Functionalization of the pyridazin-3(2H)-one ring via palladium-catalysed aminocarbonylation Attila Tak  acs a , Andrea Czompa b ,G  abor Krajsovszky b ,P  eter M  atyus b ,L  aszl  o Koll  ar a, * a Department of Inorganic Chemistry, University of P ecs and J anos Szent agothai Science Center, H-7624 P ecs, PO Box 266, Hungary b Department of Organic Chemistry, Semmelweis University, H} ogyes E. u. 7., H-1092 Budapest, Hungary article info Article history: Received 1 April 2012 Received in revised form 15 June 2012 Accepted 10 July 2012 Available online 17 July 2012 Keywords: Aminocarbonylation Carbon monoxide Palladium Pyridazin-3(2H)-one Amino acid abstract 5-Iodo- and 4,5-dibromo-2-methylpyridazin-3(2H)-ones were aminocarbonylated in the presence of various amines including amino acid methyl esters in a palladium-catalysed reaction. The iodo derivative afforded the corresponding amides with complete conversion and high isolated yields. The dibromo derivative has shown unexpectedly high reactivity in this reaction, resulting in 4,5-dicarboxamides using primary amines as N-nucleophiles. Monoaminocarbonylation has not been observed, i.e., neither 4-bromo-5-carboxamide nor 4-carboxamido-5-bromo derivatives have been formed. However, the use of secondary amines such as piperidine and morpholine resulted in the formations of mixtures of amino- substituted bromopyridazinones. That is, no carbon monoxide insertion took place in these cases. Some mechanistic details of the formation of aminocarbonylation and amination products are also discussed. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Pyridazin-3(2H)-ones and their fused ring derivatives have gained much attention recently due to their application as syn- thetic auxiliaries. 1 Their increasing interest is also due to their pharmacological importance. Pyridazin-3(2H)-one derivatives have been tested as selective histamine receptor inverse antagonists, 2 phosphodiesterase inhibitors (PDE3, PDE4), 3,4 agonists for formyl peptide receptors 5 and some compounds show excellent a-adre- noceptor blocking properties, one of which has entered Phase II clinical studies as a potential drug candidate for the treatment of benign prostatic hyperplasia. Among the wide variety of synthetic reactions the application of organometallic reagents such as Grignard-reagents of different nucleophilicity, 6,7 and especially, that of homogeneous catalysis play an important role in the functionalization of pyridazinones. As recent examples, the application of SuzukieMiyaura reaction for synthesis of 4(5)-mono and 4,5-diarylated pyridazin-3(2H)-ones 8 and that of the 4,6-diaryl/heteroarylpyridazinones 9 and 5,6- diarylpyridazinones 10 should be mentioned. A Suzuki coupling was used as a key reaction in a multistep synthesis of azecine ring systems. 11 An intramolecular Heck reaction proved to be very effi- cient for the synthesis of 5H-pyridazino[4,5-b]indoles and its benzofurane analogues. 12 Recently, a facile synthetic procedure for the synthesis of iodo- substituted pyridazin-3(2H)-ones from the corresponding chloro derivatives was published. 13 As a part of our continuing interest in the systematic investigation of palladium-catalysed carbonylation reactions, the aminocarbonylation of iodo- and bromopyridazin- 3(2H)-ones to give the corresponding carboxamides is reported, which was expected to open a direct route to otherwise not easily accessible oxopyridazinecarboxamides. 2. Results and discussion 2.1. Aminocarbonylation of 5-iodo-2-methylpyridazin-3(2H)- one (1) leading to 5-carboxamido-2-methylpyridazin-3(2H)- ones (2) 5-Iodo-2-methylpyridazin-3(2H)-one (1) was reacted with N- nucleophiles such as tert-butylamine (a) and piperidine (b) under atmospheric carbon monoxide pressure in DMF in the presence palladium(0) catalysts generated in situ from palladium(II) acetate catalytic precursor (Scheme 1). It is worth noting that although the reduction of Pd(II) precursors to Pd(0) species has been proved in the presence of various phosphines while they have been oxidised to P(V) derivatives (monophosphine oxides or diphosphine oxide/ hemioxide), 14e16 the mechanism of reduction under reductive conditions (carbon monoxide, primary or secondary amines) is still not known. * Corresponding author. E-mail address: kollar@ttk.pte.hu (L. Koll ar). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.07.030 Tetrahedron 68 (2012) 7855e7860