Organophosphorus Chemistry: A New Perspective 9783036580371

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Organophosphorus Chemistry A New Perspective

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Organophosphorus Chemistry: A New Perspective

Organophosphorus Chemistry: A New Perspective

Editor Jakub Adamek

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Editor Jakub Adamek Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology Silesian University of Technology Gliwice Poland

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This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049)

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Contents About the Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Jakub Adamek Special Issue “Organophosphorus Chemistry: A New Perspective” Reprinted from: Molecules 2023, 28, 4752, doi:10.3390/molecules28124752 . . . . . . . . . . . . . .

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Jakub Adamek, Mirosława Grymel, Anna Ku´znik and Agnieszka Pa´zdzierniok-Holewa 1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review † Reprinted from: Molecules 2022, 27, 1562, doi:10.3390/molecules27051562 . . . . . . . . . . . . . .

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Mirosława Grymel, Anna Lalik, Alicja Kazek-K˛esik, Marietta Szewczyk, Patrycja Grabiec and Karol Erfurt Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin Reprinted from: Molecules 2022, 27, 5156, doi:10.3390/molecules27165156 . . . . . . . . . . . . . . 37 Anna Ku´znik, Dominika Kozicka, Wioleta Hawranek, Karolina Socha and Karol Erfurt One-Pot and Catalyst-Free Transformation of N-Protected 1-Amino-1-Ethoxyalkylphosphonates into Bisphosphonic Analogs of Protein and Non-Protein α-Amino Acids Reprinted from: Molecules 2022, 27, 3571, doi:10.3390/molecules27113571 . . . . . . . . . . . . . . 57 Maria Vassaki, Savvina Lazarou, Petri Turhanen, Duane Choquesillo-Lazarte and Konstantinos D. Demadis Drug-Inclusive Inorganic–Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate Reprinted from: Molecules 2022, 27, 6212, doi:10.3390/molecules27196212 . . . . . . . . . . . . . . 81 Esa Kukkonen, Emilia Josefiina Virtanen and Jani Olavi Moilanen α-Aminophosphonates, -Phosphinates, and -Phosphine Oxides as Extraction and Precipitation Agents for Rare Earth Metals, Thorium, and Uranium: A Review Reprinted from: Molecules 2022, 27, 3465, doi:10.3390/molecules27113465 . . . . . . . . . . . . . . 95 Anna Brol and Tomasz K. Olszewski Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity Reprinted from: Molecules 2022, 27, 8849, doi:10.3390/molecules27248849 . . . . . . . . . . . . . . 123 Xabier del Corte, Aitor Maestro, Adrián López-Francés, Francisco Palacios and Javier Vicario Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents Reprinted from: Molecules 2022, 27, 8024, doi:10.3390/molecules27228024 . . . . . . . . . . . . . . 139 Ewa Chmielewska, Natalia Miodowska, Bła˙zej Dziuk, Mateusz Psurski and Paweł Kafarski One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates Reprinted from: Molecules 2023, 28, 3135, doi:10.3390/molecules28073135 . . . . . . . . . . . . . . 161 Ignacy Janicki and Piotr Kiełbasinski ´ Highly Z-Selective Horner–Wadsworth–Emmons Olefination Using Modified Still–Gennari-Type Reagents Reprinted from: Molecules 2022, 27, 7138, doi:10.3390/molecules27207138 . . . . . . . . . . . . . . 179 v

Marek Koprowski, Krzysztof Owsianik, Łucja Knopik, Vivek Vivek, Adrian Romaniuk and Ewa Ró˙zycka-Sokołowska et al. Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII , PIV , PV ) Substituted Acenes with More Than Two Fused Benzene Rings Reprinted from: Molecules 2022, 27, 6611, doi:10.3390/molecules27196611 . . . . . . . . . . . . . . 189

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About the Editor Jakub Adamek Jakub Adamek graduated from the Faculty of Chemistry of the Silesian University of Technology in 2008. Four years later, he completed his Ph.D. thesis entitled “Studies on the transformation of α-amino acids in their phosphorus analogs via 1-(N-acylamino)alkylphosphonium salts” and he won the Sigma-Aldrich and Polish Chemical Society Award for the best Ph.D. thesis in organic chemistry (2013). In 2023, he completed his habilitation entitled “Structure/reactivity correlation for phosphonium precursors in reactions via iminium cation/imine-type systems”. Currently, he is an Assistant Professor at the Department of Organic Chemistry, Bioorganic Chemistry, and Biotechnology of the Silesian University of Technology in Gliwice. His main research interests are focused on organic chemistry with a special emphasis on modern synthetic methodologies (electroorganic synthesis, microwave- and ultrasound-assisted synthesis), reaction mechanisms, and structure elucidation of novel organic compounds using spectroscopy. These topics are mainly associated with organophosphorus compounds. As part of the research activity, he published three chapters in monographs and more than 30 scientific papers. He is also a co-author of nine patents and over 55 oral and poster communications at national and international scientific conferences. He has participated in five national and one international research projects.

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molecules Editorial

Special Issue “Organophosphorus Chemistry: A New Perspective”

Jakub Adamek 1,2 1

2

Citation: Adamek, J. Special Issue “Organophosphorus Chemistry: A New Perspective”. Molecules 2023, 28, 4752. https://doi.org/10.3390/ molecules28124752 Received: 9 June 2023 Accepted: 12 June 2023 Published: 14 June 2023

Copyright:

© 2023 by the author.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland; [email protected]; Tel.: +48-032-237-1724; Fax: +48-032-237-2094 Biotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland

The European Chemical Society (EuChemS) and the European Parliament (Science and Policy Workshop, 25 May 2023) recognize phosphorus as one of the key chemical elements in daily life. It is not only a component of the human body but also a foundation of the agrochemical industry. Today, it is often said that we are living in “the golden age of phosphorus chemistry”. In this context, organophosphorus chemistry is also gaining importance as one of the fastest-growing branches of organic chemistry. In the laboratory, phosphoruscontaining compounds (also called P-compounds) are widely used as reagents (starting materials, precursors of active intermediates such as ylides or iminium-type cations, etc.), catalysts (PTC, organocatalysis), and solvents (PILs) [1–4]. Due to the interesting properties of P-compounds (especially their biological activity), they are used on a large scale in medicine (e.g., bone disorder drugs, anticancer and antiviral agents, and antihelminthics in veterinary applications), agriculture (e.g., pesticides), and industry (e.g., production of lubricants or plastic materials) [5–7]. However, in the age of much-needed care for the natural environment, we face new challenges. Innovative approaches to the synthesis and isolation of P-compounds (taking into account the aspects of green chemistry and sustainability), followed by their responsible use and disposal (neutralization), may prove crucial in the near future. In this Special Issue, seven original research articles and three reviews covering aspects of recent advances in the synthesis, transformation, and properties of organophosphorus compounds were published. The first two articles concern phosphonium salts and the properties of the phosphonium moiety [8,9]. In a review article, Adamek et al. collected information on the synthesis and reactivity of 1-aminoalkylphosphonium derivatives [8]. As shown, these types of compounds can be considered not only as smart synthetic equivalents of N-acyliminium-type cations in the α-amidoalkylation reaction but also as convenient reagents in cyclizations or effective precursors of ylides in the Wittig reaction. In turn, Grymel et al. described the synthesis and, subsequently, the cytotoxicity and antibacterial activity of triphenylphosphonium derivatives of betulin [9]. In total, nine new molecular hybrids of betulin with covalent linkage of the alkyltriphenylphosphonium moiety to the parent skeleton were obtained, with good to excellent yields. They showed high cytotoxicity (greater than natural betulin) toward the cell lines tested (HCT 116 and MCF-7), as well as antimicrobial properties against the Gram-positive reference Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 12228 bacteria. The next two articles address bisphosphoric systems, together with their synthesis and application [10,11]. Ku´znik et al. disclosed a simple and effective strategy for the synthesis of N-protected bisphosphoric analogs of protein and non-protein α-amino acids [10]. Indeed, the method based on the three-component reaction of 1-(N-acylamino)-1ethoxyphosphonates with triphenylphosphonium tetrafluoroborate and triethyl phosphite allowed for the acquisition of 14 compounds with yields in the range of 40–96%. The

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proposed methodology can also be used in the synthesis of unsymmetric bisphosphoric compounds via the sequential formation of C-P bonds with different phosphorus nucleophiles. The importance of research on bisphosphonates was also emphasized by Demadis et al. in their manuscript on drug-inclusive, inorganic–organic hybrid systems for the controlled release of zoledronate [11]. Two coordination polymers containing alkaline earth metal ions (Sr2+ and Ba2+ ) and zoledronate (ZOL, the anti-osteoporotic drug) were synthesized and characterized. On the basis of the conducted studies, the influences of the type of cation on both the initial rate of drug release and the final value of the plateau release were determined. The other articles are related to phosphonate compounds, their synthesis, reactivity, and biological properties [12–16]. Moilanen et al. prepared an interesting review article about the applications of α-aminophosphonates, -phosphinates, and -phosphine oxides as extraction and precipitation agents for rare earth metals, thorium, and uranium [12]. The authors described the most important methods for the synthesis of the abovementioned organophosphorus compounds and characterized their ability as extractants and precipitation agents. Some future perspectives related to the tunability of the solubility and coordination affinity of the α-amino-functionalized organophosphorus compounds were also discussed. Olszewski et al. described the deamination of 1-aminoalkylphosphonic acids in reaction with HNO2 [13]. Mechanistic research and analysis of the obtained products allowed the authors to propose a plausible mechanism reaction with the formation of 1-phosphonoalkylium ions as reactive intermediates. Vicario et al. presented a general strategy for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid with tetrasubstituted carbons via the aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates [14]. In total, more than 20 such compounds were synthesized. Their cytotoxicity was also evaluated, and the structure–activity profile was determined. A one-pot lithiation–phosphonylation protocol to prepare heteroaromatic phosphonic acids was reported by Chmielewska et al. [15]. The scope of application and limitations of the proposed method were explored. The antiproliferative activity of the compounds obtained was also tested. Kiełbasinski ´ and Janicki described the application of alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates in the highly Z-selective Horner–Wadsworth–Emmons olefination as modified Still–Gennari-type reagents [16]. Excellent results, with an up to a 98:2 Z:E product ratio and up to quantitative yield, were achieved using the abovementioned reagents in the olefination of aromatic aldehydes. Finally, the review article prepared by Bałczewski et al. introduces readers to the chemistry of linearly fused aromatics, called acenes [17]. This study is not only a retrospective investigation but also a presentation of the current state of knowledge on the synthesis, properties, and applications of phosphorus (PIII , PIV , PV )-substituted acenes. In conclusion, organophosphorus chemistry continues to attract the unwavering interest of many research groups. The level of the research presented is high, and its subject matter attracts great attention, as evidenced by increasing metrics (citations, views). Therefore, I would like to thank all the authors who chose to report their results in this Special Issue and acknowledge the contributions of the Academic Editors: Gabriele Micheletti, Constantina Papatriantafyllopoulou, Erika Bálint, and György Keglevich; all the peer reviewers; and the members of the Editorial Team, especially Marlene Zhang. Your support has been invaluable. Conflicts of Interest: The author declares no conflict of interest.

References 1. 2. 3.

He, R.; Ding, C.; Marouka, K. Phosphonium Salts as Chiral Phase-Transfer Catalysts: Asymmetric Michael and Mannich Reactions of 3-Aryloxindoles. Angew. Chem. 2009, 48, 4559–4561. [CrossRef] [PubMed] Bradaric, C.J.; Downard, A.; Kennedy, C.; Robertson, A.J.; Zhou, Y. Industrial preparation of phosphonium ionic liquids. Green Chem. 2003, 5, 143–152. [CrossRef] Allen, D.W.; Loakes, D.; Tebby, J. Organophosphorus Chemistry; The Royal Society of Chemistry: London, UK, 2016; Volume 45. [CrossRef]

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4. 5. 6. 7. 8. 9.

10.

11. 12. 13. 14. 15.

16. 17.

Maryanoff, B.E.; Reitz, A.B. The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects. Chem. Rev. 1989, 89, 863–927. [CrossRef] Kolodiazhnyi, O.I. Phosphorus Compounds of Natural Origin: Prebiotic, Stereochemistry, Application. Symmetry 2021, 13, 889. [CrossRef] Russell, R.G.G. Bisphosphonates: The first 40 years. Bone 2011, 49, 2. [CrossRef] Caminade, A.-M. Phosphorus Dendrimers as Nanotools against Cancers. Molecules 2020, 25, 3333. [CrossRef] Adamek, J.; Grymel, M.; Ku´znik, A.; Pa´zdzierniok-Holewa, A. 1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review. Molecules 2022, 27, 1562. [CrossRef] Grymel, M.; Lalik, A.; Kazek-K˛esik, A.; Szewczyk, M.; Grabiec, P.; Erfurt, K. Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin. Molecules 2022, 27, 5156. [CrossRef] [PubMed] Ku´znik, A.; Kozicka, D.; Hawranek, W.; Socha, K.; Erfurt, K. One-Pot and Catalyst-Free Transformation of N-Protected 1-Amino1-Ethoxyalkylphosphonates into Bisphosphonic Analogs of Protein and Non-Protein α-Amino Acids. Molecules 2022, 27, 3571. [CrossRef] [PubMed] Vassaki, M.; Lazarou, S.; Turhanen, P.; Choquesillo-Lazarte, D.; Demadis, K.D. Drug-Inclusive Inorganic–Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate. Molecules 2022, 27, 6212. [CrossRef] Kukkonen, E.; Virtanen, E.J.; Moilanen, J.O. α-Aminophosphonates, -Phosphinates, and -Phosphine Oxides as Extraction and Precipitation Agents for Rare Earth Metals, Thorium, and Uranium: A Review. Molecules 2022, 27, 3465. [CrossRef] [PubMed] Brol, A.; Olszewski, T.K. Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity. Molecules 2022, 27, 8849. [CrossRef] [PubMed] del Corte, X.; Maestro, A.; López-Francés, A.; Palacios, F.; Vicario, J. Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents. Molecules 2022, 27, 8024. [CrossRef] [PubMed] Chmielewska, E.; Miodowska, N.; Dziuk, B.; Psurski, M.; Kafarski, P. One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates. Molecules 2023, 28, 3135. [CrossRef] [PubMed] Janicki, I.; Kiełbasinski, ´ P. Highly Z-Selective Horner–Wadsworth–Emmons Olefination Using Modified Still–Gennari-Type Reagents. Molecules 2022, 27, 7138. [CrossRef] [PubMed] ˙ Koprowski, M.; Owsianik, K.; Knopik, Ł.; Vivek, V.; Romaniuk, A.; Rózycka-Sokołowska, E.; Bałczewski, P. Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII , PIV , PV ) Substituted Acenes with More Than Two Fused Benzene Rings. Molecules 2022, 27, 6611. [CrossRef] [PubMed]

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molecules Review

1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review † Jakub Adamek 1,2, * , Mirosława Grymel 1,2,3 , Anna Ku´znik 1,2 1

2 3

* †

Citation: Adamek, J.; Grymel, M.; Ku´znik, A.; Pa´zdzierniok-Holewa, A. 1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review. Molecules 2022, 27, 1562. https://doi.org/10.3390/ molecules27051562 Academic Editor: György Keglevich Received: 26 January 2022 Accepted: 24 February 2022 Published: 26 February 2022

and Agnieszka Pa´zdzierniok-Holewa 1,2

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland; [email protected] (M.G.); [email protected] (A.K.); [email protected] (A.P.-H.) Biotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland Department of Chemical Organic Technology and Petrochemistry, Faculty of Chemistry, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland Correspondence: [email protected]; Tel.: +48-032-237-1724; Fax: +48-032-237-2094 With a special dedication to Roman Mazurkiewicz in honor of the achievements within his career along with thanks from his scientific pupils.

Abstract: N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In this context, 1-aminoalkyltriarylphosphonium derivatives deserve particular attention. The positively charged phosphonium moiety located in the immediate vicinity of the N-acyl group significantly facilitates Cα -P+ bond breaking, even without the use of catalyst. Moreover, minor structural modifications of 1-aminoalkyltriarylphosphonium derivatives make it possible to modulate their reactivity in a simple way. Therefore, these types of compounds can be considered as smart synthetic equivalents of N-acyliminium-type cations. This review intends to familiarize a wide audience with the unique properties of 1-aminoalkyltriarylphosphonium derivatives and encourage their wider use in organic synthesis. Hence, the most important methods for the preparation of 1-aminoalkyltriarylphosphonium salts, as well as the area of their potential synthetic utilization, are demonstrated. In particular, the structure–reactivity correlations for the phosphonium salts are discussed. It was shown that 1-aminoalkyltriarylphosphonium salts are not only an interesting alternative to other α-amidoalkylating agents but also can be used in such important transformations as the Wittig reaction or heterocyclizations. Finally, the prospects and limitations of their further applications in synthesis and medicinal chemistry were considered. Keywords: phosphonium salts; N-acyliminium cations; α-amidoalkylation; α-amidoalkylating agents; ylides; Wittig reaction

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Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

1. Introduction α-Amidoalkylation reactions play an increasingly important role in organic synthesis as convenient and effective methods for the formation of C-C and C-heteroatom bonds, particularly of the intramolecular type, allowing the synthesis of carbo- or heterocyclic systems. In most cases, N-acylimine 2 or N-acyliminium cations 3 are the correct αamidoalkylating agents and they are generated from precursors with the relevant structure 1 (Scheme 1) [1–23]. Many examples of α-amidoalkylating agent precursors and their applications in α-amidoalkylations have been reported in the literature. A brief summary is given in Table 1. Compared to the precursors described therein, 1-aminoalkylphosphonium derivatives are relatively unknown compounds. However, they have unique structural features

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which promote the generation of N-acyliminium-type cations. One of the most important 2 of 34 is the presence of a positively charged phosphonium moiety (which easily departs as triarylphosphine PAr3 ) in the immediate vicinity of the acyl group.

Scheme 1. The α-amidoalkylation reaction.

Many examples of α-amidoalkylating agent precursors and their applications in αamidoalkylations have been reported in the literature. A brief summary is given in Table 1. Compared to the precursors described therein, 1-aminoalkylphosphonium derivatives are relatively unknown compounds. However, they have unique structural features which promote the generation of N-acyliminium-type cations. One of the most important is the presence of a positively charged phosphonium moiety (which easily departs as triarylphosphine PAr3) in the immediate vicinity of the acyl group. Scheme Theα-amidoalkylation α-amidoalkylation reaction. Scheme 1.1.The Moreover, the reactivity ofreaction. 1-aminoalkylphosphonium derivatives can be modulated by simple structural modifications, e.g., by changing the amino protecting group or by the Moreover, the reactivity of 1-aminoalkylphosphonium derivatives be modulated Many examples of α-amidoalkylating agent precursors and their can applications in αintroduction of electron-withdrawing substituents to the phosphonium moiety (replacing by simple structural modifications, e.g.,inbythe changing theAamino protectingisgroup orinby the amidoalkylations have been reported literature. brief summary given Table Ph3P by (3-C6H4Cl)3P or (4-C6H4CF3)3P; see Figure 1). Depending on the structure of the introduction oftoelectron-withdrawing substituents to the phosphonium moietyderivatives (replacing 1. Compared the precursors described therein, 1-aminoalkylphosphonium phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. Ph by (3-C6 Hunknown (4-C6 H4 CF3 )3However, P; see Figure 1).have Depending on the structure of 4 Cl)3 P or compounds. are3 Prelatively they unique structural features However, the introduction of the abovementioned activating structural modifications the phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. which one, promote the generation of N-acyliminium-type cations. Oneand of the most important allows in many cases, to conduct the reactions under milder even catalyst-free However, the introduction of the abovementioned activating structural modifications is the presence of a positively charged phosphonium moiety (which easily departs as conditions. Furthermore, such modifications not only affect the reactivity but also the allows one, in many cases, to conduct the reactions under milder and even catalyst-free triarylphosphine PAr 3) in the immediate vicinity of the acyl group. course of the reaction (for example, to reduce side reactions), or even make it possible to conditions. Furthermore, such of modifications not only affect thederivatives reactivity but the course Moreover, the reactivity 1-aminoalkylphosphonium canalso be the modulated change the type of reaction taking place (the α-amidoalkylation reaction vs Wittig of reaction (for example, to reduce reactions),the or amino even make it possible bythe simple structural modifications, e.g.,side by changing protecting grouptoorchange by the reaction). the type of reaction taking place (the α-amidoalkylation reaction vs the Wittig reaction). introduction of electron-withdrawing substituents to the phosphonium moiety (replacing Ph3P by (3-C6H4Cl)3P or (4-C6H4CF3)3P; see Figure 1). Depending on the structure of the phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. However, the introduction of the abovementioned activating structural modifications allows one, in many cases, to conduct the reactions under milder and even catalyst-free conditions. Furthermore, such modifications not only affect the reactivity but also the course of the reaction (for example, to reduce side reactions), or even make it possible to change the type of reaction taking place (the α-amidoalkylation reaction vs the Wittig reaction).

Figure 1. 1. Areas Areas ofofpotential potentialstructural structural modifications within phosphonium precursors of αmodifications within phosphonium precursors of α-amid amidoalkylating agents. oalkylating agents.

The main purpose of this review paper is to organize and disseminate current knowledge about 1-aminoalkylphosphonium derivatives. To help understand the presented issues, three classes of these P-compounds have been distinguished. Three separate chapters

Figure 1. Areas of potential structural modifications within phosphonium precursors of α6 amidoalkylating agents.

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3 of 34 33 of of 34 34 3 of 34

The main purpose of this review paper is to organize and disseminate current The purpose of review this review to organize and disseminate current knowledge about 1-aminoalkylphosphonium derivatives. help understand the The mainmain purpose of this paperpaper is to isorganize andTo disseminate current knowledge about 1-aminoalkylphosphonium derivatives. To help understand the presented issues, three classes of these P-compounds haveTo been distinguished. knowledge about 1-aminoalkylphosphonium derivatives. help understandThree the seppresented issues, classes these P-compounds have distinguished. separate chapters arethree dedicated toof them, where general the most important presented issues, three classes of these P-compounds haveproperties, been been distinguished. ThreeThree sep-methchapters are dedicated toas them, where general properties, the most important ods for preparation astowell synthetic applications are Particularly, the aratearate chapters are dedicated them, where general properties, thedescribed. most important meth-methare dedicated to them, where general properties, the most important methods Particularly, for prepara- the ods for preparation as well as synthetic applications are described. correlation between the structure and applications the reactivityare of phosphonium derivativesthe I-III is ods for preparation as well as synthetic described. Particularly, tion as well as synthetic applications are and described. Particularly, the correlationderivatives between the correlation between the structure the reactivity of phosphonium I-III is discussed. Scheme provides a classification and brief summaryderivatives of the chemistry of 1correlation between the 2structure and the reactivity ofaphosphonium I-III is structure and the reactivity of phosphonium derivatives I-III issummary discussed. Scheme 2 pro-of 1discussed. Scheme 2 provides a classification and a brief of the chemistry aminoalkylphosphonium discussed. Scheme 2 provides aderivatives. classification and a brief summary of the chemistry of 1videsaminoalkylphosphonium a classification and a briefderivatives. summary of the chemistry of 1-aminoalkylphosphonium aminoalkylphosphonium derivatives. derivatives.

Scheme 2. Classification and reactivity of 1-aminoalkylphosphonium derivatives. Scheme 2. Classification and reactivity of 1-aminoalkylphosphonium derivatives. Scheme 2. and of derivatives. Scheme 2. Classification Classification and reactivity reactivity of 1-aminoalkylphosphonium 1-aminoalkylphosphonium derivatives. Table 1. Summary of characteristics for the most important precursors of α-amidoalkylating agents 1. Summary of characteristics for theimportant most important precursors of α-amidoalkylating 1.1. Table of for most precursors ofof α-amidoalkylating agents 1.agents TableTable 1. Summary Summary ofcharacteristics characteristics forthe the most important precursors α-amidoalkylating agents 1. 1. of Use in αExamples of Use inExamples α-Amidoalkylation Examples of Use Amidoalkylation in α- in αStructure Summary of Characteristics (SelectedExamples Research of or Use Review Structure of of Precursor Precursor Summary of Characteristics Amidoalkylation a (Selected Research Amidoalkylation or Review Literature) Structure of Precursor Summary of Characteristics Structure of Precursor Summary of Characteristics a Review (Selected Research or Literature) (Selected Research or Review limited structural diversity, limited reactivity, aa Literature) a limitedparent structural diversity, reactivity, parent compounds for the Literature) compounds forlimited the other α-amidoalkylating limited structural diversity, limited reactivity, parent compounds for the other α-amidoalkylating agents, activation withsynthesis acidic catalysts, limited structural diversity, limited reactivity, parent compounds for synthesis the agents, activation with acidic catalysts, [3,4,6–12] [3,4,6–12] α-amidoalkylating agents, activation with acidic synthesis from amides (oragents, imides) and aldehydes (mostly in catalysts, situ)—only Nother other α-amidoalkylating activation with acidic catalysts, synthesis from amides (or imides) and aldehydes (mostly in [3,4,6–12] [3,4,6–12] amides (orN-hydoxymethylamides imides) and (mostly in situ)—only hydoxymethylamides (oraldehydes -imides) can be easily isolated situ)—only (orin -imides) from from amides (or imides) and aldehydes (mostly situ)—only N- Nhydoxymethylamides (or isolated -imides) be easily isolated can be hydoxymethylamides (oreasily -imides) can becan easily isolated limited reactivity, high structural diversity, activation with acidic [5–9,12–14] limited reactivity, high structural diversity, limited reactivity, high structural diversity, activation with acidic catalysts, main synthesis methods based on electrochemical alkoxylation limited reactivity, high structural diversity, activation with acidic [5–9,12–14] activation with acidic catalysts, main synthesis [5–9,12–14] [5–9,12–14] catalysts, synthesis methods on electrochemical alkoxylation catalysts, main main synthesis methods basedbased on electrochemical alkoxylation methods based on electrochemical alkoxylation high reactivity, rather low yields in low α-amidoalkylation reactions (lots of high reactivity, rather yields in [6–9,12] high reactivity, rather low yields in α-amidoalkylation reactions (lots of by-products), difficulties in the preparation, purification high reactivity, rather low yields in α-amidoalkylation reactionsand (lotsstorage of α-amidoalkylation reactions (lots of by-products), [6–9,12] [6–9,12] [6–9,12] by-products), difficulties inpreparation, the preparation, purification and storage difficulties in the preparation, purification andand storage by-products), difficulties in the purification storage high reactivity (good leaving group), high structural diversity, activation high catalysts, reactivity (good group), high high reactivity leaving group), high structural diversity, activation with acidic easy toleaving use and storage, diverse methods of [8,9,12,16–19] high reactivity (good(good leaving group), high structural diversity, activation structural diversity, activation with acidic catalysts, with acidic catalysts, easy to use and storage, diverse methods of [8,9,12,16–19] synthesis, broad of application [8,9,12,16–19] with acidic catalysts, easy to use andscope storage, diverse methods of [8,9,12,16–19] easy to use and storage, diverse methods of synthesis, broad scope of application synthesis, broad scope of application synthesis, broad scope of application

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Table 1. Cont.

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Examples of Use in α-Amidoalkylation 4 of 34 Structure of Precursor Summary of Characteristics (Selected Research or Review Literature) a high reactivity (good leaving group), high structural diversity, activation with catalysts, easy to use and storage, diverse high(good reactivity (good leaving group), highmethods highacidic reactivity leaving group), high structural diversity,ofactivation [8,9,12,20–23] synthesis, broad scope of application, currently the most popular and of structural diversity, activation with acidic catalysts, with acidic catalysts, easy to use and storage, diverse methods [8,9,12,20–23] easy to use and storage, diverse methods of [8,9,12,20–23] synthesis, broad scope ofconvenient application, currently the most popular and a Selected synthesis, broad scope of application, currently the examples aimed at showing the most recent interest in α-amidoalkylation reactions. convenient most popular and convenient a Selected examples aimed at showing the most recent interest in α-amidoalkylation reactions. a

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examples aimed at showing the most recent interest in α-amidoalkylation reactions. 2.Selected 1-Aminoalkyltriarylphosphonium Derivatives

2.1. 1-(N-acylamino)alkylphosphonium Salts Derivatives 2. 1-Aminoalkyltriarylphosphonium 2. 1-Aminoalkyltriarylphosphonium Derivatives Compounds with general formula (Figure 2) are often called 1-(N-acylamino)al2.1. 1-(N-acylamino)alkylphosphonium 2.1. 1-(N-acylamino)alkylphosphonium Salts4Salts kylphosphonium salts, because a lot of the described models are amide derivatives (e.g., Compounds with general formula 4 (Figure 2) are often called 1-(N-acylamino)alCompounds with general formula 4 (Figure 2) are often called 1-(N-acylamino)alkylph 3 = H). It is not an exact name because this group also R1 = kylphosphonium H, Me, Et, t-Bu, Ph, Bn, etc.; R salts, because a lot of themodels described modelsderivatives are amide (e.g., derivatives osphonium salts, because a lot of the described are amide R1 = H,(e.g., includes lactams (e.g., R1,Ph, R3 =Bn, (CH 2)3), carbamates (R1 an = t-BuO, BnO; because R3 = H) or urea de- also 1 = H, 3 = H). It is not 3 R Me, Et, t-Bu, etc.; R exact name this group Me, Et, t-Bu, Ph, 1Bn, etc.; R 3= H). It is not an exact name because this group also includes 2 = H), alkyl rivatives (e.g., R = NMe 2, R =H). In the α-position, there may be hydrogen (R 1 3 1 3 1 3 1 3 includes lactams = (CH2)3),(R carbamates (R = t-BuO, R =derivatives H) or urea delactams (e.g., R , R = (e.g., (CH2 )R3 ),, 2R carbamates = t-BuO, BnO; R = H)BnO; or urea (R2 = Me, Et, i-Bu, etc.), (R =3 =H). Ph, 2-thienyl, 1-naphtyl, etc.)may or more complex(R substitu-alkyl 1 = aryl 3R 2= NMe 2, R In the α-position, there be hydrogen (e.g., rivatives R1 = NMe(e.g., , R =H). In the α-position, there may be hydrogen (R H), alkyl (R22 ==H), Me, 2 ents (R(e.g., CH 2CO2-t-Bu, CH 2 C 6 H 4 OBn, PO(OEt) 2 etc.). The positively charged tri2 = Me, 2 2 Et, i-Bu, etc.), aryl (R = Ph, 2-thienyl, 1-naphtyl, etc.) or more complex substituEt, i-Bu, etc.), aryl (R = Ph, 2-thienyl, 1-naphtyl, etc.) or more complex substituents (e.g., arylphosphonium group PAr 3 (Ar = Ph, 3-C6H4Cl, 4-C6H4CF3) is also directly bonded to ents2 -t-Bu, (e.g.,CH CH -t-Bu,PO(OEt) CH2C6H 4OBn,The PO(OEt) 2 etc.). The triarylphosphonium positively charged triCH2 CO positively charged 2 C2CO 6 H42OBn, 2 etc.). Cα. arylphosphonium group PAr3 (Ar = Ph, 3-C6H4Cl, 4-C6H4CF3) is also directly bonded to group PAr3 (Ar = Ph, 3-C6 H4 Cl, 4-C6 H4 CF3 ) is also directly bonded to Cα . Cα.

Figure 2. 2. General General structure structure of of 1-(N-acylamino)alkylphosphonium 1-(N-acylamino)alkylphosphonium salts salts 4. 4. Figure Figure 2. General structure of 1-(N-acylamino)alkylphosphonium salts 4.

1-(N-acylamino)alkyltriphenylphosphonium areare crystalline, stable at 1-(N-acylamino)alkyltriphenylphosphoniumsalts salts4 4(Ar (Ar= =Ph) Ph) crystalline, stable room temperature compounds that can be stored under laboratory conditions for a long at room temperature compounds that can be stored under laboratory conditions for a long 1-(N-acylamino)alkyltriphenylphosphonium salts 4 (Ar = Ph) are crystalline, stable time. are well soluble in DCM and MeCN, but insoluble in diethyl ether. The most time.atThey They are well soluble in DCM and MeCN, but insoluble in diethyl ether. The most room temperature compounds that can be stored under laboratory conditions for a long effective method of their purification isiscrystallization from DCM/Et O effective theirsoluble purification crystallization DCM/Et 2Oor orMeCN/Et MeCN/Et Omost 22O time.method They areofwell in DCM and MeCN, butfrom insoluble in 2diethyl ether. The systems. 1-(N-acylamino)alkyltriarylphosphoniumsalts salts 44 which which are are derivatives derivatives of of tritrisystems. 1-(N-acylamino)alkyltriarylphosphonium effective method of their purification is crystallization from DCM/Et2O or MeCN/Et2O arylphosphines with electron-withdrawing electron-withdrawingsubstituents substituents(Ar (Ar = 3-C 4-C H43CF ) arylphosphines with 6H Cl4 Cl or or 4-C 6H46CF ) are 6 4H 3of systems. 1-(N-acylamino)alkyltriarylphosphonium salts= 43-C which are derivatives triare less stable. They are usually synthesized just before the reaction and used without less arylphosphines stable. They arewith usually synthesized just before the reaction and used without puelectron-withdrawing substituents (Ar = 3-C6H4Cl or 4-C6H4CF3) are purifiaction. The type of phosphonium group used has a huge impact on the reactivity of rifiaction. The type of phosphonium group used hasbefore a huge impact on the reactivity of the less stable. They are usually synthesized just the reaction and used without puthe whole molecule, which will be discussed later in this review. whole molecule, which be discussedgroup later inused this has review. rifiaction. The type will of phosphonium a huge impact on the reactivity of the

molecule, which will be discussed later in this review. 2.1.1.whole Preparation 2.1.1. Preparation In the last century, most of the methods for the synthesis of 1-(N-acylamino)alkyltriaryl In thePreparation last century, most of the methods for the synthesis of 1-(N-acylamino)alkyltri2.1.1. phosphonium salts 4 concerned 1-(N-acylamino)methyltriphenylphosphonium salts (4a, arylphosphonium salts 4 concerned 1-(N-acylamino)methyltriphenylphosphonium salts In the last the methods for the synthesis of 1-(N-acylamino)alkyltriR2 = H, Scheme 3). century, Betweenmost 1972ofand 1991, Drach, Brovarets and co-workers [24–27] 2 (4a, R = H, Scheme 3). salts Between 1972 and1-(N-acylamino)methyltriphenylphosphonium 1991, Drach, Brovarets and co-workers [24–27]salts arylphosphonium 4 concerned showed that 1-(N-acylamino)methylphosphonium chlorides (4a, X = Cl) can be obtained, showed that 1-(N-acylamino)methylphosphonium (4a, X = Cl) can be obtained, 2 (4a, R =reactions, H, Scheme Between of 1972 and 1991,chlorides Drach, Brovarets co-workers [24–27] in a simple by3). alkylation triphenylphosphine (but also and tributylphosphine in a showed simple reactions, by alkylation of triphenylphosphine (but also tributylphosphine that 1-(N-acylamino)methylphosphonium chlorides (4a, X = Cl) can be obtained, PBu3 or hexaethylphosphorus triamide P(NEt2 )3 ) with N-(chloromethyl)amides (5, Z = Cl) PBu3inorahexaethylphosphorus triamide P(NEt 2)3) with N-(chloromethyl)amides (5, Z = Cl) reactions, of triphenylphosphine (but (Scheme 3,simple Method A). Theyby alsoalkylation used N-(hydroxymethyl)amides (5, Z =also OH)tributylphosphine as alkylating (Scheme 3, Method A). They also used N-(hydroxymethyl)amides (5, Z = OH) as alkylatPBu 3 or hexaethylphosphorus triamide P(NEt 2 ) 3 ) with N-(chloromethyl)amides Z = Cl) agents, that were N-(chloromethyl)amides precursors (Scheme 3, Method A) [27]. In (5, 1974, ing agents, that were N-(chloromethyl)amides precursors (Scheme 3, Method A) [27]. In (Scheme 3, Method A). similar They also used N-(hydroxymethyl)amides (5, Z temperature, = OH) as alkylatDevlin and Walker reported reactions, which were carried out at room 1974,ing Devlin and Walker reported similar reactions, which were carried out at room temagents, wereThey N-(chloromethyl)amides precursors (Scheme 3, Method A) [27]. In using AcOEt as athat solvent. obtained 1-(N-benzoylamino)methyltriphenylphosphonium perature, using AcOEt solvent. Theyreactions, obtainedwhich 1-(N-benzoylamino)methyltri1974, and similar were carried out at room temX =asBr areported or Cl) from N-(bromomethyl)benzamide or N-(chloromethyl) bromide orDevlin chloride (4a,Walker phenylphosphonium bromide or chloride (4a, X = Br or Cl) N-(bromomethyl)benperature, using AcOEt as a solvent. They obtainedfrom 1-(N-benzoylamino)methyltrizamide or N-(chloromethyl)benzamide, respectively, andfrom 69% N-(bromomethyl)benyield (Scheme 3, phenylphosphonium bromide or chloride (4a, X =inBr54% or Cl) Method A) [28]. Triphenylphosphine was alsorespectively, alkylated with de- 3, zamide or N-(chloromethyl)benzamide, inN-(methoxymethyl)urea 54% and 69% yield (Scheme 8 rivative 6 (Scheme 3, Method B). Reactions were carried out in methanol by bubbling HCl Method A) [28]. Triphenylphosphine was also alkylated with N-(methoxymethyl)urea derivative 6 (Scheme 3, Method B). Reactions were carried out in methanol by bubbling HCl

Molecules 2022, 27, 1562

chloromethylisocyanate or bromomethylisocyanate and further hydrolysis of the isocyanate group (Scheme 3, Method C) [30,31]. In analogous reactions, the corresponding triphenylphosphonium iodides (4a, R1 = OR, X = I) were also obtained by adding methyl iodide in the first step of the synthesis [32]. The same authors also described reactions in which phosphonium salts 4a (R1 = OR, X = Cl) were obtained by alkylation of triphenylphosphine with N-(chloromethyl)carbamates 10, that were previously generated from alcohol and methyl isocyanide (Scheme 3, Method D) [33]. In turn, Zinner and Fehlhammer described the two-stage method for the synthesis of 1-(N-formylamino)mebenzamide, respectively, in 54% and 69% yield (Scheme 3, Method A) [28]. Triphenylphosthyltriphenylphosphonium chloride 4a (R1 = H, X = Cl). Initially, they conducted the alkylphine was also alkylated with N-(methoxymethyl)urea derivative 6 (Scheme 3, Method B). ation of triphenylphosphine using trimethylsilyl isocyanide in the presence of hexachloReactions were carried out in methanol by bubbling HCl gas through the substrate solution roethane in THF. The acidic hydrolysis of indirectly formed isocyanomethyltrior by treating it with aqueous HBr or HI [29]. 1-(N-alkoxycarbonyl)methyltriphenylpho phenylphosphonium chloride 11 finally yielded the expected phosphonium salt 4a sphonium chlorides or bromides (4a, R1 = OR, X = Cl or Br) were obtained by Kozhushko (Scheme 3, Method E) [34]. However, the authors did not report the yield of the hydrolysis et al. in the reaction of triphenylphosphine with chloromethylisocyanate or bromomethylisostep. cyanate and further hydrolysis of the isocyanate group (Scheme 3, Method C) [30,31]. In Only a few of the described methods for synthesizing 1-(N-acylamino)methyltrianalogous reactions, the corresponding triphenylphosphonium iodides (4a, R1 = OR, X = I) phenylphosphonium salts 4a were based on other approaches than the alkylation of triwere also obtained by adding methyl iodide in the first step of the synthesis [32]. The same phenylphosphine by N-(halomethyl)amides, their precursors or related compounds. One authors also described reactions in which phosphonium salts 4a (R1 = OR, X = Cl) were of these methods involved the alkylation of methyl carbamate with hydroxymethyltriobtained by alkylation of triphenylphosphine with N-(chloromethyl)carbamates 10, that phenylphosphonium chloride 12, which resulted in the production of 1-(N-methoxycarwere previously generated from alcohol and methyl isocyanide (Scheme 3, Method D) [33]. bonyl)aminomethyltriphenylphosphonium chloride 4a (R1 = OMe, X = Cl) in 73% yield In turn, Zinner and Fehlhammer described the two-stage method for the synthesis of (Scheme 3, Method F) [35]. Devlin and Walker demonstrated that the treatment of 21-(N-formylamino)methyltriphenylphosphonium chloride 4a (R1 = H, X = Cl). Initially, bromo-2-nitrostyrene 14 with triphenylphosphine in methanol gave the phosphonium they conducted the alkylation of triphenylphosphine using trimethylsilyl isocyanide in salt 15 in 47% yield. The vacuum pyrolysis of salt 15 at 150 °C, reduction with NaHBF4 in the presence of hexachloroethane in THF. The acidic hydrolysis of indirectly formed isomethanol or refluxing in chloroform with addition of bromine led to a mixture containing cyanomethyltriphenylphosphonium chloride 11 finally yielded the1 expected phosphonium 1-(N-benzoylamino)methyltriphenylphosphonium bromide 4a (R = Ph, X = Br) as the salt 4a (Scheme 3, Method E) [34]. However, the authors did not report the yield of the main product (Scheme 3, Method G) [28,36]. hydrolysis step.

Scheme 3. 3. Methods Methodsfor forthe thesynthesis synthesisofof1-(N-acylamino)methyltriphenylphosphonium 1-(N-acylamino)methyltriphenylphosphonium salts Scheme salts 4a.4a.

Only a few of the described methods for synthesizing 1-(N-acylamino)methyltriphenyl phosphonium salts 4a were based on other approaches than the alkylation of triphenylphosphine by N-(halomethyl)amides, their precursors or related compounds. One of these methods involved the alkylation of methyl carbamate with hydroxymethyltriphenylphosphonium chloride 12, which resulted in the production of 1-(N-methoxycarbonyl)aminomethylt riphenylphosphonium chloride 4a (R1 = OMe, X = Cl) in 73% yield (Scheme 3, Method F) [35]. Devlin and Walker demonstrated that the treatment of 2-bromo-2-nitrostyrene 14 with triphenylphosphine in methanol gave the phosphonium salt 15 in 47% yield. The vacuum pyrolysis of salt 15 at 150 ◦ C, reduction with NaHBF4 in methanol or refluxing in chloroform with addition of bromine led to a mixture containing 1-(N-benzoylamino)methyltriph

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enylphosphonium bromide 4a (R1 = Ph, X = Br) as the main product (Scheme 3, There few data available in the literature on the synthesis of 1-substituted phosMethod G) are [28,36]. There are few data available in the literature on the synthesis of 1-substituted phosphonium 4. data In 1975, Drach al. demonstrated that of the1-substituted reaction ofphostriThere salts are few available in theetliterature on the synthesis phonium salts 4. In 1975, Drach et al. demonstrated that the reaction of triphenylphosphine with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphophonium salts 4. In 1975, Drach et al. demonstrated that the reaction of triphenylphosphine phenylphosphine with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphonium salts 17 with a benzoyl group at the 1-position. However, salts 17 turned be with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphonium saltsout 17 to with nium salts 17 with a benzoyl group at the 1-position. However, salts 17 turned out to be hygroscopic and unstable. Thus, theHowever, authors decided transform them into more stable a benzoyl group at the 1-position. salts 17toturned out to be hygroscopic and hygroscopic and unstable. Thus, the authors decided to transform them into more stable oxazolones 18 (Scheme 4) [37].decided to transform them into more stable oxazolones 18 unstable. Thus, the authors oxazolones 18 (Scheme 4) [37]. (Scheme 4) [37].

Scheme 4. Synthesis of 1-(N-acylamino)benzoylmethyltriphenylphosphonium chlorides 17. Scheme 4. Synthesis Synthesis of of 1-(N-acylamino)benzoylmethyltriphenylphosphonium chlorides 17.

Next, Drach et al. described the route for the synthesis of various 1-(N-acylamino)Next, Drach Drach et et al. al. described described the the route route for for the the synthesis synthesis of of various various 1-(N-acylamino)1-(N-acylamino)Next, substituted vinylphosphonium salts 22, which was based on the condensation of trisubstituted vinylphosphonium salts 22, which was based on the condensation triphsubstituted vinylphosphonium salts 22, which was based on the condensationofof triphenylphosphine with N-polychloroalkylamides 19 [38,39]. As reported by the authors, 19 [38,39]. As reported by the authors, in enylphosphine with N-polychloroalkylamides phenylphosphine with N-polychloroalkylamides 19 [38,39]. As reported by the authors, in the first step, thesalts salts2020were wereprobably probablyformed, formed,which which further further split split off hydrogen chlothe first step, the off hydrogen chloin the first step, the salts 20 were probably formed, which further split off hydrogen chloride, ride, resulting resulting in in the the formation formation of of the the corresponding corresponding vinylphosphonium vinylphosphonium salts salts 22, 22, typically typically ride, resulting in the formation of the corresponding vinylphosphonium salts 22, typically in yields above 90% (Scheme 5). 1-(N-acylamino)vinylphosphonium salts (AVPOSs) in yields yields above 1-(N-acylamino)vinylphosphonium salts salts (AVPOSs) (AVPOSs) 22 22 in above 90% 90% (Scheme (Scheme 5). 5). 1-(N-acylamino)vinylphosphonium 22 are unique reagents for various types of heterocyclization, heterocyclization, which was comprehensively are unique reagents for various types of which was comprehensively are unique reagents for various types of heterocyclization, which was comprehensively discussed and co-workers co-workers in 2002 2002 [39]. discussed by by Drach, Drach, Brovarets, Brovarets, and discussed by Drach, Brovarets, and co-workers in in 2002 [39]. [39].

Scheme 5. 5. Synthesis Synthesis of of 1-(N-acylamino)vinylphosphonium 1-(N-acylamino)vinylphosphonium salts salts (AVPOSs) (AVPOSs) 22. Scheme 22. Scheme 5. Synthesis of 1-(N-acylamino)vinylphosphonium salts (AVPOSs) 22.

At about et et al.al. started more extensive research on the At about the thesame sametime, time,Mazurkiewicz Mazurkiewicz started more extensive research on synthe the same time,1-(N-acylamino)alkyltriarylphosphonium Mazurkiewicz et al. started more extensive on the thesisAtofabout structurally diverse saltsresearch 4. Wherein, synthesis of structurally diverse 1-(N-acylamino)alkyltriarylphosphonium salts the 4. synthesis of structurally diverse salts 4. common feature of these methods was1-(N-acylamino)alkyltriarylphosphonium the raw materials, which was N-protected Wherein, the common feature of these methods was the raw materials, which wasα-amino N-proWherein, the feature of these methods was raw materials, which was N-proacids. The usecommon ofacids. α-amino derivatives asthe substrates was greatly advantageous, tected α-amino Theacids use or oftheir α-amino acids or their derivatives as substrates was tected acids. The use of α-amino acids or their derivatives as substrates was due to α-amino almost unlimited availability and structural diversity ofand such compounds. greatly advantageous, due to almost unlimited availability structural diversity of greatly advantageous, duebased to almost unlimited availability and structural diversity of first approach was on using 4-triphenylphosphoranylidene-5(4H)-oxazolones such The compounds. such compounds. 24 or 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 25, obtained from glycine The first approach was based on using 4-triphenylphosphoranylidene-5(4H)-oxaThe 6) first approach was based on using 4-triphenylphosphoranylidene-5(4H)-oxa(Scheme [40]. Phosphoranylidene-5(4H)-oxazolones 24, were hydrolyzed at room temzolones 24 or 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 25, obtained from glycine 2 zolones 24 or 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 25, obtained from glycine perature 6) in[40]. the presence of HBF4 to N-acyl-α-triphenylphosphonioglycines (R tem= H, (Scheme Phosphoranylidene-5(4H)-oxazolones 24, were hydrolyzed at26 room (Scheme 6) [40].Similarly, Phosphoranylidene-5(4H)-oxazolones 24,exposed were hydrolyzed atthe room temScheme 6/A). phosphonium iodides 25 were to water in mixture 2 perature in the presence of HBF4 to N-acyl-α-triphenylphosphonioglycines 26 (R2 = H, perature in the but presence of any HBFacidic 4 to N-acyl-α-triphenylphosphonioglycines 26 (R = H, of THF/DCM, without catalyst. these conditions, Scheme 6/A). Similarly, phosphonium iodides 25 Under were exposed to water incompounds the mixture 25 of Scheme 6/A). Similarly, 25 were exposed to water in the mixture of were transformed, in a phosphonium few days, intoiodides N-acyl-1-triphenylphosphonio-α-amino acids 26 THF/DCM, but without any acidic catalyst. Under these conditions, compounds 25 were THF/DCM, but without anythe acidic Under these conditions, compounds (R2 = Me, Scheme 6/B). In nextcatalyst. stage, 1-triphenylphosphonio-α-amino acids 25 262 were transformed, in a few into N-acyl-1-triphenylphosphonio-α-amino acids 26 (R2 = Me, ◦ C days, heated at 105–115 underinto reduced pressure (5 mmHg) or treated withacids diisopropylethytransformed, in a few days, N-acyl-1-triphenylphosphonio-α-amino 26 (R = Me, Scheme 6/B). In the next stage, acids 26 were heated at ◦ C, which1-triphenylphosphonio-α-amino lamine in DCM at 20 resulted in their decarboxylation to corresponding 1-(NScheme 6/B). In the next stage, 1-triphenylphosphonio-α-amino acids 26 were heated at 105–115 °C under reduced pressure (5 mmHg) or treated with diisopropylethylamine in acylamino)alkyltriphenylphosphonium salts 4, usually in good yields (Scheme 6/C). The 105–115 °C under reduced pressure (5 mmHg) or treated with diisopropylethylamine in DCM at 20 °C, which resulted in their decarboxylation to corresponding 1-(N-acylaauthorsatalso that in the case of hydrolysis of 4-alkyl-4-triphenylphosphonio-5(4H)DCM 20 showed, °C, which resulted in their decarboxylation to corresponding 1-(N-acylamino)alkyltriphenylphosphonium salts 4, usually in good yields (Scheme 6/C). The auoxazolones 25 with a bulky substituent 4-position, the reaction proceeded with simulmino)alkyltriphenylphosphonium saltsin4,the usually in good yields (Scheme 6/C). The authors also showed, that in the case of hydrolysis of 4-alkyl-4-triphenylphosphonio-5(4H)taneous decarboxylation and 1-(N-acylamino)alkyltriphenylphosphonium thors also showed, that in thegave casethe of expected hydrolysis of 4-alkyl-4-triphenylphosphonio-5(4H)oxazolones 25 with a bulky substituent in the 4-position, the reaction proceeded with simsalts 4 in one step (Scheme 6/D) oxazolones 25reaction with a bulky substituent in [41,42]. the 4-position, the reaction proceeded with simultaneous decarboxylation and gave the expected 1-(N-acylamino)alkyltriultaneous decarboxylation and gave the expected 1-(N-acylamino)alkyltriphenylphosphonium salts 4 in one reaction step (Scheme 6/D) [41,42]. phenylphosphonium salts 4 in one reaction step (Scheme 6/D) [41,42].

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Scheme Scheme6. 6.Synthesis of1-(N-acylamino)alkylphosphonium 1-(N-acylamino)alkylphosphonium salts from oxazolones. Scheme 6. Synthesisof 1-(N-acylamino)alkylphosphoniumsalts salts444from fromoxazolones. oxazolones.

However, synthesis of 1-(NHowever, the two mostimportant importantand andgeneral generalmethods methodsfor forthe the synthesis 1-(NHowever, the the two two most most important and general methods for the synthesis ofof 1-(Nacylamino)alkylphosphonium and Adamek in acylamino)alkylphosphonium salts444were weredeveloped developedby byMazurkiewicz Mazurkiewicz and Adamek acylamino)alkylphosphoniumsalts salts were developed by Mazurkiewicz and Adamek inin the the last 10 years (Scheme 7)[43,44]. [43,44]. thelast last10 10years years(Scheme (Scheme7) 7) [43,44].

Scheme salts 4;4;4; Method Scheme 7. Modern strategy inthe the synthesisof of1-(N-acylamino)alkylphosphonium 1-(N-acylamino)alkylphosphonium salts Method Scheme7. 7.Modern Modernstrategy strategyin in thesynthesis synthesis of 1-(N-acylamino)alkylphosphonium salts Method A–Synthesis synthesis A–Synthesisbased basedon theelectrochemical electrochemicalalkoxylation; alkoxylation; Method B–Non-electrochemical synthesis A–Synthesis based on the the electrochemical alkoxylation;Method MethodB–Non-electrochemical B–Non-electrochemical synthesis based basedon onthe theone-pot, one-pot,three threecomponents componentscoupling. coupling. based on the one-pot, three components coupling.

The method begins with the protection of acid Thefirst, first, three-stage method begins with theappropriate appropriate protection ofα-amino α-amino acid The first,three-stage three-stage method begins with the appropriate protection of α-amino functional groups (the 22group susceptible to oxidafunctional groups (theNH NH group andother other groups susceptible toelectrochemical electrochemical oxidaacid functional groups (the NH2 and group andgroups other groups susceptible to electrochemical tion). decarboxylative α-methoxylation (or alkoxytion).Next, Next,electrochemical electrochemical decarboxylative α-methoxylation (ormore moregenerally, generally, alkoxyoxidation). Next, electrochemical decarboxylative α-methoxylation (or more generally, lation) takes place. As the authors noted, the electrochemical oxidations could be carried lation) takes place. As the authors noted, the electrochemical oxidations could be carriedbe alkoxylation) takes place. As the authors noted, the electrochemical oxidations could out in methanol with the addition of sodium methoxide as a base or in the presence of out in methanol with the addition of sodium methoxide as a base in the presence ofaa carried out in methanol with the addition of sodium methoxide as aorbase or in the presence solid-supported base (SiO 2 -Pip); wherein the latter process (based on a solid-supported solid-supported basebase (SiO 2-Pip); wherein thethe latter process (based onona asolid-supported of a solid-supported (SiO wherein latter process (based solid-supported 2 -Pip); base) excellent yields and had less complicated work-up. Recently, base)proceeded proceededin inexcellent excellentyields yieldsand andhad hadaaaless lesscomplicated complicatedwork-up. work-up.Recently, Recently, asimsimbase) proceeded in aasimpler pler more efficient, standardized method using plerand andeven even more efficient, standardized method forpreparation preparation ofN,O-acetals N,O-acetals 30 using and even more efficient, standardized method forfor preparation of of N,O-acetals 3030 using the the available ElectraSyn 2.0 setup (graphite electrodes, room thecommercially commercially available ElectraSyn 2.0 setup(graphite (graphiteelectrodes, electrodes,Et Et33N 3N Nas as base, room commercially available ElectraSyn 2.0 setup Et asaaabase, base, room temp.) temp.)was wasdescribed described[45]. [45]. temp.) was described [45]. The last step is the The last step is the substitutionof of the methoxy group in the reaction ofofN,O-acetals N,O-acetals The last step is thesubstitution substitution ofthe themethoxy methoxygroup groupin inthe thereaction reactionof N,O-acetals 30 with various types of phosphonium salts (Ar 3 P· HX, Scheme 7; Method A). The pro30 with with various various types types of of phosphonium phosphonium salts The pro30 salts (Ar (Ar33P· PHX, ·HX,Scheme Scheme7;7;Method MethodA). A). The proposed method allows high yields (up to 99%) to be obtained not only for the simplest 1posed method method allows bebe obtained notnot only for for the the simplest 1posed allows high highyields yields(up (uptoto99%) 99%)toto obtained only simplest 2 =but (N-acylamino)alkylphosphonium 44(e.g., RR22==RH), more complex (N-acylamino)alkylphosphoniumsalts salts (e.g., H), but also formuch much moremore complex 1-(N-acylamino)alkylphosphonium salts 4 (e.g., H),also but for also for much comstructure, including derivatives of with various substituents (Ar Ph, structure, including derivatives of phosphine phosphine with with various substituents (Ar ==(Ar Ph,=33plex structure, including derivatives of phosphine various substituents Ph, 3-C6 H4 Cl, 4-C6 H4 CF3 ) [43,46]. Moreover, the raw material base can be expanded, since

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C6H4Cl, 4-C6H4CF3) [43,46]. Moreover, the raw material base can be expanded, since Nmethoxyalkyl derivatives can bebe obtained N-methoxyalkyl derivatives can obtainedbybyelectrochemical electrochemicaloxidation oxidationof ofamides, amides,carbacarbamates or lactams. However, this is a less efficient process and an aqueous work-up the mates or lactams. However, this is a less efficient process and an aqueous work-up of of the reaction mixture is is necessary necessary [47]. [47]. reaction mixture In 2021, a procedure for the In 2021, a procedure for the prepartion prepartion of of N-protected N-protected aminoalkylphosphonium aminoalkylphosphonium salts salts (including 1-(N-acylamino)alkylphosphonium ones) in one reaction step from aldehydes (including 1-(N-acylamino)alkylphosphonium ones) in one reaction step from aldehyand either amides, carbamates, lactams, or ureaorinurea the presence of phosphonium salts 33 des and either amides, carbamates, lactams, in the presence of phosphonium -Ar 3 P· HX (Scheme 7; Method B) was described [44]. Using a one-pot methodology, the salts 33 -Ar3 P·HX (Scheme 7; Method B) was described [44]. Using a one-pot methodsimple work-up ofwork-up the reaction mixture (no chromatography) makes 1-(N-acylamino)alology, the simple of the reaction mixture (no chromatography) makes 1-(Nkylphosphonium salts obtainable inobtainable high yieldsinunder relatively mild conditions (even at acylamino)alkylphosphonium salts high yields under relatively mild condi◦ Cfar, room temperature, usually atbut 50 usually °C for 1ath). is the onlyit general method of tions (even at room but temperature, 50So for it 1 h). So far, is the only general obtaining aminoalkylphosphonium salts without use ofthe electrochemical method ofN-protected obtaining N-protected aminoalkylphosphonium saltsthe without use of electrotechniques [44]. Mechanistic studies showed that in the first step of the transformation, chemical techniques [44]. Mechanistic studies showed that in the first step of the transformaaldehydes and phosphonium saltssalts (Ar3P· HX) formform 1-hydroxyalkylphosphonium saltssalts 34, tion, aldehydes and phosphonium (Ar 1-hydroxyalkylphosphonium 3 P·HX) which then react with 31 to togive givethe the desired 1-(N-acylamino)al34, which then react withamide-type amide-typesubstrates substrates 31 desired 1-(N-acylamino)alkylp kylphosphonium 4 in good to excellent yields hosphonium salts salts 4 in good to excellent yields [44]. [44]. Next, it it was the Next, was shown shown that that by by conducting conducting the the reaction reaction step-by-step step-by-step and and changing changing the order of the reacting compounds, 1-(N-acylamino)alkylphosphonium salts 4 could also be order of the reacting compounds, 1-(N-acylamino)alkylphosphonium salts 4 could also be obtained. However, However, the the procedure procedure is is effective effective only only for for formaldehyde formaldehyde (or (or paraformaldeparaformaldeobtained. hyde). Hydroxymethylamides (see also Table 1), hyde). Hydroxymethylamides 35, 35,already alreadymentioned mentionedininthe theintroduction introduction (see also Table areare generated during such a transformation (Scheme 8). This method works wellwell for the 1), generated during such a transformation (Scheme 8). This method works for synthesis of N-protected aminomethyltriarylphosphonium saltssalts 4a, but requires a catalyst the synthesis of N-protected aminomethyltriarylphosphonium 4a, but requires a cat◦ C) [48]. (NaBr) and elevated temperatures (70–135 alyst (NaBr) and elevated temperatures (70–135 °C) [48].

Scheme 8. 8. Step-by-step Step-by-stepprocedure procedure synthesis of N-protected aminomethylphosphonium Scheme forfor thethe synthesis of N-protected aminomethylphosphonium salts 4a.

The presented 8)8) areare based on on a wide andand diverse basebase of raw The presentedmethods methods(Schemes (Schemes7 7and and based a wide diverse of materials (α-amino acids, amide-type compounds, aldehydes), and provide easy access to raw materials (α-amino acids, amide-type compounds, aldehydes), and provide easy acstructurally diversediverse 1-(N-acylamino)alkylphosphonium salts 4salts also4in theinsynthesis on a cess to structurally 1-(N-acylamino)alkylphosphonium also the synthesis larger gram-scale [44,48]. on a larger gram-scale [44,48]. 2.1.2. Synthetic Utilization 2.1.2. Synthetic Utilization Synthetic applications of 1-(N-acylamino)alkylphosphonium salts 4 are summarized Synthetic applications of 1-(N-acylamino)alkylphosphonium salts 4 are summarized in Figure 3. The high reactivity of such compounds is mainly related to the possibility of in Figure 3. The high reactivity of such compounds is mainly related to the possibility of easy cleaving of the C -P++ bond (Scheme 9). easy cleaving of the Cα α-P bond (Scheme 9). The strength of the Cα -P+ bond can be further reduced by introducing electronwithdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6 H4 Cl and 4-C6 H4 CF3 ). The equilibrium in such systems was examined and described in 2018 [46]. As can be seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphosphon ium salts (reactivity: PS-CF3 > PS-Cl > PS-H; stability: PS-CF3 < PS-Cl < PS-H). The ease of formation of iminium-type cations 3 from phosphonium salts 4 was essential in the α-amidoalkylation reactions of various types of nucleophiles (C-nucleophiles and heteronucleophiles). In many cases, the generation of such reactive intermediates can proceed without the use of any catalysts, which is an amazing advantage compared to other α-amidoalkylating agents described in the literature (e.g., N-(1-methoxyalkyl)amides, α-amido sulfones, or N-(benzotriazolylalkyl)amides) [12,20].

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99ofof3434

Figure 3. Applications of 1-(N-acylamino)alkylphosphonium salts 4.

Figure Applicationsofof 1-(N-acylamino)alkylphosphonium salts Figure3.3. 3.Applications Applications of1-(N-acylamino)alkylphosphonium 1-(N-acylamino)alkylphosphoniumsalts salts4.4. 4. Figure

Scheme 9. 1-(N-acylamino)alkyltriarylphosphonium salts 4 as precursors of N-acylimines 2 and Nacyliminium-type cations 3.

The strength of the Cα-P+ bond can be further reduced by introducing electron-withdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6H4Cl and 4C6H4CF3). The equilibrium in such systems was examined and described in 2018 [46]. As can be 9.seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphospho9.1-(N-acylamino)alkyltriarylphosphonium 1-(N-acylamino)alkyltriarylphosphonium salts as precursors N-acylimines and NScheme 1-(N-acylamino)alkyltriarylphosphonium salts 4 precursors as precursors of N-acylimines 2 and Scheme salts 44as ofofN-acylimines 22and Nacyliminium-type cations 3. nium salts (reactivity: PS-CF 3 > PS-Cl > PS-H; stability: PS-CF 3 < PS-Cl < PS-H). acyliminium-type cations 3. N-acyliminium-type cations 3. + +bond Thestrength strengthofofthe theCCα-P α-P bondcan canbe befurther furtherreduced reducedby byintroducing introducingelectron-withelectron-withThe drawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C 6H 4Cl and and 4-4drawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6H 4Cl 6H 4CF 3).The Theequilibrium equilibriumininsuch suchsystems systemswas wasexamined examinedand anddescribed describedinin2018 2018[46]. [46].As As CC6H 4CF 3). canbe beseen, seen,ititisisshifted shiftedtoward towardmore morestable stableand andless lessreactive reactive1-(N-acylamino)alkylphospho1-(N-acylamino)alkylphosphocan niumsalts salts(reactivity: (reactivity:PS-CF PS-CF3 3>>PS-Cl PS-Cl>>PS-H; PS-H;stability: stability:PS-CF PS-CF3 3