Spontaneous Aromatization Research Articles

Synthesis of 5-(trifluoroacetyl)imidazoles from Bromoenones and Benzimidamides via Aza-Michael Initiated Ring Closure Reaction.

A simple method for the preparation of 5-(trifluoroacetyl)imidazoles was elaborated. The reaction of trifluoromethyl(α-bromoalkenyl)ketones with benzimidamides was employed to afford the target heterocycles in good yields. The assembly of imidazole core proceeds via aza-Michael adduct formation followed by intramolecular nucleophilic substitution and spontaneous aromatization as an oxidation sequence. The yields of target imidazoles can be improved by the use of soft oxidizing agents.

Autoxidation of a C2-Olefinated Dihydroartemisinic Acid Analogue to Form an Aromatic Ring: Application to Serrulatene Biosynthesis.

Dihydroartemisinic acid (DHAA) is a plant natural product that undergoes a spontaneous endoperoxide-forming cascade reaction to yield artemisinin in the presence of air. The endoperoxide functional group gives artemisinin its biological activity that kills Plasmodium falciparum, the parasite that causes malaria. To enhance our understanding of the mechanism of this cascade reaction, 2,3-didehydrodihydroartemisinic acid (2,3-didehydro-DHAA), a DHAA derivative with a double bond at the C2-position, was synthesized. When 2,3-didehydro-DHAA was exposed to air over time, instead of forming an endoperoxide, this compound predominantly underwent aromatization. This olefinated DHAA analogue reveals the requirement of a monoalkene functional group to initiate the endoperoxide-forming cascade reaction to yield artemisinin from DHAA. In addition, this aromatization process was exploited to illustrate the autoxidation process of a different plant natural product, dihydroserrulatene, to form the aromatic ring in serrulatene. This spontaneous aromatization process has applications in other natural products such as leubethanol and erogorgiaene. Due to their similarity in structure to antimicrobial natural products, the synthesized compounds in this study were tested for biological activity. A group of the tested compounds had minimum inhibitory concentration (MIC) values ranging from 12.5 to 25 μg/mL against the bacterial pathogen Staphylococcus aureus and the fungal pathogen Cryptococcus neoformans.

Synthesis and Characterization of Novel Functionally Substituted Planar Pyrimidothienoisoquinolines and Nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines.

7-Acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinolin-3(2H)-thiones 2a,b are prepared and dehydrated to give 7-acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-7,8-dihydrodroisoquinolin-3(2H)-thiones 6a,b via a novel method by heating with acetyl chloride in acetic acid. The reaction of both compounds 2a,b and 6a,b with N-aryl-2-chloroacetamides 7a–c under two different conditions gave the same corresponding products, 7-acetyl-8-aryl-3-(N-aryl)carbamoylmethylsulfanyl-4-cyano-1,6-dimethyl-7,8-dihydroisoquinolines 8a–e, in high yields. On treatment of compounds 8a,b,e in methanol with a slightly excess molar amount of sodium methoxide, they underwent intramolecular Thorpe–Ziegler cyclization followed by spontaneous aromatization, providing the planar 7-acetyl-1-amino-6-aryl-2-(N-aryl)carbamoyl-5,8-dimethyl-8,9-dihydrothieno[2,3-c] isoquinolines 9a,b,e in good yield. Cyclocondensation reactions of 6a,b with phenyl hydrazine, thiosemicarbazide, or hydrazine hydrate led to the formation of nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines 11a, 11b, and 13, respectively. The reaction of compound 13 with 2-chloromethylquinazolin-4(3H)-one in the presence of anhydrous sodium acetate gave the expected thienopyrazoloisoquinolone 14. Heating the latter compound (14) with triethyl orthoformate in glacial acetic acid afforded the fused heptacyclic compound 15. All of the synthesized compounds were characterized based on their full spectral analyses such as IR, 1H nuclear magnetic resonance (NMR), and mass spectrometry (MS). Moreover, the crystal structure of compound 6a was elucidated by X-ray diffraction analysis.

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

New push-pull dyes based on 2-(3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ylidene)malononitrile: An amine-directed synthesis

A series of twelve dyes have been designed using 2-(3-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ylidene)malononitrile as the electron acceptor. While using piperidine as a classical base for the Knoevenagel reaction, a nucleophilic attack of the amine on the formed push-pull chromophore occurred, producing an azafluorenone derivative. By varying the amine, a series of azafluorenones could be obtained. By using an aldehyde of extended conjugation, a spontaneous aromatization following the cyclization reaction could also be demonstrated. The optical and electrochemical properties of the different dyes were examined. Theoretical calculations were also carried out to support the experimental results.

Facile Synthesis of Dibenzotetracenedione Derivatives by Rhodium-Catalyzed [2+2+2] Cycloaddition/Spontaneous Aromatization.

It has been established that a cationic rhodium(I)/SEGPHOS complex catalyzes the [2+2+2] cycloaddition of biphenyl-linked 1,7-diynes with 1,4-naphthoquinone and anthracene-1,4-dione. Conveniently, spontaneous aromatization proceeded upon removal of the rhodium complex by passing the reaction mixture through an alumina column, to give the corresponding dibenzotetracenediones and dibenzopentacenediones, respectively, in good yields. The obtained dibenzotetracenedione could be readily transformed into the corresponding dibenzotetracene in good yield. This dibenzotetracene showed blue fluorescence with a good quantum yield, which was significantly higher than those of tetracene, tetrabenzotetracene, and hexabenzotetracene.

Functionalization of the "Bay Region" of Perylene in Reaction with 1-Arylalk-2-yn-1-ones Catalyzed by Trifluoromethanesulfonic Acid: One-Step Approach to 1-Acyl-2-alkylbenzo[ ghi]perylenes.

We describe a convenient method of the synthesis of 1-acyl-2-alkylbenzo[ ghi]perylenes via functionalization of the "bay region" of perylene in the reaction with 1-arylalk-2-yn-1-ones catalyzed by trifluoromethanesulfonic acid. We showed that the formation of 1-acyl-2-alkylbenzo[ ghi]perylenes from perylene and 1-arylalk-2-yn-1-ones might occur via spontaneous aromatization of 1-acyl-2-alkyl-2a,12a-dihydrogenbenzo[ ghi]perylenes by oxidation with dioxygen or by the hydrogen transfer to 1-arylalk-2-yn-1-ones. These compounds are fluorescent in solution with a high Stokes shift and with a ΦF value of up to 0.17 (and 0.36 in solid).

Tandem aldol condensation-Diels–Alder-aromatization sequence of reactions: a new pathway for the synthesis of 2-tetralone derivatives

A series of new polysubstituted derivatives of 2-tetralones possessing two ester groups were synthesized via a tandem aldol condensation-Diels–Alder-aromatization sequence of reactions. All the three steps took place in one pot and in the presence of aminofunctionalized silica coated Fe3O4 nanoparticles as the catalyst. In situ formed dienes reacted with diethyl acetylenedicarboxylate at room temperature and the process was followed by spontaneous aromatization of the cycloadducts to produce high yields of the final tetralone products. Further studies suggest that the process goes through an initial aldol condensation-cycloaddition sequence followed by oxidation and rearrangement steps. After completion of the reactions, the catalyst could be recycled and reused efficiently in subsequent reactions.

4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions.

In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

Total synthesis of clostrubin.

Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014. This polyphenol possesses a fully substituted arene moiety on its pentacyclic scaffold, which poses a considerable challenge for chemical synthesis. Here we report the first total synthesis of clostrubin in nine steps (the longest linear sequence). A desymmetrization strategy is exploited based on the inherent structural feature of the natural product. Barton–Kellogg olefination forges the two segments together to form a tetrasubstituted alkene. A photo-induced 6π electrocyclization followed by spontaneous aromatization constructs the hexasubstituted B ring at a late stage. In total, 200 mg of clostrubin are delivered through this approach.

Three-Component Assembly of Structurally Diverse 2-Aminopyrimidine-5-carbonitriles

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

ChemInform Abstract: Preparation of Perfluoroalkyl Azaarenes with a Perfluoroalkyllithium- Boron Trifluoride System.

Abstract In the presence of boron trifluoride, perfluoroalkyllithiums generated in situ from tbe reaction of n-perfluoroalkyl iodides with methyllithium-lithium bromide smoothly added to a carbon-nitrogen double bond of bicyclic azaarenes and diazines to give the corresponding perfluoroalkylated dihydro heterocycles, which often underwent spontaneous aromatization in air. Perfluoroalkylation occurred preferentially at the carbon next to nitrogen in azaarenes even when the carbon atom was occupied by an alkyl substituent. Only one exception observed was the reaction of acridine where a perfluoroalkyl group was introduced at 9 position.

New and General Nitrogen Heterocycle Synthesis: Use of Heteropoly Acids as a Heterogeneous Recyclable Catalyst

An efficient synthetic method of six- and five-member nitrogen heterocyclic compounds was developed. Nitrogen heterocyclic compounds were prepared by condensation of the β-dicarbonyl compounds with the corresponding β- or γ-amino alcohols, subsequent cyclization, and spontaneous aromatization in the presence of a catalytic amount of Keggin-type heteropoly acids under very mild conditions.

Total Synthesis of the C‐1027 Chromophore Core: Extremely Facile Enediyne Formation through SmI2‐Mediated 1,2‐Elimination

The spontaneous aromatization of the enediyne chromophore of the potent antitumor agent C-1027 generates a p-benzyne biradical, which cleaves double-stranded DNA. The title reaction was developed for the construction of nine-membered-ring enediynes and applied as the final step in the synthesis of the exceptionally unstable core structure of the C-1027 chromophore (see scheme; Boc, MOM, MPM, and TES are protecting groups; Ms=methanesulfonyl).

One‐pot solvent and catalyst‐free synthesis of functionalized 1,8‐naphthyridines and quinolines by microwave irradiation

Abstractmagnified imageA series of functionalized, aryl substituted naphthyridines and quinolines has been synthesized by microwave‐assisted one‐pot two‐component synthesis under solvent‐free conditions in good yields by the reaction of a variety of aryl or heteroaryl amines and aryl vinyl ketones. A combinatorial type approach for a one‐step microwave reaction has been developed where a ring‐closing condensation is followed by a spontaneous aromatization to afford the functionalized aryl substituted 1,8‐naphthyridines and quinolines.

Microwave‐Expedited One‐Pot, Two‐Component, Solvent‐Free Synthesis of Functionalized Pyrimidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Microwave-Expedited One-Pot, Two-Component, Solvent-Free Synthesis of Functionalized Pyrimidines

The synthesis of a series of diversely substituted pyrimidines under solvent-free conditions in good yields is described. Under microwave irradiation, a variety of nucleophilic substrates containing the N–C–N unit with β-dicarbonyl compounds, ethyl cyanoacetate, malononitrile, and chalcones was cyclized to give pyrimidines. A combinatorial type approach for a one-step synthesis has been developed where a ring-closing condensation is followed by spontaneous aromatization to afford 28 functionalized and aryl/alkyl substituted pyrimidines.

New synthetic approaches to CNS drugs. A straightforward, efficient synthesis of tetrahydroindol-4-ones and tetrahydroquinolin-5-ones via palladium-catalyzed oxidation of hydroxyenaminones

We have developed a facile and efficient synthesis of new conformationally restricted butyrophenones in the indole and quinoline series via palladium-catalyzed oxidation of hydroxyenaminones, and subsequent cyclization followed by spontaneous aromatization.

The unexpected formation of bicyclo[2.2.1]heptane derivatives by Lewis acid-catalyzed transannular double cyclization

Attempted synthesis of the cyclooctanoid skeleton of taxane molecules, by an intramolecular Lewis acid catalyzed Hosomi–Sakurai cyclization of the allylsilane with the aldehyde moiety in 17, unexpectedly led to the formation of bicyclo[2.2.1]heptane derivatives 18 and 19a. Since the formation of spiro compounds by allylsilane terminated domino reaction has no precedent in literature, we extended the reaction conditions to unactivated olefins. Spontaneous aromatization accompanied by bicyclic ring formation was observed in these cases. Bicyclo[2.2.1]heptane derivative 11 was also formed in high yield by an intramolecular SmI2 mediated ketyl–olefin coupling of aldehyde in the hydroxysulfone 10.

Synthesis of N-substituted pyrrole and tetrahydroindole derivatives from alkenyl β-dicarbonyl compounds

The iodocyclization of a series of alkenyl-substituted β-enamino esters and ketones, followed by base-promoted dehydroiodination, led to the formation of the corresponding pyrrole or tetrahydroindole derivatives. In the absence of base, the iodo-β-enamino esters 5 and 7 underwent spontaneous aromatization after dehydroiodination, furnishing the 4, 5, 6, 7-N-substituted-tetrahydroindoles 19 and 20. All the elimination reactions proceeded smoothly, in yields ranging from 71% to 99%. Starting from the β-allyl-dimedone 21, it was possible to prepare the oxotetrahydroindole 24, in moderate overall yield.