A n A p p r o a c h t o P y r a z o l o p y r i d i n e s v i a a n I n t r a m o l e c u l a r R a d i c a l P a t h w a y Abstract: Intramolecular radical arylation, under thermal conditions, to a p-deficient pyridinium, linked to a p-excessive 2-azinyliminopyridine moiety is described. The method allows a new entry to pyrazolo[1,5-a]pyridine nucleus.The generation and subsequent reactions of aryl radicals, derived from aryl halides using tri-n-butyltin hydride (Bu 3 SnH) and azobisisobutyronitrile (AIBN) is now well documented, and several syntheses, based on aryl radical cyclisations have been reported. 1 Few examples of heteroaryl radicals are known, and presumably they would behave similarly to aryl radicals, since the lone electron would be in an orbital orthogonal to the aromatic p-system and hence, its nature (p-excessive or p-deficient) should have little or no effect on the reactivity of such radicals. 2 Particular attention has been devoted to pyridyl radicals; both Snieckus 3 and Nadin 4 have reported pyridyl radical cyclisations. Harrowven 5 has published some papers, which include pyridyl radical cyclisations and aryl radical cyclisations onto pyridines. Jones 6 has disclosed the use of radicals derived from 3-bromopyridine and the extension of this chemistry to pyridinium radicals. 7 However, to the best of our knowledge, pyrazinyl radical cyclisations have not been reported before.On the other hand, alkylation of heteroaromatic bases via a radical pathway is an useful synthetic method with a broad potential. Radical alkylations onto heteroaromatic systems, under oxidative conditions, were initially studied by Minisci's group, 8 but more recently, Minisci and coworkers 9 and Togo and co-workers 10 have reported intermolecular radical alkylations onto heteroaromatic substrates by alkyl halides, using tris(trimethylsilyl)silane (TTMSS) as mediator of the radical process. These authors have shown that the heterocyclic ring needs to bear a positive charge for successful attack by the nucleophilic carbon radicals.The first example of intramolecular radical addition to quaternized pyridinium salts was described by Murphy and co-workers 11 who exploited the non oxidative chemistry of Bu 3 SnH. Although arylations of aromatic and heteroaromatic compounds, via an ipso substitution radical mechanism are known, 12 to our knowledge, only one method of arylation of quaternized heteroaryl substrates has been published. In this case, a pyridinium radical was added onto another aromatic nucleus, with subsequent rearomatisation of the aryl ring. 7 Scheme 1In the course of our studies on the reactivity of heteroarylstabilized cycloimonium ylides [i.e. pyridinium N-(2¢-azinyl)aminides 1, (Scheme 1)], 13 we attempted the intramolecular arylation of ylide 1, through the radical 2. We expected to obtain the bipyridine 3, by a reaction pathway involving a 5-exo-trig cyclisation, and then, rupture of N-N bond, as previously described. 13c To our surprise, product 3 was not detected, and only reduction compounds 4 and cy...

Abstract-Tris(trimethylsilyl)silane (TTMSS) and azabisisobutyronitrile (AIBN) promoted the intermolecular arylation of aryl and heteroaryl bromides onto aromatic solvents under thermal conditions via a radical pathway. q

The synthesis of dipyridopyrazole and pyridopyrazolopyrazine derivatives--both of which incorporate a 3-aryl moiety--can be achieved in moderate yields by intramolecular radical arylation of pyridinium N-aminides using tris(trimethylsilyl)silane and azobisisobutyronitrile. Improved results were obtained on using Pd direct arylation in conjunction with microwave irradiation. A preliminary study into the fluorescent properties of the target compounds is also reported.

Abstract-Tris(trimethylsilyl)silane (TTMSS) and azobisisobutironitrile (AIBN) promote the intramolecular heteroarylation of arenesulfonamides with pyridyl radicals under thermal conditions. The arenesulfonamides are easily prepared from pyridinium N-2 0 -pyridylaminide. The heteroarylation process involves pyridyl radical cyclization and ipso substitution. q

Abstract-The synthesis of annulated 2-aminopyridines by intramolecular radical pyridylation of the appropriate substrates, obtained from pyridinium N-2 0 -pyridylaminide, can be performed using TTMSS and AIBN. Ó 2006 Elsevier Ltd. All rights reserved.Substituted 2-aminopyridines and their annulated derivatives constitute an important class of organic compounds, widely represented in the molecules of pharmacological interest, in both therapeutic 1 and recognition agent fields. 2 In recent years, particular attention has been devoted to the development of synthetic methods that provide an entry into this class of compounds. Thus, 7-azaindoline I and 1,2,3,4-tetrahydro [1,8]naphthyridine II ( Fig. 1) derivatives which have been described as therapeutically important compounds, 3 remain a somewhat inaccessible class of derivatives. Simple 7-azaindoline structures have been prepared by the sluggish hydrogenations of azaindoles. 4 More recently, a free radical-mediated aryl-amination has been reported, whereby an aryl radical adds to the nitrogen of an azomethine bond to supply the required compound. 5 Alternatively, Wijtmans et al. 6 have described a new sequence based on Van der Plas's reaction. 1,2,3,4-Tetrahydro [1,8]naphthyridines are usually prepared by the selective catalytic hydrogenations of the corresponding precursors, either prepared by Skraup, 7 Friedländer 1d,e,8 or Friedel-Crafts 6 approaches. Moreover, Palukcki and co-workers. 9 reported the preparation of 1,2,3,4-tetrahydro [1,8]naphthyridine fragments, using two different methods, one of which relied, again, on variations of Friedländer reaction, 9a the other being based in a double Suzuki-Miyaura reaction and Chichibabin cyclization. 9b,c Therefore, in addition to more specific methodologies, a universal synthetic method, which allows entry into these annulated systems would be highly desirable. Accordingly, Davies et al. 10 recently described how the ortho alkylation of Boc-protected 2-aminopyridines with a,xdihaloalkanes, followed by in situ cyclization, results in the corresponding annulated pyridine derivatives in good yields.On the other hand, Zard and coworkers 11 reported the preparation of a series of compounds containing a 2-aminopyridine nucleus fused to a saturated ring (7-azaoxindole, 7-azaindoline, tetrahydro[1,8]naphthyridine and tetrahydro-5H-pyrido[2,3-b]azepin-8-one), starting from various 2,6-dichloropyridines, through a radical xanthate-mediated cyclization. Although this approach is more general and flexible than previous traditional routes, initial studies starting from the suitable 2-aminopyridines produced unwanted reactions on the cyclic nitrogen, as a result of its higher nucleophilicity. In this context, during the past few years our research group has been interested in the chemistry of pyridinium N-2 0 -pyridylaminide 1a (Scheme 1). Compound 1a is a stable heterocyclic betaine in which the exocyclic nitrogen anion is stabilized by the presence of a pyridinium moiety. 12 Moreover, the cyclic nitrogen is partially block...