Cycloalkane Moieties Research Articles

Donor-Type Nickel–Dithiolene Complexes Fused with Bulky Cycloalkane Substituents and Their Application in Molecular Conductors

The effects of substituents on the arrangement of metal–dithiolene complexes based on π-conjugated systems, which are extensively used to synthesize various functional materials, have not been studied adequately. New donor-type nickel–dithiolene complexes fused with bulky cycloalkane substituents [Ni(Cn-dddt)2] (C5-dddt = 4a,5,6,6a-pentahydro-1,4-benzodithiin-2,3-dithiolate; C6-dddt = 4a,5,6,7,8,8a-hexahydro-1,4-benzodithiin-2,3-dithiolate; C7-dddt = 4a,5,6,7,8,9,9a-heptahydro-1,4-benzodithiin-2,3-dithiolate; and C8-dddt = 4a,5,6,7,8,9,10,10a-octahydro-1,4-benzodithiin-2,3-dithiolate) were synthesized in this study. All the complexes were crystallized in cis-[Ni(cis-Cn-dddt)2] conformations with cis-oriented (R,S) conformations around the cycloalkylene groups in the neutral state. Unique molecular arrangements with a three-dimensional network, a one-dimensional column, and a helical molecular arrangement were formed in the crystals owing to the flexible cycloalkane moieties. New 2:1 cation radical crystals of [Ni(C5-dddt)2]2(X) (X = ClO4− or PF6−), obtained by electrochemical crystallization, exhibited semiconducting behaviors (ρrt = 0.8 Ω cm, Ea = 0.09 eV for the ClO4− crystal; 4.0 Ω cm, 0.13 eV for the PF6− crystal) under ambient pressure due to spin-singlet states between the dimers of the donor, which were in accordance with the conducting behaviors under hydrostatic pressure (ρrt = 0.2 Ω cm, Ea = 0.07 eV for the ClO4− crystal; 1.0 Ω cm, 0.12 eV for the PF6− crystal at 2.0 GPa).

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes.In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained.The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.

Host-Guest Interaction of Cucurbit[8]uril with N-(3-Aminopropyl)cyclohexylamine: Cyclohexyl Encapsulation Triggered Ternary Complex.

The host-guest interaction of a series of cyclohexyl-appended guests with cucurbit[8]uril (Q[8]) was studied by 1H NMR spectroscopy, isothermal titration calorimetry (ITC), and X-ray crystallography. The X-ray structure revealed that two cycloalkane moieties can be simultaneously encapsulated in the hydrophobic cavity of the Q[8] host to form a ternary complex for the first time.

Intermolecular dissociation energies of dispersively bound 1-naphthol⋅cycloalkane complexes.

Intermolecular dissociation energies D0(S0) of the supersonic jet-cooled complexes of 1-naphthol (1NpOH) with cyclopentane, cyclohexane, and cycloheptane were determined to within <0.5% using the stimulated-emission pumping resonant two-photon ionization method. The ground state D0(S0) values are bracketed as 20.23±0.07 kJ/mol for 1NpOH⋅cyclopentane, 20.34±0.04 kJ/mol for 1NpOH⋅cyclohexane, and 22.07±0.10 kJ/mol for two isomers of 1NpOH⋅cycloheptane. Upon S0→S1 excitation of the 1-naphthol chromophore, the dissociation energies of the 1NpOH⋅cycloalkane complexes increase from 0.1% to 3%. Three dispersion-corrected density functional theory (DFT) methods predict that the cycloalkane moieties are dispersively bound to the naphthol face via London-type interactions, similar to the "face" isomer of the 1-naphthol⋅cyclopropane complex [S. Maity et al., J. Chem. Phys. 145, 164304 (2016)]. The experimental and calculated D0(S0) values of the cyclohexane and cyclopentane complexes are practically identical, although the polarizability of cyclohexane is ∼20% larger than that of cyclopentane. Investigation of the calculated pairwise atomic contributions to the D2 dispersion energy reveals that this is due to subtle details of the binding geometries of the cycloalkanes relative to the 1-naphthol ring. The B97-D3 DFT method predicts dissociation energies within about ±1% of experiment, including the cyclopropane face complex. The B3LYP-D3 and ωB97X-D calculated dissociation energies are 7-9 and 13-20% higher than the experimental D0(S0) values. Without dispersion correction, all the complexes are calculated to be unbound.

Ring Expansion and Skeletal Rearrangement of Propargyl Alcohol Substituted Aziridines Induced by Ruthenium Complexes.

The ring expansion and skeletal rearrangement of two types of propargyl alcohol substituted aziridines with or without cycloalkane moieties was induced by a ruthenium cyclopentadienyl phosphine complex. In the simple aziridine system with no cycloalkane, the unique cycloisomerization process altered the absolute connectivity of the two-carbon unit in the three-membered ring to give organometallic products with substituted pyridine or dihydropyridine ligands. For the aziridine on a cyclohexyl ring, the cycloisomerization process was controlled by an interchange process between vinylidene and allenylidene species, thus creating a better relative configuration of the aziridinyl and the alkynyl units. This determines the stereochemistry of the metal carbene products of the octahydroindole derivatives. The structures of five products were determined by X-ray diffraction analysis.

One-pot synthesis and sigma receptor binding studies of novel spirocyclic-2,6-diketopiperazine derivatives

New spirocyclic-2,6-diketopiperazine derivatives containing benzylpiperidine and cycloalkane moieties were synthesized by a one-pot two-step sequential Ugi/intramolecular N-amidation process in moderate to good yields. The in vitro ligand-binding profile studies performed on the sigma-1 and sigma-2 receptors revealed that the σ1 affinities and subtype selectivities of three spirocyclic piperidine derivatives are generally comparable to those of spirocycloalkane analogues. Compared to the low σ1 affinities obtained for cycloalkyl-substituted spirocyclic-2,6-diketopiperazines with n=2, those with n=1 proved to have optimal fitting with σ2 subtype by exhibiting higher affinities. Moreover, the best binding affinity and subtype selectivity was identified for compound 3c with Kiσ1=5.9±0.5nM and Kiσ2=563±21nM as well as 95-fold σ1/σ2 selectivity ratio, respectively.

Contiguous radical pivaloyloxymethylation–directed C(sp3)–H iodination of N-tosyl cycloalkanecarbaldimine

A reaction of N-tosyl cycloalkanecarbaldimines with iodomethyl pivalate was initiated by triethylborane to give pivaloyloxymethylated products bearing 3-iodocycloalkyl groups. Radical addition of pivaloyloxymethyl to imines generates aminyl radicals, which then regioselectively cleave CH bonds at the 3-position of the cycloalkane moieties. The resulting carbon-centered radicals are trapped with iodine. DFT calculations rationalized stereo- and regioselectivity.

Palladium-NHC Catalyzed Enantioselective Synthesis of Fused Indolines via Inert C(sp3)-H Activation

New sterically hindered chiral N-heterocyclic carbene (NHC) ligands were used in palladium catalysis to bring about a highly enantioselective C(sp(3))-H activation on the methylene site of a cycloalkane moiety. The intramolecular coupling reaction of a prochiral N-aryl-N-cycloalkyl methyl carbamate required high temperatures (140-160 °C) and afforded highly enantioenriched trans-2,3-fused indolines.

Palladium(0)‐Catalyzed Reaction of Cyclopropylidenecycloalkanes with Carbon Dioxide

AbstractCyclopropylidenecycloalkanes, which are highly strained methylenecyclopropane (MCPs) containing a cycloalkane moiety, react with carbon dioxide smoothly to give the corresponding five‐membered lactone derivatives in moderate to good yields through a cyclopropane ring‐opening process in the presence of Pd0 catalyst and PCy3 upon heating under 40 atm of CO2. The relative configuration of the major diastereomers has been determined and a plausible reaction mechanism has also been proposed.

Understanding the Torquoselectivity in 8π-Electrocyclic Cascade Reactions: Synthesis of Fenestradienes versus Cyclooctatrienes

Unusual and novel polycyclic cyclooctatrienes, fenestradienes, and fenestrenes form readily from trienynes depending on the structure of the starting trienynes and the reaction conditions. The experimentally observed high torquoselectivities and complete diastereoselectivities of the 8pi-electrocyclization products have been thoroughly studied using density functional computations at B3PW91/6-31G(d,p). The different P- and M-helical topologies for the Mobius aromatic transition structures are the origin of the observed torquoselectivities in the cyclooctatrienes. The P-helical topologies direct the newly formed single bonds into a favorable equatorial position of the neighboring cycloalkane moieties (X = ring size) that retain their most stable conformation. The M-helical transition structures lead to an axial connection for the smaller rings (X = 4-6) and an equatorial connection for the seven- and eight-membered cycloalkanes. This leads to unfavorable conformations for the larger cycloalkane moieties. Experiments and computations show that for trienynes involving small neighboring cycloalkane groups (X = 4-6) M-helical topology is preferred toward cyclooctatrienes and in the following the corresponding fenestradienes can be formed as kinetic or even thermodynamic products; they convert to their more stable cyclooctatriene valence isomers derived from P-helical transition structures at higher temperatures. For larger cycloalkane moieties with more conformational flexibility only cyclooctatrienes with torquoselectivities derived from P-helical transition structures form.

Synthesis of Cycloalkanoindoles by an Unusual DAST‐Triggered Rearrangement Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Cycloalkanoindoles by an Unusual DAST‐Triggered Rearrangement Reaction

AbstractA series of 1,1‐bis(indol‐3‐yl) and 1‐(indol‐2‐yl)‐1‐(indol‐3‐yl)‐ψ‐hydroxyalkanes, prepared from the corresponding indole derivatives and suitable hydroxyaldehydes via routine coupling reactions, were treated with DAST (diethylaminosulfur trifluoride) under mild conditions, to generate a small library of cycloalkanoindoles. Irrespective of the substitution pattern, i.e. whether they are symmetrical or unsymmetrical derivatives, the same mixture of products is produced, in which the tetrahydro‐1H‐carbazole and hexahydrocyclohepta[b]indole scaffolds are substituted by a indol‐3‐yl nucleus on one of the two α‐carbon atoms of the cycloalkane moieties. Thus, speculations on the reaction mechanism with the prediction of a common reaction intermediate are presented. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

Equatorial Preference in the C—H Activation of Cycloalkanes: GaCl3‐Catalyzed Aromatic Alkylation Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Equatorial preference in the C[bond]H activation of cycloalkanes: GaCl3-catalyzed aromatic alkylation reaction.

GaCl(3) catalyzes the aromatic alkylation of naphthalene or phenanthrene using cycloalkanes. The C[bond]C formation predominantly takes place at the least hindered positions of the substrates, and equatorial isomers regarding the cycloalkane moiety are generally obtained. The reaction of bicyclo[4.4.0]decane and naphthalene occurs at the 2-position of naphthalene and at the 2- or 3-carbons of the cycloalkane, and the products possess a trans configuration at the junctures and an equatorial configuration at the naphthyl groups. Notably, cis-bicyclo[4.4.0]decane turns out to be much more reactive than the trans isomer, and a turnover number "TON" up to 20 based on GaCl(3) is attained. 1,2-Dimethylcyclohexane reacts similarly, and the cis isomer is more reactive than the trans isomer. Monoalkylcycloalkanes react at the secondary carbons provided that the alkyl group is smaller than tert-butyl. Adamantanes react at the tertiary 1-position. The alkylation reaction is considered to involve the C[bond]H activation of cycloalkanes with GaCl(3) at the tertiary center followed by the migration of carbocations and electrophilic aromatic substitution yielding thermodynamically stable products. The stereochemistry of the reaction reveals that GaCl(3) activates the equatorial tertiary C[bond]H rather than the axial tertiary C[bond]H.

Synthesis of nitrogen-containing heterocycles 9. Preparation and carbon-carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]-triazolo[1′,5′-a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N-cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,-a][1′,3′-5′]triazine] derivatives 7–12 in moderate to high yields. Ring-opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2-methyl-7-methylthio[1,2,4]-triazolo[1,5-a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2-methylpropane from the potential precursor, 2-tert-butyl-2-methyl-7-methylthio[1,2,4]triazolo[1,5-a]-[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one-step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.

Synthesis of nitrogen‐containing heterocycles. 8. Preparation and ring‐opening of spiro[cycloalkane‐[1′,2′,4′]triazolo[1′,5′‐c]pyrimidine] derivatives

AbstractDiaminomethylene‐ and aminomethylthiomethylenehydrazones [2] of cyclic ketones 1–8 readily reacted with ethoxymethylenemalononitrile to give spiro[cycloalkane‐1,2′‐[1,2′,4′]triazolo[1,5′‐c]pyrimidine‐8′‐carbonitrile] derivatives 12–19 through the electrocyclic reaction of the initially formed condensation products 26 in moderate to high yields. The spiro[cyclopentanetriazolopyrimidine] derivatives underwent ring‐opening at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐substituted‐[1,2,4]triazolo[1,5‐c]pyrimidine‐8′‐carbonitriles 20–23. When an alkyl substituent was introduced into the cyclopentane ring, cleavage of the spiro compounds occurred preferentially at the cyclopentane moiety between the spiro carbon and the more branched one. In contrast, the cyclohexane ring, especially of spiro‐5‐amino‐triazolopyrimidines 17 and 18 strongly resisted to ring‐opening under similar conditions, but those of 5‐methylthiotriazolopyrimidines 14 gave up to 17 percent of cleavage after prolonged heating in hot ethanol. 2‐t‐Butyl‐5‐methylthio‐2,3‐dihydro[1,2,4]triazolo[1,5‐c]pyrimidine‐8‐carbonitrile 25 [R3 = C(CH3)3] was highly susceptible to the cleavage even at room temperature and produced the corresponding 2‐unsubstituted triazolopyrimidine 24 with loss of the t‐butyl group.

Structure‐Activity Relationship Studies of CNS Agents, Part 26 4‐[2‐(Cycloalkanecarboxamido)ethyl]‐1‐(2‐methoxyphenyl)‐piperazines: High‐Affinity 5‐HT1A Agonists

AbstractCycloalkanecarboxamido)ethyl‐1‐(2‐methoxyphenyl)piperazin es 8a–c, 8e, and 8h were obtained by acylation of 4‐(2‐aminoethyl)‐1‐(2‐methoxyphenyl)piperazine, and their 5‐HT1A, 5‐HT1A, 5‐HT2A and α receptor affinities were determined. It was found that the terminal cycloalkane moiety strongly stabilizes both the 5‐HT1A and 5‐HT2A receptor‐ligand complexes. It was demonstrated that the most active 5‐HT1A ligands 8e and 8h (Ki = 2.1 and 0.21 nM, respectively) behaved as potent agonists of these receptors, i.e. both derivatives mimicked 8‐OH‐DPAT in the lower lip retraction (LLR) model and the effect was susceptible to blockade by reasonable doses of the selective 5‐HT1A receptor antagonist (S)‐WAY‐100135.