Ring opening of 2-(cyanomethyl)aziridines by acid chlorides: synthesis of novel 4-amino-2-butenenitrile derivatives through intermediate aziridinium salts

1-Arylmethyl-2-(cyanomethyl)aziridines were transformed into novel N-arylmethyl-N-(2-chloro-3-cyanopropyl)amides as the major reaction products upon treatment with acid chlorides in CH₂Cl₂ through the ring opening of intermediate aziridinium salts. Subsequently, N-arylmethyl-N-(2-chloro-3-cyanopropyl)amides were converted into stable N-arylmethyl-N-(3-cyano-2-propenyl)amides for the first time by means of a dehydrochlorination mediated by Et₃N in CH₂Cl₂.     

A new approach towards 2-amino-1-aryloxy-3-methoxypropanes from 1-arylmethyl-2-(bromomethyl)aziridines

1-Arylmethyl-2-(bromomethyl)azirdines were converted into the corresponding 2-(aryloxymethyl)aziridines upon treatment with the appropriate potassium phenoxides in DMF/acetone in excellent yields, followed by regioselective ring opening towards N,N-di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines using benzyl bromide in acetonitrile. Treatment of the latter β-bromoamines with sodium methoxide afforded the desired 2-amino-1-aryloxy-3-methoxypropanes as the major compounds (49-58%) besides the isomeric 3-amino-1-aryloxy-2-methoxypropanes in minor quantities (9-15%).     

New synthesis of propargylic amines from 2-(bromomethyl)aziridines. Intermediacy of 3-bromoazetidinium salts

A new, efficient, and straightforward synthesis provides propargylamines in high overall yields (64-77%) by transformation of 1-(arylmethyl)-2-(bromomethyl)aziridines into N,N-di(arylmethyl)-N-(2-propynyl)amines via N-(2,3-dibromopropyl)amines and N-(2-bromo-2-propenyl)amines. The conversion of N-(2,3-dibromopropyl)amines into N-(2-bromo-2-propenyl)amines is based on a novel analogue of the Hofmann elimination. A Yamaguchi-Hirao alkylation, a Sonogashira coupling, or a hydroarylation reaction further functionalized these propargylamines toward potentially interesting compounds for medicinal and agrochemical use.     

Synthesis of (E)-4-(4-chlorobenzylidene)-3,4-dihydro-2H-pyrrole-based pyrrolinium salts

Pyrrolinium salts containing 3-arylidene fragment were obtained. Their synthesis is based on the reaction of (E)-4-(4-chlorobenzylidene)-3,4-dihydro-2H-pyrrole with various bromo-alkanes. Structures of the obtained compounds were confirmed by a set of physico-chemical analysis methods.

     

Enantioselective synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles from 2-iminochromenes

A series of medicinally important 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles were synthesized using enantioselective conjugate addition of nitromethane to 2-iminochromenes. The reactions were performed using L8-Cu (II) catalytic system and moderate to good enantioselectivities (62–88%) and yields (66–96%) were obtained.     

Synthesis of 1-arylmethyl-2-(cyanomethyl)aziridines and their ring transformation into methyl N-(2-cyanocyclopropyl)benzimidates

1-Arylmethyl-2-(cyanomethyl)aziridines were prepared in high yields from the corresponding 2-(bromomethyl)aziridines upon treatment with potassium cyanide in DMSO. Ring opening of the aziridine moiety with N-chlorosuccinimide in CCl4 and subsequent treatment of the thus formed 4-chloro-3-(N-chloro-N-(alpha,alpha-dichlorobenzyl)amino)butanenitriles with sodium methoxide in methanol resulted in novel methyl N-(2-chloro-1-(cyanomethyl)ethyl)benzimidates, although in low yields. The latter gamma-chloro nitriles were smoothly converted into methyl N-(2-cyanocyclopropyl)benzimidates as precursors of biologically relevant beta-ACC derivatives through a 1,3-cyclization protocol by reaction with potassium tert-butoxide in THF.     

Novel synthesis of 2-amino-3-hetaryl-4(5H)-oxothiophenes

3-Cyano-3-hetaryl-2-oxopropyl thioacetates were obtained by the acylation of hetarylacetonitriles with acetylmercaptoacetyl chloride. Their reaction with amines led to the formation of 2-amino-3-hetaryl-4(H)-oxothiophenes. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 680–685, May, 2006.     

A simple approach to the synthesis of 2-(2-amino-4-arylthiazol-5-yl)pyrimidines

The synthesis of 2-(2-amino-4-arylthiazol-5-yl)pyrimidin-4(3H)-ones from the available 2-(2-oxo-2-arylethylidene)-2,3-dihydropyrimidin-4(1H)-ones was developed.     

Electrochemical synthesis of 6-amino-5-(3,4-dihydroxyphenyl) pyrimidine

Electrochemical oxidation of several catechols is studied in the presence of 4(6)-aminouracil (3a) and 6-amino-1,3-dimethyl uracil (3b) as nucleophiles in aqueous solution using cyclic voltammetry and controlled-potential coulometry. The results reveal that quinones derived from catechols participate in Michael additions with 3a and 3b to give the corresponding catecholamine derivatives via an electron transfer followed by chemical reaction (EC) mechanistic pathway in good yields and purities.     

Reaction between 4-oxoalkane-1,1,2,2-tetracarbonitriles and morpholine: regioselective synthesis of 5-amino-2-(morpholin-4-yl)-3-(2-oxoalkyl)-3H-pyrrol-3,4-dicarbonitriles

A new approach to the regioselective synthesis of polyfunctional 3H-pyrroles from 4-oxoalkane-1,1,2,2-tetracarbonitriles is described. 5-Amino-3-(2-aryl-2-oxoethyl)-3H-pyrrol-3,4-dicarbonitriles are prepared from 4-aryl-4-oxobutane-1,1,2,2-tetracarbonitriles. Diastereomeric 5-amino-2-morpholin-4-yl-3-(2-oxocyclohexyl)-3H-pyrrole-3,4-dicarbonitriles were obtained from 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarbonitriles.     

Enantioselective one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes

An enantioselective one-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes via a Knoevenagel/Pinner/Friedel-Crafts reaction of salicylaldehyde, malononitrile, and indole is presented. Moderate to good yields (up to 89%) and high enantioselectivities (up to 90% ee) were obtained with an N,N'-dioxide-Zn(II) complex as the catalyst. This strategy provides an efficient and convenient method to access enantiomerically enriched 2-amino-4H-chromene derivatives.     

Asymmetric synthesis of nonproteinogenic amino acids with l-amino acid transaminase: synthesis of (2S)-2-amino-4-oxo-4-phenylbutyric and (3E,2S)-2-amino-4-phenylbutenoic acids

2,4-Dioxo-4-phenylbutyric acid and 2-oxo-4-phenylbut-3-enoic acid are converted to the corresponding (S)-2-amino acids by recombinant Escherichia coli whole cells over-expressing aromatic transaminase from Enterobacter sp. BK2K-1 (AroATEs) in high yields (68–78%) and high enantiomeric purity (>99%) using l-aspartic acid as an amino donor.     

One-step synthesis of the tricyclic core of martinellic acid from 2-(cyanomethyl)-3-oxo-N-arylbutanamides

A SnCl4.5H2O-mediated facile and efficient one-step synthesis of the tricyclic core of martinellic acid from readily available 2-(cyanomethyl)-3-oxo-N-arylbutanamides was developed and a mechanism involving consecutive hydrolysis of a cyano group and a double annulation process is proposed.     

Chemo-enzymatic synthesis of (R)- and (S)-3,4-dichlorophenylbutanolide intermediate in the synthesis of sertraline

3,4-Dichlorophenacylchloride was reduced with whole cell biocatalysts to give the (R)- or (S)-chlorohydrine in high yields and good to high enantiomeric excess. Yields and enantiomeric purity of the (S)-enantiomer were increased to 95 and >98%, respectively, using growing cells from Geotrichum candidum (CBS 233.76) in the presence of hydrophobic adsorbing resins at 4 g/l. The latter compound was transformed into (R)-3,4-dichlorophenylbutanolide, intermediate in the synthesis of (+)-cis-1S,4S-sertraline.     

Synthesis of Novel 2-(4-Oxo-3,4- Dihydroquinazolin-2-Ylsulfinylmethyl)-3H-Quinazolin-4-One

Abstract

Condensation of 2-mercapto-3H-quinazolin-4-one (1) with chloroacetic acid gave 4-oxo-3,4-dihydroquinazoline-2-yl-sulfanyl)-acetic acid (2) that with anthranilamide (3) gave 2-(4-oxo-3,4-dihydroquinazolin-2-ylsulfanylmethyl)-3H-quinazolin-4-one (4). Oxidation of 4 with sodium hypochlorite in alkaline medium gave the novel product, 2-(4-oxo-3,4- dihydroquinazolin-2-ylsulfinyl methyl)-3H -quinazolin-4-one) (5). The entire sequences of reactions in this work have been carried out using eco-friendly solvents and green conditions.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

One-step synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')- 2H,4H-dihydropyrazolo[3,4-b]pyrans

Three-component condensation of 4-piperidinones (7), 5-pyrazolones (8), and malononitrile (4) proceeds chemically and electrochemically and is a convenient one-step means of synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')-2H,4H-dihydropyrazolo[3,4-b]pyrans (12). The electrochemical reactions proceed under milder conditions and with yields 12-15% greater than those of the reactions catalyzed by chemical bases.     

The synthesis and biological activity of new 7-[2-(cyanomethyl)piperazinyl]- and 7-[3-(cyanomethyl)piperazinyl]quinolone antibacterials

Some novel 7-[2- or 3-(cyanomethyl)piperazinyl]quinolones have been prepared. Most notable, 2-cyanomethyl-piperazine 5 and 1-methyl-2-cyanomethylpiperazine 8 at the quinolone C-7 position produce products with good in vitro antibacterial activity. The key step in the synthesis of these products involves the regioselective deprotection of the benzyl group in function of the time reaction.     

Novel synthesis of 2-aminopentanedinitriles from 2-(bromomethyl)aziridines and their transformation into 2-imino-5-methoxypyrrolidines and 5-methoxypyrrolidin-2-ones

1-Arylmethyl-2-(bromomethyl)aziridines were transformed into 2-[N-(arylmethyl)amino]pentanedinitriles upon treatment with an excess of potassium cyanide in DMSO through an unprecedented and peculiar reaction mechanism, involving base-induced ring opening of intermediate 2-(cyanomethyl)aziridines into allylamines, followed by migration of the double bond out of the conjugation towards aldimines via enamine intermediates. The resulting aminopentanedinitriles served as substrates for the synthesis of novel 2-imino-5-methoxypyrrolidines upon treatment with sodium methoxide in methanol, which were either acetylated at the free imino group to afford the more stable N-acetylimino derivatives or hydrolyzed towards the corresponding synthetically relevant 5-methoxypyrrolidin-2-ones.     

Copper(II) halide salts and complexes of 4-amino-2-fluoropyridine: synthesis,structure and magnetic properties

Reaction of 4-amino-2-fluoropyridine (2-F-4-AP) with copper halides produced the neutral coordination complexes: (2-F-4-AP)₂CuX₂ (X = Cl(1), Br(2)). 1 crystallizes in the orthorhombic space group Pccn in a distorted square planar geometry. Magnetic susceptibility data were fit to the uniform chain Heisenberg model resulting in C = 0.439(6)emu-K/mole-Oe and J = ?28(1) K. 2 crystallizes in the monoclinic space group C2/m and is closer to distorted tetrahedral. Intermolecular Br?Cu contacts generate a square layer. Magnetic data show very weak ferromagnetic interactions [C = 0.42(1)emu-K/mol-Oe, J = 0.71(2) K]. Similarly, reaction of 2-F-4-AP with copper halides and aqueous HX in alcohol solvents produced the salts (2-F-4-APH)₂CuX₄ (X = Cl(3), Br(4)). 3 crystallizes in the triclinic space group P-1. Crystal packing reveals short Cl?Cl contacts which generate a structural ladder. However, analysis of the magnetic data suggests that only the rails of the ladder produce a viable magnetic superexchange pathway; the uniform Heisenberg chain model provides C = 0.449(1)emu-K/mol-Oe and J = -6.9(1) K. 4 is isostructural and is also best fit by a chain model [J = ?2.7(4) K]. The brominated complex (2-F-3-Br-4-APH)₂CuBr₄·2H₂O, 5, (2-F-3-Br-4-APH = 4-amino-3-bromo-2-fluoropyridinium) was serendipitously produced as a byproduct of the synthesis of 4 and was characterized by single-crystal X-ray diffraction.     

Straightforward synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone

An efficient and straightforward approach towards the synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone via imination, α-chlorination, hydride reduction and ring closure was developed. In addition, novel primary β-iodo amines were obtained by regioselective ring opening of these 2-(trifluoromethyl)aziridines using alkyl iodides, and their synthetic potential was demonstrated by converting them into novel α-CF(3)-β-phenylethylamines upon treatment with lithium diphenylcuprate.