Alkyl Heterocycles Research Articles

Catalyst-Free Intermolecular Sulfonyl/Fluoromethyl Heteroarylation of Vinyl Ethers via Visible-Light-Induced Charge Transfer.

We report a visible-light-induced three-component sulfonyl-heteroarylation of vinyl ethers with sulfinates and five-membered heteroaryl chlorides. This protocol proceeds via electron-donor-acceptor (EDA) complexes between sulfinates and heteroaryl chlorides, giving β-sulfonyl alkyl five-membered heteroarenes with high efficiency and excellent regioselectivity under mild and catalyst-free conditions. Utilization of CF3 SO2 Na or CF2 HSO2 Na as coupling partners further achieves three-component fluoromethyl-arylation of vinyl ethers, furnishing a series of valuable CF3 /CF2 H-incorporated alkyl heterocycles under mild conditions.

Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd-induced apoptosis involving suppression of endoplasmic reticulum stress

Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1–c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound 13c exhibited the best activity (cell viability = 68.6%, 25 μM). Furthermore, we found that the compound 13c could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of in silico evaluation of ADME/T properties showed that 13c exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 13c as a promising lead compound against Cd-induced neurotoxicity.

Synthesis and biological evaluation of some novel thiadiazole-benzofuran hybrids as potential antitumor agents

ABSTRACTTwo series of novel 1,3,4-thiadiazole-benzofuran and 1,3,4-thiadiazole-furochromene derivatives were synthesized through heterocyclization of alkyl 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbodithioate 3a–f and 2-(1-(5-methoxy-8-methyl-2,6-dioxo-2,6-dihydropyrano[3,2-g]chromen-3-yl)ethylidene)hydrazinecarbothioamide 9a,b with various hydrazonoyl halides, respectively. The structure of the newly synthesized products was elucidated through elemental analysis, spectral data and alternative routes whenever possible. Ten new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell lines in comparison with reference doxorubicin using MTT assay. The results showed that some new compounds have promising anticancer activity.

Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives.

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug pKa, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp3)-H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent N-fluorobenzenesulfonimide. We also report heterobenzylic trifluoromethylthiolation and 18F-fluorination, providing a suite of reactions for late-stage C(sp3)-H functionalization of drug leads and radiotracer discovery.

ChemInform Abstract: 3‐Alkenyl‐5‐chloropyrazoles: Expedient Synthesis via Heterocyclization of 1,1‐Dichloro‐4‐halo‐1‐alken‐3‐ones with Hydrazines.

Synthesis of hard-to-reach 5-chloro-3-alkenylpyrazoles was developed via heterocyclization of alkyl-, benzyl- or dialkylhydrazines with 1,1-dichloro-4-halo-1-alken-3-ones obtained from haloacyl chlorides and vinylidene chloride. The reaction process includes the formation of intermediate 5-chloro-3-(1-haloalkyl)pyrazoles followed by dehydrohalogenation.

3-Alkenyl-5-chloropyrazoles: expedient synthesis via heterocyclization of 1,1-dichloro-4-halo-1-alken-3-ones with hydrazines

Synthesis of hard-to-reach 5-chloro-3-alkenylpyrazoles was developed via heterocyclization of alkyl-, benzyl- or dialkylhydrazines with 1,1-dichloro-4-halo-1-alken-3-ones obtained from haloacyl chlorides and vinylidene chloride. The reaction process includes the formation of intermediate 5-chloro-3-(1-haloalkyl)pyrazoles followed by dehydrohalogenation.

Synthesis of trichloromethylpyrimidines and trichloromethylpyrimido [4,5-d]pyrimidines from alkyl 2-(diaminomethylidene)-3-oxobutyrates and trichloroacetonitrile

Heterocyclization of alkyl 2-(diaminomethylidene)-3-oxobutyrates with trichloroacetonitrile yields alkyl 4-mino-6-methyl-2-trichloromethylpyrimidine-5-carboxylates. The latter compounds react with aryl isocyanates to produce the corresponding pyrimidinylureas, which undergo cyclization to 3-aryl-5-methyl-7-trichloromethylpyrimido[4,5- d]pyrimidine-2,4(1H,3H)-diones under the action of MeONa in MeOH.

1-Alkylpyrazoles and 1-alkyl-5-chloropyrazoles from halovinyl ketones and 1,1-dialkylhydrazines

Regioselective heterocyclization of alkyl 2-chloro-and 2,2-dichlorovinyl ketones with 1,1-dialkyl-hydrazines to 1,3-dialkyl-1H-pyrazoles and 1,3-dialkyl-5-chloro-1H-pyrazoles involves intermediate formation of the corresponding dialkylhydrazones. Fragmentation pattern of chlorine-containing pyrazoles, 3-chloromethyl-1-methyl-1H-pyrazole and 5-chloro-1-methyl-3-propyl-1H-pyrazole, depends on the position of the halogen atom.

ChemInform Abstract: Synthesis of 7‐Azabicyclo[2.2.1]heptane and 2‐Oxa‐4‐azabicyclo[3.3.1]non‐3‐ene Derivatives by Base‐Promoted Heterocyclization of Alkyl N‐(cis(trans)‐3,trans(cis)‐4‐Dibromocyclohex‐1‐yl)carbamates and N‐(cis(trans)‐3,trans (cis)‐4‐Dibromocyclohex‐1‐yl)‐2,2,2‐trifluoroacetamides.

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Nucleophilic Addition to Iminium Ethers in the Preparation of Functionalized N-Alkyl Heterocycles

Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.

Synthesis of 7-Azabicyclo[2.2.1]heptane and 2-Oxa-4-azabicyclo[3.3.1]non-3-ene Derivatives by Base-Promoted Heterocyclization of Alkyl N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.

A New, Simple and Efficient Method for the Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives: Formal Total Synthesis of Epibatidine

The base-mediated heterocyclization of alkyl N-(c-3,t-4-dibromocyclohex-1-yl)carbamates (5, 7, 10), or N-(c-3,t-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (12) is a convenient method for the synthesis of the 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of t-butyl N-(c-3,t-4-dibromocyclohex-1- yl)carbamate (5) with sodium hydride in DMF at room temperature provided (1RS,2SR,4SR)-2-bromo-7-[(tbutoxy) carbonyl]-7-azabicyclo[2.2.1]heptane (2) in 52% yield. The t-BuOK promoted hydrogen bromide elimination of compound 2 affording 7-[(t-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (14) in 78% yield constitutes a new formal total synthesis of epibatidine (1). Keywords: Alkyl N-(c-3,t-4-dibromocyclohex-1-yl)carbamates, N-(c-3,t-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide, 7-azabicyclo[2.2.1]heptanes, epibatidine

Alkyl Heterocycles in Heterocyclic Synthesis. Part 2. Novel Synthesis of Isoquinoline, Thiazolopyridine, and Thieno[2,3‐b]pyridine Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereodynamic Coordination Complexes. Dependence of Exciton Coupled Circular Dichroism Spectra on Molecular Conformation and Shape

Chiral amino alcohols, amino ethers, and amino thioethers were converted to tetradentate ligands by alkylation with a variety of chromophore-bearing alkyl heterocycles. Copper(II) complexes of the ligands display conformational diastereomerism in solution. The resultant propeller-shaped compounds were characterized by a variety of techniques, including exciton coupled circular dichroism (ECCD). Three X-ray crystal structures of complexes are described that partially support structural assignments, but also suggest that solid state structures are not always indicative of solution species. Thus, ECCD may in some cases provide data that is strongly complimentary to X-ray crystallography. These results are presented in a larger context of coordination complexes that display dynamic behavior that can be studied by chiroptical spectroscopy.

Synthesis of Functionalized N-Alkyl Heterocycles from Ketones by a Sequential Ring Expansion/Nucleophilic Addition Process

Synthesis of Functionalized <i>N</i>-Alkyl Heterocycles from Ketones by a Sequential Ring Expansion/Nucleophilic Addition Process