Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2025 Mar 19;27(12):2879–2884. doi: 10.1021/acs.orglett.5c00412

Enantioselective Organocatalytic Addition of 1,3-Dicarbonyl Compounds to β-Arylvinyl Triflones

Michał Kopyt †,‡, Jan Dudziński †, Michał Barbasiewicz †,*, Piotr Kwiatkowski †,‡,*
PMCID: PMC11959617  PMID: 40105800

Abstract

graphic file with name ol5c00412_0008.jpg

The sulfonyl group is able to polarize adjacent C=C bonds, but strength of the effect considerably varies with sulfonyl substituents (SO2X). In this report, we present asymmetric organocatalyzed conjugate addition of 1,3-dicarbonyl compounds to β-arylvinyl triflones (ArCH=CHSO2CF3). The reaction runs under mild conditions with 5 mol % of tertiary amino-thiourea to afford Michael-type adducts in high yields and enantioselectivities. Comparative experiments reveal that electron-withdrawing properties increase in the series SO2F ≪ SO2CF3 < SO2C4F9, with the latter approaching strength of the nitro group.

Sulfonyl compounds find countless applications in organic synthesis, medicinal chemistry, and material science, spanning from the sulfur fluoride exchange (SuFEx) reaction, Julia olefination, and Oppolzer sultam, to saccharin sweetener, ‘sulfa drugs’, and sulfourea herbicides, to name just a few.1 Presence of the sulfonyl group affects bioproperties of the molecules, acting as a moderately lipophilic2 electron acceptor and mimicking tetrahedral intermediates of acyl substitution reactions.1b As expected for third-row elements of the periodic table, electronic effect of the sulfonyl group is inductive in nature, in contrast to a predominant resonance character of nitro, carbonyl, and cyano functions. Accordingly, negative charge adjacent to the sulfonyl group is stabilized mainly with nC → σ*S–X hyperconjugation3 that translates into changes of pKa values of the conjugated acids. For phenylmethanesulfonyl derivatives (PhCH2SO2X), dissociation constants in DMSO span over 10 orders of magnitude in a series: X = NMe2, pKa = 25.2; CH2Ph, 23.9; OPh, 19.9; F, 16.9; and CF3, 14.6, with the latter approaching acidity of phenylnitromethane (PhCH2NO2, pKa = 12.3).4 The sulfonyl substituents influence also adjacent π-electron systems that manifest, for example, in acidity of benzoic acids, for which Hammett constants of the SO2CF3 group (σm = 0.76 and σp = 0.96) surpass values determined for the nitro group (σm = 0.71, σp = 0.81).5

Surprisingly, relative electrophilicity of α,β-unsaturated sulfonamides, sulfonates, and sulfones remains poorly recognized in the literature, despite their desired biological activity attributed to conjugate (1,4-) addition of nucleophilic residues.6 To the best of our knowledge, only report by Roush systematically compared reaction rates of S-nucleophiles with unsaturated sulfonyl substrates, tested as model covalent inhibitors of the cysteine proteases.7 Experimental data is also available for ethenesulfonyl fluoride (CH2=CHSO2F, ESF)8 and its β-phenyl derivative, demonstrated to be 4.5 orders of magnitude less electrophilic,9 and poorly entering addition of 1,3-dicarbonyl substrates.10 Pronounced reactivity was also reported for vinyltriflone (CH2=CHSO2CF3) and its longer perfluoroalkyl analogues, designed as fluorous tagging agents for use in fluorous-organic biphasic separation techniques.11 Last, but not least, the sulfonyl Michael-type acceptors can be useful substrates for enantioselective metal-catalyzed12 and organocatalyzed13,14 addition reactions, although such processes in the latter case often require the presence of additional acceptor groups14 or use of forceful conditions. Recently, we reported addition of dialkyl malonates to β-arylethenesulfonyl fluorides15 (ArCH=CHSO2F), catalyzed with chiral tertiary amino-thiourea under pressure of 9 kbar.16 Increase of pressure is known to kinetically promote reactions that display negative volume of activation,17 and this technique is particularly useful for enantioselective processes, where higher temperatures usually decrease optical purity of the product. Based on the literature data of malonate additions to β-nitrostyrenes,18 we expected that substrates more electrophilic than sulfonyl fluorides could react under ambient conditions, and β-arylvinyl triflones (ArCH=CHSO2CF3) seemed to be promising candidates for the task.

Importantly, enantioselective syntheses of triflones19 remain scarce, and the only examples of such conjugate additions20 concern reports by Deng21 and Wennemers.22 Deng presented a few examples of Michael reactions with β-alkylvinyl triflones catalyzed by Cinchona alkaloid derivatives.21 More recently, Wennemers developed efficient tripeptide catalyzed addition of aldehydes to α-arylvinyl triflones with the formation of two nonadjacent stereogenic centers.22 In the current report, we present studies of organocatalytic enantioselective addition of 1,3-dicarbonyl substrates to β-arylvinyl triflones and compare their electrophilicity with related Michael-type acceptors.

Our project started from literature search for preparations of β-arylvinyl triflones. Surprisingly, methods of their synthesis suffer from numerous limitations;23−26 thus, for initial experimentation, we chose NaOH-promoted condensation of arylaldehydes with methyl triflone (CH3SO2CF3).27 Although expected triflones 1a,c,g,i,l (Scheme 1) were formed in the reactions, isolated yields were only moderate (43–79%), likely due to equilibrium character of the process.28

Scheme 1. Preparation of Vinyl Triflones 1a–n.

Scheme 1

Open in a new tab

Triflone 1a was synthesized at gram scale (4.53 g).

Under the piperidine-catalyzed conditions, CH3SO2F and CH3NO2 gave condensation products with PhCHO isolated in 7% and 80% of yield, respectively.

Later, the reaction course was improved by application of procedure reported for condensation of nitroalkanes.29 Accordingly, a series of aromatic aldehydes was treated with methyl triflone in a sealed tube at 115 °C in toluene in the presence of piperidine catalyst (10 mol %) and 4 Å molecular sieves to afford products 1a,b,d–f,h,j,k, isolated in much better yields of up to 98%. Finally, more demanding hydrocinnamaldehyde and trifluoroacetophenone were transformed into triflones 1m and 1n using variant of the Peterson olefination reaction.25

With the synthesized triflones in hand, we tested set of organocatalysts282a–f (5 mol %) in a model reaction of dimethyl malonate with β-phenylvinyl triflone (1a, Scheme 2). To our delight, under ambient conditions, most of the organocatalysts led to the conjugate (1,4-) adduct 3a, and best results were obtained with pyrrolidine analogue of the Takemoto catalyst (2d, 97% of NMR yield, 89% ee). It is worth to stress that the parent Takemoto system (2a) was originally developed for addition of malonates to β-nitrostyrenes,18 and only minor modifications of its tertiary amino group were required to achieve high enantioselectivities for different classes of the substrates (NMe2 for ArCH=CHNO2,18 piperidine for ArCH=CHSO2F,16 and pyrrolidine for ArCH=CHSO2CF3, reported here).

Scheme 2. Screening of the Catalysts 2a–f in Model Reaction of Dimethyl Malonate with Triflone 1a.

Scheme 2

Open in a new tab

NMR yields and enantiomeric excesses (HPLC) of adduct 3a are given below the catalysts’ structures.

Thus, the applicability of the catalytic system to various classes of the substrates inspired us to compare their reactivity with dimethyl malonate in the presence of catalyst 2d (Scheme 3).

Scheme 3. Comparative Studies of Reactivity of Michael Acceptors.

Scheme 3

Open in a new tab

Reaction of methyl styryl sulfone (PhCH=CHSO2Me, 1o) was practically ineffective under atmospheric and high-pressure conditions, whereas phenyl styryl sulfone (PhCH=CHSO2Ph, 1p) appeared to be only slightly more reactive. However, in the latter case, a combination of high pressure (9 kbar) and catalyst loading increased to 10 mol % enabled isolation of adduct 4a in 11% yield and 90% ee. Sulfonyl fluoride (PhCH=CHSO2F, 1q) required a high-pressure activation,16 giving after 20 h under 9 kbar adduct 4b with 97% of NMR yield and 89% ee. Finally, β-phenylvinyl triflone 1a and nonafluorobutyl sulfone (PhCH=CHSO2C4F9, 1r)30 reacted under atmospheric pressure to afford adducts 3a and 4c in high NMR yields and 90% ee (with 1r being ca. twice as reactive as triflone 1a).28 Last, but not least, β-nitrostyrene (1s), tested for the sake of comparison, appeared to be a superior acceptor, by combining 96% of yield and 95% ee of adduct 4d formed after only 2 h. The data revealed that under the 2d-catalyzed conditions electrophilicity of α,β-unsaturated triflones and nonaflones is much higher than that of sulfonyl fluorides16 and approaches reactivity of β-nitrostyrenes. Importantly, absolute configuration of all these products (cf. Scheme 4) turned out to be the same for catalysts derived from (1R,2R)-1,2-diaminocyclohexane (R,R-DACH).16,18,31

Scheme 4. Scope of Unsaturated Triflones 1 in 2d-Catalyzed Reactions with Dimethyl Malonate.

Scheme 4

Open in a new tab

The structure and absolute configuration of adduct 3b were established using X-ray crystallography.

Modifications of the reaction conditions: With 2 mol % of 2d for 48 h.

At −15 °C.

At c1 = 0.5 M.

At 9 kbar, rt, 2 h.

After careful optimization of model reaction with triflone 1a (including solvents, concentrations, temperatures, reaction times, etc.),28 an experiment carried out in toluene solution at +5 °C and substrate concentration c1a = 1 M afforded dimethyl malonate adduct 3a isolated in 96% of yield and improved enantioselectivity of 93% ee (Scheme 4). Based on this, we focused on scope and limitations of the procedure by screening triflones 1b–m (Scheme 4). Presence of acceptor and donor substituents at the aromatic ring of ArCH=CHSO2CF3 displayed little effect on enantioselectivity, although reactivity was diminished in the latter case. Only ortho-substitution with Cl and OMe was beneficial for the reaction course, with enantioselectivity increased to 95–97% ee (adducts 3d and 3g). Heteroaromatic rings were tolerated, but for 3-pyridyl derivative, enantioselectivity was lowered to 83% (3j). Dienyl homologue PhCH=CHCH=CHSO2CF3 reacted exclusively in a 1,4-addition fashion,32 but longer reaction time (7 d) was necessary to obtain product 3l in a reasonable yield of 82%. Finally, β-alkylvinyl triflone PhCH2CH2CH=CHSO2CF3 reacted well but also with lower enantioselectivity of adduct 3m (82% ee at +5 °C and 87% ee at −15 °C). We tested also a sterically hindered substrate 1n, with additional CF3 group attached at the β-position.12d Unfortunately, the reaction ran exceedingly slowly, and only under high-pressure (9 kbar) adduct 3n, bearing a quaternary stereogenic center, was formed in 78% yield and 61% ee (Scheme 4, bottom).

In the following step, a series of 1,3-dicarbonyl nucleophiles were combined with triflone 1a under standard conditions with the catalyst 2d (Scheme 5). Interestingly, 1,3-diesters and 1,3-diketones reacted well, except 2,2,6,6-tetramethylheptano-3,5-dione, bearing bulky tert-butyl groups, for which high pressure (9 kbar) was required to afford product 5e in high yield. In turn, β-ketoesters formed two diastereoisomers of adducts, while selectivity substantially varied with the enolate precursor. Cyclohexanone and cyclopentanone derivatives 5f,g were formed as one predominant diastereoisomer (>10:1) and with high enantioselectivities. In turn, adducts of indanone 5h and open-chain acylacetates were produced as 1.6:1 to 1:1 dr mixtures (6a–e, Table 1). Interestingly, for acyclic β-ketoesters, both diastereisomers were formed with high enantioselectivities and with the same absolute configuration at the benzylic carbon atom. The observation inspired us for further transformation of produced adducts 6 via hydrolysis and decarboxylation. Accordingly, reaction of 1a with ethyl acetylacetate catalyzed with 5 mol % of 2d at +5 °C for 20 h in toluene solution gave adduct 6a isolated in 90% yield, as a mixture of diastereoisomers (1.25:1). Then, hydrolysis and decarboxylation with a HCl/water/AcOH mixture at 95 °C led to the formal acetone adduct 7a, isolated in 90% yield and 90% ee (the process run as a one-pot from 1a gave comparable yield of 84%). Other β-ketoesters bearing n-propyl, isopropyl, phenyl, and 2-thienyl groups reacted analogously to afford products 7b–e in the two-step sequences with final enantioselectivities in range of 81–92%. Moreover, for aromatic substrates, the enantioselectivity was improved by a decrease in the reaction temperature to −15 °C (7d,e, ee 88–90%). It is worth to mention that the sequential two-step approach significantly exceeds efficiency of direct addition of acetone using covalent organocatalysis,33 which in our hands gave 7a, in only 41% of NMR yield and 63% ee.28

Scheme 5. Scope of 1,3-Dicarbonyl Compounds in 2d-Catalyzed Reactions with Triflone 1a.

Scheme 5

Open in a new tab

Modifications of the reaction conditions: 1 equiv of NaHCO3.

c1 = 0.5 M, 9 kbar, rt, 2 h.

ee after the next step (see Scheme 6).

NMR yield.

Table 1. Synthesis of Formal Adducts of Methyl Ketones (7a–e).

graphic file with name ol5c00412_0007.jpg

    Products 6a–e
 Products 7a–e
Entry R = No. Yield (%) (dr) No. Yield (%) ee (%)
1 Me 6a 90% (1.25:1); 96% of conv. 7a 90% (one-pot 84%) 90%
2 n-Pr 6b 95% (1:1) 7b 92% 92%
3 i-Pr 6c 96% (1:1) 7c 94% 91%
4 Ph 6d 94% (1.4:1) (92%/92% ee) 7d 96% 90% (83%)a
5 2-Thienyl 6e 97% (1.5:1) 7e 96% 88% (81%)a
Open in a new tab
a

Enantiomeric excesses of adducts synthesized at +5 °C.

In the last part of the project, we attempted transformations of the enantioenriched triflone adducts (Scheme 6). Surprisingly, adduct 3a subjected to an excess of DBU formed dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (8, 75%) close to a racemic mixture, in a striking contrast to the reaction course with analogous SO2F substrate.16 The unexpected behavior likely arose from stronger electron-withdrawing properties of the SO2CF3 group, and resulting ability of adduct 3a to undergo equilibration via retro-Michael reaction (adduct dissociation). In effect, the substrate racemized faster than it cyclized, as confirmed when 3a was subjected to catalytic amount of DBU (initially 92% ee; 2 h, 70% ee; 20 h, 24% ee).28,34 Cyclization of adduct 3a was also attempted in the presence of iodine as an oxidant, where carbanion is immediately trapped, prior to the retro-Michael reaction. In this case, degradation of the optical purity was not observed, and trans-cyclopropane 9 with preserved triflone group was isolated in 79% yield, and 92% ee. The triflone adduct 3a was also subjected to hydrolysis-decarboxylation conditions giving acid 10, and then, the corresponding ethyl ester 11 (92% ee). Finally, diketone adducts 5c and 5d were heated with hydroxylamine hydrochloride in EtOH to give isoxazoles 12 and 13 with 91% and 79% ee, respectively.

Scheme 6. Studies of Cyclization and Other Transformations of Adducts 3a and 5c,d.

Scheme 6

Open in a new tab

In conclusion, we developed a general and effective organocatalytic addition of 1,3-dicarbonyl compounds to β-substituted vinyl triflones, which ran in high yields and enantioselectivities under mild conditions (+5 °C, 1 bar). Comparative experiments demonstrated that substituents at the sulfonyl group (ArCH=CHSO2X) display large effect on the reactivity,35 with trifluoromethyl (SO2CF3) and nona-fluorobutyl (SO2C4F9) sulfones being the most powerful acceptors. The reactions are catalyzed with easily available tertiary-amino thioureas, derived from the Takemoto catalyst, originally developed for addition of malonates to β-nitrostyrenes.18 Importantly, adducts to the electrophilic sulfones possess the same absolute configuration, as adducts to β-nitrostyrenes,31 and both classes of the substrates differ in reactivity to only limited extent. Therefore, the NO2 and SO2CF3 groups may act as functional isosteres that pave the way for their interchangeable applications in noncovalent organocatalysis.

Acknowledgments

This work was financed by the University of Warsaw (BST Grant No. 5011000323, PI: M.B. and IDUB Grant No. BOB-661-399/2024, PI: P.K.).

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.5c00412.

  • Experimental procedures, characterization data, HPLC chromatograms, and NMR spectra reproductions of the synthesized compounds (PDF)

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Dedication

Dedicated to Professor Mieczysław Mąkosza on the occasion of his 90th birthday.

Supplementary Material

ol5c00412_si_001.pdf (11.2MB, pdf)

References

  1. For recent reviews, see:; a Dong J.; Krasnova L.; Finn M. G.; Sharpless K. B. Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angew. Chem., Int. Ed. 2014, 53, 9430–9448. 10.1002/anie.201309399. [DOI] [PubMed] [Google Scholar]; b Xu J. Synthesis of sulfonopeptides. J. Pep. Sci. 2021, 27, e3331 10.1002/psc.3331. [DOI] [PubMed] [Google Scholar]; c Wilden J. D. The sulfonamide motif as a synthetic tool. J. Chem. Res. 2010, 34, 541–548. 10.3184/030823410X12857514635822. [DOI] [Google Scholar]; d Xu L.; Wu P.; Dong J. New Polymers From SuFEx Click Chemistry: Syntheses and Perspectives. Synthetic Polymer Chemistry: Innovations and Outlook 2019, 1–31. 10.1039/9781788016469-00001. [DOI] [Google Scholar]; e Carneiro S. N.; Khasnavis S. R.; Lee J.; Butler T. W.; Majmudar J. D.; am Ende C. W.; Ball N. D. Sulfur(VI) fluorides as tools in biomolecular and medicinal chemistry. Org. Biomol. Chem. 2023, 21, 1356–1372. 10.1039/D2OB01891H. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Blakemore P. R.; Milicevic Sephton S.; Ciganek E. The Julia-Kocienski Olefination. Org. React. 2018, 95, 1–422. 10.1002/0471264180.or095.01. [DOI] [Google Scholar]; g Lou T. S.-B.; Willis M. C. Sulfonyl fluorides as targets and substrates in the development of new synthetic methods. Nature Rev. Chem. 2022, 6, 146–162. 10.1038/s41570-021-00352-8. [DOI] [PubMed] [Google Scholar]
  2. Hansch C.; Muir R. M.; Fujita T.; Maloney P. P.; Geiger F.; Streich M. The Correlation of Biological Activity of Plant Growth Regulators and Chloromycetin Derivatives with Hammett Constants and Partition Coefficients. J. Am. Chem. Soc. 1963, 85, 2817–2824. 10.1021/ja00901a033. [DOI] [Google Scholar]
  3. Hellmann G.; Hack A.; Thiemermann E.; Luche O.; Raabe G.; Gais H.-J. Chiral Fluorinated α-Sulfonyl Carbanions: Enantioselective Synthesis and Electrophilic Capture, Racemization Dynamics, and Structure. Chem. Eur. J. 2013, 19, 3869–3897. 10.1002/chem.201204014. [DOI] [PubMed] [Google Scholar]
  4. Bordwell F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456–463. 10.1021/ar00156a004. [DOI] [Google Scholar]
  5. Goumont R.; Kizilian E.; Buncel E.; Terrier F. Super acidifiers: the origin of the exceptional electron transmission capability of the SO2CF3 group in carbanion stabilization. Org. Biomol. Chem. 2003, 1, 1741–1748. 10.1039/B302029K. [DOI] [PubMed] [Google Scholar]; and references cited therein.
  6. For a recent example, see:Baltgalvis K. A.; Lamb K. N.; Symons K. T.; Wu C.-C.; Hoffman M. A.; Snead A. N.; Song X.; Glaza T.; Kikuchi S.; Green J. C.; et al. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase. Nature 2024, 629, 435–442. 10.1038/s41586-024-07318-y. [DOI] [PubMed] [Google Scholar]
  7. Reddick J. J.; Cheng J.; Roush W. R. Relative Rates of Michael Reactions of 2’-(Phenethyl)thiol with Vinyl Sulfones, Vinyl Sulfonate Esters, and Vinyl Sulfonamides Relevant to Vinyl Sulfonyl Cysteine Protease Inhibitors. Org. Lett. 2003, 5, 1967–1970. 10.1021/ol034555l. [DOI] [PubMed] [Google Scholar]
  8. Meng Y.-P.; Wang S.-M.; Fang W.-Y.; Xie Z.-Z.; Leng J.; Alsulami H.; Qin H.-L. Ethenesulfonyl Fluoride (ESF) and Its Derivatives in SuFEx Click Chemistry and More. Synthesis 2020, 52, 673–687. 10.1055/s-0039-1690038. [DOI] [Google Scholar]
  9. Chen Q.; Mayer P.; Mayr H. Ethenesulfonyl Fluoride: The Most Perfect Michael Acceptor Ever Found?. Angew. Chem., Int. Ed. 2016, 55, 12664–12667. 10.1002/anie.201601875. [DOI] [PubMed] [Google Scholar]
  10. Chen X.; Zha G.-F.; Bare G. A. L.; Leng J.; Wang S.-M.; Qin H.-L. Synthesis of a Class of Fused δ-Sultone Heterocycles via DBU-Catalyzed Direct Annulative SuFEx Click of Ethenesulfonyl Fluorides and Pyrazolones or 1,3-Dicarbonyl Compounds. Adv. Synth. Catal. 2017, 359, 3254–3260. 10.1002/adsc.201700887. [DOI] [Google Scholar]; and references cited therein.
  11. Magnier-Bouvier C.; Blazejewski J.-C.; Larpent C.; Magnier E. Selective Michael additions of primary and secondary amines to perfluoroalkylated sulfoxides and sulfones as a tool for fluorous tagging. Tetrahedron Lett. 2006, 47, 9121–9124. 10.1016/j.tetlet.2006.10.077. [DOI] [Google Scholar]
  12. For examples of metal-catalyzed enantioselective additions to α,β-unsaturated sulfonyl systems, see:; a Nishimura T.; Takiguchi Y.; Hayashi T. Effect of Chiral Diene Ligands in Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to α,β-Unsaturated Sulfonyl Compounds. J. Am. Chem. Soc. 2012, 134, 9086–9089. 10.1021/ja303109q. [DOI] [PubMed] [Google Scholar]; b Moku B.; Fang W.-Y.; Leng J.; Li L.; Zha G. F.; Rakesh K. P.; Qin H.-L. Rh-Catalyzed Highly Enantioselective Synthesis of Aliphatic Sulfonyl Fluorides. iScience 2019, 21, 695–705. 10.1016/j.isci.2019.10.051. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Li Y.-N.; Chang X.; Xiong Q.; Dong X.-Q.; Wang C.-J. Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides: Efficient access to chiral pyrrolidine-3-sulfonyl fluorides. Chin. Chem. Lett. 2021, 32, 4029–4032. 10.1016/j.cclet.2021.05.063. [DOI] [Google Scholar]; d Cheng F.; Kalita S. J.; Zhao Z.-N.; Yang X.; Zhao Y.; Schneider U.; Shibata N.; Huang Y.-Y. Diastereodivergent Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides and β-Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies. Angew. Chem., Int. Ed. 2019, 58, 16637–16643. 10.1002/anie.201908227. [DOI] [PubMed] [Google Scholar]; e Lu J.; Ye J.; Duan W.-L. Palladium-Catalyzed Asymmetric Addition of Diarylphosphines to α,β-Unsaturated Sulfonic Esters for the Synthesis of Chiral Phosphine Sulfonate Compounds. Org. Lett. 2013, 15, 5016–5019. 10.1021/ol402351c. [DOI] [PubMed] [Google Scholar]; f Bos P. H.; Minnaard A. J.; Feringa B. L. Catalytic Asymmetric Conjugate Addition of Grignard Reagents to α,β-Unsaturated Sulfones. Org. Lett. 2008, 10, 4219–4222. [DOI] [PubMed] [Google Scholar]
  13. For examples of organocatalyzed enantioselective additions to α,β-unsaturated sulfonyl systems, see:; a Kondoh A.; Ojima R.; Ishikawa S.; Terada M. Construction of 1,3-Nonadjacent Stereogenic Centers Through Enantioselective Addition of α-Thioacetamides to α-Substituted Vinyl Sulfones Catalyzed by Chiral Strong Brønsted Base Stereocenter. Adv. Sci. 2024, 11, 2308020. 10.1002/advs.202308020. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Landa A.; Maestro M.; Masdeu C.; Puente Á.; Vera S.; Oiarbide M.; Palomo C. Highly Enantioselective Conjugate Additions of Aldehydes to Vinyl Sulfones. Chem. Eur. J. 2009, 15, 1562–1565. 10.1002/chem.200802441. [DOI] [PubMed] [Google Scholar]; c Simlandy A. K.; Mukherjee S. Catalytic asymmetric formal γ-allylation of deconjugated butenolides. Org. Biomol. Chem. 2016, 14, 5659–5664. 10.1039/C5OB02362A. [DOI] [PubMed] [Google Scholar]
  14. a Aitken L. S.; Hammond L. E.; Sundaram R.; Shankland K.; Brown G. D.; Cobb A. J. A. Asymmetric cyclopropanation of conjugated cyanosulfones using a novel cupreine organocatalyst: rapid access to δ3-amino acids. Chem. Commun. 2015, 51, 13558–13561. 10.1039/C5CC05158D. [DOI] [PubMed] [Google Scholar]; b Rajkumar S.; Shankland K.; Goodman J. M.; Cobb A. J. A. Organocatalytic Domino Reaction of Cyanosulfones: Access to Complex Cyclohexane Systems with Quaternary Carbon Centers. Org. Lett. 2013, 15, 1386–1389. 10.1021/ol400356k. [DOI] [PubMed] [Google Scholar]; c Alexakis A.; Mosse S. First Organocatalyzed Asymmetric Michael Addition of Aldehydes to Vinyl Sulfones. Org. Lett. 2005, 7, 4361–4364. [DOI] [PubMed] [Google Scholar]; For a review, see:; d Liang X.; Shen Y. Advances in Synthesis of Enantioenriched Chiral Sulfones by Enantioselective Conjugate Addition Reactions. Asian J. Org. Chem. 2022, 11, No. e202100598. [Google Scholar]
  15. Tryniszewski M.; Basiak D.; Barbasiewicz M. Olefination with Sulfonyl Halides and Esters: Synthesis of Unsaturated Sulfonyl Fluorides. Org. Lett. 2022, 24, 4270–4274. 10.1021/acs.orglett.2c01604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kopyt M.; Tryniszewski M.; Barbasiewicz M.; Kwiatkowski P. Enantioselective Addition of Dialkyl Malonates to β-Arylethenesulfonyl Fluorides under High-Pressure Conditions. Org. Lett. 2023, 25, 6818–6822. 10.1021/acs.orglett.3c02302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. a Grochala W.; Hoffmann R.; Feng J.; Ashcroft N. W. The Chemical Imagination at Work in Very Tight Places. Angew. Chem., Int. Ed. 2007, 46, 3620–3642. 10.1002/anie.200602485. [DOI] [PubMed] [Google Scholar]; b Margetic D.High Pressure Organic Synthesis; De Gruyter, 2019. [Google Scholar]; c Cholewiak A.; Adamczyk K.; Kopyt M.; Kasztelan A.; Kwiatkowski P. High pressure-assisted low-loading asymmetric organocatalytic conjugate addition of nitroalkanes to chalcones. Org. Biomol. Chem. 2018, 16, 4365–4371. 10.1039/C8OB00561C. [DOI] [PubMed] [Google Scholar]; d Połosak A. J.; Głowacki M. P.; Kwiatkowski P. Enantioselective Organocatalytic Conjugate Addition of Malonates to β,β-Disubstituted β-Trifluoromethyl Enones under High Pressure. Org. Lett. 2025, 27, 2087–2092. 10.1021/acs.orglett.5c00065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Okino T.; Hoashi Y.; Takemoto Y. Enantioselective Michael Reaction of Malonates to Nitroolefins Catalyzed by Bifunctional Organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672–12673. 10.1021/ja036972z. [DOI] [PubMed] [Google Scholar]
  19. Wen M.; Erb W.; Mongin F.; Hurvois J.-P.; Blot M.; Roisnel T.; Halauko Y. S.; Matulis V. E.; Koike Y.; Kitazawa Y.; Kimura M.; Uchiyama M. Enantioselective Synthesis of Planar Chiral Ferrocene Triflones. Adv. Synth. Catal. 2024, 366, 4984–4993. 10.1002/adsc.202400834. [DOI] [Google Scholar]
  20. Franco F.; Meninno S.; Overgaard J.; Rossi S.; Benaglia M.; Lattanzi A. Catalytic Enantioselective Entry to Triflones Featuring a Quaternary Stereocenter. Org. Lett. 2022, 24, 4371–4376. 10.1021/acs.orglett.2c01589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Li H.; Song J.; Deng L. Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones. Tetrahedron 2009, 65, 3139–3148. 10.1016/j.tet.2008.11.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Budinská A.; Wennemers H. Organocatalytic Synthesis of Triflones Bearing Two Non-Adjacent Stereogenic Centers. Angew. Chem., Int. Ed. 2023, 62, e202300537 10.1002/anie.202300537. [DOI] [PubMed] [Google Scholar]
  23. a Hua L.-N.; Li H.; Qing F.-L.; Huang Y.; Xu X.-H. Iodine-mediated regioselective synthesis of vinyl triflones from styrenes with CF3SO2Na. Org. Biomol. Chem. 2016, 14, 8443–8447. 10.1039/C6OB01567K. [DOI] [PubMed] [Google Scholar]; b Huang T.-S.; Chen C.-L.; Tsai M.-H.; Chen Y.-C.; Hsu C.-S. Synthesis of Polysubstituted Vinyl Sulfones by Direct C–S Cross-Coupling. Chem. Eur. J. 2025, 31, No. e202403947. [DOI] [PubMed] [Google Scholar]
  24. Xu X.-H.; Taniguchi M.; Wang X.; Tokunaga E.; Ozawa T.; Masuda H.; Shibata N. Stereoselective Synthesis of Vinyl Triflones and Heteroaryl Triflones through Anionic O→Cvinyl and N→Cvinyl Trifluoromethanesulfonyl Migration Reactions. Angew. Chem., Int. Ed. 2013, 52, 12628–12631. 10.1002/anie.201307535. [DOI] [PubMed] [Google Scholar]
  25. Mahadevan A.; Fuchs P. L. A Mild And Convenient Synthesis Of Functionalized Methyl Triflones And Vinyl Triflones. Tetrahedron Lett. 1994, 35, 6025–6028. 10.1016/0040-4039(94)88065-4. [DOI] [Google Scholar]
  26. Attempts at F → CF3 exchange at the α,β-unsaturated system have failed in our hands. Compare:Smedley C. J.; Zheng Q.; Gao B.; Li S.; Molino A.; Duivenvoorden H. M.; Parker B. S.; Wilson D. J. D.; Sharpless K. B.; Moses J. E. Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides. Angew. Chem., Int. Ed. 2019, 58, 4552–4556. 10.1002/anie.201813761. [DOI] [PubMed] [Google Scholar]
  27. Yagupolskii L. M.; Panteleimonov A. G. Condensation of trihalomethyl alkyl sulfones with aldehydes. J. General Chem. USSR 1966, 36, 433–437. [Google Scholar]; (Zh. Obshch. Khim.1966, 36, 416–421).
  28. See the Supporting Information for details.
  29. Fioravanti S.; Pellacani L.; Tardella P. A.; Vergari M. C. Facile and Highly Stereoselective One-Pot Synthesis of Either (E)- or (Z)-Nitro Alkenes. Org. Lett. 2008, 10, 1449–1451. 10.1021/ol800224k. [DOI] [PubMed] [Google Scholar]
  30. For a discussion of differences between the electron-acceptor groups SO2CF3 and SO2C4F9, see:Kotani A.; Yanai H.; Matsumoto T.; Hakamata H. pKa Determination of Strongly Acidic C-H Acids Bearing a (Perfluoroalkyl)sulfonyl Group in Acetonitrile by Means of Voltammetric Reduction of Quinone. Electrochemistry 2021, 89, 121–124. 10.5796/electrochemistry.20-65154. [DOI] [Google Scholar]
  31. The same direction of asymmetric induction and absolute configuration of products 3a, 4b, and 4d obtained in (1R,2R)-2d-catalyzed reactions of triflone 1a, β-phenylethenesulfonyl fluoride, and β-nitrostyrene suggest a similar mode of complexation and mechanism of action.
  32. Moku B.; Fang W.-Y.; Leng J.; Kantchev E. A. B.; Qin H.-L. Rh(I)Diene-Catalyzed Addition of (Hetero)aryl Functionality to 1,3-Dienylsulfonyl Fluorides Achieving Exclusive Regioselectivity and High Enantioselectivity: Generality and Mechanism. ACS Catal. 2019, 9, 10477–10488. 10.1021/acscatal.9b03640. [DOI] [Google Scholar]
  33. Günler Z. A.; Alfonso I.; Jimeno C.; Pericàs M. A. Concentration Effect in the Asymmetric Michael Addition of Acetone to β-Nitrostyrenes Catalyzed by Primary Amine Thioureas. Synthesis 2016, 49, 319–325. 10.1055/s-0036-1589408. [DOI] [Google Scholar]; and references cited therein.
  34. The equilibration was further supported when the same reaction was repeated in the presence of diethyl malonate. In this case, recovered 3a of diminished ee (40%) was accompanied with a racemic diethyl malonate adduct (5a) formed by exchange of the enolate. An alternative pathway of exchange by transesterification would give mixtures of methyl-ethyl esters, which actually were not observed.
  35. For an analogous discussion of the carbonyl series, seeRozsar D.; Formica M.; Yamazaki K.; Hamlin T. A.; Dixon D. J. Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides. J. Am. Chem. Soc. 2022, 144, 1006–1015. 10.1021/jacs.1c11898. [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

ol5c00412_si_001.pdf (11.2MB, 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