Direct Uncatalyzed Amination of 2-Chloropyridine Using a Flow Reactor

Abstract

Chloropyridines are efficiently converted into 2-amino­pyridines by uncatalyzed nucleophilic aromatic substitution (S_NAr) in NMP using a continuous-flow reactor. A variety of secondary amines undergo S_NAr with both electron-rich and electron-deficient 2-chloropyridines to afford 2-aminopyridines in good to excellent yield. The flow reactor, which provides a short reaction time and high temperatures up to 300 °C, can overcome the activation barrier for reactions with unactivated substrates. Short reaction times result in fewer side products and can afford milligram to multigram ­quantities of product using continuous flow.

amination - nucleophilic aromatic substitution - flow synthesis - microflow reactor

References and Notes

For examples of 2-aminopyridine structural motifs in pharmaceuticals, see:

<A NAME="RS01807ST-1A">1a</A> Landriscina M. Prudovsky I. Carreira CM. Soldi R. Tarantini F. Maciag T. J. Biol. Chem.  2000,  275:  32753 

<A NAME="RS01807ST-1B">1b</A> Rabasseda X. Hopkins SJ. Drugs Today  1994,  30:  557 

<A NAME="RS01807ST-1C">1c</A> Heykants J. Pardoel L. Janssen PA. Arzneim. Forsch.  1971,  21:  982 

<A NAME="RS01807ST-1D">1d</A> Huttrer CP. Djerassi C. Beears WL. Mayer RL. Scholz CR. J. Am. Chem. Soc.  1946,  68:  1999 

<A NAME="RS01807ST-2A">2a</A> Deeken S. Proch S. Casini E. Braun HF. Mechtler C. Marschner C. Motz G. Kempe R. Inorg. Chem.  2006,  45:  1871 

<A NAME="RS01807ST-2B">2b</A> Kempe R. Brenner S. Perdita A. Organometallics  1996,  15:  1071 

<A NAME="RS01807ST-3">3</A> Araki K. Mutai T. Shigemitsu Y. Yamada M. Nakajima T. Kuroda S. Shimao I. J. Chem. Soc., Perkin Trans. 2  1996,  613 

<A NAME="RS01807ST-4">4</A> Henrie RN. inventors; WO  8702665.  ; Chem. Abstr. 1988, 109, 230807

<A NAME="RS01807ST-5">5</A> Hashimoto M. Izuchi N. Sakata K. Heterocycles  1988,  27:  319 

<A NAME="RS01807ST-6">6</A> Grube H. Suhr H. Chem. Ber.  1969,  102:  1570 

<A NAME="RS01807ST-7">7</A> Narayan S. Seelhammer T. Gawley RE. Tetrahedron Lett.  2004,  45:  757 

<A NAME="RS01807ST-8A">8a</A> Hartwig JF. Synlett  2006,  1283 

<A NAME="RS01807ST-8B">8b</A> Muci AR. Buchwald SL. Top. Curr. Chem.  2002,  219:  131 

<A NAME="RS01807ST-8C">8c</A> Wolfe JP. Wagaw S. Marcoux J.-F. Buchwald SL. Acc. Chem. Res.  1998,  31:  805 

<A NAME="RS01807ST-9">9</A> Desmarets C. Schneider R. Fort Y. J. Org. Chem.  2002,  67:  3029 

<A NAME="RS01807ST-10">10</A> For an example of a Suzuki-type coupling in the absence of transition-metal catalyst, see: Leadbeater NE. Marco M. Angew. Chem. Int. Ed.  2003,  42:  1407 

<A NAME="RS01807ST-11A">11a</A> Comer and Organ, J. Am. Chem. Soc.  2005,  127:  8160 

<A NAME="RS01807ST-11B">11b</A> Schwalbe T. Kadzimirsz D. Jas G. QSAR Comb. Sci.  2005,  24:  758 

See leading examples and references therein:

<A NAME="RS01807ST-12A">12a</A> Tanaka K. Motomatsu S. Koyama K. Tanaka S. Fukase K. Org. Lett.  2007,  9:  299 

<A NAME="RS01807ST-12B">12b</A> Wiles C. Watts P. Haswell SJ. Chem. Commun.  2007,  966 

<A NAME="RS01807ST-12C">12c</A> Baxendale I. Deeley J. Griffiths-Jones CM. Ley S. Saaby S. Tranmer GK. Chem. Commun.  2006,  2566 

<A NAME="RS01807ST-12D">12d</A> Shore G. Morin S. Organ MG. Angew. Chem. Int. Ed.  2006,  45:  2761 

<A NAME="RS01807ST-12E">12e</A> Kawaguchi T. Miyata H. Ataka K. Mai K. Yoshida J. Angew. Chem. Int. Ed.  2005,  44:  2413 

<A NAME="RS01807ST-13">13</A> Jähnisch K. Hessel V. Löwe H. Baerns M. Angew. Chem. Int. Ed.  2004,  43:  406 

<A NAME="RS01807ST-14">14</A>

In addition, the reactions we wished to investigate required pressures and temperatures beyond the range of commercially available chip-based devices.