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Synthesis 2009(5): 721-730
DOI: 10.1055/s-0028-1083354
DOI: 10.1055/s-0028-1083354
PAPER
© Georg Thieme Verlag
Stuttgart ˙ New York
Synthesis of 5,7-Dichloro-6-azaindoles and Functionalization via a Highly Selective Lithium-Chlorine Exchange
Further Information
Received
8 October 2008
Publication Date:
02 February 2009 (online)
Publication History
Publication Date:
02 February 2009 (online)
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Abstract
The synthesis of a range of novel 5,7-dichloro-6-azaindoles through the use of a Fischer cyclization with pyridine hydrochloride in N-methylpyrrolidin-2-one is described. Dichloro-6-azaindoles are versatile compounds that can be selectively substituted through a palladium-catalyzed cross-coupling reaction or a high-yielding lithium-chlorine exchange.
Key words
azaindole - pyrrolopyridine - Fischer cyclizations - metalations - palladium
- For leading references to the physiological activity of indole derivatives, see:
-
1a
Sturino CF.O’Neill GP.Lachance N.Boyd MJ.Berthelette C.Labelle M.Li LH.Roy B.Scheigetz J.Tsou NN.Bateman KP.Day SH.Levesque JF.Seto C.Silva JM.Carriere M.Denis D.Greig GM.Kargman SL.Lamontagne S.Mathieu M.Sawyer N.Slipetz DM.Jones TR.Mcauliffe M.Piechuta H.Nicoll-Griffith DA.Wang Z.Zamboni RJ.Young RN.Metters KM. J. Med. Chem. 2007, 50: 794 -
1b
Van Zandt MC.Jones ML.Gunn DE.Geraci LS.Jones JH.Sawicki DR.Sredy J.Jacot JL.DiCioccio AT.Petrova T.Mitschler A.Podjarny AD. J. Med. Chem. 2005, 48: 3141 -
1c
Kuethe JT.Wong A.Qu C.Smitrovich J.Davies IW.Hughes DL. J. Org. Chem. 2005, 70: 2555 - 2 For review on indoles synthesis,
see:
Gribble GW. J. Chem. Soc., Perkin Trans. 1 2000, 1045 ; and references therein - For recent reviews on palladium-catalyzed synthesis of indoles, see:
-
3a
Humphrey GR.Kuethe JT. Chem. Rev. 2006, 106: 2875 ; and references therein -
3b
Cacchi S.Fabrizi G. Chem. Rev. 2005, 105: 2873 ; and references therein - For leading reference to the physiological activity of azaindole derivatives, see:
-
4a
Kim KS.Zhang L.Schmidt R.Cai Z.-W.Wei D.Williams DK.Lombardo LJ.Trainor GL.Xie D.Zhang Y.An Y.Sack JS.Tokarski JS.Darienzo C.Kamath A.Marathe P.Zhang Y.Lippy J.Jeyaseelan RSr.Wautlet B.Henley B.Gullo-Brown J.Manne V.Hunt JT.Fargnoli J.Borzilleri RM. J. Med. Chem. 2008, 51: 5330 -
4b
Lu R.-J.Tucker JA.Zinevitch T.Kirichenko O.Konoplev V.Kuznetsova S.Sviridov S.Pickens J.Tandel S.Brahmachary E.Yang Y.Wang J.Freel S.Fisher S.Sullivan A.Zhou J.Stanfield-Oakley S.Greenberg M.Bolognesi D.Bray B.Koszalka B.Jeffs P.Khasanov A.Ma Y.-A.Jeffries C.Liu C.Proskurina T.Zhu T.Chucholowski A.Li R.Sexton C. J. Med. Chem. 2007, 50: 6535 -
4c
Cooper LC.Chicchi GG.Dinnell K.Elliott JM.Hollingworth GJ.Kurtz MM.Locker KL.Morrison D.Shaw DE.Tsao K.-L.Watt AP.Williams AR.Swain CJ. Bioorg. Med. Chem. Lett. 2001, 11: 1233 - For reviews on azaindoles synthesis, see:
-
5a
Popowycz F.Mérour J.-Y.Joseph B. Tetrahedron 2007, 63: 8689 -
5b
Song JJ.Reeves JT.Gallou F.Tan Z.Yee NK.Senanayake CH. Chem. Soc. Rev. 2007, 36: 1120 -
5c
Popowycz F.Routier S.Joseph B.Mérour J.-Y. Tetrahedron 2007, 63: 1031 -
5d
Le Hyaric M.Vieira de Almeida M.Nora de Souza MV. Quim. Nova 2002, 25: 1165 -
5e
Mérour J.-Y.Joseph B. Curr. Org. Chem. 2001, 5: 471 ; and references therein - 6
Lachance N.April M.Joly M.-A. Synthesis 2005, 2571 - 7
Roy PJ.Dufresne C.Lachance N.Leclerc J.-P.Boisvert M.Wang Z.Leblanc Y. Synthesis 2005, 2751 - 8
Seela F.Bourgeois W. Synthesis 1988, 938 -
9a
Charrier N.Demont E.Dunsdon R.Maile G.Naylor A.O’Brien A.Redshaw S.Theobald P.Vesey D.Walter D. Synthesis 2006, 3467 -
9b
Allegretti M.Arcadi A.Marinelli F.Nicolini L. Synlett 2001, 609 - 10
Nazaré M.Schneider C.Lindenschmidt A.Will DW. Angew. Chem. Int. Ed. 2004, 43: 4526 -
11a
Ishii H. Acc. Chem. Res. 1981, 14: 275 -
11b
Yakhontov LN.Marshalkin MF. Chem. Heterocycl. Compd. (Engl. Transl.) 1972, 8: 1486 -
11c
Kelly AH.Parrick J. J. Chem. Soc., C 1970, 303 - 14
Tacconi G.Perotti A. Ann. Chim. (Rome) 1965, 55: 1223 - For selective lithium-bromine exchange on indoles, see:
-
15a
Li L.Martins A. Tetrahedron Lett. 2003, 44: 5987 -
15b
Li L.Martins A. Tetrahedron Lett. 2003, 44: 689 - 16
Peterson MA.Mitchell JR. J. Org. Chem. 1997, 62: 8237 -
17a
Naruse Y.Ito Y.Inagaki S. J. Org. Chem. 1999, 64: 639 -
17b
Naruse Y.Ito Y.Inagaki S. J. Org. Chem. 1991, 56: 2256 -
17c
Katritzky AR.Rewcastle GW.Vazquez de Miguel LM. J. Org. Chem. 1988, 53: 794 - 18
L’Heureux A.Thibault C.Ruel R. Tetrahedron Lett. 2004, 45: 2317 - For leading references on ortho-lithiation of halogenated pyridines, see:
-
19a
Pierrat P.Gros P.Fort Y. Synlett 2004, 2319 -
19b
Bracher F. J. Heterocycl. Chem. 1993, 30: 157 -
19c
Mallet M. J. Organomet. Chem. 1991, 406: 49 -
19d Review:
Mongin F.Quéguiner G. Tetrahedron 2001, 57: 4059 ; and references therein - 20
Schlosser M.Heiss C. Eur. J. Org. Chem. 2003, 4618 - 21
Guram AS.Wang X.Bunel EE.Faul MM.Larsen RD.Martinelli MJ. J. Org. Chem. 2007, 72: 5104 - 23
Fort Y.Rodriguez AL. J. Org. Chem. 2003, 68: 4918
References
The use of a condenser is not recommended.
13Typically, aminopyridine 1 was isolated in less than 5%.
22Starting material 6 was observed in less than 5% on the ¹H NMR of the unpurified reaction mixture.