Palladium-catalysed reactions of 8-hydroxy- and 8-benzyloxy-5,7- diiodoquinoline under aminocarbonylation conditions

Various 5-carboxamido-7-iodo-8-benzyloxyquinolines were synthesised via selective aminocarbonylation of 5,7-diiodo-8-benzyloxyquinoline in the presence of ‘in situ’ generated palladium(0) catalysts. Under similar conditions (50C, 80 bar CO), 5,7-bis(N-tert-butylglyoxylamido)8-hydroxyquinoline was obtained using tert-butylamine as N-nucleophile. The unprotected 5,7-diiodo8-hydroxyquinoline underwent dehydroiodination resulting in 8-hydroxyquinoline as the major product. Key-words: Iodo-aromatics, 8-hydroxyquinoline, aminocarbonylation, carbon monoxide, palladium M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Introduction The introduction of a carboxamide moiety into a skeleton of practical importance, via simple homogeneous catalytic methods, is of high interest. 1,2 There are a number of applications both for the synthesis of simple building blocks and for the functionalization of biologically important skeletons. 3,4 The aminocarbonylation of aryland enol-triflates leading to aryl and unsaturated carboxamides, respectively, has been carried out. 5 Recently, iodoarenes and iodoalkenes, the corresponding synthetic analogues of aryl triflates, have found important applications as substrates in carbonylation reactions. Palladium-catalysed cross-coupling reactions of iodoquinoline derivatives with alkynes have been carried out in order to synthesise tri-substituted pyrroloquinolines 6 and 4-substituted quinolines. 7 Recently, we published carbonylation reactions of 5-chloro-7-iodoquinoline derivatives. 8 The improvement of alternative synthetic methods for alkoxyquinoline derivatives is of great interest due to their potential biological activity as PDE4 inhibitors 9 as well as for the preparation of electroluminescent materials for organic LEDs. 10 As for our parent model compound, 5,7-diiodoquinoline-8-ol, it was used as a ligand for the spectrophotometric determination of yttrium 11 and erbium 12 in a ternary ion-association complex. 3,6Diiodoquinoline served as a coupling partner to 1,4-diethynyl-benzene derivative in palladium-catalysed reaction providing a novel copolymer. 13 Accordingly, due to the importance of diiodoquinolines, the facile, selective, high-yielding palladiumcatalysed aminocarbonylation of 5,7-diiodo-8-benzyloxyquinoline with various N-nucleophiles, as well as the dehydroiodination of its 8-hydroxy analogue are described in the present paper. Results and Discussion Aminocarbonylation of 5,7-diiodo-8-benzyloxyquinoline (1) 5,7-Diiodo-8-benzyloxyquinoline (1), prepared from 5,7-iodo-8-hydroxyquinoline (4) with benzyl bromide, 14 was reacted with various amines and carbon monoxide in the presence of ‘in situ’ palladium(0) catalysts (Scheme 1). The formation of highly active, low-ligated palladium(0) complexes from the palladium(II) precursors, such as Pd(OAc)2 used in our systems, was proved by cyclic voltammetry and NMR measurements. 15,16 The aminocarbonylation under high pressure (80 bar) was unexpectedly regioselective at position-5 resulting in 2a and 2b by using secondary amines such as morpholine (a) and piperidine (b), respectively (Table 1, entry 1 and 2). Carrying out the reaction under the same carbon monoxide pressure even 5-(N-phenylcarboxamide) derivative (2c) could be isolated by using aniline (entry 3). Arylamines of low basicity have shown low reactivity in aminocarbonylation of both iodoarene and iodoalkene type substrates. 17,18 When the reaction was carried out by using one of the most reactive primary amines, tert-butylamine (d), much lower carbon monoxide pressure proved to be sufficient to yield the same type of carboxamide, 2d (entry 4). M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT It is worth noting that the aminocarbonylation proceeds with high regioselectivity leading to 5carboxamido derivatives, i.e., the 7-iodoaryl functionality remained untouched. The characterization of the products were carried out by detailed NMR measurements including 2D NMR techniques (HMBC, HSQC). Even the practically unchanged chemical shift of the sharp singlet in H NMR, assigned to the methylene protons (at ca. 5.5 ppm), suggests that carbonylation occurred in position-5 in case of the monocarbonylated products 4a-d. When carbonylation took place in position-7 as well (4d’ and 4d”) the above signal has a downfield shift of 0.1 and 0.2 ppm, respectively. The expected 5,7-dicarboxamide can be obtained with 40 % isolated yield only with tert-butylamine (d) as N-nucleophile under optimized reaction conditions (58 h, 20 bar CO) (entry 5). Under these reaction conditions the corresponding carboxamide-ketocarboxamide derivative (2d’’) resulting from double carbonyl insertion in position-5 was isolated as minor product (8%). It is worth noting that the aminocarbonylation of simple iodoarenes such as iodobenzene or 2-iodo-naphthalene provided a mixture of the corresponding carboxamides and 2-ketocarboxamides with the prevailing formation of the latter product under similar reaction conditions. 19 However, the use of tert-butylamine (d) for aminocarbonylation under high carbon monoxide pressure resulted in the formation of 5,7-bis(tert-butyl-glyoxylamido)-8-hydroxyquinoline (3) as a major product (entry 6). The expected 5,7-bis(tert-butyl-glyoxylamido)-8-benzyloxyquinoline (3’) was formed as a minor product only (<6%) and was detected by NMR spectroscopy as a minor component of a mixture formed with 3. The most interesting feature of the latter reaction is the almost complete deprotection of the 8-benzyloxy functionality while double carbonylation occurred at both iodoarene functionalities. R' R'' Pd(OAc)2 / PPh3 N I I b -(CH2)5N I O NR'R"