Expanding the azaspiro[3.3]heptane family: synthesis of novel highly functionalized building blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.     

Chemistry of amidrazones—IV : Addition-cyclisation of amidrazones with isocyanate esters and ethoxycarbonyl isothiocyanate

The interaction of amidrazones and isocyanate esters in dimethylformamide produces good yields of 4-substituted -1-imidoylsemicarbazides. They are unaffected by acids, but are cyclised to 3-alkyl (or aryl)-1,2,4-triazol-3-ones or their 4-substituted analogues in alkaline media. Analogous linear adducts arising in good yields from amidrazones and ethoxycarbonyl isothiocyanates are cyclised to 3-substituted 5-ethoxycarbonamido-1,3,4-thiadiazoles by acids, but are cleaved into small fragments by alkalis.     

Rearrangements of 1-oxa-2-azoles 8. Synthesis and rearrangement of amidrazones of 1,2,4-oxadiazole-3-carboxylic acid

The possible isolation of amidrazones of 1,2,4-oxadiazole-3-carboxylic acid by three reaction schemes was studied. It was established that the given amidrazones are unstable and undergo rearrangement to derivatives of 4,5-diaminotriazole.For Communication 7, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 964–968, July, 1992.     

Synthesis of Condensed and Uncondensed Tetrazolo[1,5-<Emphasis Type="Italic">b</Emphasis>][1,2,4]triazines as Potential Antimicrobial Agents

Summary. Reactions of two cyclic amidrazones, the 6-methyl and 6-phenyl derivatives of 7-hydrazinotetrazolo[1,5-b][1,2,4]triazines with mono- and dicarbonyl compounds afforded various heterocyclic systems. Thus, acetic acid, benzoyl chloride, or ethyl chloroformate reacted with the former cyclic amidrazones to yield the corresponding [1,2,4]triazolo[4,3-d]tetrazolo[1,5-b][1,2,4]triazines. With pyruvic acid or ethyl pyruvate the corresponding hydrazone derivatives were obtained, which then cyclized to tetrazolo[1′,5′:2,3][1,2,4]triazino[5,4-c][1,2,4]triazines. The 9,10-dioxotetrazolo-triazinotriazine structures were synthesized by condensative cyclization of the cyclic amidrazones with diethyl oxalate, whereas the reaction of these amidrazones with acetylacetone or ethyl acetoacetate furnished pyrazolyltetrazolo[1,5-b][1,2,4]triazines through the isolable hydrazone intermediates. Some of the representative members of the prepared compounds were screened for antimicrobial activity.     

Chemistry of amidrazones—II : Synthesis and cyclisation of 1-thioacylamidrazones

1-Thioaroylamidrazones are formed by the action of carboxymethyl dithioates on unsubstituted amidrazones; they are cyclised by acids to 2,5-disubstituted 1,3,4-thiadiazoles. 1-(Ethoxythiocarbonyl)amidrazones are similarly accessible by the use of ethoxythiocarbonylthioacetic acid. They yield 3-ethoxy (or hydroxy)-5-substituted-1,3,4-thiadiazoles under the influence of acids, but are cleaved into smaller fragments by alkalis.     

Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles and bicyclobutane precursors is described. The strain-release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale-up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.     

α‐Amino Acid‐Isosteric α‐Amino Tetrazoles

The synthesis of all 20 common natural proteinogenic and 4 otherα‐amino acid‐isosteric α‐amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5‐tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α‐amino acid‐isosteric α‐amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non‐natural derivatives is of high interest to advance the field.     

Microwave-assisted preparations of amidrazones and amidoximes

In an operationally straightforward and efficient method, amidrazones and amidoximes are prepared in yields of 65-87% from imidoylbenzotriazoles by microwave heating for 5-20 min with the appropriate hydrazine or hydroxylamine.     

Synthesis, structure, and properties of phosphorus-containing bis(amidrazones)

Previously unknown ethenylphosphonic derivatives of bis(amidrazones) were prepared. According to spectroscopic data and quantum-chemical calculations, these compounds exist as phosphonium salts of a symmetrical linear structure with trans arrangement of the amidrazone fragments. In alkaline solutions, they are unstable and decompose to form triarylphosphine oxides. In contrast to ordinary amidrazones, their phosphorus-containing derivatives do not tend to form complexes with transition metals.     

Unsaturated four-membered N-heterocycles: From synthesis to applications

The ubiquity of strained motifs in drug discovery has recently witnessed a large regain of interest, as such scaffold can be used to modulate the properties of drug candidates. Unsaturated N-containing four-membered heterocycles present unique opportunities to access functionalized azetidines, which play an essential role in pharmacological studies. Even though those unsaturated patterns have been much less reported than the corresponding saturated versions, the consequent impact that those structures could have on molecular design with implementation of strained modules deserves to be summarized. In this review, synthetic accesses to substituted azetes, 1-azetines and 2-azetines are depicted, as well as their involvement in further transformations.     

Novel and efficient synthesis of 4-sulfonyl-2-pyridones

Heterocyclic 4-sulfonyl-2-pyridones represent useful scaffolds for drug discovery, and are also versatile synthetic building blocks. Herein, we describe a novel and efficient synthesis of this heterocyclic ring system utilizing an acid-mediated cyclo-condensation reaction. This synthetic method affords convenient access to structurally diverse N-substituted 4-sulfonyl-2-pyridones in moderate to good yields.     

Synthesis of fluorinated amino acid derivatives through late-stage deoxyfluorinations

Fluorine chemistry has represented a hot topic in drug research over the last decade. Because of their pharmaceutical potential, fluorine-containing amino acids and related derivatives have acquired high importance among medicinal chemists. Therefore their synthesis and the development of various synthetic methods for these types of molecular scaffolds have gained increasing interest in synthetic organic chemistry. The current review focuses on synthetic protocols towards fluorine-containing amino acid derivatives through late-stage fluorination with various nucleophilic reagents, describing the access of various open-chain and cyclic α-, β-, γ-amino acid derivatives.     

Asymmetric organocatalytic Biginelli reactions: a new approach to quickly access optically active 3,4-dihydropyrimidin-2-(1H)-ones

The Biginelli reaction, known for over 100 years, is an important multicomponent reaction for accessing dihydropyrimidinones (DHPMs). The individual enantiomers of DHPMs exhibit different or even opposite pharmaceutical activities, which require synthetic methods to easily access the optically pure DHPMs. In recent decades, many efforts have focused on developing procedures for the preparation of optically active Biginelli products. In this article, we will summarize the developments in the synthetic methods to access optically active DHPMs with an emphasis on the recent advances in the asymmetric catalytic Biginelli reactions, along with concepts to design the organocatalytic asymmetric variants.     

Catalytic Synthesis of β-(Hetero)arylethylamines: Modern Strategies and Advances

β-(Hetero)arylethylamines appear in a myriad of pharmaceuticals due to their broad spectrum of biological properties, making them prime candidates for drug discovery. Conventional methods for their preparation often require engineered substrates that limit the flexibility of the synthetic routes and the diversity of compounds that can be accessed. Consequently, methods that provide rapid and versatile access to those scaffolds remain limited. To overcome these challenges, synthetic chemists have designed innovative and modular strategies to access the β-(hetero)arylethylamine motif, paving the way for their more extensive use in future pharmaceuticals. This review outlines recent progresses in the synthesis of (hetero)arylethylamines and emphasizes how these innovations have enabled new levels of molecular complexity, selectivity, and practicality.     

Late-Stage Amination of Drug-Like Benzoic Acids: Access to Anilines and Drug Conjugates through Directed Iridium-Catalyzed C−H Activation

The functionalization of C−H bonds, ubiquitous in drugs and drug-like molecules, represents an important synthetic strategy with the potential to streamline the drug-discovery process. Late-stage aromatic C−N bond–forming reactions are highly desirable, but despite their significance, accessing aminated analogues through direct and selective amination of C−H bonds remains a challenging goal. The method presented herein enables the amination of a wide array of benzoic acids with high selectivity. The robustness of the system is manifested by the large number of functional groups tolerated, which allowed the amination of a diverse array of marketed drugs and drug-like molecules. Furthermore, the introduction of a synthetic handle enabled expeditious access to targeted drug-delivery conjugates, PROTACs, and probes for chemical biology. This rapid access to valuable analogues, combined with operational simplicity and applicability to high-throughput experimentation has the potential to aid and considerably accelerate drug discovery.     

Chalcone derived benzoheterodiazepines for medicinal applications: A Two-pot and one-pot synthetic approach

The production of effective drugs has continuously been a challenging process for researchers due to the occurrence of resistive diseases. Drugs derived from natural product-based compounds as an active scaffold have gained interest in drug development due to a wide range of biological properties. Benzoheterodiazepines, a natural product derivative of bicyclic chalcones have been widely reported with various therapeutic potentials. This review discusses current synthetic methods in the preparation of benzoheterodiazepine derivatives (i.e., homocyclic benzoheterodiazepine, heterocyclic benzoheterodiazepine, bis-benzoheterodiazepine, and fused benzoheterodiazepine) via two-pot and one-pot synthetic routes. Several reaction protocols following both synthetic routes have been developed for efficient and higher yields that offer access to different functionalization of benzoheterodiazepines are comprehensively described. This review is important in the heterocyclic chemistry of benzoheterodiazepines and pharmacological industries in drug development processes.     

Beyond mere diversity: tailoring combinatorial libraries for drug discovery

Combinatorial library design attempts to choose the best set of substituents for a combinatorial synthetic scheme to maximize the chances of finding a useful compound, such as a drug lead. Initial efforts were focused primarily on maximizing diversity, perhaps allowing some bias by the inclusion of a small, fixed set of pharmacophoric substituents. However, many factors besides diversity impact good library design for drug discovery. A library can be better "tailored" by assigning the candidate substituents to categories such as polar, pharmacophoric, rigid, low molecular weight, and expensive. Stratified sampling by successive steps of D-optimal design generates diverse designs which are also consistent with desirable profiles of these properties. Comparing the diversity scores among design profiles reveals the tradeoffs between diversity, physical property distributions, synthetic difficulty, expense, and pharmacophoric bias. The diversity scores can be calibrated by scoring the best designs from subsets of the candidates made either from specific classes of substituents or by randomly eliminating candidates. This procedure shows how poor random designs are compared even to highly biased optimal designs. Library design requires a synergistic effort between computational and synthetic medicinal chemists, so specialized interactive software has been developed to integrate substructure searching, display, and statistical experimental design to facilitate this interaction for the effective design of well-tailored libraries.     

The. Synthesis and chelation properties of N-substituted amidrazones and related azines containing the 2-pyridyl group

The. preparation and properties of certain N-substituted amidrazones from thioamides containing the 2-pyridyl group and the azines derived from them by reaction with benzaldehyde and 2-pyridinecarboxaldehyde is described.     

Selective Synthesis of Fluorine‐Containing Cyclic β‐Amino Acid Scaffolds

Fluorine‐containing organic molecules have generated increasing impact in drug research over the past decade. Their preparation and development of novel synthetic methods towards new types of fluorinated molecules among them of β‐amino acid derivatives has received large interest. Our research group have designed various highly selective and stereocontrolled methods for the construction of fluorine‐containing cyclic β‐amino acid derivatives. The synthetic approaches developed for the synthesis of various pharmacologically interesting cyclic β‐amino acid derivatives as monomers with multiple stereogenic centers might be valuable protocols for the access of other classes of organic compounds.