Mild Palladium-Catalyzed Regioselective Direct Arylation of Azoles Promoted by Tetrabutylammonium Acetate

A mild, general, and convenient palladium-catalyzed direct arylation of the 5-position of azoles with aryl bromides, efficiently promoted by tetrabutylammonium acetate, is described. 1-Methylpyrazole, oxazole, and thiazole reacted at 70 degrees C in N,N-dimethylacetamide by using Pd(OAc)(2) as the catalyst precursor. Electron-poor and -rich functional groups, including the free hydroxy group, are well tolerated in the electrophilic partner. A variety of 5-aryl-1-methylimidazoles were also very efficiently obtained simply by raising the reaction temperature to 110 degrees C. This ligand-free protocol was successfully applied to the one-pot synthesis of two bioactive natural compounds, balsoxin and texaline, starting from oxazole by sequential direct arylation of the 5- and 2-positions

Development and applications of new protocols for the Pd-catalyzed direct arylation of azoles with aryl halides

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

Quantum kinetic models of open quantumsystems in semiconductors theory

From the introduction: The aim of the developed research is to contribute to the analytical study of quantum kinetic models of certain quantum systems, whose dynamics is time-irreversible due to the interaction with the environment; accordingly, they are called open. In particular, the models under examination have a well-grounded application to the simulation of nanoscale semiconductor devices, thus semiconductor physics is the background of reference for our work. The models are formulated according to the Wigner-function formalism, a well-known tool in both the physical and the mathematical literatures, which provides a quantum-mechanically consistent, phase-space description of the dynamics of the systems of interest. The leitmotiv of our investigation is the attempt of keeping to a purely kinetic analysis. More precisely, our aim is to obtain results that are physically-consistent and in agreement with those achieved via other formalisms, but independently of them. The way we pursue that end is by developing new analytical tools, in some cases inspired by formal analogies with other problems. The motivation for that type of study is that, apart from being analytically challenging, it is naturally suitable to numerical reformulation for applications to real devices simulation. The aspects of our research we have here presented will be widely discussed, in comparison with the existing literature, according to the following sectioning: In Part I, we will present an overview of the possible mathematical descriptions of semiconductor physics. In particular, in Chapter 1, we will introduce the (semi-)classical kinetic approach and start to discuss possible ways of modelling the irreversible dynamics of certain systems. In Chapter 2, we will focus on quantum systems, since we are interested in the applications to semiconductor devices reaching quantum regimes and we will present the quantum-statistical formalism. In Section 2.2 we will brie\ufb02y introduce the theory of open quantum systems, which constitutes the reference frame of our work, and proceed in the discussion of the literature related to the description of irreversible quantum dynamics. Thus, the background is complete. The aim of Chapter 3, in Part II, is to present the quantum kinetic description of the quantum systems, and, to compare it with the quantum-statistical one. By that discussion we will derive the motivation for our analytical study: in particular, in Section 3.4, we will describe the starting point of our investigation, namely, the choice of the Hilbert space of L2-functions de\ufb01ned on the phase-space, as the state space for the successive well-posedness studies. In Chapter 4 are introduced new tools we have employed in the cited articles, which are also promising in view of the resolution of open problems. We will compare them with similar instruments used in classical kinetic theory, which in many cases have directly inspired their derivation in the quantum framework. The tools presented constitute a contribution to the discussion in literature about the analogies between the Schr\ua8odinger and the Vlasov equations. We anticipate that we will recover a further a posteriori motivation for our choice of the functional setting: according to our investigation, the analogy with the classical kinetic formalism can indeed be exploited just in the L2-context. Part III and Part IV contain the bodies of the above cited articles: in particular, Part III those related to the Wigner-Poisson system on bounded spatial domains, while Part IV, the one about the (all-space) Wigner-Poisson-Fokker-Planck model. At the beginning of each part we will provide both a description of the physical system they are meant to describe and a discussion of the related literature. We remark that, in the three cases, the well-posedness result will be obtained in the Hilbert space of L2-functions de\ufb01ned on the phase-space, modi\ufb01ed by an appropriate weight in the velocity-direction. Accordingly, the result we present in Part IV is a slightly improved version of the one presented in the above cited paper, where also a weight in the space-direction was used. Relatively to both problems (in the all-space formulation), we also discuss possible perspectives for attaining the same well-posedness theorems in a L2-setting, without using the weights

Loss of the Intellectual Disability and Autism Gene Cc2d1a and Its Homolog Cc2d1b Differentially Affect Spatial Memory, Anxiety, and Hyperactivity

Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1Acause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a-deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila, loss of the only ortholog of Cc2d1a, lgd, is embryonically lethal, while in vertebrates, Cc2d1a has a homolog Cc2d1b which appears to be compensating, indicating that Cc2d1a and Cc2d1b have a redundant function in humans and mice. Here, we generate an allelic series of Cc2d1a and Cc2d1b LOF to determine the relative role of these genes during behavioral development. We generated Cc2d1b knockout (KO), Cc2d1a/1b double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that Cc2d1a and Cc2d1b have partially overlapping roles. Overall, loss of Cc2d1b is less severe than loss of Cc2d1a, only leading to cognitive deficits, while Cc2d1a/1b double heterozygous animals are similar to Cc2d1a-deficient mice. These results will help us better understand the deficits in individuals with CC2D1A mutations, suggesting that recessive CC2D1B mutations and trans-heterozygous CC2D1A and CC2D1B mutations could also contribute to the genetics of ID

Translating genetic and preclinical findings into autism therapies

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations on cellular function leading to disease. Efforts to translate these findings into successful therapies have yet to bear fruit. We discuss how the valuable insight into the disorder provided by these new models can be used to better understand ASD and develop future clinical trials

Primary Hyperparathyroidism in Older People: Surgical Treatment with Minimally Invasive Approaches and Outcome

Introduction. Elderly patients with primary hyperparathyroidism (pHPT) are often not referred to surgery because of their associated comorbidities that may increase surgical risk. The aim of the study was to review indications and results of minimally invasive approach parathyroidectomy in elderly patients to evaluate its impact on outcome. Materials and Methods. All patients of 70 years of age or older undergoing minimally approach parathyroidectomy at our Department from May 2005 to May 2011 were reviewed. Data collected included patients demographic information, biochemical pathology, time elapsed from pHPT diagnosis to surgical intervention, operative findings, complications, and results of postoperative biochemical studies. Results and Discussion. 37 patients were analysed. The average length of stay was 2.8 days. 11 patients were discharged within 24 hours after their operation. Morbidity included 6 transient symptomatic postoperative hypocalcemias while one patient developed a transient laryngeal nerve palsy. Time elapsed from pHPT diagnosis to first surgical visit evidences that the elderly patients were referred after their disease had progressed. Conclusions. Our data show that minimally invasive approach to parathyroid surgery seems to be safe and curative also in elderly patients with few associated risks because of combination of modern preoperative imaging, advances in surgical technique, and advances in anesthesia care