Skip to main content
SpringerLink
Log in

Isothiazoles and Benzisothiazoles

  • Chapter
  • First Online:
Metalation of Azoles and Related Five-Membered Ring Heterocycles

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 29))

Abstract

In this study, metalation chemistry of isothiazoles, benz[c]isothiazoles, and benz[d]isothiazoles is discussed, and examples of ring metalation, lateral metalation, and utilization of metalated isothiazoles in transition metal-catalyzed coupling reactions are presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Iddon B (1995) Synthesis and reactions of lithiated monocyclic azoles containing two or more hetero-atoms. Part V: isothiazoles and thiazoles. Heterocycles 41:533–593

    Article  CAS  Google Scholar 

  2. Brown DW, Sainsbury M (2002) Product class 15: isothiazoles. Sci Synth 11:507–572

    CAS  Google Scholar 

  3. Brown DW, Sainsbury M (2002) Product class 16: benzisothiazoles. Sci Synth 11:573–625

    CAS  Google Scholar 

  4. Elgazwy A-SSH (2003) The chemistry of isothiazoles. Tetrahedron 59:7445–7463

    Article  Google Scholar 

  5. Sainsbury M (2010) Isothiazoles. Science of synthesis. Knowledge Updates:207–248

    Google Scholar 

  6. Sainsbury M (2010) Benzisothiazoles. Science of synthesis. Knowledge Updates:249–265

    Google Scholar 

  7. Cutrì CCC, Garozzo A, Siracusa MA, Castro A, Tempera G, Sarva MC, Guerrera F (2002) Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum. Antiviral Res 45:357–368

    Article  Google Scholar 

  8. Wu Z, Fraley ME, Bilodeau MT, Kaufman ML, Tasber ES, Balitza AE, Hartman GD, Coll KE, Rickert K, Shipman J, Shi B, Sepp-Lorenzino L, Thomas KA (2004) Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR. Bioorg Med Chem Lett 14:909–912

    Article  CAS  Google Scholar 

  9. Timms GH, Boot JR, Broadmore RJ, Carney SL, Cooper J, Findlay JD, Gilmore J, Mitchell S, Moore NA, Pullar I, Sanger GJ, Tomlinson R, Tree BB, Wedley S (2004) SAR development of a selective 5-HT1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis. Bioorg Med Chem Lett 14:2469–2472

    Article  CAS  Google Scholar 

  10. Lippa B, Morris J, Corbett M, Kwan TA, Noe MC, Snow SL, Gant TG, Mangiaracina M, Coffey HA, Foster B, Knauth EA, Wessel MD (2006) Discovery of novel isothiazole inhibitors of the TrkA kinase: structure-activity relationship, computer modeling, optimization, and identification of highly potent antagonists. Bioorg Med Chem Lett 16:3444–3448

    Article  CAS  Google Scholar 

  11. Abdellaoui HE, Varaprasad CVNS, Barawkar D, Chakravarty S, Maderna A, Tam R, Chen H, Allan M, Wu JZ, Appleby T, Yan S, Zhang W, Lang S, Yao N, Hamatake R, Hong Z (2006) Identification of isothiazole-4-carboxamidines derivatives as a novel class of allosteric MEK1 inhibitors. Bioorg Med Chem Lett 16:5561–5566

    Article  Google Scholar 

  12. Larson G, Yan S, Chen H, Rong F, Hong Z, Wu JZ (2007) Identification of novel, selective and potent Chk2 inhibitors. Bioorg Med Chem Lett 17:172–175

    Article  CAS  Google Scholar 

  13. Yan S, Appleby T, Gunic E, Shim JH, Tasu T, Kim H, Rong F, Chen H, Hamatake R, Wu JZ, Hong Z, Yao N (2007) Isothiazoles as active-site inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 17:28–33

    Article  CAS  Google Scholar 

  14. Zeng L-F, Zhang H-S, Wang Y-H, Sanchez T, Zheng Y-T, Neamati N, Long Y-Q (2008) Efficient synthesis and utilization of phenyl-substituted heteroaromatic carboxylic acids as aryl diketo acid isosteres in the design of novel HIV-1 integrase inhibitors. Bioorg Med Chem Lett 18:4521–4524

    Article  CAS  Google Scholar 

  15. Geronikaki A, Eleftheriou P, Vicini P, Alam I, Dixit A, Saxena AK (2008) 2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action. J Med Chem 51:5221–5228

    Article  CAS  Google Scholar 

  16. Kiselyov AS, Semenova M, Semenov VV (2009) 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2. Bioorg Med Chem Lett 19:1195–1198

    Article  CAS  Google Scholar 

  17. Matzen L, Engesgaard A, Ebert B, Didriksen M, Frølund B, Krogsgaard-Larsen P, Jaroszewski JW (1997) AMPA receptor agonists: synthesis, protolytic properties, and pharmacology of 3-isothiazolol bioisosteres of glutamic acid. J Med Chem 40:520–527

    Article  CAS  Google Scholar 

  18. Stensbol TB, Jensen HS, Nielsen B, Johansen TN, Egebjerg J, Frydenvang K, Krogsgaard-Larsen P (2001) Stereochemistry and molecular pharmacology of (S)-thio-ATPA, a new potent and selective GluR5 agonist. Eur J Pharmacol 411:245–253

    Article  CAS  Google Scholar 

  19. Caton MPL, Jones DH, Slack R, Wooldridge KRH (1964) Isothiazoles. Part III. Reactions of isothiazol-5-yl-lithium compounds. J Chem Soc:446–451

    Google Scholar 

  20. Beringer M, Prijs B, Erlenmeyer H (1966) Schwefel als ligandatom in aromatischen verbindungen. III. Synthese einer isothiazol-carbonsaure. Helv Chim Acta 8:2466–2469

    Article  Google Scholar 

  21. Layton AJ, Lunt E (1968) Isothiazoles. Part XI. Carbinols, aryl ketones, and aminomethyl derivatives of isothiazoles. J Chem Soc (C):611–614

    Google Scholar 

  22. Naito T, Nakagawa S, Takahashi K (1968) Studies on isothiazoles. I. 3-Arylisothiazole-4-carboxylic acids. Chem Pharm Bull 16:148–159

    Article  CAS  Google Scholar 

  23. Rajappa S, Akerkar AS, Iyer VS (1969) Isothiazoles: part I – some 4-substituted derivatives. Ind J Chem 7:103–108

    CAS  Google Scholar 

  24. Micetich RG (1970) Lithiation of five-membered heteroaromatic compounds. The methyl substituted 1,2-azoles, oxadiazoles, and thiadiazoles. Can J Chem 48:2006–2015

    Article  CAS  Google Scholar 

  25. Micetich RG, Raap R (1971) Arylglyoxylic esters via aryllithium compounds. Org Prep Proc Int 3:167–169

    Article  CAS  Google Scholar 

  26. Hatanaka M, Ishimaru T (1973) Synthetic penicillins. Heterocyclic analogs of ampicillin. Structure-activity relationships. J Med Chem 16:978–984

    Article  CAS  Google Scholar 

  27. Noyce DS, Sandel BB (1975) Solvolysis of isothiazole analogs of cumyl chloride. Determination of the brown electrophilic substituent constants for isothiazole derivatives. J Org Chem 40:3381–3383

    Article  CAS  Google Scholar 

  28. Kalish R, Broger E, Field GF, Anton T (1975) Quinazolines and 1,4-benzodiazepines. LXVIII. 5-Heterocyclic-substituted benzodiazepinones. J Heterocycl Chem 12:49–57

    Article  CAS  Google Scholar 

  29. Ashton MJ, Ashford A, Loveless AH, Riddell D, Salmon J, Stevenson GVW (1984) Heterocyclic analogues of chlorcyclizine with potent hypolipidemic activity. J Med Chem 27:1245–1253

    Article  CAS  Google Scholar 

  30. Katritzky AR, Laurenzo KS (1988) The preparation and fungicidal activity of a series of thiazolyl- and isothiazolyl-diarylcarbinols. Can J Chem 66:1617–1624

    Article  CAS  Google Scholar 

  31. Buttimore D, Jones DH, Slack R, Wooldridge KRH (1963) Isothiazoles. Part II. Isothiazolealdehydes and isothiazolyl ketones. J Chem Soc:2032–2039

    Google Scholar 

  32. Toerien JG, Desmet M, Kruger GJ, Raubenheimer HG (1994) Carbene complexes of FeII prepared from a precursor complex containing a remote nucleophilic heteroatom. J Organomet Chem 479:C12–C15

    Article  CAS  Google Scholar 

  33. Raubenheimer HG, Desmet M (1995) A new method and a new concept for the preparation of dihydrothiazolylidene- and dihydroisothiazolylidene tungsten complexes. J Chem Res (S):30–31

    Google Scholar 

  34. Alberola A, Alonso F, Cuadrado P, Sanudo MC (1987) 3,5-Dimethyl-4-isothiazolylmagnesium iodide and its reactions with some electrophilic reagents. Synth Commun 17:1207–1215

    Article  CAS  Google Scholar 

  35. Guilloteau F, Miginiac L (1995) A convenient regiospecific synthesis of isothiazol-4-yl derivatives. Synth Commun 25:1383–1389

    Article  CAS  Google Scholar 

  36. Bunch L, Krogsgaard-Larsen P, Madsen U (2002) Regioselective lithiation and functionalization of 3-(benzyloxy)isothiazole: application to the synthesis of thioibotenic acid. J Org Chem 67:2375–2377

    Article  CAS  Google Scholar 

  37. Kang YK, Lee KS, Yoo KH, Shin KJ, Kim DC, Lee C-S, Kong JY, Kim DJ (2003) Synthesis and biological evaluation of novel 1β-methylcarbapenems with isothiazoloethenyl side chains. Bioorg Med Chem Lett 13:463–466

    Article  CAS  Google Scholar 

  38. Singerman GM (1975) A new synthesis of 2,1-benzisothiazoles. J Heterocycl Chem 12:877–882

    Article  CAS  Google Scholar 

  39. Okazaki R, Takahashi M, Inamoto N, Sugawara T, Iwamura H (1989) Photoreaction of 3-azido-di-t-butyl-2,1-benzisothiazole. Spectroscopic detection of a thionitroso intermediate. Chem Lett:2083–2086

    Google Scholar 

  40. Clarke K, Carrington DEL, Scrowston RM (1971) 1,2-Benzisothiazoles. I. Reaction of 3-chloro-1,2-benzisothiazole with nucleophiles. J Chem Soc C:3262–3265

    Google Scholar 

  41. Blanchet J, Macklin T, Ang P, Metallinos C, Snieckus V (2007) Directed ortho-metalation-cross coupling strategies. N-cumyl arylsulfonamides. Facile deprotection and expedient route to 7- and 4,7-substituted saccharins. J Org Chem 72:3199–3206

    Article  CAS  Google Scholar 

  42. Alberola A, Calvo L, Rodríguez MTR, Sañudo MC (1993) The reactivity of 3-methyl-5-phenylisothiazole with carbonyl compounds. J Heterocycl Chem 30:393–396

    Article  CAS  Google Scholar 

  43. Alberola A, Calvo L, Rodríguez MTR, Sañudo MC (1995) Comparative reactivity of 3-methyl-5-phenylisoxazole and 3-methyl-5-phenylisothiazole against electrophilic compounds. J Heterocycl Chem 32:537–541

    Article  CAS  Google Scholar 

  44. Alberola A, Andrés C, Casado JL, Alfonso G, Pedrosa R (1990) Alkylation of 3,5-dimethylisothiazole. A regioselective synthesis of 5-alkyl-3-methylisothiazoles. Synth Commun 20:617–624

    Article  CAS  Google Scholar 

  45. Alberola A, Alonso F, Cuadrado P, Sañudo MC (1987) Production and transformation of carbanions derived from C4α-functionalized 3,5-dimethylisothiazoles. Gazz Chim Ital 117:461–467

    CAS  Google Scholar 

  46. Suzuki A (2011) Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew Chem Int Ed 50:6722–6737

    Article  CAS  Google Scholar 

  47. Jana R, Pathak TP, Sigman MS (2011) Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem Rev 111:1417–1492

    Article  CAS  Google Scholar 

  48. Wu X-F, Anbarasan P, Neumann H, Matthias B (2010) From Noble metal to Nobel prize: palladium-catalyzed coupling reactions as key methods in organic synthesis. Angew Chem Int Ed 49:9047–9050

    Article  CAS  Google Scholar 

  49. Zlotin SG, Kislitsin PG, Luk’yanov OA (1998) Alkynylisothiazoles. Russ Chem Bull 47:519–523

    Article  CAS  Google Scholar 

  50. Christoforou IC, Koutentis PA, Rees CW (2003) Regiospecific Suzuki coupling of 3,4-dichloroisothiazole-4-carbonitrile. Org Biomol Chem 1:2900–2907

    Article  CAS  Google Scholar 

  51. Lu Z, Raghavan S, Bohn J, Charest M, Stahlhut MW, Rutkowski CA, Simcoe AL, Olsen DB, Schleif WA, Carella A, Gabryelski L, Jin L, Lin JH, Emini E, Chapman K, Tata JR (2003) Design and synthesis of highly potent HIV protease inhibitors with activity against resistant virus. Biorg Med Chem Lett 13:1821–1824

    Article  CAS  Google Scholar 

  52. Kaae BH, Krogsgaard-Larsen P, Johansen TN (2004) Synthesis of aryl- and heteroaryl-substituted 3-benzyloxyisothiazoles via Suzuki and Negishi cross-coupling reactions. J Org Chem 69:1401–1404

    Article  CAS  Google Scholar 

  53. Schröter S, Stock C, Bach T (2005) Regioselective cross-coupling reactions of multiple halogenated nitrogen-, oxygen-, and sulfur-containing heterocycles. Tetrahedron 61:2245–2267

    Article  Google Scholar 

  54. Christoforou IC, Koutentis PA (2006) New regiospecific isothiazole C–C coupling chemistry. Org Biomol Chem 4:3681–3693

    Article  CAS  Google Scholar 

  55. Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P (2006) Cross-coupling reactions on azoles with two and more heteroatoms. Eur J Org Chem:3283–3307

    Google Scholar 

  56. Christoforou IC, Koutentis PA (2007) 3,4,5-Triarylisothiazoles via C–C coupling chemistry. Org Biomol Chem 5:1381–1390

    Article  CAS  Google Scholar 

  57. Zhou H, Danger DP, Dock ST, Hawley L, Roller SG, Smith CD, Handlon AL (2010) Synthesis and SAR of benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors of SGLT2. ACS Med Chem Lett 1:19–23

    Article  CAS  Google Scholar 

  58. Badland M, Compère D, Courté K, Dublanchet A-C, Blais S, Manage A, Peron G, Wrigglesworth R (2011) Thiophene and bioisostere derivatives as new MMP12 inhibitors. Bioorg Med Chem Lett 21:528–530

    Article  CAS  Google Scholar 

  59. Albrecht BK, Harmange J-C, Bauer D, Berry L, Bode C, Boezio AA, Chen A, Choquette D, Dussault I, Fridrich C, Hirai S, Hoffman D, Larrow JF, Kaplan-Lefko P, Lin J, Lohman J, Long AM, Moriguchi J, O’Connor A, Potashman MH, Reese M, Rex K, Siegmund A, Shah K, Shimanovich R, Springer SK, Teffera Y, Yang Y, Zhang Y, Bellon SF (2008) Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. J Med Chem 51:2879–2882

    Article  CAS  Google Scholar 

  60. Boezio AA, Berry L, Albrecht BK, Bauer D, Bellon SF, Bode C, Chen A, Choquette D, Dussault I, Hirai S, Kaplan-Lefko P, Larrow JF, Lin M-HJ, Lohman J, Potashman MH, Rex K, Santostefano M, Shah K, Shimanovich R, Springer SK, Teffera Y, Yang Y, Zhang Y, Harmange J-C (2009) Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Lett 19:6307–6312

    Article  CAS  Google Scholar 

  61. Powell SN, DeFrank JS, Connell P, Eogan M, Preffer F, Dombkowski D, Tang W, Friend S (1995) Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 55:1643–1648

    CAS  Google Scholar 

  62. Zhou B-BS, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    Article  CAS  Google Scholar 

  63. Li Q, Zhu G-D (2002) Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem 2:939–971

    Article  CAS  Google Scholar 

  64. Dwyer MP, Paruch K, Labroli M, Alvarez C, Keertikar KM, Poker C, Rossman R, Fischmann TO, Duca JS, Madison V, Parry D, Davis N, Seghezzi W, Wiswell D, Guzi TJ (2011) Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach – part 1. Bioorg Med Chem Lett 21:467–470

    Article  CAS  Google Scholar 

  65. Stec MM, Andrews KL, Booker SK, Caenepeel S, Freeman DJ, Jiang J, Liao H, McCarter J, Mullady EL, Miguel TS, Subramanian R, Tamayo N, Wang L, Yang K, Zalameda LP, Zhang N, Hughes PE, Norman MH (2011) Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability. J Med Chem 54:5174–5184

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Hugel Science Center, Lafayette College, Easton, PA, 18042, USA

    Charles F. Nutaitis

Authors
  1. Charles F. Nutaitis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles F. Nutaitis .

Editor information

Editors and Affiliations

  1. Dept. Chemistry, Dartmouth College, Burke Laboratory 6128, Hanover, 03755, New Hampshire, USA

    Gordon W. Gribble

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Nutaitis, C.F. (2012). Isothiazoles and Benzisothiazoles. In: Gribble, G. (eds) Metalation of Azoles and Related Five-Membered Ring Heterocycles. Topics in Heterocyclic Chemistry, vol 29. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_2012_77

Download citation

Publish with us

Policies and ethics

Search

Navigation