Ugi Adducts Research Articles

New Cytotoxic α‐Aminoacylamide and bis‐1,5‐Disubstituted Tetrazole Adducts From Amino‐Diterpene Molecules by Ugi Reaction

ABSTRACTIn search for new molecules of diterpene origin with promising anticancer activity, two amino‐derivatives (methyl maleopimarate aminoimide and methyl 1β,13‐epoxydihydroquinopimarate C4‐hydrazone) were involved in the 4‐component Ugi reaction (Ugi‐4CR) and pseudo‐7‐component azido‐Ugi condensation (azido‐Ugi‐7CR) to afford a series of adducts holding α‐aminoacylamide and bis‐1,5‐disubstituted tetrazole substituents. The NCI‐60 cancer cell panel screening revealed diterpene‐type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2–15.4 μM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.

Synergistic Insights: Synthesis, Characterization, Biological Evaluation, and Molecular Docking Studies of TMS-N3 UGI–Adduct

Synergistic Insights: Synthesis, Characterization, Biological Evaluation, and Molecular Docking Studies of TMS-N3 UGI–Adduct

Post-Ugi Acid-Catalyzed Fragmentation and Trapping: An Unprecedented Approach towards Novel Bis(indolyl)acetamides

AbstractAn unprecedented post-Ugi Brønsted acid catalyzed fragmentation followed by in situ trapping of the alkylideneindolenine intermediate by indole nucleophiles was developed to furnish novel bis(indolyl)acetamides. The amide fragment formed during this acid-catalyzed fragmentation of the Ugi adduct was also isolated and characterized. The carboxylic acid and amine components of the Ugi reaction were carefully chosen to permit a simple water wash for the removal of the amide fragment to obtain the desired bis(indolyl)acetamides in a pure form.

Construction of [1,4]oxazepin-2-ones via catalyst-free intramolecular C–O bond formation from Ugi adducts

A novel cyclization of Ugi adducts through a base-mediated system has been reported. The process entails an oxygen nucleophilic attack on the alkyl halide moiety, subsequently leading to an intramolecular cyclization. These consecutive reactions are straightforward to execute, occur under mild conditions, and do not require a catalyst. This catalyst-free attribute enhances the method’s utility and eco-friendliness, rendering it an appealing approach for producing this significant category of heterocyclic compounds.

Concise Approach towards Tetramic Acid Derivatives via Ugi Reaction/Dieckmann Cyclization Sequence

AbstractTetramic acids exhibit intriguing biological activity and are particularly attractive scaffolds for drug design. In this paper, we present a convenient approach based on the Dieckmann cyclization of Ugi adducts of malonic monoesters to afford a series of medically important polysubstituted tetramic acid derivatives. This simple and versatile method tolerates various substituents in both the amine, aldehyde and isocyanide moieties allowing the use of α‐substituted malonic acid monoesters. Examples of further functionalization of the free methylene group in the synthesized compounds have been presented.

Design and Synthesis of Quinoline‐Pyrazine Based Carboxamides: Leukemic Cancer Active Ugi Adducts

AbstractThe design and synthesis of new chemical entities (NCEs) with suitable physicochemical properties are playing a key role in medicinal research areas. Hence, we have designed and synthesized the 10 diverse scaffolds by rightly selecting the quinoline and pyrazine to articulate carboxamide derivatives in a single‐step process with maximum conversation in a shorter time through diverse studies of Ugi multi‐component reaction. Molecular docking studies against FMS‐like tyrosine kinase‐3 (FLT3) provided well‐clustered solutions for the binding modes of these molecules and shed light on the key structural features governing the binding affinity. Two carboxamides derivatives with 3,4,5‐trimethoxy, and chloro substituents showed comparable potency in Leukemia cell lines and medium efficacy in Breast and Melanoma cancer. These results suggest that pyrazine and quinoline‐based carboxamides may be prominent as new anti‐cancer agents in chemotherapy. Additionally, in silico analysis was employed to predict the comprehensive physicochemical ADME profile (absorption, distribution, metabolism, and excretion) of the carboxamide derivatives which was proven drug‐like properties.

Two distinct protocols for the synthesis of unsymmetrical 3,4-disubstituted maleimides based on transition-metal catalysts.

Two tandem catalytic systems are described for the synthesis of novel 3,4-disubstituted maleimides using the same Ugi adducts as starting materials. 4-Aryl-3-pyrrolyl- and 4-aryl-3-indolyl-maleimides were successfully obtained via a Pd(OAc)2/PPh3 based protocol. In contrast, maleimide-fused pyrrolo and indolo[1,2-a]quinolines were obtained in a complementary methodology using CuI/L-proline. These strategies involved a combination of benzylic amine oxidation, trans-amidation, intramolecular Knoevenagel condensation, and N-arylation reactions. Computational investigations provide further insights into this reaction sequence.

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles.

Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed drugs highlighting their importance in the discovery of novel bioactive compounds. However, their synthesis often faces challenges, including complex functionalization and lengthy reaction sequences. Multicomponent reactions, notably the Ugi reaction, have emerged as powerful tools to address these hurdles. Here, we have demonstrated the possibility of using the combination of arylglyoxals and carboxylic acids tethered to nonprotected deactivated amines as a powerful strategy for the synthesis of complex fused heterocycles. The limited nucleophilic character of the amino group of the anthranilic acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine has allowed the use of these compounds in the Ugi reaction without triggering competitive reactions. The additional functional group present in the resulting Ugi adduct can be leveraged in different post-condensation strategies to easily generate multiple fused nitrogen heterocycles including benzodiazepinone and piperazinone cores.

Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach.

Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.

Diversification of 4-bromo-1H-indole-3-carbaldehyde-derived Ugi adducts: Access to the azepino[3,4,5-cd]indoles and spiroindolines

4-Bromo-1H-indole-3-carbaldehyde has been explored as a key building block for a post-Ugi assembly of azepino[3,4,5-cd]indoles and spiroindolines. First, the corresponding Ugi adducts were successfully employed in palladium-catalyzed reductive Heck cyclization producing a range of azepinoindoles. Then, 4-bromo-1H-indole-3-carbaldehyde-derived Ugi adducts were subjected to cationic gold catalysis affording tetracyclic spiroindolines. Furthermore, the aryl bromide moiety retained in the resulting spiroindolines was found to be amendable to further functionalization via Suzuki and Sonogashira couplings.

Strain and Complexity, Passerini and Ugi Reactions of Four-Membered Heterocycles and Further Elaboration of TOSMIC Product.

Straightforward and general Passerini and Ugi procedures have been developed to incorporate four-membered heterocycles into highly functionalized scaffolds. Additionally, toslymethyl isocyanide (TosMIC)-derived Ugi adducts have been prepared, showcasing the prospect of the multicomponent reaction.

C−C Bond Cleavage of α‐Pyridinium Amides: A Synthetic Approach to Hydantoin Structures

AbstractThis study reports a mild reaction‐condition approach for the direct C−C bond cleavage of amides to form hydantoin structures in the presence of 4‐methylpyridine and a base. This approach presents an amide C−C bond cleavage strategy enabling nucleophilic addition to the amide carbonyl involving a reactive spiro intermediate. A broad spectrum of pseudo peptide Ugi adducts as bifunctional starting materials was synthesized and used in this transformation. The mechanistic pathway of this reaction was investigated using experimental and theoretical studies.

Merging Electrochemical Synthesis and Post-Ugi Cyclization for the Synthesis of Diverse 4-Imidazolidinones.

Despite the appreciation for electro-organic synthesis, postmulticomponent reaction transformation chemistry rarely exploits this powerful technology. Herein, we explore post-Ugi cyclization reactions using N-centered radical-mediated intramolecular ipso cyclization to synthesize diverse spirocyclic variants of 4-imidazolidinones through the use of electrochemically generated amidyl radicals from the bis-amides of the Ugi adducts. This protocol features an undivided cell setup under constant-current conditions with carbon-platinum electrodes. These metal- and reagent-free reactions are scalable and have broad substrate scope.

Unexpected Cascade Sequence Forming the C(sp3)-N/C(sp2)-C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed a high cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 μM). Taken together, our findings revealed new insights into the molecular mechanisms underlying compound 7l and provided potential usage of this scaffold for cancer therapeutics.

KOtBu-catalyzed protocol for the post-ugi synthesis of spiro-γ-lactam-pyrrolo[2,3-b]quinoline derivatives in one-pot

This presentation describes an efficient and facile preparation of a series of new spiro-γ-lactam-pyrrolo[2,3-b]quinoline scaffolds. The Ugi adducts obtained via four-component condensation of 2-chloroquinoline-3-carbaldehydes, amines, trans-cinnamic acids and isocyanides underwent metal-free KOtBu-catalyzed bis-annulation processes to afford a diastereomeric mixture of the desired tetracyclic building blocks in moderate to good yields.

Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

A Mn(OAc)3-Triggered Formation of Cyclopropanes from Ugi Adducts

AbstractUgi adducts involving malonic acid monoesters and dialkoxy-substituted aromatic aldehydes can undergo an oxidative dearomatization when treated with Mn(OAc)3 leading to the formation of fused cyclopropanes as observed in the Buchner reaction of diazo compounds.

Cover Feature: Synthesis of Azaspiro Tricyclic Scaffolds through Post‐Ugi Modifications: Scope and Limitation of Aza‐Michael Cyclization (Eur. J. Org. Chem. 10/2023)

The Cover Feature depicts a gradual process for synthesizing complex azaspiro tricyclic scaffolds starting from common building blocks through substrate-selective post-Ugi modifications that involve spirocyclization and aza-Michael addition, which is depicted by analogy with a tree. The starting materials are illustrated as the soil nutrients that are taken up by roots to generate Ugi adducts. The cover picture was designed by Mr. Kazim, Mr. Mayur D. Ambule, Mr. Mandweep Bhumij, and Dr. Ajay Kumar Srivastava. More information can be found in the Research Article by A. Kumar Srivastava et al.

Recent Access to Polycycles via Post-Ugi Reactions

Ugi reactions have been widely studied due to their mild reaction conditions, high structural variability, and wide applications. Ugi adducts have proved to be highly efficient for different kinds of post-transformations by carefully choosing the starting four components. Considering the importance of polycycles, diverse post-Ugi transformations have been employed for the construction of structurally novel polycyclic N-heterocycles. This minireview summarizes the recent developments of post-Ugi reactions for the synthesis of polycycles after the year 2019. Through transition metal catalysis from gold, rhodium, silver, copper, and palladium, as well as transition metal-free approaches, versatile polycycles are constructed in a highly efficient and step-economical manner.

Propargyl Amines: Versatile Building Blocks in Post-Ugi Transformations.

The Ugi reaction, a multicomponent reaction, allows diversity-oriented synthesis Its importance is recognized by an exponential increase in the publications utilizing the post-Ugi transformations as a strategy to build complex molecules via simple and sustainable processes in the recent literature. A second concept, alkyne activation through metal-, acid-, iodine-catalysis and base-mediated transformations, also leads to wonderful molecules in short and efficient synthetic routes. Combination of these two approaches via application of an alkyne-containing component in the Ugi reaction brings the benefits of both protocols into one synthetic sequence. The propargyl amines come as an obvious choice in this context as they work wonderfully as an amine component in the Ugi reaction, while post-Ugi alkyne activation has the potential to generate biologically interesting carbo- and hetero-cyclic systems. Thus, one can compare the Ugi adduct with a pupa which has inherent property of metamorphosis into biologically interesting molecules. In this review, application of propargyl amines in the Ugi reaction is discussed with a focus on post-Ugi transformations.