Woollins’ Reagent: A Graphical Review of Its Main Synthetic Uses

Abstract

Woollins’ reagent (W.R.) was initially used for the selenation of carbonyl compounds. However, various synthetic applications utilizing this reagent have since been discovered, making it increasingly useful. Examples include the formation of heterocycles, the stereospecific reduction of olefins, and the synthesis of selenoic acids, among others. Consequently, synthetic studies of W.R. derivatives have become increasingly relevant due to the growing demand for selenated compounds in various applications. Two notable examples are the agricultural sector, with the development of pesticides, and the pharmaceutical sector, with the development of antivirals, antioxidants, and neuroprotectors, among others. Hence, this graphical review aims to address the synthetic diversity that W.R. can provide, presenting examples of its main synthetic uses.

Key words

carbonyl selenation - cyclization - stereoselectivity - heterocycles - macrocycles - (E)-olefination - regioselective reduction - selenoamide

Biographical Sketches

João V. X. da Silva is a chemistry student at the Federal University of Rio de Janeiro (UFRJ) and is currently an intern under the supervision of Prof. Sabrina B. Ferreira and Dr. Ingrid­ C. Chipoline. His work involves the synthesis and evaluation of substances generated by artificial intelligence, which are potentially active against SARS-CoV-2. Additionally, he has experience in medicinal organic synthesis for neglected diseases, focusing on leishmaniasis and tuberculosis.

Ingrid C. Chipoline holds a bachelor’s degree in industrial chemistry from the Universidade Federal Fluminense (2016), a master’s degree (2018), and a Ph.D. in chemistry (2022) from the same university. She is currently undertaking postdoctoral research in the field of organic synthesis, with an emphasis on the production of molecules generated by artificial intelligence through flow chemistry on a chip.

Sabrina B. Ferreira received her Ph.D. from the Federal University of Rio de Janeiro (UFRJ) in 2008 under the supervision of Prof. Carlos R. Kaiser and Prof. Vitor F. Ferreira. After postdoctoral studies at Fluminense Federal University (UFF) with Prof. Vitor F. Ferreira, she became a professor at UFRJ in 2010, where she is the head of the Laboratory of Organic Synthesis and Biological Prospecting. Her research efforts focus on organic synthesis in the following areas: heterocycles, carbohydrates, natural products, and the search for biologically active compounds.

Woollins’ reagent (W.R.; C₁₂H₁₀P₂Se₄) is a dark red solid with an unpleasant odor. While this compound poses no inherent risks during handling, it should be stored at approximately 2 °C in an inert environment to maintain its integrity due to its hygroscopic nature.[1a] W.R. has emerged as an analogue to Lawesson’s reagent (LR), both functioning as chalcogen-donating agents for carbonyl compounds, with selenium replacing the oxygen and sulfur in LW.[1b] [c]

In addition to its role as a selenium donor to carbonyl compounds, W.R. has found applications in various other reactions, including the formation of heterocycles containing phosphorus and/or selenium, macrocycle formation, stereospecific generation of (E)-olefins, and regioselective reduction of unsaturated bonds, among others. The synthesis of the reagent employs recent and optimized methodologies, resulting in a high level of purity and excellent yields (96–99%).[1d] [e]

It is noteworthy that selenium compounds have diverse applications across various industrial sectors, contributing to their economic value. These applications span multiple fields, such as the pharmaceutical sector,[1`] [g] [h] including veterinary pharmacology;[1i] agricultural practices using selenium compounds in fertilizers, pesticides and fungicides;[1j] the synthesis of natural products and their analogs;[1k] modification of the mechanical properties of polymeric materials;[1l] and cosmetics.[1m] Hence, the synthetic exploration of selenium-derived compounds assumes increasing importance and necessity.

Figure 1 Formation of Woollins’ reagent and carbonyl selenylation

Figure 2 Formation of heterocycles containing selenium, nitrogen, and oxygen atoms

Figure 3 Chemoselective reduction of conjugated 1,4-dicarbonyl compounds, stereoselective synthesis of (E)-olefins by a reductive coupling reaction and the respective mechanistic proposals

Figure 4 Preparation of heterocycles containing phosphorus, and the formation of macrocyclic compounds along with mechanistic proposals

Figure 5 Selenoic acid formation, sulfoxide reduction (with a mechanistic proposal), hydrogen replacement and organometallic transformations/formation

Figure 6 Natural product applications

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

I extend my gratitude to the Institute of Chemistry at the Federal University of Rio de Janeiro (UFRJ) and to Professor Sabrina Ferreira’s research group for providing me with the knowledge necessary to realize this work.

• References

• 1a Safety Data Sheet, Sigma-Aldrich, 2024 (accessed Sep. 04, 2024); https://www.sigmaaldrich.com/GB/en/sds/aldrich/572543
• 1b Wood PT, Woollins JD. J. Chem. Soc., Chem. Commun. 1988; 1190
• 1c Ozturk T, Ertas E, Mert O. Chem. Rev. 2007; 107: 5210
• 1d Holler S, Tüchler M, Roschger MC, Belaj F, Veiros LF, Kirchner K, Mösch-Zanetti NC. Inorg. Chem. 2017; 56: 12670
• 1e Hua G, Woollins JD. ACS Omega 2021; 6: 31226
• 1f May SW. Selenium-Based Drug Design . In Atypical Elements in Drug Design . Schwarz J. Topics in Medicinal Chemistry, Vol. 17; Springer International Publishing; Switzerland: 2016. 87
• 1g Debnath S, Agarwal A. Kumar N. R., Bedi A. 2022; 2: 595
• 1h Rataan AO, Geary SM, Zakharia Y, Rustum Y, Salem AK. Int. J. Mol. Sci. 2022; 23: 2215
• 1i Humann-Ziehank E. J. Trace Elem. Med. Biol. 2016; 37: 96
• 1j Huang J, Wang Z, Sun L, Wang L, Yin Y. Mod. Agric. 2023; 1: 34
• 1k Cheng K, Sun Y, Liu B, Ming J, Wang L, Xu C, Xiao Y, Zhang C, Shang L. Foods 2023; 12: 3773
• 1l Wojaczynska E, Trochimczuk A. ARKIVOC 2019; 144
• 1m Wei K, Guo C, Zhu J, Wei Y, Wu M, Huang X, Zhang M, Li J, Wang Y, Wei X. Front. Nutr. 2022; 9: 837168
• 2a Bethke J, Karaghiosoff K, Wessjohann LA. Tetrahedron Lett. 2003; 44: 6911
• 2b Jaiswal V, Godara M, Das D, Gandon V, Saha J. J. Org. Chem. 2022; 87: 613
• 2c Zhao Q, Li G, Nareddy P, Jordan F, Lalancette R, Szostak R, Szostak M. Angew. Chem. Int. Ed. 2022; 61: e202207346
• 2d Murai T, Yamaguchi K, Hori F, Maruyama T. J. Org. Chem. 2014; 79: 4930
• 2e Kang X, Huang H, Jiang C, Cheng L, Sang Y, Cai X, Dong Y, Sun L, Wen X, Xi Z, Yi L. J. Am. Chem. Soc. 2022; 144: 3957
• 2f Gray IP, Bhattacharyya P, Slawin AM. Z, Woollins JD. Chem. Eur. J. 2005; 11: 6221
• 3a Hua G, Li Y, Slawin AM. Z, Woollins JD. Org. Lett. 2006; 8: 5251
• 3b Thurow S, Lenardão EJ, Just-Baringo X, Procter DJ. Org. Lett. 2017; 19: 50
• 4a Hua G, Henry JB, Li Y, Mount AR, Slawina AM. Z, Woollins JD. Org. Biomol. Chem. 2010; 8: 1655
• 4b Chen W, Long G, Kanehira K, Zhang M, Michinobu T, Liu M, Zhang Q. Asian J. Org. Chem. 2018; 7: 2213
• 4c Tozawa H, Kitamura K, Hamura T. Chem. Lett. 2017; 46: 703
• 4d Takehiro I, Takashi F. JP Patent 2016160239, 2016
• 4e Hua G, Li Y, Fuller AL, Slawin AM. Z, Woollins JD. Eur. J. Org. Chem. 2009; 1612
• 4f Varshney H, Ahmad A, Rauf A. Arabian J. Chem. 2018; 11: 143
• 4g Zoroddu S, Corona P, Sanna L, Borghi F, Bordoni V, Asproni B, Pinna GA, Bagella L, Murineddu G. Eur. J. Med. Chem. 2022; 238: 114440
• 4h Hua G, Du J, Fuller AL, Arachchige KS. A, Cordes DB, Slawin AM. Z, Woollins JD. Synlett 2015; 26: 839
• 4i Ostrowski W, Gierczyk B, Frański R. J. Heterocycl. Chem. 2012; 49: 1266
• 4j Mandal M, Chatterjee S, Jaisankar P. Synlett 2012; 23: 2615
• 5 Pizzo C, Mahler G. Tetrahedron Lett. 2017; 58: 1445
• 6a Hua G, Li Y, Slawina AM. Z, Woollins JD. Dalton Trans. 2007; 1477
• 6b Zhang A, Jiang W, Wang Z. Angew. Chem. Int. Ed. 2020; 59: 752
• 7a Hua G, Cordes DB, Slawin AM. Z, Woollins JD. Eur. J. Inorg. Chem. 2019; 4682
• 7b Hua G, Du J, Slawin AM. Z, Woollins JD. Chem. Eur. J. 2016; 22: 7782
• 7c Hua G, Fuller AL, Slawin AM. Z, Woollins JD. Eur. J. Org. Chem. 2010; 2607
• 8a Castaño JA. G, Romano RM, Beckers H, Willner H, Boese R, Védova CO. D. Angew. Chem. Int. Ed. 2008; 47: 10114
• 8b Yoshimoto N, Sasaki T, Sugimoto K, Ishii H, Yamamoto K. J. Med. Chem. 2012; 55: 7696
• 8c Itoh T, Yoshimoto N, Hirano Y, Yamamoto K. Bioinorg. Chem. Appl. 2018; 28: 2256
• 8d Tjin CC, Otley KD, Baguley TD, Kurup P, Xu J, Nairn AC, Lombroso PJ, Ellman JA. ACS Cent. Sci. 2017; 3: 1322
• 9 Hua G, Woollins JD. Tetrahedron Lett. 2007; 48: 3677
• 10a Gray IP, Slawina AM. Z, Woollins JD. Dalton Trans. 2005; 2188
• 10b Hua G, Du J, Cordes DB, Slawin AM, Woollins JD. Tetrahedron Lett. 2015; 71: 1792
• 10c Hua G, Li Y, Slawin AM, Woollins JD. Tetrahedron Lett. 2008; 64: 5442
• 10d Ascherl L, Nordheider A, Arachchige KS. A, Cordes DB, Karaghiosoff K, Bühl M, Slawin AM. Z, Woollins JD. Chem. Commun. 2024; 50: 6214
• 10e Hua G, Randall RA. M, Slawin AM. Z, Woollins JD. Z. Anorg. Allg. Chem. 2011; 637: 1800
• 10f Hua G, Du J, Cordes DB, Arachchige KS. A, Slawin AM. Z, Woollins JD. Phosphorus, Sulfur Silicon Relat. Elem. 2016; 191: 341
• 10g Hua G, Randall RA, Slawin AM, Woollins JD. Tetrahedron 2013; 69: 5299
• 10h Hua G, Arachchige KS. A, Slawin AM. Z, Woollins JD. Eur. J. Org. Chem. 2013; 7402
• 10i Hua G, Cordes DB, Slawin AM. Z, Woollins JD. ARKIVOC 2016; (iii): 9
• 11a Wong RC, Ooi ML. Inorg. Chim. Acta 2011; 366: 350
• 11b Ooi ML, Wong RC. S, Robinson WT. Inorg. Chim. Acta 2016; 440: 1
• 11c Shi W, Shafaei-Fallah M, Zhang L, Anson CE, Matern E, Rothenberger A. Chem. Eur. J. 2006; 13: 598
• 11d Shi W, Shafaei-Fallaha M, Rothenberger A. Dalton Trans. 2007; 4255
• 11e Shi W, Zhang L, Shafaei-Fallah M, Rothenberger A. Z. Anorg. Allg. Chem. 2007; 633: 440
• 12a Iwaoka M, Ito S, Miyazaki I. Proc. Natl. Acad. Sci., India Sect. A Phys. Sci. 2016; 86: 499
• 12b Martins IL, Miranda JP, Oliveira NG, Fernandes AS, Gonçalves S, Antunes AM. M. Molecules 2013; 18: 5251
• 12c Martins I, Charneira C, Gandin V, Silva J, Justion G, Telo J, Vieira A, Marzano C, Antunes A. J. Med. Chem. 2015; 58: 4250

Publication History

Received: 24 June 2024

Accepted after revision: 23 August 2024

Article published online:
07 October 2024