Aryl Substitution Research Articles

ChemInform Abstract: Structure Modification and Spectroscopic Properties of Artificial Porphyrinoids

AbstractReview: 48 refs.

Novel B(Ar')2(Ar'') hetero-tri(aryl)boranes: a systematic study of Lewis acidity.

A series of homo- and hetero-tri(aryl)boranes incorporating pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, and pentachlorophenyl groups, four of which are novel species, have been studied as the acidic component of frustrated Lewis pairs for the heterolytic cleavage of H2. Under mild conditions eight of these will cleave H2; the rate of cleavage depending on both the electrophilicity of the borane and the steric bulk around the boron atom. Electrochemical studies allow comparisons of the electrophilicity with spectroscopic measurements of Lewis acidity for different series of boranes. Discrepancies in the correlation between these two types of measurements, combined with structural characterisation of each borane, reveal that the twist of the aryl rings with respect to the boron-centred trigonal plane is significant from both a steric and electronic perspective, and is an important consideration in the design of tri(aryl)boranes as Lewis acids.

ChemInform Abstract: Lithium Borohydride for Achiral and Stereospecific Reductive Boronation at Phosphorus: Lack of Electronic Effects on Stereoselective Formation of Alkoxyphosphonium Salts.

We report LiBH4 as a preferred, simple and effective reagent for reductive boronation of achiral and racemic chlorophosphonium salts (CPS) and for diastereomeric alkoxyphosphonium salts (DAPS), both of which are, in turn, easily generated from either the corresponding phosphane or, more conveniently, the phosphane oxide. Further, we have shown that the DAPS reduction/boronation could be achieved with complete stereocontrol to give scalemic phosphane–borane directly in excellent yield and enantiomeric excess (ee). This new methodology was employed to investigate the effects of aryl substitution on the outcome of dynamic kinetic resolution of arylmethylphenylphosphanes and phosphane oxides via DAPS. It was found that substitution at the ortho position strongly affects the degree of stereoselection. However, surprisingly, we confirmed that there was no variation of stereoselectivity seen with the electronic effect of substituents on the para position.

ChemInform Abstract: Truce—Smiles Rearrangement of Substituted Phenyl Ethers.

AbstractThe substrate scope of the title reaction with regard to the electronic and steric properties of the aryl substitution pattern is thoroughly evaluated.

Structure Modification and Spectroscopic Properties of Artificial Porphyrinoids

AbstractIn this review article, we summarize our recent progress in rational structure modification and spectroscopic studies of artificial porphyrinoids. Structural modifications, including meso aryl substitution, peripheral aromatic ring fusion, ring contraction and expansion, and core modification with heterocyclic subunits other than pyrrole, perturb the electronic structures and aromaticity of porphyrinoids, thus regulating their electronic properties. The relationship between structure and spectroscopic properties as well as the applications of these porphyrinoids are also reviewed.

Lithium Borohydride for Achiral and ­Stereospecific Reductive Boronation at Phosphorus: Lack of Electronic Effects on Stereoselective Formation of Alkoxyphosphonium Salts

AbstractWe report LiBH4 as a preferred, simple and effective reagent for reductive boronation of achiral and racemic chlorophosphonium salts (CPS) and for diastereomeric alkoxyphosphonium salts (DAPS), both of which are, in turn, easily generated from either the corresponding phosphane or, more conveniently, the phosphane oxide. Further, we have shown that the DAPS reduction/boronation could be achieved with complete stereocontrol to give scalemic phosphane–borane directly in excellent yield and enantiomeric excess (ee). This new methodology was employed to investigate the effects of aryl substitution on the outcome of dynamic kinetic resolution of arylmethylphenylphosphanes and phosphane oxides via DAPS. It was found that substitution at the ortho position strongly affects the degree of stereoselection. However, surprisingly, we confirmed that there was no variation of stereoselectivity seen with the electronic effect of substituents on the para position.

Modular Synthesis of Elongated Phosphonate Bipyridines

AbstractThe synthesis and the photophysical properties of a series of bpy‐R2 derivatives L1–L3 (bpy = 2,2′‐bipyridine, R represents the substitution at the 4‐ and 4′‐positions of the bpy) are described. R includes phosphonic ester groups as precursors for potent phosphonate anchoring groups, which enable immobilization on transition metal oxide semiconductor surfaces for applications like dye‐sensitized solar cells (DSSCs) or dye‐sensitized photoelectrosynthesis cells (DSPECs). The ligands L1–L3 differ in the length of conjugated linker units between bpy core and anchoring groups. Phenylene and triazole moieties serve as building blocks for linker elongation. The resulting adjustability of the distance between semiconductor and chromophore represents a viable route to improve cell efficiency, as it will allow tuning of charge carrier recombination and dye aggregation. Furthermore the photophysical studies of the free ligands reveal a pronounced effect of the aryl substitution. The solid‐state structures of L1 and L2 are reported within this contribution, enabling the determination of distances between bipyridine nitrogen donor and anchoring group.

Abstract 1963: Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade

Abstract Mitogen Activated Protein Kinase (MAPK) pathways initiate with external signaling, proceed through a sequence of protein kinases, and alter cell proliferation, growth, and survival. MAPK pathways proceed through a well-ordered sequence but are interconnected and modified by the cell's internal needs. The MEK-catalyzed phosphorylation of its target ERK represents the most selective interaction of MAPK signaling cascades. The type III MEK1/2 inhibitor, Mekinist, was recently approved by the FDA for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. This success suggests inhibitors of other MEK/ERK cascades may be reasonable strategies for anti-cancer therapeutic strategies. Despite the likely involvement of MEK5 phosphorylation of ERK5 in early and triple negative breast cancers, prostate cancer, and renal cancer, little work has been focused on developing selective MEK5 inhibitors. We have previously described an initial series of anthranilic acid derivatives structurally derived from the known non-selective MEK inhibitor PD0325901. To explore structural requirements for selective inhibition of MEK5 versus MEK1/2, aryl substitution and the role of proposed internal hydrogen bonding of the ligand were examined with novel compounds. These were tested at 10 μM in MDB-MB-213 cells subsequently treated with EGF to induce MEK1/2 and MEK5 phosphorylation. Western blot analysis following electrophoresis using IR-tagged antibodies raised against pERK1/2, pERK5, ERK1/2, or ERK5 permitted determination of total and relative inhibition of MEK-mediated generation of pERK. Incubation with PD0325901 resulted in full suppression of both pERK1/2 and pERK5. For the aryl substitutions examined, omission of the halogens on the pendant phenyl group (SC-1-181) abolished MEK1/2 inhibition(0% decrease in pERK1/2) yet retained good MEK5 inhibition (82% decrease in pERK5). Disruption of an internal nitrogen-acyl hydrogen bond preferentially decreased MEK5 inhibition (SC-2-32: 40% and 16% decrease in pERK5 and pERK1/2 respectively). This establishes early evidence of significant variation in specificity of MEK type III binding sites that may be exploited as pharmacological tools and possibly as therapeutic agents for cancers overexpressing MEK5. Citation Format: Patrick T. Flaherty, Jane C. Cavanaugh, Mohit Gupta, Colin Vechery, Suravi Chakrabarty, Darlene Monlish, Thomas Wright. Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1963. doi:10.1158/1538-7445.AM2015-1963

ChemInform Abstract: Diastereoselective 1,3‐Dipolar Cycloaddition of Nitrones to Donor—Acceptor Cyclopropanes Catalyzed by a Calcium(II) Complex.

Calcium triflate has been identified as an efficient catalyst for the cycloaddition of nitrones to donor–acceptor cyclopropanes. The reaction proceeds with good to excellent yields of the corresponding tetrahydro-1,2-oxazines with high levels of diastereoselectivity. The generality of the reaction allowed for the synthesis of tetrahydro-1,2-oxazines bearing alkyl, aryl, and heteroaromatic substitution.

Symmetrical and non-symmetrical 2,5-diaryl-1,3,4-oxadiazoles: synthesis and photophysical properties

We report herein the synthesis of 2,5-diaryl-1,3,4-oxadiazoles containing both electron-donating and withdrawing substituents as well as bis- and tris-2,5-disubstituted-1,3,4-oxadiazoles containing electron-donating substituents. The photophysical properties of the synthesized compounds were studied using UV–Vis and fluorescence spectroscopy. The aryl substitution pattern was found to have a marked impact on both luminescence efficiency and other photophysical properties. An increase in the number of electron-donating groups and/or the number of heterocyclic rings provided a red shift of the emission maxima, as well as an increase of the Stokes shifts. The same effect was observed for mono-1,3,4-oxadiazoles containing push–pull substituents on the aryl rings.

ChemInform Abstract: Enantioselective N‐Allylic Alkylation of N‐Propargylsulfonamides with Morita—Baylis—Hillman Carbonates and Sequential Electrophilic Cyclization.

The enantioselective N-allylic alkylation of N-propargylsulfonamides with racemic Morita–Baylis–Hillman (MBH) carbonates catalyzed by modified cinchona alkaloids has been investigated. The alkylation products from MBH carbonates with a 4-methoxyphenyl group underwent ipso-iodocyclization to give optically active azaspirocyclohexadienones via electrophilic activation of alkyne group with iodine monochloride. In contrast, ortho-selective intramolecular Friedel–Crafts reaction occurred for intermediates from MBH carbonates with other electron-rich or neutral aryl or heteroaryl substitutions via the same activation strategy, delivering multifunctional 2-benzazepine frameworks in a highly enantioenriched­ form.

Comparative measure of the electronic influence of highly substituted aryl isocyanides.

To assess the relative electronic influence of highly substituted aryl isocyanides on transition metal centers, a series of C4v-symmetric Cr(CNR)(CO)5 complexes featuring various alkyl, aryl, and m-terphenyl substituents have been prepared. A correlation between carbonyl-ligand (13)C{(1)H} NMR chemical shift (δCO) and calculated Cotton-Kraihanzel (C-K) force constant (kCO) is presented for these complexes to determine the relative changes in isocyanide σ-donor/π-acid ratio as a function of substituent identity and pattern. For nonfluorinated aryl isocyanides possessing alkyl or aryl substitution, minimal variation in effective σ-donor/π-acid ratio is observed over the series. In addition, aryl isocyanides featuring strongly electron-releasing substituents display an electronic influence that nearly matches that of nonfluorinated alkyl isocyanides. Lower σ-donor/π-acid ratios are displayed by polyfluorinated aryl isocyanide ligands. However, the degree of this attenuation relative to nonfluorinated aryl isocyanides is not substantial and significantly higher σ-donor/π-acid ratios than CO are observed in all cases. Substituent patterns for polyfluorinated aryl isocyanides are identified that give rise to low relative σ-donor/π-acid ratios but offer synthetic convenience for coordination chemistry applications. In order to expand the range of available substitution patterns for comparison, the syntheses of the new m-terphenyl isocyanides CNAr(Tripp2), CNp-MeAr(Mes2), CNp-MeAr(DArF2), and CNp-FAr(DArF2) are also reported (Ar(Tripp2) = 2,6-(2,4,6-(i-Pr)3C6H2)2C6H3); p-MeAr(Mes2) = 2,6-(2,4,6-Me3C6H2)2-4-Me-C6H2); p-MeAr(DArF2) = 2,6-(3,5-(CF3)2C6H3)2-4-Me-C6H2); p-FAr(DArF2) = 2,6-(3,5-(CF3)2C6H3)2-4-F-C6H2).

Experimental mechanistic insight into the BINOL-catalyzed enantioselective conjugate addition of boronates to enones

The diol-catalyzed enantioselective conjugate addition of boronic acids and boronate esters has seen significant development in the last decade. However, no experimental mechanistic studies related to this transformation have been reported to date. Hammett plot-based analysis of reaction rates has been performed with aryl substitution both at the carbonyl and at the olefin of an enone electrophile. The resulting trends indicate that C–C bond formation is the likely rate limiting step.

Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread.

The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.

Diastereoselective 1,3-dipolar cycloaddition of nitrones to donor-acceptor cyclopropanes catalyzed by a calcium(II) complex.

Calcium triflate has been identified as an efficient catalyst for the cycloaddition of nitrones to donor-acceptor cyclopropanes. The reaction proceeds with good to excellent yields of the corresponding tetrahydro-1,2-oxazines with high levels of diastereoselectivity. The generality of the reaction allowed for the synthesis of tetrahydro-1,2-oxazines bearing alkyl, aryl, and heteroaromatic substitution.

Palladium complexes with chelating bis-NHC ligands in the Mizoroki-Heck reaction—mechanism and electronic effects, a DFT study.

Experimental results have shown that palladium complexes with chelating aryl- and alkyl-substituted bis-NHC ligands, including [(H3C-Im)2CH2]PdBr2, [(C6H5-Im)2CH2]PdBr2, and [(H3CO-C6H4-Im)2CH2]PdBr2 are excellent catalysts for the Mizoroki-Heck reaction. To better understand and improve the catalysts, a density functional theory (DFT) study of the Heck reaction has been performed at the B3LYP/6-31G* level of theory, complemented by M06/def2-TZVP single-point calculations. Different mechanistic pathways have been investigated and compared to available experimental results. The most likely mechanism is a cationic catalytic cycle involving the palladium oxidation states 0 and +II. We also looked at other oxidation states, but on the basis of the calculated Gibbs free energy a +II/+IV mechanism can be excluded. Aryl substitution with electron-donating groups at the para position (e.g., the methoxy group in [(H3CO-C6H4-Im)2CH2]PdBr2) was found to reduce the reaction barrier of the rate-determining step. This is in agreement with the experimental findings for the catalysts. The experimentally observed cis selectivity could also be explained by the DFT study.

Synthesis and photophysical studies of heteroaryl substituted-BODIPy derivatives for biological applications

Mono and di-heteroaryl-4,4′-difluoro-8-(aryl)-4-bora-3a,4a-diaza-s-indacene (BODIPy) (1–5) were synthesized using Suzuki–Miyaura couplings. Hetero aryl substitution on 3- or 3,5-positions caused large bathochromic shifts (up to ∼150nm) in absorption (569–652nm) and fluorescence maxima (586–679nm) in comparison to classical BODIPy. Quantum yields were found to be as high as 0.65. Singlet oxygen production activities of these compounds were studied by monitoring the absorbance quenching of 1,3-diphenylisobenzofuran, on exposure to light (>600nm). Cellular uptake of compound 4 was demonstrated using cervical cancer cells and fibroblast cell line and was confirmed by the images obtained using confocal microscope.

Copper(I) Halides (X = Br, I) Coordinated to Bis(arylthio)methane Ligands: Aryl Substitution and Halide Effects on the Dimensionality, Cluster Size, and Luminescence Properties of the Coordination Polymers

Bis(phenylthio)methane (L1) reacts with CuI to yield the 1D-coordination polymer [{Cu4(μ3-I)4}(μ-L1)2]n (1) bearing cubane Cu4I4 clusters as connecting nodes. The crystal structures at 115, 155, 195, and 235 K provided evidence for a phase transition changing from the monoclinic space group C2/c to P21/c. The self-assembly process of CuI with bis(p-tolylthio)methane (L2), bis(4-methoxyphenylthio)methane (L3), and bis(4-bromo-phenylthio)methane (L4) affords the 1D-coordination polymers [{Cu4(μ3-I)4}(μ-Lx)2]n (x = 2, 3, or 4). Compounds 2 and 4 are isostructural with C2/c low temperature polymorph of 1, whereas the inversion centers and 2-fold axes are lost in 3 (space group Cc). The use of bis(m-tolylthio)methane (L5) has no impact on the composition and overall topology of the resulting 1D ribbon of [{Cu4(μ3-I)4}(μ-L5)2]n (5). Even the coordination of the sterically crowded dithioether bis(5-tert-butyl-2-methylphenylthio)methane (L8) does not alter the network topology generating the 1D polymer [{Cu4(μ3-I)4}(μ-L8)2]n (8). The 1D polymer [{Cu(μ2-Br)2Cu}(L1)2] (9) results from the coordination of L1 with CuBr in a 1:1 metal-to-ligand ratio. In contrast to the mean Cu···Cu distances, which are <2.8 Å noted for the Cu4(μ3-I)4 clusters in the 1D polymers 1–8, the Cu···Cu contact within the Cu(μ2-Br)2Cu rhomboids of 9 [2.9194(8) Å] is above the sum of the van der Waals radii of two Cu atoms. The structural arrangement of 1D polymer [{Cu(μ2-Br)2Cu}(L3)2]n (11) is quite similar to that of 9. While the reaction of CuBr with L5 results in a similar 1D polymer [{Cu(μ2-Br)2Cu}(L5)2]n (12), the reaction of CuBr with L2 leads to the dinuclear complex [{Cu(μ2-Br)2Cu}(η1-L2)4] (10) ligated by four pendent bis(p-tolylthio)methane ligands. The ligation of bis(o-tolylthio)methane, L6, on CuBr also yields a discrete complex [{Cu(μ2-Br)2Cu}(MeCN)2(η1-L6)2] (13) bearing MeCN and dangling dithioether ligands. A strong luminescence is detected for all CuI polymers, all exhibiting emission lifetimes in the microsecond time scale (i.e., phosphorescence). The polymers containing the Cu4I4 core (1–8) exhibit the typically observed low-energy band and sometimes a weaker high-energy band. The nature of the low-energy band was proposed based on literature DFT and TDDFT computations and is predicted to be a mixture of cluster-centered (CC*) and metal/halide-to-ligand charger transfer (M/XLCT). An approximate relationship between the Cu···Cu distance and the emission maxima corroborates the CC* contribution to the nature of the excited states. The emission of the rhomboid-containing materials is assigned to M/XLCT based on literature works on similar motifs.

Enantioselective N-Allylic Alkylation of N-Propargylsulfonamides with Morita­–Baylis–Hillman Carbonates and Sequential Electrophilic Cyclization

The enantioselective <i>N</i>-allylic alkylation of <i>N</i>-propargylsulfonamides with racemic Morita–Baylis–Hillman (MBH) carbonates catalyzed by modified cinchona alkaloids has been investigated. The alkylation products from MBH carbonates with a 4-methoxyphenyl group underwent <i>ipso</i>-iodocyclization to give optically active azaspirocyclohexadienones via electrophilic activation of alkyne group with iodine monochloride. In contrast, <i>ortho</i>-selective intramolecular Friedel–Crafts reaction occurred for intermediates from MBH carbonates with other electron-rich or neutral aryl or heteroaryl substitutions via the same activation strategy, delivering multifunctional 2-benzazepine frameworks in a highly enantioenriched­ form.

Synthesis of pyrazoline–thiazolidinone hybrids with trypanocidal activity

A series of novel 4-thiazolidinone–pyrazoline conjugates have been synthesized and tested for anti-Trypanosoma brucei activity. Screening data allowed us to identify five thiazolidinone–pyrazoline hybrids, which possess promising trypanocidal activity, with IC50 ≤ 1.2 μM. The highest active thiazolidinone–pyrazoline conjugates 3c and 6b (IC50 values of 0.6 μM and 0.7 μM, respectively) were 6-times more potent antitrypanosomal agents than nifurtimox. In addition, these compounds, as well as 6d and 6e had selectivity index higher than 50, and were more selective than nifurtimox. SAR study included substituent variations at the pyrazoline moiety, modifications of N3 position of the thiazolidinone portion, elongation of the linker between the heterocycles, as well as rhodanine–isorhodanine isomerism. It was also shown that methyl or aryl substitution at the thiazolidinone N3-position is crucial for trypanocidal activity.