Ferrocene catalyzed redox-neutral difunctionalization of alkenes using cycloketone oxime esters: access to distal imido-nitriles.

A novel ferrocene-catalyzed cyanoalkyl-imidation of aryl alkenes utilizing cycloketone oxime esters in MeCN under redox-neutral conditions is described. In this three-component reaction, the cycloketone oxime ester is employed as a bifunctional reagent, enabling easy access to diverse distal imido-nitriles with 100% atomic utilization. Preliminary mechanistic studies suggest that the ferrocene-ferrocenium catalytic cycle is responsible for the deconstructive functionalization of cycloketone oxime esters.

From ferrocene to decasubstituted enantiopure ferrocene-1,1'-disulfoxide derivatives.

The functionalization of (R,R)-S,S'-di-tert-butylferrocene-1,1'-disulfoxide by deprotolithiation-electrophilic trapping sequences was studied towards polysubstituted, enantiopure derivatives for which the properties were determined. While the 2,2'-disubstituted ferrocene derivatives were obtained as expected, subsequent functionalization of the 2,2'-di(phenylthio) and 2,2'-bis(trimethylsilyl) derivatives occurred primarily at the 4- or 4,4'-positions. This unusual regioselectivity was discussed in detail in light of pKa values and structural data. The less sterically hindered 2,2'-difluorinated derivative yielded the expected 1,1',2,2',3,3'-hexasubstituted ferrocenes by the deprotometallation-trapping sequence. Further functionalization proved possible, leading to early examples of 1,1',2,2',3,3',4,4'-octa, nona and even decasubstituted ferrocenes. Some of the newly prepared ferrocene-1,1'-disulfoxides were tested as ligands for enantioselective catalysis and their electrochemical properties were investigated.

Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3α (GSK-3α): Development and impact on temozolomide treatment of glioblastoma cells.

The 2-(3-pyridyl)oxazolo[5,4-f]quinoxalines CD-07 and FL-291 are ATP-competitive GSK-3 kinase inhibitors. Here, we investigated the impact of FL-291 on neuroblastoma cell viability and showed that treatment at 10 µM (i.e. ∼500 times the IC50 against the GSK-3 isoforms) has no significant effect on the viability of NSC-34 motoneuron-like cells. A study performed on primary neurons (non-cancer cells) led to similar results. The structures co-crystallized with GSK-3ß revealed similar binding modes for FL-291 and CD-07, with their hinge-oriented planar tricyclic system. Both GSK isoforms show the same orientations for the amino acids at the binding pocket except for Phe130 (α) and Phe67 (ß), leading to a larger pocket on the opposite side of the hinge region for the α isoform. Calculations of the thermodynamic properties of the binding pockets highlighted the required features of potential ligands; these should have a hydrophobic core (which could be larger in the case of GSK-3ß) surrounded by polar areas (a little more polar in the case of GSK-3α). A library of 27 analogs of FL-291 and CD-07 was thus designed and synthesized by taking advantage of this hypothesis. While the introduction of substituents at different positions of the pyridine ring, the replacement of the pyridine by other heterocyclic moieties, or the replacement of the quinoxaline ring by a quinoline moiety did not lead to any improvement, the replacement of the N-(thio)morpholino of FL-291/CD-07 by a slightly more polar N-thiazolidino led to a significant result. Indeed, the new inhibitor MH-124 showed clear selectivity for the α isoform, with IC50 values of 17 nM and 239 nM on GSK-3α and GSK-3ß, respectively. Finally, the efficacy of MH-124 was evaluated on two glioblastoma cell lines. Although MH-124 alone did not have a significant impact on cell survival, its addition to temozolomide (TMZ) significantly reduced the TMZ IC50 values on the cells tested. The use of the Bliss model allowed a synergy to be evidenced at certain concentrations.

Bisphosphonylallenes as Suitable Scaffolds for Unprecedented 4,5-Diphosphonyldihydropyridazines and 3,4-Diphosphonylpyrroles Displaying Antimelanoma Activity.

An efficient and simple approach has been developed for the synthesis of unprecedented 4,5-diphosphonyldihydropyridazines and 3,4-diphosphonylpyrroles, through the condensation of bisphosphonylallenes with hydrazines and primary amines, respectively. The reactions proceed under operationally simple, mild, and catalyst-free conditions, for a wide substrate scope. The synthesized compounds were screened for their antiproliferative activity against melanoma cancer cells, and they showed promising growth inhibition.

Synthesis of Polysubstituted Ferrocenesulfoxides.

The purpose of the study is to design synthetic methodologies, especially directed deprotometalation using polar organometallic reagents, to access polysubstituted ferrocenesulfoxides. From enantiopure 2-substituted (SiMe3, PPh2) S-tert-butylferrocenesulfoxides, a third substituent was first introduced at the 5 position (SiMe3, I, D, C(OH)Ph2, Me, PPh2, CH2NMe2, F) and removal of the trimethylsilyl group then afforded 2-substituted ferrocenesulfoxides unreachable otherwise. Attempts to apply the "halogen dance" reaction to the ferrocenesulfoxide series led to unexpected results although rationalized in light of calculated pKa values. Further functionalizations were also possible. Thus, new enantiopure, planar chiral di- and trisubstituted ferrocenes have been obtained, in addition to several original 2-substituted, 2,3- and 2,5-disubstituted, 2,3,5-trisubstituted and even 2,3,4,5-tetrasubstituted ferrocenesulfoxides, also enantiopure.

Enantiopure ferrocene-1,2-disulfoxides: synthesis and reactivity.

The rational use of directed deprotometallation, sulfur oxidation and sulfoxide/lithium exchange allowed the synthesis of enantiopure ferrocene-1,2-disulfoxide derivatives. Not only do they represent the first members of this original family, but some of them have shown promise as ligands in rhodium-catalysed conjugate addition.

From ferrocene to 1,2,3,4,5-pentafluoroferrocene: halogen effect on the properties of metallocene.

The sequentially fluorinated ferrocenes (1-, 1,2-di, 1,2,3-tri, 1,2,3,4-tetra and 1,2,3,4,5-pentafluoroferrocene) have been synthesized from ferrocene. Rather than a 'perfluoro' effect, experimental and computational analysis of the complete series robustly demonstrates a linear additive effect of fluorine on the electrochemical and spectroscopic properties of ferrocene.

Deprotometalation-Iodolysis and Direct Iodination of 1-Arylated 7-Azaindoles: Reactivity Studies and Molecule Properties.

Five protocols were first compared for the copper-catalyzed C-N bond formation between 7-azaindole and aryl/heteroaryl iodides/bromides. The 1-arylated 7-azaindoles thus obtained were subjected to deprotometalation-iodolysis sequences using lithium 2,2,6,6-tetramethylpiperidide as the base and the corresponding zinc diamide as an in situ trap. The reactivity of the substrate was discussed in light of the calculated atomic charges and the pKa values. The behavior of the 1-arylated 7-azaindoles in direct iodination was then studied, and the results explained by considering the HOMO orbital coefficients and the atomic charges. Finally, some of the iodides generated, generally original, were involved in the N-arylation of indole. While crystallographic data were collected for fifteen of the synthesized compounds, biological properties (antimicrobial, antifungal and antioxidant activity) were evaluated for others.

Functionalization of 9-thioxanthone at the 1-position: From arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest.

Original 1-amino substituted thioxanthone derivatives were easily prepared from the bare heterocycle by a deprotometalation-iodolysis-copper-catalyzed CN bond formation sequence. This last reaction delivered mono- or/and diarylated products depending on the aniline involved. 1-Amino-9-thioxanthone was also prepared and reacted with 2-iodoheterocycles. Interestingly, while 1-(arylamino)-9-thioxanthones could be isolated, their subsequent cyclization was found to deliver original hexacyclic derivatives of helicoidal nature. Evaluation of their photophysical properties revealed high fluorescence in polar media, indicating potential applications for biological imaging. These compounds being able to inhibit PIM1 kinase, their putative binding mode was examined through molecular modeling experiments. Altogether, these results tend to suggest the discovery of a new family of fluorescent PIM inhibitors and pave the way for their future rational optimization.

From simple quinoxalines to potent oxazolo[5,4-f]quinoxaline inhibitors of glycogen-synthase kinase 3 (GSK3).

2,7-Disubstituted oxazolo[5,4-f]quinoxalines were synthesized from 6-amino-2-chloroquinoxaline in four steps (iodination at C5, substitution of the chloro group, amidation and copper-catalysed cyclization) affording 28 to 44% overall yields. 2,8-Disubstituted oxazolo[5,4-f]quinoxaline was similarly obtained from 6-amino-3-chloroquinoxaline (39% overall yield). For the synthesis of other oxazolo[5,4-f]quinoxalines, amidation was rather performed before substitution; moreover, time-consuming purification steps were avoided between the amines and the final products (38 to 54% overall yields). Finally, a more efficient method involving merging of the last two steps in a sequential process was developed to access more derivatives (37 to 65% overall yields). Most of the oxazolo[5,4-f]quinoxalines were evaluated for their activity on a panel of protein kinases, and a few 2,8-disubstituted derivatives proved to inhibit GSK3 kinase. While experiments showed an ATP-competitive inhibition on GSK3ß, structure-activity relationships allowed us to identify 2-(3-pyridyl)-8-(thiomorpholino)oxazolo[5,4-f]quinoxaline as the most potent inhibitor with an IC50 value of about 5 nM on GSK3α.

From ferrocene to fluorine-containing penta-substituted derivatives and all points in-between; or, how to increase the available chemical space.

In spite of the growing interest in fluorine-containing compounds, and the improvements in materials, optical and biological properties that can arise from substitution of a phenyl ring by ferrocene within a molecular scaffold, synthetic strategies that allow the efficient preparation of fluoroferrocene derivatives are scarce. Following conversion of ferrocene to fluoroferrocene, we have developed routes to fluorine-containing di-, tri-, tetra- and penta-substituted ferrocene derivatives to extend the available chemical space. Our approach is based on the identification of suitable reagents and conditions to achieve fluorine-directed deprotometalation, and exploitation of the halogen 'dance' rearrangement in the ferrocene series.

A Halogen-Bond Donor Catalyst for Templated Macrocyclization.

A halogen-bond templated 1:1 macrocyclization in solution is reported. Tetra(iodoperfluorophenyl) ethers were used as halogen-bonded exotemplates in a substoichiometric amount (5 mol %). Pyridine-containing macrocyclic architectures were formed by ruthenium-catalyzed tandem metathesis/transfer hydrogenation sequence using sodium borohydride and methanol as non-dihydrogen hydrogen source. The halogen-bonded stabilization energies were analyzed relying on density functional theory.

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines.

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2',3':5,6] pyrido[4,3-b]indole and pyrazino[2',3':4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

Deprotonative Metalation of Methoxy-Substituted Arenes Using Lithium 2,2,6,6-Tetramethylpiperidide: Experimental and Computational Study.

The reaction pathways of lithium 2,2,6,6-tetramethylpiperidide (LiTMP)-mediated deprotonative metalation of methoxy-substituted arenes were investigated. Importantly, it was experimentally observed that, whereas TMEDA has no effect on the course of the reactions, the presence of more than the stoichiometric amount of LiCl is deleterious, in particular without an in situ trap. These effects were corroborated by the DFT calculations. The reaction mechanisms, such as the structure of the active species in the deprotonation event, the reaction pathways by each postulated LiTMP complex, the stabilization effects by in situ trapping using zinc species, and some kinetic interpretation, are discussed herein.

Ferrocenecarboxylic anhydride: identification of a new polymorph.

A new monoclinic polymorph of ferrocenecarboxylic anhydride, [Fe2(C5H5)2(C12H8O3)], was obtained. Three molecules are present in the asymmetric unit, two of them being nearly identical (r.m.s. deviation = 0.11 Å), with the Fe atoms on the same side of the anhydride functional group. In the third molecule, the two Fe atoms are located at opposite sides of the functional group (ferrocene-ferrocene pseudo-torsion angle = 146.2°), a very unsual feature in metallocene anhydrides. A network of weak intermolecular hydrogen bonds was also disclosed.

Synthetic, Optical and Theoretical Study of Alternating Ethylenedioxythiophene-Pyridine Oligomers: Evolution from Planar Conjugated to Helicoidal Structure towards a Chiral Configuration.

A series of alternating 3,4-ethylenedioxythiophene-alkynylpyridine oligomers (DA)n with increased solubility are synthesized and their photophysical properties and nonlinear optical properties are investigated. Their quadratic polarizabilities are determined from hyper-Rayleigh scattering experiments to obtain information on their conformations in solution. These chromophores, based on the alternation of electron-rich (D) and electron-deficient (A) moieties, exhibit optical properties that arise from the combination of dipolar and helicoidal features in the (DA)n homologue series where n=1-4. The transition from dipolar conjugated planar structures (n=1, 2) to helicoidal structures (n=3, 4) is clearly evidenced by results from symmetry-sensitive second-order nonlinear optical experiments. This suggests an approach towards highly efficient chiral chromophores for second-order nonlinear optics. Interestingly, this structural evolution also has significant impact on the photophysical properties: both absorption and fluorescence emission show bathochromic and hyperchromic shifts with increasing number of repeating units in the dipolar planar derivatives (n=1-2) but show saturation effects in the helicoidal structures (n=2-4). In addition, the helicoidal structures show sizeable two-photon absorption at 700-750 nm (40-100 GM) for compounds lacking either electron-donating or electron-withdrawing substituents.

Long-range Effect of Bromine in the Deprotonative Metalation of Aromatic Compounds.

Deprotonative metalation has been largely used to functionalize aromatic compounds. The efficiency of such reactions, as well as their regioselectivity, depends on the substituents connected to the rings. In contrast with other groups such as fluorine and methoxy, bromine exhibits a long-range acidifying effect. Here we try to depict this particular effect of bromine through different examples in which deprotometalation takes place at a remote position.

Extending motifs in lithiocuprate chemistry: unexpected structural diversity in thiocyanate complexes.

The new area of lithio(thiocyanato)cuprates has been developed. Using inexpensive, stable and safe CuSCN for their preparation, these complexes revealed Lipshutz-type dimeric motifs with solvent-dependent point group identities; planar, boat-shaped and chair shaped conformers are seen in the solid state. In solution, both Lipshutz-type and Gilman structures are clearly seen. Since the advent in 2007 of directed ortho cupration, effort has gone into understanding the structure-reactivity effects of amide ligand variation in and alkali metal salt abstraction from Lipshutz-type cuprates such as (TMP)2Cu(CN)Li2(THF) 1 (TMP = 2,2,6,6-tetramethylpiperidide). The replacement of CN(-) with SCN(-) is investigated presently as a means of improving the safety of lithium cuprates. The synthesis and solid state structural characterization of reference cuprate (TMP)2Cu(CN)Li2(THP) 8 (THP = tetrahydropyran) precedes that of the thiocyanate series (TMP)2Cu(SCN)Li2(L) (L = OEt29, THF 10, THP 11). For each of 9-11, preformed TMPLi was combined with CuSCN (2 : 1) in the presence of sub-stoichiometric Lewis base (0.5 eq. wrt Li). The avoidance of Lewis basic solvents incurs formation of the unsolvated Gilman cuprate (TMP)2CuLi 12, whilst multidimensional NMR spectroscopy has evidenced the abstraction of LiSCN from 9-11 in hydrocarbon solution and the in situ formation of Gilman reagents. The synthetic utility of 10 is established in the selective deprotometalation of chloropyridine substrates, including effecting transition metal-free homocoupling in 51-69% yield.

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium-zinc base and regioselectivity-computed CH acidity relationship.

The synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation using the base in situ prepared from LiTMP and ZnCl2·TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing substituent (OMe, Br). The CH acidities of the substrates were determined in THF solution using the DFT B3LYP method in order to rationalize the experimental results.

Deprotometalation-iodolysis and computed CH acidity of 1,2,3- and 1,2,4-triazoles. Application to the synthesis of resveratrol analogues.

1-Aryl- and 2-aryl-1,2,3-triazoles were synthesized by N-arylation of the corresponding azoles using aryl iodides. The deprotometalations of 1-phenyl-1,2,3-triazole and -1,2,4-triazole were performed using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination and occurred at the most acidic site, affording by iodolysis the 5-substituted derivatives. Dideprotonation was noted from 1-(2-thienyl)-1,2,4-triazole by increasing the amount of base. From 2-phenyl-1,2,3-triazoles, and in particular from 2-(4-trifluoromethoxy)phenyl-1,2,3-triazole, reactions at the 4 position of the triazolyl, but also ortho to the triazolyl on the phenyl group, were observed. The results were analyzed with the help of the CH acidities of the substrates, determined in THF solution using the DFT B3LYP method. 4-Iodo-2-phenyl-1,2,3-triazole and 4-iodo-2-(2-iodophenyl)-1,2,3-triazole were next involved in Suzuki coupling reactions to furnish the corresponding 4-arylated and 4,2'-diarylated derivatives. When evaluated for biological activities, the latter (which are resveratrol analogues) showed moderate antibacterial activity and promising antiproliferative effect against MDA-MB-231 cell line.