Ortho Substituents Research Articles

Di-tert-butyl thiopyridazine boratrane complexes of Co, Ni and Cu

The thiopyridazine based scorpionate ligand sodium tris(3,5-di-tert-butyl-6-thioxopyridazin-1(6H)-yl)hydroborate (NaTntBu,tBu) with two tert-butyl substituents in ortho- and para-position of the thio group was synthesized and fully characterized. Corresponding metallaboratrane complexes [M{B(PntBu,tBu)3}Cl] (M=Co, Ni, Cu) as well as [M{B(PnMe,tBu)3}Cl] (M=Co, Ni) were prepared in good yields. All complexes were characterized by spectroscopic means as well as by single crystal X-ray diffraction studies exhibiting short metal boron bonds (between 2.0186(17)Å and 2.069(3)Å) compared to previously reported boratranes. The two tert-butyl groups attached to the heterocycle significantly increases the solubility of NaTntBu,tBu and the derived metal complexes in apolar solvents compared to the system bearing the smaller substituents. The higher steric demand of the tert-butyl versus methyl group enhances the distortion from trigonal bipyramidal towards square pyramidal which effects the electronic situation within the complexes evidenced by the elongated metal chlorine bond trans to boron.

Preparation of an N-sec-alkyl 2,6-disubstituted aniline: a key intermediate in the divergent synthesis of S-Metolachlor metabolites

A simple method to prepare a 2,6-disubstituted aniline containing a N-sec-alkyl group and a carbonyl on one ortho substituent is reported. This method was used to accomplish the first synthesis of side chain oxidized ethylsulfonic acid (ESA) and oxanilic acid (OXA) metabolites of S-Metolachlor (S-Moc) herbicide. The 2,6-disubstituted aniline functionality was installed by a Sugasawa reaction of readily available ortho-toluidine. The N-sec alkyl group was introduced by a Mitsunobu alkylation of the nosyl-activated 2-acetyl-6-methyl-substituted aniline. This crucial step enabled access to the key 2,6-disubstituted aniline intermediate which was used in the divergent synthesis of S-Moc metabolites. A bioinspired synthesis of the keto-ESA metabolite was achieved in one step from the hydroxyl-ESA metabolite using a ruthenium-catalyzed oxidation. [Display omitted]

Nucleophilic aromatic substitution in chlorinated aromatic systems with a glutathione thiolate model

The conjugation of glutathione with chlorobenzene and di-, tri-, tetra-, and hexa-chlorinated benzenes via nucleophilic aromatic substitution was modeled for isolated reacting species by ab initio molecular orbital theory to provide an understanding of the intrinsic reactivity of unactivated chloroaromatic systems. Computations at the HF/6-31+G(d,p) level were augmented with electron correlation corrections using MP2 theory and density functional theory at the B3LYP level. Features of the reaction hypersurface were elaborated using thiolate (thiomethoxide) as the model for an enzyme-activated glutathione molecule. Unlike the similar reaction with 1-chloro-2, 4-dinitrobenzene a known substrate with glutathione, no σ-complex or Meisenheimer complex was isolated as a true intermediate on the hypersurface. Instead, the σ-complex appears as a transition state, preceded and followed by two ion-molecule complexes in which the approaching and departing anions reside in the plane of the aromatic ring. Solvent calculations show a very similar hypersurface landscape with only one transition state and no intermediate. Activation energies are somewhat greater than for 1-chloro-2, 4-dinitrobenzene owing to the lack of nitro substituents, which provide stabilization in these systems. Nevertheless, activation energies calculated at correlated levels indicate that these reactions are still feasible and consistent with experiment. Transition states and activation energies for dichlorobenzenes and polychlorobenzenes are lower in energy than for chlorobenzene implying greater stability conferred to the transition state by ortho and para substituents.

Enantioselective hydroformylation of 2- and 4-substituted styrenes with PtCl2[(R)-BINAP] + SnCl2 ‘in situ’ catalyst

Two sets of styrenes possessing various substituents either in ortho or para position were hydroformylated in the presence of ‘in situ’ catalyst formed from PtCl2[(R)-BINAP] and tin(II) chloride. The reversal of the absolute configuration of the preferred enantiomers was observed using both sets of substrates by the variation of the reaction temperature in the range of 40–100 °C. In case of the 4-substituted styrenes, the reversal temperature of the enantioselectivity shows correlation with the Hammett substituent constants, i.e., with the electron donor or electron acceptor properties of the para-substituents. This phenomenon was explained by the reversible formation of the Pt-branched alkyl intermediates, leading to the corresponding (R)- and (S)-enantiomers of 2-arylpropanals.Strong substituent effect on the regioselectivity was observed in the hydroformylation of 2-substituted styrenes: the presence of substituents characterised by larger steric parameter resulted in the highly favoured formation of the linear aldehyde. For instance, regioselectivities of 45%, 22% and 7% towards branched aldehyde were obtained with styrene, 2-fluoro- and 2-bromostyrene, respectively, at 80 °C reaction temperature. In addition to the characteristic change of regioselectivity, the reversal of absolute configuration as a function of reaction temperature was also observed.

ChemInform Abstract: Divergent Reaction Pathways in Gold‐Catalyzed Cycloisomerization of 1,5‐Enynes Containing a Cyclopropane Ring: Dramatic ortho Substituent and Temperature Effects.

A gold(I)-catalyzed cycloisomerization of easily available 1,5-enynes containing a cyclopropane ring has been developed, efficiently providing cyclobutane-fused 1,4-cyclohexadiene, tricyclic cyclobutene, biscyclopropane and 1,3-cyclohexadiene derivatives in moderate to excellent yields. When the phenyl group was not ortho substituted, 1,4-cyclohexadienes could be produced. With an ortho substituent, three different products could be selectively synthesized by control of the temperature and the used gold(I) catalyst. The 1,5-enyne substrate first undergoes a classical enyne cycloisomerization to form a tricyclic cyclobutene key intermediate, which undergoes subsequent transformation to produce the desired products. A plausible reaction mechanism was proposed according to deuterium labeling experiments and intermediate trapping experiments, as well as DFT calculations. In our current reaction, the ortho substituent on the phenyl group controls the reaction outcome and the ortho substituent effect was found to originate from steric and electronic factors.

Investigations into the reactivity of lithium indenyl with alpha diimines with chlorinated backbones and formation of related functional ligands and metal complexes

Reaction between lithium indenyl and a chlorine substituted alpha diimine of the form [{Cl(NPh)2}C)]2 unexpectedly yielded the corresponding NH rearranged derivative [PhN(H)C(C9H6)]2 (1) rather than the predicted symmetrical α-diimine. This compound 1 was characterised by 1H NMR, 13C{1H} NMR and mass spectrometry, and additionally by X-ray diffraction. It was found that 1 was the first indene-substituted and symmetric secondary amine which was also highly fluorescent in DMSO. The reactivity of 1 towards simple inorganic and organometallic transition metals precursors based on the MX2 fragments, where M=Group 10 metals and X=halides or methyl groups, has been investigated. Surprisingly, the reaction with [PtMe2(COD)] led to the coupling reaction between the indenyl groups incorporated at the C–C ligand backbone and a new ligand (2) was discovered, in an attempt to synthesise the metal-linked diamine. Single crystal X-ray diffraction studies confirm this compound 2 to feature coupled indenyl residues and delocalised C–C bonds in the solid state. Structural authentication by X-ray crystallography showed compound 2 to be a very rare example of flat and extended aromatic organic molecule and mass spectrometry, IR and NMR spectroscopy were carried out to gain further insight into the solid state and solution phase structures. Further experiments to synthesise analogues of [PhN(H)C(Ind)]2 aiming to shift a likely equilibrium in favour the imine tautomer, by introducing bulky ortho substituents onto the benzene ring (R=Me, iPr) showed the presence of the imine tautomer to be increasingly favoured in 1H NMR spectra, with an increase in the steric bulk of the ortho substituents. However, the enamine tautomer is still observed to a minor extent even with isopropyl substituents and yields of these desired compounds were low on steric grounds.

ChemInform Abstract: Rhodium‐Catalyzed Atroposelective [2 + 2 + 2] Cycloaddition of ortho‐Substituted Phenyl Diynes with Nitriles: Effect of ortho Substituents on Regio‐ and Enantioselectivity.

AbstractThe regio‐ and enantioselectivity of the title cycloaddition highly depends on ortho‐substituents on the phenyl group of the diynes.

SYNTHESIS OF 2,1-BENZISOXAZOLES (MICROREVIEW)

This microreview summarizes data published over the past 10 years devoted to the synthesis of substituted 2,1-benzisoxazoles. The major synthetic approaches aim at increasing either the electrophilicity or nucleophilicity of ortho substituents or other substrates. Ortho-substituted aryl azides, anilines, nitroso- and nitrobenzenes were used as starting compounds. Authors: Budruev, A. V.; Dzhons, D. Yu.

Synthesis of 2,1-benzisoxazoles (microreview)

This microreview summarizes data published over the past 10 years devoted to the synthesis of substituted 2,1-benzisoxazoles. The major synthetic approaches aim at increasing either the electrophilicity or nucleophilicity of ortho substituents or other substrates. Ortho-substituted aryl azides, anilines, nitroso- and nitrobenzenes were used as starting compounds.

Conformational Transformations in Aromatic Nitroso Oxides.

A systematic theoretical study on conformational transformations of monosubstituted (ortho- and para-) aromatic nitroso oxides R-C6H4NOO was performed. The existence of two rotation axes enables two types of conformational transitions in substituted arylnitroso oxides: trans/cis (rotation around the N-O bond) and syn/anti (rotation around the C-N bond, which is important in ortho isomers). The complete set of conformers was localized for R-C6H4NOO using four selected density functional (M06-L, mPWPW91, OLYP, and HCTH) and augmented polarization basis set of triple splitting. It was found that the activation enthalpy of the trans-cis conformational transition is nearly insensitive to the nature of R and ranges within 58-60 kJ/mol for para isomers. The ortho substituent has an insignificant effect on ΔH(≠)trans→cis: it increases this value by ∼5 kJ/mol in syn isomers and decreases it by ∼3 kJ/mol in anti isomers. On the contrary, the syn-anti conformational barrier is considerably affected by the substituent R; an increase in the electron-withdrawing properties of R decreases ΔH(≠)syn→anti. The activation enthalpies grow with increasing polarity of the solvent, as it was found using IEFPCM calculation. The values of relaxation time for all conformational equilibria were calculated and compared with known lifetimes of aromatic nitroso oxides. Our results suggest that syn/anti transitions occur fast enough in the scale of the experimental lifetime. However, trans/cis transformations proceed more slowly. And under certain conditions discussed in the paper, the rate of this conformational transition limits that of irreversible decay of nitroso oxide.

A new ligand H4Lox and its iron(III) complex as a platform for the development of heterotrimetallic complexes

The combination of multiple metal ions of different nature, in a single coordination compound, can provide a unique set of properties suitable for applications such as mimetization of the active site of enzymatic systems, development of new molecular magnetic materials and catalysts for photoinduced water splitting. Nonetheless, the preparation of heteromultimetallic complexes, in a controlled way, is a challenging task. In this work, we present a new ligand, H4Lox, designed as a platform for the synthesis of heterotrimetallic complexes. From H4Lox and its precursor H2L, two mononuclear iron(III) complexes, [Fe(L)]NO3·MeOH·2H2O (1) [Fe(H2Lox)]NO3·XH2O (2) were synthesized and fully characterized. The structure of 2 revealed a N2O2 vacant coordination site comprised by two phenolate oxygen atoms and two oxime nitrogen atoms. DFT calculations and ESI-MS data demonstrate that complex 2 can accommodate two additional metal ions, in a stable heterotrimetallic complex. The effect of the ortho substituents of the phenolate groups (CHO and CNOH) in the electronic states of 1 and 2, respectively, was evaluated by UV–Vis spectroscopy, cyclic voltammetry and DFT calculations. A free energy correlation was found between the calculated electrophilicity index ω and the experimental half wave potentials of 1, 2 and their analogous complex [Fe(bbpen-Me)]+ [33]. The electrophilicity index ω was used to estimate the FeIII/FeII redox potential of the hypothetical [FeZnCl2(Lox)Ga(tpa)]2+ complex.

Aldol Reactions of Axially Chiral 5-Methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones.

Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products.

Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents

Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity.

Nucleophilic Aromatic Substitution Reactions for the Synthesis of Ferrocenyl Aryl Ethers

A range of ferrocenyl aryl ethers of type Fc–O–Ar (Fc = Fe(η5-C5H5)(η5-C5HnX4–n); n = 2–4; X = H, P(O)(OEt)2, SO2CF3; Ar = 2,4-(NO2)2-C6H3, 4-NO2-C6H4) have been successfully prepared by using the nucleophilic aromatic substitution reaction (SNAr) of Fc–OLi (1a–Li) and electron-deficient aryl fluorides, enabling a new pathway to this rarely described family of organometallic compounds. Initial studies of 1a–Li and o-phosphonato-substituted hydroxyferrocenes (1b–Li) have also been performed, indicating a low nucleophilicity of the oxygen atom. The SNAr reaction protocol tolerates ortho substituents, e.g. phosphonato and sulfonyl groups, resulting in 1,2-X,O (X = S, P) ferrocenyl ethers that can be obtained in a one-pot synthesis procedure including 1,3-O → C anionic phospho- and thia-Fries rearrangements. Within these studies, the first 1,3-diortho-functionalized ferrocenyl aryl ether could be synthesized. An electrochemical study of the redox potentials of the obtained compounds allows conclusions on the reactivity of the varying electronic properties and the electrophilicity of different aryl fluorides and the nucleophilicity of the functionalized hydroxyl ferrocenes, which is directly reflected by the potential of the first ferrocene related redox processes. Chiral-pool-based phosphonates rearrange to the aryl ethers with diastereomeric excesses of 74 and 81% after the anionic Fries rearrangement. The usage of aryl 1,2-/1,3-difluorides resulted in the synthesis of the first examples of bis(FcO)-substituted benzenes. Their electrochemical investigations reveal a splitting of the two redox processes of the ferrocenyls that decreases from 155 mV (1,2-substitution) to 130 mV (1,3-substitution) on the basis of electrostatic interactions.

Rhodium-Catalyzed Atroposelective [2 + 2 + 2] Cycloaddition of Ortho-Substituted Phenyl Diynes with Nitriles: Effect of Ortho Substituents on Regio- and Enantioselectivity.

Axially chiral 3-(2-halophenyl)pyridines were successfully synthesized in high yields with excellent enantioselectivity by the cationic rhodium(I)/(S)-H8-BINAP complex-catalyzed atroposelective [2 + 2 + 2] cycloaddition of (o-halophenyl)diynes with nitriles. Interestingly, regio- and enantioselectivity highly depend on ortho substituents on the phenyl group of diynes. When the ortho substituents were methoxy and methoxycarbonyl groups, axially chiral 3-arylpyridines were obtained as a major product, while enantioselectivity was lowered significantly. On the other hand, when the ortho substituents were alkyl groups, regioselectivity was switched to give achiral 6-arylpyridines in high yields.

ChemInform Abstract: Hypervalent Activation as a Key Step for Dehydrogenative ortho C—C Coupling of Iodoarenes.

Building on earlier results, a direct metal-free α-arylation of substituted cyclic 1,3-diones using ArI(O2CCF3)2 reagents has been developed; unlike other arylative approaches, the arylated products retain the iodine substituent ortho to the newly formed C-C bond. The mechanism is explored by using DFT calculations, which show a vanishingly small activation barrier for the C-C bond-forming step. In fact, taking advantage of an efficient in situ hypervalent activation, the iodoarenes are shown to undergo a cross-dehydrogenative C-C coupling at the C-H ortho to the iodine. When Oxone is used as terminal oxidant, the process is found to benefit from a rapid initial formation of the hypervalent ArI(OR)2 species and the sulfate-accelerated final coupling with a ketone. This method complements the ipso selectivity obtained in the metal-catalyzed α-arylation of carbonyl compounds.

Synthesis, structures and catalytic activity of 1,3-bis(aryl)triazenide(p-cymene)ruthenium(II) complexes

The synthesis, characterization, crystal structures and catalytic activity of four new 1,3-bis(aryl)triazenide(p-cymene)ruthenium(II) complexes bearing methoxycarbonyl (5), hydroxymethyl (6), acetylphenyl (7) in the ortho position, and methyl in the para position (8) of the bis(aryl)triazenide ligand are reported. These complexes were used as catalysts in the transfer hydrogenation reactions of ketones and alkenone with good to excellent yields of the corresponding alcohol. Remarkable differences in yields were obtained with those complexes with ortho substituents on the aryl group of the triazenide ligand (5–7) compared to that without ortho substituent (8). Good selectivity was also observed in the reduction of the alkenone towards the carbonyl group.

ChemInform Abstract: Synthesis of Terphenyl Derivatives by Pd‐Catalyzed Suzuki—Miyaura Reaction of Dibromobenzene Using 2N2O‐Salen as a Ligand in Aqueous Solution.

A simple and efficient catalytic system for Na2PdCl4 catalyzing the Suzuki-Miyaura reaction of dibromobenzene and arylboronic acid has been developed by using 2N2O-salen as a ligand in H2O/EtOH (V:V=4:1) at 100°C. Using this method, the reactions of substrates containing sterically demanding ortho substituents (e.g. dibromobenzene and/or arylboronic acids) proceeded efficiently, with the corresponding terphenyl derivatives being produced in moderate to excellent yields. Furthermore, this method offers interesting features for the multi-gram scale synthesis of terphenyl compound.

Highly Active and Isospecific Styrene Polymerization Catalyzed by Zirconium Complexes Bearing Aryl-substituted [OSSO]-Type Bis(phenolate) Ligands.

[OSSO]-type dibenzyl zirconium(IV) complexes 9 and 10 possessing aryl substituents ortho to the phenoxide moieties (ortho substituents, phenyl and 2,6-dimethylphenyl (Dmp)) were synthesized and characterized. Upon activation with dMAO (dried methylaluminoxane), complex 9 was found to promote highly isospecific styrene polymerizations ([mm] = 97.5%–99%) with high molecular weights Mw up to 181,000 g·mmol−1. When the Dmp-substituted pre-catalyst 10/dMAO system was used, the highest activity, over 7700 g·mmol(10)−1·h−1, was recorded involving the formation of precisely isospecific polystyrenes of [mm] more than 99%.

Divergent reaction pathways in gold-catalyzed cycloisomerization of 1,5-enynes containing a cyclopropane ring: dramatic ortho substituent and temperature effects.

A gold(i)-catalyzed cycloisomerization of easily available 1,5-enynes containing a cyclopropane ring has been developed, efficiently providing cyclobutane-fused 1,4-cyclohexadiene, tricyclic cyclobutene, biscyclopropane and 1,3-cyclohexadiene derivatives in moderate to excellent yields. When the phenyl group was not ortho substituted, 1,4-cyclohexadienes could be produced. With an ortho substituent, three different products could be selectively synthesized by control of the temperature and the used gold(i) catalyst. The 1,5-enyne substrate first undergoes a classical enyne cycloisomerization to form a tricyclic cyclobutene key intermediate, which undergoes subsequent transformation to produce the desired products. A plausible reaction mechanism was proposed according to deuterium labeling experiments and intermediate trapping experiments, as well as DFT calculations. In our current reaction, the ortho substituent on the phenyl group controls the reaction outcome and the ortho substituent effect was found to originate from steric and electronic factors.