Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jan 20;25(4):671–675. doi: 10.1021/acs.orglett.2c04310

Metal-Free S-Arylation of Phosphorothioate Diesters and Related Compounds with Diaryliodonium Salts

Sudeep Sarkar †,‡, Marcin Kalek †,*
PMCID: PMC9903330  PMID: 36662120

Abstract

graphic file with name ol2c04310_0006.jpg

We developed a direct metal-free S-arylation of phosphorothioate diesters using diaryliodonium salts. The method allows for the preparation under simple conditions of a broad range of S-aryl phosphorothioates, including complex molecules (e.g., dinucleotide or TADDOL derivatives), as well as other related organophosphorus compounds arylated at a chalcogen. The reaction proceeds with a full retention of the stereogenic center at the phosphorus atom, opening convenient access to P-chiral products. The mechanism of the reaction was established using DFT calculations.

Sulfur-containing organophosphorus compounds display an array of interesting and valuable properties from both biological and chemical viewpoints. Accordingly, they have found widespread applications ranging from agrochemicals and pharmaceuticals (including oligonucleotide therapeutics), through building blocks for material and synthetic chemistry, to chiral catalysts.1,2

An important subset of the sulfur-containing organophosphorus compounds are S-aryl phosphorothioates. Many of them are useful in their own right as pesticides3 as well as biologically active agents.4 Moreover, due to the intrinsic lability of the P–S–Ar linkage, this class of compounds has received considerable interest as intermediates in synthetic organic chemistry. In this context, the S-aryl phosphorothioate moiety has been used, for instance, as a protecting group during the synthesis of modified oligonucleotides.5 Their other synthetic applications include serving as a convenient precursor for the construction of diverse classes of organophosphorus compounds, such as phosphates,6 pyrophosphates,7 phosphine oxides,8 and aryl-2e,9 and vinylphosphonates.10

The traditional approaches for the synthesis of S-aryl phosphorothioates involve the construction of the P–S bond,11 either via the phosphorylation of aryl thiols12 or by the reaction of P(III) species with sulfur-centered electrophiles.13 Except for a single isolated example,14 these methods do not allow for effective stereoselective access to P-stereogenic molecules. Conversely, in the context of recent developments in the stereoselective preparation of P-chiral phosphorothioate diesters,15 the alternative synthetic strategy, that is, via the formation of the S–Ar bond, would provide a superior entry to S-aryl phosphorothioates in a stereopure form. Such synthetic pathway has, however, been explored to a much lesser extent. Specifically, there exist few reports on oxidative couplings of phosphorothioate diesters with arylboronic acids or electron-rich arenes as well as Sandmeyer reactions employing diazonium and iodonium salts.16 Yet most of these processes employ phosphorothioates generated in situ by the sulfurization of corresponding H-phosphonates, which cannot be readily accessed as pure enantiomers. Moreover, probable free-radical mechanisms of some of these reactions create additional challenges for performing them in a stereocontrolled manner. Indeed, the synthesis of even a single example of a chiral S-aryl phosphorothioate using the above methods has not been demonstrated.

In this context, the group of Schoenebeck disclosed in 2019 a direct S-arylation of phosphorothioate diesters with aryl iodides using a dinuclear Pd(I) catalyst (Scheme 1). Although it has been shown that these cross-coupling conditions preserve the stereochemical configuration of chiral centers in the carbon backbone, the method has not been applied to molecules, in which the phosphorus atom itself is a stereocenter.17 Building on previous studies by us and others showing that hypervalent iodine(III) reagents allow for a highly efficient aryl transfer to sulfur-based nucleophiles18 as well as on seminal preliminary results by Chen et al.,19 herein we report the synthesis of S-aryl phosphorothioates by the direct arylation of phosphorothioate diesters with diaryliodonium salts (Scheme 1). The developed method is not only efficient, general, and metal-free, but it also maintains the stereochemical integrity of P-stereogenic compounds, enabling for the first time to harness the potential provided by the access to stereopure phosphorothioate diesters.15

Scheme 1. Synthesis of S-Aryl Phosphorothioates by Direct S-Arylation.

Scheme 1

Open in a new tab

We were able to establish a set of conditions, consisting simply of heating the starting materials overnight in 1,4-dioxane at 100 °C under inert atmosphere, under which the arylation of model diphenyl phosphorothioate (1a) with diphenyliodonium tetrafluoroborate (2a) provides a nearly quantitative yield of the desired product 3a (see the SI for details). With the optimized reactions conditions in hand, we set out to explore the scope and limitations of this metal-free S-arylation of phosphorothioate diesters, first, with regard to the aryl group that can be transferred (Scheme 2). The reaction works well for halide-substituted aryl rings (3b–3e). Noteworthy, contrary to the palladium-catalyzed counterpart,17 aryl bromide is tolerated (3d), providing a convenient handle for further functionalization. Aryls containing both diverse electron-withdrawing (3f–3i) and electron-donating (3j–3l) substituents in various positions of the ring furnish the desired products with good efficiency. Extended aryl systems, such as 1- and 2-naphthyl, can also be transferred (3m,3n). Regarding the steric factors, though the considerably hindered mesityl does not interfere with the S–Ar bond formation (3j), there is a slight decrease in the yield in the case of the 1-naphthyl moiety (3n).

Scheme 2. Scope with Regard to the Diaryliodonium Salt.

Scheme 2

Open in a new tab

Isolated yields.

Synthesized using unsymmetrical (4-nitrophenyl)(phenyl)iodonium tetrafluoroborate.

Next, we moved to explore the scope with respect to the phosphorothioate diester (Scheme 3). For simple starting materials, the reaction is uneventful, both in the case of O,O-diaryl and O,O-dialkyl substrates (3a, 3o–3q). The single limitation is a very sterically hindered O,O-di-tert-butyl phosphorothioate, which was found to be completely unreactive (3r). The reaction was then tested using more complex molecules, relevant to asymmetric catalysis and biological applications. To this end, a TADDOL-derived phosphorothioate could be S-arylated in a nearly quantitative yield without any disruption to the backbone stereocenters (3s). This result demonstrates that the developed method is fully interchangeable with the palladium-catalyzed cross-coupling reported previously,17 while it avoids a possible contamination of the chiral product with trace transition metal residues, which may be of importance in downstream catalytic applications. Moreover, the enantiopurity of an axially chiral BINOL-containing substrate also remained intact, although the reaction proceeds in much lower yield in this case (3t). Most importantly, however, the S-arylation with a diaryliodonium salt could be performed with a complete stereospecificity on dinucleoside phosphorothioates having the opposite sense of chirality at the phosphorus stereocenter (3u; Figure 1).20 Not only these are the first instances of such transformation, but they also show the applicability of this chemistry for a selective late-stage functionalization of complex, functional-group-rich molecules.

Scheme 3. Scope with Regard to the Phosphorothioate Diester and Related Compounds.

Scheme 3

Open in a new tab

Isolated yields. DMT = 4,4′-dimethoxytrityl, T = thymin-1-yl, TBS = tert-butyldimethylsilyl.

Figure 1.

Figure 1

Open in a new tab

31P NMR spectra demonstrating complete stereospecificity of the reaction with P-stereogenic dinucleoside phosphorothioates. R1 = 5′-O-DMT-thymidin-3′-yl, R2 = 3′-O-TBS-thymidin-5′-yl.

To further extend the scope, other P–S nucleophiles and related selenium compounds were subjected to the developed arylation conditions. Thus, S-aryl phosphorodithioates, both O,O-diaryl (4a) and O,O-dialkyl (4b), were successfully obtained in high yields. Moreover, the aryl transfer to the selenium atom of phosphoroselenoates could also be achieved, although with considerably lower efficacy (5a,5b). Finally, it was determined that replacing alkoxy groups at phosphorus with carbon substituents gradually decreases the reactivity toward diaryliodonium salts. Namely, the introduction of a single P–C bond into the starting material resulted in a 20–30% drop in the yield of the corresponding S-aryl phosphonate products (6a vs 3a; 6b vs 3o). However, a synthetically useful yield was obtained in the case of a phosphonate(−)-menthol derivative (6c), for which the S-arylation was found to also be fully stereospecific. In turn, the presence of two P–C bonds leads to the formation of only 31% of S-phenyl diphenylphosphinothioate (7a) and a complete loss of the reactivity for dimethylphosphinothioate substrate (7b).

To obtain some insight into the mechanism of the S-arylation of phosphorothioate diesters with diaryliodonium salts, the reaction between 1a and 2a was performed in the presence of either 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or 1,1-diphenylethylene (DPE) (1 equiv. each). In both cases, the yield was not affected (>95%), speaking against the involvement of radical intermediates.

The mechanism of the reaction was also subject to computational investigations using density functional theory calculations. In particular, we sought to elucidate the details of the S–Ar bond formation and to rationalize the selectivity in terms of S- over O-arylation. The computed free energy profile for the reaction is depicted in Figure 2.

Figure 2.

Figure 2

Open in a new tab

Free energy profile of aryl transfer from diaryliodonium salt to phosphorothioate diester calculated at the B3LYP-D3BJ(SMD)/Def2-QZVP//B3LYP-D3BJ(SMD)/Def2-SVP level of theory in 1,4-dioxane.

Despite multiple attempts, we could not locate a transition state for the outer sphere pathway, that is, a direct nucleophilic attack of model phosphorothioate 1b, neither with sulfur nor oxygen, on the phenyl ring of 2a, substituting an iodine-based leaving group in an SN2 fashion.21 Conversely, the incorporation of phosphorothioate as a ligand into the inner coordination sphere of iodine generates intermediates with either P–S–I or P–O–I linkages (INT-S and INT-O, respectively), which are relatively close in energy to both 1b and each other, implying that these species can exist in an equilibrium. A homolytic cleavage of the S/O–I bond in INT-S/INT-O is calculated to be highly endergonic (∼30 kcal/mol), precluding the radical course of the reaction, as already indicated by the experiments with TEMPO and DPE. From both intermediates, the aryl transfer may take place via two distinct pathways, involving either three- or five-membered cyclic transition states (TS1 and TS2, respectively) that diverge into the S- and O-arylation products. The S–Ar-forming TS1-S (from INT-S) and TS2-S (from INT-O) are clearly energetically preferred to the O–Ar-forming TS1-O (from INT-O) and TS2-O (from INT-S), explaining the completely selective S-arylation observed experimentally. Interestingly, the five-membered cyclic structures are favored in both pairs of the respective transition states, likely due to their less strained nature. In general, the inner sphere mechanism established by the current computations shares similarities to those found for other aryl transfers employing diaryliodonium salts.18e,22 However, the five-membered cyclic TS is unique, attributed to the intrinsic structure of a phosphorothioate diester, bearing two nucleophilic sites in a 1,3-arrangement. The computational studies also indicate that the S-arylation of P-chiral phosphorothioates should proceed stereospecifically, as indeed observed experimentally, with the retention of configuration at the phosphorus atom, whose integrity is maintained throughout the mechanistic pathway.

In conclusion, we have successfully developed an efficient protocol for the direct S-arylation of phosphorothioate diesters with diaryliodonium salts. The method constitutes an operationally simple and metal-free entry to a variety of S-aryl phosphorothioates and related compounds that is also suitable for a late-stage functionalization of complex molecules. Very importantly, the reaction proceeds with a full retention of the stereochemical configuration at the phosphorus atom, as proven experimentally and computationally, thus, benefiting from the easily accessible pool of stereodefined P-stereogenic phosphorothioate diesters. Finally, with the use of DFT calculations, the arylation has been shown to proceed via an inner sphere mechanism, through a five-membered cyclic transition state.

Acknowledgments

We thank Dr. Adam A. Rajkiewicz (Centre of New Technologies, University of Warsaw) for performing preliminary experiments. We acknowledge financial support from the National Science Centre Poland (grant no. 2016/22/E/ST5/00566). Computer time was generously provided by the Interdisciplinary Centre for Mathematical and Computational Modeling of the University of Warsaw (G75-0) and generous access to an NMR spectrometer was granted by the Faculty of Physics of the University of Warsaw.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.2c04310.

  • Experimental procedures, effect of reaction parameters, preparation of starting materials, characterization data and NMR spectra, computational details and data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol2c04310_si_001.pdf (6.3MB, pdf)

References

  1. Preprint with the preliminary version of this work has been deposited in ChemRxiv 2022, 10.26434/chemrxiv-2022-v1zwx. [DOI] [Google Scholar]
  2. a Wing K. D.; Glickman A. H.; Casida J. E. Phosphorothiolate Pesticides and Related Compounds: Oxidative Bioactivation and Aging of the Inhibited Acetylcholinesterase. Pestic. Biochem. Phys. 1984, 21, 22–30. 10.1016/0048-3575(84)90070-1. [DOI] [Google Scholar]; b Matolcsy G.; Nadasy M.; Andriska V. In Studies in Environmental Science 32: Pesticide Chemistry; Elsevier: Amsterdam, 1988; pp 122–161. [Google Scholar]; c Li N.-S.; Frederiksen J. K.; Piccirilli J. A. Synthesis, Properties, and Applications of Oligonucleotides Containing an RNA Dinucleotide Phosphorothiolate Linkage. Acc. Chem. Res. 2011, 44, 1257–1269. 10.1021/ar200131t. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Eckstein F. Phosphorothioates, Essential Components of Therapeutic Oligonucleotides. Nucleic Acid Ther 2014, 24, 374–387. 10.1089/nat.2014.0506. [DOI] [PubMed] [Google Scholar]; e Qiu Y.; Worch J. C.; Chirdon D. N.; Kaur A.; Maurer A. B.; Amsterdam S.; Collins C. R.; Pintauer T.; Yaron D.; Bernhard S.; Noonan K. J. T. Tuning Thiophene with Phosphorus: Synthesis and Electronic Properties of Benzobisthiaphospholes. Chem. Eur. J. 2014, 20, 7746–7751. 10.1002/chem.201402561. [DOI] [PubMed] [Google Scholar]; f Shapiro N. D.; Rauniyar V.; Hamilton G. L.; Wu J.; Toste F. D. Asymmetric Additions to Dienes Catalysed by a Dithiophosphoric Acid. Nature 2011, 470, 245–249. 10.1038/nature09723. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Robertson F. J.; Wu J. Phosphorothioic Acids and Related Compounds as Surrogates for H2S—Synthesis of Chiral Tetrahydrothiophenes. J. Am. Chem. Soc. 2012, 134, 2775–2780. 10.1021/ja210758n. [DOI] [PubMed] [Google Scholar]
  3. a Murdock L. L.; Hopkins T. L. Insecticidal, Anticholinesterase, and Hydrolytic Properties of O,O-Dialkyl S-Aryl Phosphorothiolates in Relation to Structure. J. Agric. Food Chem. 1968, 16, 954–958. 10.1021/jf60160a021. [DOI] [Google Scholar]; b Lee A.-H.; Metcalf R. L. In Vitro Inhibition of Acetylcholinesterase by O,O-Dimethyl S-Aryl Phosphorothioates. Pestic. Biochem. Physiol. 1973, 2, 408–417. 10.1016/0048-3575(73)90053-9. [DOI] [Google Scholar]; c Lee A.-H.; Metcalf R. L.; Booth G. M. House Cricket Acetylcholinesterase: Histochemical Localization and in Situ Inhibition by O,O-Dimethyl S-Aryl Phosphorothioates. Ann. Entomol. Soc. Am. 1973, 66, 333–343. 10.1093/aesa/66.2.333. [DOI] [Google Scholar]
  4. a Kazuo H.; Katsuki S.; Mitsuo H.; Masaru N.; Kenji T.; Masaaki Y., Jpn. Tokkyo Koho, JP 48018461 B 19730606, 1973.; b Yasuhiko M.; Yasuyuki K.; Harumi T.; Takashi Y., Jpn. Kokai Tokkyo Koho, JP 51033200 A 19760322, 1976.; c Reddy E. P.; Reddy M. V. R.; Bell S. C., PCT Int. Appl., WO 2005089269 A2 20050929, 2005.
  5. a Sekine M.; Hata T. Synthesis of Short Oligoribonucleotides Bearing a 3′- or 5′-Terminal Phosphate by Use of 4,4’,4″-Tris(4,5-dichlorophthalimido)trityl as a New 5′-Hydroxyl Protecting Group. J. Am. Chem. Soc. 1986, 108, 4581–4586. 10.1021/ja00275a052. [DOI] [Google Scholar]; b Hotoda H.; Koizumi M.; Koga R.; Kaneko M.; Momota K.; Ohmine T.; Furukawa H.; Agatsuma T.; Nishigaki T.; Sone J.; Tsutsumi S.; Kosaka T.; Abe K.; Kimura S.; Shimada K. Biologically Active Oligodeoxyribonucleotides. 5. 5‘-End-Substituted d(TGGGAG) Possesses Anti-Human Immunodeficiency Virus Type 1 Activity by Forming a G-Quadruplex Structure. J. Med. Chem. 1998, 41, 3655–3663. 10.1021/jm970658w. [DOI] [PubMed] [Google Scholar]; c Seio K.; Wada T.; Sakamoto K.; Yokoyama S.; Sekine M. Chemical Synthesis and Properties of Conformationally Fixed Diuridine Monophosphates as Building Blocks of the RNA Turn Motif. J. Org. Chem. 1998, 63, 1429–1443. 10.1021/jo971797o. [DOI] [Google Scholar]
  6. Ohuchi S.; Ayukawa H.; Hata T. Transformation of Dinucleoside S-Aryl Phosphorothioates into the Corresponding O-Alkyl Phosphates by Use of Tributyltin Alkoxides. Chem. Lett. 1992, 21, 1501–1504. 10.1246/cl.1992.1501. [DOI] [Google Scholar]
  7. a Fukuoka M.; Shuto S.; Minakawa N.; Ueno Y.; Matsuda A. Alternative Synthesis of Cyclic IDP-Carbocyclic Ribose. Efficient Cyclization of an 8-Bromo-N1-[5-(Phosphoryl)carbocyclic-ribosyl]inosine 5′-Phenylthiophosphate Derivative Mediated by Iodine. Tetrahedron Lett. 1999, 40, 5361–5364. 10.1016/S0040-4039(99)00977-6. [DOI] [Google Scholar]; b Fukuoka M.; Shuto S.; Minakawa N.; Ueno Y.; Matsuda A. An Efficient Synthesis of Cyclic IDP- and Cyclic 8-Bromo-IDP-Carbocyclic-Riboses Using a Modified Hata Condensation Method To Form an Intramolecular Pyrophosphate Linkage as a Key Step. An Entry to a General Method for the Chemical Synthesis of Cyclic ADP-Ribose Analogues1. J. Org. Chem. 2000, 65, 5238–5248. 10.1021/jo0000877. [DOI] [PubMed] [Google Scholar]; c Huang L.-J.; Zhao Y.-Y.; Yuan L.; Min J.-M.; Zhang L.-H. Syntheses and Calcium-Mobilizing Evaluations of N-Glycosyl-Substituted Stable Mimics of Cyclic ADP-Ribose. J. Med. Chem. 2002, 45, 5340–5352. 10.1021/jm010530l. [DOI] [PubMed] [Google Scholar]
  8. Nishiyama Y.; Hazama Y.; Yoshida S.; Hosoya T. Synthesis of Unsymmetrical Tertiary Phosphine Oxides via Sequential Substitution Reaction of Phosphonic Acid Dithioesters with Grignard Reagents. Org. Lett. 2017, 19, 3899–3902. 10.1021/acs.orglett.7b01796. [DOI] [PubMed] [Google Scholar]
  9. Masson S.; Saint-Clair J.-F.; Saquet M. Two Methods for the Synthesis of (2-Mercaptophenyl)phosphonic Acid. Synthesis 1993, 1993, 485–486. 10.1055/s-1993-25889. [DOI] [Google Scholar]
  10. Han L.-B.; Tanaka M. Novel Palladium-Catalyzed Thiophosphorylation of Alkynes with Phosphorothioate: An Efficient Route to (Z)-1-(Diphenoxyphosphinyl)-2-(Phenylthio)alkenes. Chem. Lett. 1999, 28, 863–864. 10.1246/cl.1999.863. [DOI] [Google Scholar]
  11. Jones D. J.; O’Leary E. M.; O’Sullivan T. P. Synthesis and Application of Phosphonothioates, Phosphonodithioates, Phosphorothioates, Phosphinothioates and Related Compounds. Tetrahedron Lett. 2018, 59, 4279–4292. 10.1016/j.tetlet.2018.10.058. [DOI] [Google Scholar]
  12. Selected examples:; a Zhu Y.; Chen T.; Li S.; Shimada S.; Han L.-B. Efficient Pd-Catalyzed Dehydrogenative Coupling of P(O)H with RSH: A Precise Construction of P(O)–S Bonds. J. Am. Chem. Soc. 2016, 138, 5825–5828. 10.1021/jacs.6b03112. [DOI] [PubMed] [Google Scholar]; b Song S.; Zhang Y.; Yeerlan A.; Zhu B.; Liu J.; Jiao N. Cs2CO3-Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling of Thiols with Phosphonates and Arenes. Angew. Chem., Int. Ed. 2017, 56, 2487–2491. 10.1002/anie.201612190. [DOI] [PubMed] [Google Scholar]; c Huang H.; Denne J.; Yang C.-H.; Wang H.; Kang J. Y. Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates. Angew. Chem., Int. Ed. 2018, 57, 6624–6628. 10.1002/anie.201802082. [DOI] [PubMed] [Google Scholar]; d Shen J.; Li Q.-W.; Zhang X.-Y.; Wang X.; Li G.-Z.; Li W.-Z.; Yang S.-D.; Yang B. Tf2O/DMSO-Promoted P–O and P–S Bond Formation: A Scalable Synthesis of Multifarious Organophosphinates and Thiophosphates. Org. Lett. 2021, 23, 1541–1547. 10.1021/acs.orglett.0c04127. [DOI] [PubMed] [Google Scholar]
  13. Selected examples:; a Bai J.; Cui X.; Wang H.; Wu Y. Copper-Catalyzed Reductive Coupling of Aryl Sulfonyl Chlorides with H-Phosphonates Leading to S-Aryl Phosphorothioates. Chem. Commun. 2014, 50, 8860–8863. 10.1039/C4CC02693D. [DOI] [PubMed] [Google Scholar]; b Liu Y.-C.; Lee C.-F. N-Chlorosuccinimide-Promoted Synthesis of Thiophosphates from Thiols and Phosphonates under Mild Conditions. Green Chem. 2014, 16, 357–364. 10.1039/C3GC41839A. [DOI] [Google Scholar]; c Wang D.; Zhao J.; Xu W.; Shao C.; Shi Z.; Li L.; Zhang X. Metal- and Base-Free Reductive Coupling Reaction of P(O)–H with Aryl/Alkyl Sulfonyl Chlorides: A Novel Protocol for the Construction of P–S–C Bonds. Org. Biomol. Chem. 2017, 15, 545–549. 10.1039/C6OB02364A. [DOI] [PubMed] [Google Scholar]; d Choudhary R.; Singh P.; Bai R.; Sharma M. C.; Badsara S. S. Highly Atom-Economical, Catalyst-Free, and Solvent-Free Phosphorylation of Chalcogenides. Org. Biomol. Chem. 2019, 17, 9757–9765. 10.1039/C9OB01921A. [DOI] [PubMed] [Google Scholar]; e Shen B.-R.; Annamalai P.; Wang S.-F.; Bai R.; Lee C.-F. Blue LED-Promoted Syntheses of Phosphorothioates and Phosphorodithioates. J. Org. Chem. 2022, 87, 8858–8870. 10.1021/acs.joc.2c00323. [DOI] [PubMed] [Google Scholar]
  14. Wang W.-M.; Liu L.-J.; Yao L.; Meng F.-J.; Sun Y.-M.; Zhao C.-Q.; Xu Q.; Han L.-B. Stereospecific Preparations of P-Stereogenic Phosphonothioates and Phosphonoselenoates. J. Org. Chem. 2016, 81, 6843–6847. 10.1021/acs.joc.6b01192. [DOI] [PubMed] [Google Scholar]
  15. a Knouse K. W.; deGruyter J. N.; Schmidt M. A.; Zheng B.; Vantourout J. C.; Kingston C.; Mercer S. E.; Mcdonald I. M.; Olson R. E.; Zhu Y.; Hang C.; Zhu J.; Yuan C.; Wang Q.; Park P.; Eastgate M. D.; Baran P. S. Unlocking P(V): Reagents for Chiral Phosphorothioate Synthesis. Science 2018, 361, 1234–1238. 10.1126/science.aau3369. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Featherston A. L.; Kwon Y.; Pompeo M. M.; Engl O. D.; Leahy D. K.; Miller S. J. Catalytic Asymmetric and Stereodivergent Oligonucleotide Synthesis. Science 2021, 371, 702–707. 10.1126/science.abf4359. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Knouse K. W.; Flood D. T.; Vantourout J. C.; Schmidt M. A.; McDonald I. M.; Eastgate M. D.; Baran P. S. Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies. ACS Cent. Sci. 2021, 7, 1473–1485. 10.1021/acscentsci.1c00487. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Huang Y.; Knouse K. W.; Qiu S.; Hao W.; Padial N. M.; Vantourout J. C.; Zheng B.; Mercer S. E.; Lopez-Ogalla J.; Narayan R.; Olson R. E.; Blackmond D. G.; Eastgate M. D.; Schmidt M. A.; McDonald I. M.; Baran P. S. A P(V) Platform for Oligonucleotide Synthesis. Science 2021, 373, 1265–1270. 10.1126/science.abi9727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. a Xu J.; Zhang L.; Li X.; Gao Y.; Tang G.; Zhao Y. Phosphorothiolation of Aryl Boronic Acids Using P(O)H Compounds and Elemental Sulfur. Org. Lett. 2016, 18, 1266–1269. 10.1021/acs.orglett.6b00118. [DOI] [PubMed] [Google Scholar]; b Shi S.; Chen J.; Zhuo S.; Wu Z. A.; Fang M.; Tang G.; Zhao Y. Iodide-Catalyzed Phosphorothiolation of Heteroarenes Using P(O)H Compounds and Elemental Sulfur. Adv. Synth. Catal. 2019, 361, 3210–3216. 10.1002/adsc.201900291. [DOI] [Google Scholar]; c Kovács S.; Bayarmagnai B.; Aillerie A.; Gooßen L. J. Practical Reagents and Methods for Nucleophilic and Electrophilic Phosphorothiolations. Adv. Synth. Catal. 2018, 360, 1913–1918. 10.1002/adsc.201701549. [DOI] [Google Scholar]; d Zhang L.; Zhang P.; Li X.; Xu J.; Tang G.; Zhao Y. Synthesis of S-Aryl Phosphorothioates by Copper-Catalyzed Phosphorothiolation of Diaryliodonium and Arenediazonium Salts. J. Org. Chem. 2016, 81, 5588–5594. 10.1021/acs.joc.6b00925. [DOI] [PubMed] [Google Scholar]; e Wang L.; Yang S.; Chen L.; Yuan S.; Chen Q.; He M.-Y.; Zhang Z.-H. Magnetically Recyclable Cu-BTC@Fe3O4 Composite-Catalyzed C(aryl)–S–P Bond Formation Using Aniline, P(O)H Compounds and Sulfur Powder. Catal. Sci. Technol. 2017, 7, 2356–2361. 10.1039/C7CY00467B. [DOI] [Google Scholar]
  17. Chen X.-Y.; Pu M.; Cheng H.-G.; Sperger T.; Schoenebeck F. Arylation of Axially Chiral Phosphorothioate Salts by Dinuclear PdI Catalysis. Angew. Chem., Int. Ed. 2019, 58, 11395–11399. 10.1002/anie.201906063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. a Wagner A. M.; Sanford M. S. Transition-Metal-Free Acid-Mediated Synthesis of Aryl Sulfides from Thiols and Thioethers. J. Org. Chem. 2014, 79, 2263–2267. 10.1021/jo402567b. [DOI] [PubMed] [Google Scholar]; b Zhang B.; Kang Y.; Yang L.; Chen X. A S-Arylation of 2-Mercaptoazoles with Diaryliodonium Triflates under Metal-Free and Base-Free Conditions. ChemistrySelect 2016, 1, 1529–1532. 10.1002/slct.201600204. [DOI] [Google Scholar]; c Villo P.; Kervefors G.; Olofsson B. Transition Metal-Free, Chemoselective Arylation of Thioamides Yielding Aryl Thioimidates or N-Aryl Thioamides. Chem. Commun. 2018, 54, 8810–8813. 10.1039/C8CC04795B. [DOI] [PubMed] [Google Scholar]; d Parida S. K.; Jaiswal S.; Singh P.; Murarka S. Multicomponent Synthesis of Biologically Relevant S-Aryl Dithiocarbamates Using Diaryliodonium Salts. Org. Lett. 2021, 23, 6401–6406. 10.1021/acs.orglett.1c02220. [DOI] [PubMed] [Google Scholar]; e Sarkar S.; Wojciechowska N.; Rajkiewicz A. A.; Kalek M. Synthesis of Aryl Sulfides by Metal-Free Arylation of Thiols with Diaryliodonium Salts under Basic Conditions. Eur. J. Org. Chem. 2022, e202101408 10.1002/ejoc.202101408. [DOI] [Google Scholar]
  19. Liu D.-D.; Chen D.-w.; Chen Z.-C. Hypervalent Iodine in Synthesis: XII. A New and Convenient Method for Preparation of O,O-Dialkyl S-Aryl Phosphoro Thiolates. Synth. Commun. 1992, 22, 2903–2908. 10.1080/00397919208021113. [DOI] [Google Scholar]
  20. Both (RP)- and (SP)-3u are not crystalline (as evidenced by XRD powder crystallography), and (SP)-6c is a liquid, preventing determining their absolute configuration by X-ray or microED crystallography. However, the much more likely retention of configuration during the S-arylation (as opposed to 100% inversion) is supported by the DFT computations (see below).
  21. a Wodrich M. D.; Caramenti P.; Waser J. Alkynylation of Thiols with Ethynylbenziodoxolone (EBX) Reagents: α- or β- π-Addition?. Org. Lett. 2016, 18, 60–63. 10.1021/acs.orglett.5b03241. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Ghosh M. K.; Rzymkowski J.; Kalek M. Transition-Metal-Free Aryl–Aryl Cross-Coupling: C–H Arylation of 2-Naphthols with Diaryliodonium Salts. Chem. Eur. J. 2019, 25, 9619–9623. 10.1002/chem.201902204. [DOI] [PubMed] [Google Scholar]; c Rajkiewicz A. A.; Wojciechowska N.; Kalek M. N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H Alkynylation of Aldehydes with Alkynyliodonium Salts—Evidence for Alkynyl Transfer via Direct Substitution at Acetylenic Carbon. ACS Catal. 2020, 10, 831–841. 10.1021/acscatal.9b04394. [DOI] [Google Scholar]
  22. a Norrby P.-O.; Petersen T. B.; Bielawski M.; Olofsson B. α-Arylation by Rearrangement: On the Reaction of Enolates with Diaryliodonium Salts. Chem. Eur. J. 2010, 16, 8251–8254. 10.1002/chem.201001110. [DOI] [PubMed] [Google Scholar]; b Malmgren J.; Santoro S.; Jalalian N.; Himo F.; Olofsson B. Arylation with Unsymmetrical Diaryliodonium Salts: A Chemoselectivity Study. Chem. Eur. J. 2013, 19, 10334–10342. 10.1002/chem.201300860. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Stridfeldt E.; Lindstedt E.; Reitti M.; Blid J.; Norrby P.-O.; Olofsson B. Competing Pathways in O-Arylations with Diaryliodonium Salts: Mechanistic Insights. Chem. Eur. J. 2017, 23, 13249–13258. 10.1002/chem.201703057. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol2c04310_si_001.pdf (6.3MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Articles from Organic Letters are provided here courtesy of American Chemical Society

RESOURCES