Directed regioselective ortho,ortho′-magnesiations of aromatics and heterocycles using sBu2Mg in toluene

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base sBu₂Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several double ortho,ortho′-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes.

A toluene solution of sBu₂Mg allowed a regioselective ortho-magnesiation of aromatic and heterocyclic systems. A second ortho,ortho′-functionalization was achieved in the case of aryl oxazolines, N-aryl pyrazoles as well as N-aryl triazoles.     

Synthesis of chiral,non-racemic ferrocene derivatives by ortho-metallation and partial reductive removal of ortho-directing amino groups

Chiral, non-racemic 1,2-disubstituted ferrocenes have been prepared from monosubstituted ferrocene derivatives by amine-mediated ortho-directed reactions and subsequent partial reductive removal of the stereogenic ortho-directing group. It was found that the ortho-directing amino group of 2-substituted derivatives of N,N-dimethylaminoethyl-ferrocene and similar compounds can, after quaternisation with methyl iodide, be reductively removed with sodium borohydride to give 2-substituted methyl- or ethylferrocenes. In most cases the substituents I, Br, COOEt, P(O)Ph₂ and CN tolerate the reaction conditions used. In addition, a few examples are reported that show how the use of LiTMP allows 2-bromo- and especially 2-cyano-substituted derivatives to be further ortho-lithiated and reacted to give 1,2,3-trisubstituted ferrocenes.     

Chemical behavior of ortho-hydroquinone-based bis(pyrazol-1-yl)methane ligands in the presence of palladium(II) chloride

The synthesis, structural characterization, and coordination behavior of ditopic ortho-hydroquinone-based bis(pyrazol-1-yl)methane ligands (ortho-(OH)₂C₆H₃-4-CHpz₂, ortho-(OH)₂C₆H₃-4-CH(3-Phpz)₂, and ortho-(OH)₂C₆H₃-4-CH(3-tBupz)₂) with pyrazole, 3-phenylpyrazole, and 3-tert-butylpyrazole as donors are described. The reaction of a soluble PdCl₂-source with ortho-(OH)₂C₆H₃-4-CHpz₂ in acetonitrile yielded the related square-planar N,N-coordinated Pd(II) dichloride complex, whereas treatment of ortho-(OH)₂C₆H₃-4-CH(3-Phpz)₂ or ortho-(OH)₂C₆H₃-4-CH(3-tBupz)₂ with PdCl₂ in acetonitrile resulted in degradation of these ligands. The Pd(II) complexes trans-(3-PhpzH)₂PdCl₂ and trans-(3-tBupzH)₂PdCl₂ were isolated and fully characterized including X-ray diffraction analyses.     

Copper-catalyzed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones from ortho-bromobenzamides and isothiocyanates

Copper-catalyzed tandem reaction of ortho-bromobenzamides and isothiocyanates is described, which provides an efficient and practical route for the synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones. The optimal condition involved the following parameters: CuI as precatalyst, Cs₂CO₃ as base, N,N′-dimethylethane-1,2-diamine as ligand, and toluene as solvent, with reaction temperature at 120 °C.     

Synthesis of substituted salicylamines and dihydro-2H-1,3-benzoxazines

Phenols were converted to their magnesium salts with the MgCl₂-Et₃N base system and subsequently reacted with Eschenmoser's salt, affording N,N-dimethyl substituted benzylamines in high to excellent yields. A series of mono N-substituted benzylamines were prepared in one-pot syntheses by ortho-formylation of phenols to corresponding salicylaldehydes, which in turn reacted with amines to imines. The imines were subsequently reduced to mono N-substituted benzylamines. Some of these benzylamines were further converted, without work-up, to mono N-substituted dihydro-2H-1,3-benzoxazines.     

Transition-metal-free approach to synthesis of indolines from N-(ortho-chloromethyl)aryl amides and iodonium ylides

A transition-metal-free method for the synthesis of indolines has been developed. In the presence of K₂CO₃, the cyclization reaction of N-(ortho-chloromethyl)aryl amides and iodonium ylides proceeded smoothly at room temperature in moderate to good yields.     

Sterically Facilitated Intramolecular Nucleophilic NMe2 Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study

The influence of steric repulsion between the NMe₂ group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe₂ group’s intramolecular nucleophilic substitution is studied. Possible reaction intermediates for three mechanisms are calculated (ωB97xd/def-2-TZVP), and their free Gibbs energies are compared to model reaction profiles. Supporting experiments have proved the absence of studied reactivity in the case of simple 2-dimethylaminobenzaldoxime, which allowed us to establish reactivity limits. The significant facilitation of NMe₂ group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe₂ group in the aniline and naphthalene series is predicted.     

A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid-Lewis base bifunctional catalyst

A new family of bifunctional catalysts (N-oxides-Ti(OⁱPr)₄ (2:1)) containing a Lewis acid and a Lewis base was developed and applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex as catalysts, the cyanosilylation products were obtained in 42-97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex should promote the reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.     

Infrared spectroscopic study of the configuration of some alkylaryl ureas

The conformation of a series of 1-aryl-3-(n-butyl)ureas and 1-aryl-1-methyl-3-(n-butyl)-ureas having an orthohydroxyl group in the aromatic ring is studied by infrared spectroscopy. The spectral data show that in organic solvents (CHCl₃, CH₂Cl₂, CCl₄) the compounds are in a Z,Z-conformation. Conclusive evidence is obtained for the existence of an intramolecular hydrogen bond between the OH and CO groups in all N-methylated ureas.     

Structure-biodistribution relation of neutral Tc(CO)3-complexes with tridentate N-substituted derivatives of aminoethylglycine and phenylenediamine

Derivatives of ethylenediamine-N-acetic acid (EDAA = N-aminoethylglycine = AEG) and ortho-phenylenediamine-N-acetic acid (PDAA) with uncharged substituents on one or both of the amines form neutral complexes with a [^99mTc(CO)₃]⁺-moiety. We studied the influence of different modifications at the amines (e.g., with methyl, ethyl, butyl or benzyl groups) on the behaviour of the ^99mTc(CO)₃-complexes in vivo in mice, with special focus on blood-brain barrier (BBB) passage. The complexes have been characterised by reversed phase HPLC, log P, electrophoresis and some of them also by LC-MS. Log P values of the ^99mTc-tricarbonyl complexes varied from −0.52 (AEG) to 2.5 (N,N′-dibenzyl-EDAA). With increasing lipophilicity, more of the activity was found in liver and intestines as compared to kidneys and urine for the more polar complexes. Brain uptake was found for the ^99mTc(CO)₃-complexes with N,N′-dibutyl-ethylenediamine-N-acetic acid (0.34% of I.D. after 2 min) and ortho-phenylenediamine-N-acetic acid (0.22% of I.D. after 2 min).     

Shape- and stereo-selective esterase activities of cross-linked polymers imprinted with a transition-state analogue for the hydrolysis of amino acid esters

Various cross-linked (with N,N′-ethylene (C₂), butylene (C₄), hexamethylene (C₆), or decamethylene (C₁₀)-bisacrylamide) polymer catalysts containing l-histidine and quaternary trimethylammonium groups were imprinted with a racemic transition-state analogue of phenyl 1-benzyloxycarbonyl-3-methylpentylphosphonate for the hydrolysis of p-nitrophenyl N-(benzyloxycarbonyl)-l (or d)-leucinate (Z-l (or d)-Leu-PNP). Among these polymer catalysts, N,N′-C₄-bisacrylamide-cross-linked polymer catalyst, which was copolymerized with styrene monomer, exhibited the notable substrate-stereospecificity for the Z-l-Leu-PNP hydrolysis among the hydrolyses of enantiomeric l (or d)-N-protected (such as tert-butyloxycarbonyl (Boc-), acetyl (C₂-), decanoyl (C₁₀-) or benzyloxycarbonyl (Z-)) amino acid (Leu, Ala, or Phe) p-nitrophenyl esters in 10 vol.% MeCN-Tris buffer (pH 7.15) at 30°C.     

Decomposition of halophenols in room-temperature ionic liquids by ionizing radiation

In this article, we report the reaction of halophenols with solvated electrons in room-temperature ionic liquids (RTILs) initiated by γ-ray and pulsed electron radiolyses. The decomposition G-values of ortho-chlorophenol (CP) in N-methyl-N-propylpyrrolidinium–bis(trifluoromethanesulfonyl)imide (TFSI), N-butyl-N-methylpyrrolidinium–TFSI and N-methyl-N-propylpiperidinium–TFSI were estimated to be 1.4, 1.6, and 1.7 molecules 10^?2 eV^?1 under γ-ray irradiation; these values were almost the same as the yield of solvated electron formation. The second-order rate constant for the reaction of CP with solvated electrons in diethylmethyl(2-methoxyethyl)ammonium (DEMMA)–tetrafluoroborate (BF₄) was one order of magnitude lower than that in DEMMA–TFSI although the G-values of CP decomposition and phenol formation in DEMMA-BF₄ were higher. The decomposition yield of ortho-iodophenol in DEMMA–TFSI was slightly higher than that of the other halophenol (ortho-fluorophenol, CP, and ortho-bromophenol), and the formation yield of phenol for the decomposition of only ortho-fluorophenol was lower.     

2,2′-Bipyridyl formation from 2-arylpyridines through bimetallic diyttrium intermediate

An alkylyttrium complex supported by an N,N′-bis(2,6-diisopropylphenyl)ethylenediamido ligand, (ArNCH₂CH₂NAr)Y(CH₂SiMe₃)(THF)₂ (1, Ar = 2,6-ⁱPr₂C₆H₃), activated an ortho-phenyl C–H bond of 2-phenylpyridine (2a) to form a (2-pyridylphenyl)yttrium complex (3a) containing a five-membered metallacycle. Subsequently, a unique C(sp²)–C(sp²) coupling of 2-phenylpyridine proceeded through a bimetallic yttrium intermediate, derived from an intramolecular shift of the yttrium center to an ortho-position of the pyridine ring in 3a, to yield a bimetallic yttrium complex (4a) bridged by two-electron reduced 6,6′-diphenyl-2,2′-bipyridyl. Aryl substituents at the ortho-position of the pyridine ring were key in order to destabilize the μ,κ²-(C,N)-pyridyldiyttrium intermediate prior to the C(sp²)–C(sp²) bond formation.     

{Bis[N,N′-(2-alkyl-6-para-methylphenyl)phenyl)imino]acenaphthene}dibromonickel catalysts bearing bulky methylphenyl groups: synthesis,characterization, crystal structures and application in catalytic polymerization of ethylene and styrene

Two new Ni(II) complexes containing methylphenyl groups, {bis[N,N′-(2,6-dimethyl-4-p-methylphenylphenyl)imino]acenaphthene}dibromonickel 4a and {bis[N,N′-(2-ethyl-4,6-di(p-methylphenyl)phenyl)imino]acenaphthene}dibromonickel 4b, were synthesized and characterized. The molecular structures of both complexes were determined by single-crystal X-ray diffraction. Both complexes have pseudo-tetrahedral geometry about the nickel center, showing pseudo C _2v and C ₂ molecular symmetry, respectively. Complex 4c, {bis[N,N′-(2,4,6-trimethylphenyl)imino]acenaphthene}dibromonickel, was also synthesized for comparison. These complexes were tested as catalysts for the polymerization of ethylene and styrene under mild conditions using diethylaluminum chloride. The precatalyst 4b bearing one ortho-ethyl group and two bulky p-methylphenyl groups in the ortho- and para-aryl position of the ligand, displayed highly catalytic activity for the polymerization of ethylene [4.70 × 10⁶ g PE/(mol Ni h bar)], and produced branched polyethylene (76 methyl, 8 ethyl, 5 propyl and 22 butyl or longer branches/1,000 C at 60 °C). Interestingly, complex 4b also displays high catalytic activity [5.46 × 10⁵ g polystyrene/(mol Ni·h)] for styrene polymerization and produces nearly atactic polystyrene at 70 °C (stereo-triad distributions: rr, 39.9 %; mr, 30.4 %; mm, 29.8 %; stereo-diad distributions: r, 55.1 %; m, 44.9 %).     

Application of directed metalation in synthesis. Part 7: Synthesis of suitably functionalised benzo[b]thiophenes as key intermediates in the synthesis of benzothienopyranones

One-pot syntheses of (3-hydroxybenzo[b]thiophen-2-yl) aryl methanones from ortho-methylsulfanylaryl N,N-diethyl amides and of 1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone and 1-(3-hydroxybenzo[b]thiophen-2-yl)propan-1-one via an anionic ortho-Fries rearrangement are described. The hydroxy ketones were used as key intermediates in the synthesis of benzothienopyranones.     

Palladium catalyzed Suzuki-Miyaura coupling with aryl chlorides using a bulky phenanthryl N-heterocyclic carbene ligand

A novel bis-phenanthryl N-heterocyclic carbene (NHC) based palladium acetate catalyst was effective for the coupling of various aryl and vinyl chlorides with organoboron compounds. N,N-Bis-(2,9-dicyclohexyl-10-phenanthryl)-4,5-dihydroimidazolium chloride 8 (H₂ICP·HCl) with Pd(OAc)₂ and KF·18-c-6 in THF at room temperature gave Suzuki-Miyaura coupling of aryl and vinyl chorides, including unactivated and di-ortho substituted substrates in high yields. Hindered tri- and tetra-ortho substituted products were also efficiently produced. Benzyl chloride was also found to be a useful coupling partner and trimethylboroxine was used to give methylated products. The effect of ligand, base, temperature, solvent, and reaction time are reported along with various substrates including halides and triflates.     

Stereospecific co-crystallization of reactant and palladium complex in the resolution of stilbendiamine using N*-chiral ortho-palladated matrix

Resolution of racemic 1,2-diphenyl-1,2-ethanediamine was performed through recrystallization of its diastereomeric adducts 2a,b with N*-chiral ortho-palladated complex (S_CR_N)-1. The structure and absolute configuration of the less soluble (S_CR_N,SS)-2a diastereomer was determined by X-ray diffraction. The complex has an unusual dimeric structure with a palladacycle:diamine ratio of 2:3; the association of 2a with an additional diamine molecule of the same (SS) absolute configuration is achieved due to hydrogen bonds between the coordinated and solvate diamine.     

New protocol for allylic substitution with aryl and alkenyl copper reagents derived from organolithiums

Substitution of allylic picolinoates with copper reagents derived from sp²-carbon-lithiums and CuBr·Me₂S was established to furnish anti S_N2′ products with almost perfect regioselectivity and chirality transfer. The preparations of organolithiums such as lithium-halogen exchange and ortho lithiation were coupled to the substitution to install various sp²-carbon groups, which include Ph, 2,6-Me₂C₆H₃, 4-Me-2,6-(MOMO)C₆H₂, and cis and trans 1-heptenyl groups.     

An environmentally benign procedure for the Cu-catalyzed cyanation of aryl bromides

The development of a general Cu-catalyzed synthesis of (hetero)aromatic nitriles from the corresponding aryl bromides and potassium hexacyanoferrate(II) is described. This novel protocol avoids the use of highly toxic alkali cyanides and precious palladium catalysts. Best results were achieved applying Cu(BF₄)₂·6H₂O (0.1 equiv) and N,N′-dimethyl ethylenediamine (DMEDA; 1.0 equiv) in N,N-dimethyl acetamide (DMAc).     

Tris-(1,2-N,N-dimethylaminomethylferrocenyl)stibine and its heterotrimetallic complex

New tertiary chloro-bis(1,2-N,N-dimethylaminomethylferrocenyl)stibine (1) and tris-(1,2-N,N-dimethylaminomethylferrocenyl)stibine ligand (2) containing CH₂NMe₂ pendenant arm at the ortho-position have been synthesized. Stibine (2) reacts with PtCl₄^2? and hetero trimetallic cis-PtCl₂L (3) complex is obtained, where stibine (2) acts as a bidentate ligand. All these compounds were characterized by various physicochemical methods and their molecular structures were determined by X-ray diffraction analyses. It is to be noted that tris(1,2-aminomethylferrocenyl)stibine represents the first example of a structurally characterized ferrocenyl pnictogen where three 1,2-disubstituted ferrocenyl groups are attached to the central antimony atom and phosphorus analogue of the stibine is missing in the literature. Stibine (1) shows a hypervalent Sb–N interaction while stibine (2) does not show this interaction in solid state.