Nature offers plenty of opportunities to the research.( )of different communities to explore heterocyclic compounds. Among the various magic heterocyclic scaffolds, chromane and chromanone are the most privileged heterocycles due to their omnipresence in most value-added chemical entities. On the other hand, spirocyclic heterocyclic moieties offer unique three-dimensional frameworks which can fit into the cavity of the proteins, including enzymes, thereby enhancing the biological properties. Considering the remarkable significance of spirocyclic systems of chromanes and chromanones, various novel strategies such as Kabbe condensation, organocatalyzed reactions, oxa/sulfa-Michael-aldol cascade reaction, oxa-Michael/addition and 1,3-dipolar cycloaddition, among others, have emerged to access this precious heterocyclic architecture in good to excellent yields. This review summarizes the synthesis of a variety of spirochromane and spirochromanone derivatives covering the literature from 1991-2020.

A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl) pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7/5-HT2AR ligand, and 13 as a multi-receptor (5-HT7, 5-HT2A, 5-HT6 and D-2) agent.

The reaction of 2-(perfluoroethyl)aniline and its higher perfluoroalkyl analogues with an arylmagnesium bromide substituted with a methyl or ethyl group at the ortho position furnishes an acridine containing a shorter perfluoroalkyl group at the 9-position and devoid of the methyl or ethyl group of the Grignard reagent. Yields are in the range of 46–93 %. The intermediary of a substituted aza-ortho-xylylene has been postulated for related transformations in the literature previously, but this intermediate product has never been isolated. As part of this work, the labile product E-27 (half-life of 6 h at 23°C) was isolated for the first time and characterized by infrared spectroscopy, electron impact mass spectrometry, fast atom bombardment mass spectrometry, and 1H NMR. Experimental evidence was also obtained regarding the elimination of the ortho-alkyl group of the Grignard reagent during the course of the reaction as an alcohol.

This review summarizes the synthesis of quinolines and acridines by the reactions of anionically activated 2-(perfluoroalkyl)anilines. Mechanistic studies including isolation of the intermediate aza-ortho-xylylene are discussed.

The treatment of 2-(trifluoromethyl) aniline with 2,6-dimethylphenylmagnesium bromide yields 1-methyl-9-( 2,6-dimethylphenyl) acridine by the formal reaction of one equivalent of the aniline and two equivalents of the Grignard reagent. Interestingly, one of the methyl groups is eliminated during the reaction, and the product contains three methyl groups only. In a similar way, the reaction of 2-(trifluoromethyl) aniline with 2-ethylphenylmagnesium bromide furnishes 9-(2-ethylphenyl) acridine devoid of one ethyl group. The mechanism is discussed.

Treatment of 2-(perfluoroalkyl)aniline with 2-tolylmagnesium bromide or chloride or their substituted analogs yields an acridine containing a shorter perfluoroalkyl group at the 9 position and devoid of the methyl group of the Grignard substrate. Interestingly, no acridine is produced in an attempted reaction with aryl magnesium bromide without the ortho methyl group. With 2-fluoro-6-methylphenylmagnesium bromide the methyl group is eliminated and the fluorine is retained in the acridine product. Results of the mechanistic studies strongly suggest that loss of the methyl group occurs as methanol during air oxidation and hydrolysis of the intermediate products during aqueous workup.

The application of simple pyridines in organic synthesis is reviewed. All pyridine derivatives under discussion are either inexpensive commercial products or can easily be synthesised from readily available substrates. The catalytic pyridines include 2-(dimethylamino)pyridine, 4-(dimethylamino)pyridine and chiral (2 S )-2[(2-pyridyloxy)methyl]pyrrolidine. Other substituted pyridines are stoichiometric reagents in the synthesis of fundamental classes of organic compounds.

Fused dihydrooxazoles are produced by the reaction of 8-bromoteophylline (1), 6-bromo-2-pyridone (7), or 2-bromobenzimidazole (11) with an N-substituted N-(2,3-epoxypropyl)amine. The product derived from 1 undergoes rearrangement to a fused dihydrooxazine while the fused dihydrooxazoles derived from 7 and 11 are stable.

The compounds (III) and (V) are stable dihydrooxazoles, whereas the reaction of the compound (VI) leads to an unstable dihydrooxazole, which undergoes rearrangement to the compound (VII).

To address two fundamental and unsolved problems in optical imaging (nonspecific uptake of near-infrared fluorophores by normal tissues and organs and incomplete elimination of unbound targeted fluorophores from the body), novel zwitterionic near-infrared fluorophores (e.g., ZW800-1) were synthesized and their performance compared in vivo to conventional molecules (e.g., ICG) as a function of charge, charge distribution, and hydrophobicity (see picture).

Purpose: Near-IR fluorescence imaging has great potential for noninvasive in vivo imaging of tumors. In this study, we show the preferential uptake and retention of two hepatamethine cyanine dyes, IR-783 and MHI-148, in tumor cells and tissues. Experimental Design: IR-783 and MHI-148 were investigated for their ability to accumulate in human cancer cells, tumor xenografts, and spontaneous mouse tumors in transgenic animals. Time- and concentration-dependent dye uptake and retention in normal and cancer cells and tissues were compared, and subcellular localization of the dyes and mechanisms of the dye uptake and retention in tumor cells were evaluated using organelle-specific tracking dyes and bromosulfophthalein, a competitive inhibitor of organic anion transporting peptides. These dyes were used to detect human cancer metastases in a mouse model and differentiate cancer cells from normal cells in blood. Results: These near-IR hepatamethine cyanine dyes were retained in cancer cells but not normal cells, in tumor xenografts, and in spontaneous tumors in transgenic mice. They can be used to detect cancer metastasis and cancer cells in blood with a high degree of sensitivity. The dyes were found to concentrate in the mitochondria and lysosomes of cancer cells, probably through organic anion transporting peptides, because the dye uptake and retention in cancer cells can be blocked completely by bromosulfophthalein. These dyes, when injected to mice, did not cause systemic toxicity. Conclusions: These two heptamethine cyanine dyes are promising imaging agents for human cancers and can be further exploited to improve cancer detection, prognosis, and treatment. Clin Cancer Res; 16(10); 2833-44. (C) 2010 AACR.

Near-Infrared (NIR) fluorescence has been valuable in analytical and bioanalytical chemistry. NIR probes and labels have been used for several applications, including hydrophobicity of protein binding sites, DNA sequencing, immunoassays, CE separations, etc. The NIR region (700-1100 nm) has advantages for the spectroscopist due to the inherently lower background interference from the biological matrix and the high molar absorptivities of NIR chromophores. During the studies we report here several NIR dyes were prepared to determine the role of the hydrophobicity of NIR dyes and their charge in binding to amino acids and proteins, e. g., serum albumins. We synthesized NIR dye homologs containing the same chromophore but substituents of varying hydrophobicity. Hydrophobic moieties were represented by alkyl and aryl groups. These NIR dyes of varying hydrophobicity exhibited varying degrees of H-aggregation in aqueous solution indicating that the degree of H-aggregation could be used as an indicator to predict binding characteristics to serum albumins. In order to understand what factors may be important in the binding process, spectral behavior of these varying hydrophobicity dyes were examined in the presence of amino acids. Typical dye structures that exhibit large binding constants to biomolecules were compared in order to optimize applications utilizing non-covalent interactions.

The synthesis of a series of substituted benzofurans is reported. Selected compounds have been shown to bind strongly and with high selectivity to the serotonin receptor 5-HT2A in the presence of the receptor 5-HT7 in vitro.

An improved synthesis of the title compounds is reported.

Conjugate addition reaction of various nucleophiles across the vinyl group of 2-chloro-4-vinylpyrimidine, 2-chloro-4-(1-phenylvinyl)pyrimidine and 2-chloro-4-vinylquinazoline provides the corresponding 2-chloro-4-(2-substituted ethyl)pyrimidines and 2-chloro-4-(2-substituted ethyl)quinazolines. Treatment of these products, without isolation, with N-methylpiperazine results in nucleophilic displacement of chloride and yields the corresponding 2,4-disubstituted pyrimidines and quinazolines.