Cycloalkylcarboxylic Acids Research Articles

Tandem dehydrogenation-olefination-decarboxylation of cycloalkyl carboxylic acids via multifold C–H activation

Dehydrogenation chemistry has long been established as a fundamental aspect of organic synthesis, commonly encountered in carbonyl compounds. Transition metal catalysis revolutionized it, with strategies like transfer-dehydrogenation, single electron transfer and C–H activation. These approaches, extended to multiple dehydrogenations, can lead to aromatization. Dehydrogenative transformations of aliphatic carboxylic acids pose challenges, yet engineered ligands and metal catalysis can initiate dehydrogenation via C–H activation, though outcomes vary based on substrate structures. Herein, we have developed a catalytic system enabling cyclohexane carboxylic acids to undergo multifold C–H activation to furnish olefinated arenes, bypassing lactone formation. This showcases unique reactivity in aliphatic carboxylic acids, involving tandem dehydrogenation-olefination-decarboxylation-aromatization sequences, validated by control experiments and key intermediate isolation. For cyclopentane carboxylic acids, reluctant to aromatization, the catalytic system facilitates controlled dehydrogenation, providing difunctionalized cyclopentenes through tandem dehydrogenation-olefination-decarboxylation-allylic acyloxylation sequences. This transformation expands carboxylic acids into diverse molecular entities with wide applications, underscoring its importance.

2-Сycloalkyl-(hetaryl-)-[1,2,4]triazol[1,5-с]quinazolines: synthesis, physical and chemical properties and antibacterial activity

In spite of the achievements in the chemistry of triazoloquinazolines, the synthetic possibilities of this class of compounds are not exhausted, some problems remain unresolved and require further study. 2-R-[1,2,4]triazolo[1,5-с]quinazolines are among them due to insufficiently explored but at the same time interesting in both chemical and biological aspects.
 Undoubtedly «pharmacophore» has the crucial role in the response of a biological action. It is contained in this heterocycle namely the substitute position 2.
 In view of the above, we attempted to modify triazolo[1,5-с]quinazoline by introducing a methyl group or halogens (fluorine, chlorine, bromine) into a benzene moiety and a triazole moiety of a cycloalkyl or heterocyclic substituent molecule.
 The aim of this work is to develop simple and affordable methods of the synthesis of new 2-cycloalkyl-(hetaryl-)-[1,2,4]triazolo[1,5-с]quinazolines, quinazolines, to study their physical and chemical properties and to conduct primary screening for antibacterial activity
 The antimicrobial activity of the synthesized chemical compounds was performed by the method of two-fold serial dilutions in Mueller–Hinton broth (for strains of Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and in Saburo broth (for Candida albicans ATCC 885–653). MIC (minimum inhibitory concentration), MBсC and MFсC (minimum bactericidal and fungicidal concentrations respectively) was determined.
 The optimal method of synthesis of 2-cycloalkyl-(hetaryl-)-[1,2,4]triazolo[1,5-с]quinazolines, which represent value as chemical reagents for further transformations and study of biological activity is substantiated and developed. The possibility of «one-pot» synthesis of the target compounds with 4-hydrazinoquinazolines and cycloalkylcarboxylic acids under conditions of activation of the carboxyl group N,N¢-carbonyldiimidazole is shown. Conducted microbiological screening of 2-cycloalkyl-(hetaryl-)-[1,2,4]triazolo[1,5-с]quinazolines revealed a number of promising compounds that inhibit the growth of St. aureus (МІС 25‒50 μg/ml) and C. albicans (25‒50 μg/ml).
 The optimal method of synthesis of 2-cycloalkyl-(hetaryl-)-[1,2,4]triazolo[1,5-с]quinazolin by cyclocondensation (3Н-quinazoline-4-ylidene)­hydrazides withcycloalkyl-(hetaryl)carboxylic acidsis substantiated and developed. The structure and individuality of the synthesized compounds were confirmed by elemental analysis, physicochemical methods (1H NMR-spectroscopy, HPLC/MS). The peculiarity of the 1H NMR spectra of this heterocycle is discussed, namely the significant paramagnetic shift of benzene protons and the characteristic weak-field single-proton singlet of the proton of position 5 of the heterocycle, which is a confirmation of recycling isomerization by Dimrot rearrangement. The structure-activity relationship is discussed and the study of the most active compounds for a wider range of strains and resistant strains of bacteria and fungi is recommended.

Synthesis of polycyclic polyolefins by a Pd-catalyzed isomerization polymerization of vinylcycloalkanes

Vinylcycloalkanes with 12-, 15-, and 21-membered rings were synthesized from commercially available cycloalkanones or cycloalkyl carboxylic acids derived from malonate and ω-bromo-α-alkenes. Pd complexes with diimine ligands promoted the isomerization polymerization of vinylcycloalkanes with 15- and 21-membered rings to afford polymers having cycloalkylene groups in the main chain. Vinylcycloheneicosane with a 21-membered ring afforded polymers with Mn up to 9700, whereas vinylcycloalkanes with smaller ring sizes (8- and 12-membered rings) yielded oligomers with Mn = 720–1600. Vinylcycloalkanes with 12-, 15-, and 21-membered rings were synthesized from commercially available cycloalkanones or cycloalkyl carboxylic acids derived from malonate and ω-bromo-α-alkenes. Pd complexes with diimine ligands promoted the isomerization polymerization of vinylcycloalkanes with 15- and 21-membered rings to afford polymers having cycloalkylene groups in the main chain. Vinylcycloheneicosane with a 21-membered ring afforded polymers with Mn up to 9700, whereas vinylcycloalkanes with smaller ring sizes (8- and 12-membered rings) yielded oligomers with Mn = 720–1600.

ChemInform Abstract: Palladium‐Catalyzed Arylation of β‐Methylene C(sp3)—H Bonds at Room Temperature: Desymmetrization of Simple Cycloalkyl Carboxylic Acids.

AbstractIn most cases, the β methylene C—H bonds of cycloalkylcarboxamides of varied ring size are monoarylated giving products with excellent cis‐diastereoselectivity whereby, diarylated products are also observed as by‐products.

Palladium-catalyzed arylation of β-methylene C(sp3)–H bonds at room temperature: desymmetrization of simple cycloalkyl carboxylic acids

A new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides at room temperature is reported.

ChemInform Abstract: Minisci Alkylations of Electron‐Deficient Pyrimidines with Alkyl Carboxylic Acids.

Abstract A practical method for the Minisci reaction of electron-deficient pyrimidines with carboxylic acids is described. The one-step protocol allows for the alkylation of halo- and trifluoromethyl pyrimidines with a variety of readily available alkyl and (hetero)cycloalkyl carboxylic acids. These conditions permitted the facile synthesis of substituted pyrimidines, which are poised for further elaboration through divergent means.

Minisci alkylations of electron-deficient pyrimidines with alkyl carboxylic acids

A practical method for the Minisci reaction of electron-deficient pyrimidines with carboxylic acids is described. The one-step protocol allows for the alkylation of halo- and trifluoromethyl pyrimidines with a variety of readily available alkyl and (hetero)cycloalkyl carboxylic acids. These conditions permitted the facile synthesis of substituted pyrimidines, which are poised for further elaboration through divergent means.

Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

The mechanism of the photo-decarboxylation of alkyl- and arylmethyl-carboxylates using visible light and iron(III) tetra(2-N-methylpyridyl)porphyrin pentachloride in aqueous solution

The photo-decarboxylations of a selection of alkyl-, arylmethyl- and cycloalkyl-carboxylate complexes of iron(III) tetra(2-N-methylpyridyl)porphyrin pentachloride in aqueous solution have been studied. An analysis of the influence of substituent electronic effects, σ* for alkyl- and σ for arylmethyl-carboxylic acids, and α,α-deuteration on the rates of reaction indicates that the reactions involve the discrete formation of a carboxyl radical. Thus after the initial photo-excitation, there is a rate-determining homolytic cleavage of the iron–carboxylate bond followed by rapid decarboxylation of the resultant carboxyl radical. Support for this two-step mechanism, over an alternative synchronous process, comes from a study of the influence of ring size on the reactions of five cycloalkylcarboxylic acids.

Unusual products from dirhodium tetraacylate-catalyzed decomposition of diazoacetylcycloalkanes

Abstract Rh 2 (OAc) 4 -assisted decompositions of diazoacetylcycloalkanes are shown to yield cycloalkylacetic acids (Wolff rearrangement), unexpected cycloalkylcarboxylic acids and bicyclic ketones (intramolecular CH bond insertion). Rh 2 (OCOCF 3 ) 4 -promoted reactions, on the other hand, have furnished bicyclic ketones and ketene dimers.

Synthesis of novel ring-substituted histidines and histamines

Abstract Synthesis of novel 2-cycloalkyl-L-histidines and 2-cycloalkylhistamines via radical alkylation with cycloalkylcarboxylic acids and silver nitrate in the presence of 10% H2SO4 by ammonium persulfate is described. The method is also extended to the synthesis of 1,2-dialkyl-L-histidines and 1,2-dialkylhistamines.

ChemInform Abstract: Stable Carbocations. Part 300. 13C NMR Spectroscopic and Density Functional Theory (DFT), ab initio, and IGLO Theoretical Study of Protonated Cycloalkylcarboxylic Acids (Carboxonium Ions) and Their Acyl Cations (Oxocarbenium Ions).

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereospecific Biohydroxylations of Protected Carboxylic Acids with Cunninghamella blakesleeana

Cunninghamella blakesleeana DSM 1906 was found to be an efficient biocatalyst for the biotransformation of cycloalkylcarboxylic acids into hydroxy and oxo derivatives. When cultivated in submerged culture, the fungus grew in pellets. In comparison with malt extract-glucose-peptone-yeast extract medium (medium E), Czapek-Dox medium was found to reduce pellet size. Cycloalkylcarboxylic acids were protected against microbial degradation by chemical transformation into 2-cycloalkyl-1,3-benzoxazoles. The transformations of protected cyclopentyl-, cyclohexyl-, cycloheptyl-, and cyclooctylcarboxylic acids by C. blakesleeana were investigated. The biotransformations were performed in medium E by using an aerated, stirred-tank bioreactor. The transformation of 2-cyclopentyl-1,3-benzoxazole yielded (1S,3S)-3-(benz-1,3-oxazol-2-yl)cyclopentan-1-ol as the main product. The main by-product was (1R)-3-(benz-1,3-oxazol-2-yl)cyclopentan-1-one, and 2-(benz-1,3-oxazol-2-yl)cyclopentan-1-ol was also obtained in small amounts. During the experiment, the enantiomeric excess of the main product increased up to 64%. 2-Cyclohexyl-1,3-benzoxazole was hydroxylated to 4-(benz-1,3-oxazol-2-yl)cyclohexan-1-ol. 2-Cycloheptyl-1,3-benzoxazole and 2-cyclooctyl-1,3-benzoxazole were transformed into several alcohols and ketones, all in low yields (2 to 19%).

13C NMR Spectroscopic and Density Functional Theory (DFT), ab Initio, and IGLO Theoretical Study of Protonated Cycloalkylcarboxylic Acids (Carboxonium Ions) and Their Acyl Cations (Oxocarbenium Ions)

A series of protonated cycloalkylcarboxylic acids (carboxonium ions) and their corresponding acyl cations (oxocarbenium ions) were investigated in FSO3H−SbF5−SO2ClF solution by 13C NMR spectroscopy. The ions were also studied by density functional theory (DFT) and ab initio and IGLO theoretical methods. The study shows that the various cycloalkyl groups have little effect on the 13C NMR chemical shift of the carbocationic carbons of the ions. Charge calculations show that the delocalization into the cycloalkyl group is greater for the oxocarbenium ions than for the carboxonium ions. This is consistent with the greater electronic demand in oxocarbenium ions wherein one adjacent oxygen atom effects stabilization.

A STUDY OF REACTIONS BETWEEN CARBOETHOXYMETHYLENETRIPHENYL-PHOSPHORANE AND ALKYL DIBROMIDES

Abstract Carboethoxymethylenetriphenylphosphorane 1 reacts with 1,4-dibromobutane and 1,5-dibromopentane under transylidation conditions in refluxing anhydrous benzene affording the cyclization products, 1-carboethoxycyclopentyl and 1-carboethoxycyclohexyltriphenylphosphonium bromides, 6, which by alkaline hydrolysis produce the corresponding cycloalkylcarboxylic acids and esters. Phosphorane 1 and its phosphonium salt 5 formed in the transylidation step also lead to 3-carboethoxy-3-triphenylphosphoranyliden-2-oxopropanetriphenylphosphonium bromide (9) as a secondary reaction product.

Angiotensin-converting enzyme inhibitors: importance of the amide carbonyl of mercaptoacyl amino acids for hydrogen bonding to the enzyme.

A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.

SYNTHÈSES DE COURTS PEPTIDES RENFERMANT DES ACIDES AMINO-1 CYCLOALKYL CARBOXYLIQUES

Using classical methods of synthesis nine small peptides containing amino-1 cycloalkyl carboxylic acids have been synthesized. The cyclic acids have been placed either at the N-terminal or at the C-terminal positions or in between two natural amino acids, glycine and DL-phenylalanine.The cyclization of two dipeptides into a substituted diketopiperazine, and the subsequent hydrolysis of this compound have been studied.