Aryl-azoles

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

Elguero, J., Jacquier, R. and Mondon, S. (1970) NMR studies in the heterocyclic series, IV conformation of N-aryl azoles influence of sp hybridized nitrogen atoms on the deshielding of o-protons of the neighboring aromatic nucleus. Bull. Soc. Chim. Fr. 1346-1351. 

Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-ary I hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140]. 

N-Arylation. The development of palladium chemistry now allows relatively easy N-arylations of pyrroles and indoles, using aryl iodides and bromides <1998JA827, 20000L1403>. The combination of Pd(OAc)2 and DPPF catalyzes the formation of N-aryl azoles 45 in the presence of CS2CO3 or /-BuONa with electron-rich, electron-neutral, or electron-poor aryl halides (Scheme 12) <1998JA827>. The system Pd(OAc)2, SIPrnHCl, NaOH [where SIPr= 1,3-bis... 

As is the case for cross-coupling reactions, arylstannanes and aryltriaUcoxysilanes can be substituted for boronic acids in this method, but would appear to offer few advantages. A number of other, usually Cu(II)-catalysed, reagents can be used to arylate azoles and indoles, of which diaryliodonium salts are the most useful. Aryllead triacetates and triarylbismuth diacetates may find very occasional use, but A-cyclopropylation using tricyclopropylbismuth with cupric acetate is possibly more interesting. ... 

During the same year, nano-Cu20 was employed to facilitate the N-arylation of azoles and amines with arylboronic acids (Scheme 4.34). Several Af-aryl azole derivatives could be efficiently assembled at room temperature under base-free conditions (Sreedhar et al., 2008). 

Under nickel catalysis, it was foimd that both azoles (Figure 13.13) [36] and tertiary ammonium salts (Figure 13.14) [37] can serve as effective coupling partners. Carbohydrate-based azoles, as well as aryl-azole substrates, were effective coupling partners. The use of ammonium salts was restricted to aromatic systems however, the use of a common structural motif is a significant improvement to the coupling methodology. 

N-Arylation of azoles is achieved either by using arynes, activated halobenzenes (e.g. dinitro) or under Ullmann conditions. Thus benzyne reacts with imidazoles to give N-arylimidazoles (70AHC(12)103), and these compounds have also been prepared under modified Ullmann conditions. 

Electrophilic substitution occurs readily in Af-phenyl groups, e.g. 1-phenyI-pyrazoIes, -imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The aryl group is attacked preferentially when the reactions are carried out in strongly acidic media, where the azole ring is protonated. 

If the fV-aryl group is strongly activated, then it can be removed in nucleophilic substitution reactions in which the azole anion acts as leaving group. Thus l-t2,4-dinitrophenyl)pyrazole reacts with N2H4 or NaOMe. 

Abbreviations aapy, 2-acetamidopyridine Aik, alkyl AN, acetoniuile Ar, aryl Bu, butyl cod, 1,5-cyclooctadiene COE, cyclooctene COT, cyclooctatetraene Cp, cyclopentadienyl Cp , penta-methylcyclopentadienyl Cy, cyclohexyl DME, 1,2-dimethoxyethane DME, dimethylformamide DMSO, dimethyl sulfoxide dmpe, dimethylphosphinoethane dppe, diphenylphosphinoethane dppm, diphenylphosphinomethane dppp, diphenylphosphinopropane Et, ethyl Ec, feirocenyl ind, inda-zolyl Me, methyl Mes, mesitylene nb, norbomene orbicyclo[2.2.1]heptene nbd, 2,5-norbomadiene OTf, uiflate Ph, phenyl PPN, bis(triphenylphosphoranylidene)ammonium Pi , propyl py, pyridine pz, pyrazolate pz, substituted pyi azolate pz , 3,5-dimethylpyrazolate quin, quinolin-8-olate solv, solvent tfb, teti afluorobenzobaiTelene THE, tetrahydrofuran THT, tetrahydrothiophene tmeda, teti amethylethylenediamine Tol, tolyl Tp, HB(C3H3N2)3 Tp , HB(3,5-Me2C3HN2)3 Tp, substituted hydrotiis(pyrazol-l-yl)borate Ts, tosyl tz, 1,2,4-triazolate Vin, vinyl. 

From the point of view of reactivity, there is little difference between 2-amino-selenazoles and aryl- or alkyl-2-aminoselen azoles, except that the A -arvl derivatives are generally less basic and that their salts are more easily hydrolyzed. 

The catalytic arylation of SEM-protected azoles (SEM = [2-(trimethylsilyl) ethoxy]methyl) with monocarbene-Pd(ll) complexes [72], and the reductive Heck or hydroarylation of norbomenes with NHC-phosphine chelating ligands... 

H-Pyr azoles readily undergo photochemically induced elimination of nitrogen to yield the corresponding cyclopropenes, often by way of detectable vinyl diazo intermediates. l-Aryl-3-methyl-2-phenyl-l-diazobut-2-enes have, in fact, been prepared in this way from the appropriate pyrazoles.345 The vinyl diazo compounds 416, obtained by irradiation of the 3//-pyrazoles 417, were further converted to cyclopropenes 418 via vinylmethylene intermediates 419 by irradiation at 10°C.346 1-Acylcyclopropenes have been... 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

The reaction of 5-aryl-3-(chloromethyl)[l,3,4]oxadiazole-2(3//)-thiones 100 with hydrazine or methylhydrazine yields the corresponding 2,3-dihydro[l,2,4]triazolo[3,4-A][l,3,4]oxadiazole derivatives 102 <1984JCED477>. By analogy, hydrazine and phenylhydrazine convert the [l,2,4]triazole-2(3//)-thiones 101 into 3,7-dihydro-2//-[l,2,4 tria-zolo[4,3-r][ 1,2,4] triazoles 103 <1992PS99, 2002JCCS1035>. Finally, the azole-2(3//)-thiones 101 react with hydroxylamine to form the 3,7-dihydro[l,2,4]triazolo[5,l-d[l,2,4]oxadiazoles 104 (Scheme 8) <1992PS99>. 

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