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CC BY 4.0 · SynOpen 2025; 09(04): 214-235
DOI: 10.1055/a-2713-6067
graphical review

Approaches to the Construction of Endocyclic Sulfoximines

Autoren

  • Alexey V. Dobrydnev  ∗

    a   Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine
    b   Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine
    c   SMC Ecopharm Ltd., Naberezhno-Korchuvatska Street 136-B, Kyiv 03045, Ukraine
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Graphical Abstract

This work is dedicated to individuals and organizations supporting Ukrainian chemists

Abstract

Endocyclic sulfoximines are a relatively novel class of cyclic sulfoximines where the S(O)=N group is a part of a ring structure. They possess unique physicochemical and structural features, including three-dimensionality and chirality, amid chemical and thermal stability. This graphical review presents a comprehensive compilation of synthetic approaches toward endocyclic sulfoximines, organized by the type of reaction employed. The reaction conditions are presented in a detailed manner; the proposed reaction mechanisms and the catalytic cycles are also provided.


Key words

sulfoximines - S–N bonds - heterocycles - cyclization - catalysis - chirality

Biosketch

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Alexey V. Dobrydnev was born in Kyiv, Ukraine. He received his MS (2006) and Ph.D. (2014) in organic chemistry from the Taras Shevchenko National University of Kyiv. Currently­, he is a postdoctoral, enrolled in a Doctor of Science degree program at the same University and divides his time between Enamine Ltd. (Kyiv, Ukraine) and SMC Ecopharm Ltd. (Kyiv, Ukraine). Alexey is a co-author of more than 60 papers and 8 patents. His scientific interests include synthetic organic, pharmaceutical, and food chemistry, focusing on spirocyclic and heterocyclic compounds, especially those containing sulfur. He collaborates closely with European universities in the above fields, but since 2022, he has been forced to stop active cooperation because of the closed Ukrainian borders for the male population.

Sulfoximines are a relatively novel class of compounds – acyclic representatives have been known since the late 1940s. For around 50 years, sulfoximines were of minor scientific interest only, but nowadays they have been the focus of significant practical interest, garnering attention from organic and medicinal chemists as well as materials scientists. The sulfoximine fragment S(O)=N possesses unusual structural and electronic features,[1] and therefore imparts a unique combination of polarity, hydrogen bonding ability, and three-dimensionality to host molecules. Specifically, the sulfoximine fragment has a pyramidal shape with three points of attachment in orthogonal vectors, owing to which sulfoximines represent the first compounds exhibiting chirality at a sulfur(VI) atom. Besides, sulfoximines are stable toward increased temperature and many common reaction conditions; they do not undergo inversion or racemization upon standing and reacting. Their functionalization is largely related to the reactivity of the nitrogen and carbon atoms α to the sulfur atom. These characteristics allow chemists to escape from flatland,[2] modulate the physicochemical characteristics, and improve pharmacological profiles when creating a new generation of lead compounds or drug candidates.

Cyclic sulfoximines, regarded as separate classes: endocyclic and exocyclic, are even newer. In particular, endocyclic sulfoximines (i.e., those where the S(O)=N group is a part of a ring structure (see Figure 1a)) were synthesized for the first time in 1971 by three independent research groups led by Gerhard Satzinger (Gödecke AG) from Germany, and Carl R. Johnson (Wayne State University) and Donald J. Cram (University of California at Los Angeles) from the United States. Tellingly, cyclic sulfoximines are superior to their linear counterparts concerning their ADME (absorption, distribution, metabolism, and excretion) profile.[3]

Several thematic reviews have been published to date devoted to either the chemistry of sulfoximines[4`] [b] [c] [d] [e] [f] or their applications in medicinal chemistry.[4`] [h] [i] The present graphical review provides a comprehensive compilation of synthetic approaches toward endocyclic sulfoximines, from the historical initial research based on conventional reactions to contemporary noble-metal-catalyzed stereoselective methods. The reviewed synthetic methods are structured according to the type of reaction applied to construct the framework of the endocyclic sulfoximines. The reaction conditions are provided in a detailed manner for a deeper and speculative understanding of the transformations.

With an aim to highlight particular substructures and other aspects, several colors and frames are used. The common substrates and reagents are shown in black, while the sulfoximine group is colored in brown, and the ring of the endocyclic sulfoximine is presented in blue. Compound numbers for endocyclic sulfoximines are given in blue font. The reacting and leaving groups that participate in the cyclizations are colored in green; metal catalysts and ligands are shown in purple. Furthermore, the structure of the target endocyclic sulfoximine in each scheme is placed within a gray rectangular frame, while representative examples (graphical or as a table) are placed on a gray background. The proposed reaction mechanisms and catalytic cycles are placed on a turquoise background.

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Figure 1 Synthesis of endocyclic sulfoximines through CH- and NH-alkylation reactions[3] [5] [6a]
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Figure 2 Synthesis of endocyclic sulfoximines through an electrochemically driven reaction[6b] and Friedel–Crafts alkylation[7]
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Figure 3 Synthesis of endocyclic sulfoximines through a Michael addition strategy,[8] acylation,[9] and a condensation reaction (part 1)[10a]
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Figure 4 Synthesis of endocyclic sulfoximines through a condensation reaction (part 2)[10`] [c] [d]
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Figure 5 Synthesis of endocyclic sulfoximines through a condensation reaction (part 3)[8a] [11] [12]
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Figure 6 Synthesis of endocyclic sulfoximines through a condensation reaction (part 4)[13] and an oxidation reaction (part 1)[9a] [b] , [14] [15] [16a]
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Figure 7 Synthesis of endocyclic sulfoximines through an oxidation reaction (part 2)[16`] [b] [c] [d]
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Figure 8 Synthesis of endocyclic sulfoximines through Pd-catalyzed ring-closing metathesis (RCM),[17a] ring-closing enyne metathesis (RCEYM),[17b] and intramolecular arylation (part 1)[18]
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Figure 9 Synthesis of endocyclic sulfoximines through Pd-catalyzed intramolecular arylation (part 2)[18c] and Rh-catalyzed oxidative annulation (part 1)[19`] [b] [c] [d]
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Figure 10 Synthesis of endocyclic sulfoximines through Pd- and Rh-catalyzed oxidative annulation (part 2)[19d] [e] [20a]
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Figure 11 Synthesis of endocyclic sulfoximines through Cu- and noble-metal-catalyzed annulative coupling (part 3)[20b] [21]
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Figure 12 Synthesis of endocyclic sulfoximines through Rh-catalyzed annulative coupling (part 4)[19c] [22a] [b]
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Figure 13 Synthesis of endocyclic sulfoximines through Rh-catalyzed annulative coupling (part 5)[22b] [c]
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Figure 14 Synthesis of endocyclic sulfoximines through Ir- and Rh-catalyzed annulative coupling (part 6)[22`] [e] [f] [g]
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Figure 15 Synthesis of endocyclic sulfoximines through Fe- and Rh-catalyzed annulative coupling (part 7)[22h] [23] and Rh-catalyzed C–H amidation (part 1)[24a]
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Figure 16 Synthesis of endocyclic sulfoximines through Co- and Ir-catalyzed C–H amidation (part 2)[24`] [c] [d]
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Figure 17 Synthesis of endocyclic sulfoximines through Rh-catalyzed C–H functionalization[25] and Ru-catalyzed asymmetric [4+3] annulation[26]
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Figure 18 Synthesis of endocyclic sulfoximines through stereoselective [3+2] cycloaddition[27] and cycloisomerization of propargyl sulfonamides (part 1)[28]
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Figure 19 Synthesis of endocyclic sulfoximines through stereoselective cycloisomerization of propargyl sulfonamides (part 2)[28a] and sigmatropic rearrangement of N-sulfinyl vinyl aziridines[29]

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

This graphical review was written during a very challenging time in Ukraine. The author, together with the majority of the Ukrainian population, regularly faced military drone and missile attacks as well as experienced other wartime hardships. Therefore, I am deeply grateful to all organizations, institutions, and individuals who support Ukrainian scientists in various ways. Specifically, I express my appreciation to the ‘II European Chemistry School for Ukrainians’ (https://acmin.agh.edu.pl/en/detail/s/ii-european-chemistry-school-for-ukrainians) for the educational opportunities that have been very useful for scientists in Ukraine.


Corresponding Author

Alexey V. Dobrydnev
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01033
Ukraine   

Publikationsverlauf

Eingereicht: 25. August 2025

Angenommen nach Revision: 29. September 2025

Accepted Manuscript online:
29. September 2025

Artikel online veröffentlicht:
29. Oktober 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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Figure 1 Synthesis of endocyclic sulfoximines through CH- and NH-alkylation reactions[3] [5] [6a]
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Figure 2 Synthesis of endocyclic sulfoximines through an electrochemically driven reaction[6b] and Friedel–Crafts alkylation[7]
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Figure 3 Synthesis of endocyclic sulfoximines through a Michael addition strategy,[8] acylation,[9] and a condensation reaction (part 1)[10a]
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Figure 4 Synthesis of endocyclic sulfoximines through a condensation reaction (part 2)[10`] [c] [d]
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Figure 5 Synthesis of endocyclic sulfoximines through a condensation reaction (part 3)[8a] [11] [12]
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Figure 6 Synthesis of endocyclic sulfoximines through a condensation reaction (part 4)[13] and an oxidation reaction (part 1)[9a] [b] , [14] [15] [16a]
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Figure 7 Synthesis of endocyclic sulfoximines through an oxidation reaction (part 2)[16`] [b] [c] [d]
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Figure 8 Synthesis of endocyclic sulfoximines through Pd-catalyzed ring-closing metathesis (RCM),[17a] ring-closing enyne metathesis (RCEYM),[17b] and intramolecular arylation (part 1)[18]
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Figure 9 Synthesis of endocyclic sulfoximines through Pd-catalyzed intramolecular arylation (part 2)[18c] and Rh-catalyzed oxidative annulation (part 1)[19`] [b] [c] [d]
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Figure 10 Synthesis of endocyclic sulfoximines through Pd- and Rh-catalyzed oxidative annulation (part 2)[19d] [e] [20a]
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Figure 11 Synthesis of endocyclic sulfoximines through Cu- and noble-metal-catalyzed annulative coupling (part 3)[20b] [21]
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Figure 12 Synthesis of endocyclic sulfoximines through Rh-catalyzed annulative coupling (part 4)[19c] [22a] [b]
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Figure 13 Synthesis of endocyclic sulfoximines through Rh-catalyzed annulative coupling (part 5)[22b] [c]
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Figure 14 Synthesis of endocyclic sulfoximines through Ir- and Rh-catalyzed annulative coupling (part 6)[22`] [e] [f] [g]
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Figure 15 Synthesis of endocyclic sulfoximines through Fe- and Rh-catalyzed annulative coupling (part 7)[22h] [23] and Rh-catalyzed C–H amidation (part 1)[24a]
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Figure 16 Synthesis of endocyclic sulfoximines through Co- and Ir-catalyzed C–H amidation (part 2)[24`] [c] [d]
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Figure 17 Synthesis of endocyclic sulfoximines through Rh-catalyzed C–H functionalization[25] and Ru-catalyzed asymmetric [4+3] annulation[26]
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Figure 18 Synthesis of endocyclic sulfoximines through stereoselective [3+2] cycloaddition[27] and cycloisomerization of propargyl sulfonamides (part 1)[28]
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Figure 19 Synthesis of endocyclic sulfoximines through stereoselective cycloisomerization of propargyl sulfonamides (part 2)[28a] and sigmatropic rearrangement of N-sulfinyl vinyl aziridines[29]