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We describe here a method to generate both benzoyl fluorides and benzoic acids using 2,5-cyclohexadienones prepared from phenols.

Cytochrome P450 1B1 (CYP1B1) is highly expressed in a variety of tumors and implicated to drug resistance. More and more researches have suggested that CYP1B1 is a new target for cancer prevention and therapy. Various CYP1B1 inhibitors with a rigid polycyclic skeleton have been developed, such as flavonoids, trans-stilbenes, and quinazolines. To obtain a new class of CYP1B1 inhibitors, we designed and synthesized a series of bentranil analogues, moreover, IC

A convenient and efficient domino aryne process was developed under transition-metal-free conditions to generate a range of tetra- and pentacyclic ring systems. This transformation was realized via a 1,2-benzdiyne through a nucleophilic and Diels-Alder reaction cascade using styrene as the diene moiety. Three new chemical bonds, namely one C-N and two C-C bonds, and two benzofused rings could be constructed concomitantly, which was made possible by distinct chemoselective control at both the 1,2-aryne and 2,3-aryne stages. Moreover, in-depth studies were carried out on the domino aryne precursors and controlling the diastereoselectivity.

Polysubstituted arenes are prevalent in numerous natural products, medicines, agrochemicals, and organic functional materials. Among methods to prepare polysubstituted arenes, pathways involving benzyne intermediates are particularly attractive given they can readily assemble highly diverse vicinal difunctionalized benzenes in a step-economical manner under transition-metal-free conditions. In order to incorporate more than two substituents on a benzene ring via a benzyne intermediate, methodologies involving benzdiyne and benztriyne have been developed, which significantly expand the current difunctionalization strategies in benzyne chemistry. In the past years, our group has been focusing on pushing the frontier of traditional benzyne chemistry and exploring new applications. In an aim to efficiently and conveniently construct polysubstituted arenes, we developed several aryne multifunctionalization strategies. The first strategy is through the 1,2-benzdiyne processes, which can be divided into a domino aryne approach and stepwise 1,2-benzdiyne approach. In our domino aryne study, we developed three domino aryne reagents as "sesquibenzyne" synthons, which are complementary in terms of reactivity and could adapt different modes of cascade transformations. By employing these domino aryne precursors, we were able to accomplish several cascade transformations, including double nucleophilic reactions, i.e., the reaction with carbonyl protected benzothioamides, 1,2-diamination, and 1,3-diamination. In addition, two cascade processes involving nucleophilic and pericyclic reactions, namely, domino aryne annulation via nucleophilic-ene cascade and domino aryne nucleophilic, Diels-Alder process, were successfully achieved as well. Meanwhile, with our desire to expand the scope of 1,2-benzdiyne transformations, we employed stepwise 1,2-benzdiyne tactics to access polysubstituted arenes. Depending on the property of the substituent on the C3-position of a benzyne intermediate, either an electron-withdrawing or electron-donating group, the incoming ortho groups were chosen accordingly. Consequently, we realized a [2 + 2] cycloaddition-Grob fragmentation process using 3-triflyloxybenzyne and a 1,2-benzdiyne process using 3-(trimethylsilyl)benzyne. Our second research strategy is to use single benzyne to access trisubstituted arenes, which represents a more atom- and step-economical protocol. With our deliberate design, we discovered a tandem benzyne S═O bond insertion/C-H functionalization process using single benzyne and aryl allyl sulfoxides, furnishing three chemical bonds of different types in a single process. This transformation is the first 1,2,3-trisubstitution example using single benzyne intermediate. At last, we developed an oxidative dearomatization strategy on Kobayashi benzyne precursors, which led to the preparation of various cyclohexenynone precursors with diverse substituents in highly efficient manner. In this study, we also demonstrated a new reaction mode of these cyclohexenynones with allyl sulfoxides, which involves a deeper utilization of the cyclohexyne triple bond. This work is the first example of successful connection of precursors of benzyne with cyclohexyne together, revealing a new research direction in the field of cyclohexyne.

A unique approach toward the preparation of cyclohexenynone equivalents was successfully developed via oxidative dearomatization of aryne precursors, featuring multiple functionalities on the target rings. Upon activation, these in situ formed cyclohexenynone intermediates exhibit good to excellent reactivity with various trapping agents. Moreover, an unprecedented cascade was discovered with aryl allyl sulfoxides, revealing a deeper utilization of the alkyne bond by concomitantly introducing one nucleophile and two electrophiles.

Vicinal diamination of domino aryne precursors was achieved with sulfamides. The reaction proceeds through a two-aryne pathway, accepting two N-nucleophiles at the 1,2-positions of an arene ring. Symmetrical and unsymmetrical diaminobenzenes were readily obtained.

In an aim to expand the scope of aryne chemistry with new synthons, a domino aryne precursor bearing an additional ortho-OTf group on Kobayashi reagent is proposed and synthesized. 2,4-Disubstituted benzothiazole could be achieved from benzothioamide derivatives and this reagent with a sequential incorporation of C–S, C–N, and C–C bonds on the consecutive positions of the aryne precursor.

A chemoselective ring-opening protocol of the formal [2+2] cycloadducts of 3-triflyloxyarynes was developed to generate 2,3-aryne intermediate via Grob fragmentation. A variety of 1,3-di- and 1,2,3-trisubstituted arenes could be readily accessed through this [2+2] cycloaddition-2,3-aryne formation sequence. The regioselectivity in these transformations originates from the steric repulsion of the aliphatic chain.

The reaction of a domino aryne precursor with sulfonamides efficiently afforded both 1,3-diaminobenzenes and trisubstituted 1,3-diaminobenzenes by simply varying the reaction conditions. Mechanistic study supports the sequential formation of two transient aryne intermediates involved in the reaction.

An aryne 1,2,3-trisubstitution with aryl allyl sulfoxides is accomplished, featuring an incorporation of C–S, C–O, and C–C bonds on the consecutive positions of a benzene ring. The reaction condition is mild with broad substrate scope. Preliminary mechanistic study suggests a cascade formal [2 + 2] reaction of aryne with S═O bond, an allyl S → O migration, and a Claisen rearrangement.

The reaction of a domino aryne precursor with sulfonamides efficiently afforded both 1,3-diaminobenzenes and trisubstituted 1,3-diaminobenzenes by simply varying the reaction conditions. Mechanistic study supports the sequential formation of two transient aryne intermediates involved in the reaction.

Aryne precursors bearing an additional ortho-OTf group react with benzothioamides to give 2,4-disubstituted benzothiazoles [e.g. (III)].

An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C–S, C–N, and C–C bonds on the consecutive three positions of the aryne precursor.

An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C–S, C–N, and C–C bonds on the consecutive three positions of the aryne precursor.