Abstract
The synthesis of a novel class of 6-amino-5-hydroxypyridazin-3(2H )-ones (3-oxo-2,3-dihydropyridazines) is described. These compounds also contain an ethoxycarbonyl moiety at the 4-position of the pyridazinone ring. They are prepared in good to moderate yields (30-72%) by the condensation of disubstituted amines with (alkylhydrazono)- or (arylhydrazono)(chloro)acetates followed by subsequent acylation with ethyl malonyl chloride and Dieckmann cyclization. An initial assessment of the scope and limitations of the new methodology is described along with the novel synthesis of several (alkylhydrazono)(chloro)acetate substrates utilized in the pyridazinone preparations.
Key words
pyridazin-3(2H )-ones - Dieckmann cyclization - hydrazones - amino- and chloro(hydrazono)acetates - heterocycles
References
1 Corsano S.
Strappaghetti G.
Barbaro R.
Giannaccini G.
Betti L.
Lucacchini A.
Bioorg. Med. Chem.
1999,
7:
933
2 Corsano S.
Strappaghetti G.
Leonardi A.
Rhazri K.
Barbaro R.
Eur. J. Med. Chem.
1997,
32:
339
3 Corsano S.
Vezza R.
Scapicchi R.
Foresi S.
Strappaghetti G.
Nenci GG.
Gresele P.
Eur. J. Med. Chem.
1995,
30:
627
4 Park J.-W.
Kim J.-J.
Kim H.-K.
Kang Y.-J.
Lee WS.
Yoon Y.-J.
J. Heterocycl. Chem.
2000,
37:
1603
5 Li L.-S.
Zhou Y.
Zhao J.
Dragovich PS.
Stankovic N.
Bertolini TM.
Murphy DE.
Sun Z.
Tran CV.
Ayida BK.
Ruebsam F.
Webber SE.
Synthesis
2007,
3301
6 Murphy DE.
Dragovich PS.
Ayida BK.
Bertolini BM.
Li L.-S.
Ruebsam F.
Stankovic NS.
Sun Z.
Zhao J.
Zhou Y.
Tetrahedron Lett.
2008,
49:
811
7 Frohberg P.
Kupfer C.
Stenger P.
Baumeister U.
Nuhn P.
Arch. Pharm. (Weinheim, Ger.)
1995,
328:
505
8 Phillips RR.
Org. React.
1959,
10:
143
9 Catarzi D.
Colotta V.
Varano F.
Lenzi O.
Filacchioni G.
Trincavelli L.
Martini C.
Montopoli C.
Moro S.
J. Med. Chem.
2005,
48:
7932
10a Conti P.
Grazioso G.
di Ventimiglia SJ.
Pinto A.
Roda G.
Madsen U.
Bräuner-Osborne H.
Nielsen B.
Costagli C.
Galli A.
Chem. Biodiversity
2005,
2:
748
10b Bach KK.
El-Seedi HR.
Jensen HM.
Nielsen HB.
Thomsen I.
Torssell KBG.
Tetrahedron
1994,
50:
7543
11 Unless otherwise noted, all hydrazones described in this work were isolated and characterized as single isomers. No attempt was made to assign hydrazone stereochemistry (E or Z ) or to rigorously identify any minor amounts of alternate isomers that may have been formed during a given synthetic transformation.
12 Reversing the order of the chlorination and Boc-deprotection steps also afforded 3a , but in significantly lower yield.
13 The major amino(hydrazono)acetate acylation products described in this work are inferred to be those depicted in Scheme
[1 5 ) by their successful conversion into 6-aminopyridazin-3(2H )-ones in reasonable yields (Scheme
[1 6 ). Significant amounts of alternate acylation products were not detected by LCMS analysis of the reaction mixtures and no other attempts were made to identify and/or quantify such entities.
14 The reaction was performed in an open flask. We have observed that the chlorination rate and yield can vary with the source of the N -chlorosuccinimide employed in the reaction.
