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A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)–H functionalization reactions, which is facilitated by a DoE optimization. A one-pot C–H functionalization-epimerization procedure provides the trans-3,4-disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall fragment compounds suitable for screening are generated in 3–4 steps from readily-available heterocyclic carboxylic acids.

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines were designed as non-nucleoside anti-HIV inhibitors targeting reverse transcriptase by a fragment-based replacement strategy with the purpose of improving the druggability. Hopping five- or six-membered heterocycle groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl gave 23 derivatives. All of these compounds possessed excellent HIV-1 inhibitory activity in the nanomolar range. Among them, 12g with a 4-pyridine group displayed excellent inhibitory activity toward WT and mutant HIV virus possessing significant selectivity. Moreover, this compound exhibited a decent improvement in druggability than etravirine and rilpivirine: (1) The hydrochloric acid salt of 12g exhibited significantly improved water solubility in different pH conditions. (2) 12g did not show apparent CYP enzymatic inhibitory activity or acute toxicity. (3) Excellent oral bioavailability was also revealed (F = 126%, rats) in 12g. Collectively, these novel heteroaromatic-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:64 issue:14 pages:10297-10311 ispartof: location:United States status: published

A simple "reagent-free" thermal air treatment turns active carbon into a mildly oxidized material with increased quinoidic content that catalytically dehydrogenates saturated N-heterocycles to the corresponding aromatic compounds. Thermal decarboxylation improves the activity of the catalyst further, making it overall more efficient compared to other widely used carbocatalysts such as oxidized carbon nanotubes, graphene oxide and untreated active carbons. The substrate scope covers 1,2,3,4-tetrahydroquinolines (THQ), 1,2,3,4-tetrahydro-beta-carbolines and related N-heterocyclic structures. The developed protocol also successfully dehydrogenates 3-(cyclohexenyl)indoles to 3-aryl indoles, opening a concise transition metal-free approach to (hetero)biaryls as exemplified with the synthesis of the core structure of progesterone receptor antagonist. Hammett plots, deuterium KIE measurements and computations at DFT level suggest that bimolecular hydride transfer mechanism is more likely to operate between THQs and the o-quinoidic sites of the catalyst, than the addition-elimination hemiaminal route. Comparison of structural parameters and catalytic performance of various oxidized carbon materials, prepared by different oxidative and optional post treatments, revealed that quinoidic content and surface area correlate with the obtained yields, while carboxylic acid content has a clear inhibiting effect for the studied oxidative dehydrogenations (ODHs). The carbocatalyst itself can be prepared from inexpensive and environmentally benign starting materials and its catalytic activity can be enhanced by a simple thermal oxidation in air that produces no reagent waste. Furthermore, oxygen is used as terminal oxidant, and the carbocatalyst is recyclable at least six times without a notable loss of activity.

Isocyanides have long been known as versatile chemical reagents in organic synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C1 building blocks, whose inherent N-substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products. Recent developments in palladium catalyzed isocyanide insertion reactions have significantly expanded the scope and applicability of these imidoylative cross-couplings. This review highlights the advances made in this field over the past eight years.

Isocyanides have long been known as versatile chemical reagents in organic synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C-1 building blocks, whose inherent N-substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products. Recent developments in palladium catalyzed isocyanide insertion reactions have significantly expanded the scope and applicability of these imidoylative cross-couplings. This review highlights the advances made in this field over the past eight years.

gem-Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4- to 6-membered O- and N-heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3-Diaryltetrahydrofurans, 4,4 diaryltetrahydropyrans, 3,3-diarylpyrrolidines, 4,4-diaryl-piperidines, as well as diarylcyclobutanes are examined, with results for 3,3-diaryloxetanes and 3,3-diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5- and 6-membered substrates by elimination of water are obtained under the same reaction conditions.

Isocyanide-based MCRs (IMCRs) involving for the first time the biological and pharmaceutical active indoleacetic acids are studied. In particular, the catalytic behavior of 2-acetyl-indoleacetic acid in the Ugi three-component reaction with TosMIC is emphasized. The reaction was optimized, revealing the catalytic role of aromatic carboxylic acids as well, yielding a small library of a-aminoamides. Full assignment of all H-1 and C-13 NMR chemical shifts has been unambiguously achieved. (C) 2016 Elsevier Ltd. All rights reserved.

Triarylamine derivatives are often implemented in organic optoelectronic devices due to their excellent hole-transport properties and their versatile structural tuneability. Common synthetic routes to obtain functionalized triarylamines follow multi-step procedures utilizing transition metal catalysts. Here, we investigate the synthesis of a series of star-shaped tris(biphenylamines) by a one-step base-promoted homolytic aromatic substitution (BHAS), simultaneously attaching three peripheral arenes to the triarylamine core. We demonstrate the versatility of this synthetic route by coupling four different functionalized arenes to the core and study their influence on the optoelectronic properties. BHAS as a metal-free synthetic route produces pure organic semiconductors without transition metal residues.

We report a facile and efficient synthesis of highly func- tionalized cyclooctanoid derivatives by employing a dimerization reaction of 3-oxidopyrylium ylides. Different substituents are intro- duced on the dimer and the stereochemical outcome of the resultant cyclooctanoids is unambiguously established by single-crystal X- ray analysis. The synthesis of cyclooctanoid systems from acyclic pre- cursors remains a challenging problem, mainly because of the unfavorable entropic and enthalpic factors that pre- clude ring closure. The difficulty associated with the con- struction of cyclooctanoids and their ubiquity in numerous diverse natural products have prompted the search for novel methods for their construction. 1-3 3-Oxi- dopyrylium ylide (1) (Scheme 1), generated by base treat- ment of acetoxypyranones, readily undergoes cycloadditions with various dienophiles to produce the corresponding cycloadducts. This approach has been proved to be a highly useful method for the synthesis of seven-membered carbocycles and natural products. 4 However, in the absence of suitable dienophiles, the reac- tive 3-oxidopyrylium ylide readily undergoes self-dimer- ization and generates the polycyclic structures with excellent regio- and stereoselectivity (Scheme 1). This re- action was first reported by Hendrickson and Farina in 1980, but, surprisingly, no further studies have been re- ported until we disclosed our investigations on exploring the use of dimer 2 towards the synthesis of functionally rich cyclooctanoid derivatives. 5-7 In this paper, we wish to present a detailed account of our investigations into the stereocontrolled transformation of cycloadduct 2 into highly functionalized cyclooctanoid 8-13 systems. We demonstrate that different substituents can be introduced onto the cycloadduct 2 in a stereoselective manner by virtue of conformational rigidity imparted by the oxa bridge to the flexible systems. We believe that the results reported herein may be useful for the application of dimerization reactions of oxidopyrylium ions in the total synthesis of cyclooctanoid natural products.

Enantiomerically pure disubstituted pyrrolidines, recently synthesized from commercially available enantiomerically pure β-aminoalcohol, were used as starting materials to synthesize enantiomerically pure hexahydro-1 H -pyrrolizines and octahydroindolizine through a cyclization reaction promoted by N -(phenylseleno)phthalimide. Similarly, starting from enantiopure 5-(hydroxymethyl)pyrrolidin-2-ones, enantiopure hexahydro-3 H -pyrrolizin-3-ones were obtained.

The bis-isocyanide aminocarbyne diiron complexes [Fe2{μ-CN- (Me)(R)}(μ-CO)(CNR′)2(Cp)2][SO3CF3] (R = R′ = Xyl, 1a; R = Me, R′ = Xyl, 1b; R = Xyl, R′ = tBu, 1c; Xyl = 2,6-C6H3Me2) and the analogous thiocarbyne complex [Fe2{μ-CS(Me)}(μ-CO)(CNXyl)2(Cp)2][SO3CF3], 2, were prepared in high yields from [Fe2{μ-C(E)}(μ-CO)(CO)2(Cp)2][SO3CF3] [E = N(Me)(R) or SMe, respectively], by reaction with Me3NO in the presence of the appropriate isocyanide. The addition of LiCCR′′ to 1a−b promoted intramolecular C−N coupling between the two isocyanide moieties, resulting in the formation of [Fe2(μ- CO){μ-CN(Me)(R)}{μ-C(NXyl)N(Xyl)C(CCR′′)}(Cp)2] (R = Xyl, R″ = Ph, 3a; R = Xyl, R″ = Tol, 3b; R = Me, R″ = Ph, 3c; Tol = 4-C6H5Me), in ca. 60% yields. The reaction of 1a with LiCCSiMe3 proceeded with coupling between two dinuclear units, to give the tetranuclear complex C2[Fe2(μ-CO)(Cp)2{μ- CN(Me)(Xyl)}{μ-C(NXyl)N(Xyl)C}]2, 4, in 65% yield. The reaction of 2 with LiCCTol resulted in the formation of a mixture of nonidentified products. The new complexes were purified by alumina chromatography and fully characterized by analytical techniques, IR and NMR spectroscopy. The molecular structures of 3b and 4 were ascertained by X-ray diffraction studies.

A highly efficient copper(I)-catalyzed N -arylation of azaheterocycles with various aryl halides is reported. The N -arylation reaction can be carried out using as low as 0.5 mol % of (Cu(I)OTf) 2 ·PhH and 1.0 mol % of 4,7-dichloro-1,10-phenanthroline as the ligand. Furthermore, cheap and stable copper precursors like Cu(I)I and Cu(II)(OAc) 2 ·H 2 O and the cheap and mild base K 2 CO 3 can be used.

A simple and high yielding method for the synthesis of tri-substituted pyrazoles via iron(III) catalyzed aerobic oxidative aromatization of pyrazolines has been reported. The process demonstrates a variety of functional group tolerance. (C) 2013 Elsevier B.V. All rights reserved.

The self-dimerization of 3-oxidopyrylium leading to stereocontrolled formation of highly functionalized cyclo-octanoids is described. Different functionalities were introduced on the dimer (3) and the stereochemical outcome was determined by single-crystal X-ray analysis. It is noteworthy that the hydrogenation of 3 in ethanol solvent gave the transannulated product 5, whereas the expected dihydro product 4 was obtained when the reaction was run in nonnucleophilic solvents. The mechanistic pathway is discussed.

To endow metal-free materials with the high catalytic activity that is typically featured by a metal-based catalyst is yet a constant pursuit in the field of catalytic chemistry. In this work, novel functional biochars (DCNs) were prepared from wheat straw for the first time via a simple strategy of reconstructing the catalytic active sites in carbon precursors and subsequent controlled carbonization, which may be further applied in the oxidative dehydrogenation of N-heterocycles with ambient air as the oxidant. Whereas the superhydrophobicity of DCN-850 can effectively remove the only byproduct water to effectively reduce the possible effects of water on the catalyst, it also can decrease mass transfer resistance on active sites, thereby ensuring the reaction with high efficiencies and good generality. Especially, after several reuses, the activity and structures of DCN-850 remained unchanged in the catalytic system with water as a solvent. Furthermore, various characterization technologies and the model reaction were used to investigate the architectural attributes of DCNs, and the results show that there is a positive correlation between the catalytic performance and hydrophobicity of DCNs, as well as reveal that the catalytic active sites may be made up of a five-membered-ring ketone or its enol form and possibly a phenolic unit, which could be encapsulated in internal structures of catalysts and promote the reaction via the recycling of -C-C-OH and -C-C=O groups by the pathway of catalytic hydrogen transfer.