• aryl halides
• azoles
• C-H activation
• CMD
• direct arylation
• Pd-catalyzed cross coupling

Our own interest in the development of new and convenient protocols for the highly regioselective synthesis of (hetero)arylazoles via palladium-catalyzed intermolecular direct (hetero)arylation reactions of azoles with (hetero)aryl halides prompted us to design general and selective procedures for the synthesis of 5-aryl-1-methyl-1H-pyrazoles, 5-aryl- oxazoles, 5-aryl-thiazoles and 5-aryl-1-methyl-1H-imidazoles, that were obtained by regioselective Pd-catalyzed direct C-5 arylation reactions of the corresponding azoles. In particular, we demonstrated that a variety of 5-aryl-1-methyl-1H-pyrazoles can be prepared in moderate-to-good yields by a highly regioselective procedure involving the Pd(OAc)2-catalyzed direct C-5 arylation of commercially available 1-methyl-1H-pyrazole with activated, unactivated and deactivated, para- and ortho-substituted aryl bromides in the presence of Bu4NOAc as the base in DMA at 70 °C.
Then, we applied these unprecedented reaction conditions promoted by Bu4NOAc to the direct C-5 arylation of oxazole, thiazole and 1-methyl-1H-imidazole. With our pleasure, we found that a variety of 5-aryl-oxazoles and 5-aryl-thiazoles can be prepared in high yields and selectivities performing the reactions at only 70 °C. Moreover, 5- aryl-1H-imidazoles can be efficiently synthesized in terms of activity and selectivity by using the same reaction conditions, but rising the reaction temperature at 110 °C.
Next, our attention was focused on a preliminary screening of the selective direct C-5 arylation of 1-phenyl-1H-pyrazole with bromotoluene, chosen as model coupling partners. During this screening we observed the formation of three main products: 1-phenyl- 5-p-tolyl-1H-pyrazole, 1-(4'-methyl-[1,1'-biphenyl]-2-yl)-1H-pyrazole and 1-(4'- methyl-[1,1'-biphenyl]-2-yl)-5-(p-tolyl)-1H-pyrazole. At the end of this in-depth study, we found that the best conditions for the C-5 direct arylation of commercially available 1-phenyl-pyrazole with bromotoluene consist in the use of PdCl2(MeCN)2 as the precatalyst in the presence of K2CO3 as base, pivalic acid and Bu4NBr as additives in DMA at 110 °C. Under these conditions, the required 1-phenyl-5-p-tolyl-1H-pyrazole was obtained in 43 % GLC yield with a selectivity higher than 80 %.
Direct arylation of azoles promoted by Bu4NOAc was also employed as key-step for the synthesis of useful organic materials. Firstly, we synthesized the 2,5-diaryl substituted oxazoles balsoxin and texaline, two bioactive compounds isolated from the plant Amyris spp. in the Caribbean. In order to prepare these compounds, we tested a one-pot sequential diarylation of oxazole with different aryl bromides by pairing the C-5 arylation procedure promoted by Bu4NOAc for the first step with the protocol for the direct C-2 arylation mediated by CuI, previously reported by our research group, for the second-one.
Balsoxin and texaline were obtained with an overall yield of 39 and 38 %, respectively.
After that, we focused our attention on the synthesis of resveratrol analogues. These 2,5-diarylated imidazoles were obtained by applying again the one-pot sequential procedure, this time starting from the 1-methyl-1H-imidazole. The relative unprotected derivatives of 2,5-diaryl-imidazoles were also synthesized by reacting the first analogues with BBr3 in CH2Cl2 at -60 °C. The biological activity of all these molecules was then evaluated and we found that they show cytotoxic activity against the 60 human tumoral cell line panel of the National Cancer Institute of USA. Moreover, in a separate screening, one of them resulted to be a NQO2 inhibitor in vitro and showed cytotoxicity higher than resveratrol.
Finally, we devoted part of our synthetic efforts to the preparation of new push-pull fluorophores, consisting in unsymmetrically substituted p-phenylene-linked imidazole- benzimidazoles, imidazole-benzothiazoles and thiazole-benzothiazoles. In this context, we used a two-step procedure that involved the palladium-catalyzed direct C-5 arylation of azoles with aryl bromides promoted by Bu4NOAc developed in this Ph.D. work for the first step, and the ligandless direct arylation at the C-2 position promoted by CuI with aryl bromides previously developed by Bellina’s group for the second step. Afterwards, their spectroscopic properties were evaluated by analysing their absorbance and emission spectra. All the fluorophores presented high quantum yields and Stokes shifts up to 114 nm.
As regards the final part of this Ph.D. work, it was carried out at the University of York, in collaboration with Professor Ian Fairlamb. We synthesize three new CuI-NHC: (1,3- dibenzylbenzo[d]imidazolin-2-ylidene)copper(I) bromide, (1,3- diphenylbenzo[d]imidazolin-2-ylidene)copper(I) bromide, and (1,3-bis(2,4,6- trimethylphenyl)imidazolin-2-yliden)copper(I) chloride. We demonstrated that (1,3- diphenylbenzo[d]imidazolin-2-ylidene)copper(I) bromide undergoes a direct reaction with PhI, both in the presence and in the absence of Pd(OAc)2, to give the arylated product (1,3-diphenyl)-2-phenylbenzo[d]imidazolium bromide.