L.N. Gumilyov Eurasian National University, a dissertation defense for the degree of Doctor of Philosophy (PhD) by Махмет Азат Максатулы on the topic «Synthesis of diverse heterocycles using multicomponent reactions» by specialty «6D060600 – Chemistry».
The dissertation was carried out at the «Chemistry education department» of L.N. Gumilyov Eurasian National University.
The language of defense is russian
Official reviewers:
Fazylov Serik Drakhmetovich – Doctor of Chemical Sciences, Professor, Chief Researcher of the Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan (Karaganda, Republic of Kazakhstan);
Turmukhanova Mirgul Zhuragatovna – Doctor of Chemical Sciences, Professor of the Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers of the National Joint-Stock Company «Al-Farabi Kazakh National University» (Almaty, Republic of Kazakhstan).
Temporary members of the Dissertation Council:
Chugunova Elena Aleksandrovna – Doctor of Chemical Sciences, Professor, Leading Researcher at the A.E. Arbuzov Institute of Organic and Physical Chemistry (Kazan, Russia);
Dzhalmakhanbetova Roza Ilemisovna – Doctor of Chemical Sciences, Associate Professor, Docent of the Department of Chemistry of the L.N. Gumilyov Eurasian National University (Astana, Republic of Kazakhstan);
Appazov Nurbol Orynbasaruly – Candidate of chemical sciences, Professor, Professor-Researcher at Korkyt Ata Kyzylorda State University (Kyzylorda, Republic of Kazakhstan).
Scientific advisors:
Rakhmetulla Sharapidenovich Yerkasov, Doctor of Chemical Sciences, Professor at the Department of Chemistry, L.N. Gumilyov Eurasian National University.
Dmitry Viktorovich Dar’in, Doctor of Chemical Sciences, Professor at the Institute of Chemistry, Saint Petersburg State University.
The defense will take place on February 27, 2026, at 03:00 PM in the Dissertation Council for the training direction «8D053 – Physical and chemical sciences» in the specialty «6D060600 – Химия » of L.N. Gumilyov Eurasian National University. The dissertation council meetings will be held offline and online.
Link: https://clck.ru/3RJMhd
Address: Satpayev Street, 2, Room: 302., Astana
Abstract (English): ABSTRACT of the Dissertation Submitted for the Degree of Doctor of Philosophy (PhD) in the Educational Program “6D060600 – Chemistry” by Makhmet Azat Maksatuly “Synthesis of Various Heterocycles via Multicomponent Reactions” General Characteristics of the Dissertation. The combination of two or more reagents into a single product in a strictly defined, controlled, and predictable manner is made possible through multicomponent reactions (MCRs). Several key features distinguish these reactions. Among them are their exceptional efficiency—typically providing high product yields—and their dual economy: first, atom economy, as most atoms from the starting reagents are incorporated into the final product; and second, resource economy, as MCRs minimize the need for excess reagents in organic synthesis. Furthermore, MCRs are technically simple and robust, often requiring only basic laboratory equipment, with many reactions proceeding in open air at ambient temperature (298 K) or with mild heating. The rapid advancement of "multicomponent chemistry" has led to its significant diversification. One of the leading branches involves isocyanide-based multicomponent reactions (IMCRs). In addition to the general advantages of MCRs, IMCRs possess several specific benefits. These include the high reactivity of isocyanide-containing compounds. Few other functional groups—except carbenes and carbon monoxide—can simultaneously react with both nucleophiles and electrophiles at a single carbon center. This unique property of the isocyanide group leads to the formation of so-called α-adducts. Most of the stable covalent C–C bonds formed via IMCRs are chemo-, regio-, and stereoselective. Relevance of the Research Topic. It should be noted that at present, the pharmaceutical industry demonstrates a pressing need not only for new synthetic methodologies for already known biologically active compounds, but also for novel organic molecules with high potential. This demand shapes the agenda of modern fundamental research in the field of organic chemistry. Compounds identified as biologically active in screening campaigns (so-called hits) often possess complex molecular structures; however, from a patentability perspective, the most attractive compounds are those accessible through simple and efficient synthetic methods. Considering current trends in pharmacology, new strategies in organic synthesis are only beginning to emerge, aiming to broaden the structural diversity of compound libraries. As existing experience clearly shows, this demand from the pharmaceutical industry is being increasingly met by such synthetic innovations. The novelty and patentability of newly synthesized biologically active compounds are primarily determined by the uniqueness of their core structure—be it a heterocycle or a linear scaffold. State of the Art. Multicomponent reactions (MCRs) are being actively developed as efficient tools in medicinal chemistry. Among the most thoroughly studied in the pharmacological context are the Ugi, Biginelli, and Castagnoli–Cushman reactions. These processes allow for rapid and diverse molecular modifications, enabling the synthesis of structures with pronounced biological activity, including antitumor, anti-inflammatory, antimicrobial, and neurotropic properties. Reaction products include γ-lactams, dihydropyrimidines, morpholines, and piperidines—structural motifs commonly found in known pharmaceutical agents. Post-Ugi transformations and asymmetric modifications are also widely applied. Despite a high level of development, ongoing challenges remain, such as improving selectivity, achieving stereocontrol, optimizing scalability, and predicting biological activity. These tasks make MCRs a relevant and promising area for further investigation. Multicomponent reactions are a focus of many leading research groups worldwide. These include the laboratory of Jieping Zhu (EPFL, Switzerland), which explores cascade and asymmetric MCRs; the group of Sukbok Chang (KAIST, South Korea), which studies copper-catalyzed transformations; the team of Andrea Basso (Groningen, Netherlands), working on Ugi–azide pathways; and the group of Guangbin Dong (University of Chicago, USA), researching programmable cascades with C–H functionalization. The Krasavin Group (Saint Petersburg State University, Russia) is also actively contributing. Significant advancements are made by institutes of the Max Planck Society and the IBS/KAIST Center. Collectively, these groups shape the current theoretical and practical foundation for MCR-based synthesis of biologically active compounds. Relevance to National Research Programs. The dissertation was carried out as part of joint scientific research conducted at the Department of Chemistry, Faculty of Natural Sciences of L.N. Gumilyov Eurasian National University (Astana, Republic of Kazakhstan), at the Institute of Chemistry of Saint Petersburg State University, in the Laboratory of Bioactive Small Molecule Synthesis (Saint Petersburg, Russian Federation), as well as at the Department of Chemistry, School of Sciences and Humanities of Nazarbayev University (Astana, Republic of Kazakhstan). Research Aim and Objectives The aim of this dissertation is to develop new synthetic strategies based on three distinct multicomponent reactions — the Ugi, Biginelli, and Castagnoli–Cushman reactions — and to provide a comprehensive account of the methodologies for synthesizing structurally complex heterocyclic compounds. This goal reflects an intention to expand the toolbox of organic synthesis by employing efficient one-pot approaches for the construction of biologically relevant scaffolds. To achieve this aim, the following key objectives were addressed: • To implement a new version of the Castagnoli–Cushman reaction based on a three-component process aimed at the synthesis of spirocyclic 2-oxopiperidines and their reduced analogues. • To develop a new approach to the three-component Biginelli reaction involving 2-oxoaldehydes and cyclic 1,3-diketone compounds, followed by photocyclization of the resulting trisubstituted imidazoles into condensed imidazole-containing polycyclic systems. • To carry out a targeted search for new post-Ugi transformations based on the reactivity of the triple bond, exploring changes in regioselectivity of known reactions using hydroxy-propargylamide Ugi adducts. • To provide full spectral characterization of the synthesized compounds, including 1H, 13C NMR, mass spectrometry, and SCXRD data. Objects of the Research. The objects of the research are multicomponent reactions (Ugi, Biginelli, and Castagnoli–Cushman) and their respective post-reaction modifications, employed for the synthesis of novel heterocyclic compounds. In other words, the work focuses on multistep one-pot synthetic processes that enable the construction of structurally complex heterocyclic systems with potentially significant properties from simple starting materials. Subject of the Research. The subject of the research encompasses methodological approaches and specific implementation strategies for the aforementioned multicomponent reactions (including their cascade post-Ugi transformations) aimed at the targeted synthesis of novel heterocyclic compounds—such as morpholines, spiro-lactams of the piperidine series, polycondensed imidazoles, and other structurally complex scaffolds. Thus, the study covers the development of new synthetic routes for these compounds and the optimization of the corresponding reaction conditions. Scientific Novelty The dissertation presents findings that demonstrate significant scientific novelty: • For the first time, a novel variant of the three-component Castagnoli–Cushman reaction has been developed, enabling the synthesis of previously undescribed spirocyclic 2-oxopiperidines and their reduced derivatives (spiropiperidines). • A new three-component Biginelli reaction involving 2-oxoaldehydes and cyclic 1,3-dicarbonyl compounds has been implemented for the first time, followed by photocyclization of the resulting trisubstituted imidazoles into imidazole-fused polycyclic structures. • A novel post-Ugi transformation based on hydroxypropargylamide adducts has been discovered, exhibiting altered regioselectivity and leading to the formation of previously inaccessible heterocyclic systems. • The feasibility of integrating several synthetic approaches—including multicomponent reactions and subsequent modifications—into a single sequence has been demonstrated for the first time, paving the way for the creation of fundamentally new classes of compounds. Theoretical Significance of the Study. The theoretical significance of the dissertation lies in the substantial advancement of knowledge regarding multicomponent reactions (MCRs) and their potential in organic synthesis. The findings contribute to a deeper scientific understanding of the mechanisms and synthetic capabilities of the Ugi, Biginelli, and Castagnoli–Cushman reactions, including their cascade transformations. In particular, the study reveals novel aspects of isocyanide reactivity and the diversity of mechanistic pathways in post-Ugi modifications. The crystal structures of compounds 6c and 7b (from the Castagnoli–Cushman reaction) and 13b (from the Biginelli reaction), determined by single-crystal X-ray diffraction, have been registered in the Cambridge Structural Database. Practical Significance of the Study. The practical significance of the study is defined by the development of efficient methods for the synthesis of novel potentially bioactive compounds. The proposed synthetic strategies enable the formation of structurally diverse and complex heterocycles (morpholine derivatives, spiro-2-oxopiperidines, and fused imidazoles) under mild conditions and with high yields, which is particularly relevant for medicinal chemistry and pharmacology. The research outcomes may be directly applied in the creation of chemical libraries for drug screening. Notably, several of the synthesized compounds have demonstrated biological activity: for example, a series of lactams showed specific agonist activity toward the TAAR1 receptor (EC50 in the low micromolar range), confirming the potential of these structures as scaffolds for the development of novel neurotropic agents. Author’s Contribution. The author’s personal contribution includes the collection, processing, and analysis of literature data related to the dissertation topic, as well as the planning and execution of the experimental work. The PhD candidate participated in the analysis, interpretation, and documentation of the research results, their discussion, and the preparation of scientific articles for publication in international peer-reviewed journals. Main Findings Submitted for Defense The following main results and conclusions are submitted for the defense: • A new three-component method for the synthesis of spiro-2-oxopiperidines (Castagnoli–Cushman reaction) was developed, and subsequent post-Castagnoli transformations were carried out, expanding the range of accessible nitrogen-containing heterocycles. • A modified three-component Biginelli reaction involving 2-oxoaldehydes and cyclic 1,3-diketones has been carried out, resulting in the formation of trisubstituted imidazoles. It has been shown that subsequent photochemical cyclization of these imidazoles leads to the formation of novel condensed polycyclic systems. • A new post-Ugi transformation of hydroxypropargylamides was discovered and investigated, revealing a change in regioselectivity and enabling access to previously inaccessible heterocyclic frameworks; approaches to post-Ugi modifications were developed to increase the structural complexity of the products. • A series of new heterocyclic compounds (morpholines, spiro-lactams, imidazole polycycles) has been synthesized and characterized. It has been shown that some of the obtained compounds exhibit biological activity. Approval of the Research Findings. The results of the dissertation research have been presented through oral and poster communications at the following conferences and symposia: the international conference “XXT-2021: Chemistry and Chemical Technology in the 21st Century” (Tomsk, Russia, 2021). Publications: The main content of the dissertation is presented in two publications published in journals indexed in the international databases Web of Science Core Collection and Scopus (Elsevier) that have an impact factor (IF), as well as in one conference abstract presented at an international scientific conference. 1. Gapanenok Diana, Makhmet Azat, Peshkov Anatoly A., Smirnova Darya, Amire Niyaz, Peshkov Vsevolod A., Spiridonova Darya, Dar’In Dmitry, Balalaie Saeed, Krasavin Mikhail. Multicomponent Assembly of Trisubstituted Imidazoles and Their Photochemical Cyclization into Fused Polyheterocyclic Scaffolds // Journal of Organic Chemistry. – 2022. – Vol. 87, Issue 12. – pp. 7839–7851. https://doi.org/10.1021/acs.joc.2c00475. At the time of its publication in 2022, the Journal of Organic Chemistry had an Impact Factor for 2021 of 4.198, was ranked Q1 in Organic Chemistry, and had a CiteScore of 7.2, and percentile in Organic Chemistry 82. 2. Peshkov Anatoly A., Makhmet Azat, Bakulina Olga, Kanov Evgeny, Gainedtinov Raul, Peshkov Vsevolod A., Dar’In Dmitry, Krasavin Mikhail. A General Approach to Spirocyclic Piperidines via Castagnoli–Cushman Chemistry // Synthesis. – 2022. – Vol. 54, Issue 11. – pp. 2604–2615. https://doi.org/10.1055/s-0040-1719878. At the time of its publication in 2022, the journal Synthesis had an Impact Factor for 2020 of 3.157, was ranked Q2 in Organic Chemistry, had a CiteScore of 5.5, and 75 percentile in Organic Chemistry, and percentile in Catalysis 51. 3. A.M. Makhmet, M. Zaman, M. Hasan, A.A. Peshkov, V.A. Peshkov. Diastereoselective synthesis of tetrahydroisoquinolines through the Pd-catalyzed post-Ugi transformation // Chemistry and Chemical Technology in the 21st Century: Proceedings of the International Scientific and Practical Conference. Thesis. – Tomsk, 2021. – Vol. 2. – pp. 205–206. Structure of the Dissertation. The dissertation consists of 107 pages and includes 6 tables, 7 figures, 66 schemes, 193 references, and three appendices with a total volume of 54 pages. The main body comprises the following sections: a literature review, the main theoretical and experimental research part, a conclusion, and a list of references.
Conclusion of the Research Ethics Committee
Defense of the dissertation: https://youtu.be/ecwQZOeWPXI?si=-s_tZ5ESnwwNGc-C
