Ligand-Controlled Site-Selective Cross-Coupling

  • Miyuki Yamaguchi
  • Kei ManabeEmail author
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 372)


Site-selective mono-cross-coupling reactions involving dichloro- or dibromo(hetero)aryl substrates are utilized to prepare substituted monochloro- or monobromo(hetero)arenes, which are used as drug components and synthetic precursors. In these reactions, selectivity toward the preferred reaction site of a dihalo(hetero)arene can vary depending on the ancillary ligand of the transition metal catalyst. This review summarizes the examples of ligand-controlled site-selective cross-coupling reactions, specifically those mediated by Pd complexes.


Kumada–Tamao–Corriu coupling Palladium Sonogashira coupling Suzuki–Miyaura coupling Transition metal catalyst 











Bis[2-(diphenylphosphino)phenyl] ether






Lowest unoccupied molecular orbital






Dichloro(chlorodi-tert-butylphosphine)palladium(II) dimer




Tetrabutylammonium chloride






Tosyl, p-toluenesulfonyl






  1. 1.
    Negishi E (2002) Handbook of organopalladium chemistry for organic synthesis. Wiley, New YorkCrossRefGoogle Scholar
  2. 2.
    Tsuji J (2004) Palladium reagents and catalysts. Wiley, West SussexCrossRefGoogle Scholar
  3. 3.
    de Meijere A, Bräse S, Oestreich M (2014) Metal-catalyzed cross-coupling reactions and more. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  4. 4.
    Unrau CM, Campbell MG, Snieckus V (1992) Directed ortho metalation – Suzuki cross coupling connections. Convenient regiospecific routes to functionalized m-and p-teraryls and m-quinquearyls. Tetrahedron Lett 33:2773–2776CrossRefGoogle Scholar
  5. 5.
    Goodby JW, Hird M, Lewis RA, Toyne KJ (1996) 5-Bromo-2-iodopyrimidine: a novel, useful intermediate in selective palladium-catalysed cross-coupling reactions for efficient convergent syntheses. Chem Commun 2719–2720Google Scholar
  6. 6.
    Heinrich ACJ, Thiedemann B, Gates PJ, Staubitz A (2013) Dual selectivity: electrophile and nucleophile selective cross-coupling reactions on a single aromatic substrate. Org Lett 15:4666–4669CrossRefGoogle Scholar
  7. 7.
    Montoir D, Tonnerre A, Duflos M, Bazin MA (2014) Differential functionalization of 1,6-naphthyridin-2(1H)-ones through sequential one-pot Suzuki–Miyaura cross-couplings. Eur J Org Chem 1487–1495Google Scholar
  8. 8.
    Wang JR, Manabe K (2009) Transition-metal-catalyzed site-selective cross-coupling of di- and polyhalogenated compounds. Synthesis 1405–1427Google Scholar
  9. 9.
    Schröter S, Stock C, Bach T (2005) Regioselective cross-coupling reactions of multiple halogenated nitrogen-, oxygen-, and sulfur-containing heterocycles. Tetrahedron 61:2245–2267CrossRefGoogle Scholar
  10. 10.
    Fairlamb IJS (2007) Regioselective (site-selective) functionalization of unsaturated halogenated nitrogen, oxygen and sulfur heterocycles by Pd-catalysed cross-couplings and direct arylation processes. Chem Soc Rev 36:1036–1045CrossRefGoogle Scholar
  11. 11.
    Hassan Z, Patonay T, Langer P (2013) Regioselective Suzuki–Miyaura reactions of aromatic bis-triflates: electronic versus steric effects. Synlett 24:412–423CrossRefGoogle Scholar
  12. 12.
    Singh R, Just G (1989) Rates and regioselectivities of the palladium-catalyzed ethynylation of substituted bromo- and dibromobenzenes. J Org Chem 54:4453–4457CrossRefGoogle Scholar
  13. 13.
    Handy ST, Zhang Y (2006) A simple guide for predicting regioselectivity in the coupling of polyhaloheteroaromatics. Chem Commun 299–301Google Scholar
  14. 14.
    Legault CY, Garcia Y, Merlic CA, Houk KN (2007) Origin of regioselectivity in palladium-catalyzed cross-coupling reactions of polyhalogenated heterocycles. J Am Chem Soc 129:12664–12665CrossRefGoogle Scholar
  15. 15.
    Garcia Y, Schoenebeck F, Legault CY, Merlic CA, Houk KN (2009) Theoretical bond dissociation energies of halo-heterocycles: trends and relationships to regioselectivity in palladium-catalyzed cross-coupling reactions. J Am Chem Soc 131:6632–6639CrossRefGoogle Scholar
  16. 16.
    Herrebout WA, Nagels N, Verbeeck S, van der Veken BJ, Maes BUW (2010) A DFT study of site-selectivity in oxidative addition reactions with Pd0 complexes: the effect of an azine nitrogen and the use of different types of halogen atoms in the substrate. Eur J Org Chem 3152–3158Google Scholar
  17. 17.
    Manabe K, Yamaguchi M (2014) Catalyst-controlled site-selectivity switching in Pd-catalyzed cross-coupling of dihaloarenes. Catalysts 4:307–320CrossRefGoogle Scholar
  18. 18.
    Newman SG, Lautens M (2010) The role of reversible oxidative addition in selective palladium(0)-catalyzed intramolecular cross-couplings of polyhalogenated substrates: synthesis of brominated indoles. J Am Chem Soc 132:11416–11417CrossRefGoogle Scholar
  19. 19.
    Hayashi T (2002) Palladium-catalyzed asymmetric cross-coupling. In: Negishi E, de Meijere A (eds) Handbook of organopalladium chemistry for organic synthesis, vol 1. Wiley, New York, pp p791–806, Chapter III.2.16CrossRefGoogle Scholar
  20. 20.
    Kamikawa T, Hayashi T (1997) Control of reactive site in palladium-catalyzed Grignard cross-coupling of arenes containing both bromide and triflate. Tetrahedron Lett 38:7087–7090CrossRefGoogle Scholar
  21. 21.
    Littke AF, Dai C, Fu GC (2000) Versatile catalysts for the Suzuki cross-coupling of arylboronic acids with aryl and vinyl halides and triflates under mild conditions. J Am Chem Soc 122:4020–4028CrossRefGoogle Scholar
  22. 22.
    Ashcroft CP, Fussell SJ, Wilford K (2013) Catalyst controlled regioselective Suzuki cross-coupling of 2-(4-bromophenyl)-5-chloropyrazine. Tetrahedron Lett 54:4529–4532CrossRefGoogle Scholar
  23. 23.
    Suzuki A (2011) Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel lecture). Angew Chem Int Ed 50:6722–6737CrossRefGoogle Scholar
  24. 24.
    Yang W, Wang Y, Corte JR (2003) Efficient synthesis of 2-aryl-6-chloronicotinamides via PXPd2-catalyzed regioselective Suzuki coupling. Org Lett 5:3131–3134CrossRefGoogle Scholar
  25. 25.
    Li GY (2002) Catalysis using phosphine oxide and phosphine sulfide complexes with Pd and Ni for the synthesis of biaryls and arylamines. Int Patent WO2002000574A2, 3 Jan 2002Google Scholar
  26. 26.
    Houpis IN, Huang C, Nettekoven U, Chen JG, Liu R, Canters M (2008) Carboxylate directed cross-coupling reactions in the synthesis of trisubstituted benzoic acids. Org Lett 10:5601–5604CrossRefGoogle Scholar
  27. 27.
    Houpis IN, Liu R, Wu Y, Yuan Y, Wang Y, Nettekoven U (2010) Regioselective cross-coupling reactions of boronic acids with dihalo heterocycles. J Org Chem 75:6965–6968CrossRefGoogle Scholar
  28. 28.
    Dai X, Chen Y, Garrell S, Liu H, Zhang LK, Palani A, Hughes G, Nargun R (2013) Ligand-dependent site-selective Suzuki cross-coupling of 3,5-dichloropyridazines. J Org Chem 78:758–7763Google Scholar
  29. 29.
    Shelby Q, Kataoka N, Mann G, Hartwig J (2000) Unusual in situ ligand modification to generate a catalyst for room temperature aromatic C–O bond formation. J Am Chem Soc 122:10718–10719CrossRefGoogle Scholar
  30. 30.
    Strotman NA, Chobanian HR, He J, Guo Y, Dormer PG, Jones CM, Steves JE (2010) Catalyst-controlled regioselective Suzuki couplings at both positions of dihaloimidazoles, dihalooxazoles, and dihalothiazoles. J Org Chem 75:1733–1739CrossRefGoogle Scholar
  31. 31.
    Tamao K, Sumitani K, Kumada M (1972) Selective carbon–carbon bond formation by cross-coupling of Grignard reagents with organic halides. Catalysis by nickel–phosphine complexes. J Am Chem Soc 94:4374–4376CrossRefGoogle Scholar
  32. 32.
    Corriu RJP, Masse JP (1972) Activation of Grignard reagents by transition-metal complexes. A new and simple synthesis of trans-stilbenes and polyphenyls. J Chem Soc Chem Commun 144aGoogle Scholar
  33. 33.
    Ishikawa S, Manabe K (2007) Ortho-selective cross coupling of dibromophenols and dibromoanilines with Grignard reagents in the presence of palladium catalysts bearing hydroxylated oligoarene-type phosphine. Chem Lett 36:1304–1305CrossRefGoogle Scholar
  34. 34.
    Ishikawa S, Manabe K (2007) Oligoarene strategy for catalyst development hydroxylated oligoarene-type phosphines for palladium-catalyzed cross coupling. Chem Lett 36:1302–1303CrossRefGoogle Scholar
  35. 35.
    Ishikawa S, Manabe K (2010) Synthesis of hydroxylated oligoarene-type phosphines by a repetitive two-step method. Tetrahedron 66:297–303CrossRefGoogle Scholar
  36. 36.
    Ishikawa S, Manabe K (2010) DHTP ligands for the highly ortho-selective, palladium-catalyzed cross-coupling of dihaloarenes with Grignard reagents: a conformational approach for catalyst improvement. Angew Chem Int Ed 49:772–775CrossRefGoogle Scholar
  37. 37.
    Ishikawa S, Manabe K (2011) Hydroxylated terphenylphosphine ligands for palladium-catalyzed ortho-selective cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents. Tetrahedron 67:10156–10163Google Scholar
  38. 38.
    Boymond L, Rottländer M, Cahiez G, Knochel P (1998) Preparation of highly functionalized Grignard reagents by an iodine–magnesium exchange reaction and its application in solid-phase synthesis. Angew Chem Int Ed 37:1701–1703CrossRefGoogle Scholar
  39. 39.
    Heravi MM, Sadjadi S (2009) Recent advances in the application of the Sonogashira method in the synthesis of heterocyclic compounds. Tetrahedron 65:7761–7775CrossRefGoogle Scholar
  40. 40.
    Najera C, Chinchilla R (2007) The Sonogashira reaction: a booming methodology in synthetic organic chemistry. Chem Rev 107:874–922CrossRefGoogle Scholar
  41. 41.
    Wang JR, Manabe K (2010) Hydroxyterphenylphosphine–palladium catalyst for benzo[b]furan synthesis from 2-chlorophenols bifunctional ligand strategy for cross-coupling of chloroarenes. J Org Chem 75:5340–5342CrossRefGoogle Scholar
  42. 42.
    Yamaguchi M, Katsumata H, Manabe K (2013) One-pot synthesis of substituted benzo[b]furans from mono- and dichlorophenols using palladium catalysts bearing dihydroxyterphenylphosphine. J Org Chem 78:9270–9281CrossRefGoogle Scholar
  43. 43.
    Yamaguchi M, Manabe K (2014) One-pot synthesis of 2,4-disubstituted indoles from N-tosyl-2,3-dichloroaniline using palladium–dihydroxyterphenylphosphine catalyst. Org Lett 16:2386–2389CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesUniversity of ShizuokaSuruga-kuJapan

Personalised recommendations