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Unsymmetrical 1,1,2-triacylalkenes were conveniently prepared by the oxidative coupling of 1,3-keto esters with terminal alkynes by employing 4.0 equivalents of inexpensive ceric ammonium nitrate (CAN) as the oxidant in acetonitrile as the solvent at 0 °C. The method is milder than previously reported methods and can be conducted under air, thereby demonstrating its practicality and versatility for preparing these useful building blocks. The reaction is believed to occur by a single-electron-transfer process of the 1,3-keto ester substrate initiated by CAN to generate an α-radical species that quickly adds to the terminal alkyne partner in the reaction. Subsequent oxidation of the resulting vinyl radical by air and CAN then leads to the formation of the triacylalkene product as a mixture of E- and Z-isomers. The reaction was shown to be general, with 27 illustrative examples of the formation of the desired products in up to quantitative yield and with moderate to excellent alkene geometrical selectivities.

A mild and convenient method for the synthesis of 2,2-dihaloketones and gem-dihalolactols has been developed. For the synthesis of 2,2-dihaloketones, alkynes were employed as substrates to react with halogenating agents, Cl2 or ClBr, that were generated in situ from aqueous HCl and NCS or NBS, respectively. On the other hand, gem-dihalolactols could be prepared from alkynol substrates by using the same reaction conditions. This method could be applied to a broad range of substrates to give the corresponding products in low to good yields.

[Image: see text] 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 (IC(50) = 65.68 μM) among tested compounds, which was comparable with the antianxiety drug diazepam (IC(50) = 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.

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.

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.

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.

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.

4-Chloroisocoumarins can be conveniently prepared from 2-alkynylaryloate esters via the activation of alkynes by electrophilic chlorine, generated in situ from N-chlorosuccinimide (NCS) in the presence of 10 mol % trimethylsilyl chloride (TMSCl), which leads to 6-endo-dig-selective chlorinative annulation to give the desired products in moderate to quantitative yields. The procedure employs readily available reagents and can be conveniently carried out on a wide scope of substrates under mild conditions (0 °C to rt). Furthermore, the reaction is scalable for gram-scale preparation of 4-chloroisocoumarins. Additionally, 4-bromo- and 4-iodoisocoumarins can be prepared in moderate to good yields by replacing NCS with N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS), respectively.

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.

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.

A divergent synthesis of 3-hydroxyfluorene and 4-azafluorene derivatives has been developed. ortho-Alkynylarylketone was employed as the substrates to react with molecular iodine leading to the generation of a common intermediate, indenone precursor. This precursor could lead to the diversified products when the reaction was carried out under different conditions. The indenone intermediate was converted to the corresponding 3-hydroxyfluorene products under basic conditions while the reaction in the presence of ammonium salt provided 4-azafluorene products. This divergent method could be applied to a broad range of substrates to give the corresponding products in moderate to good yields.

1,1-Disubstituted vinyl triflates are synthesized by direct hydrotriflation of terminal alkynes employing a combination of TfOH and TMSN3 in DCM at room temperature. Interestingly, under these cond...

A novel synthetic approach for the synthesis of 5-aminotetrazoles has been developed by employing simple ketones as substrates. This methodology involved the N2-extrusion/aryl migration of azido complexes as the key step for the in situ generation of carbodiimidium ion, which could further react with hydrazoic acid and cyclize intramolecularly to provide 5-aminotetrazoles in good to excellent yields. In addition, the regioselectivity of the reaction was studied and rationalized by density functional theory calculations.

Stoichiometric ceric ammonium nitrate (CAN) and a catalytic amount of Pd(PPh3)2Cl2 (5 mol %) can rapidly produce multisubstituted 2-ketofuran-4-carboxylate esters from 2-propargylic 1,3-ketoesters via oxidative O-cyclization reaction. Pd(PPh3)2Cl2 was found to be the crucial catalyst as its inclusion greatly enhanced the rate of the reaction and cleanly afforded the products within minutes. Over 30 substrates were successfully converted to the desired compounds in mostly moderate to good yields.

The development of novel methods for the construction of valuable fluorophores, 3-carbonyl-4-arylbenzo[f]indoles and 3-carbonyl-4-arylnaphthofurans, is described. In this protocol, the important polycarbonyl key intermediate was generated via the ketonization of ortho-alkynylarylketone tethered with a 1,3-dicarbonyl moiety. This intermediate reacted with an amine to selectively form a pyrrole intermediate, followed by cyclization in acetic acid to provide 3-carbonyl-4-arylbenzo[f]indole. Importantly, these conditions did not cause any epimerization of the stereogenic center in chiral amine substrates. Moreover, the polycarbonyl intermediate could also be utilized to prepare 3-carbonyl-4-arylnaphthofuran using In(OTf)3 as a catalyst for double cyclization under thermal conditions. In addition, the fluorescence properties of both fluorophores were also studied.

New synthetic approaches for the synthesis of indoloquinolines and carbocycle-fused quinolines have been developed employing alkynylketone substrates. These synthetic transformations involved the application of N2-extrusion of azido complexes as a key step to generate carbodiimidium ion and nitrilium ion in situ, which further cyclized intramolecularly with alkyne via a domino process to provide indoloquinolines and carbocycle-fused quinolines, respectively, in moderate to good yields.

An efficient synthesis of N-acetyl-2-substituted indole derivatives via direct intramolecular hydroamination of N-acetyl-2-alkynylaniline derivatives was developed. The reaction could be applied to a wide range of substrates employing only 1–2 mol% of PtCl4 as the catalyst to furnish the desired indole products in moderate to excellent yields. The current protocol is efficient, reliable and scalable, and could serve as an important tool for convenient and rapid access to this important class of N-heterocyclic skeleton from readily available substrates.

A method for the TfOH-promoted (Tf=trifluoromethanesulfonyl) cyclization of alkyne-tethered 1,3-ketoesters to afford 2-cyclohexenone-2-carboxylate derivatives has been developed. The procedure requires no transition-metal reagent or catalyst and is practical to conduct under mild conditions. 2-Cyclohexenone-2-carboxylate derivatives were obtained in moderate to good yields without any evidence of decarboxylation. In addition, the approach can be easily adapted as a one-pot sequential cyclization/chlorination protocol that selectively provides access to 4-chloro-2-cyclohexenone-2-carboxylate derivatives in moderate to good yields.

A new approach for the synthesis of indenone derivatives using I2-promoted cyclization of ortho-alkynylarylketones has been developed. This method provides a metal-free and convenient route for regioselective synthesis of indenones employing ortho-alkynylarylketones with predefined substituents to obtain indenone products in moderate to good yields.

ortho-Carbonylarylacetylenols have been employed for the synthesis of dihydronaphthofurans via AgTFA-catalyzed annulation reaction. A broad range of substrates both ortho-keto- and ortho-formylarylacetylenols could be employed in this transformation providing the desired products in good yields. However, the reaction pathways of these two substrates are different. The reaction of the ketone precursors could directly lead to the desired products in a single operation while the reaction of the aldehyde precursors required a one-pot two-step approach, without isolation of the bicyclic acetal intermediates. In addition, this method was also successfully used for the synthesis of dihydronaphthopyrans in very good yields.

For the first time, 4-chloroisoxazoles are directly synthesized in moderate to excellent yields from (E/Z)-alkynyl-O-methyl oximes via chlorinative cyclization. The synthesis employs the combination of N-chlorosuccinimide (NCS) and chlorotrimethylsilane (TMSCl) in nitromethane solvent where chlorine (Cl2) and hydrochloric acid (HCl) are generated in situ. In addition, the current protocol is applicable to the synthesis of 4-bromo- and 4-iodoisoxazoles when N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS), respectively, are employed in place of NCS. The current method can improve the overall efficiency of the preparation of 4-haloisoxazoles starting from the step where alkynyl-O-methyl oximes are prepared since (E)-isomers can isomerize and cyclize under the conditions.

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.

Regioselective synthesis of 3-bromoquinoline derivatives was achieved via a formal [4 + 2]-cycloaddition between N-aryliminium ion, generated from arylmethyl azides, and 1-bromoalkynes. This method could also be applied to other quinoline derivatives using appropriate alkynes. Moreover, the current strategy could be utilized for the diastereoselective synthesis of tetrahydroquinoline derivatives employing alkenyl substrates in good to excellent yields.

sec-Benzyl azides were efficiently prepared by bismuth(III)-catalyzed direct azidation of sec-benzyl alcohols. The reaction was applied to a variety of substrates to provide the desired products in up to 99% yield within a short reaction time.

Zirconium(IV) chloride effectively activates nitrogen (N2) extrusion from aryl azidoacrylates followed by annulation to provide the desired indole products in moderate to good yields. The reaction proceeds at low temperature and in short reaction time and is applicable to a variety of substrates.

Substituted furans are conveniently synthesized from acyclic secondary 1-alkyl-2-alkynylallylic alcohol precursors via an ICl-promoted cyclization reaction. The furans generated by this method incorporate both iodine and chlorine atoms which may be useful for further elaborations via many known methods. The methodology is suitable for generating a wide array of furan products which can serve as useful building blocks for the synthesis of various biologically active molecules.

An acid-promoted Aube–Schmidt's rearrangement of arylmethyl azides provides a useful in situ iminium ion intermediate, which can be efficiently trapped by various nucleophiles. We report here the reaction of this iminium ion with aromatic nucleophiles to give N-arylmethyl arenes and the reaction with heteroaromatic compounds to give fused polycyclic heteroaromatic products in a formal [4+2] cycloaddition. The short synthesis of isocrytolepine, an antimalarial agent, further demonstrated the utility of this process.

Preliminary studies related to the design and development of new cycloalkyne reagents for metal-free click coupling are reported. Cyclononynes are more stable than cyclooctynes, and the robust benzocyclononyne platform offers spontaneous reactivity toward azides at rates competitive with other azidophiles that have been employed for metal-free click coupling. Benzocyclononynes (e.g., 1) provide valuable insight into the design of new cycloalkynes for strain-promoted azide-alkyne cycloaddition (SPAAC) couplings for applications in which side reactions and decomposition of the reagent must be kept to a minimum.

Novel intermolecular and intramolecular generations of ortho-quinone methides and their formal [4+2]-cycloaddition reactions with olefins catalyzed by PtCl4 and AuCl3 under mild conditions have been developed. Good to excellent yields (up to 99%) and diastereoselectivity (up to >99:1) of the chromans were obtained. PtCl4 was found to be effective and compatible with various functional groups present in the substrates. A mechanism accounting for its catalytic cycle is proposed and discussed.

Reductive cyclization of aryl and vinyl iodides tethered to vinylogous acyl triflates (VATs) induces a ring-expanding fragmentation to provide cyclic alkynyl ketones, including strained nine-membered cycloalkynes, in fair to excellent yield. The tandem cyclization/C-C bond-cleavage is initiated under carefully optimized conditions by halogen-metal exchange in the presence of carbonyl and vinyl triflate functionality. A modified protocol for alkylation of 1,3-cyclohexanedione is described for preparing the relevant VAT substrates.

Two new cleistanthane-type diterpenoids, 3-hydroxycleistantha-13(17),15-diene (1) and 3,4-seco-cleistantha4(18),13(17),15-trien-3-oic acid (2), were isolated from the stem bark of Croton oblongifolius Roxb. Epoxidation of 2 gave two epoxides 3 and 4. Their structures were established on the basis of spectroscopic data. Compound 1 showed nonspecific strong cytotoxicity against human tumor cell lines, compound 2 showed weak activity, and compounds 3 and 4 were inactive.

Synthesis of dehydrorotenoid (1) was successfully achieved via an intramolecular aldol reaction of the corresponding 1,2-diaryl diketone intermediate. The 1,2-diaryl diketone was prepared using a ruthenium-catalyzed oxidation of the corresponding substituted diaryl acetylene. Treatment of this 1,2-diketone with l -proline induced a selective intramolecular aldol condensation reaction, forming the desired benzopyranone over the alternative benzofuran. Deprotection, cyclization, and dehydration gave the target compound in good overall yield.

The utility of the nitrogen extrusion reaction of azido complexes, generated in situ from the corresponding aldehydes or ketones with TMSN3 in the presence of ZrCl4 or TfOH, has been described. These azido complexes could undergo three different pathways, depending on the substrates. First, azido methanolate complexes or imine diazonium ions could lead to benzisoxazole products via an intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the elimination of proton to provide nitrile products in good to excellent yields or an aryl migration, followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields.

This direct azidation process provides secondary and tertiary benzyl azides in high yields and short reaction times, whereas primary benzyl alcohol (Ig) fails to react.

Zirconium(IV) chloride effectively activates nitrogen extrusion from aryl azidoacrylates followed by annulation to provide indoles at low temperature and in short reaction times.

A new synthesis of (−)-angustureine is described, featuring an annulation and fragmentation sequence that formally results in alkynylation of a β-amino ester. The six-step sequence from a readily available chiral β-amino ester to the natural product was achieved in 46% yield, with no protecting groups and three purifications.

Dihydropyridone (DHPD) triflates undergo nucleophile-triggered fragmentation to provide homopropargyl amine derivatives, the stereochemistry of which is defined by starting from readily available β-amino esters.

A total synthesis of the rotenoid, 6-deoxyclitoriacetal, a cytotoxic natural product, was successfully achieved by using platinum-catalysed hydroarylation, Sharpless asymmetric dihydroxylation, regioselective IBX diol oxidation and stereoselective intramolecular keto-aldehyde pinacol coupling as the key steps.