Unveiling Route for the Synthesis of Tröger's Bases through Azide Rearrangement.

This study introduces a novel method for producing Tröger's bases by utilizing the rearrangement chemistry of benzyl azide. This method offers a convenient and adaptable pathway for synthesizing these important molecular structures with potential for further advancements. By reacting benzyl azide derivatives with TfOH under the presence of water, this process generates iminium ion, formaldehyde, and aniline intermediates in situ. Notably, this conversion is reversible under acidic conditions, allowing for the regeneration of the iminium ion and ultimately leading to the formation of the desired Tröger's base product. Additionally, this method could decrease the risk of exposure to an excess amount of formaldehyde.

Controllable Chemoselectivity Cascade Reactions for the Synthesis of Phenanthrenols via Palladium-Catalyzed-Suzuki/Heck Reaction and Michael Addition.

Palladium serves as a multi-functional catalyst which is controllable by tuning reaction conditions. This work demonstrated the utilization of a palladium catalyst for the synthesis of phenanthrenols by cascade palladium-catalyzed Suzuki/Heck reaction between chalcone and 2-bromophenylboronic acid, followed by Michael addition. The sequential reaction could be controlled by reactivity of the palladium catalyst in different solvents and concentrations of reagents. This protocol could be applied to a broad range of substrates to give products in low to good yields.

Anthelmintic efficacy evaluation and mechanism of N-methylbenzo[d]oxazol-2-amine.

Parasitic roundworms cause significant sickness and mortality in animals and humans. In livestock, these nematodes have severe economic impact and result in losses in food production on a global scale. None of the currently available drugs ideally suit all treatment circumstances, and the development of drug-resistant nematode strains has become a challenge to control the infection. There is an urgent need to develop novel anthelmintic compounds. According to our previous report, N-methylbenzo[d]oxazol-2-amine (1) showed anthelmintic activity and lowest cytotoxicity. In this study, in vivo anthelmintic properties were evaluated using Trichinella spiralis infected mice. Toxicity was evaluated using the rats and mode of action using molecular docking and metabolomics approaches. The in vivo results demonstrate that a dose of 250 mg/kg reduced the T. spiralis abundance in the digestive tract by 49%. The 250 mg/kg Albendazole was served as control. The relatively low acute toxicity was categorized into chemical category 5, with an LD50 greater than 2000 mg/kg body. Molecular docking analysis showed the T. spiralis tubulin beta chain and glutamate-gated channels might not be the main targets of compound 1. Metabolomics analysis was used to explain the effects of compound 1 on the T. spiralis adult worm. The results demonstrated that compound 1 significantly up-regulated the metabolism of purine, pyrimidine and down-regulated sphingolipid metabolism. In conclusion, compound 1 could be a potential molecule for anthelmintic development. The bioavailability, pharmacokinetics, and absorption of this compound should be studied further to provide information for its future efficacy improvement.

Divergent synthesis of 3,4-dihydro-2H-benzo[h]chromen-2-one and fluorenone derivatives from ortho-alkynylarylketones.

Our research has led to the development of a divergent synthesis approach for the synthesis of 3,4-dihydro-2H-benzo[h]chromen-2-one 3 and fluorenone 9 derivatives using ortho-alkynylarylketones as common precursors. The synthesis of 3,4-dihydro-2H-benzo[h]chromen-2-ones 3 employed silver catalyzed ketonization to form polycarbonyl intermediates which underwent double intramolecular cyclization and decarboxylation to generate a lactone and a phenyl ring in a one-pot fashion. In addition, the same precursor could be used to prepare fluorenone derivatives 9 under acidic conditions. The reaction proceeded via the formation of indenone analogs, followed by the generation of the para-quinone methide intermediate and intramolecular cyclization to provide the corresponding products in good yields.

Selective electrophilic cyclization of ortho-carbonylarylacetylenols for the synthesis of cyclopenta[a]naphthalenol and 2-phenylnaphthalen-1-ol analogs.

This work demonstrates a new method for the synthesis of cyclopenta[a]naphthalenol and 2-phenylnaphthalen-1-ol analogs via selective cyclization. ortho-Alkynylarylkenones were employed as the common substrates that could be prepared by Sonogashira coupling between 2-haloarylacetophenone and pent-4-yn-1-ol derivatives. These precursors were used without purification to construct 2-phenylnaphthalen-1-ol intermediates by treating with (+)-CSA under heating conditions. Selective cyclization occurred when the reaction was conducted in methyl trimethylacetate solvent which predominantly produced the 2-phenylnaphthalen-1-ol product through 6-endo-dig cyclization without elimination or the formation of cyclopenta[a]naphthalenol via shutting down the 5-exo-dig mode of cyclization. Switching the acid from a Brønsted acid to Bi(OTf)3 led to smooth reactions, providing the cyclopenta[a]naphthalenol products in moderate to good yields. Moreover, we also demonstrated the utilization of 2-phenylnaphthalen-1-ol to prepare naphthoquinone, which is an important core structure of bioactive and natural product compounds.

Mn(OAc)3-Mediated One-Pot Condensation-Oxidative Annulation of 2-Alkynylanilines and 1,3-Ketoesters: Synthesis of 2-Substituted Quinolines.

A general protocol for oxidative annulation was developed for the preparation of 2-methyl-3,4-diacylquinolines directly from 2-alkynylanilines and 1,3-ketoesters. The reactions were mediated by Mn(OAc)3 in acetic acid at room temperature, which led to the desired quinoline products in one-pot in low to good overall yields on a wide range of substrates. The current method was convenient to conduct and proceeded under mild conditions in short reaction times.

A Mechanistically Deceiving Formation of Aryl(1-indanyl)ketones via Acid-Catalyzed Cyclization of ortho-Alkynylarylmethanols.

The generation of reactive carbocation intermediates from ortho-alkynylarylmethanol substrates was utilized as a means for the synthesis of aryl(1-indanyl)ketones . Substrates with a tertiary carbon at the ß-position to the arene generated a carbocation intermediate via dehydration/protonation, followed by cyclization and hydration to give indanylketone products. For substrates with a quaternary carbon at that position, a carbocation intermediate was generated by protonation/elimination of water, followed by a 1,2-shift and a subsequent cyclization/hydration to give highly substituted indanylketones.

Synthesis of Naphtho[2,3-d]oxazoles via Ag(I) Acid-Mediated Oxazole-Benzannulation of ortho-Alkynylamidoarylketones.

A cascade oxazole-benzannulation for the synthesis of naphtho[2,3-d]oxazoles has been developed employing ortho-alkynylamidoarylketones as substrates. This procedure provides the advantage of preparing a wide variety of substituents on naphtho[2,3-d]oxazole structures. In addition, o-alkynylamidoarylketones could be prepared from easily accessible and a wide variety of commercially available starting materials. Therefore, this method is a judicious choice of strategy to synthesize naphtho[2,3-d]oxazoles with a great variety of substituents. In this work, 27 examples were demonstrated to provide the desired products in moderate to good yields.

Discovery of N-methylbenzo[d]oxazol-2-amine as new anthelmintic agent through scalable protocol for the synthesis of N-alkylbenzo[d]oxazol-2-amine and N-alkylbenzo[d]thiazol-2-amine derivatives.

We discovered a lead compound, N-methylbenzo[d]oxazol-2-amine (2a), which had comparable potency to albendazole, an orally administered anthelminticdrug, against Gnathostoma spinigerum, Caenorhabditis elegans and Trichinella spiralis. Compound 2a showed about 10 times lower cytotoxicity towards normal human cell line (HEK293) than albendazole. Moreover, we have developed new processes for the synthesis of N-alkylbenzo[d]oxazol-2-amine and N-alkylbenzo[d]thiazol-2-amine derivatives via metal-free conditions. This protocol could serve as a robust and scalable method, especially, to synthesize N-methylbenzo[d]oxazol-2-amine and N-methylbenzo[d]thiazol-2-amine derivatives which were difficult to prepare using other metal-free conditions. The method employed benzoxazole-2-thiol or benzothiazole-2-thiol as the substrate. The reaction was triggered by methylation of the thiol functional group to form the methyl sulfide intermediate, a crucial tactic, which facilitated in a smooth nucleophilic addition-elimination reaction with gaseous methylamine generated in situ from N-methylformamide. In addition, the proteomic analysis of compound 2a was also studied in this work.

Synergistic Lewis-Brønsted Acid Catalysis in Cascade Cyclization of ortho-Alkynylaryl Cyclopropylketones for the Synthesis of 2,3-Dihydronaphtho[1,2-b]furans.

In this work, a synthetic method for the synthesis of 2,3-dihydronaphtho[1,2-b]furans employing synergistic Lewis-Brønsted Acid catalyzed cyclization of ortho-alkynylarylcyclopropylketones has been developed. Benefits of our method included low catalyst loading, low cost of catalyst, short reaction time, and mild conditions which could be applied to a broad range of substrates, including a terminal alkyne (R = H), to provide generally high yields of the desired products. In addition, we found that 2,3-dihydronaphtho[1,2-b]furan derivatives could be isomerized to give 5,6-dihydrotetraphen-7-ol anaologs under acidic conditions via Friedel-Crafts-type alkylation in good to excellent yields. However, these products were not stable and gradually converted to the corresponding quinones. The competent transformation was successfully obtained by treating with m-CPBA in the presence of NaHCO3 to provide the desired quinone products in good to excellent yields.

Photoinduced C-C bond cleavage for the synthesis of 2,4-disubstituted-1-naphthols from indenone derivatives and sulfoxonium ylide.

The synthesis of 2,4-disubstituted-1-naphthols has been developed employing photomediated C-C bond cleavage (UV-LED 390 nm) of cyclopropane fused-indanones generated in situ from the reaction between indenones and trimethylsulfoxonium chloride under basic conditions at room temperature. Seventeen substrates were examined in this study. The results showed that indenone precursors containing aryl substituents could smoothly provide the desired products in up to 81% yield.

A Compilation of Synthetic Strategies to Access the Most Utilized Indoloquinoline Motifs.

Indoloquinoline alkaloids constitute an important class of aromatic heterocycles consisting of quinoline and indole fused together in various orientations. These compounds, both natural and synthetic, often display various bioactivities which have established them to be one of the interesting medicinal targets. This class of compounds have stimulated much interest among synthetic and medicinal chemists as evidenced by growth in the number of synthetic methods to prepare and study this class of alkaloids. This review compiles the synthetic strategies and methods currently known in the literature for the construction of four important indoloquinoline skeletons.

Ag(I)-Catalyzed/Acid-Mediated Cascade Cyclization of ortho-Alkynylaryl-1,3-dicarbonyls to Access Arylnaphthalenelactones and Furanonaphthol Libraries via Aryl-Disengagement.

ortho-Alkynylarylketone derivatives were employed as key precursors for a one-pot synthesis of arylnaphthalenelactone and furanonaphthol libraries. In this work, we discovered a cost-effective protocol to prepare arylnaphthalenelactones in one-pot using inexpensive starting material, malonate ester, which was conveniently functionalized leading to a variety of structures. Moreover, we also found an unexpected oxy-dearylation reaction which could be used to synthesize furanonaphthol analogs. These novel methods could be applied to a broad range of substrates to give the corresponding products in up to 83% yield. Notably, these classes of compounds exhibited more significant inhibition against protein-tyrosine phosphatase 1B (PTP1B) enzyme than a standard compound, ursolic acid.

Synthesis of Isocryptolepine-Triazole Adducts and Evaluation of Their Cytotoxic Activity.

Eighteen hybrid compounds between 8-bromo-2-fluoro-isocryptolepine (4) and 1,2,3-triazole were synthesized via azide rearrangement-annulation reaction. Compound 4 underwent regioselective N-propargylation and click reaction to form 8-bromo-2-fluoro-isocryptolepine-triazole hybrids 11 which were evaluated for cytotoxic activity. Compound 11 c containing 1-anisyltriazole was the most effective in inhibiting HepG2, HuCCA-1 and A549 cell lines (IC50 values of 1.65-3.07 µM) while compounds 11 a (1-phenyltriazole), 11 j (1-para-CF3 -benzyltriazole) and 11 l (1-meta-Cl-benzyltriazole) were potent inhibitors of HuCCA-1, HepG2 and A549 cell lines, respectively. Moreover, 11 l showed the lowest cytotoxicity to normal human kidney cell line. Compounds 11 c and 11 l provided improvement of cytotoxic activity over 4. Compounds 4, 11 c and 11 l were selected to investigate their mechanisms of action. The results showed that 4 could induce G2/M cell cycle arrest and was involved in the upregulation of p53 and p21 proteins. However, the mechanisms of growth inhibition by 11 c and 11 l were associated with G0/G1 cell cycle arrest and mediated by induction of oxidative stress.

Synthesis of Benzoazepine Derivatives via Azide Rearrangement and Evaluation of Their Antianxiety Activities.

A new synthetic method for the construction of benzoazepine analogues has been developed employing ortho-arylmethylbenzyl azide derivatives as precursors using an azide rearrangement reaction. In this work, 14 benzoazepine compounds were successfully synthesized in moderate to excellent yields. All synthetic benzoazepines were evaluated for their cytotoxicity against normal human kidney cell line (HEK cell). The results showed that compound 18c had the lowest cytotoxicity (IC50 = 65.68 µM) among tested compounds, which was comparable with the antianxiety drug diazepam (IC50 = 87.90 µM). Based on the cytotoxicity results, five benzoazepine analogues (compounds 18c, 18h, 18j, 18n, and 18p) were selected to determine the antianxiety effect on stressed rats using elevated plus maze (EPM) and open field test (OFT) methods. Interestingly, compound 18c showed better anxiolytic activity than diazepam without a sedative effect by showing superior hyperlocomotor activity. Therefore, this discovery could pave the way for drug development to treat patients with anxiety disorder.

Utilization of ortho-alkynylarylcarbonyl derivatives for creating structurally diverse chemical compounds.

ortho-Alkynylarylcarbonyl compounds, including ketones, aldehydes, carboxylic acids, carboxylate esters and amides, have served as useful building blocks for synthetic chemists to prepare numerous classes of important molecules. Various synthetic conversions starting from ortho-alkynylarylcarbonyl precursors are made possible by their unique and enabling structures embedded with reactive carbonyl and alkyne functional groups. These functional groups can be converted directly and independently to other compounds by several reactions. This review highlights the use of these compounds as common precursors for the divergent synthesis of valuable molecules. Moreover, these ortho-alkynylarylcarbonyl compounds can be decorated with other functional group tethers which can lead to an even greater diversity of molecular scaffolds.

Dibrominative Spirocyclization of 2-Butynolyl Anilides: Synthesis of gem-Dibromospirocyclic Benzo[d][1,3]oxazines and Their Application in the Synthesis of 4H-Furo[3,2-b]indoles.

The combination of catalytic aqueous hydrochloric acid (HCl) and N-bromosuccinimide (NBS) generated electrophilic bromine monochloride (BrCl), which readily induced spiroannulation of 2-alkynolyl anilides (n = 1-3) to form gem-dibromospirocyclic benzo[d][1,3]oxazines in up to 92% yield. The reaction occurred under mild and metal-free conditions using EtOAc as a green solvent. The resulted spirocyclic products contained benzo[d][1,3]oxazine, which was useful both as a pharmacophore and synthetic precursor. In addition, the current protocol allowed to effortlessly introduce the sp3-gem-dibromide carbon adjacent to the sterically demanding spiroketal center. These spiroheterocycles (n = 1) were shown to be synthetically versatile and conveniently maneuvered. Base-promoted debrominative aromatization of these spirocycles unmasked rare and synthetically useful 2-aryl-3-bromofurans in mostly excellent yields. These 3-bromofurans were well-suited substrates for intramolecular Ullmann C-N bond coupling to construct difficult-to-prepare 4H-furo[3,2-b]indoles. Additionally, the current protocol was flexible and adaptable to preparing the gem-dichloride variants.

Synthesis of 4-Acylchromene via Highly Chemoselective Iodine-Catalyzed Cyclization of Alkynylarylether Dimethylacetals.

4-Acylchromene is an important core structure found in bioactive natural products and bioactive synthetic compounds. Moreover, this core structure is frequently used as a key precursor for the synthesis of more complex molecules. In this work, we discovered that a combination of acetone and catalytic I2 could lead to selective activation of acetal in alkynylarylether dimethylacetal substrates while alkyne moiety remained intact. This activation of acetal led to the generation of oxonium ion intermediate which triggered intramolecular cyclization and elimination of methanol to provide the desired 4-acylchromene as the sole product in up to 95% yield. Moreover, this method could be applied in a broad range of substrates under a mild and metal-free catalytic conditions for the synthesis of 4-acylchromene derivatives.

Synthesis of neocryptolepines and carbocycle-fused quinolines and evaluation of their anticancer and antiplasmodial activities.

This study reported the discovery of novel compounds containing five-membered ring fused quinoline core structures as anticancer and antimalarial agents. Two libraries containing these core structures, neocryptolepines and carbocycle-fused quinolines, were prepared and evaluated. Compound 3h was found to be much more potent than other analogs against cancer cell lines with high selectivity. Meanwhile, carbocycle-fused quinolines 5h and 5s showed moderate anticancer properties but much less cytotoxicity to normal cell than doxorubicin. In addition, compound 3h also showed much lower cytotoxic against human normal kidney cell line compared to doxorubicin standard. However, only compounds 3s and 3p provided acceptable results for antimalarial activities.