Two-step Synthetic Sequence Research Articles

Discovery of 5-sulfonyltetrazoles as neuroblastoma differentiation agents

Previously, we developed an innovative high-content screening (HCS) approach to quantify neuroblastoma cell differentiation based on neurite outgrowth, a morphological differentiation marker of neuroblastoma cells. Here, we report the utilization of this platform to identify 1-methyl-5-(ethylsulfonyl)-1H-tetrazole (3a) as a new neuroblastoma differentiation agent using the ChemBridge DiversetTM commercial synthetic small molecule compound library. We show that this activity can be extended to a group of analogues, which can be accessed via a short two-step synthetic sequence. A new analogue, 5-(allylsulfonyl)-1-methyl-1H-tetrazole (3c) was identified in this synthetic effort as a compound that has even more pronounced differentiation and cytotoxic activities than the original hit compound 3a.

Efficient synthesis of novel colchicine-magnolol hybrids and evaluation of their inhibitory activity on key proteases of 2019-nCoV replication and acute lung injury

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), is a life-threatening infectious condition. Acute lung injury is a common complication in patients with COVID-19. 3-chymotrypsin-like protease (3CLpro) of 2019-nCoV and neutrophil elastase are critical targets of COVID-19 and acute lung injury, respectively. Colchicine and magnolol are reported to exert inhibitory effects on inflammatory response, the severe comorbidity in both COVID-19 and acute lung injury. We thus designed and synthesized a series of novel colchicine-magnolol hybrids based on a two-step synthetic sequence. It was found that these novel hybrids provided unexpected inhibition on 3CLpro and neutrophil elastase, a bioactivity that colchicine and magnolol did not possess. These findings not only provide perquisites for further in vitro and in vivo investigation to confirm the therapeutic potentiality of novel colchicine-magnolol hybrids, but also suggest that the concurrent inhibition of 3CLpro and neutrophil elastase may enable novel colchicine-magnolol hybrids as effective multi-target drug compounds.

One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles.

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl2·2H2O (3.3 eq) and alcohols (R1OH, 2.0 eq) for 1–2 h at 40 °C and then, base (10 eq) and alkyl halides (R2Y, 2.0 eq) for 1–4 h at 25–50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles.

D-Penicillamine and l-cysteine derived thiazolidine catalysts: an efficient approach to both enantiomers of secondary alcohols

d-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature. Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous l-cysteine derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute configurations.

α-(Difluoromethyl)styrene: Improved approach to grams scale synthesis

Improved, efficient, grams scale synthesis of α-(difluoromethyl)styrene (DFMST) based on nucleophilic difluoromethylation process using difluoromethylphenyl sulfone, is presented. Difluoromethylating agent (PhSO2CF2H) was obtained in two-step synthetic sequence with 69% overall yield. Three-step DFMST synthetic route was easily implemented for the preparation of gram quantities of the monomer, allowing for polymerization studies. The syntheses were based on the use of commercially available and reasonable in price starting materials and reagents.

Synthesis of Highly Substituted Pyrrolidines Through 1,3-Dipolar Cycloaddition Reaction of N-Metalated Azomethine Ylides with Triarylideneacetylacetone as Dipolarophile Using Titanocene Dichloride

The 1,3-dipolar cycloaddition reaction of tryarylideneacetyacetone derivatives with N-metalated azomethine ylides in the presence of titanocene dichloride and triethylamine has been investigated. This two-step synthetic sequence is very efficient and yielded the highly substituted pyrrolidines in good yields. The structure and stereochemistry of one of the products has been established by single-crystal x-ray structure and spectroscopic techniques.

INDOLPhosphole and INDOLPhos Palladium−Allyl Complexes in Asymmetric Allylic Alkylations

The new INDOLPhosphole ligands 3a,b are obtained in good yield in a two-step synthetic sequence from 3-methylindole, (S)-BINOL, and the corresponding cyanophosphole. Palladium−allyl complexes have been prepared from INDOLPhosphole (3b) and INDOLPhos (1a) of the type [Pd(INDOLPhos(phole))(η3-C3H5)]PF6 and studied by multidimensional NMR spectroscopy and X-ray crystallography. The allyl ligand undergoes a η3−η1−η3 isomerization in these complexes, which is selective when 1a is the ligand. A tetrameric, boxlike structure, encapsulating a PF6− counteranion, is formed in the solid state in the case of complex 5 ([Pd(3b)(η3-C3H5)]PF6). INDOLPhosphole ligands 3a,b and a small library of INDOLPhos ligands were screened in the Pd-catalyzed asymmetric allylic alkylation of mono- and disubstituted allylic acetates. The catalysts derived from these ligands were highly active, and enantioselectivities were obtained for 1,3-diphenylprop-2-enyl acetate up to 90% ee. Cinnamyl acetate was converted quantitatively with low...

New chiral diamino ligands as sparteine analogues. Application to the palladium-catalyzed kinetic oxidative resolution of 1-phenyl ethanol

Novel chiral 9-keto-bispidines were investigated as ligands in the palladium-catalyzed kinetic oxidative resolution (KOR) of 1-phenyl ethanol. The ligands were easily prepared by means of a two-step synthetic sequence starting from commercially available products.

Synthesis of 3,3-disubstituted oxindoles

A novel and efficient two-step synthetic sequence for the preparation of 3,3-disubstituted oxindoles was developed starting from arylhydrazines and α-branched aldehydes via Fischer indole type synthesis followed by imine oxidation.

Synthesis of Functionalized Quinolines via Ugi and Pd-Catalyzed Intramolecular Arylation Reactions

Two types of quinoline scaffolds were constructed in a combinatorial format via the Ugi four-component reaction (U-4CR) and Pd-catalyzed intramolecular arylation reaction. The scope of this two-step synthetic sequence was examined from commercially available and synthetically accessible starting materials.

An Efficient Two‐Step Synthesis of 3‐Allylindoles

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An efficient two-step synthesis of 3-allylindoles

A two-step synthetic sequence for an efficient synthesis of 3-allylindoles is described.

Zirconium‐Mediated Conversion of Amides to Nitriles: A Surprising Additive Effect.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Carbon-14 labelling of selective H3 receptor antagonists

The fast and efficient carbon-14 labelling of the three potent H3 antagonists NNC 38-1202, NNC 38-1384, and NNC 38-1401 is reported. The two-step synthetic sequence, which included a Knoevenagel reaction, provided the carbon-14-labelled compounds in 38–55% overall yield starting from [2-14C]malonic acid. The compounds were all obtained in high radiochemical purity ( > 99%) and with high specific activity (55.8 mCi/mmol). Copyright © 2005 John Wiley & Sons, Ltd.

A New Entry to Isoxazolo[4,5-d]pyridazin-4(5H) [and 7(6H)]-ones from Functionalized Vinyl Sulfoxides

Isoxazolo[4,5-d]pyridazin-4(5H) [and 7(6H)]-ones can be respectively synthesised in a one-pot two-step synthetic sequence from 4 or 3-arylsulfinyl-5-alkoxyfuran-2(5H)-ones, involving their reactions with nitrile oxides and subsequent reflux with hydrazine hydrate into a 4:3 mixture of water/acetic acid. The 1,3-dipolar reaction takes place with complete regioselectivity, which is controlled by the position of the sulfinyl group at the dipolarophile, yielding, after desulfinylation and subsequent opening of the lactone ring, the two possible regioisomeric 3-substituted isoxazoles bearing formyl and carboxylic acid moieties at C-4 and C-5. These compounds, as well as their methyl esters, can be independently transformed into the corresponding isoxazolopyridazinones in high yields by reaction with hydrazine hydrate.

Directed Electrophilic Cyclizations: Efficient Methodology for the Synthesis of Fused Polycyclic Aromatics

A versatile method for the synthesis of complex, fused polycyclic aromatic systems in high chemical yield is described. Construction is achieved using a general two-step synthetic sequence. Pd-catalyzed Suzuki and Negishi type cross-coupling chemistries allow for the preparation of nonfused skeletal ring systems in yields consistently >80%. The critical ring-forming step, which generally proceeds in very high to quantitative yield, utilizes 4-alkoxyphenylethynyl groups and is induced by strong electrophiles such as trifluoroacetic acid and iodonium tetrafluoroborate. The reaction in essence produces phenanthrene moieties which are integrated into extended polycyclic aromatic structures. Fused polycyclic benzenoids as well as benzenoid/thiophene systems may be prepared utilizing this methodology. The scope of the described cross-coupling/cyclization chemistry including mechanistic insights and problematic side reactions are described.

From cyclohexanol to diethyl hexanedioate (diethyl adipate): A two-step synthetic sequence for microscale organic laboratory

The authors have developed a two-step microscale sequence from cyclohexanol through adipic acid to diethyl adipate that has proved to be successful in the first year organic laboratory.