Lithiation and Side-Chain Substitution of 3-Alkyl-1H-quinoxalin-2-ones

Abstract

3-Methyl-1H-quinoxalin-2-one has been doubly lithi­ated with n-butylithium at -78 °C in THF. The dilithio reagent thus obtained reacts with various electrophiles (iodomethane, iodoethane, D₂O, benzaldehyde, benzophenone, cyclohexanone) to give modified 3-substituted 1H-quinoxalin-2-ones in good yields. In the reaction of the dilithio reagent with phenyl isothiocyanate the product was a tautomer of the simple substitution product. Reaction of the dilithio reagent with iodine gives an oxidatively dimerised product instead of the 3-iodomethyl derivative. Lithiations of 3-ethyl- and 3-propyl-1H-quinoxalin-2-ones, followed by reactions with representative electrophiles (benzaldehyde, benzophenone, cyclohexanone), behaved in a similar manner to give the corresponding modified 3-substituted derivatives in good yields.

double lithiation - 1H-quinoxalin-2-ones - electrophiles - tautomerisation - oxidative dimerisation

References

<A NAME="RZ08103SS-1">1</A>

Permanent address: G. A. El-Hiti, Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt.

<A NAME="RZ08103SS-2A">2a</A> Slocum DW. Jennings CA. J. Org. Chem.  1976,  41:  3653 

<A NAME="RZ08103SS-2B">2b</A> Gschwend HW. Rodriguez HR. Org. React.  1979,  26:  1 

<A NAME="RZ08103SS-2C">2c</A> Beak P. Zajdel WJ. Reitz DB. Chem. Rev.  1984,  84:  471 

<A NAME="RZ08103SS-2D">2d</A> Führer W. Gschwend HW. J. Org. Chem.  1979,  44:  1133 

<A NAME="RZ08103SS-2E">2e</A> Snieckus V. Chem. Rev.  1990,  90:  879 

<A NAME="RZ08103SS-2F">2f</A> Anctil EJ.-G. Snieckus V. J. Organomet. Chem.  2002,  653:  150 

<A NAME="RZ08103SS-3A">3a</A> Quéguiner G. Marsais F. Snieckus V. Epsztajn J. Adv. Heterocycl. Chem.  1991,  52:  187 

<A NAME="RZ08103SS-3B">3b</A> Turck A. Plé N. Quéguiner G. Heterocycles  1994,  37:  2149 

<A NAME="RZ08103SS-3C">3c</A> El-Hiti GA. Heterocycles  2000,  53:  1839 

<A NAME="RZ08103SS-4A">4a</A> Gros P. Choppin S. Fort Y. J. Org. Chem.  2003,  68:  2243 

<A NAME="RZ08103SS-4B">4b</A> Katritzky AR. Manju K. Steel PJ. J. Org. Chem.  2003,  68:  407 

<A NAME="RZ08103SS-4C">4c</A> Toudic F. Plé N. Turck A. Quéguiner G. Tetrahedron  2002,  58:  283 

<A NAME="RZ08103SS-4D">4d</A> Rhonnstad P. Wensbo D. Tetrahedron Lett.  2002,  43:  3137 

<A NAME="RZ08103SS-4E">4e</A> Mukherjee C. De A. Synlett  2002,  325 

<A NAME="RZ08103SS-4F">4f</A> Gros P. Louërat F. Fort Y. Org. Lett.  2002,  4:  1759 

<A NAME="RZ08103SS-4G">4g</A> Cuperly D. Gros P. Fort Y. J. Org. Chem.  2002,  67:  238 

<A NAME="RZ08103SS-4H">4h</A> Gros P. Choppin S. Fort Y. J. Org. Chem.  2002,  67:  2243 

<A NAME="RZ08103SS-4I">4i</A> Gros P. Choppin S. Mathieu J. Fort Y. Eur. J. Org. Chem.  2002,  20:  3325 

<A NAME="RZ08103SS-4J">4j</A> Kondo Y. Asai M. Miura T. Uchiyama M. Sakamoto T. Org. Lett.  2001,  3:  13 

<A NAME="RZ08103SS-4K">4k</A> Choppin S. Gros P. Fort Y. Org. Lett.  2000,  2:  803 

<A NAME="RZ08103SS-4L">4l</A> Pollet P. Turck A. Plé N. Quéguiner G. J. Org. Chem.  1999,  64:  4512 

See for example:

<A NAME="RZ08103SS-5A">5a</A> Smith K. El-Hiti GA. Hamilton A. J. Chem. Soc., Perkin Trans. 1  1998,  4041 

<A NAME="RZ08103SS-5B">5b</A> Smith K. El-Hiti GA. Pritchard GJ. Hamilton A. J. Chem. Soc., Perkin Trans. 1  1999,  2299 

<A NAME="RZ08103SS-5C">5c</A> Smith K. El-Hiti GA. Shukla AP. J. Chem. Soc., Perkin Trans. 1  1999,  2305 

<A NAME="RZ08103SS-5D">5d</A> Smith K. El-Hiti GA. Hawes AC. Synlett  1999,  945 

<A NAME="RZ08103SS-6A">6a</A> Smith K. El-Hiti GA. Abdo MA. Abdel-Megeed MF. J. Chem. Soc., Perkin Trans. 1  1995,  1029 

<A NAME="RZ08103SS-6B">6b</A> Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  647 

<A NAME="RZ08103SS-6C">6c</A> Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  656 

<A NAME="RZ08103SS-6D">6d</A> Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. Collect. Czech. Chem. Commun.  1999,  64:  515 

<A NAME="RZ08103SS-6E">6e</A> Smith K. El-Hiti GA. Abdel-Megeed MF. Russ. J. Org. Chem.  2003,  39:  430 

<A NAME="RZ08103SS-7A">7a</A> Kaiser EM. Tetrahedron  1983,  39:  2055 

<A NAME="RZ08103SS-7B">7b</A> Turck A. Plé N. Tallon V. Quéguiner G. J. Heterocycl. Chem.   1993,  30:  1491 

<A NAME="RZ08103SS-7C">7c</A> Chapoulaud V. Salliot I. Plé N. Turck A. Quéguiner G. Tetrahedron  1999,  55:  5389 

<A NAME="RZ08103SS-7D">7d</A> Parra S. Laurent F. Subra G. Deleuze-Masquefa C. Benezch V. Fabreguettes J.-R. Vidal J.-P. Pocock T. Elliott K. Small R. Escale R. Michel A. Chapat J.-P. Bonnet P.-A. Eur. J. Med. Chem.  2001,  36:  255 

See for example:

<A NAME="RZ08103SS-8A">8a</A> Asano K. Asai S. Yakugaku Zasshi  1959,  79:  567 ; Chem. Abstr. 1959, 53: 21979

<A NAME="RZ08103SS-8B">8b</A> Hofmann CW. Krajeurski JJ. Kutz PJ. Traxler JT. Ristich SS. J. Agric. Food Chem.  1971,  1:  298 

<A NAME="RZ08103SS-8C">8c</A> Bucchini D. Fiszman M. Girad M. Intervirology  1974,  3:  281 

<A NAME="RZ08103SS-8D">8d</A> Spada AP, He W, and Myers MR. inventors; PCT Int. Appl. WO  3149.  ; Chem. Abstr. 2000, 133, 17477

<A NAME="RZ08103SS-8E">8e</A> Myers MR, Spada AP, Persons PE, and Maguire MP. inventors; PCT Int. Appl. WO  3150.  ; Chem. Abstr. 2000, 133, 17478

<A NAME="RZ08103SS-8F">8f</A> Myers MR, He W, and Spada AP. inventors; PCT Int. Appl. WO  3151.  ; Chem. Abstr. 2000, 133, 17479

<A NAME="RZ08103SS-9">9</A> Morrison DC. J. Am. Chem. Soc.  1954,  76:  4483 

<A NAME="RZ08103SS-10">10</A> Watson SC. Eastham JF. J. Organomet. Chem.  1967,  9:  165 

<A NAME="RZ08103SS-11">11</A> Tennant G. J. Chem. Soc. C  1966,  2285