Synthesis 2022; 54(22): 5055-5063 DOI: 10.1055/s-0037-1610786
special topic
Aryne Chemistry in Synthesis
Regioselective Amination or Alkoxylation of Halogenated Amino-, Thio- or Alkoxypyridines via Pyridyne Intermediates
Benjamin Heinz
a
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Dimitrije Djukanovic
a
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Fiona Siemens
a
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Mohamed Idriess
a
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Benjamin Martin
b
Novartis Pharma AG, Chemical Development, Fabrikstraße, 4056 Basel, Switzerland
,
a
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
› Author Affiliations We thank the DFG and Novartis (Basel) for generous financial support.
Abstract
The treatment of 3-halopyridines (Cl, Br) bearing an R-substituent in position 2 (R = OEt, NEt2 , N -piperidyl, or SEt) or in position 5 (R = OMe, OEt, SEt, NMe2 , NEt2 , or aryl) with KHMDS and an amine at 25 °C for 12 hours in THF provided regioselectively 3- and 4-aminated pyridines in 56–90% yields. The reaction of 3-bromo-2-diethylaminopyridine with various alcohols in the presence of t -BuOK/18-crown-6 in THF at 80 °C for 20–60 hours gave various 4-alkoxy-2-diethylaminopyridines in 61–81% yields. These substitution reactions were proposed to proceed via pyridyne intermediates.
Key words
potassium bases -
pyridines -
amination -
alkoxylation -
pyridynes
Supporting Information
Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610786.
Supporting Information
Publication History
Received: 15 September 2021
Accepted after revision: 29 September 2021
Article published online: 11 November 2021
© 2021. Thieme. All rights reserved
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
References
1a
Eicher T,
Hauptmann S,
Speicher A.
The Chemistry of Heterocycles , 2nd ed. Wiley-VCH; Weinheim: 2003
1b
Alvarez-Builla J,
Vaquero JJ,
Barluenga J.
Modern Heterocyclic Chemistry ,1st ed. Wiley-VCH; Weinheim: 2011
2a
Bisai V,
Sarpong R.
Org. Lett. 2010; 12: 2551
2b
Fischer DF,
Sarpong R.
J. Am. Chem. Soc. 2010; 132: 5926
2c
Newton JN,
Fischer DF,
Sarpong R.
Angew. Chem. Int. Ed. 2013; 52: 1726
2d
Rouquet G,
Blakemore DC,
Ley SV.
Chem. Commun. 2014; 50: 8908
2e
Rouquet G,
Moore DE,
Spain M,
Allwood DM,
Battilocchio C,
Blakemore DC,
Fish PV,
Jenkinson S,
Jessiman AS,
Ley SV,
McMurray G,
Storer RA.
ACS Med. Chem. Lett. 2015; 6: 329
2f
Xie L.-G,
Shaaban S,
Chen X,
Maulide N.
Angew. Chem. Int. Ed. 2016; 128: 13056
2g
Ekar J,
Kranjc K.
Synthesis 2021; 53: 1112
2h
Casadia I,
Daher TO,
Moura S,
Back DF,
Faoro E,
Schwalm CS,
Casagrande GA,
Paveglio GC,
Pizzuti L.
Synthesis 2021; 53: 365
2i
Desaintjean A,
Danton F,
Knochel P.
Synthesis 2021; 53: in press
For recent publications on the functionalization of other heterocycles, see:
3a
Li X,
Jandl C,
Bach T.
Synthesis 2021; 53: 723
3b
Ohno S,
Miyoshi M,
Murai K,
Arisawa M.
Synthesis 2021; 53: 2947
3c
Jeminejs A,
Goliskina SM,
Novosjolova I,
Stepanovs D,
Turks M.
Synthesis 2021; 53: 1443
3d
Ye X,
Huang J,
Deng Z,
Yua J,
Peng Y.
Synthesis 2021; 53: 383
3e
Weidmann N,
Nishimura RH. V,
Harenberg JH,
Knochel P.
Synthesis 2021; 53: 557
3f
Sanchez F,
Desaintjean A,
Danton F,
Knochel P.
Synthesis 2021; 53: in press
4a
Comins DL,
Killpack MO.
J. Org. Chem. 1990; 55: 69
4b
Gros P,
Fort Y,
Queguiner G,
Caubère P.
Tetrahedron Lett. 1995; 36: 4791
4c
Choppin S,
Gros P,
Fort Y.
Eur. J. Org. Chem. 2001; 603
4d
Balkenhohl M,
François C,
Roman DS,
Quinio P,
Knochel P.
Org. Lett. 2017; 19: 536
4e
Balkenhohl M,
Heinz B,
Abegg T,
Knochel P.
Org. Lett. 2018; 20: 8057
4f
Bellan AB,
Knochel P.
Angew. Chem. Int. Ed. 2019; 58: 1838
5a
Balkenhohl M,
Knochel P.
SynOpen 2018; 2: 78
5b
Balkenhohl M,
Jangra H,
Makarov IS,
Yang S.-M,
Zipse H,
Knochel P.
Angew. Chem. Int. Ed. 2020; 59: 14992
6a
Mallet M,
Quenguiner G.
Tetrahedron 1982; 38: 3035
6b
Gribble GW,
Saulnier MG.
Heterocycles 1993; 35: 151
6c
Vinter-Pasquier K,
Jamart-Gregoire B,
Caubère P.
Heterocycles 1997; 45: 2113
6d
Connon SJ,
Hegarty AF.
J. Chem. Soc., Perkin Trans. 1 2000; 1245
6e
Lin W,
Chen L,
Knochel P.
Tetrahedron 2007; 63: 2787
6f
Cant AA,
Bertrand GH. V,
Henderson JL,
Roberts L,
Greaney MF.
Angew. Chem. Int. Ed. 2009; 48: 5199
For more recent contributions, see:
7a
Goetz AE,
Bronner SM,
Cisneros JD,
Melamed JM,
Paton RS,
Houk KN,
Garg NK.
Angew. Chem. Int. Ed. 2012; 51: 2758
7b
Fang Y,
Larock RC.
Tetrahedron 2012; 68: 2819
7c
Goetz AE,
Garg NK.
Nat. Chem. 2013; 5: 54
7d
Goetz AE,
Garg NK.
J. Org. Chem. 2014; 79: 846
7e
Medina JM,
Jackl MK,
Susick RB,
Garg NK.
Tetrahedron 2016; 72: 3629
8
Heinz B,
Djukanovic D,
Filipponi P,
Martin B,
Karaghiosoff K,
Knochel P.
Chem. Sci. 2021; 12: 6143
9a
Biehl ER,
Smith SM,
Reeves PC.
J. Org. Chem. 1971; 36: 1841
9b
Xin HY,
Biehl ER.
J. Org. Chem. 1983; 48: 4397
9c
Biehl ER,
Razzuk A,
Jovanovic MV,
Khanapure SP.
J. Org. Chem. 1986; 51: 5157
9d
Razuk A,
Biehl ER.
J. Org. Chem. 1987; 52: 2619
9e
Lin W,
Sapountzis I,
Knochel P.
Angew. Chem. Int. Ed. 2005; 44: 4258
9f
Medina JM,
Mackey JL,
Garg NK,
Houk KN.
J. Am. Chem. Soc. 2014; 136: 15798
9g
Nagaki A,
Ichinari D,
Yoshida J.
J. Am. Chem. Soc. 2014; 136: 12245
9h
Garcia-Lopez J.-A,
Cetin M,
Greaney MF.
Angew. Chem. Int. Ed. 2015; 54: 2156
9i
Garcia-Lopez J.-A,
Cetin M,
Greaney MF.
Org. Lett. 2015; 17: 2649
9j
Ghorai S,
Lee D.
Synlett 2020; 31: 750
9k
Cho S,
Wang Q.
Org. Lett. 2020; 22: 1670
10a
Bayracharya GB,
Daugulis O.
Org. Lett. 2008; 10: 4625
10b
Dong Y,
Lipschutz MI,
Tilley TD.
Org. Lett. 2016; 18: 1530
10c
Hazarika H,
Gogoi P.
Org. Biomol. Chem. 2020; 18: 2727
11 The reaction of 3-chloro-2-ethoxypyridine gave 57% GC-yield compared to 90% GC-yield with 3-bromo-2-ethoxypyridine (4a ).
12 To demonstrate the importance of the presence of a substituent in position 2, we examined the reaction of 3-bromopyridine under the optimized conditions. Compared to 3-bromo-2-ethoxypyridine (90% GC-yield), the unsubstituted 3-bromopyridine gave only 32% GC-yield, presumably due to lower stability of the pyridyne intermediate.
13
Koley M,
Wimmer L,
Schnürch M,
Mihovilovic MD.
Eur. J. Org. Chem. 2011; 1972