• Jiao Jiao
  • Yasushi NishiharaEmail author
Part of the Lecture Notes in Chemistry book series (LNC, volume 80)


This chapter describes the design and development of biologically active compounds using cross-coupling reactions as key steps. These biologically active compounds are of both academic and industrial importance. Drug candidates can be prepared from easily available substrates in a few steps through cross-coupling—underscoring the versatility, effectiveness, functional group tolerance, and mild reaction conditions of the cross-coupling methods. Due to these advantages, palladium-catalyzed cross-coupling reactions are being utilized in the industrial production of pharmaceuticals.


Pharmaceutical Large-scale synthesis Functional group tolerance 


  1. 1.
    Li JJ, Gribble GW (2000) Palladium in heterocyclic chemistry. A Guide for the Synthetic Chemist. Pergamon Amsterdam, The NetherlandsGoogle Scholar
  2. 2.
    Miyaura N (2001) Organoboron compounds. Top Curr Chem 219:11–59CrossRefGoogle Scholar
  3. 3.
    Hassan J, Sévignon M, Gozzi C, Schulz E, Lemaire M (2002) Aryl—aryl bond formation one century after the discovery of the Ullmann reaction. Chem Rev 102:1359–1470CrossRefGoogle Scholar
  4. 4.
    Littke A, Fu GC (2002) Palladium-catalyzed coupling reactions of aryl chlorides. Angew Chem Int Ed 41:4176–4211CrossRefGoogle Scholar
  5. 5.
    King AO, Yasuda N (2004) Palladium-catalyzed cross-coupling reactions in the synthesis of pharmaceuticals. Topics Organomet Chem 6:205–245Google Scholar
  6. 6.
    Nicolaou KC, Bulger PG, Sarlah D (2005) Palladium-catalyzed cross-coupling reactions in total synthesis. Angew Chem Int Ed 44:4442–4489CrossRefGoogle Scholar
  7. 7.
    Marion N, Nolan SP (2008) Well-defined N-heterocyclic carbenes—palladium (II) precatalysts for cross-coupling reactions. Acc Chem Res 41:1440–1449CrossRefGoogle Scholar
  8. 8.
    Fu GC (2008) The development of versatile methods for palladium-catalyzed coupling reactions of aryl electrophiles through the use of P(t-Bu)3 and PCy3 as ligands. Acc Chem Res 41:1555–1564CrossRefGoogle Scholar
  9. 9.
    Cahiez G, Moyeux A (2010) Cobalt-catalyzed cross-coupling reactions. Chem Rev 110:1435–1462CrossRefGoogle Scholar
  10. 10.
    Vo TC, Mitchell TA, Bode JW (2011) Expanded substrate scope and improved reactivity of ether-forming cross-coupling reactions of organotrifluoroborates and acetals. J Am Chem Soc 133:14082–14089CrossRefGoogle Scholar
  11. 11.
    Bai Y, Zeng J, Cai S, Liu X (2011) Palladium-catalyzed direct cross-coupling reaction of glycals with activated alkenes. Org Lett 13:4394–4397CrossRefGoogle Scholar
  12. 12.
    Naso F, Babudr F, Farinola GM (1999) Organometallic chemistry directed towards the synthesis of electroactive materials: stereoselective routes to extended polyconjugated systems. Pure Appl Chem 71:1485–1492CrossRefGoogle Scholar
  13. 13.
    Schlummer B, Scholz U (2004) Palladium-catalyzed C = N and C = O coupling—a practical guide from an industrial vantage point. Adv Synth Catal 346:1599–1626CrossRefGoogle Scholar
  14. 14.
    Blaser HU, Indolese A, Naud F, Nettekoven U, Schnyder A (2004) Industrial R&D on catalytic C = C and C = N coupling reactions: a personal account on goals, approaches and results. Adv Synth Catal 346:1583–1598CrossRefGoogle Scholar
  15. 15.
    Buchwald SL, Mauger C, Mignani G, Scholz U (2006) Industrial-scale palladium-catalyzed coupling of aryl halides and amines—a personal account. Adv Synth Catal 348:23–39CrossRefGoogle Scholar
  16. 16.
    Torborg C, Beller M (2009) Recent applications of palladium-catalyzed coupling reactions in the pharmaceutical, agrochemical, and fine chemical industries. Adv Synth Catal 351:3027–3043CrossRefGoogle Scholar
  17. 17.
    Ennis DS, McManus J, Wood-Kaczmar W, Richardson J, Smith GE, Carstairs A (1999) Multikilogram-scale synthesis of a biphenyl carboxylic acid derivative using a Pd/C-mediated Suzuki coupling approach. Org Process Res Dev 3:248–252CrossRefGoogle Scholar
  18. 18.
    Cameron M, Foster BS, Lynch JE, Shi Y, Dolling UH (2006) The expedient synthesis of 4,2′-difluoro-5′-(7-trifluoromethyl-imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile, a GABA α2/3 agonist. Org Process Res Dev 10:398–402CrossRefGoogle Scholar
  19. 19.
    Snieckus V (1990) Directed ortho metalation. Tertiary amide and o-carbamate directors in synthetic strategies for polysubstituted aromatics. Chem Rev 90:879–933CrossRefGoogle Scholar
  20. 20.
    Kalinin AV, Bower JF, Riebel P, Snieckus V (1999) The directed ortho metalation—Ullmann connection. A new Cu(I)-catalyzed variant for the synthesis of substituted diaryl ethers. J Org Chem 64:2986–2987CrossRefGoogle Scholar
  21. 21.
    Caron S, Massett SS, Bogle DE, Castaldi MJ, Braish TF (2001) An efficient and cost-effective synthesis of 2-phenyl-3-aminopyridine. Org Process Res Dev 5:254–256CrossRefGoogle Scholar
  22. 22.
    Jensen MS, Hoerrner RS, Li W, Nelson DP, Javadi GJ, Dormer PG, Cai D, Larsen RD (2005) Efficient synthesis of a GABAA α2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling approach. J Org Chem 70:6034–6039CrossRefGoogle Scholar
  23. 23.
    Tonogaki K, Soga K, Itami K, Yoshida J (2005) Versatile synthesis of 1,1- diaryl-1-alkenes using vinylboronate ester as a platform. Synlett, 1802–1804Google Scholar
  24. 24.
    Paunescu E, Matuszak N, Melnyk P (2007) Suzuki-Miyaura cross-coupling reaction as the key step for the synthesis of some new 4-aryl and alkyl substituted analogues of amodiaquine and amopyroquine. Tetrahedron 63:12791–12810CrossRefGoogle Scholar
  25. 25.
    Nishihara Y, Miyasaka M, Okamoto M, Takahashi H, Inoue E, Tanemura K, Takagi K (2007) Zirconocene-mediated highly regio- and stereoselective synthesis of multisubstituted olefins starting from 1-alkynylboronates. J Am Chem Soc 129:12634–12635CrossRefGoogle Scholar
  26. 26.
    Wehn PM, Harrington PE, Eksterowicz JE (2009) Facile synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles from a common precursor. Org Lett 11:5666–5669CrossRefGoogle Scholar
  27. 27.
    Saadeh HA, Mosleh IM, El-Abadelah MM (2009) New synthesis and antiparasitic activity of model 5-aryl-1-methyl-4-nitroimidazoles. Molecules 14:2758–2767Google Scholar
  28. 28.
    Jiang X, Lee G, Villhauer EB, Prasad K, Prashad M (2010) A scalable synthesis of a 1,7-naphthyridine derivative, a PDE-4 inhibitor. Org Process Res Dev 14:883–889CrossRefGoogle Scholar
  29. 29.
    Kabri Y, Verhaeghe P, Gellis A, Vanelle P (2010) Regioselective Suzuki-Miyaura reaction: application to the microwave-promoted synthesis of 4,7-diarylquinazolines. Molecules 15:2949–2961CrossRefGoogle Scholar
  30. 30.
    Kumar MR, Park K, Lee S (2010) Synthesis of amido-N-imidazolium salts and their applications as ligands in Suzuki-Miyaura reactions: coupling of hetero-aromatic halides and the synthesis of milrinone and irbesartan. Adv Synth Catal 352:3255–3266CrossRefGoogle Scholar
  31. 31.
    Xie L, Cui J, Qian X, Xu Y, Liu J, Xu R (2011) 5-Non-amino aromatic substituted naphthalimides as potential antitumor agents: synthesis via Suzuki reaction, antiproliferative activity, and DNA-binding behavior. Bioorg Med Chem 19:961–967CrossRefGoogle Scholar
  32. 32.
    Schumacher RF, Rosário AR, Souza Ana.CG, Acker CI, Nogueira CW, Zeni G (2011) The potential antioxidant activity of 2,3-dihydroselenophene, a prototype drug of 4-aryl-2,3-dihydroselenophenes. Bioorg Med Chem 19:1418–1425Google Scholar
  33. 33.
    Urawa Y, Miyazawa M, Ozeki N, Ogura K (2003) A novel methodology for efficient removal of residual palladium from a product of the Suzuki—Miyaura coupling with polymer-supported ethylenediamine derivatives. Org Process Res Dev 7:191–195CrossRefGoogle Scholar
  34. 34.
    Keen SP, Cowden CJ, Bishop BC, Brands KMJ, Davies AJ, Dolling UH, Lieberman DR, Stewart GW (2005) Practical asymmetric synthesis of a non-peptidic αvβ3 antagonist. J Org Chem 70:1771–1779CrossRefGoogle Scholar
  35. 35.
    Allwein SP, McWilliams JC, Secord EA, Mowrey DR, Nelson TD, Kress MH (2006) Efficient synthesis of chiral phenethylamines: preparation, asymmetric hydrogenation, and mild deprotection of ene-trifluoroacetamides. Tetrahedron Lett 47:6409–6412CrossRefGoogle Scholar
  36. 36.
    Ager DJ, Anderson K, Oblinger E, Shi Y, VanderRoest J, (2007) An epoxidation approach to a chiral lactone: application of the Shi epoxidation. J Org Process Res Dev 11:44–51Google Scholar
  37. 37.
    Menzel K, Machrouhi F, Bodenstein M, Alorati A, Cowden C, Gibson AW, Bishop B, Ikemoto N, Nelson TD, Kress MH, Frantz DE (2009) Process development of a potent bradykinin 1 antagonist. Org Process Res Dev 13:519–524CrossRefGoogle Scholar
  38. 38.
    Whiting M, Harwood K, Hossner F, Turner PG, Wilkinson MC (2010) Selection and development of the manufacturing route for EP1 antagonist GSK269984B. Org Process Res Dev 14:820–831CrossRefGoogle Scholar
  39. 39.
    Lipton MF, Mauragis MA, Maloney MT, Veley MF, VanderBor DW, Newby JJ, Appell RB, Daugs ED (2003) The synthesis of OSU 6162: efficient, large-scale implementation of a Suzuki coupling. Org Process Res Dev 7:385–392CrossRefGoogle Scholar
  40. 40.
    Negishi E, King AO, Okukado N (1977) Selective carbon–carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides. J Org Chem 42:1821–1823CrossRefGoogle Scholar
  41. 41.
    King AO, Okukado N, Negishi E (1977) Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides. J Chem Soc Chem Commun, 683–684Google Scholar
  42. 42.
    Phapale VB, Cardenas DJ (2009) Nickel-catalysed Negishi cross-coupling reactions: scope and mechanisms. Chem Soc Rev 38:1598–1607CrossRefGoogle Scholar
  43. 43.
    Krasovskiy A, Malakhov V, Gavryushin A, Knochel P (2006) Efficient synthesis of functionalized organozinc compounds by the direct insertion of zinc into organic iodides and bromides. Angew Chem Int Ed 45:6040–6044CrossRefGoogle Scholar
  44. 44.
    Uchiyama M, Furuyama T, Kobayashi M, Matsumoto Y, Tanaka K (2006) Toward a protecting-group-free halogen metal exchange reaction: practical, chemoselective metalation of functionalized aromatic halides using dianion- type zincate, tBu4ZnLi2. J Am Chem Soc 128:8404–8405CrossRefGoogle Scholar
  45. 45.
    Furuyama T, Yonehara M, Arimoto S, Kobayashi M, Matsumoto Y, Uchiyama M (2008) Development of highly chemoselective bulky zincate complex, tBu4ZnLi2: design, structure, and practical applications in small-/macromolecular synthesis. Chem Eur J 14:10348–14356CrossRefGoogle Scholar
  46. 46.
    Ku Y, Grieme T, Raje P, Sharma P, Morton HE, Rozema M, King SA (2003) A practical and scaleable synthesis of A-224817.0, a novel nonsteroidal ligand for the glucocorticoid receptor. J Org Chem 68:3238–3240CrossRefGoogle Scholar
  47. 47.
    Scott RW, Neville SN, Urbina A, Camp D, Stankovic N (2006) Development of a scalable synthesis to VEGFR inhibitor AG-28262. Org Process Res Dev 10:296–303CrossRefGoogle Scholar
  48. 48.
    Dutheuil G, Paturel C, Lei X, Couve-Bonnaire S, Pannecoucke X (2006) First stereospecific synthesis of (E)- or (Z)-α-fluoroenones via a kinetically controlled Negishi coupling reaction. J Org Chem 71:4316–4319CrossRefGoogle Scholar
  49. 49.
    Liu Z, Xiang J (2006) A High yield and pilot-scale process for the preparation of adapalene. Org Process Res Dev 10:285–288CrossRefGoogle Scholar
  50. 50.
    Denni-Dischert D, Marterer W, Bänziger M, Yusuff N, Batt D, Ramsey T, Geng P, Michael W, Wang R, Taplin F Jr, Versace R, Cesarz D, Perez LB (2006) The Synthesis of a novel inhibitor of B-Raf kinase. Org Process Res Dev 10:70–77CrossRefGoogle Scholar
  51. 51.
    Pérez-Balado C, Willemsens A, Ormerod D, Aelterman W, Mertens N (2007) Development of a concise scaleable synthesis of 2-chloro-5-(pyridin-2-yl) pyrimidine via a Negishi cross-coupling. Org Process Res Dev 11:237–240CrossRefGoogle Scholar
  52. 52.
    Manolikakes G, Dong MZ, Mayr H, Li J, Knochel P (2009) Negishi cross-couplings compatible with unprotected amide functions. Chem Eur J 15:1324–1328CrossRefGoogle Scholar
  53. 53.
    Kwak Y, Kanter AD, Wang B, Liu Y (2009) Efficient and convenient preparation of 3-aryl-2,2-dimethylpropanoates via Negishi coupling. Chem Commun, 2145–2147Google Scholar
  54. 54.
    Kennedy-Smith JJ, Arora N, Billedeau JR, Fretland J, Hang J, Heilek GM, Harris SF, Hirschfeld D, Javanbakht H, Li Y, Liang W, Roetz R, Smith M, Su GP, Suh JM, Villaseňor AG, Wu J, Yasuda D, Klumpp K, Sweeney ZK (2010) Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase. Med Chem Commun 1:79–83CrossRefGoogle Scholar
  55. 55.
    Ragan JA, Raggon JW, Hill PD, Jones BP, McDermott RE, Munchhof MJ, Marx MA, Casavant JM, Cooper BA, Doty JL, Lu Y (2003) Cross-coupling methods for the large-scale preparation of an imidazole-thienopyridine: synthesis of [2-(3-methyl-3H-imidazol-4-yl)-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. Org Process Res Dev 7:676–683CrossRefGoogle Scholar
  56. 56.
    Brændvang M, Bakken V, Gundersen L (2009) Synthesis, structure, and antimycobacterial activity of 6-[1(3H)-isobenzofuranylidenemethyl]purines and analogs. Bioorg Med Chem 17:6512–6516CrossRefGoogle Scholar
  57. 57.
    Okitsu T, Nakazawa D, Nakagawa K, Okano T, Wada A (2010) Synthesis and biological evaluation of 9Z-retinoic acid analogs having 2-substituted benzo[b]furan. Chem Pharm Bull 58:418–422CrossRefGoogle Scholar
  58. 58.
    Gao Y, Wang H, Mease RC, Pomper MG, Horti AG (2010) Improved syntheses of precursors for PET radioligands [18F]XTRA and [18F]AZAN. Tetrahedron Lett 51:5333–5335CrossRefGoogle Scholar
  59. 59.
    Fan X, Song Y, Long Y (2008) An efficient and practical synthesis of the HIV protease inhibitor atazanavir via a highly diastereoselective reduction approach. Org Process Res Dev 12:69–75CrossRefGoogle Scholar
  60. 60.
    Manley PW, Acemoglu M, Marterer W, Pachinger W (2003) Large-scale Negishi coupling as applied to the synthesis of PDE472, an inhibitor of phosphodiesterase type 4D. Org Process Res Dev 7:436–445CrossRefGoogle Scholar
  61. 61.
    Marzoni G, Varney MD (1997) An improved large-scale synthesis of benz[cd]indol-2(1H)-one and 5-methylbenz[cd]indol-2(1H)-one. Org Process Res Dev 1:81–84CrossRefGoogle Scholar
  62. 62.
    Königsberger K, Chen G, Wu R, Girgis MJ, Prasad K, Repic O, Blacklock TJ (2003) A practical synthesis of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-ethylquinazoline and the art of removing palladium from the products of Pd-catalyzed reactions. Org Process Res Dev 7:733–742CrossRefGoogle Scholar
  63. 63.
    Hartner FW, Hsiao Y, Eng KK, Rivera NR, Palucki M, Tan L, Yasuda N, Hughes DL, Weissman S, Zewge D, King T, Tschaen D, Volante RP (2004) Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for αvβ 3 integrin antagonists. J Org Chem 69:8723–8730CrossRefGoogle Scholar
  64. 64.
    Ripin DHB, Bourassa DE, Brandt T, Castaldi MJ, Frost HN, Hawkins J, Johnson PJ, Massett SS, Neumann K, Phillips J, Raggon JW, Rose PR, Rutherford JL, Sitter B, Stewart AM III, Vetelino MG, Wei L (2005) Evaluation of kilogram-scale Sonogashira, Suzuki, and Heck coupling routes to oncology candidate CP-724,714. Org Process Res Dev 9:440–450CrossRefGoogle Scholar
  65. 65.
    Xia Y, Liu Y, Wan J, Wang M, Rocchi P, Qu F, Iovanna JL, Peng L (2009) Novel triazole ribonucleoside down-regulates heat shock protein 27 and induces potent anticancer activity on drug-resistant pancreatic cancer. J Med Chem 52:6083–6096CrossRefGoogle Scholar
  66. 66.
    Yu S, Haight A, Kotecki B, Wang L, Lukin K, Hill DR (2009) Synthesis of a TRPV1 receptor antagonist. J Org Chem 74:9539–9542CrossRefGoogle Scholar
  67. 67.
    Old DW, Wolfe JP, Buchwald SL (1998) A highly active catalyst for palladium-catalyzed cross-coupling reactions: Room-temperature Suzuki couplings and amination of unactivated aryl chlorides. J Am Chem Soc 120:9722–9723CrossRefGoogle Scholar
  68. 68.
    Berliner MA, Cordi EM, Dunetz JR, Price KE (2010) Sonogashira reactions with propyne: Facile synthesis of 4-hydroxy-2-methylbenzofurans from iodoresorcinols. Org Process Res Dev 14:180–187CrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Division of Earth, Life, and Molecular SciencesGraduate School of Natural Science and Technology Okayama UniversityOkayamaJapan

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