4-Functionally-substituted 3-heterylpyrazoles: XVI. 3-(3-Arylpyrazol-4-yl)propyonic acids

Bromination of 3-(3-arylpyrazol-4-yl)acrylic acids led to the formation of 2-bromo-3-(3-arylpyrazol-4-yl)acrylic acids that were converted into 3-(3-arylpyrazol-4-yl)propynoic acids by treatment of potassium hydroxide with an alcoholic solution.     

Polyfunctional pyrazoles. 4. Synthesis of 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]acrylic and-propionic acids

3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids are converted by Knoevenagel condensation under conditions of microwave activation into 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]acrylic acids. Reduction of the latter with hydrazine hydrate in the presence of Raney nickel gives 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]propionic acids. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 686–690, May, 2006.     

Synthesis of 2-Deoxy-2-[(3R)-3-Hydroxyacyl]Amino-4-O-Phosphono-3-O-[(3R)-3-Tetradecanoyloxytetradecanoyl]-D-Glucopyranose Derivatives Related to Bacterial Lipid A

ABSTRACT

Lipid A subunit analogs, the 4-O-phosphono-D-glucosamine derivatives (14-16: GLA 93-95) which carry 2-N-linked 3-hydroxyacyl groups, were synthesized. 2-(Trimethylsilyl)ethyl 2-amino-2-deoxy-4,6-O-isopropylidene-ß-D-glucopyranoside (1) was transformed into 2-(trimethylsilyl)ethyl 2-amino-6-O-tert-butyldimethylsilyl-2-deoxy-4-O-diphenylphosphono-3-O-[(3R)-3-tetradecanoyloxytetradecanoyl]-ß-D-glucopyranoside (7) through several steps. N-Acylation of 7 with 3-hydroxyl fatty acids gave the corresponding 8-10, which were converted, via the cleavage of protecting groups, into a series of desired compounds.     

Functionally Substituted 3-Heterylpyrazoles: XI. 3-[3-Aryl(heteryl)pyrazol-4-yl]propenoic and Propanoic acids

3-Aryl(heteryl)-4-formylpyrazoles by condensation with malonic acid furnish 3-[3-aryl(heteryl)- pyrazol-4-yl]propenoic acids that in the presence of Raney nickel are reduced by hydrazine hydrate to 3-[3-aryl(heteryl)pyrazol-4-yl]propanoic acids. The successive conversion of both type acids into the corresponding acyl chlorides, esters, and amides was performed.     

Polyfunctional pyrazoles. 3.* Synthesis of 3-(3-aryl-4-formyl-1-pyrazolyl)propionic acids and their amides

3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids were synthesized by the reaction of 3-aryl-1-(2-cyanoethyl)-4-formylpyrazoles with concentrated hydrochloric acid. They were converted into the corresponding amides by the carbodiimide method.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1483–1486, October, 2004.For Communication 2, see [1].     

Synthesis of novel 1-phenyl-1H-indole-2-carboxylic acids. II. Preparation of 3-dialkylamino, 3-alkylthio, 3-alkylsulfinyl,and 3-alkylsulfonyl derivatives

The synthesis of novel indole-2-carboxylic acids with amino- and sulfur-containing substituents in the indole 3-position is described. An Ullmann reaction with bromobenzene converted 1H-indoles with 3-(acetylamino)- and 3-(diethylamino)-substituents into 1-phenyl-1H-indoles. Reaction of 3-unsubstituted indoles with thionyl chloride provided indole 3-sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.     

Recent Applications of α-Metalated Isocyanides in Organic Synthesis

Being both nucleophilic and electrophilic, α-metalated isocyanides can add to polar double bonds, forming heterocycles. They are also synthons for α-metalated primary amines. This article describes recent or improved procedures for their use in organic synthesis: (1) In heterocyclic syntheses to give 2-oxazolines, 2-imidazolines, 2-thiazolines, oxazoles and oligooxazoles, thiazoles, triazoles, imidazolinones, pyrroles, 5,6-dihydro-1,3-oxazines and -thiazines, and (via cycloaddition with nitrones) 2-imidazolidinones. (2) In the field of formylaminomethylenation, for example transformation of estrone methyl ether and a keto sugar into the corresponding α-formylaminoacrylic esters, and the conversion of aldehydes and ketones by 3- and 4-pyridyl-methyl isocyanides into N-(1-pyridyl-1-alkenyl)formamides and their hydrolysis to 3- and 4-acylpyridines. (3) In connection with the use of α-metalated isocyanides as synthons for α-metalated primary amines, the author demonstrates how they may be used for preparation of 1,2- and 1,3-amino alcohols, 1,2-diamines, 2,3-diaminoalkanoic acids and for synthesis of higher amino acids starting from simple amino acids.     

The first synthesis of 3-nitro-4-[(s-tetrazin-3-yl)amino]furazans

Oxidation of 3-amino-4-[(s-tetrazin-3-yl)amino]furazans with peroxy acids or 30% H2O2/Na2WO4/H2SO4 system results in transformation of the amino group into the nitro one and is accompanied by formation of N-oxides at tetrazine moiety.     

Novel approach to the synthesis of 3-acyl substituted indolizines. The synthesis of 3-(indolizinyl-2)alanine and 4-(indolizinyl-3) homoalanine derivatives

A novel approach to the synthesis of 3-acylindolizines and the transformations of some acids into tryptophane analogues are described. Reaction of ethyl 2-pyridinylacetate and methyl 2-quinolinylacetate with N-trifluoroacetyl-5-bromo-4-oxonorvaline methylester led to N-trifluoroacetyl-3-(1-ethoxycarbonylindolizinyl-2) alanine methyl ester and N-trifluoroacetyl-3-(3-methoxycarbonylpyrrolo [1,2-a]quinolinyl-2) alanine methyl ester, respectively. Treatment of ethyl 2-pyridinylacetate and 2-pyridinylacetonitrile, first with N,N-dimethylformamide dimethyl acetal (DMFDMA), followed by reaction with phenacyl bromide, gave the corresponding 3-benzoylindolizines, while the reaction of ethyl 2-pyridinylacetate and 2-pyridinylacetonitrile with DMFDMA, followed by treatment with (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester, gave the corresponding N-trifluoroacetyl-4-oxo-4-(indolizinyl-3)homoalanine methyl esters.     

γγ-Disubstituted Itaconic Acids. Part 1. The Stobbe condensation of 1-arylnaphthyl ketones with diethyl succinate

Arylnaphthyl ketones condense with diethyl succinate yielding the stereoisomeric half-esters 2a–2d which were subjected to a series of reactions leading to 1-phenylphenanthrene and 1,1′-binaphthyl derivatives. (E)-3-Ethoxycarbonyl-4-(4-methoxynaphth-1-yl)-4-arylbut-3-enoic acids ( 2b–d ) were converted finally into the corresponding naphtho[1,2-c]fluorenones ( 9 ). The structure of the products was established by IR. and UV. spectroscopy. The effect of substituents on the relative proportions of (E)- and (Z)-half-esters 2 was determined by chromatography and UV. spectroscopy.     

Synthesis and Reaction of 2-Mercapto-3-Arylpropanoic Acids

Abstract

Two synthetic pathways for the preparation of 2-mercapto-3-arylpropanoic acids were developed. First, by the reaction of arenediazonium bromides with acrylic esters in the presence of CuBr, alkyl (2-bromo-3-aryl)propanoates were formed. Their cyclization with thiourea produced 5-(R-benzyl)-2-imino-4-thiazolidinones, which yielded 3-aryl-2-mercaptopropanoic acids by alkaline hydrolysis. Second, direct Meerwein arylation of acrylates in the presence of S-nucleophile (NaSH) allowed isolation of 3-phenyl-2-mercaptopropanoic acid in 8% yield. Such acids were used for cyclization with cyanoguanidine and phenyl isothiocyanate yielding 1-[5-(R-benzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidines and new 5-(R-benzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (rhodanine) derivatives correspondingly.     

A Short Synthesis of Allene- and [3] Cumulenecarboxylates

It is shown that carboxylic acids, in the presence of Bu₃N and 2-chloro-1-methylpyridinium iodide in toluene or CH₂Cl₂, react with [(alkoxycarbonyl)methylidene]phosphoranes to yield the corresponding esters of allene carboxylic acids (ef. Scheme 1 and Table 1). This procedure can also be applied to cinnamic acids which form [3]cumulenecarboxylates in low yield (Table 3). Under the same conditions 4-methyl-2-pentynoic acid can be transformed into (2E)-4-chloro-2,6-dimethylhepta-2,4,5-trienoate (Scheme 4).     

Synthesis and Characterization of Di-[3-(Trimethylsilyl)-1-Propylene] Alkylenediphosphonic Acids

A homologous series of alkylenediphosphonic acids was successfully esterified with 3-(trimethylsilyl)-1-propanol to the symmetrically-substituted diesters. The procedure, which has general applicability for incorporating silicon heteroatoms into diphosphonic acids, utilizes the esterification reagent dicyclohexyl-carbodiimide (DCC) to activate the acid. The aggregation properties of the di-[3-(trimethylsilyl)-1-propylene] alkylenediphosphonic acids were measured in toluene and 1-decanol.     

Dehydration of 3- and 4-aryl- substituted 3-hydroxy acids in acetic anhydride in presence of zinc chloride

The reaction of several di- and triaryl-substituted 3-aryl-3-hydroxy acids and a 4-aryl-3-hydroxy acid in acetic anhydride in the presence of anhydrous zinc chloride has been investigated. It has been shown that the reaction discovered with 3-(2′-thienyl)-substituted 3-hydroxy acids, namely, their conversion under the above stated conditions into α, β-unsaturated methyl ketones,^1,2 occurs also with 3-aryl 3-hydroxy acids but to a smaller degree due to the concurrent cyclization reaction which leads to indene-1-ones. It has been established that the unsaturated methyl-ketones obtained, containing three aromatic substituents at the CC bond, exist in s-cis-(CC, CO)-conformation. It has been found that with the 4-aryl-substituted 3-hydroxy acid almost no unsaturated ketone is obtained, whereas instead the main product is a 2,3-disubstituted 1-naphthol which is acetylated under the conditions of the reaction. Its structure has been proved by its UV, IR and NMR spectra and confirmed by the mass spectrum of the compound.     

2-(3-Acetylamino-2,2-dimethylcyclobutyl)-methyl-4(3H)-quinazolinones

Beckmann rearrangement of N-[3-(1-hydroxyimino)ethyl-2,2-dimethylcyclobutyl]acetylanthranilic acid, and its 5-bromo and 4-chloro derivatives gives the corresponding N-(3-acetylamino-2,2-dimethylcyclobutyl)acetylanthranilic acids. Treatment of these acylanthranilic acids with formamide gives 2-(3-acetylamino-2,2-dimethylcyclobutyl)methyl-4(3H)-quinazoline and its 6-bromo and 7-chloro derivatives.     

A new method for the synthesis of N-substituted (4-oxo-4,5,6,7-tetrahydroindol-3-yl)acetic acids

A new method for the synthesis of N-substituted 2-(4-oxo-4,5,6,7-tetrahydroindol-3-yl)acetic acids was developed. Alkylation of cyclic 1,3-diketones with 3,5,5,5-tetrachloropentan-2-one affords 1,4-diketones, which undergo cyclization with different primary amines into N-substituted 3-(2,2,2-trichloroethyl)-4,5,6,7-tetrahydroindol-4-ones. Acid hydrolysis of the latter gives the corresponding indol-3-ylacetic acids. The structures of the compounds obtained were confirmed by ¹H and ¹³C NMR data.     

ortho-metalation of unprotected 3-bromo and 3-chlorobenzoic acids with hindered lithium dialkylamides

Upon treatment of 3-chloro/bromobenzoic acids with hindered lithium dialkylamides (LDA or LTMP) at -50 degrees C, lithium 3-chloro/bromo-2-lithiobenzoates are generated. These dianions can be trapped as such to afford after electrophilic quenching a variety of simple 2-substituted-3-chloro/bromobenzoic acids. The 3-bromo-2-lithiobenzoate is less stable than the corresponding 3-chloro derivative and partly eliminates lithium bromide, thus setting free lithium 2,3- and 3,4-dehydrobenzoates that can be intercepted in situ with the hindered base.     

Solution-phase synthesis of a combinatorial library of 3-[4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides

The parallel solution-phase synthesis of a new combinatorial library of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9 has been developed. The synthesis involves two steps: 1) the synthesis of core building blocks - 3- [4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids, 6 - by the reaction of 3-(omega-bromacetyl)coumarins 1 with 3-amino(thioxo)methylcarbamoylpropanoic acid (5); 2) the synthesis of the corresponding 3-[4-(coumarin-3-yl)-1,3-thiazol-2-yl- carbamoyl]propanoic acids amides 9 using 1,1'-carbonyldimidazole as a coupling reagent. The advantages of the method compared to existing ones are discussed.     

Photolabile protection of alcohols, phenols, and carboxylic acids with 3-hydroxy-2-naphthalenemethanol

Irradiation of alcohols, phenols, and carboxylic acids "caged" with the (3-hydroxy-2-naphthalenyl)methyl group results in fast (k(release) approximately = 10(5) s(-1)) release of the substrates with good quantum (Phi = 0.17-0.26) and chemical (>90%) yields. The initial byproduct of the photoreaction, 2-naphthoquinone-3-methide, reacts rapidly with water (k(H2O) = 144 +/- 11 s(-1)) to produce parent 3-hydroxy-2-naphthalenemethanol. The o-quinone methide intermediate can be also trapped by other nucleophiles or converted into a photostable Diels-Alder adduct with ethyl vinyl ether.     

Chemoselective Alkylation of 3- and 4-(5-Amino-4-hetaryl-2,3-dihydro-3-oxopyrrol-1-yl)benzoic Acids

Alkylation of 3- and 4-(5-amino-4-hetaryl-2,3-dihydro-3-oxopyrrol-1-yl)benzoic acids with phenacyl bromides or chloroacetanilides in DMF in the presence of triethylamine occurs at the carboxy group with high selectivity and yields the corresponding phenacyl and arylcarbamoylmethyl esters. The initial pyrrolylbenzoic acids were synthesized by reaction of 3- and 4-aminobenzoic acids with 4-chloro-2-hetaryl-3-oxo-butyronitriles.