Electron-deficient dendralenes, bearing enone substructures and possessing an unfavorable disposition of like charges at the neighboring carbons, undergo nucleophilic 1,4-addition (Michael) or 1,6-addition (anti-Michael). Diverse products are obtained, including those of simple addition as well as cyclic and ortho-fused systems arising via multistep sequences, depending on the structure of the substrate and the nature of the nucleophile. Attack of a hydride at an enone fragment triggers the formation of multisubstituted pyranones and furans; furan formation was also initiated by thiolates. A notable exception is the derivative with a five-membered cyclic enone, which prefers simple additions followed by the reshuffling of the double bonds for both H- and RS- nucleophiles. By contrast, the latter enone is the only one that can react with stabilized C-nucleophiles, yielding bicyclic compounds. Domino cyclizations can also be induced by the enolization of the enone with DBU, giving mostly polysubstituted furans. However, the dendralene with a five-membered cyclic enone and its analogue with a six-membered ring behave differently: The former gives a mixture, while the latter prefers the formation of an isocoumarin derivative, which is driven by aromatization. DFT calculations have shown that the additions of thiolates are mostly governed by the thermodynamic stability of possible products arising from complex equilibrium processes.

Department of General and Inorganic Chemistry University of Pardubice Faculty of Chemical Technology 532 10 Pardubice Czech Republic

Department of Organic and Bioorganic Chemistry Charles University Faculty of Pharmacy in Hradec Králové Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Organic Chemistry Charles University Faculty of Science Hlavova 8 128 43 Prague 2 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542 2 160 00 Prague 6 Czech Republic

Zobrazit více v PubMed

Hopf H.. The Dendralenes - A Neglected Group of Highly Unsaturated-Hydrocarbons. Angew. Chem., Int. Ed. 1984;23(12):948–960. doi: 10.1002/anie.198409481. DOI

Hopf H.. Dendralenes: The Breakthrough. Angew. Chem., Int. Ed. 2001;40(4):705–707. doi: 10.1002/1521-3773(20010216)40:4<705::AID-ANIE7050>3.0.CO;2-8. PubMed DOI

Hopf H., Sherburn M. S.. Dendralenes Branch Out: Cross-Conjugated Oligoenes Allow the Rapid Generation of Molecular Complexity. Angew. Chem., Int. Ed. 2012;51(10):2298–2338. doi: 10.1002/anie.201102987. PubMed DOI

Hopf, H. ; Sherburn, M. S. . Cross Conjugation: Modern Dendralene, Radialene and Fulvene Chemistry; John Wiley & Sons: Hoboken, NJ, 2016.

Payne A. D., Willis A. C., Sherburn M. S.. Practical Synthesis and Diels-Alder Chemistry of [4]­Dendralene. J. Am. Chem. Soc. 2005;127(35):12188–12189. doi: 10.1021/ja053772+. PubMed DOI

Chung S.-I., Seo J., Cho C.-G.. Tandem Diels-Alder Cycloadditions of 2-Pyrone-5- acrylates for the Efficient Synthesis of Novel Tetracyclolactones. J. Org. Chem. 2006;71(17):6701–6704. doi: 10.1021/jo061119e. PubMed DOI

M. Brummond K., Mitasev B., Yan B.. Cycloaddition Reactions of Amino-Acid Derived Cross-Conjugated Trienes: Stereoselective Synthesis of Novel Heterocyclic Scaffolds. Heterocycles. 2006;70:367–388. doi: 10.3987/COM-06-S(W)36. DOI

Cergol K. M., Newton C. G., Lawrence A. L., Willis A. C., Paddon-Row M. N., Sherburn M. S.. 1,1-Divinylallene. Angew. Chem., Int. Ed. 2011;50(44):10425–10428. doi: 10.1002/anie.201105541. PubMed DOI

Lindeboom E. J., Willis A. C., Paddon-Row M. N., Sherburn M. S.. Computational and Synthetic Studies with Tetravinylethylenes. J. Org. Chem. 2014;79(23):11496–11507. doi: 10.1021/jo5021294. PubMed DOI

George J., Sherburn M. S.. Diene-Transmissive Enantioselective Diels–Alder Reactions and Sequences Involving Substituted Dendralenes. J. Org. Chem. 2019;84(22):14712–14723. doi: 10.1021/acs.joc.9b02296. PubMed DOI

Fan Y.-M., Yu L.-J., Gardiner M. G., Coote M. L., Sherburn M. S.. Enantioselective oxa-Diels–Alder Sequences of Dendralenes. Angew. Chem., Int. Ed. 2022;61(39):e202204872. doi: 10.1002/anie.202204872. PubMed DOI PMC

Kostikov R. R., Molchanov A. P.. Reaction of Dichlorocarbene with 2-Vinylbuta-1,3-diene. J. Org. Chem. USSR (English Transl.) 1975;11(2):438–449.

Bojase G., Nguyen T. V., Payne A. D., Willis A. C., Sherburn M. S.. Synthesis and properties of the ivyanes: the parent 1,1-oligocyclopropanes. Chem. Sci. 2011;2:229–232. doi: 10.1039/C0SC00500B. DOI

Zhang C., Tian J., Ren J., Wang Z.. Intramolecular Parallel [4+3] Cycloadditions of Cyclopropane 1,1-Diesters with [3]­Dendralenes: Efficient Construction of [5.3.0]­Decane and Corresponding Polycyclic Skeletons. Chem. - Eur. J. 2017;23(6):1231–1236. doi: 10.1002/chem.201605190. PubMed DOI

For anionic polymerization, see:

Takamura Y., Takenaka K., Toda T., Takeshita H., Miya M., Shiomi T.. Anionic Polymerization of 2-Hexyl[3]­dendralene. Macromol. Chem. Phys. 2018;219(1):1700046. doi: 10.1002/macp.201700046. DOI

Takagi T., Toda T., Miya M., Takenaka K.. Stable and Highly Regioselective Anionic Polymerization of (Z)-1-Phenyl­[3]­dendralene. Macromolecules. 2021;54(9):4326–4332. doi: 10.1021/acs.macromol.1c00260. DOI

Desfeux C., Besnard C., Mazet C.. [n]­Dendralenes as a Platform for Selective Catalysis: Ligand-Controlled Cu-Catalyzed Chemo-, Regio-, and Enantioselective Borylations. Org. Lett. 2020;22(21):8181–8187. doi: 10.1021/acs.orglett.0c01892. PubMed DOI

Antal R., Staś M., Perdomo S. M., Štemberová M., Brůža Z., Matouš P., Kratochvíl J., Růžička A., Rulíšek L., Kuneš J., Kočovský P., Andris E., Pour M.. Synthesis of highly polarized [3]­dendralenes and their Diels–Alder reactions. Org. Chem. Front. 2023;10:5568–5578. doi: 10.1039/D3QO01221B. DOI

The term “dissonant compounds” was suggested by D. A. Evans for the description of such species in the 1970s. For a thorough discussion of this topic, see: Hudlický, T. ; Reed, J. W. . The Way of Synthesis; Wiley-VCH Verlag GmbH & KGaA: Wienheim, Germany, 2007; pp 186–187.

Breugst M., Detmar E., von der Heiden D.. Origin of the Catalytic Effects of Molecular Iodine: A Computational Analysis. ACS Catal. 2016;6(5):3203–3212. doi: 10.1021/acscatal.6b00447. DOI

von der Heiden D., Bozkus S., Klussmann M., Breugst M.. Reaction Mechanism of Iodine-Catalyzed Michael Additions. J. Org. Chem. 2017;82(8):4037–4043. doi: 10.1021/acs.joc.7b00445. PubMed DOI

Čebular K., Stavber S.. Molecular iodine as a mild catalyst for cross-coupling of alkenes and alcohols. Pure Appl. Chem. 2018;90(2):377–386. doi: 10.1515/pac-2017-0414. DOI

von der Heiden D., Detmar E., Kuchta R., Breugst M.. Activation of Michael Acceptors by Halogen-Bond Donors. Synlett. 2018;29(8):1307–1313. doi: 10.1055/s-0036-1591841. DOI

Marsili L. A., Pergomet J. L., Gandon V., Riveira M.. Iodine-Catalyzed Iso-Nazarov Cyclization of Conjugated Dienals for the Synthesis of 2-Cyclopentenones. Org. Lett. 2018;20(22):7298–7303. doi: 10.1021/acs.orglett.8b03229. PubMed DOI

Breugst M., von der Heiden D.. Mechanisms in Iodine Catalysis. Chem. - Eur. J. 2018;24(37):9187–9199. doi: 10.1002/chem.201706136. PubMed DOI

Tran U. P. N., Oss G., Breugst M., Detmar E., Pace D. P., Liyanto K., Nguyen T. V.. Carbonyl–Olefin Metathesis Catalyzed by Molecular Iodine. ACS Catal. 2019;9(2):912–919. doi: 10.1021/acscatal.8b03769. DOI

Oss J., Nguyen T. V.. Iodonium-Catalyzed Carbonyl–Olefin Metathesis Reactions. Synlett. 2019;30(17):1966–1970. doi: 10.1055/s-0039-1690297. DOI

Bandi V., Kavala V., Konala A., Hsu C.-H., Villuri B. K., Reddy S. R., Lin L.-C., Kuo C. W., Yao C.-F.. Synthesis of Polysubstituted Cyclopentene and Cyclopenta­[b]­carbazole Analogues from Unsymmetrical 4-Arylidene-3,6-diarylhex-2-en-5-ynal and Indole Derivatives via an Iodine Mediated Electrocyclization Reaction. J. Org. Chem. 2019;84(6):3036–3044. doi: 10.1021/acs.joc.8b02168. PubMed DOI

Koenig J. J., Arndt T., Gildemeister N., Neudörfl J.-M., Breugst M.. Iodine-Catalyzed Nazarov Cyclizations. J. Org. Chem. 2019;84(12):7587–7605. doi: 10.1021/acs.joc.9b01083. PubMed DOI

Hamlin T. A., Fernández I., Bickelhaupt F. M.. How Dihalogens Catalyze Michael Addition Reactions. Angew. Chem., Int. Ed. 2019;58(26):8922–8926. doi: 10.1002/anie.201903196. PubMed DOI PMC

Hamlin T. A., Bickelhaupt F. M., Fernández I.. The Pauli Repulsion-Lowering Concept in Catalysis. Acc. Chem. Res. 2021;54(8):1972–1981. doi: 10.1021/acs.accounts.1c00016. PubMed DOI

Arndt T., Wagner P. K., Koenig J. J., Breugst M.. Iodine-Catalyzed Diels-Alder Reactions. ChemCatChem. 2021;13(12):2922–2930. doi: 10.1002/cctc.202100342. DOI

Bulfield D., Huber S. M.. Halogen Bonding in Organic Synthesis and Organocatalysis. Chem. - Eur. J. 2016;22(41):14434–14450. doi: 10.1002/chem.201601844. PubMed DOI

Kolář M. H., Hobza P.. Computer modelling of halogen bonds and other σ-hole interactions. Chem. Rev. 2016;116(9):5155–5187. doi: 10.1021/acs.chemrev.5b00560. PubMed DOI

Costa P. J.. The halogen bond: Nature and applications. Phys. Sci. Rev. 2017;2(11):20170136. doi: 10.1515/psr-2017-0136. DOI

Breugst M., von der Heiden D., Schmauck J.. Novel Noncovalent Interactions in Catalysis: A Focus on Halogen, Chalcogen, and Anion-π Bonding. Synthesis. 2017;49(15):3224–3236. doi: 10.1055/s-0036-1588838. DOI

Kesharwani M. K., Manna D., Sylvetsky N., Martin J. M. L.. The X40 × 10 Halogen Bonding Benchmark Revisited: Surprising Importance of (n–1)­d Subvalence Correlation. J. Phys. Chem. A. 2018;122(8):2184–2197. doi: 10.1021/acs.jpca.7b10958. PubMed DOI

Breugst M., Koenig J. J.. σ-Hole Interactions in Catalysis. Eur. J. Org. Chem. 2020;2020(34):5473–5487. doi: 10.1002/ejoc.202000660. DOI

Mallada B., Gallardo A., Lamanec M., de la Torre B., Špirko V., Hobza P., Jelínek P.. Real-space imaging of anisotropic charge of σ-hole by means of Kelvin probe force microscopy. Science. 2021;374:863–877. doi: 10.1126/science.abk1479. PubMed DOI

Ballini R., Palmieri A.. Formation of Carbon-Carbon Double Bonds: Recent Developments via Nitrous Acid Elimination (NAE) from Aliphatic Nitro Compounds. Adv. Synth. Catal. 2019;361(22):5070–5097. doi: 10.1002/adsc.201900563. DOI

Roy S.. An Unusual Route to Synthesize Indolizines through a Domino SN2/Michael Addition Reaction Between 2-Mercaptopyridine and Nitroallylic Acetates. Eur. J. Org. Chem. 2019;2019(4):765–769. doi: 10.1002/ejoc.201801426. DOI

Chen W. T., Luo F., Wu Y., Cen J., Shao J. A., Yu Y. P.. Efficient access to fluorescent benzofuro­[3,2-b]­carbazoles via TFA-promoted cascade annulations of sulfur ylides, 2-hydroxy-β-nitrostyrenes and indoles. Org. Chem. Front. 2020;7:873–878. doi: 10.1039/D0QO00137F. DOI

Thomas B. E., Kollman P. A.. An ab initio molecular orbital study of the first step of the catalytic mechanism of thymidylate synthase: the Michael addition of sulfur and oxygen nucleophiles. J. Org. Chem. 1995;60:8375–8381. doi: 10.1021/jo00131a012. DOI

Raycroft M. A. R., Racine K. É., Rowley C. N., Keillor J. W.. Mechanisms of Alkyl and Aryl Thiol Addition to N-Methylmaleimide. J. Org. Chem. 2018;83:11674–11685. doi: 10.1021/acs.joc.8b01638. PubMed DOI

Awoonor-Williams E., Isley W. C., Dale S. G., Johnson E. R., Yu H., Becke A. D., Roux B., Rowley C. N.. Quantum Chemical Methods for Modeling Covalent Modification of Biological Thiols. J. Comput. Chem. 2020;41:427–438. doi: 10.1002/jcc.26064. PubMed DOI

Costa A. M., Bosch L., Petit E., Vilarrasa J.. Computational Study of the Addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines. J. Org. Chem. 2021;86:7107–7118. doi: 10.1021/acs.joc.1c00349. PubMed DOI PMC

Watt S. K. I., Charlebois J. G., Rowley C. N., Keillor J. W.. A mechanistic study of thiol addition to N-acryloylpiperidine. Org. Biomol. Chem. 2023;21:2204–2212. doi: 10.1039/D2OB02223K. PubMed DOI

Liu R., Vázquez-Montelongo E. A., Ma S., Shen J.. Quantum Descriptors for Predicting and Understanding the Structure–Activity Relationships of Michael Acceptor Warheads. J. Chem. Inf. Model. 2023;63:4912–4923. doi: 10.1021/acs.jcim.3c00720. PubMed DOI PMC

Ma S., Patel H., Peeples C. A., Shen J.. QM/MM Simulations of Afatinib-EGFR Addition: The Role of β-Dimethylaminomethyl Substitution. J. Chem. Theory Comput. 2024;20:5528–5538. doi: 10.1021/acs.jctc.4c00290. PubMed DOI PMC

Brown J. S., Ruttinger A. W., Vaidya A. J., Alabi C. A., Clancy P.. Decomplexation as a rate limitation in the thiol-Michael addition of N-acrylamides. Org. Biomol. Chem. 2020;18:6364–6377. doi: 10.1039/D0OB00726A. PubMed DOI

Berne D., Lemouzy S., Guiffrey P., Caillol S., Ladmiral V., Manoury E., Poli R., Leclerc E.. Catalyst-Free Thia-Michael Addition to α-Trifluoromethylacrylates for 3D Network Synthesis. Chem. - Eur. J. 2023;29:e202203712. doi: 10.1002/chem.202203712. PubMed DOI

Roseli R. B., Keto A. B., Krenske E. H.. Mechanistic aspects of thiol additions to Michael acceptors: Insights from computations. WIREs Comput. Mol. Sci. 2023;13:e1636. doi: 10.1002/wcms.1636. DOI

Smith J. M., Jami Alahmadi Y., Rowley C. N.. Range-Separated DFT Functionals are Necessary to Model Thio-Michael Additions. J. Chem. Theory Comput. 2013;9:4860–4865. doi: 10.1021/ct400773k. PubMed DOI

Ting J. Y. C., Roseli R. B., Krenske E. H.. How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin. Org. Biomol. Chem. 2020;18:1426–1435. doi: 10.1039/C9OB02709B. PubMed DOI

Takagi T., Toda T., Miya M., Takenaka K.. DFT study on the anionic polymerization of phenyl-substituted [3]­dendralene derivatives: reactivities of monomer and chain end carbanion. Polym. J. 2022;54:643–652. doi: 10.1038/s41428-022-00615-1. DOI

Mardirossian N., Head-Gordon M.. ωB97M-V: A combinatorially optimized, range-separated hybrid, meta-GGA density functional with VV10 nonlocal correlation. J. Chem. Phys. 2016;144(21):214110. doi: 10.1063/1.4952647. PubMed DOI

Weigend F., Ahlrichs R.. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005;7:3297–3305. doi: 10.1039/b508541a. PubMed DOI

Rappoport D., Furche F.. Property-optimized Gaussian basis sets for molecular response calculations. J. Chem. Phys. 2010;133(13):134105. doi: 10.1063/1.3484283. PubMed DOI

Vosko S. H., Wilk L., Nusair M.. Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can. J. Phys. 1980;58(8):1200–1211. doi: 10.1139/p80-159. DOI

Lee C., Yang W., Parr R. G.. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B. 1988;37:785–789. doi: 10.1103/PhysRevB.37.785. PubMed DOI

Becke A. D.. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993;98(7):5648–5652. doi: 10.1063/1.464913. DOI

Stephens P. J., Devlin F. J., Chabalowski C. F., Frisch M. J.. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994;98(45):11623–11627. doi: 10.1021/j100096a001. DOI

Grimme S., Antony J., Ehrlich S., Krieg H.. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010;132(15):154104. doi: 10.1063/1.3382344. PubMed DOI

Grimme S., Ehrlich S., Goerigk L.. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011;32(7):1456–1465. doi: 10.1002/jcc.21759. PubMed DOI

Knizia G.. Intrinsic Atomic Orbitals: An Unbiased Bridge between Quantum Theory and Chemical Concepts. J. Chem. Theory Comput. 2013;9(11):4834–4843. doi: 10.1021/ct400687b. PubMed DOI

Knizia G., Klein J. E. M. N.. Electron Flow in Reaction Mechanisms Revealed from First Principles. Angew. Chem., Int. Ed. 2015;54(18):5518–5522. doi: 10.1002/anie.201410637. PubMed DOI

Chatani S., Nair D. P., Bowman C. N.. Relative reactivity and selectivity of vinyl sulfones and acrylates towards the thiol–Michael addition reaction and polymerization. Polym. Chem. 2013;4:1048–1055. doi: 10.1039/C2PY20826A. DOI

Shiobara Y., Asakawa Y., Kodama M., Takemoto T.. Zedoarol, 13-Hydroxygermacrone and Curzeone, Three Sesquiterpenoids from Curcuma zedoaria . Phytochemistry. 1986;25(6):1351–1353. doi: 10.1016/S0031-9422(00)81288-1. DOI

Jogia M. K., Andersen R. J., Parkanyi L., Clardy J., Dublin H. T., Sinclair A. R. E.. Crotofolane Diterpenoids from the African Shrub Croton dichogamus Pax. J. Org. Chem. 1989;54(7):1654–1657. doi: 10.1021/jo00268a029. DOI

Kupchan S. M., Shizuri Y., Baxter R. L., Haynes H. R.. Gnididione, a New Furanosesquiterpene from Gnidia latifolia . J. Org. Chem. 1977;42(2):348–350. doi: 10.1021/jo00422a040. PubMed DOI

Nakamura H., Kobayashi J., Kobayashi M., Ohizumi Y., Hirata Y.. Xestoquinone. A Novel Cardiotonic Marine Natural Product Isolated From The Okinawan Sea Sponge Xestospongia sapra . Chem. Lett. 1985;14(6):713–716. doi: 10.1246/cl.1985.713. DOI

Hikino H., Agatsuma K., Takemoto T.. Structure of Curzerenone, Epicurzerenone, and Isofuranogermacrene (Curzerene) Tetrahedron Lett. 1968;9(24):2855–2858. doi: 10.1016/S0040-4039(00)75646-2. DOI

McPherson D. D., Che Ch.-T., Cordell G. A., Doel Soejarto D., Pezzuto J. M., Fong H. H. S.. Diterpenoids from Caesalpinia pulcherrima . Phytochemistry. 1985;25(1):167–170. doi: 10.1016/S0031-9422(00)94522-9. DOI

Macias F. A., Fronczek F. R., Fischer N. H.. Menthofurans from Calamintha ashei and the Absolute Configuration of Desacetylcalaminthone. Phytochemistry. 1989;28(1):79–82. doi: 10.1016/0031-9422(89)85013-7. DOI

Ryu S. Y., Lee Ch. O., Choi S. U.. In Vitro Cytotoxicity of Tanshinones from Salvia miltiorrhiza . Planta Med. 1997;63(4):339–342. doi: 10.1055/s-2006-957696. PubMed DOI

Syu W.-J., Shen Ch.-Ch., Don M.-J., Ou J.-Ch., Lee G.-H., Sun Ch.-M.. Cytotoxicity of Curcuminoids and Some Novel Compounds from Curcuma zedoaria . J. Nat. Prod. 1998;61(12):1531–1534. doi: 10.1021/np980269k. PubMed DOI