Synlett

The present article provides an overview of our work related to cyclization reactions of nitro-substituted electrophilic building blocks with various nucleophiles. As electrophiles, we used nitro-substituted benzoylacetones, 3-ethoxy-2-nitro-2-en-1-ones, 2-nitrobenzoyl chlorides, 4-chloro-3-nitrocoumarin, 2-nitromalonic aldehyde, 3-nitrochromone and 1-(2-chloro-5-nitrophenyl)prop-2-yn-1-ones. As nucleophiles, 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, (heterocyclic) enamines, hydroxylamine, hydrazines, amines and amino esters were employed. The products include a variety of nitro-substituted carbo- and heterocycles that are not readily available by other methods. The electron-withdrawing nitro group can be easily transformed into an electron-donating amino group which is not only pharmacologically relevant, but can also act as a nucleophile in inter- and intramolecular reactions with electrophiles, such as aldehydes, and can be converted into other functional groups. The nitro group has the capacity to activate compounds for regioselective palladium-catalyzed CH-arylation reactions. Inter- and intramolecular CH arylations of nitro-substituted heterocyclic building blocks, such as 4-nitropyrazoles, 4-nitroimidazoles, 2-nitroindole and nitro-substituted purine analogues, allow for a convenient diversity-oriented approach to the corresponding arylated products. In addition, the nitro group can act as a leaving group in SNAr reactions. Various fused benzofuro[3,2-b]pyridines were prepared by intramolecular SNAr reactions of 2-(hydroxyphenyl)-3-nitropyridines.1 Introduction2 Cyclizations of 1,3-Bis(silyloxy)-1,3-butadienes3 Cyclizations of Heterocyclic Enamines4 Reactions of Simple Nitro-Substituted Heterocycles5 Hydroamination Reactions of Alkynes6 Miscellaneous7 Conclusions

Water-soluble peptidomimetics, including peptoids, are promising functional surrogates for biologically relevant, amphiphilic, helical peptides. Twenty amphiphilic peptoid hexamers with predicted helical structures were designed, prepared, and studied using circular dichroism (CD) spectroscopy. The site-specific contributions of aromatic and charged residues to the helical structure of peptoid hexamers in aqueous solution was evaluated, revealing that aromatic residue positioning most significantly impacts structure.

Cannabinoid receptor type 2 (CB2R) agonists have therapeutic potential for the treatment of (neuro)inflammatory diseases. Fluorescent probes enable the detection of CB2R in relevant cell types and serve as a chemical tool in cellular target engagement studies. Here, we report the structure-based design and synthesis of a new CB2R selective fluorescent probe. Based on the cryo-EM structure of LEI-102 in complex with the CB2R, we synthesized 5-fluoropyridin-2-yl-benzyl-imidazolidine-2,4-dione analogues in which we introduced a variety of linkers and fluorophores. Molecular pharmacological characterization showed that compound 22, containing a Cy5-fluorophore with an alkyl-spacer, was the most potent probe with a pK
i of 6.2 ± 0.6. It was selective over the cannabinoid CB1 receptor and behaved as an inverse agonist (pEC50 5.3 ± 0.1, E
max –63% ± 6). Probe 22 may serve as a chemical tool in target and lead validation studies for the CB2R.

A palladium-catalyzed cycloisomerization of carbamimidothioates with the formation of a quaternary carbon and a sulfide is described. The use of (IPr)Pd(allyl)Cl (CX21), K3PO4, and Me-C(OTBS)=NTBS in refluxing xylenes was optimal, and the methoxycarbonyl group was the most suitable substituent for the nitrogen atom of the carbamimidothioate. Phenyl and alkyl groups can be used as tethers for carbamimidothioates, and alkyl and aryl carbamimidothioates can undergo Pd-catalyzed cycloisomerization in high yields.

Pyrylium salts based on a cationic oxygen heterocycle are a key class of chromophores. However, synthesis of these salts generally requires use of harsh acids, copious organic solvents, and in many cases, hazardous conditions. This work provides a two-pot synthesis for substituted triphenyl pyrylium salts wherein chalcone intermediates are first prepared and then mild methanesulfonic acid is used in combination with a dehydrating agent to drive pyrylium cyclization. Purification is achieved through a simple, aqueous workup involving counterion metathesis which avoids the need for environmentally unfriendly organic solvents. This mild, green approach has been applied to synthesize a collection of known pyryliums as well as a new family of red-shifted pyrylium chromophores bearing p-pyrrolidinylphenyl substituents. The synthesis of the latter group demonstrates that unlike other current methods, our approach offers enhanced functional group tolerance as well as finer control over substituent placement.

Since the pioneering work by Grignard in 1900, organomagnesium reagents, the so-called Grignard reagents, have been indispensable in organic synthesis. Alkyl Grignard reagents are usually prepared from the corresponding alkyl iodides, bromides, or chlorides with Mg, whereas alkyl fluorides are not viable substrates under conventional conditions due to the high stability of the C–F bonds. We report that Al–Rh bimetallic complexes catalyze the magnesiation of C(sp3)–F bonds of alkyl fluorides using easy-to-handle Mg powder. The present conditions can accommodate primary, secondary, or tertiary alkyl fluorides to afford the corresponding alkylmagnesium reagents, which can be successfully converted into various functionalities.

Baclofen is an active pharmaceutical ingredient used for the treatment of muscle spasticity. We describe our efforts to develop a novel synthetic approach through C–C bond formation and a cost-effective route to baclofen. The synthesis involved a two-step approach through C–C bond formation using the extensively and commercially available starting material 4-chlorobenzyl cyanide with chloroacetic acid as a reagent in an aprotic solvent, followed by reduction of the nitrile functional group. The synthetic route to baclofen has been demonstrated to be commercially viable, cost-effective, and environmentally friendly. Execution of the developed process led to the isolation of (+)-baclofen in an overall yield of 60% at a multikilogram scale with >99.5% HPLC purity. This article also discusses the cost-effectiveness of the process, the impurity profiling, and the product quality.

A photooxidation approach to the conversion of phosphines into the corresponding phosphine oxides is reported. By taking advantage of O2 in the air as an oxidant and oxygen source, phosphine oxides were obtained efficiently in moderate to excellent yields. A four-coordinated organoboron compound was used as the photocatalyst to activate O2 to its singlet state. This photooxidation method features mild reaction conditions, broad functional-group tolerance, and a wide substrate scope.

Synlett 2024; 35: VIII-DOI: 10.1055/s-0043-1763678Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, GermanyArticle in Thieme eJournals:Table of contents

Synlett 2024; 35: A22-A35DOI: 10.1055/s-0040-1720622Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, GermanyArticle in Thieme eJournals:Table of contents