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Synthesis 2001(14): 2175-2179
DOI: 10.1055/s-2001-18070
PAPER
© Georg Thieme Verlag Stuttgart · New York

Mild Regioselective Halogenation of Activated Pyridines with N-Bromosuccinimide

Victoria Cañibanoa, Justo F. Rodrígueza, Mercedes Santosa, M. Ascensión Sanz-Tejedor*a, M. Carmen Carreñob, Gema Gonzálezb, José L. García-Ruano*b
Organic Chemistry Department (E.T.S.I.I.), Universidad de Valladolid, Pº del Cauce s/n, 47011-Valladolid, Spain
Fax: +34(983)423310; e-Mail: atejedor@dali.eis.uva.es;
Organic Chemistry Department (C-I), Universidad Autónoma, Cantoblanco, 28049-Madrid, Spain
Further Information

Publication History

Received 4 July 2001
Publication Date:
09 August 2004 (online)

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Abstract

Regioselective mono and dihalogenations of amino, hydroxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as 2,6-dimethoxy pyridine with N-bromosuccinimide in different solvents have been studied. Reactivity of the substrates decreases in the order amino>hydroxy>methoxy and regioselectivity depends on the position of the substituent (2-substituted > 3-substituted). In most of the cases we obtained monobrominated derivatives regioselectively and in high yields. Hydroxy and amino pyridines can also be dibrominated in almost quantitative yield with 2 equivalents of NBS.

Key words

halogenation - pyridines - N-bromosuccinimide (NBS) - regioselective bromination - substituent effects

    References

  • See:
  • 1a Beschke H. Kleemann A. Claus W. Kurze W. Mathes K. Habersang S. In Ullmanns Encyklopädie der technischen Chemie   Verlag Chemie; Weinheim, Florida: 1980.  Ed. 19. p.592-617  
  • 1b Lednicer D. In Strategies for Organic Drug Synthesis and Design.   John Wiley & Sons; New York: 1988.  p.242-257  ; and references cited therein
  • 2a Barbera J. Meléndez E. Romero P. Serrano JL. Mol. Cryst. Liq. Cryst.  1985,  126:  259 
    Search in Google Scholar
  • 2b Seto K. Shimojitosyo H. Matsubara H. Takahashi S. Chem. Lett.  1990,  323 
  • 3a Oae S. Kawi T. Furukawwa N. Phosphorus and Sulfur  1987,  34:  123 
    CrossrefSearch in Google Scholar
  • 3b Lee AWM. Chan WH. Wong MS. J. Chem. Soc, Chem. Commun.  1988,  1585 
    Crossref
  • 3c Vögtle F. In Supramolecular Chemistry   Wiley; New York: 1991. 
    Crossref
  • 4a Meyer TJ. Acc. Chem. Res.  1989,  22:  163 
    CrossrefSearch in Google Scholar
  • 4b Pyle AM. Barton JK. Prog. Inorg. Chem.  1990,  38:  413 
    CrossrefSearch in Google Scholar
  • 4c Gittins DI. Bethell D. Nichols RJ. Schiffrin DJ. Advanced Materials  1999,  737 
    Crossref
  • For reviews see:
  • 5a Yates FS. In Comprehensive Heterocyclic Chemistry   Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  Vol. 2. p.263-359  
  • 5b Joule JA. Mills K. Smith GF. In Heterocyclic Chemistry   Chapman & Hall; London: 1995.  3rd ed.. p.64-144  
  • For more recent references see:
  • 6a Mongin F. Fourquez JM. Rault S. Levacher V. Godard A. Trécourt F. Quéguiner G. Tetrahedron Lett.  1995,  36:  8415 
    CrossrefSearch in Google Scholar
  • 6b Zoltewicz MP. Cruskie MP. J. Org. Chem.  1995,  60:  3487 
    CrossrefSearch in Google Scholar
  • 6c Bérillon L. Leprêtre A. Turck A. Plé N. Quéguiner G. Gahiez G. Knochel P. Synlett  1998,  1359 
    Crossref
  • 6d Legros JY. Primault G. Toffano M. Riviere MA. Fiaud JC. Org. Lett.  2000,  2:  433 
    CrossrefSearch in Google Scholar
  • 7a Yates FS. In Comprehensive Heterocyclic Chemistry   Vol. 2, part 2a:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.511-523  
    Search in Google Scholar
  • 7b Koch V, Wilms L, Fuss A, Bauer K, Bieringer H, and Buerstell H. inventors; Eur. Patent Application,  227045. 
  • 8a Koch V, Fuss A, Bonin W, Knauf W, and Waltersdorfer A. inventors; Eur. Patent Application  227046. 
  • 9a Gershon H. Clarke DD. Gershon M. Monatsh. Chem.  1994,  125:  723 
    CrossrefSearch in Google Scholar
  • 9b Gershon H. Gershon M. Monatsh. Chem.  1995,  126:  1303 
    CrossrefSearch in Google Scholar
  • 9c Gershon H. Clarke DD. Gershon M. Monatsh. Chem.  1996,  127:  331 
    CrossrefSearch in Google Scholar
  • 10a Yates FS. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.198-205  
    Search in Google Scholar
  • 10b Brignell PJ. Jones PE. Katrizky AR. J. Chem. Soc. (B)  1970,  117 
  • 11 Paudler WW. Jovanovic MV. J. Org. Chem.  1983,  48:  1064 
    CrossrefSearch in Google Scholar
  • For 2-methoxypyridine see:
  • 12a Kompis I. Mueller W. Boehni E. Then R. Montavon M. Eur. J. Med. Chem.  1977,  12:  531 
    Thieme ConnectSearch in Google Scholar
  • 12b Comins DL. Killpack MO. J. Org. Chem.  1990,  55:  69 
    Thieme ConnectSearch in Google Scholar
  • 12c Windscheif P.-M. Vögtle F. Synthesis  1994,  87 
    Thieme Connect
  • 13 Koch V. Schnatterer S. Synthesis  1990,  497 
    Thieme Connect
  • 14a Gershon H. McNeil MW. Grefig AT. J. Org. Chem.  1969,  34:  3268 
    Search in Google Scholar
  • 14b Gershon H. McNeil MW. J. Org. Chem.  1970,  35:  3993 
    Search in Google Scholar
  • 14c Clarke DD. Gershon H. Shoja M. Yen M.-W. Monatsh Chem.  1998,  129:  419 ; see also refs 9a, 9c, 12c
    Search in Google Scholar
  • 14d For a 4-quinolinol derivative see: Jaroszewski JW. J. Heterocyclic Chem.  1990,  27:  1227 
    Search in Google Scholar
  • 15a Beugelmans R. Chbani M. Bull. Soc. Chim. Fr.  1995,  132:  290 
    CrossrefSearch in Google Scholar
  • 15b Moutou JL. Schmitt M. Collot V. Bourguignon JJ. Heterocycles  1997,  45:  897 
    CrossrefSearch in Google Scholar
  • 15c Hirokawa Y. Yoshida N. Kato S. Bioorg. Med. Chem. Lett.  1998,  1551 
    Crossref
  • 16a Adams R. Schrecker AW. J. Am. Chem. Soc.  1949,  71:  1186 
    Search in Google Scholar
  • 16b Mariella RP. Belcher EP. J. Am. Chem. Soc.  1952,  74:  1916 
    Search in Google Scholar
  • 16c Cook DJ. Bowen ER. Sorter P. Daniels E. J. Org. Chem.  1961,  26:  4949 
    Search in Google Scholar
  • 16d Morrow CJ. Rapoport H. J. Org. Chem.  1974,  39:  2116 
    Search in Google Scholar
  • 16e Comins DL. Lyle RE. J. Org. Chem.  1976,  41:  2065 
    Search in Google Scholar
  • 16f Venischi J. Tanaka T. Nishiwaki K. Wakabayashi S. Oae S. Tsukube H. J. Org. Chem.  1993,  58:  4382 
    Search in Google Scholar
  • 16g For a review about N-halosuccinimides see: Pizey JS. In Synthetic Reagents   John Wiley & Sons; New York: 1974.  Vol II. p.9-27  
  • 17a Carreño MC. García Ruano JL. Sanz G. Toledo MA. Urbano A. J. Org. Chem.  1995,  60:  5328 
    CrossrefSearch in Google Scholar
  • 17b Carreño MC. García Ruano JL. Sanz G. Toledo MA. Urbano A. Tetrahedron. Lett.  1996,  37:  4081 
    CrossrefSearch in Google Scholar
  • 18 Carreño MC. García Ruano JL. Sanz G. Toledo MA. Urbano A. Synlett  1997,  1241 
    Thieme Connect
  • 19 For another preparation of 2-amino-5-bromo and 2-amino-3,5-dibromo pyridines that involves a π-deficient pyridinium-N-(2’-pyridyl)aminide and subsequent reduction of the N-N bond (56% and 54% overall yield respectively) see: Burgos C. Delgado F. García-Navío JL. Izquierdo ML. Alvárez-Builla J. Tetrahedron  1995,  51:  8649 
    CrossrefSearch in Google Scholar