Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regioirregular and catalytic Mizoroki–Heck reactions


The palladium-catalysed cross-coupling reaction between alkenes and aryl halides (the Mizoroki–Heck reaction) is a powerful methodology to construct new carbon–carbon bonds. However, the success of this reaction is in part hampered by an extremely marked regioselectivity on the double bond, which dictates that electron-poor alkenes react exclusively on the β-carbon. Here, we show that ligand-free, few-atom palladium clusters in solution catalyse the α-selective intramolecular Mizoroki–Heck coupling of iodoaryl cinnamates, and mechanistic studies support the formation of a sterically encumbered cinnamate–palladium cluster intermediate. Following this rationale, the α-selective intermolecular coupling of aryl iodides with styrenes is also achieved with palladium clusters encapsulated within fine-tuned and sterically restricted zeolite cavities to produce 1,1-bisarylethylenes, which are further engaged with aryl halides by a metal-free photoredox-catalysed coupling. These ligand-free methodologies significantly expand the chemical space of the Mizoroki–Heck coupling.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Expanding the chemical space of the Mizoroki–Heck reaction.
Fig. 2: Scope for the α-selective intramolecular coupling.
Fig. 3: DFT calculations of the α-selective intramolecular coupling.
Fig. 4: Pd-containing base zeolites for the α-selective intermolecular coupling.
Fig. 5: Steric effects and in-flow reaction.
Fig. 6: Scope for α-selective intermolecular coupling.

Data availability

The datasets generated during and/or analysed during the current study are included in this Article (and its Supplementary Information) or are available from the corresponding authors upon reasonable request. If possible, datasets will also be deposited in public repositories of the UPV and CSIC. Source data are provided with this paper.


  1. 1.

    Phan, N. T. S., Van Der Sluys, M. & Jones, C. W. On the nature of the active species in palladium catalysed Mizoroki–Heck and Suzuki–Miyaura couplings—homogeneous or heterogeneous catalysis, a critical review. Adv. Synth. Catal. 348, 609–679 (2006).

    CAS  Google Scholar 

  2. 2.

    Mo, J. & Xiao, J. The Heck reaction of electron-rich olefins with regiocontrol by hydrogen-bond donors. Angew. Chem. Int. Ed. 45, 4152–4157 (2006).

    CAS  Google Scholar 

  3. 3.

    Wucher, P. et al. Breaking the regioselectivity rule for acrylate insertion in the Mizoroki–Heck reaction. Proc. Natl Acad. Sci. USA 108, 8955–8959 (2011).

    CAS  PubMed  Google Scholar 

  4. 4.

    Barluenga, J., Moriel, P., Valdés, C. & Aznar, F. N. Tosylhydrazones as reagents for cross-coupling reactions: a route to polysubstituted olefins. Angew. Chem. Int. Ed. 46, 5587–5590 (2007).

    CAS  Google Scholar 

  5. 5.

    Zou, Y. et al. Selective arylation and vinylation at the α position of vinylarenes. Chem. Eur. J. 19, 3504–3511 (2013).

    CAS  PubMed  Google Scholar 

  6. 6.

    Tang, J., Hackenberger, D. & Goossen, L. J. Branched arylalkenes from cinnamates: selectivity inversion in Heck reactions by carboxylates as deciduous directing groups. Angew. Chem. Int. Ed. 55, 11296–11299 (2016).

    CAS  Google Scholar 

  7. 7.

    Sullivan, R. J., Freure, G. P. R. & Newman, S. G. Overcoming scope limitations in cross-coupling of diazo nucleophiles by manipulating catalyst speciation and using flow diazo generation. ACS Catal. 9, 5623–5630 (2019).

    CAS  Google Scholar 

  8. 8.

    Nakashima, Y., Hirata, G., Sheppard, T. D. & Nishikata, T. The Mizoroki–Heck reaction with internal olefins: reactivities and stereoselectivities. Asian J. Org. Chem. 9, 480–491 (2020).

    CAS  Google Scholar 

  9. 9.

    Torborg, C. & Beller, M. Recent applications of palladium-catalysed coupling reactions in the pharmaceutical, agrochemical and fine chemical industries. Adv. Synth. Catal. 351, 3027–3043 (2009).

    CAS  Google Scholar 

  10. 10.

    Dounay, A. B. & Overman, L. E. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 103, 2945–2963 (2003).

    CAS  PubMed  Google Scholar 

  11. 11.

    Tsvelikhovsky, D. & Buchwald, S. L. Synthesis of heterocycles via Pd-ligand controlled cyclization of 2-chloro-N-(2-vinyl)aniline: preparation of carbazoles, indoles, dibenzazepines and acridines. J. Am. Chem. Soc. 132, 14048–14051 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Wu, X.-F., Anbarasan, P., Neumann, H. & Beller, M. From noble metal to Nobel prize: palladium-catalysed coupling reactions as key methods in organic synthesis. Angew. Chem. Int. Ed. 49, 9047–9050 (2010).

    CAS  Google Scholar 

  13. 13.

    Beletskaya, I. P. & Cheprakov, A. V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 100, 3009–3066 (2000).

    CAS  PubMed  Google Scholar 

  14. 14.

    Weng, S.-S., Ke, C.-S., Chen, F.-K., Lyu, Y.-F. & Lin, G.-Y. Transesterification catalysed by iron(iii) β-diketonate species. Tetrahedron 67, 1640–1648 (2011).

    CAS  Google Scholar 

  15. 15.

    Nájera, C. Oxime-derived palladacycles: applications in catalysis. ChemCatChem 8, 1865–1881 (2016).

    Google Scholar 

  16. 16.

    Leyva-Pérez, A., Oliver-Meseguer, J., Rubio-Marqués, P. & Corma, A. Water-stabilized three- and four-atom palladium clusters as highly active catalytic species in ligand-free C–C cross-coupling reactions. Angew. Chem. Int. Ed. 52, 11554–11559 (2013).

    Google Scholar 

  17. 17.

    Zhu, F., Li, Y., Wang, Z. & Wu, X.-F. Iridium-catalysed carbonylative synthesis of chromenones from simple phenols and internal alkynes at atmospheric pressure. Angew. Chem. Int. Ed. 55, 14151–14154 (2016).

    CAS  Google Scholar 

  18. 18.

    Li, X. et al. Palladium-catalysed enantioselective intramolecular dearomative Heck reaction. J. Am. Chem. Soc. 140, 13945–13951 (2018).

    CAS  PubMed  Google Scholar 

  19. 19.

    Fernández, E. et al. Base-controlled Heck, Suzuki and Sonogashira reactions catalysed by ligand-free platinum or palladium single atom and sub-nanometer clusters. J. Am. Chem. Soc. 141, 1928–1940 (2019).

    PubMed  Google Scholar 

  20. 20.

    Sperger, T., Stirner, C. K. & Schoenebeck, F. Bench-stable and recoverable palladium(i) dimer as an efficient catalyst for Heck cross-coupling. Synthesis 49, 115–120 (2017).

    CAS  Google Scholar 

  21. 21.

    Fortea-Pérez, F. R. et al. The MOF-driven synthesis of supported palladium clusters with catalytic activity for carbene-mediated chemistry. Nat. Mater. 16, 760–766 (2017).

    PubMed  Google Scholar 

  22. 22.

    von Schenck, H., Åkermark, B. & Svensson, M. Electronic control of the regiochemistry in the Heck reaction. J. Am. Chem. Soc. 125, 3503–3508 (2003).

    Google Scholar 

  23. 23.

    Deeth, R. J., Smith, A. & Brown, J. M. Electronic control of the regiochemistry in palladium-phosphine catalysed intermolecular Heck reactions. J. Am. Chem. Soc. 126, 7144–7151 (2004).

    CAS  PubMed  Google Scholar 

  24. 24.

    Djakovitch, L. & Koehler, K. Heck reaction catalysed by Pd-modified zeolites. J. Am. Chem. Soc. 123, 5990–5999 (2001).

    CAS  PubMed  Google Scholar 

  25. 25.

    Dams, M. et al. Pd-zeolites as heterogeneous catalysts in Heck chemistry. J. Catal. 209, 225–236 (2002).

    CAS  Google Scholar 

  26. 26.

    Marqués, P., Rivero-Crespo, M. A., Leyva-Pérez, A. & Corma, A. Well-defined noble metal single sites in zeolites as an alternative to catalysis by insoluble metal salts. J. Am. Chem. Soc. 137, 11832–11837 (2015).

    Google Scholar 

  27. 27.

    Corma, A., García, H., Leyva, A. & Primo, A. Basic zeolites containing palladium as bifunctional heterogeneous catalysts for the Heck reaction. Appl. Catal. A 247, 41–49 (2003).

    CAS  Google Scholar 

  28. 28.

    Sun, T., Seff, K., Heo, N. H. & Petranovskii, V. P. A cationic cesium continuum in zeolite X. Science 259, 495–497 (1993).

    CAS  PubMed  Google Scholar 

  29. 29.

    Agostini, G. et al. Preparation of supported Pd catalysts: from the Pd precursor solution to the deposited Pd2+ phase. Langmuir 26, 11204–11211 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Cerrillo, J. L. et al. Nature and evolution of Pd catalysts supported on activated carbon fibers during the catalytic reduction of bromate in water. Catal. Sci. Technol. 10, 3646–3653 (2020).

    CAS  Google Scholar 

  31. 31.

    Liu, L. & Corma, A. Metal catalysts for heterogeneous catalysis: from single atoms to nanoclusters and nanoparticles. Chem. Rev. 118, 4981–5079 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Liu, L. et al. Regioselective generation and reactivity control of subnanometric platinum clusters in zeolites for high-temperature catalysis. Nat. Mater. 18, 866–873 (2019).

    CAS  PubMed  Google Scholar 

  33. 33.

    Liu, L. et al. Structural modulation and direct measurement of subnanometric bimetallic PtSn clusters confined in zeolites. Nat. Catal. 3, 628–638 (2020).

    CAS  Google Scholar 

  34. 34.

    Liu, L. et al. Tutorial: structural characterization of isolated metal atoms and subnanometric metal clusters in zeolites. Nat. Protoc. (2020).

  35. 35.

    Li, P. et al. Explaining the influence of the introduced base sites into alkali oxide modified CsX towards side-chain alkylation of toluene with methanol. RSC Adv. 9, 13234–13242 (2019).

    CAS  Google Scholar 

  36. 36.

    Concepcion-Heydorn, P. et al. Structural and catalytic properties of sodium and cesium exchanged X and Y zeolites, and germanium substituted X zeolite. J. Mol. Catal. A 162, 227–246 (2000).

    CAS  Google Scholar 

  37. 37.

    Seo, D.-W., Rahma, S. T., Reddy, B. M. & Parka, S.-E. Carbon dioxide assisted toluene side-chain alkylation with methanol over Cs-X zeolite catalyst. J. CO2 Util. 26, 254–261 (2018).

    CAS  Google Scholar 

  38. 38.

    Rivero-Crespo, M. Á. et al. Intermolecular carbonyl-olefin metathesis with vinyl ethers catalysed by homogeneous and solid acids in flow. Angew. Chem. Int. Ed. 59, 3846–3849 (2020).

    CAS  Google Scholar 

  39. 39.

    Kashani, S. K., Jessiman, J. E. & Newman, S. G. Exploring homogeneous conditions for mild Buchwald–Hartwig amination in batch and flow. Org. Process Res. Dev. (2020).

  40. 40.

    Alami, M., Liron, F., Gervais, M., Peyrat, J.-F. & Brion, J.-D. Ortho substituents direct regioselective addition of tributyltin hydride to unsymmetrical diaryl (or heteroaryl) alkynes: an efficient route to stannylated stilbene derivatives. Angew. Chem. Int. Ed. 41, 1578–1580 (2002).

    CAS  Google Scholar 

  41. 41.

    Onuigbo, L., Raviola, C., Di Fonzo, A., Protti, S. & Fagnoni, M. Sunlight-driven synthesis of triarylethylenes (TAEs) via metal-free Mizoroki–Heck-type coupling. Eur. J. Org. Chem. 38, 5297–5303 (2018).

    Google Scholar 

  42. 42.

    Wang, H., Gao, Y., Zhou, C. & Li, G. Visible-light-driven reductive carboarylation of styrenes with CO2 and aryl halides. J. Am. Chem. Soc. 142, 8122–8129 (2020).

    CAS  PubMed  Google Scholar 

  43. 43.

    Zuo, Z. & MacMillan, D. W. C. Decarboxylative arylation of α-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J. Am. Chem. Soc. 136, 5257–5260 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Bardagi, J. I., Ghosh, I., Schmalzbauer, M., Ghosh, T. & König, B. Anthraquinones as photoredox catalysts for the reductive activation of aryl halides. Eur. J. Org. Chem. 1, 34–40 (2018).

    Google Scholar 

  45. 45.

    Majek, M., Faltermeier, U., Dick, B., Pérez-Ruiz, R. & Jacobi von Wangelin, A. Application of visible-to-UV photon upconversion to photoredox catalysis: the activation of aryl bromides. Chem. Eur. J. 21, 15496–15501 (2015).

    CAS  PubMed  Google Scholar 

  46. 46.

    López-Calixto, C. G., Liras, M., de la Peña O’Shea, V. A. & Pérez-Ruiz, R. Synchronized biphotonic process triggering C–C coupling catalytic reactions. Appl. Catal. B 237, 18–23 (2018).

    Google Scholar 

  47. 47.

    Martínez-Gualda, A. M. et al. Chromoselective access to Z- or E-allylated amines and heterocycles by a photocatalytic allylation reaction. Nat. Commun. 10, 2634 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Yang, J. et al. Direct synthesis of adipic acid esters via palladium catalysed carbonylation of 1,3-dienes. Science 366, 1514–1517 (2019).

    CAS  PubMed  Google Scholar 

  49. 49.

    Uehling, M. R., King, R. P., Krska, S. W., Cernak, T. & Buchwald, S. L. Pharmaceutical diversification via palladium oxidative addition complexes. Science 363, 405–408 (2019).

    CAS  PubMed  Google Scholar 

  50. 50.

    Ross, S. P., Rahman, A. A. & Sigman, M. S. Development and mechanistic interrogation of interrupted chain-walking in the enantioselective relay Heck reaction. J. Am. Chem. Soc. 142, 10516–10525 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by MINECO (Spain, projects CTQ 2017-86735-P, PID2019-105391GB-C22 and MAT2017-82288-C2-1-P, Severo Ochoa programme SEV-2016-0683 and the Juan de la Cierva programme). F.G.-P. and R.G. thank ITQ for the concession of a contract. J.O.-M. acknowledges the Juan de la Cierva programme for the concession of a contract, and R.P.-R. and J.C.-S. thank the Plan GenT programme (CIDEGENT/2018/044) funded by Generalitat Valenciana. HR STEM measurements were performed at DME-UCA in Cadiz University, with financial support from FEDER/MINECO (PID2019-110018GA-I00 and PID2019-107578GA-I00). We acknowledge ALBA Synchrotron for allocating beamtime and CLÆSS beamline staff for their technical support during our experiment.

Author information




F.G.-P. performed the synthesis and characterization of Pd catalysts and the corresponding reactions. R.G. carried out and interpreted the computational studies. J.O.-M. performed and interpreted the synchrotron studies and the in-flow reactions. R.P.-R. and M.C.J. designed and supervised the investigations on photoredox-catalysed coupling between aryl bromides and 1,1-diphenylethylenes. M.L.-H. and J.C.H.-G. carried out and interpreted HR STEM measurements, image analysis and simulations. M.B. carried out and supervised the computational studies. J.C.-S and R.P.-R. performed the photoredox-catalysed reactions together with the isolation, purification and characterization of TAEs. A.L.-P. performed the synthesis and characterization of Pd catalysts and the corresponding reactions, supervised the whole study and wrote the manuscript (all authors contributed to the manuscript).

Corresponding authors

Correspondence to Raúl Pérez-Ruiz or Antonio Leyva-Pérez.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Catalysis thanks Ataualpa A. C. Braga, Xiaoning Guo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Scope for the coupling of aryl bromides with polysubstituted ethylenes by means of TFU photoredox catalysis.

Examples of Mizoroki–Heck couplings between aryl bromides and polysubstituted alkenes using TFU technology. Reaction conditions: aryl bromide (10−2 M), polysubstituted alkenes (0.1 M), BOPHY (10−4 M) and DPA (10−3 M), 3 ml of ACN/DMA 5/1 v/v using a blue laser pointer (445 nm ± 10) under nitrogen atmosphere during 5 h. i This reaction was carried out using 2–acetyl–5–chlorothiophene.

Extended Data Fig. 2 Mechanism of the TFU photoredox catalysed Heck coupling of polysubstituted ethylenes.

a, Transient absorption spectra of BOPHY (0.001 mM) and DPA (1 mM) in N2 ACN/DMA (5/1 v/v) solution (λexc = 485 nm). b, Proposed photocatalytic mechanism of the Mizoroki–Heck coupling reaction between aryl bromides and polysubstituted alkenes. Cascade processes involving: ISC (intersystem crossing), TTEnT (triplet–triplet energy transfer), TFU (triplet fusion upconversion), SET (single electron transfer), C‒C bond formation and BET (back electron transfer). c, Delayed emission spectra of a mixture of BOPHY (0.1 mM) and DPA (1 mM) in bubbled (N2) ACN/DMA (5/1 v/v) after excitation (485 nm) with a pulsed laser in the absence (black) and in the presence of 4–bromoacetophenone (10 mM). d, Transient absorption spectrum recorded at 2 μs after the laser pulse of BOPHY (10−4 M) and DPA (10−3 M) in the presence of 4–bromoacetophenone (10−2 M) and 1,1-diphenylethylene (0.1 M) in 3 ml of N2 ACN/DMA (5/1 v/v); inset: decay kinetic monitored at 500 nm after 485 nm TAS.

Supplementary information

Supplementary Information

Supplementary Figs. 1–31, Tables 1–3, Discussion and Methods.

Supplementary Data

Atomic coordinates for the computational calculations, in a flat text file.

Source data

Source Data Fig. 5

Statistical source data.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Garnes-Portolés, F., Greco, R., Oliver-Meseguer, J. et al. Regioirregular and catalytic Mizoroki–Heck reactions. Nat Catal 4, 293–303 (2021).

Download citation


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing