugar biosynthesis involves a key intermediate 5'-deoxy-5'-dimethylarsinoyl-adenosine (DDMAA), but how DDMAA is produced remains elusive. Now, we report characterization of ArsS as a DDMAA synthase, which catalyzes a radical S-adenosylmethionine (SAM)-mediated alkylation (adenosylation) of dimethylarsenite (DMAsIII ) to produce DDMAA. This radical-mediated reaction is redox neutral, and multiple turnover can be achieved without external reductant. Phylogenomic and biochemical analyses revealed that DDMAA synthases are widespread in distinct bacterial phyla with similar catalytic efficiencies; these enzymes likely originated from cyanobacteria. This study reveals a key step in arsenosugar biosynthesis and also a new paradigm in radical SAM chemistry, highlighting the catalytic diversity of this superfamily of enzymes.

For the first time we have been able to employ enantiopure 1,2‐amino alcohols derived from abundant amino acids in C−C bond‐forming hydrogen‐borrowing alkylation reactions. These reactions are facilitated by the use of the aryl ketone Ph*COMe. Racemisation of the amine stereocentre during alkylation can be prevented by the use of sub‐stoichiometric base and protection of the nitrogen with a sterically hindered triphenylmethane (trityl) or benzyl group. The Ph* and trityl groups are readily cleaved in one pot to give γ‐aminobutyric acid (GABA) products as their HCl salts without further purification. Both steps may be performed in sequence without isolation of the hydrogen‐borrowing intermediate, removing the need for column chromatography., The scope of carbon–carbon bond‐forming hydrogen‐borrowing reactions has been expanded to include 1,2‐amino alcohols derived from both natural and unnatural amino acids. The vulnerable amine stereocentre is preserved in the reaction by the use of a bulky nitrogen protecting group (trityl or benzyl), with the products being readily cleaved under acidic conditions to the corresponding γ‐aminobutyric acids without further purification.

The synthesis of robust high-spin carbon radicals is an important topic in organic chemistry. Toward this end, several porphyrin-stabilized radicals have been systematically explored. A singly naphthalene-fused porphyrin radical was synthesized by a reaction sequence consisting of a Suzuki-Miyaura coupling of β-borylated porphyrin with 2-bromobenzaldehyde, addition of mesityl Grignard reagent, intramolecular Friedel-Crafts alkylation, and final oxidation with DDQ or tBuOK/O2 . This strategy was also used to synthesize doubly naphthalene-fused porphyrins and syn- and anti-fused-anthracene-bridged porphyrin dimers. While singly naphthalene-fused porphyrin radical has been shown to be a stable monoradical, doubly naphthalene-fused porphyrins and anti-fused-anthracene-bridged porphyrin dimers have been shown to be closed-shell molecules. Finally, the syn-dimer was characterized as a surprisingly stable radical (t1/2 =28 days under ambient air and at 80 °C) that is storable for more than several months, despite its high-spin triplet ground-state carbon diradical.

Fukuyama reaction for the synthesis of multifunctional aldehydes, secondary amines and ketones has gained considerable importance in synthetic organic chemistry because of mild reaction conditions. The use of thioesters in both Fukuyama aldehydes and ketones synthesis is highly attractive for organic chemists as they are easily accessible from corresponding carboxylic acids. Fukuyama-Mitsunobu reaction utilizes 2-nitrobenzenesulfonyl (Ns) for the protection/activation/deprotection of primary amines to afford secondary amines in good yields and high enantioselectivities. This review presents recent synthetic developments and applications of Fukuyama reaction for the synthesis of aldehydes, secondary amines and ketones.

Synthesis of (+)-solenopsin, a 2,6-disubstituted piperidine alkaloid, isolated from fire ants (Solenopsis), was achieved. Stereoselective construction of trans-2,6-piperidine ring moiety was performed using palladium-catalyzed cyclization. Chain elongation using Grubbs 2nd catalyst followed by the reduction of double bond and the deprotection of the Cbz group afforded (+)-solenopsin.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach. Dirección General de Investigación de España. CTQ2016-78703-P Junta de Andalucía. FQM134 Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465 Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C22

The elaboration of easy and affordable highly selective methods for the synthesis of thieno[2,3-d]pyrimidine derivatives, which operate on none toxic reagents and energy-saving techniques, is an urgent task of organic chemistry. Among the large number of functional derivatives of the title heterocycle, the most interesting objects for our research group are 2-oxo-(thio)-3-phenyl-thieno[2,3-d]pyrimidinones, which contain several reactive nucleophilic centers (nitrogen, oxygen and sulfur atoms), which determines their ambidenties in reactions with electrophilic reagents. Many approaches to the introduction of substituents and functional groups into the thieno[2,3-d]pyrimidine system have been developed, among which the alkylation reactions are the most common. In our previous study, we theoretically predicted the regioselectivity of the alkylation of 2-oxo(thioxo)-3-phenyl-thieno[2,3-d]pyrimidin-4-ones and investigated possible influencing factors. In continuation of this study, in order to reliably validate the results of previous computer simulations, we alkylated the title heterocyclic system with a number of alkylating reagents under the same synthetic conditions, which involve the alkylation of the most thermodynamically advantageous anionic form. 2-Oxo-(thio-)-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidinones were used as starting compounds. To provide alkylation conditions for the most thermodynamically advantageous anion, the starting compounds were heated with excess of potassium hydroxide in ethanol until completely dissolving. The resulting solution of the corresponding potassium salts was cooled and kept at room temperature, after which an excess of alkylating reagent was added and kept at room temperature an additional time. As a result of research, a preparative method of alkylation of 2-oxo-(thio-)-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno [2,3-d] pyrimidinones was developed, which corresponds to the principles of green chemistry (operates with none toxic solvents, easy to perform and does not require long-term heating). The sixteen new previously undescribed thieno[2,3-d]pyrimidine derivatives were obtained.

Nucleophilic substitutions, including SN 1 and SN 2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An SRN 1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non-chiral or chiral α-bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Synthetic routes for heteroatom-containing polycyclic aromatic hydrocarbons (H-PAHs) with alkyl and aryl substitution are demonstrated. Three H-PAHs, including heteroatom-containing rubicenes (H-rubicenes), angular-benzothiophenes (ABTs), and indenothiophene (IDTs) were successfully synthesized by two key steps, including polysubstituted olefin formation and cyclization. Specifically, ABT and H-rubicenes were comprehensively investigated by single-crystal X-ray diffraction, NMR spectroscopy, UV-vis absorption, cyclic voltammetry, transient absorption, and single-crystal OFET measurements.

Linear, α-branched, and β-branched aliphatic amines are widespread in pharmaceuticals, agrochemicals, and fine chemicals. Thus, the development of direct and efficient methods to these structures in a tunable manner is highly desirable yet challenging. Herein, a catalyst-controlled synthesis of α-branched, β-branched and linear aliphatic amines from Ni/Co-catalyzed regio- and site-selective hydroalkylations of alkenyl amines with alkyl halides is developed. This catalytic protocol features the reliable prediction and control of the coupling position of alkylation to provide orthogonal access to α-branched, β-branched and linear alkyl amines from identical starting materials. This platform unlocks orthogonal reactivity and selectivity of nickel hydride and cobalt hydride chemistry to catalytically repurpose three types of alkyl amines under mild conditions.

In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3-c]-2,7-naphthyridines 6, as well as a new method for the preparation of 1,3-diamino-2,7-naphthyridines 11. For the first time, a Smiles rearrangement was carried out in the 2,7-naphthyridine series, thus gaining the opportunity to synthesize 1-amino-3-oxo-2,7-naphthyridines 4, which are the starting compounds for obtaining furo[2,3-c]-2,7-naphthyridines. The cyclization of alkoxyacetamides 9 proceeds via two different processes: the expected formation of furo[2,3-c]-2,7-naphthyridines 10 and the ‘unexpected’ formation of 1,3-diamino-2,7-naphthyridines 11 (via a Smiles type rearrangement).

N-Alkyl pyrazoles are important heterocycles in organic and medicinal chemistry, demonstrating a wide range of biological activity. A new method for the N-alkylation of pyrazoles has been developed using trichloroacetimidate electrophiles and a Brønsted acid catalyst. These reactions provide ready access to N-alkyl pyrazoles which are present in a variety of medicinally relevant lead structures. Benzylic, phenethyl and benzhydryl trichloroacetimidates provide good yields of the N-alkyl pyrazole products. Unsymmetrical pyrazoles provide a mixture of the two possible regioisomers, with the major product being controlled by sterics. This methodology provides an alternative to other alkylation methods that require strong base or high temperature.

A strategically distinct dehydroxylative alkylation reaction of α-hydroxy carboxylic acid derivatives with alkenes is developed. The reaction starts with the attack of a 4-dimethylaminopyridine (DMAP)-boryl radical to the carbonyl oxygen atom, followed by a spin-center shift (SCS) to trigger the C-O bond scission. The resulting α-carbonyl radicals couple with a wide range of alkenes to furnish various alkylated products. This strategy allows for the efficient conversion of a wide array of α-hydroxy amides and esters derived from several biomass molecules and natural products to value-added compounds. Experimental and computational studies verified the reaction mechanism.

CAAC precursors 2‐chloro‐3,3‐dimethylindole 1 and 2‐chloro‐1‐ethyl‐3,3‐dimethylindolium tetrafluoroborate 2BF4 have been prepared and oxidatively added to [M(PPh3)4] (M=Pd, Pt). Salt 2BF4 reacts with [Pd(PPh3)4] in toluene at 25 °C over 4 days to yield complex cis‐[3]BF4 featuring an N‐ethyl substituted CAAC, two cis‐arranged phosphines and a chloro ligand. Compound trans‐[3]BF4 was obtained from the same reaction at 80 °C over 1 day. Salt 2BF4 reacts with [Pt(PPh3)4] to give cis‐[4]BF4. The neutral indole derivative 1 adds oxidatively to [Pt(PPh3)4] to give trans‐[5] featuring a CAAC ligand with an unsubstituted ring‐nitrogen atom. This nitrogen atom has been protonated with py⋅HBF4 to give trans‐[6]BF4 bearing a protic CAAC ligand. The PdII complex trans‐[7]BF4 bearing a protic CAAC ligand was obtained in a one‐pot reaction from 1 and [Pd(PPh3)4] in the presence of py⋅HBF4., Cyclic (alkyl)(amino)carbene (CAAC) precursor salt 2BF4 reacts with [M(PPh3)4] (M=Pd, Pt) to give cis/trans‐[3]BF4 and cis‐[4]BF4, in which the CAAC ligand bears an unusual N‐alkyl substituent. trans‐[5] has a unique anionic CAAC ligand with an unsubstituted ring‐nitrogen atom which can be protonated to give trans‐[6]BF4 bearing a protic CAAC (pCAAC) ligand.

The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein–protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1‐derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K D value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono‐ and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure‐based design is a suitable strategy for inhibitor development targeting PPIs., Potent bicyclic peptide inhibitors of the RbAp48‐MTA1 interaction were developed by structure based stepwise optimization of the cyclization linker. The strategy exemplifies design of peptide derived inhibitors of protein–protein interactions involving large surface areas.

Despite extensive efforts by many practitioners in the field, methods for the direct α-C–H bond functionalization of unprotected alicyclic amines remain rare. A new advance in this area utilizes N-lithiated alicyclic amines. These readily accessible intermediates are converted to transient imines through the action of a simple ketone oxidant, followed by alkylation with a β-ketoacid under mild conditions to provide valuable β-amino ketones with unprecedented ease. Regioselective α′-alkylation is achieved for substrates with existing α-substituents. The method is further applicable to the convenient one-pot synthesis of polycyclic dihydroquinolones through the incorporation of a S(N)Ar step.

Background: Pyrazol-5-amine derivatives are an important class of heterocyclic compounds. However, there are less 4-alkyl substituted pyrazoles reported. Objective: Here reported are the design, synthesis and biological evaluation of 3-aryl-4- alkylpyrazol-5-amines derivatives. Methods: A serials of 3-aryl-4-alkylpyrazol-5-amines were designed and the biological action targets were screened by target fishing function of Discovery Studio software. The synthesis route involved 3-oxo-3-arylpropanenitrile formation, alkylation, pyrazole formation, and amides formation. The antitumor activities of these compounds were carried out by thiazolyl blue tetrazolium bromide (MTT) method using U-2 OS (osteosarcoma) and A549 (lung cancer) tumor cells. Results: Eight 3-aryl-4-alkylpyrazol-5-amines were synthesized, and their structures were verified by 1H NMR, 13C NMR, and HRMS. Thirteen pharmacophores were mapped out by target fishing. Compound 5h showed anti-proliferation activities against U-2 OS and A549 tumor cell with IC50 value of 0.9 μM and 1.2 μM, respectively. Conclusion: Compound 5h might represent a promising scaffold for the further development of novel antitumor drugs.

The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp2 )-H methylation of iminoamido heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional-group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

This work establishes the ‘click’ nature of the base-catalyzed oxirane ring opening reaction by the selenolate nucleophile. The ‘click’-generated ß-hydroxy selenide can be alkylated to afford cationic selenium species. Hemolytic studies suggest that selenonium cations do not lyse red blood cells even at high concentrations. Overall, these results indicate the future applicability of the developed organo-selenium chemistry in the preparation of a new class of cationic materials based on the seleno-ether motif.

We report a new air‐stable PdI dimer, [Pd(μ‐I)(PCy2 tBu)]2, which triggers E‐selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C−C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C−Br, C−OTf/OFs, and C−Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous PdI dimer generations for substrates that bear substituents ortho to C−OTf., A novel air‐stable PdI dimer is reported that triggers E‐selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C−C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion.

Herein we describe the first organocatalytic asymmetric C(sp2 )-H allylation of racemic trisubstituted allenoates with Morita-Baylis-Hillman (MBH) carbonates to access axially chiral tetrasubstituted allenoates. Various trisubstituted allenoates and MBH carbonates were well tolerated under mild reaction conditions, providing novel chiral tetrasubstituted allenoates with adjacent axial chirality and tertiary carbon stereocenters in high yields with good to excellent diastereoselectivities and enantioselectivities.

The Catellani reaction has received substantial attention because it enables rapid multiple derivatization on aromatics. While using alkyl electrophiles to achieve ortho-alkylation was one of the earliest applications of the Catellani reaction, ipso-alkylation-terminated reactions with β-H-containing reactants has not been realized to date. Herein, we report alkylation-terminated Catellani reaction using alkyl carbagermatranes (abbreviated as alkyl-Ge) as nucleophiles. The reactivity of alkyl-Ge and alkyl-B(OH)2 in this reaction is discussed. This approach enables efficient dialkylation with β-H-containing reactants, which was previously inaccessible by Catellani reactions.

An efficient copper-catalyzed regioselective C-H alkenylation and borylative alkylation of quinoline N-oxides with vinyl arenes in the presence of pinacol diborane has been developed. The reaction proceeds through the borylcupration of the vinyl arenes followed by nucleophilic attack of the resulting alkyl copper species to the quinoline N-oxides. Benzoquinone and KOt Bu were identified as the necessary additives at the second step of the reaction that are crucial for the success of the reaction. A wide range of C2-functionalizaed quinolines were obtained with good functional group tolerance, which may find utilities in pharmaceuticals and synthetic chemistry.

An enantioselective bifunctional squaramide-catalyzed detrifluoroacetylative alkylation reaction has been developed under electrochemical conditions. The unified strategy based on this key tandem methodology has been divergently explored for the asymmetric synthesis of fluorine-containing target molecules with good stereocontrol (up to 95 % ee). Furthermore, this asymmetric catalytic reaction combines the benefits of electrosynthesis and organocatalysis for the preparation of biologically relevant products containing C-F tertiary stereogenic centers.