Direct alkenylation of arylamines at the ortho-position with magnesium alkylidene carbenoids and some theoretical studies of the reactions

1-Chlorovinyl p-tolyl sulfoxides were synthesized from ketones and chloromethyl p-tolyl sulfoxide in high yields. Treatment of the sulfoxides with isopropylmagnesium chloride at −78 °C in toluene gave magnesium alkylidene carbenoids (α-chloro alkenylmagnesium chlorides), which were treated with N-lithio arylamines to afford ortho-alkenylated arylamines in moderate yields. The reaction, in some cases, proceeded in a highly stereospecific manner at the carbon bearing the chlorine and the sulfinyl group. The structures of the α-chloro alkenylmagnesium chlorides and the reactivity of the N-lithio meta-substituted anilines were studied at the B3LYP and MP2 levels of theory with the 6-31(+)G* basis set. This reaction offers a quite novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.     

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.     

Rh(I)-catalyzed solvent-free ortho-alkylation of aromatic imines under microwave irradiation

The synthesis of ortho-alkylated ketones through a chelation-assisted Rh (I) catalyzed ortho-alkylation reaction of aromatic imines under microwave activated solvent-free conditions in monomode reactors was performed. These conditions have been also applied to hydroacylation and ortho-alkylation reactions with aldimines.     

Cyclopropylation of arylamines at the 2-position with cyclopropylmagnesium carbenoids

Direct cyclopropylation of arylamines at the 2-position with 1-chlorocyclopropyl phenyl sulfoxides was achieved. The reaction of N-lithio arylamines with cyclopropylmagnesium carbenoids, which are generated from 1-chlorocyclopropyl phenyl sulfoxides with i-PrMgCl via the sulfoxide-magnesium exchange reaction, is the key of this procedure. This method offers an unprecedented way for the synthesis of arylamines having a cyclopropane ring at the 2-position directly from arylamines.     

Selective hydrodechlorination of fluorinated arylamines

Chlorine-containing polyfluorinated anilines and meta-phenylenediamines undergo selective hydrodechlorination easily upon reduction by zinc in aqueous ammonia. A new approach is thus provided to synthetically valuable, partially fluorinated arylamines based on utilizing polyfluorochloroarenes, which are available as intermediates of perfluoroarene production from perchloroarenes. When chlorine atoms are present in positions both ortho and para to the amino group, para chlorine is initially eliminated. Based on this reaction, a one-pot synthesis of partially fluorinated 4-aminopyridines from 3,5-dichlorotrifluoro- and 3-chlorotetrafluoropyridine has been realized.     

Lithiation of 2-(chloroaryl)-2-methyl-1,3-dioxolanes and application in synthesis of new ortho-functionalized acetophenone derivatives

2-(4-Chlorophenyl)-2-methyl-1,3-dioxolane 2a was lithiated ortho to the ketal group by treatment with butyllithium in THF at 0°C. Related 2-aryl-2-methyl-1,3-dioxolanes possessing a chlorine substituent at the meta position of the aryl group 2b,c were lithiated with butyllithium in THF at −78°C at the position between the two directing groups. The lithio species thus generated were treated with various electrophiles to give ortho-functionalized acetophenone derivatives.     

An efficient synthesis of ortho-N-Boc-arylmethyl ketone derivatives

A new and efficient method for the preparation of ortho-N-Boc-arylmethyl ketone derivatives is reported. The reaction involves the intermediacy of a 4-methylene-3,1-benzoaxin-2-one moiety which smoothly converts to the target compounds under acidic conditions. The ortho-N-Boc-arylmethyl ketone derivatives can be formed in a one-pot reaction or alternatively the 4-methylene-3,1-benzoaxin-2-ones can be isolated and subsequently transformed into the desired products.     

Reaction of magnesium carbenoids with N-lithio arylamines: a novel method for generation of non-stabilized α-amino-substituted carbanions and a new synthesis of α-amino acid derivatives

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature afforded magnesium carbenoids in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines and N-lithio arylamines. The reaction with N-lithio alkylamines afforded an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. The reaction with N-lithio arylamines gave the adducts, α-amino-substituted carbanions, in good yields. From these intermediates, a novel synthesis of α-amino acid derivatives and N,N-dialkyl arylamines having a deuterium at the α-position was realized.     

An efficient catalyst for the synthesis of ortho-substituted biaryls by the Suzuki cross-coupling: Triphenylphosphine adduct of cyclopalladated ferrocenylimine

The air and moisture stable triphenylphosphine adduct of cyclopalladated ferrocenylimine 2 has been successfully used in palladium-catalyzed Suzuki cross-coupling for the synthesis of ortho-substituted biaryls in air. In the presence of 0.05 mol% of 2 as catalyst and 3 equivalent of CsF as base in dioxane at 100 °C, ortho-substituted biaryls were synthesized with moderate to high yields in the reactions of 2-methoxy-1-naphthylboronic acid with aryl halides, and 14 new ortho-substituted biaryls were obtained and characterized.     

AuCl-catalyzed reaction of ortho-alkynyl(oxo)benzene with benzenediazonium 2-carboxylate as a synthetic method towards anthracene, triptycene, and phthalazine derivatives

The AuCl-catalyzed benzannulation of ortho-alkynylphenyl ketones with benzenediazonium 2-carboxylate proceeded efficiently at 40 °C in (CH₂Cl)₂ and a variety of anthracene derivatives, having a ketone group at 9-position, were produced in good to high yields. On the other hand, the reaction of ortho-alkynylbenzaldehydes with benzenediazonium 2-carboxylate afforded triptycyl ketones. The reactions most probably proceed through the formation of a zwitterionic intermediate by the gold-induced electrophilic cyclization of ortho-alkynyl(oxo)benzenes, followed by the cycloaddition of benzyne. In contrast, when the above reaction was carried out at rt in 1,4-dioxane, phthalazine derivative was produced without the generation of benzyne.     

GaCl3-Catalyzed ortho-ethynylation reaction of N-benzylanilines

Lithiated N-benzylanilines were ethynylated at the ortho-position with silylchloroethyne at 120 °C in the presence of a catalytic amount of GaCl₃. Trimethylsilylated N-methylaniline could also be used for this transformation.     

Expeditious synthesis of 3,4-dihydroisocoumarins and phthalides using the Heck-Matsuda reaction

Several 3,4-dihydroisocoumarins and phthalides were synthesized by an effective Heck-Matsuda reaction involving an ortho carboxybenzenediazonium salt with a series of styrenes bearing electron donating and electron withdrawing groups, methylvinyl ketone, and methyl acrylate. The reaction was carried out in an open-flask with 1% mol of palladium acetate in aqueous ethanol at ∼80 °C, giving the correspondent 3-aryl-3,4-dihydroisocoumarins and phthalides with good overall yields. The electronic nature of the group attached to the olefin is a key feature for the regioselectivity of the cyclization step.     

2-Halogeno-N-phenacylimidazolium salts and their reactions with active methylene species,arylamines and thiocyanate ions

This study describes the reactivity of 2-halogeno-N-phenacylimidazolium salts towards active methylene species, arylamines and thiocyanate ions. The 2-chloro-N-phenacylimidazolium salt undergoes unexpected reactions in the presence of active methylene species and a tertiary amine as the base. The reaction of 2-bromo-N-phenacylimidazolium salts with arylamines led to a mixture of the corresponding 2-(arylamino)-N-phenacylimidazolium salts and imidazolone. The reaction of 2-bromo-N-phenacylimidazolium bromide with KSCN led to the corresponding imidazole-2-thione. The crystal structures of five compounds are reported.     

Stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines to maleimides

A library of 15 1,6,7,9-tetrasubstituted 6,7,9,9a-tetrahydro-5H-pyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3,5(2H,3aH)-triones was prepared by combinatorial stereoselective cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines to N-substituted maleimides. Stereochemistry was controlled by the stereodirecting phenyl group at position-3 and by the ortho-substituents at the aromatic ring at position-1′ in azomethine imines. Consequently, two sets of diastereomeric cycloadducts were obtained, one set from the ortho-unsubstituted dipoles and the other set from the ortho-disubstituted dipoles.     

An effective procedure for the preparation of 3-substituted-4- or 6-azaindoles from ortho-methyl nitro pyridines

3-Substituted-4- and 6-azaindoles were prepared from ortho-methyl-nitropyridines in a practically convenient, one-pot process based on the Leimgruber-Batcho reaction. The procedure comprises a sequence of (a) condensation of an ortho-methyl-nitropyridine with N,N-dimethylformamide dimethyl acetal; (b) alkylation or acylation of the enamine intermediate; (c) reduction of the nitro group to an aniline with in situ cyclization and elimination of dimethylamine to generate the 3-substituted azaindole heterocycle.     

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.     

Synthesis of 1,2-dihydroisoquinolines via the reaction of ortho-alkynylarylimines with bis-π-allylpalladium

The reaction of the ortho-alkynylarylimines 1 with allyltributylstannane and allyl chloride in the presence of allylpalladium chloride dimer (5 mol %) and Cu(OAc)₂ (20 mol %) in CH₃CN at 50 °C gave the 1,4-diallyl-1,2-dihydroisoquinolines 2 in good yields. Most probably, the reaction proceeds through tandem bis-allylation of the imine-alkyne functional groups with bis-π-allylpalladium.     

Efficient synthesis of phosphorylated ortho-fused azaheterocycles

A simple and efficient two-step synthesis of various ortho-fused azaheterocycles, containing phosphorylated pyrimidinones as a parent component, was accomplished by the reaction of 2-diethoxyphosphoryl-3-methoxyacrylate with heteroaromatic amines followed by intramolecular N-acylation of the obtained substitution products. Optimization studies performed for the N-acylation reaction revealed that heating the addition products in Dowtherm A at 250 °C gave the best results. The same conditions applied in the intramolecular cyclization of ethyl 2-diethoxyphosphoryl-3-aminophenylacrylate gave expected product of the electrophilic aromatic substitution, but in low yield.     

An efficient microwave-assisted solvent-free synthesis of pyrido-fused ring systems applying the tert-amino effect

Significant improvements in the synthesis of pyrido-fused heterocycles were observed when performing the reaction under solvent-free conditions, applying the tert-amino effect as the key ring closure methodology. An unexpected cyclization of ortho-(1′-azacycloalkyl)benzaldehydes has been studied in water and on solid support.