New Advances in Sultine Chemistry

Abstract

Sultines (lactones of sulfinic acids), as a fascinating class of sulfur heterocycles, has been found tremendous applications in the field of chemistry, pharmaceutical, and materials sciences due to the unique chemical, biological, and pharmaceutical activities. However, the chemistry of sultines long remains less developed because of their challenging to access with traditional routes. The recent years have witnessed an increasing interest in sultines preparation and new methods were reported with modern methodologies and technologies. The main objective of this Synpacts article is to summarize the latest major developments for the synthesis of sultine frameworks/ring systems, mainly covering radical relay, anion relay cyclization and radical anion relay cyclization. We wish to bring readers a comprehensive understanding about the state of play of sultines formation and make contribution for future research.

1 Introduction

2 Radical Relay Cyclization

3 Anion Relay Cyclization

4 Radical Anion Relay Cyclization

5 Conclusion

Introduction

The sultines are one of the long history known and important sulfur heterocycles, which were first mentioned as early as the end of the last century through a dehydration reaction of sulfinic acid and alcohol.[1] They are not only present in various natural products and biologically and pharmaceutically active molecules (Figure [1]).[2] They are also involved as significantly valuable heterocycle building blocks in the field of industrial and pharmacological chemistry.[3] Moreover, sultines are potential found usefulness as models for asymmetric transformations as well, since the S atom of sultines is located at a vertex of a stable pyramid and does not have identical substituents, therefore, it is a chiral center.[4] Surprisingly, compared with the significant importance of sultine skeletons, synthesis of these fundamental sulfur heterocycles is very challenging, especially for the six-ring δ-sultines. The early synthesis approaches mainly relied on the direct rearrangements of sulfones or cyclization of bifunctional sulfur-containing compounds, which are general suffer from low atom-economy, elaborate starting materials, hash/toxic conditions and limited functional group tolerance and substrate scope, which are severely obstructs the potential applications of sultines.[2] [5]

To this end, the development of new methods for the efficient and selective construction of this skeleton is highly desirable, especially those with different ring sizes and substitution patterns. Indeed, recently, significant improvements on the new strategies have been developed in the synthesis of sultines. However, to date, the comprehensive summarization of these advances is missing. So herein, we summarized the latest and a more comprehensive understanding of this topic with emphasis on the product diversity, selectivity, and applicability, and the mechanistic rationale is presented where possible. Structures are displayed with S=O in representing these polar bonds usually that are more correctly written as > S⁺–O^– due to the sulfur atom is a chiral center.

We hope this Synpacts article will bring readers a comprehensive understanding about the state of play of sultine synthesis and motivate further contribution to this fascinating field. Radical relay cyclization, anion relay cyclization, and radical anion relay cyclization are discussed in this work.

Radical Relay Cyclization

In 2006, Fensterbank and co-workers developed an efficient radical relay cyclization involving the generation of carbon radical followed by intramolecular homolytic substitution at sulfur atom, affording the various functionalized purely alkyl-substituted and benzofused sultine products in moderate to excellent yields (Scheme [1]).[6] Treatment of aryl bromide or iodine substrates under radical conditions (Bu₃SnH and AIBN) with benzene as solvent, aryl radical was formed and then added to the sulfinate moiety to yield the desired benzofused sultines by removing of the stable leaving group (LG, Scheme [1a]). Substrates scope revealed that both the electron-withdrawing and electron-donating substituents on the aryl ring reacted smoothly to yield the sultines in 45–99% yields and, of note, the nature of tethering radical leaving group played a key role for the success of the reaction. In addition, further efforts were made by the same group to produce alkyl-substituted γ-sultines as well. While some of the γ-sultine products could not be separated as pure from the AIBN residues, TTMSS as mediator and V-501 (azobis-4-cyanovaleric acid) as initiator were used instead (Scheme [1b]). Homolytic substitution of primary, secondary, or tertiary alkyl radical generated from alkylbromides led predominantly to the γ-sultines, in the dr ratio ranging from 2:1 to >25:1 depending on the steric hindrance of the R¹ and R² substituents. However, alkyl-substituted six-ring δ-sultines was not suitable for this procedure, only dehalogenation hydrogen alkylation product was observed. The same group then studied the homolytic substitution of oxidized sulfur functions reactivity systematically, such as the nature of the radical leaving group, the nature of the tethering heteroatom, the size of the ring, the incoming radical, and the stereochemical outcome at sulfur atom.[7]

In general, this work represented a remarkable advance in sultine synthesis compared with traditional synthetic efforts even if it regularly depends on stoichiometric amounts of toxic, unstable metal-based H-atom donors and radical initiators and very limited starting materials.

Another interesting photoinduced radical relay cyclization approach for the synthesis of benzosultines under mild conditions was recently reported by Maestro and co-workers in 2019 (Scheme [2]).[8] Visible-light photoredox catalysis has emerged as a powerful tool in organic synthesis because of its economical, mild, and simple conditions and environmental friendliness for green chemistry.[9] A number of benzofused heterocycles, ranging from sultines and cyclic sulfinamides to S-, P- and Si-centric benzofused structures, were delivered through the reductive dehalogenation of aryl halides radical relay cyclization protocol, for example, as displayed in Scheme [2], the reaction of aryl sulfinyl derivatives with DIPEA in the presence of 10-phenylphenothiazine (PTH, 5 mol%) as organic photocatalyst in MeCN at room temperature under near UV (385 nm) blue LED light irradiation to lead to the five- and six-membered benzosultines in 97% and 83% yield, respectively.

The proposed mechanism for this visible-light-catalyzed intramolecular radical relay cyclization reaction is depicted in Scheme [2] as well. First, single-electron transfer (SET) between photoexcited catalyst PTH and the corresponding aryl halide A generates oxidized state photocatalyst and the aryl radical B, which was transformed to sultine product C by intramolecular homolytic substitution process subsequently. At last, PTH was regenerated via SET between oxidized PTH and DIPEA and closed this photocatalytic cycle. The current procedure integrates the classical Bu₃SnH/AIBN-initiated intramolecular homolytic substitution reaction with the modern visible-light catalysis, providing an efficient route to benzofused sultines under metal-free conditions.

Anion Relay Cyclization

An elegant and efficient anion relay Julia–Kocienski cyclization protocol of epoxides was reported by Bray and co-workers in 2015, mediated with base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to afford functionalized γ-sultine motifs in 21–99% yields with moderate diastereoselectivities (trans isomer was the main isomer, Scheme [3]).[10] Upon treatment of γ-hydroxysulfones with DBU, sulfinate anion forms first, then direct cyclization takes place to give the sultine product by releasing OTBT anion. The authors explored the reaction scope and found that softer or less electron-rich (withdrawing) groups on the sulfones are conducive to the formation of γ-sultines, and sultone was formed as side product in some cases. It should be mentioned that stereocontrolled γ-sultines could be synthesized under current conditions from the corresponding original chiral epoxides as well.

Radical Anion Relay Cyclization

Over the last decade, photoredox chemistry has transformed the synthesis landscape, especially in the field of olefin radical polar/anion cyclization reactions, which is a highly attractive strategy in organic synthesis as it has the benefit of rapidly generating complex molecular scaffolds from simple precursors under simple conditions.[11]

In 2023, Shu and co-workers disclosed a unique and unprecedented photoinduced multifluoromethylated γ-sultines construction through a radical anion relay cyclization cascade with SO₂ insertion from multifluoroalkanesulfinates (Scheme [4]).[12] The treatment of halo- or tosyl-substituted olefins with sodium multifluoromethanesulfinates in the presence of 4CzIPN (0.1–5 mol%) as an organic photocatalyst in MeCN at room temperature under visible-light irradiation could allow the efficient formation of functionalized fluoromethylated γ-sultines in generally good to excellent yields and moderate to good trans/cis diastereoselectivities. A diverse range of readily available sodium multifluoromethanesulfinates and LG-tethered alkenes were found to react efficiently to give structurally diverse sultines, which are highly valuable moieties in drug development and now easily accessible from safe, simple, and readily available building blocks. For examples, even complex carboxylic acids containing drugs such as ibuprofen, fenbufen, probenecid, and etodolac were smoothly cyclized to yield densely functionalized γ-sultine derivatives in moderate to good yields, highlighting the potential feasibility and practicality in late-stage functionalization of pharmaceutically relevant compounds. Additionally, it was worth of note that the formation of the corresponding γ-sultine from probenecid derivative was also performed on a gram scale with retention of a good yield and using this photoreaction procedure, difluoromethylated γ-sultines as well as multifluoromethylated γ-sultines can be prepared without any problem.

The mechanism of this radical anion relay cyclization shown in Scheme [5] was proposed. Firstly, visible-light-excited 4CzIPN* was reductively quenched with multifluoroalkanesulfinate anion via SET process, leading to the generation of multifluoroalkyl radical A and releases SO₂. Giese-type addition of the fluoromethyl radical A to the olefin regioselectively to generate the tertiary carbon radical B. Then, the key incorporation of SO₂ with B can give the sulfonyl radical C, which undergoes SET with the reduced state of the photocatalyst, leading to sulfonyl anion D. The sulfonyl anion D priors to sulfinate specie E with a negative charge on the O atom in a polar aprotic solvent. Intermediate D turns back to B by SET oxidation or comes from carbon anion by SO₂ addition are possible side patterns. Finally, the resulting sulfinate specie E rapidly underwent an anionic 5-exo-tet cyclization to give target γ-sultine with the release of the leaving group. Notably, no cyclopropanation and protonation product of carbanion intermediate were observed.

Of note, this is an inaugural metal-free photoredox-catalyzed multifluoromethylated γ-sultines synthesis procedure via a radical anion relay cyclization, i.e., multifluoromethylation/SO₂ incorporation/5-exo-tet cyclization cascade sequence, using multifluoroalkanesulfinates as dual inexpensive and practical multifluoroalkyl and SO₂ sources. This protocol features simple conditions, readily available substrates, high efficiency, and excellent functional group compatibility.

It is worth stressing that sultines have been proved to be versatile building blocks in synthetic chemistry. Such as challenging sultones and bulky mercaptoalkanols could be convenient obtained by oxidation and reduction, respectively, both of them are important skeletons in the pharmaceutical industry and material chemistry.

Conclusion

In summary, as demonstrated in this work, significant advances have been made in the development of efficient and functional group tolerant synthesis methods to access sultines. A variety of complementary strategies have been discovered so far, making these interesting and useful targets accessible from different easily available starting materials. However, the chemistry of the field has not yet been adequately developed, which is due at least in part to the lack of convenient synthesis methods. The syntheses of these important targets, either in a racemic or in an asymmetric fashion, were found to be a challenging task. Accordingly, despite these significant achievements, there is still much room for the development of new strategies to access sultines. For example, the known procedures developed so far are far from enough compared to the importance potential application in pharmaceutical, agrochemical, and materials. New endeavors to prepare sultines with broad scope from feedstock chemicals is still highly desirable, especially, with high atom-economic and environmentally friendly features. In addition, catalytic asymmetric synthesis sultines have been rarely demonstrated, which are always challenging in this field.

We anticipate that this work will attract more interest by chemists to contribute to the development of this research field. We expect new strategies to be disclosed in the near future, together with the boundaries of the above-described strategies that are just around the corner to be extended and pushed further by our group and others.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

All authors wish CCNU a happy 120 anniversary.

• References

• 1a Baumann E, Walter G. Chem. Ber. 1893; 26: 1124
  CrossrefSearch in Google Scholar
• 1b Krauthausen E. In Methoden der Organischen Chemie, Vol. E 11. Klamann D. Thieme; Stuttgart: 1985: 640
  Search in Google Scholar
• 1c Krauthausen E. In Methoden der Organischen Chemie, Vol. E 11. Klamann D. Thieme; Stuttgart: 1985: 655
  Search in Google Scholar

For selected reviews, see:
• 2a Dittmer DC, Hoey MD. Cyclic Sulfinic Acid Derivatives (Sultines and Sulfinamides). In The Chemistry of Sulphinic Acids, Esters, and their Derivatives. Patai S. Wiley; Chichester: 1990: 239
  CrossrefSearch in Google Scholar
• 2b Bondarenko OB, Saginova LG, Zyk NV. Russ. Chem. Rev. 1996; 65: 147
  CrossrefSearch in Google Scholar
• 2c Kotha S, Khedkar P. Chem. Rev. 2012; 112: 1650
  CrossrefPubMedSearch in Google Scholar

For selected examples, see:
• 3a Jung F, Molin M, Van Den Elzen R, Durst T. J. Am. Chem. Soc. 1974; 96: 935
  CrossrefSearch in Google Scholar
• 3b Oppolzer W. Synthesis 1978; 793
  Thieme Connect
• 3c Squires TG, Venier CG, Hodgson BA, Chang LW, Davis FA, Panunto TW. J. Org. Chem. 1981; 46: 2373
  CrossrefSearch in Google Scholar
• 3d Charlton JL, Alauddin MM. Tetrahedron 1987; 43: 287
  CrossrefSearch in Google Scholar
• 3e Roberts DW, Williams DL. Tetrahedron 1987; 43: 1027
  CrossrefSearch in Google Scholar
• 3f Liu W.-D, Chi C.-C, Pai I.-F, Wu A.-T, Chung W.-S. J. Org. Chem. 2002; 67: 9267
  CrossrefPubMedSearch in Google Scholar
• 4a Kawecki R. Tetrahedron: Asymmetry 2003; 14: 2827
  CrossrefSearch in Google Scholar
• 4b Vogel P, Turks M, Bouchez L, Craita C, Huang XG, Murcia MC, Fonquerne F, Didier C, Flowers C. Pure Appl. Chem. 2008; 80: 791
  CrossrefSearch in Google Scholar
• 5a King JF, de Mayo P, Mclntosh CL, Piers K, Smith DJ. H. Can. J. Chem. 1970; 48: 3704
  CrossrefSearch in Google Scholar
• 5b Dodson RM, Hammen PD, Davis RA. J. Org. Chem. 1973; 36: 2693
  CrossrefSearch in Google Scholar
• 5c Bondareko OB, Saginova LG, Shabarov YuS. Zh. Org. Khim. 1987; 23: 1114
  Search in Google Scholar
• 5d Vogel P, Turks M, Bouchez L, Markovic D, Varela-Alvarez A, Sordo JA. Acc. Chem. Res. 2007; 40: 931
  CrossrefPubMedSearch in Google Scholar
• 6 Coulomb J, Certal V, Fensterbank L, Lacôte E, Malacria M. Angew. Chem. Int. Ed. 2006; 45: 633
  CrossrefPubMedSearch in Google Scholar
• 7 Coulomb SH. J, Certal V, Larraufie MH, Ollivier C, Corbet G, Mignani JP, Fensterbank L, Lacôte E, Malacria M. Chem. Eur. J. 2009; 15: 10225
  CrossrefPubMedSearch in Google Scholar
• 8 Garrido-Castro AF, Salaverri N, Maestro MC, Alemán J. Org. Lett. 2019; 21: 5295
  CrossrefPubMedSearch in Google Scholar

For selected reviews, see:
• 9a Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
  Search in Google Scholar
• 9b Skubi KL, Blum TR, Yoon TP. Chem. Rev. 2016; 116: 10035
  CrossrefPubMedSearch in Google Scholar
• 9c Chen Y, Lu L.-Q, Yu D.-G, Zhu C.-J, Xiao W-J. Sci. China: Chem. 2019; 62: 24
  CrossrefSearch in Google Scholar
• 9d Xiao Y, Chen J.-R, Xiao W.-J. Chem. Rev. 2021; 121: 506
  CrossrefPubMedSearch in Google Scholar
• 10 Smith GM. T, Burton PM, Bray CD. Angew. Chem. Int. Ed. 2015; 54: 15236
  CrossrefPubMedSearch in Google Scholar

For selected reviews, see:
• 11a Pitzer L, Schwarz JL, Glorius F. Chem. Sci. 2019; 10: 8285
  CrossrefPubMedSearch in Google Scholar
• 11b Wiles RJ. Isr. J. Chem. 2020; 60: 281
  CrossrefPubMedSearch in Google Scholar
• 11c Donabauer K, König B. Acc. Chem. Res. 2021; 54: 242
  CrossrefPubMedSearch in Google Scholar
• 11d Sharma S, Singh J, Sharma A. Adv. Synth. Catal. 2021; 363: 3146
  CrossrefSearch in Google Scholar
• 12 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 62: e202300159
  CrossrefPubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 03 April 2023

Accepted after revision: 25 April 2023

Accepted Manuscript online:
25 April 2023

Article published online:
02 June 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1a Baumann E, Walter G. Chem. Ber. 1893; 26: 1124
  CrossrefSearch in Google Scholar
• 1b Krauthausen E. In Methoden der Organischen Chemie, Vol. E 11. Klamann D. Thieme; Stuttgart: 1985: 640
  Search in Google Scholar
• 1c Krauthausen E. In Methoden der Organischen Chemie, Vol. E 11. Klamann D. Thieme; Stuttgart: 1985: 655
  Search in Google Scholar

For selected reviews, see:
• 2a Dittmer DC, Hoey MD. Cyclic Sulfinic Acid Derivatives (Sultines and Sulfinamides). In The Chemistry of Sulphinic Acids, Esters, and their Derivatives. Patai S. Wiley; Chichester: 1990: 239
  CrossrefSearch in Google Scholar
• 2b Bondarenko OB, Saginova LG, Zyk NV. Russ. Chem. Rev. 1996; 65: 147
  CrossrefSearch in Google Scholar
• 2c Kotha S, Khedkar P. Chem. Rev. 2012; 112: 1650
  CrossrefPubMedSearch in Google Scholar

For selected examples, see:
• 3a Jung F, Molin M, Van Den Elzen R, Durst T. J. Am. Chem. Soc. 1974; 96: 935
  CrossrefSearch in Google Scholar
• 3b Oppolzer W. Synthesis 1978; 793
  Thieme Connect
• 3c Squires TG, Venier CG, Hodgson BA, Chang LW, Davis FA, Panunto TW. J. Org. Chem. 1981; 46: 2373
  CrossrefSearch in Google Scholar
• 3d Charlton JL, Alauddin MM. Tetrahedron 1987; 43: 287
  CrossrefSearch in Google Scholar
• 3e Roberts DW, Williams DL. Tetrahedron 1987; 43: 1027
  CrossrefSearch in Google Scholar
• 3f Liu W.-D, Chi C.-C, Pai I.-F, Wu A.-T, Chung W.-S. J. Org. Chem. 2002; 67: 9267
  CrossrefPubMedSearch in Google Scholar
• 4a Kawecki R. Tetrahedron: Asymmetry 2003; 14: 2827
  CrossrefSearch in Google Scholar
• 4b Vogel P, Turks M, Bouchez L, Craita C, Huang XG, Murcia MC, Fonquerne F, Didier C, Flowers C. Pure Appl. Chem. 2008; 80: 791
  CrossrefSearch in Google Scholar
• 5a King JF, de Mayo P, Mclntosh CL, Piers K, Smith DJ. H. Can. J. Chem. 1970; 48: 3704
  CrossrefSearch in Google Scholar
• 5b Dodson RM, Hammen PD, Davis RA. J. Org. Chem. 1973; 36: 2693
  CrossrefSearch in Google Scholar
• 5c Bondareko OB, Saginova LG, Shabarov YuS. Zh. Org. Khim. 1987; 23: 1114
  Search in Google Scholar
• 5d Vogel P, Turks M, Bouchez L, Markovic D, Varela-Alvarez A, Sordo JA. Acc. Chem. Res. 2007; 40: 931
  CrossrefPubMedSearch in Google Scholar
• 6 Coulomb J, Certal V, Fensterbank L, Lacôte E, Malacria M. Angew. Chem. Int. Ed. 2006; 45: 633
  CrossrefPubMedSearch in Google Scholar
• 7 Coulomb SH. J, Certal V, Larraufie MH, Ollivier C, Corbet G, Mignani JP, Fensterbank L, Lacôte E, Malacria M. Chem. Eur. J. 2009; 15: 10225
  CrossrefPubMedSearch in Google Scholar
• 8 Garrido-Castro AF, Salaverri N, Maestro MC, Alemán J. Org. Lett. 2019; 21: 5295
  CrossrefPubMedSearch in Google Scholar

For selected reviews, see:
• 9a Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
  Search in Google Scholar
• 9b Skubi KL, Blum TR, Yoon TP. Chem. Rev. 2016; 116: 10035
  CrossrefPubMedSearch in Google Scholar
• 9c Chen Y, Lu L.-Q, Yu D.-G, Zhu C.-J, Xiao W-J. Sci. China: Chem. 2019; 62: 24
  CrossrefSearch in Google Scholar
• 9d Xiao Y, Chen J.-R, Xiao W.-J. Chem. Rev. 2021; 121: 506
  CrossrefPubMedSearch in Google Scholar
• 10 Smith GM. T, Burton PM, Bray CD. Angew. Chem. Int. Ed. 2015; 54: 15236
  CrossrefPubMedSearch in Google Scholar

For selected reviews, see:
• 11a Pitzer L, Schwarz JL, Glorius F. Chem. Sci. 2019; 10: 8285
  CrossrefPubMedSearch in Google Scholar
• 11b Wiles RJ. Isr. J. Chem. 2020; 60: 281
  CrossrefPubMedSearch in Google Scholar
• 11c Donabauer K, König B. Acc. Chem. Res. 2021; 54: 242
  CrossrefPubMedSearch in Google Scholar
• 11d Sharma S, Singh J, Sharma A. Adv. Synth. Catal. 2021; 363: 3146
  CrossrefSearch in Google Scholar
• 12 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 62: e202300159
  CrossrefPubMedSearch in Google Scholar