Synthetic Routes to Pyrazole‐3(5)‐carboxylates

The data on the synthetic methods of the pyrazole‐3(5)‐carboxylates published over the last years are reviewed here for the first time.     

Synthetic and Structural Studies of 1‐Halo‐8‐(alkylchalcogeno)naphthalene Derivatives

A series of eight 1‐halo‐8‐(alkylchalcogeno)naphthalene derivatives ( 1 – 8 ; halogen=Br, I; alkylchalcogen=SEt, SPh, SePh, TePh) containing a halogen and a chalcogen atom occupying the peri positions have been prepared and fully characterised by using X‐ray crystallography, multinuclear NMR spectroscopy, IR spectroscopy and MS. Naphthalene distortion due to non‐covalent substituent interactions was studied as a function of the bulk of the interacting chalcogen atoms and the size and nature of the alkyl group attached to them. X‐ray data for 1 , 2 , 4 and 5 – 8 were compared. Molecular structures were analysed in terms of naphthalene ring torsions, peri‐atom displacement, splay angle magnitude, X???E interactions, aromatic ring orientations and quasi‐linear X???E? C arrangements. A general increase in the X???E distance was observed for molecules that contain bulkier atoms at the peri positions. The I???S distance of 4 is comparable with the I???Te distance of 8 , and is ascribed to a stronger lone pair–lone pair repulsion due to the presence of an axial S(naphthyl) ring conformation. Density functional theory (B3LYP) calculations performed on 5 – 8 revealed Wiberg bond index values of 0.05–0.08, which indicate minor interactions taking place between the non‐bonded atoms in these compounds.     

Synthesis of （S）-2-Ethoxy-3-Phenylpropanoic Acid Derivatives and Their Insulin-Sensitizing Activity

A series of （S）-2-ethoxy-3-phenylpropanoic acid derivatives were synthesized and their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Compounds 1b, 1d, 1e and 1f exhibited more potent insulin-sensitizing activity than rosiglitazone.     

Synthetic Applications of 3‐(Phenylsulfinyl)‐3‐sulfolene

The title compound 2 was readily prepared by MCPBA oxidation of the sulfide 1. Thermal desulfonylation of 2 gave the sulfoxide‐substituted diene 3. The Diels‐Alder reactions of 3 with various dienophiles gave the cyclized products 4‐9 in good yields. The regiochemistry was found to be dominated by the phenylsulfinyl group, but could be reversed by the presence of a Lewis acid. Deprotonation of 2 by BuLi, followed by the reaction with alkyl halides, gave the substituted 2‐sulfolenes 10. A synthetic application of 10 was demonstrated by converting 10e to the bicyclic product 11.     

pH‐Directed Synthesis of Two Luminescent Zinc(II) Coordination Compounds based on 5‐Aminotetrazole‐1‐propanoic Acid

Two Zn^II‐tetrazole‐carboxylate coordination compounds are reported, mononuclear [Zn(atzpa)₂(H₂O)₄] · 2H₂O ( 1 ) and one‐dimensional [Zn(atzpa)₂(H₂O)₂]_n ( 2 ), derived from 5‐aminotetrazole‐1‐propanoic acid (Hatzpa). The structures of both compounds are determined by the pH value of the reaction system. The luminescence properties of Hatzpa and the compounds were investigated at room temperature in the solid state. Furthermore, differential scanning calorimetry (DSC) and thermogravimetric‐differential thermogravimetric (TG‐DTG) analyses were applied to evaluate the thermal decomposition behavior of such compounds. The relevant thermodynamic parameters (ΔH, ΔS, and ΔG) of the decompostion process of compound 1 were calculated, as well.     

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.     

Cyclization Reactions of 5‐Aminopyrazoles with β‐Ketoesters,Enamines and β‐Keto Anilides: New Synthetic Routes to Pyrazolo[1,5‐a]Pyrimidine Derivatives

The pyrazolo[1,5‐a]pyrimidines 4, 10, 11 and 14 were synthesized from reaction of 4‐aryazo‐2,5‐diaminopyrazoles 1 with cyclic β‐ketoesters 2a,b or cyclic β‐ketoesters 7, 8 or acetoacetanilide 12 , respectively. The reaction of 1 with the enamines 15, 16 and 17 yielded also the pyrazolo[1,5‐a]pyrimidines 18, 20 and 21 , respectively.     

3‐Hydrazido and 3‐Hydrazono Derivatives of Tenuazonic Acid and their Herbicide Evaluation

With the aim of optimizing the structure of tenuazonic acid and improving the herbicidal activity, hydrazine moieties were introduced to the 3‐position of pyrrolidine‐2,4‐dione scaffold of tenuazonic acid. 3‐Hydrazido‐pyrrolidine‐2,4‐dione compounds ( 4a , 4b , 4c , 4d , 4e ) were prepared from corresponding carboxylates and hydrazines via a microwave‐assisted amidation, whereas 3‐hydrazono compounds ( 7a , 7b , 7c , 7d , 7e ) were prepared from corresponding 3‐acetyl pyrrolidine‐2,4‐dione. Both of the two structures also exhibited herbicidal activities, especially against the dicotyledonous species amaranth pigweed (Amaranthus retroflexus), but with different structure‐activity relationship.     

Supramolecular Architectures of Four New Transition Metal Complexes with 3‐[4‐(Carboxymethoxy)phenyl]propanoic Acid and N‐[4‐(Carboxymethoxy)phenyl]iminodiacetic Acid

Four new transition metal complexes: [Cu(Hcppa)₂(H₂O)₂] ( 1 ), [Co₂(cppa)₂(H₂O)₁₀] ( 2 ), [Co₃(cpia)₂(H₂O)₈] · 2H₂O ( 3 ) and [Ni₃(cpia)₂(H₂O)₁₂] · 6H₂O ( 4 ) {H₂cppa = 3‐(4‐(carboxymethoxy)phenyl]propanoic acid; H₃cpia = N‐[4‐(carboxymethoxy)phenyl]iminodiacetic acid} were synthesized and characterized. Complexes 1 and 2 show mononuclear structures, complexes 3 and 4 exhibit dinuclear structures. All complexes extend to 3D supramolecular networks through hydrogen bonds, of which complexes 3 and 4 display microporous structures. In complexes 2 – 4 the water clusters are trapped by the cooperative association of coordinate interactions as well as hydrogen bonds, forming different 1D metal‐water chain structures. Thermal stabilities of complexes 1 – 4 were discussed.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Synthesis of Non‐Racemic 1‐Hydroxycycloalkene‐1‐carboxylic‐Acid Derivatives by Metathesis of α,α‐Dialkylated Glycolate Derivatives

A particularly flexible general way to synthesize 1‐hydroxycycloalkene‐1‐carboxylic‐acid derivatives from 2‐(tert‐butyl)‐2‐methyl‐1,3‐dioxolan‐4‐one ( 1 ), a chiral equivalent of glycolic acid, is reported. The method is based on a double enolate alkylation of the glycolate derivative, followed by ring closing metathesis. A formal synthesis of (−)‐quinic acid is reported to demonstrate the potential of this approach.     

Synthesis of 3‐Aryl/methoxycarbonyl‐3,4‐dihydroisocoumarin‐6‐carboxylic Acid Derivatives

3‐Substituted methyl 3,4‐dihydroisocoumarin‐6‐carboxylates were obtained by the intramolecular cyclization of 2,5‐dimethoxycarbonyl benzenediazonium bromides with methyl/ethyl acrylate and styrenes under Meerwein's arylation conditions.     

D(−)- and L(+)-γ-Carboxyglutamic Acid (Gla): Resolution of Synthetic Gla Derivatives

The chemical resolution of γ,γ′-di-t-butyl DL -N-benzyloxycarbonyl-γ-carboxy-glutamate is described in detail (preliminary account see [1]). The D (?)-derivative was obtained as a crystalline quinine salt, and the L (+)-derivative as a crystalline salt with (?)-ephedrine in yields of 44 and 70%, respectively. Physical data are indicated for the enantiomers of γ,γ′-di-t-butyl N-benzyloxycarbonyl-γ-carboxyglutamate, γ,γ′-di-t-butyl γ-carboxyglutamate, and γ-carboxyglutamic acid. The absolute configurations and optical purities of the γ,γ′-di-t-butyl (+)- and (?)-N-benzyloxycarbonyl-γ-carboxyglutamates were determined by removal of the protecting groups and decarboxylation to optically active glutamic acid.     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.     

On the Structure of PHB (=Poly[(R)‐3‐hydroxybutanoic Acid]) in Phospholipid Bilayers: Preparation of Trifluoromethyl‐Labeled Oligo[(R)‐3‐hydroxybutanoic Acid] Derivatives

Oligomers of (R)‐3‐hydroxybutanoate (OHB) have previously been shown to transport cations through lipid bilayers. The ion‐transport activity has been attributed to the formation of hydrophobic aggregates or pores, which have been identified by fluorescence‐microscopy measurements of membrane‐incorporated fluorescence‐labeled OHBs. To obtain more information about these aggregates, we describe here the synthesis of the specifically F‐labeled HB oligomers II – IV for structural investigation by means of solid‐state ¹⁹F‐NMR spectroscopic techniques.     

Behavior of 3‐benzylamino‐5‐aryl‐2(3H)‐furanones towards some nitrogen nucleophiles

Ring closure of 2‐N‐benzylamino‐3‐aroylpropionic acids ( 3 ) with acetic anhydride afforded 3‐N‐benzylamino‐5‐aryl‐2(3H)‐furanones ( 4 ). The reaction of the furanones ( 4 ) with benzylamine in benzene was found to be time dependent. Thus refluxing the reaction mixture for 1 h only afforded the open‐chain amides ( 5a‐c ). When the reaction was conducted for 3 h the 2(3H)‐pyrrolones ( 6 ) were obtained. Hydrazine hydrate affected ring opening of the furanones to give the hydrazides ( 5d‐f ). Also, semicarbazide converted ( 4 ) into the corresponding semicarbazide derivatives ( 5g‐i ). The hydrazides ( 5d‐f ) were reacted with benzoyl chloride to give the corresponding diaroylhydrazines ( 5j‐l ). The open‐chain derivatives ( 5 ) were converted into a variety of heterocycles: isothiazolones ( 7 ), dihydropyridazinones ( 8 ), 1,3,4‐oxadiazoles ( 9 ) and 1,2,4‐triazole derivatives ( 10 ) via cyclization reactions.     

Synthesis of 6‐ and 8‐Halogenosubstituted 3‐Quinoline‐Sulfonic Acid Derivatives[1]

Treatment of 3,6‐di‐ and 3,6,8‐trihalogenosubstituted quinolines 1 with sodium alkanethiolates was carried out regioselectively at C3 of the pyridine ring, affording the corresponding halogenosubstituted 3‐methylsulfanylquinolines 2 and 3‐phenylmethylsulfanylquinolines 3 . The structures of 2 and 3 were assigned by NMR studies, including ¹H‐detected one‐bond (C–H) HSQC and long‐range HMBC, in addition to NOE experiments. Benzyl derivatives 3 were oxidatively chlorinated to obtain the title quinolinesulfonyl chlorides.