Synthesis and Functionalization of S-heterocycles via CDC Reactions



Cross-dehydrogenative coupling has become a powerful tool in organic synthesis. The current developments in the assembly and functionalization of S-heterocycles using this strategy are highlighted in this chapter. The preparation of benzothiophenes, benzothiazoles and cyclic sultams and sulfoxides by intramolecular C(sp2)–H/S–H and C(sp2)–H/C(sp2)–H coupling is discussed. In addition, the coupling of S-heterocycles to arenes and aliphatic compounds is also presented.


Benzothiazole Benzothiophene Cross-dehydrogenative coupling Cyclic sulfoxide Cyclic sultam 


  1. 1.
    Barrett OV, Downer-Riley NK, Jackson YA (2012) thermally induced cyclization of electron-rich N-Arylthiobenzamides to benzothiazoles. Synthesis 44(16):2579–2586CrossRefGoogle Scholar
  2. 2.
    Bose DS, Idrees M (2006) Hypervalent iodine mediated intramolecular cyclization of thioformanilides: expeditious approach to 2-substituted benzothiazoles. J Org Chem 71(21):8261–8263PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Bose DS, Idrees M (2010) Dess-Martin periodinane mediated intramolecular cyclization of phenolic azomethines: a solution-phase strategy toward benzoxazoles and benzothiazoles. Synthesis 2010(03):398–402CrossRefGoogle Scholar
  4. 4.
    Bose DS, Idrees M, Srikanth B (2007) Synthesis of 2-arylbenzothiazoles by DDQ-promoted cyclization of thioformanilides; a solution-phase strategy for library synthesis. Synthesis 2007(06):819–823CrossRefGoogle Scholar
  5. 5.
    Cano-Yelo H, Deronzier A (1984) Photocatalysis of the Pschorr reaction by tris-(2,2′-bipyridyl) ruthenium (II) in the phenanthrene series. J Chem Soc Perkin Trans 2(6):1093–1098CrossRefGoogle Scholar
  6. 6.
    Cano-Yelo H, Deronzier A (1984) Photo-oxidation of some carbinols by the Ru (II) polypyridyl complex-aryl diazonium salt system. Tetrahedron Lett 25(48):5517–5520CrossRefGoogle Scholar
  7. 7.
    Cano-Yelo H, Deronzier A (1984) Photo-oxidation of tris (2,2′-bipyridine) ruthenium (II) by para-substituted benzene diazonium salts in acetonitrile. Two-compartment photoelectrochemical cell applications. J Chem Soc Faraday Trans 1: Phys Chem Condens Phases 80(11):3011–3019CrossRefGoogle Scholar
  8. 8.
    Che R, Wu Z, Li Z, Xiang H, Zhou X (2014) Synthesis of dibenzothiophenes by Pd‐catalyzed dual C–H activation from Diaryl sulfides. Chem A Eur J 20(24):7258–7261CrossRefGoogle Scholar
  9. 9.
    Chen S, Wang M, Jiang X (2018) Pd-catalyzed C–S cyclization via C–H functionalization strategy: access to sulfur-containing Benzoheterocyclics. Chin J Chem 36(10):921–924CrossRefGoogle Scholar
  10. 10.
    Chen X, Cui X, Yang F, Wu Y (2015) Base-promoted cross-dehydrogenative coupling of Quinoline N-Oxides with 1,3-azoles. Org Lett 17(6):1445–1448PubMedCrossRefGoogle Scholar
  11. 11.
    Cheng Y, Yang J, Qu Y, Li P (2012) Aerobic visible-light photoredox radical C–H functionalization: catalytic synthesis of 2-substituted benzothiazoles. Org Lett 14(1):98–101PubMedCrossRefGoogle Scholar
  12. 12.
    Dong J, Huang Y, Qin X, Cheng Y, Hao J, Wan D, Li W, Liu X, You J (2012) Palladium (II)‐catalyzed oxidative C–H/C–H cross‐coupling between two structurally similar azoles. Chem A Eur J 18(20):6158–6162CrossRefGoogle Scholar
  13. 13.
    Downer-Riley NK, Jackson YA (2007) Iodine-mediated cyclisation of thiobenzamides to produce benzothiazoles and benzoxazoles. Tetrahedron 63(41):10276–10281CrossRefGoogle Scholar
  14. 14.
    Downer-Riley NK, Jackson YA (2008) Conversion of thiobenzamides to benzothiazoles via intramolecular cyclization of the aryl radical cation. Tetrahedron 64(33):7741–7744CrossRefGoogle Scholar
  15. 15.
    Fan S, Chen Z, Zhang X (2012) Copper-catalyzed dehydrogenative cross-coupling of benzothiazoles with thiazoles and polyfluoroarene. Org Lett 14(18):4950–4953PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Folgueiras-Amador AA, Qian XY, Xu HC, Wirth T (2018) Catalyst‐and supporting‐electrolyte‐free electrosynthesis of benzothiazoles and thiazolopyridines in continuous flow. Chem A Eur J 24(2):487–491CrossRefGoogle Scholar
  17. 17.
    Fruit C, Müller P (2004) Intramolecular asymmetric amidations of sulfonamides and sulfamates catalyzed by chiral dirhodium (II) complexes. Helv Chim Acta 87(7):1607–1615CrossRefGoogle Scholar
  18. 18.
    Fu XP, Xuan QQ, Liu L, Wang D, Chen YJ, Li CJ (2013) Dual C-H activations of electron-deficient heteroarenes: palladium-catalyzed oxidative cross coupling of thiazoles with azine N-oxides. Tetrahedron 69(22):4436–4444CrossRefGoogle Scholar
  19. 19.
    Ganín J, Melendez E, Merchan FL, Merino P, Orduna J, Tejero T (1990) Chemoselectivity in the oxidation of unsymmetrical Thioureas with NBS/sulfuric acid: Benzothiazoles vs. 1,2,4-Thiadiazoles. Synth Commun 20(15):2327–2334CrossRefGoogle Scholar
  20. 20.
    Han W, Mayer P, Ofial AR (2011) Palladium-catalyzed Dehydrogenative cross-couplings of benzazoles with azoles. Angew Chem Int Ed 50(9):2178–2182CrossRefGoogle Scholar
  21. 21.
    He CY, Fan S, Zhang X (2010) Pd-catalyzed oxidative cross-coupling of perfluoroarenes with aromatic heterocycles. J Am Chem Soc 132(37):12850–12852PubMedCrossRefGoogle Scholar
  22. 22.
    Huang Q, Fu S, Ke S, Xiao H, Zhang X, Lin S (2015) Rhodium-catalyzed sequential dehydrogenation/deoxygenation in one-pot: efficient synthesis of dibenzothiophene derivatives from diaryl sulfoxides. Eur J Org Chem 2015(30):6602–6605CrossRefGoogle Scholar
  23. 23.
    Inamoto K, Arai Y, Hiroya K, Doi T (2008) Palladium-catalysed direct synthesis of benzo [b] thiophenes from thioenols. Chem Commun 43:5529–5531CrossRefGoogle Scholar
  24. 24.
    Inamoto K, Hasegawa C, Hiroya K, Doi T (2008) Palladium-catalyzed synthesis of 2-substituted benzothiazoles via a C–H functionalization/intramolecular C–S bond formation process. Org Lett 10(22):5147–5150PubMedCrossRefGoogle Scholar
  25. 25.
    Inamoto K, Nozawa K, Kondo Y (2012) Palladium-catalyzed C–H cyclization in water: a milder route to 2-arylbenzothiazoles. Synlett 23(11):1678–1682CrossRefGoogle Scholar
  26. 26.
    Jordan AD, Luo C, Reitz AB (2003) Efficient conversion of substituted aryl thioureas to 2-aminobenzothiazoles using benzyltrimethylammonium tribromide. J Org Chem 68(22):8693–8696PubMedCrossRefGoogle Scholar
  27. 27.
    Joyce LL, Batey RA (2009) Heterocycle formation via palladium-catalyzed intramolecular oxidative C–H bond functionalization: an efficient strategy for the synthesis of 2-aminobenzothiazoles. Org Lett 11(13):2792–2795PubMedCrossRefGoogle Scholar
  28. 28.
    Kalkhambkar RG, Laali KK (2012) Pd (OAc) 2 catalyzed synthesis of 2-aryl-and 2-heteroaryl-benzoxazoles and benzothiazoles in imidazolium ionic liquids (ILs) without additives and with recycling/reuse of the IL. Tetrahedron Lett 53(32):4212–4215CrossRefGoogle Scholar
  29. 29.
    Kaur N, Jangid NK, Sharma V (2018) Metal-and nonmetal-catalyzed synthesis of five-membered S. N-heterocycles. J Sulfur Chem 39(2):193–236CrossRefGoogle Scholar
  30. 30.
    Kortan AM, Cannizzaro RJ, Robb MJ, Knauss DM (2016) Poly (ether sulfone) s using a rigid dibenzothiophene dioxide heterocycle. J Polym Sci, Part A: Polym Chem 54(19):3127–3131CrossRefGoogle Scholar
  31. 31.
    Kuhl N, Hopkinson MN, Glorius F (2012) Selective rhodium (III)-catalyzed cross-dehydrogenative coupling of furan and thiophene derivatives. Angew Chem Int Ed 51(33):8230–8234CrossRefGoogle Scholar
  32. 32.
    Laha JK, Jethava KP, Dayal N (2014) Palladium-catalyzed intramolecular oxidative coupling involving double C (sp2)–H bonds for the synthesis of annulated Biaryl Sultams. J Org Chem 79(17):8010–8019PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Li NN, Zhang YL, Mao S, Gao YR, Guo DD, Wang YQ (2014) Palladium-catalyzed C–H homocoupling of furans and thiophenes using oxygen as the oxidant. Org Lett 16(10):2732–2735PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Liu ZQ, Li Z (2016) Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles. Chem Commun 52(99):14278–14281CrossRefGoogle Scholar
  35. 35.
    Mao Z, Wang Z, Xu Z, Huang F, Yu Z, Wang R (2012) Copper (II)-mediated dehydrogenative cross-coupling of heteroarenes. Org Lett 14(15):3854–3857PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Mariappan A, Rajaguru K, Merukan Chola N, Muthusubramanian S, Bhuvanesh N (2016) Hypervalent Iodine (III) mediated synthesis of 3-substituted 5-amino-1, 2, 4-thiadiazoles through intramolecular oxidative S-N bond formation. J Org Chem 81(15):6573–6579PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Metzger J, Planck H (1956) Methods of synthesis of benzothiazoles. Chim Ind 75:929–939Google Scholar
  38. 38.
    Mitsuda S, Fujiwara T, Kimigafukuro K, Monguchi D, Mori A (2012) Copper-catalyzed oxidative C–H, N–H coupling of azoles and thiophenes. Tetrahedron 68(18):3585–3590CrossRefGoogle Scholar
  39. 39.
    Miyasaka M, Hirano K, Satoh T, Miura M (2010) Palladium-catalyzed direct oxidative alkenylation of azoles. J Org Chem 75(15):5421–5424PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Moghaddam FM, Boeini HZ (2005) Oxidative cyclization of thiobenzanilides to benzothiazoles using N-benzyl-DABCO tribromide under mild conditions. Synlett 2005(10):1612–1614CrossRefGoogle Scholar
  41. 41.
    Monguchi D, Yamamura A, Fujiwara T, Somete T, Mori A (2010) Oxidative dimerization of azoles via copper (II)/silver (I)-catalyzed CH homocoupling. Tetrahedron Lett 51(5):850–852CrossRefGoogle Scholar
  42. 42.
    Mu XJ, Zou JP, Zeng RS, Wu JC (2005) Mn (III)-Promoted cyclization of substituted thioformanilides under microwave irradiation: a new reagent for 2-substituted benzothiazoles. Tetrahedron Lett 46(25):4345–4347CrossRefGoogle Scholar
  43. 43.
    Nishino K, Ogiwara Y, Sakai N (2017) Green preparation of dibenzothiophene derivatives using 2-Biphenylyl disulfides in the presence of molecular iodine and its application to Dibenzoselenophene synthesis. Eur J Org Chem 2017(39):5892–5895CrossRefGoogle Scholar
  44. 44.
    Nishino K, Ogiwara Y, Sakai N (2018) Palladium (II)-catalyzed synthesis of dibenzothiophenes from 2-Biphenylyl Disulfides by C-H functionalization. Chem Eur J 4(43):10971–10974CrossRefGoogle Scholar
  45. 45.
    Ohgaki H, Mitsuhashi H, Suzuki H (2003) Tert-BuOK/BuLi-Induced facile cyclodehydrogenation of diphenyl sulfide to dibenzothiophene. J Chem Res 2003(5):264–265CrossRefGoogle Scholar
  46. 46.
    Pan X, Hu Q, Chen W, Liu X, Sun B, Huang Z, Zeng Z, Wang L, Zhao D, Ji M, Liu L (2014) Copper (II) catalyzed cross-dehydrogenative coupling of cyclic benzylic ethers with simple carbonyl compounds by Na2S2O8. Tetrahedron 70(21):3447–3451CrossRefGoogle Scholar
  47. 47.
    Prajapati NP, Vekariya RH, Borad MA, Patel HD (2014) Recent advances in the synthesis of 2-substituted benzothiazoles: a review. Rsc Adv 4(104):60176–60208CrossRefGoogle Scholar
  48. 48.
    Qian XY, Li SQ, Song J, Xu HC (2017) TEMPO-catalyzed electrochemical C–H thiolation: synthesis of benzothiazoles and thiazolopyridines from thioamides. ACS Catal 7(4):2730–2734CrossRefGoogle Scholar
  49. 49.
    Qin X, Feng B, Dong J, Li X, Xue Y, Lan J, You J (2012) Copper (II)-catalyzed dehydrogenative cross-coupling between two azoles. J Org Chem 77(17):7677–7683PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Qin X, Liu H, Qin D, Wu Q, You J, Zhao D, Qiang G, Huang X, Lan J (2013) Chelation-assisted Rh (III)-catalyzed C2-selective oxidative C–H/C–H cross-coupling of indoles/pyrroles with heteroarenes. Chem Sci 4(5):1964–1969CrossRefGoogle Scholar
  51. 51.
    Ra CS, Jung BY, Park G (2004) The fungicidal benzothiazole methoxyacrylates: Synthesis, conformational analysis and fungicidal activity. Heterocycles 62:793–802CrossRefGoogle Scholar
  52. 52.
    Ranjit S, Lee R, Heryadi D, Shen C, Wu JE, Zhang P, Huang KW, Liu X (2011) Copper-mediated C–H activation/C–S cross-coupling of heterocycles with thiols. J Org Chem 76(21):8999–9007PubMedCrossRefGoogle Scholar
  53. 53.
    Rey V, Soria-Castro SM, Argüello JE, Peñéñory AB (2009) Photochemical cyclization of thioformanilides by chloranil: an approach to 2-substituted benzothiazoles. Tetrahedron Lett 50(33):4720–4723CrossRefGoogle Scholar
  54. 54.
    Sahoo SK, Jena HS, Majji G, Patel BK (2014) Formation of Imidazolidine-benzothiazole–Copper (II) complexes via a copper-mediated room-temperature C–H activation of imidazolidinecarbothioamides. Synthesis 46(14):1886–1900CrossRefGoogle Scholar
  55. 55.
    Samanta R, Antonchick AP (2011) Palladium-catalyzed double C–H activation directed by sulfoxides in the synthesis of dibenzothiophenes. Angew Chem Int Ed 50(22):5217–5220CrossRefGoogle Scholar
  56. 56.
    Shaikh MM, Patel AP, Chikhalia KH (2019) Copper catalysed cross-dehydrogenative coupling (CDC) reaction of 4-thiazolidinone with terminal alkyne. Tetrahedron 75(4):475–485CrossRefGoogle Scholar
  57. 57.
    Shan Y, Lai M, Li R, Wu Z, Zhao M (2017) Synthesis of pyrazine-thiazole biheteroaryl compounds through base-promoted oxidative cross-dehydrogenative Coupling reactions. Asian J Org Chem 6(12):1715–1718CrossRefGoogle Scholar
  58. 58.
    Sharma S, Pathare RS, Maurya AK, Gopal K, Roy TK, Sawant DM, Pardasani RT (2016) Ruthenium catalyzed intramolecular C–S coupling reactions: synthetic scope and mechanistic insight. Org Lett 18(3):356–359PubMedCrossRefGoogle Scholar
  59. 59.
    Stevens MF, McCall CJ, Lelievald P, Alexander P, Richter A, Davies DE (1994) Structural studies on bioactive compound. 23. Synthesis of polyhydroxylated 2-phenylbenzothiazoles and a comparison of their cytotoxicities and pharmacological properties with genistein and quercetin. J Med Chem 37(11):1689–1695PubMedCrossRefGoogle Scholar
  60. 60.
    Sudo Y, Yamaguchi E, Itoh A (2017) Photo-oxidative cross-dehydrogenative coupling-type reaction of thiophenes with α-position of carbonyls using a catalytic amount of molecular iodine. Org Lett 19(7):1610–1613PubMedCrossRefGoogle Scholar
  61. 61.
    Tayade DT, Thombare RD, Waghmare SA (2017) Synthesis of 3-[4-Amino-N-Substituted-o-AnisamidO-5-yl] Amino-5-Substituted-1,2,4-Dithiazole. Indo Am J Pharm Sci 4(10):3890–3894Google Scholar
  62. 62.
    Tobisu M, Masuya Y, Baba K, Chatani N (2016) Palladium (II)-catalyzed synthesis of dibenzothiophene derivatives via the cleavage of carbon–sulfur and carbon–hydrogen bonds. Chem Sci 7(4):2587–2591PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Wang Z, Kuninobu Y, Kanai M (2013) Copper-catalyzed intramolecular N–S bond formation by oxidative dehydrogenative cyclization. J Org Chem 78(14):7337–7342PubMedCrossRefGoogle Scholar
  64. 64.
    Wang R, Liu D, Ren H, Zhang T, Wang X, Li J (2011) Homoleptic tris-cyclometalated iridium complexes with 2-phenylbenzothiazole ligands for highly efficient orange OLEDs. J Mater Chem 21(39):15494–15500CrossRefGoogle Scholar
  65. 65.
    Wang B, Liu Y, Lin C, Xu Y, Liu Z, Zhang Y (2014) Synthesis of sulfur-bridged polycycles via Pd-catalyzed dehydrogenative cyclization. Org Lett 16(17):4574–4577PubMedCrossRefGoogle Scholar
  66. 66.
    Wang J, Zong Y, Zhang X, Gao Y, Li Z, Yue G, Quan Z, Wang X (2014) Synthesis of N-benzothiazol-2-yl-amides by an iron-catalyzed oxidative C (sp2)–H functionalization. Synlett 25(15):2143–2148CrossRefGoogle Scholar
  67. 67.
    Wang B, Meng Y, Zhou Y, Ren L, Wu J, Yu W, Chang J (2017) Synthesis of 5-amino and 3, 5-diamino substituted 1,2,4-thiadiazoles by I2-mediated oxidative N–S bond formation. J Org Chem 82(11):5898–5903PubMedCrossRefGoogle Scholar
  68. 68.
    Wang X, Lei B, Ma L, Zhu L, Zhang X, Zuo H, Zhuang D, Li Z (2017) Cobalt-catalyzed cross-dehydrogenative c (sp2)–C (sp3) coupling of oxazole/thiazole with ether or cycloalkane. Chem Asian J 12(21):2799–2803PubMedCrossRefGoogle Scholar
  69. 69.
    Wen ZK, Song TT, Liu YF, Chao JB (2018) Palladium-catalyzed dehydrogenative coupling of cyclic enones with thiophenes: a rapid access to β-heteroarylated cyclic enones. Chem Commun 54(29):3668–3671CrossRefGoogle Scholar
  70. 70.
    Wigglesworth TJ, Sud D, Norsten TB, Lekhi VS, Branda NR (2005) Chiral discrimination in photochromic helicenes. J Am Chem Soc 127(20):7272–7273PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Willis NJ, Smith JM (2014) An operationally simple, palladium catalysed dehydrogenative cross-coupling reaction of pyridine N-oxides and thiazoles “on water”. RSC Adv 4(22):11059–11063CrossRefGoogle Scholar
  72. 72.
    Wirtanen T, Muuronen M, Hurmalainen J, Tuononen HM, Nieger M, Helaja J (2016) Intermolecular oxidative dehydrogenative 3,3′-coupling of benzo [b] furans and benzo [b] thiophenes promoted by DDQ/H + : total synthesis of shandougenine B. Org Chem Front 3(12):1738–1745CrossRefGoogle Scholar
  73. 73.
    Xi P, Yang F, Qin S, Zhao D, Lan J, Gao G, Hu C, You J (2010) Palladium (II)-catalyzed oxidative C–H/C–H cross-coupling of heteroarenes. J Am Chem Soc 132(6):1822–1824PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Xie Z, Cai Y, Hu H, Lin C, Jiang J, Chen Z, Wang L, Pan Y (2013) Cu-catalyzed cross-dehydrogenative coupling reactions of (benzo) thiazoles with cyclic ethers. Org Lett 15(17):4600–4603PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Yadav PS, Devprakash SG, Senthilkumar GP (2011) Benzothiazole: different methods of synthesis and diverse biological activities. Int J Pharm Sci Drug Res 3(1):01–07Google Scholar
  76. 76.
    Yu X, Huang Z, Liu W, Shi S, Kuang C (2015) Palladium-catalyzed oxidative C–H/C–H cross-coupling of 1-substituted 1,2,3-triazoles with furans and thiophenes. Org Biomol Chem 13(15):4459–4465PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Zeller KP, Petersen H (1975) Photochemische Herstellung von Dibenzofuranen und dibenzothiophenen. Synthesis 1975(08):532–533CrossRefGoogle Scholar
  78. 78.
    Zhang G, Liu C, Yi H, Meng Q, Bian C, Chen H, Jian JX, Wu LZ, Lei A (2015) External oxidant-free oxidative cross-coupling: a photoredox cobalt-catalyzed aromatic C–H thiolation for constructing C–S bonds. J Am Chem Soc 137(29):9273–9280PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Zhang T, Deng G, Li H, Liu B, Tan Q, Xu B (2018) Cyclization of 2-Biphenylthiols to dibenzothiophenes under PdCl2/DMSO catalysis. Org Lett 20(17):5439–5443PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Zhao DY, Guo XK, Li JH, Tang RY (2012) Iodine-mediated intramolecular oxidative cyclization of 2-(Styrylthio) anilines: synthesis of 2-substituted benzothiazoles. Synthesis 44(06):927–933CrossRefGoogle Scholar
  81. 81.
    Zhao S, Yuan J, Li YC, Shi BF (2015) Copper-catalyzed oxidative C–H/C–H cross-coupling of benzamides and thiophenes. Chem Commun 51(64):12823–12826CrossRefGoogle Scholar
  82. 82.
    Zhu J, Xie H, Li S, Chen Z, Wu Y (2011) Switching reaction pathways of trifluoromethylated thiobenzanilides by choice of different oxidative systems. J Fluor Chem 132(5):306–309CrossRefGoogle Scholar
  83. 83.
    Zhu M, Fujita KI, Yamaguchi R (2011) Efficient synthesis of biazoles by aerobic oxidative homocoupling of azoles catalyzed by a copper (I)/2-pyridonate catalytic system. Chem Commun 47(48):12876–12878CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of ChemistryThe University of the West IndiesKingston 7Jamaica

Personalised recommendations