Access to N-Fused Quinazolinones by Radical-Promoted Cascade Annulations of Alkenyl N-Cyanamides with Aromatic Aldehydes.

A cascade radical cyclization of alkenyl N-cyanamides with aromatic aldehydes has been achieved for an expeditious synthesis of keto-methylated dihydropyrrolo-quinazolinones. Benzoyl radicals, generated from aryl aldehydes in the presence of di-tert-butyl peroxide (DTBP), promoted the domino annulations leading to distinctive functionalized quinazolinones in good yields. In addition, the robustness of the present protocol is validated by employing heterocyclic and natural product-based aldehydes.

Radical-mediated sulfonylative/thiolative cyclization of biaryl enones to phenanthrone derivatives.

An approach for the assembly of phenanthrone derivatives bearing all carbon quaternary centres has been developed through visible light-promoted tandem sulfonylation/intramolecular-arylation of biaryl enones with sulfonyl chlorides. A series of sulfonylated 10,10-dialkylphenanthrones were obtained in good yields. In addition, the approach has been extended to thiotrifluoromethyl (SCF3) and thiocyanato (SCN) radicals to obtain the corresponding phenanthrones under oxidative conditions. The synthetic utility was also illustrated by the scalability and further transformations of the product.

Tandem 1,6-Addition/Annulations of Alkynyl p-Quinone Methides with Bis-nucleophiles: Entry to Functionalized Furans, Isoxazoles, Pyrazoles, and Pyridines.

The reaction of alkynyl p-quinone methide (pQM) with keto-methylenes through a base-mediated tandem 1,6-addition/annulation sequence, [2 + 3] annulation, affording the furans is reported for the first time. A variety of functionalized furans, including fused derivatives, were obtained in good to excellent yields under mild reaction conditions. The efficacy of alkynyl pQMs is highlighted by extending their use to access isoxazoles, pyrazoles via [3 + 2] annulation, and pyridines through [3 + 3] annulation in the presence of different bis-nucleophiles.

Domino alkyne insertion/aldol reaction/aromatization of 2-alkynyl indole-3-carbaldehyde with 1,3-diketones: entry to 2-indolyl phenols.

A novel one-pot base-promoted insertion of indolyl 2-alkynes into a C-C single bond of 1,3-diketones, followed by intramolecular aldol reaction and dehydrative aromatization is described. This reaction cascade leads to the construction of 2-indolyl phenols involving the formation of the C1-C2 and C3-C4 bonds of phenols resulting from the formal insertion process with a good substrate scope. Further, these bifunctional compounds were used in a novel arylative annulation in the presence of Grignard reagents to provide chromeno-indole frameworks.

Access to Diverse Seleno-spirocyclohexadienones via Ag(II)-Catalyzed Selenylative ipso-Annulation with Se and Boronic Acids.

An efficient and straightforward synthesis of diversified seleno-azaspiro-2,5-cyclohexadienones from N-(4-methoxy aryl)propiolamides using elemental selenium and boronic acids has been demonstrated. The reaction proceeds through silver-catalyzed oxidative dearomatization in the presence of potassium persulfate (K2S2O8) as the oxidant. Further, this approach was extended to N-(4-methoxy aryl)propiolates and biaryl ynones to access the corresponding selenylated oxospiro-2,5-cyclohexadienones and spiro[5,5]trienones, respectively. The present three-component method offers the diverse substitutions on selenium involving two C-Se and one C-C bond formations.

Domino Aza-Annulations of Enynyl-/(Alkynyl)aryl-acetonitriles to Access Nitrogen-Enriched Heterocycles.

Unprecedented domino aza-annulations of (E)-2-en-4-ynyl-acetonitriles (generated from the Morita-Baylis-Hillman acetates of propiolaldehydes for the first time) with sodium azide under metal- and oxidant-free conditions for the assembly of triazolo-pyridines are accomplished. The developed strategy offers broad substrate scope, extending to (2-alkynyl)aryl and indolyl-acetonitriles to provide the corresponding triazolo-fused isoquinolines and ß-carbolines, respectively, in good yields. Additionally, the synthetic utility of the products is demonstrated via denitrogenative coupling of fused triazoles with different nucleophiles.

Copper(II)-catalyzed oxidative ipso-annulation of N-arylpropiolamides and biaryl ynones with 1,3-diketones: construction of diketoalkyl spiro-trienones.

An unprecedented copper-catalyzed ipso-annulation reaction of N-(p-methoxyaryl)propiolamides with 1,3-diketones has been developed, which enables the assembly of diketoalkylated spiro[4.5]trienones involving oxidative dearomatization in the presence of ammonium persulfate [(NH4)2S2O8] as the oxidant. This protocol was extended to biaryl ynones, efficiently affording the diketoalkylated spiro[5.5]trienones in good yields. The significance of the diketoalkyl functionality has been illustrated by further transformation into 3-pyrazoyl spiro-trienone, a structurally unique motif.

FeCl3-mediated selenylative benzannulation of aryl alkynones to 3-selenyl ß-naphthols.

An efficient selenylative cyclization of aryl-alkynones with diselenides in the presence of iron(III)chloride at room temperature to prepare 3-seleno-2-naphthols in good yields has been described. Furthermore, the resulting products were transformed into selenyl-naphthofuran and selenyl-1,2-naphthoquinone derivatives.

Total synthesis of remdesivir.

Remdesivir, the first drug approved by the FDA to treat COVID-19, is in high demand for patients infected with the SARS-CoV-2 virus. Herein, we report a facile approach minimizing the protecting group manipulations to afford remdesivir in good overall yield.

Electrochemical Selenylative Carbannulation of Biaryl Ynones to Seleno-Dibenzocycloheptenones/Spiro[5.5]Trienones.

Electrooxidative-induced synthesis of structurally diverse seleno-dibenzocyclohepten-5-ones and seleno-spiro[5.5]trienones by selenylative carbannulation of biaryl ynones with diaryl diselenide has been developed. The switchable reactivity, intramolecular ortho-annulation or dearomative ipso-annulation, is directed by the substituent present on the ortho-aryl group of aryl-ynone. The prominent features of this method include metal-free, external chemical oxidant-free conditions, and readily accessible substrates.

Chemoselective [3 + 2] annulation of oxime acetate with 2-aryl-3-ethoxycarbonyl-pyrroline-4,5-dione: an entry to pyrrolo[2,3-b]pyrrole derivatives.

A novel chemoselective [3 + 2] annulation reaction of easily accessible ketoxime acetate with 2-aryl-3-ethoxycarbonyl pyrroline-4,5-dione has been developed for the synthesis of unknown pyrrolo[2,3-b]pyrrole frameworks. This method involves copper-mediated N-O bond cleavage followed by the formation of carbon-carbon and carbon-nitrogen bonds. This operationally simple protocol provides broader functional group compatibility and good yields.

Domino Reaction of 2,4-Diyn-1-ols with 1,3-Dicarbonyl Compounds: Direct Access to Aryl/Heteroaryl-Fused Benzofurans and Indoles.

A domino propargylation/furanylation (intramolecular exo-dig-cyclization)/benzannulation reaction of 2,4-diyn-1-ols with 1,3-dicarbonyl compounds has been developed for the first time. This provides a novel and effective method for the preparation of aryl/heteroaryl-fused benzofurans from easily accessible starting materials in a single step. The methodology was extended to pyrrolyl-benzannulation to obtain aryl/heteroaryl-fused indoles. Further, application of this approach in the synthesis of eustifoline D and dictyodendrin structural frameworks has been demonstrated.

Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase.

We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 µM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.

Expeditious Access to Spiro-Fused 2,5-Cyclohexadienones via Thio(seleno)cyanative ipso-Cyclization.

A facile oxidative dearomatization of N-(p-methoxyaryl)propiolamides has been established for the synthesis of spiro-fused 2,5-cyclohexadienone frameworks via thio(seleno)cyanative ipso-cyclization in the presence of ceric ammonium nitrate (CAN) as the oxidant. The present method, involving the formation of C-S and C-C bonds, was also extended to (p-methoxyaryl)propiolates for thiocyanative ipso-cyclization. Furthermore, the obtained chalcogeno-spirocyclohexadienones were transformed into uniquely functionalized spirocyclohexadienone derivatives.

Rh(III)-Catalyzed Domino [4 + 2] Annulation/Aza-Michael Addition of N-(Pivaloyloxy)benzamides with 1,5-Enynes via C-H Activation: Synthesis of Functionalized Aromathecins.

Reported herein are the Rh(III)-catalyzed cascade annulation reactions of N-(pivaloyloxy)benzamides with 1,5-enynes to access diversely substituted aromathecin derivatives involving C-H activation. The developed procedure offers an efficient synthetic tool for the assembly of a wide range of N-(pivaloyloxy)benzamides and 1,5-enynes with good atom economy and functional group tolerance. The key reactions involved in this annulation are alkyne insertion and aza-Michael addition under oxidant-free mild reaction conditions.

One-Pot Assembly of 3-Hydroxycarbazoles via Uninterrupted Propargylation/Hydroxylative Benzannulation Reactions.

A novel strategy for the synthesis of 3-hydroxycarbazoles involving the consecutive propargylation/palladium-catalyzed hydroxylative benzannulation of indole-2-carbonyls with propargylic alcohols has been exploited. This one-pot procedure leads to a wide range of substituted 3-hydroxycarbazoles in high yield with a broad substrate scope. The method was further extended to access furano-carbazole derivatives from dialkynols via tandem annulations.

E-Z isomerization of 3-benzylidene-indolin-2-ones using a microfluidic photo-reactor.

Here, we report controlled E-Z isomeric motion of the functionalized 3-benzylidene-indolin-2-ones under various solvents, temperature, light sources, and most importantly effective enhancement of light irradiance in microfluidic photoreactor conditions. Stabilization of the E-Z isomeric motion is failed in batch process, which might be due to the exponential decay of light intensity, variable irradiation, low mixing, low heat exchange, low photon flux etc. This photo-µ-flow light driven motion is further extended to the establishment of a photostationary state under solar light irradiation.

[4 + 2]-Annulation of MBH-Acetates of Acetylenic Aldehydes with Imidazoles/Benzimidazoles To Access Imidazo[1,2-a]pyridines/Benzimidazo[1,2-a]pyridines.

An unprecedented one-pot successive base-mediated allylic amination/cycloisomerization reaction strategy has been developed to construct diversely substituted imidazo[1,2-a]pyridines and benzimidazo[1,2-a]pyridines in good to excellent yield. The advantage of this unique [4 + 2]-annulation lies in the employment of readily accessible starting materials, Morita-Baylis-Hillman acetates of acetylenic aldehydes as C4 synthons, and simple imidazoles or benzimidazoles as C2 synthons.

Synthetic Studies toward (±)-Furanocembranoid 1: Construction of the Acyclic Carbon Framework.

Herein, we report the synthesis of the entire acyclic carbon framework toward (±)-furanocembranoid 1 via the longest linear sequence of 12 steps from commercially available linalool and diethyl 2-isopropylmalonate. Key to the success of this synthetic approach is a silver-catalyzed enyne-annulation reaction for the formation of 2,4-disubstituted furan motif of unique furanocembranoid 1, isolated from Croton oblongifolius. Construction of macrocycle has also been explored using the ring-closing metathesis reaction.

Synthetic Access to Cyclopenta[a]inden-2(1H)-ones from Morita-Baylis-Hillman Products of 2-Alkynyl Benzaldehydes.

A new strategy for the synthesis of cyclopenta[a]inden-2(1H)-ones has been developed. An intramolecular Pauson-Khand reaction of the Morita-Baylis-Hillman (MBH) adducts, derived from 2-alkynyl benzaldehydes, provided the consequent novel cyclopenta[a]inden-2(1H)-ones bearing multifunctionalities including an ester group at the fused ring junction (tert-carbon center). The generality of this approach was illustrated by studying the several MBH derivatives containing diverse substitutions/functionalities.