MAOS protocols for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.     

Synthesis and properties of dimetallic M1[Pz]-M2[Schiff base] complexes

We report the synthesis and physical characterization of a series of peripherally functionalized porphyrazines (pz's) 1[M(1); M(2); R], where M(1) is a metal ion incorporated into the pz core, M(2) is a metal ion bound to a bis(5-tert-butyl-salicylidenimine) chelate built onto two amino nitrogen attached to the pz periphery, and R is a solubilizing group (either n-propyl (Pr) or 3,4,5-trimethoxyphenyl (TMP) group) attached to the remaining carbons of the pz periphery. The 1[M(1); M(2); R] species are prepared from precursor pz's with a selenodiazole ring; they are deprotected to form the diamino pz, which reacts with two moles of 5-tert-butyl-2-hydroxybenzaldehyde to form the Schiff base pz. This is metalated to form 1[M(1); M(2); R]. The crystal structures of 1[2H; Ni; Pr] and 1[Cu; ClMn; Pr] are presented. The EPR spectra of the M(1)-M(2) "isomers" prepared with Cu(II) (S = (1)/(2)) and ClMn(III) (S = 2) ions, 1[ClMn; Cu; Pr] and 1[Cu; ClMn; TMP], are a superposition of spectra expected for the S = (3)/(2) and S = (5)/(2) total-spin manifolds that result from strong Heisenberg coupling between the partner spins. The exchange splitting between the two manifolds, as determined by temperature-dependent magnetic susceptibility measurements, is equivalent for the two M(1)-M(2) "isomers", Delta/k(B) approximately 20-25 K, which suggests a sigma-pathway for exchange coupling.     

Helic[6]arene-Based Chiral Pseudo[1]rotaxanes and [1]Rotaxanes

Chiral pseudo[1]rotaxanes and [1]rotaxanes constructed from macrocyclic arenes still remain a big challenge mainly owing to the lack of such chiral macrocycles. In this work, a new system of chiral pseudo[1]rotaxanes formed by self-inclusion of helic[6]arene containing amide linked with the terminal tertiary amines was first discovered. Based on an atom-economic stopping strategy, a pair of chiral [1]rotaxanes were conveniently obtained in almost quantitative yields by blocking the pseudo[1]rotaxanes with monobenzyl bromide of tetraphenylethene. The structures of pseudo[1]rotaxanes and [1]rotaxanes were characterized by 2D NMR spectra in solution, combined with DFT calculations. The photophysical properties further revealed the efficient chirality transfer of helic[6]arene to the tetraphenylethene moiety, compared to their unthreaded chiral isomers. The discovery of the chiral pseudo[1]rotaxanes allows for a wide and available synthesis of chiral [1]rotaxanes, and also opening a new avenue to the design of chiral supramolecular materials.     

Synthesis and Molecular Recognition of Water‐Soluble S6‐Corona[3]arene[3]pyridazines

We report the efficient and scalable synthesis and molecular‐recognition properties of novel and water‐soluble S₆‐corona[3]arene[3]pyridazines. The synthesis comprises a one‐pot nucleophilic aromatic substitution reaction between diesters of 2,5‐dimercaptoterephthalate and 3,6‐dichlorotetrazine followed by the inverse electron‐demand Diels–Alder reaction of the tetrazine moieties with an enamine and exhaustive saponification of esters. The resulting S₆‐corona[3]arene[3]pyridazines, which adopt a 1,3,5‐alternate conformation in the crystalline state, are able to selectively form stable 1:1 complexes with dicationic guest species in water with association constants ranging from (1.10±0.06)×10³ M ^?1 to (1.18±0.06)×10⁵ M ^?1. The easy availability, large cavity size, strong and selective binding power render the water‐soluble S₆‐corona[3]arene[3]pyridazines useful macrocyclic hosts in various disciplines of supramolecular chemistry.     

Functional [6]pericyclynes: synthesis through [14+4] and [8+10] cyclization strategies

Critical analysis of possible strategies for the synthesis of novel carbo-benzene derivatives suggests several [(18-n)+n] routes for the preparation of hexaoxy[6]pericyclyne precursors. Beyond the previously attempted [9+9] symmetrical scheme (n=9), the a priori most selective strategies are those for which n=1, 4, 7, 10, 13, and 16. They involve a cyclizing double-propargylation of a C(18-n) omega-bis-terminal-skipped oligoyne containing (19-n)/3 triple bonds with a C(n) omega-dicarbonyl-skipped oligoyne containing (n-1)/3 triple bonds. To complement the previously used [11+7] strategy, the [14+4] and [8+10] strategies were thus explored. They proved to be efficient, affording seven novel hexaoxy[6]pericyclynes corresponding to six different substitution patterns. These compounds were obtained in 7-15 steps as mixtures of stereoisomers. Thus, by using dibenzoylacetylene as the C(4) electrophile, a [14+4] strategy allowed the synthesis of two hexaphenyl representatives with two or four free carbinol vertices. This approach also afforded tetraphenyl representatives in which the two remaining carbinoxy vertices were substituted with either two alkynyl or one 4-anisyl and one 4-pyridyl groups. By using the hexacarbonyldicobalt complex of butynedial as the C(4) electrophile, a [14+4] strategy also allowed the isolation of a tetraphenylhexaoxy[6]pericyclyne with two adjacent unsubstituted carbinol vertices. A regioisomer with two opposite unsubstituted carbinol vertices was obtained through an [8+10] strategy and its oxidation afforded the corresponding pericyclynedione. Several attempts at synthesizing diphenylhexaoxy[6]pericyclynes with four unsubstituted carbinoxy vertices are described. Only an [8+10] strategy allowed the generation of a fragile diphenylhexaoxy[6]pericyclyne with four adjacent unsubstituted carbinoxy vertices, which could be partly characterized. These results show that the synthesis of the nonsubstituted hexahydroxy[6]pericyclyne, the ring carbo-mer of [6]cyclitol, is a difficult challenge.     

Synthesis of Cucurbit[5]uril-Spermine-[2]Rotaxanes

Cucurbit[5]uril and decamethylcucurbit[5]uril are cyclic pentamers built from glycoluril or dimethylglycoluril respectively. Two different experimental methods have been used for the synthesis of the different [2]rotaxanes. The formed rotaxanes are characterized using ¹H-NMR spectroscopy, mass spectrometry and elemental analysis. In contrast to cucurbit[5]uril no [2]rotaxane could be obtained with decamethylcucurbit[5]uril.     

Synthesis of [1,4]dioxino[2,3-c]quinolines and [1,4]dioxepino-[2,3-c]quinolines and their 1-sulfur analogues

The synthesis of [1,4]dioxino[2,3-c]quinolines and [1,4]dioxepino[2,3-c]quinolines with restrained conformation of the piperidine ring, which represent 1,2,3,4-tetrahydroquinolines containing two heteroatom substituents at positions 3 and 4, is described. In addition, the application of this approach for the synthesis of 1-sulfur analogues is discussed. Both series are helpful tools for three-dimensional quantitative structure-activity relationship studies in the field of modulators of multidrug resistance.     

Flavin-based [2]rotaxanes

[reaction: see text] We report the synthesis of flavin-stoppered hydrogen bonded [2]rotaxanes 1 and 2. We also report the electrochemically controllable properties of these systems in solution, and for derivative 2, as an electropolymerized thin film.     

New heterocyclic systems based on 1-hydrazino-5,6,7,8-tetrahydro[2,7]naphthyridine: 7,8,9,10-tetra-hydro[1,2,4]triazolo[3,4-a]- and 7,8,9,10-tetra-hydro[1,2,4]triazolo[5,1-a][2,7]naphthyridines

Methods have been developed for the synthesis of new substituted 7,8,9,10-tetrahydro[1,2,4]triazolo-[3,4-a][2,7]naphthyridines from 3-chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile. It was shown that on heating in an amine (ethanolamine, pyrrolidine, 2-hydroxy-propylamine), they undergo a Dimroth rearrangement at the triazole fragment, being converted into 7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridine derivatives.     

Application of technetium and rhenium carbonyl chemistry to nuclear medicine. Preparation of [NEt4]2[TcCl3(CO)3] from [NBu4][TcO4] and structure of [NEt4][Tc2(μ-Cl)3(CO)6]; structures of the model complexes [NEt4][Re2(μ-OEt)2(μ-OAc)(CO)6] and [ReBr({-CH2S(CH2)2Cl}2)(CO)3]

Transition Metal Chemistry - A detailed investigation of the one-pot synthesis of [NEt4]2[MX3(CO)3] [M=Tc (1a) or Re (1b); X= Cl?, Br?] is presented. The intermediates...     

Synthesis of dl-[2-13C]leucine and it use in the preparation of [3-dl-[2-13C]leucine]oxytocin and [8-dl-[2-13C]leucine]oxytocin: Preparative separation of diastereoisomeric peptides by partition chromatography and high pressure liquid chromatography

dl-[2-¹³C]Leucine was prepared by condensing the sodium salt of ethyl acetamido-[2-¹³C]cyanoacetate with isobutylbromide in hexamethylphosphoroustriamide followed by acid hydrolysis. N-Boc-dl-[2-¹³C]Leucine was prepared and incorporated into [8-dl-[2-¹³C]leucine]oxytocin by total synthesis. The ¹³C-labeled hormone derivative [8-[2-¹³C]leucine]oxytocin was separated from its 8-position diastereoisomer by partition chromatography. The specifically ¹³C-labeled peptide hormone diastereoisomeric analog [3-dl-[2-¹³C]leucine]oxytocin also was prepared by solid phase peptide synthesis. No suitable solvent system for partition chromatography separation of the latter diastereoisomeric peptide mixture could be found. However an excellent preparative separation of the diastereoisomers could be obtained by reverse phase high pressure liquid chromatography on a partisil 10 M9 ODS column using the solvent system 0.05 M ammonium acetate (pH 4.0), acetonitrile (81:19, $\text{v}\text{v}$) to give pure [3-(2-¹³C]leucine]oxytocin and [3-D-(2-¹³C]leucine]oxytocin. An excellent separation of [8[2-¹³C]leucine]oxytocin and the corresponding 8-D-leucine diastereoisomer derivative could also be accomplished by high pressure liquid chromatography.     

Synthèse des pyrido[2,3-d] el [3,2-d] -s-triazolo[3,4-f] pyrimidines el de (pyrazolyl-1')-4 pyrido[2,3-d] et [3,2-d] pyrimidines

The synthesis of two new heterocycles is described: pyrido-[2,3-d]-.s-triazolo[ 3,4-f] pyrimidine and pyrido[3,2-d]-.s-triayzolo-[3,4-f] pyrimidine. 4-[I'-Pyrazolyl]pyrido[2,3-d]pyrimidines and 4-[1′-pyrazoly1] pyrido[ 3,2-d] pyrimidine are obtained by the action of 4-hydrazinopyrido[2,3-d]pyrimidine and 4-hydrazinopyrido-[3,2-d]pyrimidine with several β-diketones.     

Theophylline as a new and green catalyst for the one-pot synthesis of spiro[benzo[a]pyrano[2,3-c]phenazine] and benzo[a]pyrano[2,3-c]phenazine derivatives under solvent-free conditions

A green, convenient, high yielding and one-pot procedure for the synthesis of novel spiro[benzo[a]pyrano[2,3-c]phenazine] derivatives by domino multi-component condensation reaction between 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, ninhydrine, and malononitrile in the presence of a catalytic amount of 1,3-dimethyl-7H-purine-2,6-dione (theophylline) as an expedient, eco-friendly and reusable solid base catalyst under thermal, microwave irradiation and solvent-free conditions. This procedure has also been applied successfully for the synthesis of benzo[a]pyrano[2,3-c]phenazines.     

Chromogenic indoaniline armed-calix[4]azacrowns

Two novel chromogenic 1,3-alternate calix[4]azacrown (1) and calix[4]-bis-azacrown (2) in which an indoaniline chromophore was attached on the nitrogen atom of the azacrown unit with one methylene spacer were synthesized. The 1H NMR spectrum of the ligand 1 and Ca2+ proved that the metal ion is entrapped by the calix[4]azacrown unit and by the conjugated indoaniline system. From the UV/vis band shifts upon metal ion complexation, Zn2+ ion was found to give the largest band shifts compared to other metal cations, indicating that Zn2+ ion (K(a) = 18 760 M(-)(1) for 1 and K(a) = 19 930 M(-1) for 2) was selectively encapsulated by the calix[4]azacrown cavity with assistance of the pendent indoaniline sidearm.     

A New and Concise Synthesis of 3-Hydroxybenzo[c]phenanthrene and 12-Hydroxybenzo[g]chrysene, Useful Intermediates for the Synthesis of Fjord-Region Diol Epoxides of Benzo[c]phenanthrene and Benzo[g]chrysene

A new strategy which involves a palladium-catalyzed cross-coupling reaction has been developed for the rapid synthesis of 3-hydroxybenzo[c]phenanthrene (5) and 12-hydroxybenzo[g]chrysene (6). These phenolic compounds are the key intermediates for the synthesis of highly carcinogenic fjord-region diol epoxide metabolites 3 and 4 of benzo[c]phenanthrene (1) and benzo[g]chrysene (2). The cross-coupling reaction of 2-bromo-5-methoxybenzaldehyde (9) with naphthalene-1-boronic acid (7) and phenanthrene-9-boronic acid (8) produced 2-(1-naphthyl)-5-methoxybenzaldehyde (10) and 2-(9-phenanthryl)-5-methoxybenzaldehyde (11), respectively, in quantitative yields. After reaction of these aldehydes with trimethylsulfonium iodide under phase-transfer conditions or with the Wittig reagent obtained from (methoxymethyl)triphenylphosphonium bromide and phenyllithium to generate an oxiranyl or methoxyethene side chain, the acid-catalyzed cyclization with methanesulfonic acid (or boron trifluoride) produced 3-methoxybenzo[c]phenanthrene (16) and 12-methoxybenzo[g]chrysene (17) in 61-64% yields. Finally, demethylation of these methoxy derivatives 16 and 17 with boron tribromide resulted in the formation of the hydroxy analogues 5 and 6, respectively. The availability of this short and high-yielding regiospecific method for the synthesis of phenols 5 and 6 should allow the preparative-scale synthesis of the fjord-region diol epoxides 3 and 4. These diol epoxides are required as starting compounds for the synthesis of site-specifically modified oligonucleotides which are critically needed to elucidate the mechanism of carcinogenesis at the molecular level.     

A Synthesis of Two Novel Benzo[f]ninhydrin Analogs: 6-Methoxybenzo[f]ninhydrin and Thieno[f]ninhydrin

Improved methodology for the synthesis of benzo[f]ninhydrin (1) is described. The generality of this approach is illustrated with the synthesis of two novel analogs, 6-methoxybenzo[f]ninhydrin (3) and thieno[f]ninhydrin (4).     

The efficient synthesis of 3-[6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-1H-indazole

This study presents an efficient synthesis of 3-[6-(substituted-phenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-yl]-1H-indazole via dehydrative condensation with cyclization of 4-amino-5-(1H-indazol-3-yl)-4H-[1,2,4]triazole-3-thiol and fluorinated or nonfluorinated carboxylic acids in presence of phosphorous oxychloride. The multistep reaction pathway proceeds through different compounds. Present synthesis has the advantages of easily accessible starting materials, convenient synthesis, simple reaction condition, wider substrate scope, and higher yield (75% to 90% isolated).     

The first enantiomerically pure [n]triangulanes and analogues: sigma-[n]helicenes with remarkable features

(M)-(-)- and (P)-(+)-Trispiro[2.0.0.2.1.1]nonanes [(M)- and (P)-3] as well as (M)-(-)- and (P)-(+)-tetraspiro[2.0.0.0.2.1.1.1]undecanes [(M)- and (P)-4]-enantiomerically pure unbranched [4]- and [5]triangulanes-have been prepared starting from racemic bicyclopropylidenecarboxylic [(1RS)-12] and exo-dispiro[2.0.2.1]heptane-1-carboxylic [(1RS,3SR)-13] acids. The optical resolutions of rac-12 and rac-13 furnished enantiomerically pure acids (S)-(+)-12, (R)-(-)-12, (1R,3S)-(-)-13, and (1S,3R)-(+)-13. The ethyl ester (R)-25 of the acid (R)-(-)-12 was cyclopropanated to give carboxylates (1R,3R)-26 and (1R,3S)-26. The ester (1R,3S)-26 and acids (1R,3S)-13 and (1S,3R)-13 were converted into enantiomerically pure methylene[3]triangulanes (S)-(-)- and (R)-(+)-28. An alternative approach consisted of an enzymatic deracemization of endo-[(1SR,3SR)-dispiro[2.0.2.1]heptyl]methanol (rac-20) or anti-[(1SR,3RS)-4-methylenespiropentyl]methanol (rac-18). This afforded (S)-(-)- and (R)-(+)-28 (starting from rac-20), as well as enantiomerically pure (M)-(-)- and (P)-(+)-1,4-dimethylenespiropentanes [(M)- and (P)-23] starting from rac-18. The methylenetriangulanes (S)-(-)- and (R)-(+)-28 were cyclopropanated furnishing (M)- and (P)-3. The rhodium-catalyzed cycloaddition of ethyl diazoacetate onto (S)-(-)- and (R)-(+)-28 yielded four diastereomeric ethyl trispiro[2.0.0.2.1.1]nonane-1-carboxylates in approximately equal proportions. The enantiomerically pure esters (1R,3S,4S)- and (1S,3R,4R)-30 were isolated by careful distillation and then transformed into [5]triangulanes (M)- and (P)-4 using the same sequence of reactions as applied for (M)- and (P)-3. The structures of the key intermediates (R)-12 and rac-31 were confirmed by X-ray analyses. Although [4]- and [5]triangulanes have no chromophore which would lead to any significant absorption above 200 nm, they have remarkably high specific rotations even at 589 nm with [alpha](20)D=-192.7 [(M)-3, c=1.18, CHCl(3))] or +373.0 [(P)-4, c=1.18, CHCl(3))]. This remarkable optical rotatation is in line with their helical arrangement of sigma bonds, as confirmed by a full valence space single excitation configuration interaction treatment (SCI) in conjunction with DFT computations at the B3LYP/TZVP//B3LYP/6-31+G(d,p) level of theory which reproduce the ORD very well. Thus, it is appropriate to call the helically shaped unbranched [n]triangulanes the "sigma-[n]helicenes", representing the sigma-bond analogues of the aromatic [n]helicenes.     

Synthesis and characterization of [1,2,5]chalcogenazolo[3,4-f]benzo[1,2,3]triazole and [1,2,3]triazolo[3,4-g]quinoxaline derivatives

The synthesis and characterization is reported of low bandgap [1,2,5]chalcogenazolo[3,4-f]benzo[1,2,3]triazole and [1,2,3]triazolo[3,4-g]quinoxaline derivatives that display higher solubility and stability then their thiadiazole counterparts, [1,2,5]chalcogenazolo[3,4-f]benzo[2,1,3]thiadiazole and [1,2,5]thiadiazolo[3,4-g]quinoxaline, respectively.     

Mechanism of the conversion of inverted CB[6] to CB[6

Inverted cucurbit[n]urils (iCB[n]) form as intermediates during the synthesis of cucurbit[n]urils from glycoluril and formaldehyde in HCl (85 degrees C). Product resubmission experiments establish that the diastereomeric iCB[6] and iCB[7] are kinetic products that are less stable thermodynamically than CB[6] or CB[7] (>2.8 kcal mol(-1)). When iCB[6] or iCB[7] is heated under aqueous acidic conditions, a preference for ring contraction is noted in the formation of CB[5] and CB[6], respectively. Interestingly, under anhydrous acidic conditions ring size is preserved with iCB[6] delivering CB[6] cleanly. To establish the intramolecular nature of the iCB[6] to CB[6] conversion under anhydrous, but not aqueous, acidic conditions we performed crossover experiments involving mixtures of iCB[6] and its (13)C=O labeled isotopomer (13)C(12)-iCB[6]. An unusual diastereomeric CB[6] with a M?bius geometry (13) is proposed as a mechanistic intermediate in the conversion of iCB[6] to CB[6] under anhydrous acidic conditions. The improved mechanistic understanding provided by this study suggests improved routes to CB[n]-type compounds.