A domino three-component condensation of ortho-haloacetophenones with urea or amines: a novel one-pot synthesis of halogen-substituted quinolines

Halogen-substituted quinolines have been synthesized in good yields by the condensation and cyclization of two molecules of ortho-haloacetophenones with urea or primary amines. The formation of halogen-substituted quinolines takes place through the unexpected catalyst-free cleavage of C(sp²)-X (X=Cl, Br), α-C(sp³)-H bonds and formation of C-C, C-N bonds in a selective manner. The attractive features of the present synthetic method for halogen-substituted quinolines include catalyst-free, one-pot process, easy availability of starting materials, and introduction of halogen on the quinoline ring for further transformation.     

A stereochemical study of optically active thiazolidines

We report a stereochemical study of a series of free N-H and N-methylated 1,3-thiazolidines bearing H or CH₃ at C-(2). These compounds were readily prepared from ephedrine and pseudoephedrines. The stereochemistry of the compounds under study was deduced using ¹H and ¹³C NMR spectroscopy. Two isomers were found for compounds having a methyl group at C-(2) (i.e. C-(2)HCH₃); interconversion of these isomers, presumably via a non-cyclic zwitterionic intermediate, was observed.     

Native amine-directed site-selective C(sp3)-H arylation of primary aliphatic amines with aryl iodides

Direct C(sp³)-H functionalization of N-unprotected aliphatic amines represents one of the most efficient and straightforward strategies for amine synthesis. Despite some recent progress in this field, the NH₂-directed γ-C(sp³)-H arylation of primary aliphatic amines except α-amino esters remained an unmet challenge. In this report, we established a simple and efficient method for site-selective C(sp³)-H arylation of primary aliphatic amines by aryl iodides. In the presence of only 5 mol% Pd(OAc)₂, a wide range of aliphatic amines including O-benzyl and O-silyl amino alcohols were arylated at γ- or δ-positions by aryl iodides containing a broad scope of functional groups. The synthetic application of this method had also been demonstrated by large-scale synthesis, the synthesis of a fingolimod analogue, and the conjugation with natural d-menthol and fluorescent 1,8-naphthalimide.     

Cyclopenta[g]quinazolinone-based inhibitors of thymidylate synthase targeting α-folate receptor overexpressing tumours: synthetic approaches to 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid

An advanced intermediate for the synthesis of cyclopenta[g]quinazolinone-based antifolates such as (6RS)-CB300945 was prepared by a convergent methodology. The oxo-functionality required for the formation of the C-6-N-10 bond in 4 was introduced in the initial steps of the synthesis, then the tricyclic ring was constructed and finally the propargyl group was introduced using the (propargyl)Co₂(CO)₆⁺ complex without the need to protect the N-3-H or 2-hydroxymethyl functionalities.     

Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative,Leishmanicidal and Anti-Inflammatory Properties

sp²-Iminosugar glycolipids (sp²-IGLs) represent a consolidated family of glycoconjugate mimetics encompassing a monosaccharide-like glycone moiety with a pseudoamide-type nitrogen replacing the endocyclic oxygen atom of carbohydrates and an axially-oriented lipid chain anchored at the pseudoanomeric position. The combination of these structural features makes them promising candidates for the treatment of a variety of conditions, spanning from cancer and inflammatory disorders to parasite infections. The exacerbated anomeric effect associated to the putative sp²-hybridized N-atom imparts chemical and enzymatic stability to sp²-IGLs and warrants total α-anomeric stereoselectivity in the key glycoconjugation step. A variety of O-, N-, C- and S-pseudoglycosides, differing in glycone configurational patterns and lipid nature, have been previously prepared and evaluated. Here we expand the chemical space of sp²-IGLs by reporting the synthesis of α-d-gluco-configured analogs with a bicyclic (5N,6O-oxomethylidene)nojirimycin (ONJ) core incorporating selenium at the glycosidic position. Structure–activity relationship studies in three different scenarios, namely cancer, Leishmaniasis and inflammation, convey that the therapeutic potential of the sp²-IGLs is highly dependent, not only on the length of the lipid chain (linear aliphatic C₁₂ vs. C₈), but also on the nature of the glycosidic atom (nitrogen vs. sulfur vs. selenium). The ensemble of results highlights the α-dodecylseleno-ONJ-glycoside as a promising multitarget drug candidate.     

Acyclic tertiary diamines and 1,4,7,10-tetraazacyclododecane with fluorine-containing β-diketones: Leading to low melting ionic adducts

N,N,N′,N′-Tetramethylmethanediamine (1a), N,N,N′,N′-tetramethylethanediamine (1b), N,N,N′,N′-tetramethyl-1,3-propanediamine (1c), and N,N,N′,N′-tetramethyl-1,6-hexanediamine (1d) were reacted at 25 °C with 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (2a), 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedione (2b), 2-thenoyltrifluoroacetone (2c), and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2d) to form the ionic adducts 3-18. 1,4,7,10-Tetraazacyclododecane (1e) reacted at 25 °C with β-diketones (2a-d) and 1,1,1-trifluoro-2,4-pentanedione (2e) to give ionic solids 19-23 in good yields. Some of the products are liquid at 25 °C and are thermally stable over long liquid ranges as determined by thermal gravimetric analyses. Single-crystal X-ray structure determinations show that compounds 9 and 21 crystallize in the monoclinic space groups P2(1)/c and P2(1)/n, respectively. All the new compounds were characterized by ¹H, ¹⁹F and ¹³C NMR, electrospray MS and/or elemental analyses.     

Rapid and efficient microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles

The microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles starting from N¹-aralkoxy-(methoxy)-N³-cyano-O-phenylisoureas and hydroxylamine is described. N¹-Aralkoxy(methoxy)-N³-cyano-O-phenylisoureas are readily accessible by treatment of diphenyl N-cyanimidocarbonate with O-substituted hydroxylamines.     

Ring-fluorinated naphthalene and indene synthesis via 6- and 5-endo-trig cyclizations of gem-difluoroalkenes by carbon nucleophiles

The intramolecular vinylic substitution of gem-difluoroalkenes is accomplished with sp³ and sp² carbon nucleophiles (2-arylethyllithium and aryllithium) in a 6-endo-trig and a normally disfavored 5-endo-trig fashion, leading to the synthesis of 3-fluoro-1,2-dihydronaphthalenes and 3-fluoroindenes, respectively. The dihydronaphthalenes are readily aromatized on treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to afford 2-fluoronaphthalenes.     

The effect of spiroadamantane substitution on the conformational preferences of N-Me pyrrolidine and N-Me piperidine: a description based on dynamic NMR spectroscopy and ab initio correlated calculations

Dynamic NMR spectroscopy and ab initio correlated calculations revealed that the attachment of a spiroadamantane entity at the C-2 position of N-methylpyrrolidine or N-methylpiperidine induces a severe steric crowding around nitrogen, which changes the conformational space of the heterocycle resulting in: (a) the complete destabilization of the N-Me(eq) conformer in spiranic structures; in contrast the N-Me(eq) conformer corresponds to the global minimum in N-methylpyrrolidine or N-methylpiperidine. The spiroadamantane structure raises the energy of the equatorial conformer because of the severe van der Waals repulsion between the N-Me(eq) group and adamantane C-H bonds. (b) The interconversion between the only populated enantiomeric N-Me(ax) conformers ax→[eq]→ax′; the interconversion eq→ax between N-Me(eq) and N-Me(ax) conformers, which are both populated, is observed in N-methylpyrrolidine or N-methylpiperidine. (c) The raising of ring and nitrogen inversion barriers ax→ts by ∼4-6 kcal mol⁻¹. The dynamic NMR study provides evidence that the most important process required for the enantiomerization between the axial N-Me conformers in spiropiperidine 4 and spiropyrrolidine 5 are different, i.e., a nitrogen inversion in 5 (9.10 kcal mol⁻¹) and a ring inversion in 4 (15.2 kcal mol⁻¹). While an enantiomerization interconverts N-Me axial conformers in spiropiperidine 5 and spiropyrrolidine 4, substitution of the pyrrolidine ring of 5 with a C-Me group effects a diastereomerization between two N-Me axial conformers and reduces effectively the nitrogen inversion barrier according to the protonation experiments and the calculations. In general, all the calculations levels used, i.e., the MM3, B3LYP/6-31+G^∗∗ and MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗, predict correctly the different stability of the local minima; however only MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗ was found to be reliable for the calculation of the nitrogen inversion barriers.     

Synthesis of protected derivatives and short peptides of antAib, a novel C-tetrasubstituted α-amino acid of the Ac5c type possessing a fused anthracene fluorophore

The N^α-Boc and N^α-Fmoc protected derivatives of 2-amino-2,3-dihydro-1H-cyclopenta[b]anthracene-2-carboxylic acid (antAib), a novel fluorescent, achiral, α-amino acid, rigid analogue of the known 9-antAla and 2-antAla residues, and belonging to the class of C_i^α→C_i^α cyclized, C^α,α-disubstituted glycines (strong β-turn and helix inducers in peptides), were synthesized in seven steps from 1,2,4-trimethylbenzene. The UV absorption and fluorescence properties of Boc-antAib-OEt and Boc-antAib-OH are also described. Solution syntheses of the short peptides Boc-antAib-l-Ala-OMe, Fmoc-l-Ala-antAib-l-Ala-OMe, as well as Boc-Aib-antAib-l-Ala-OMe and the side product 2,5-dioxopiperazine cyclo-[antAib-l-Ala], are presented as examples of the coupling ability at both C- and N-termini of the antAib residue.     

Synthesis of 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline: two new unnatural isoquinoline isomers of the cryptolepine series

11H-indolo[3,2-c]isoquinoline has been synthesized in two steps starting from 4-bromoisoquinoline and 2-bromoaniline via a selective Buchwald-Hartwig reaction followed by a Pd-catalyzed intramolecular direct arylation involving C(sp²)-H activation. The synthesis of 7H-indolo[2,3-c]isoquinoline was achieved by a combination of a Suzuki reaction with an intramolecular nitrene insertion reaction starting from 4-bromoisoquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of the tetracyclic skeletons yielded the title compounds 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline, which have never been described in the literature before.     

Synthesis of substituted tetrahydron-1H-carbazol-1-one and analogs via PhI(OCOCF3)2-mediated oxidative C–C bond formation

A variety of tetrahydro-1H-carbazol-1-ones and analogs were conveniently synthesized from the reaction of the corresponding 2-(phenylamino)cyclohex-2-enone with hypervalent iodine reagent PhI(OCOCF₃)₂ (PIFA), through a direct intramolecular oxidative C(sp²)–C(sp²) bond formation. This approach realized the construction of the biologically important tetrahydro-1H-carbazol-1-one and tetrahydrocyclohepta[b]indol-6(5H)-one skeletons. The mechanism of the process was proposed and briefly discussed.     

Pd-catalyzed intramolecular direct arylations at high temperature

Pd-catalyzed cyclodehydrohalogenation involving oxidative addition of aromatic C-Br or activated azaheteroaromatic C-Cl bonds and C(sp²)-H activation have been investigated at high reaction temperatures (180-200 °C). This allowed the fast (10-30 min) synthesis of a variety of azaheteroaromatic ring systems (dibenzo[f,h]phthalazine, dibenzo[f,h]cinnoline, benzofuro[2,3-d]pyridazine, 5H-pyridazino[4,5-b]indole, 7H-indolo[2,3-c]quinoline and 5H-δ-carboline) in moderate to good yields.     

A DFT study on pyridine-derived N-heterocyclic carbenes

To appreciate the chemistry of N-heterocyclic carbenes (NHCs), eight carbenic tautomers of pyridine (azacyclohexadienylidenes) are studied at B3LYP/AUG-cc-pVTZ//B3LYP/6-31+G^∗ and B3LYP/6-311++G^∗∗//B3LYP/6-31+G^∗ levels of theory. Various thermodynamic parameters are calculated for these minima, along with a kinetic focus on carbene-pyridine tautomerization. Appropriate isodesmic reactions show stabilization energies of 2-azacyclohexa-3,5-dienylidene (1) and 4-azacyclohexa-2,5-dienylidene (6) as 119.4 and 104.1 kcal/mol, rather close to that of the synthesized 1,3-dimethylimidazol-2-ylidene (129.2 kcal/mol). Three different mechanisms are suggested for the tautomerizations including: [1,2]-H shift, [1,4]-H shift, and three sequential [1,2]-H shifts. The calculated energy barrier for [1,2]-H shift of 1 is 44.6 kcal/mol, while the first [1,2]-H shift for the proposed sequential mechanism of 6 requires 65.1 kcal/mol. Three preliminary minimum templates are introduced, which may possess the potential of synthetic consideration: 2,6-di(X)-3,5-dichloro-4-azacyclohexa-2,5-dienylidene for X=Mes, t-Bu, and Ad.     

Novel diapocarotenoid dications with VIS/NIR absorption

Isoprenoid acyclic polyene carbodications with 6, 14 and 18 π electrons have been synthesized and characterized in comparison with previously prepared dicyclic C₄₀-carotenoid dications. An equation correlating λ_max (400-1100 nm region) and the number of sp² hybridized carbon atoms in the dication is presented.     

Synthesis of 13a-methylphenanthroindolizidines using radical cascade cyclization: synthetic studies toward (±)-hypoestestatin 1

A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is demonstrated.     

Direct C(sp3)-H functionalization of 2-methylazaarenes using 4-substituted-TEMPO

An efficient and direct C(sp³)-H functionalization of 2-methyl azaarenes with persistent nitroxide radical 4-substituted-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) under neutral conditions has been developed. A broad of 2-methylazaarenes could be reacted with 4-substituted TEMPOs to afford corresponding azaarene 2-methoxylamines by using cheaper copper (II) acetate hydrate as oxidant.     

Crystal and molecular structure of polyunsaturated macrobicyclic carbosilane C24H38Si6

The crystal and molecular structure of the polyunsaturated macrocyclic carbosilane 1,4,4,7,7,10,13, 13,16,16-decamethyl-1,4,7,10,13,16-hexasilabicyclo-[8.8.2]-eucosa-5,14-diene-2,8,11,17-tetrain containing SiC(sp), SiC(sp ²), and SiC(sp ₃) endocyclic bonds was studied by XRD. The two strained 12-membered rings of this molecule have different (trans-zigzag and staggered) conformations. The lengths of the endocyclic bonds SiC(sp) are 1.821–1.852 Å, SiC(sp ²) 1.855–1.874 Å, and SiC(sp ³) 1.847–1.853 Å. The structure of the rings was solved by direct methods and refined by the full-matrix least-squares method. Calculations were carried out with SHELXTL PLUS 5.1 software.     

Synthesis of β-lactam peptidomimetics through Ugi MCR: first application of chiral N-Fmoc amino alkyl isonitriles in MCRs

Chiral N^β-Fmoc amino alkyl isonitriles were employed in Ugi multi component reactions (Ugi 4C-3CR) to obtain functionalized β-lactam peptidomimetics with l-aspartic acid α-methyl ester/peptide ester and organic aldehydes. The reactions were carried out in MeOH. Thirteen Ugi products have been prepared in good to moderate yields with good diastereoselectivities.     

Mononuclear hydridocarbonyl ruthenium complexes incorporating N2O2 bis-chelating ligands

The reactions of [RuH(CO)Cl(PPh₃)₃] with N,N^′-bis(salicylidine)-hydrazine (H₂bsh) and N,N^′-bis(salicylidine)-p-phenylene diammine (H₂bsp) in presence of KOH in methanol led in the formation of neutral mononuclear complexes with the formulations [RuH(CO)(PPh₃)₂(L)] (LHbsh or Hbsp). These present the first examples where the ligands H₂bsh or H₂bsp provide only two of its available donor sites for interaction with the metal centre. The complexes have been characterized by elemental analyses, FAB-MS, IR, ¹H, ¹³C, ³¹P NMR and electronic spectral studies. Molecular structure of the representative complex [RuH(CO)(PPh₃)₂(Hbsh)] have been determined by single crystal X-ray analysis.