Smiles rearrangement for the synthesis of 5-amino-substituted [1]benzothieno[2,3-b]pyridine

The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/electrocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate. The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide structure mimic, was successfully achieved.     

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.     

Synthesis of maleopimaric and citraconopimaric acids N-[3-(pyrimidin-2-yl)aryl]amides

Acylation of 6-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine, 4-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine, and N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine with maleopimaric and citraconopimaric acid chlorides, with benzotriazolyl maleopimarate afforded N-[3-(pyrimidin-2-yl)aryl]amides of maleopimaric and citraconopimaric acids. By the reaction of substituted N-arylamides of maleopimaric acid with methanesulfonic acid biologically active methanesulfonates were obtained.     

Synthesis of new N-aryl oxindoles as intermediates for pharmacologically active compounds

Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active 2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles.     

Synthesis of pyrimidinyl arylglycines through subsequent Mitsunobu and Petasis reactions

The synthesis of highly functionalized pyrimidinyl arylglycines is presented. The highlight in our synthetic sequence includes selective O-alkylation of 2-(benzylsulfanyl)-4(3H)-pyrimidinones with N-Boc β-aminoalcohols under Mitsunobu conditions, Petasis reaction with glyoxylic acid and phenylboronic acid and nucleophilic ipso-substitution of the activated sulfur with morpholine. The unexpected spontaneous Smiles rearrangement of several pyrimidinyl amines is also discussed.     

Electroreductive five- and six-membered cyclization of aromatic β- and γ-imino esters derived from (S)-aspartic acid and (S)-glutamic acid

The electroreduction of aromatic β-dimethylcarbamoyl-β-imino esters, prepared from (S)-aspartic acid, in the presence of chlorotrimethylsilane gave five-membered cyclized products, 1-benzoyl-4-hydroxy-5-aryl-N,N-dimethylpyrrolidine-2-carboxamides and 5-(dimethylcarbamoyl)-2-aryl-1H-pyrrol-3-yl benzoates, depending on the post-treatment after the electroreduction. The electroreduction of aromatic γ-dialkylcarbamoyl-γ-imino and γ-methoxylmethyl-γ-imino esters, prepared from (S)-glutamic acid, and following transformation gave six-membered cyclized products, 1-benzoyl-5-hydroxy-N,N-dialkyl-6-phenylpiperidine-2-carboxamides and 3-hydroxy-6-(methoxymethyl)-2-phenylpiperidin-1-yl)(phenyl)methanones, respectively.     

N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

Application of directed metalation in synthesis. Part 8: Interesting example of chemoselectivity in the synthesis of thioaurones and hydroxy ketones and a novel anionic ortho-Fries rearrangement used as a tool in the synthesis of thienopyranones and thiafluorenones

Chemoselective synthesis of thioaurones or 3-hydroxy benzo[b]thiophen-2-aryl ketones, 1-hydroxy naphtho[2,1-b]thiophen-2-aryl ketones and chalcones from N,N-diethyl-ortho-methyl sulfanyl aryl amides were described. (Benzo[b]thiophen-2-yl) alkylates and (naphtho[2,1-b]thiophen-2-yl) alkylates undergo a novel anionic ortho-Fries rearrangement leading to (3-hydroxy benzo[b]thiophen-2-yl) and (1-hydroxy naphtho[2,1-b]thiophen-2-yl) alkyl ketones. The hydroxy ketones were used as intermediates in the synthesis of wide range of benzothienopyranones and thiafluorenones.     

Maleic acid derivatives in the synthesis of 3-substituted 3,4-dihydroquinoxalin-2(1H)-ones

A process for preparing 3-substituted 3,4-dihydroquinoxalin-2(1H)-ones is proposed. It is based on the reaction of o-phenylenediamine with amides, di- and mono-esters of maleic acid as well as (E)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)acrylic acid in the presence of N,N′-carbonyl-diimidazole.     

New atropoisomeric alkenylphenylglycine derivatives: Synthesis of (5R*)- and (5S*)-isomers of (1R*,3aR*,4S*,11S*)-3a,5,9,11-tetramethyl-4,5-dihydro-3aH-1,4-methano[1,3]oxazolo[3,2-a]quinolin-2-one

We synthesized methyl ester of N-(1-methylbut-2-en-1-yl)-N-phenylglycine which underwent acid catalyzed aromatic amino Claisen rearrangement to provide methyl-N-[2-(1-methylbut-2-en-1-yl)phenyl]glycinate. A mixture of syn- and anti-atropisomeric methyl-N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycinates was obtained either by the reaction of this ester with acetyl bromide or by the reaction of the sodium salt of N-acetyl-2-(1-methylbut-2-en-1-yl)-4-methylaniline with methyl bromoacetate. Upon saponification of the synthesized ester mixture the syn-atropisomer of N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycine was isolated by fractional crystallization. Treatment of the obtained acids with acetic anhydride, ethyl chloroformate, dicyclohexylcarbodiimide or isopropenylacetate leads to compounds of 4,5-dihydro-3aH-methano[1,3]oxazolo[3,2-a]quinolin-2-one structure.     

Synthesis of a new series of ditopic proligands for metal salts: differing regiochemistry of electrophilic attack at 3{5}-amino-5{3}-(pyrid-2-yl)-1H-pyrazole

An improved synthesis of 3{5}-amino-5{3}-(pyrid-2-yl)-1H-pyrazole (I) is described, which affords the compound on a multi-gram scale. Reaction of I with acid chloride and isothiocyanate electrophiles in MeCN cleanly results in attack at its amino group, yielding N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)amide and N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)thiourea products. These are good candidates as proligands for the simultaneous complexation of metal cations and anions. However, treatment of I with isocyanates under the same conditions instead yields attack at the pyrazole ring, giving 3-(pyridin-2-yl)-5-aminopyrazole-1-carboxylic acid amides as the only isolable products. The differing regiochemistries of these reactions were confirmed by ¹H NMR and X-ray crystallography.     

Synthesis and Biological Activity of Compounds Obtained by Reacting Methyl Aroylpyruvates with Sulfadimidine

The reaction of methyl aroylpyruvates and 2-(4-aminobenzenesulfamido)-4,6-dimethylpyrimidine in glacial acetic acid in the presence of anhydrous sodium acetate afforded (2Z)-4-aryl-2-hydroxy-N-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-4-oxobut-2-enamides. Reaction of the above reagents in a mixture of acetic acid and ethanol (1: 1) in the absence of anhydrous sodium acetate gave methyl (2Z)-4-aryl-2-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenylamino}-4-oxobut-2-enoates. Analgesic and anti-inflammatory activities of the synthesized compounds was studied.     

Six-Step Continuous Flow Synthesis of Diclofenac Sodium via Cascade Etherification/Smiles Rearrangement Strategy: Tackling the Issues of Batch Processing

Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2-chloro-N-phenylacetamide and 2,6-dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205 min.     

A mild, expedient, one-pot trifluoromethanesulfonic anhydride mediated synthesis of N-arylimidates

The direct transformation of various secondary amides into N-arylimidates via mild electrophilic amide activation with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of 2-chloropyridine (2-ClPyr) is described. Low-temperature amide activation followed by C-O bond formation with 2-naphthol provides the desired N-arylimidates in short overall reaction times. In contrast, reaction with oxindole proceeds via formation of a C-C bond to give 1-(1H-indol-2-yl)naphthalene-2-ol.     

Cascade Transformations of (2,2-Diaryl-3,3-dichloroaziridin-1-yl)acetates

Esters of (2,2-diaryl-3,3-dichloroaziridin-1-yl)acetic acid prepared from glycine derivatives under alkylation conditions afford esters of 2-[N-alkyl-N-(2,2-diaryl-1-cyanovinyl)amino]-3,3-diarylacrylic acid in 20-40% yield. The reaction resulting in these compounds proceeds through a cascade of 3-chloro-2-azadiene and ylide intermediates. 3-Chloro-2-azadienes originating from (2,2-diaryl-3,3-dichloroaziridin-1-yl)acetates react with primary and secondary amines at the carbon atom of imine group providing ketenimines which undergo ketenimine-nitrile rearrangement or fragmentation. The other bases (KOH, MeONa, DBU) effect dehydrochlorination of the mentioned 3-chloro-2-azadienes giving nitrile-ylides which are trapped by nucleophilic reagents. The 3-chloro-2-azadiene obtained from methyl (2,2-diaryl-3,3-dichloroaziridin-1-yl)acetate and DBU was relatively stable and was isolated as an individual compound. (2,2-diaryl-3,3-dichloroaziridin-1-yl)propionates behave as nonfunctionalized dichloroaziridines.     

The chemistry of polycyclic arene imines. VII. Reactions of phenanthrene 9,10-imine with aromatic carboxaldehydes,carboxylic acids and acetylenic esters

The reactions of phenanthrene 9,10-imine ( 1 ) with aromatic aldehydes, benzoic acids and acetylenedi-carboxylic esters were investigated. The aldehydes were shown to give 1-[N-(arylmethylidene)-9-phenanthreneamine-10-yl]-1a,9b-dihydrophenanthro[9,10-b]azirine 2. The ‘dimeric’ structure of these products was established by X-ray diffraction analysis. The carboxylic acids proved to form in the presence of dicyclohexylcarbodiimide, N-aroylphenanthrene 9,10-imines 7 , that readily undergo rearrangement to N-aroyl-9-phenanthrenamines 8. Esters of acetylenedicarboxylic acid gave the corresponding esters of (Z)-2-(1a,9b-dihydrophenanthro[9,10-b]azirine-1-yl)-2-butendioic acid 10 .     

N-(2-formyl-1-methylimidazol-4-yl)-2,2-dimethylpropanamide: a versatile reagent for preparing imidazole-amine ligands with variable second-coordination spheres

Two synthetic pathways to N-(2-formyl-1-methylimidazol-4-yl)-2,2-dimethylpropanamide from 1-methyl-2-carboxaldehyde are described. The reagent serves as a useful synthon for reductive amination reactions with primary and secondary amines in the presence of sodium cyanoborohydride to yield a series of ligands with second coordination sphere functional groups. Protocols for the syntheses of related imidazole synthons functionalized in the 4-position with amino acids, Schiff bases, and other amides are also reported.     

Preparation of methano[1,3]oxazolo[3,2-a]quinolin-2-ones from 2-(pent-3-en-2-yl)anilines

Acid-catalyzed Claisen aromatic rearrangement of ethyl N-(pent-3-en-2-yl)-N-phenylglycinate leads to the formation of ethyl N-[2-(pent-3-en-2-yl)phenyl]glycinate. The reaction of sodium salt of N-acetyl-2-(pent-3-en-2-yl)-4-methylaniline with methyl bromoacetate afforded ethyl N-acetyl-N-[4-methyl-2-(pent-3-en-2-yl)phenyl]glycinate. The hydrolysis of synthesized esters, the conversion of the obtained acids by treating with ethyl chloroformate into munchnones, and the subsequent [3+2]-cycloaddition provided methoxazoloquinoline structures.     

Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium cyclization and O-N Smiles rearrangement

The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O-N Smiles rearrangement. The present cascade exhibited a different profile compared to the previously reported ones, which consisted of N-N Smiles rearrangement. Lewis acid (TiCl₄) under carefully controlled conditions was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives with potential biological activities.     

Facile synthesis of pseudo-C-glycosyl p-amino-dl-phenylalanine building blocks via Amadori rearrangement

We studied the synthesis of pseudo-C-glycosyl amino acid via an Amadori rearrangement in aqueous solution using unprotected d-lactose and a tyrosine analogue: the p-amino-dl-phenylalanine. Two steps were necessary. In the first step, the N-glycosylation of d-lactose was carried out in aqueous conditions. The synthesized N-glycosylamine was stabilized in a second step by the formation of Amadori compound, the N-[β-d-galactosyl-1-4-(1-deoxyfructos-1-yl)]-p-amino-dl-phenylalanine. Products were purified and characterized by mass spectrometry and by ¹H and ¹³C NMR. The influence of the temperature, the pH, the nature of acid and the concentration of the acid on the synthesis yield was examined in order to determine the optimum conditions of Amadori rearrangement. In the best conditions, 35% of p-amino-dl-phenylalanine was converted into N-[β-d-galactosyl-1-4-(1-deoxyfructos-1-yl)]-p-amino-dl-phenylalanine. For the N-glycosylation, a specific base catalysis took place in the media whereas a general acid catalysis was observed for the Amadori rearrangement using weak acids and with a temperature close to 75 °C. The Amadori compound from glucose [N-(1-deoxyfructopyranos-1-yl)-p-amino-dl-phenylalanine] was also synthesized and characterized by mass spectrometry and by ¹H and ¹³C NMR.