Regioselective and Transition-Metal-Free Addition of tert-Butyl Magnesium Reagents to Pyridine Derivatives: A Convenient Method for the Synthesis of 3-Substituted 4-tert-Butylpyridine Derivatives

Sebastian Rappenglück; Karin V. Niessen; Thomas Seeger; Franz Worek; Horst Thiermann; Klaus T. Wanner

doi:10.1055/s-0036-1589025

Synthesis, Table of Contents

Synthesis 2017; 49(17): 4055-4064
DOI: 10.1055/s-0036-1589025

paper

Regioselective and Transition-Metal-Free Addition of tert-Butyl Magnesium Reagents to Pyridine Derivatives: A Convenient Method for the Synthesis of 3-Substituted 4-tert-Butylpyridine Derivatives

Sebastian Rappenglück

^aLudwig-Maximilians-Universität München, Department für Pharmazie – Zentrum für Pharmaforschung, Butenandtstr. 5-13, Haus C, 81377 Munich, Germany Email: klaus.wanner@cup.uni-muenchen.de

,

Karin V. Niessen

^bBundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany

,

Thomas Seeger

^bBundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany

,

Franz Worek

^bBundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany

,

Horst Thiermann

^bBundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany

,

Klaus T. Wanner *

^aLudwig-Maximilians-Universität München, Department für Pharmazie – Zentrum für Pharmaforschung, Butenandtstr. 5-13, Haus C, 81377 Munich, Germany Email: klaus.wanner@cup.uni-muenchen.de

› Author Affiliations

Abstract

All articles of this category

Abstract

A variety of 3,4-disubstituted pyridine derivatives with a tert-butyl group in the 4-position were synthesized in a transition-metal-free, two-step reaction sequence from 3-substituted pyridine precursors. Highly regioselective addition of t-Bu₂Mg to TIPS-activated pyridines and an efficient microwave-assisted aromatization with sulfur as oxidant afforded the desired 3,4-disubstituted pyridine derivatives in moderate to excellent yields. The method is compatible with many functional groups such as ester, amide, halide, nitrile or alkyne groups present in the 3-position.

Key words

3,4-disubstituted pyridines - N-activation - heterocycles - diorganomagnesium - nucleophilic addition - microwave

Full Text

References

References
1 Henry GD. Tetrahedron 2004; 60: 6043
2 Baumann M. Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265
3 Isambert N. Lavilla R. Chem. Eur. J. 2008; 14: 8444
4 Doherty EM. Fotsch C. Bo Y. Chakrabarti P. Chen N. Gavva N. Han N. Kelly MG. Kincaid J. Klionsky L. Liu Q. Ognyanov VI. Tamir R. Wang X. Zhu J. Norman MH. Treanor JJ. S. J. Med. Chem. 2005; 48: 71
5 Hopkins BT. Ma B. Chan TR. Kumaravel G. Miao H. Bertolotti-Ciarlet A. Otipoby K. PCT Int. Appl WO 2015/089327, 2015

6a Eatherthon AJ. Giblin GM. P. Jandu KS. Mitchell WL. Naylor A. Palombi G. Rawlings DA. Slingsby BP. Whittington AR. PCT Int. Appl WO 2004/029026, 2004
6b Price EM. Docx CJ. Rice H. Fairhall SJ. Poole SJ. C. Bird M. Whiley L. Flint DP. Green AC. Timperley CM. Tattersall JE. H. Toxicol. Lett. 2016; 244: 154

7 Bierer D. McClure A. Fu W. Achebe F. Ladouceur GH. Burke MJ. Bi C. Hart B. Dumas J. Sibley R. Scott WJ. Johnson J. Asgari D. PCT Int. Appl WO 03/027085, 2003

8a Doebelin C. Wagner P. Bertin I. Simonin F. Schmitt M. Bihel F. Bourguignon J.-J. RSC Adv. 2013; 3: 10296
8b Dias Pires MJ. Poeira DL. Marques MB. B. Eur. J. Org. Chem. 2015; 7197
8c Tamao K. Komada S. Nakajima I. Kumada M. Tetrahedron 1982; 38: 3347
8d Hintermann L. Xiao L. Labonne A. Angew. Chem. Int. Ed. 2008; 47: 8246
8e Piller FM. Appukkuttan P. Gavryushin A. Helm M. Knochel P. Angew. Chem. Int. Ed. 2008; 47: 6802

9 Chen X. Goodhue CE. Yu J.-Q. J. Am. Chem. Soc. 2006; 128: 12634

10a Vila C. Giannerini M. Hornillos V. Fananas-Mastral M. Feringa BL. Chem. Sci. 2014; 5: 1361
10b Joshi-Pangu A. Wang C.-Y. Biscoe M. J. Am. Chem. Soc. 2011; 133: 8478

For more information about addition of organometallic nucleophiles on N-acylpyridinium ions, see:

11a Lavilla R. J. Chem. Soc., Perkin Trans. 1 2002; 1141
11b Bull JA. Mousseau JJ. Pelletier G. Charette AB. Chem. Rev. 2012; 112: 2642
11c Lyle RE. Marshall JL. Comins DL. Tetrahedron Lett. 1977; 1015
11d Lyle RE. Comins DL. J. Org. Chem. 1976; 41: 3250
11e Yamaguchi R. Nakazono Y. Kawanisi M. Tetrahedron Lett. 1983; 24: 1801
11f Yamaguchi R. Nakazono Y. Matsuki T. Hata E. Kawanisi M. Bull. Chem. Soc. Jpn. 1987; 60: 215
11g Yamaguchi R. Moriyasu M. Yoshioka M. Kawanisi M. J. Org. Chem. 1988; 53: 3507
11h Piers E. Soucy M. Can. J. Chem. 1974; 52: 3563
11i Chia W.-L. Shiao M.-J. Tetrahedron Lett. 1991; 32: 2033
11j Beveridge RE. Black DA. Arndtsen BA. Eur. J. Org. Chem. 2010; 3650
11k Comins DL. O’Connor S. Tetrahedron Lett. 1987; 28: 1843
11l Shiao M.-J. Chia W.-L. Peng C.-J. Shen C.-C. J. Org. Chem. 1993; 58: 3162
11m Wang X. Kauppi AM. Olsson R. Almqvist F. Eur. J. Org. Chem. 2003; 4586
11n Comins DL. King LS. Smith ED. Février FC. Org. Lett. 2005; 7: 5059
11o Fraenkel G. Cooper JW. Fink CM. Angew. Chem., Int. Ed. Engl. 1970; 9: 523
11p Comins DL. Abdullah AH. J. Org. Chem. 1982; 47: 4135

12 Wallace DJ. Gibb DA. Cottrell FI. Kennedy DJ. Brands KM. J. Dolling UH. Synthesis 2001; 1784
13 Chen Q. du Jourdin XM. Knochel P. J. Am. Chem. Soc. 2013; 135: 4958
14 Panda S. Coffin A. Nguyen QN. Tantillo DJ. Ready JM. Angew. Chem. Int. Ed. 2016; 55: 2205
15 Braeckow J. Wanner KT. Tetrahedron 2006; 62: 2395
16 Sperger CA. Wanner KT. Tetrahedron 2009; 65: 5824
17 Claridge TD. W. Davies SG. Polywka ME. C. Roberts PM. Russell AJ. Savory ED. Smith AD. Org. Lett. 2008; 10: 5433
18 Wallace DL. Gibb AD. Cottrell IF. Kennedy DJ. Brands KM. J. Dolling UH. Synthesis 2001; 1784
19 Bagley MC. Lubinu MC. Synthesis 2006; 1283
20 Comins DL. Mantlo NB. J. Org. Chem. 1985; 50: 4410
21 Pabel J. Dissertation. LMU München; Germany: 2001: 99
22 Shiao M.-J. Chia W.-L. Peng C.-J. Shen C.-C. J. Org. Chem. 1993; 58: 3162
23 Comins DL. King LS. Smith ED. Février FC. Org. Lett. 2005; 7: 5059
24 Bowman ER. McKennis HJr. Martin BR. Synth. Commun. 1982; 12: 871
25 Sperger C. Dissertation. LMU München; Germany: 2007: 73
26 Bleicher LS. Cosford ND. P. J. Org. Chem. 1999; 64: 5299
27 Perrin DD. Armarego WL. F. Purification of Laboratory Chemicals . Pergamon; New York: 1988
28 Hünig S. Kreitmeier P. Märkl G. Sauer J. Arbeitsmethoden in der organischen Chemie . Lehmanns; Berlin: 2006
29 Wakefield BJ. Organomagnesium Methods in Organic Synthesis . Academic; New York: 1995
30 Yong KH. Taylor NJ. Chong JM. Org. Lett. 2002; 4: 3553

Supplementary Material

Supporting Information