A One-Pot Method for the Synthesis of Naphthyridines via Modified Friedländer Reaction

Abstract

A one-pot method for the preparation of 1,8-naphthyridine derivatives is reported. The method involves the dimetalation of an appropriate N-2-pyridylpivalamide or tert-butylcarbamate ­followed by reaction with a β-dimethylamino or β-alkoxyacrolein derivative. This method is also applicable to 1,6-naphthyridines.

pyridines - directed ortho-metalation - cyclization - naphthyridines

References and Notes

<A NAME="RS10305ST-1">1</A> Litvinov VP. Russ. Chem. Rev.  2004,  73:  637 

<A NAME="RS10305ST-2">2</A> Lowe PA. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Pergamon Press; New York: 1984.  p.581 

<A NAME="RS10305ST-3">3</A>For example, preparation of 2-methyl-1,8-naphthyridine from 2-amino-6-methylpyridine via EMME synthesis required five steps and afforded only 22% overall yield, see:

<A NAME="RS10305ST-3">3</A> Brown EV. J. Org. Chem.  1965,  30:  1607 

<A NAME="RS10305ST-4A">4a</A> Paudler WW. Kress TJ. J. Org. Chem.  1966,  31:  3055 

<A NAME="RS10305ST-4B">4b</A> Paudler WW. Kress TJ. J. Org. Chem.  1967,  32:  832 

<A NAME="RS10305ST-4C">4c</A> Vu C. Walker D. Wells J. Fox S. J. Heterocycl. Chem.  2002,  39:  829 

<A NAME="RS10305ST-5A">5a</A> Hawes EM. Wibberly DG. J. Chem. Soc. C  1966,  315 

<A NAME="RS10305ST-5B">5b</A> Hawes EM. Gorecki DKJ. J. Heterocycl. Chem.  1972,  9:  703 

<A NAME="RS10305ST-5C">5c</A> Hawes EM. Gorecki DKJ. Johnson DD. J. Med. Chem.  1973,  16:  849 

<A NAME="RS10305ST-5D">5d</A> Hawes EM. Gorecki DKJ. J. Heterocycl. Chem.  1974,  11:  151 

For more recent applications of the Friedländer methodology to the synthesis of naphthyridines see:

<A NAME="RS10305ST-6A">6a</A> Estel L. Linard F. Marsais F. Godard A. Queguiner G. J. Heterocycl. Chem.  1989,  26:  105 

<A NAME="RS10305ST-6B">6b</A> Hsiao Y. Rivera NR. Yasuda N. Hughes D. Reider PJ. Org. Lett.  2001,  3:  1101 

<A NAME="RS10305ST-6C">6c</A> Dormer PG. Eng KK. Farr RN. Humphrey GR. McWilliams JC. Reider PJ. Sager JW. Volante RP. J. Org. Chem.  2003,  68:  467 

Yields are generally below 60%, for example see:

<A NAME="RS10305ST-7A">7a</A> Turner JA. J. Org. Chem.  1983,  48:  3401 

<A NAME="RS10305ST-7B">7b</A> Tamura Y. Masanobu F. Ling-Ching C. Inoue M. Kita Y. J. Org. Chem.  1981,  46:  3564 

<A NAME="RS10305ST-7C">7c</A> Eldrup AB. Christensen C. Haaima G. Nielsen PE. J. Am. Chem. Soc.  2002,  124:  3254 

<A NAME="RS10305ST-7D">7d</A> Takayama K. Iwata M. Hisamichi H. Okamoto Y. Aoki M. Niva A. Chem. Pharm. Bull.  2002,  50:  1050 

<A NAME="RS10305ST-7E">7e</A> The only paper reporting higher yields is: Turner JA. J. Org. Chem.  1990,  55:  4744 

<A NAME="RS10305ST-8A">8a</A> Hamada Y. Takeuchi I. Hirota M. Chem. Pharm. Bull.  1971,  19:  1751 

<A NAME="RS10305ST-8B">8b</A> Hamada Y. Takeuchi I. Chem. Pharm. Bull.  1971,  19:  1857 

<A NAME="RS10305ST-9">9</A>

For example, Hamada^8b reported preparation of 4-methyl-1,8-naphthyridine in 38% yield. We repeatedly obtained 10-17% yield following his procedure, which is consistent with the yield reported by Paudler and Kress (17%).^4b

<A NAME="RS10305ST-10">10</A> Cho I.-S. Gong L. Muchowski JM. J. Org. Chem.  1991,  56:  7288 

<A NAME="RS10305ST-11A">11a</A> Metalation conditions for multiple pyridines are collected in the table on p 234-237 in the excellent review by: Rewcastle GW. Katritzky AR. In Advances in Heterocyclic Chemistry   Vol. 56:  Katritzky AR. Academic Press; New York: 1993.  p.157 

For further examples, see:

<A NAME="RS10305ST-11B">11b</A> Queguiner G. Marsais F. Snieckus V. Epsztajn J. In Advances in Heterocyclic Chemistry   Vol. 52:  Katritzky AR. Academic Press; New York: 1991.  p.187 

<A NAME="RS10305ST-11C">11c</A> Mongin F. Queguiner G. Tetrahedron  2001,  57:  4060 

<A NAME="RS10305ST-12A">12a</A> Savage SA. Smith AP. Fraser CL. J. Org. Chem.  1998,  63:  10048 

<A NAME="RS10305ST-12B">12b</A> Smith AP. Corbin PS. Fraser CL. Tetrahedron Lett.  2000,  41:  2787 

<A NAME="RS10305ST-12C">12c</A> Fraser CL. Anastasi NR. Lamba JJS. J. Org. Chem.  1997,  62:  9314 

<A NAME="RS10305ST-13">13</A> Paudler WW. Kress TJ. J. Heterocycl. Chem.  1967,  4:  284 

<A NAME="RS10305ST-14">14</A> Pokorny DJ. Paudler WW. J. Org. Chem.  1972,  37:  3101 

<A NAME="RS10305ST-15">15</A> Phuan P.-W. Kozlowski MC. Tetrahedron Lett.  2001,  42:  3963