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. 2022 Mar 23;144(11):4764-4769.
doi: 10.1021/jacs.2c00923. Epub 2022 Mar 14.

One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones

Myunggi Jung  1 , Vincent N G Lindsay  1
Affiliations

One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones

Myunggi Jung et al. J Am Chem Soc. .

Abstract

Sulfone-substituted bicyclo[1.1.0]butanes and housanes have found widespread application in organic synthesis due to their bench stability and high reactivity in strain-releasing processes in the presence of nucleophiles or radical species. Despite their increasing utility, their preparation typically requires multiple steps in low overall yield. In this work, we report an expedient and general one-pot procedure for the synthesis of 1-sulfonylbicyclo[1.1.0]butanes from readily available methyl sulfones and inexpensive epichlorohydrin via the dialkylmagnesium-mediated formation of 3-sulfonylcyclobutanol intermediates. Furthermore, the process was extended to the formation of 1-sulfonylbicyclo[2.1.0]pentane (housane) analogues when 4-chloro-1,2-epoxybutane was used as the electrophile instead of epichlorohydrin. Both procedures could be applied on a gram scale with similar efficiency and are shown to be fully stereospecific in the case of housanes when an enantiopure epoxide was employed, leading to a streamlined access to highly valuable optically active strain-release reagents.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Syntheses and Applications of Sulfonyl-Substituted BCB and Housane Reagents
Scheme 2.
Scheme 2.. Scope of Accessible Bicyclo[1.1.0]butanesa
aIsolated yields from 1a–1r on a 0.5 mmol scale. bIsolated yield on a 1 g scale (6.4 mmol) 1a in parentheses. ct-BuLi (1.2 equiv) was used in the third stage. dFirst and third stages were performed at −78 to −20 or 0 °C. e1.0 equiv of n-BuLi was used in the third stage. fKOt-Bu (1.5–2.5 equiv) was used in the third stage after aqueous workup. gTHF/HMPA (9:1) was used as solvent instead of pure THF.
Scheme 3.
Scheme 3.. Direct Access to Substituted BCB Derivativesa
aIsolated yields from 1a on a 0.5 mmol scale.
Scheme 4.
Scheme 4.. Scope of Accessible Bicyclo[2.1.0]pentanesa
aIsolated yields from 1a–1h, 1k–1l, and 1q–1r on a 0.5 mmol scale. bIsolated yield on a 1 g scale (6.4 mmol) 1a in parentheses. cFirst stage was performed at −20 °C (then 0 °C, 1 h) and third stage at −78 to −20 °C. dn-Bu2Mg (1 equiv) was used at −20 °C in the first stage instead of (n-Bu)(s-Bu)Mg (without HMPA).
Scheme 5.
Scheme 5.. Stereospecific Synthesis of Chiral Housanesa
aIsolated yields from 1e or 1g on a 0.25 mmol scale.
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References

    1. Liebman JF; Greenberg A A survey of strained organic molecules. Chem. Rev 1976, 76, 311–365.
    2. Wiberg KB The Concept of Strain in Organic Chemistry. Angew. Chem., Int. Ed. Engl 1986, 25, 312–322.
    3. Liebman JF; Greenberg A Survey of the heats of formation of three-membered-ring species. Chem. Rev 1989, 89, 1225–1246.
    4. Advances in Strain in Organic Chemistry; Halton B, Ed.; JAI Press: London, 1997.
    5. Dudev T; Lim C Ring Strain Energies from ab Initio Calculations. J. Am. Chem. Soc 1998, 120, 4450–4458.
    6. Advances in Strained and Interesting Organic Molecules; Halton B, Ed.; JAI Press: Stamford, CT, 2020.
    7. Khoury PR; Goddard JD; Tam W Ring strain energies: substituted rings, norbornanes, norbornenes and norbornadienes. Tetrahedron 2004, 60, 8103–8112.
    8. Bach RD; Dmitrenko O The Effect of Carbonyl Substitution on the Strain Energy of Small Ring Compounds and Their Six-Member Ring Reference Compounds. J. Am. Chem. Soc 2006, 128, 4598–4611. - PubMed
    9. Schneider TF; Kaschel J; Werz DB A New Golden Age for Donor–Acceptor Cyclopropanes. Angew. Chem., Int. Ed 2014, 53, 5504–5523. - PubMed
    10. Pirenne V; Muriel B; Waser J Catalytic Enantioselective Ring-Opening Reactions of Cyclopropanes. Chem. Rev 2021, 121, 227–263. - PubMed

    1. For reviews on the synthesis and applications of strain-release reagents, see:

    2. Turkowska J; Durka J; Gryko D Strain release – an old tool for new transformations. Chem. Commun 2020, 56, 5718–5734. - PubMed
    3. Wiberg KB; Lampman GM; Ciula RP; Connor DS; Schertler P; Lavanish J Bicyclo[1.1.0]butane. Tetrahedron 1965, 21, 2749–2769.
    4. Hoz S Chapter 19 -Bicyclo[1.1.0]butane. In The Chemistry of the Cyclopropyl Group; Rappoport Z, Ed.; Wiley: New York, 1987; Vol. 1, pp 1121–1191. .
    5. Delia EW; Lochert IJ Synthesis of Biudgehead-Substituted Bicyclo[1.1.1]pentanes. A Review. Org. Prep. Proced. Int 1996, 28, 411–441.
    6. Bartnik R; Marchand AP Synthesis and Chemistry of Substituted 1-Azabicyclo[1.1.0]butanes. Synlett 1997, 1997, 1029–1039.
    7. Levin MD; Kaszynski P; Michl J Bicyclo[1.1.1]pentanes, [n]Staffanes, [1.1.1]Propellanes, and Tricyclo[2.1.0.02,5]pentanes. Chem. Rev 2000, 100, 169–234. - PubMed
    8. Ramazanov IR; Yaroslavova AV; Dzhemilev UM Russ. Chem. Rev 2012, 81, 700–728.
    9. Walczak MAA; Krainz T; Wipf P Ring-Strain-Enabled Reaction Discovery: New Heterocycles from Bicyclo[1.1.0]butanes. Acc. Chem. Res 2015, 48, 1149–1158. - PubMed
    10. Dilmaç AM; Spuling E; de Meijere A; Bräse S Propellanes—From a Chemical Curiosity to “Explosive” Materials and Natural Products. Angew. Chem., Int. Ed 2017, 56, 5684–5718. - PubMed
    11. Kanazawa J; Uchiyama M Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane. Synlett 2019, 30, 1–11.
    12. Ma X; Nhat Pham L Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues. Asian J. Org. Chem 2020, 9, 8–22.
    13. Pramanik MMD; Qian H; Xiao W-J; Chen J-R Photoinduced strategies towards strained molecules. Org. Chem. Front 2020, 7, 2531–2537.
    14. Anderson JM; Measom ND; Murphy JA; Poole DL Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives. Angew. Chem., Int. Ed 2021, 60, 24754–24769. - PMC - PubMed

    1. For structural analyses of strain-release reagents, see:

    2. Suenram RD; Harmony MD Microwave Spectrum, Structure, and Dipole Moment of Bicyclo[2.1.0]pentane. J. Chem. Phys 1972, 56, 3837–3842.
    3. Irngartinger H; Lukas KL Bonding in Bicyclo[1.1.0]butane Derivatives. Angew. Chem., Int. Ed. Engl 1979, 18, 694–695.
    4. Gassman PG; Greenlee ML; Dixon DA; Richtsmeier S; Gougoutas JZ X-ray and theoretical analysis of the relationship between substituent steric effects and the structure of bicyclo[1.1.0]butane. The unexpected flexibility of the bicyclo[1.1.0]butane skeleton. J. Am. Chem. Soc 1983, 105, 5865–5874.
    5. Ioffe AI; Svyatkin VA; Nefedov OM Molecular-mechanical analysis of the structure of strained organic molecules. 6. [m.n.k]-Propellanes. Russ. Chem. Bull 1988, 37, 1827–1836.
    6. Saettel NJ; Wiest O Sterically Crowded Bicyclo[1.1.0]butane Radical Cations. J. Org. Chem 2003, 68, 4549–4552. - PubMed
    7. Polo V; Andres J; Silvi B New insights on the bridge carbon–carbon bond in propellanes: A theoretical study based on the analysis of the electron localization function. J. Comput. Chem 2007, 28, 857–864. - PubMed
    8. Sterling A; Smith R; Anderson E; Duarte F Beyond strain release: Delocalisation-enabled organic reactivity. ChemRxiv 2021, DOI: 10.26434/chemrxiv-2021-n0xm9-v2. - DOI - PMC - PubMed
    1. Lemal DM; Menger F; Clark GW Bicyclobutane. J. Am. Chem. Soc 1963, 85, 2529–2530.
    2. Srinivasan R A Simple Synthesis of Bicyclo[1.1.0]butane and its Relation to the Internal Conversion of Electronic Energy in 1,3-Butadiene. J. Am. Chem. Soc 1963, 85, 4045–4046.
    3. Frey HM; Stevens IDR Carbenoid Decomposition of Cyclopropanecarboxaldehyde Tosylhydrazone: Formation of Bicyclobutane. Proc. Chem. Soc. (London) 1964, 144.
    4. Bayless J; Friedman L; Smith JA; Cook FB; Shechter H Intramolecular Reactions of Cyclopropylcarbinyl, Cyclobutyl, and Allylcarbinyl Cationic Systems. J. Am. Chem. Soc 1965, 87, 661–663.
    5. Lampman GM; Aumiller JC Bicyclo[1.1.0]butane. Org. Synth 1971, 51, 55.
    6. Chang MH; Dougherty DA 2,3-Diazabicyclo-[2.1.1]hex-2-ene. Synthesis and thermal decomposition. J. Org. Chem 1981, 46, 4092–4093.
    1. Criegee R; Rimmelin A Darstellung und Eigenschaften von Bicyclo-[0.1.2]-Pentan. Chem. Ber 1957, 90, 414–417.

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