MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes: Application to the Synthesis of 2-Substituted 3-Bromobenzofurans and -Benzo[b]thiophenes

International audienceA convenient and general approach to the synthesis of 2‐substituted 3‐bromobenzofurans and ‐benzothiophenes was developed. The procedure is based on the cyclization of ortho‐substituted arylalkynes in the presence of N‐methylpyrrolidin‐2‐one hydrotribromide (MPHT) as a soft and easy‐to‐handle electrophilic brominating reagent. Under mild reaction conditions, MPHT promoted the bromocyclization of various enynes and diynes as well as arylalkynes to give 2‐substituted 3‐bromobenzofurans and ‐benzothiophenes in high to excellent yields. Subsequent functionalization by palladium‐catalyzed coupling reactions at the C–Br bond afforded general access to 2,3‐disubstituted benzofurans and benzothiophenes of biological interest

p-Toluenesulfonic acid-promoted selective functionalization of unsymmetrical arylalkynes: a regioselective access to various arylketones and heterocycles

International audienceRegioselective hydration of a wide range of internal alkynes has been afforded in high to good yields by using PTSA in EtOH. The scope of the reaction of alkynes has been delineated. Arylaliphatic alkynes and diarylalkynes were regioselectively hydrated in good to excellent yields and short reaction times when the reaction was achieved under microwave irradiation. Moreover, diarylalkynes, arylenynes as well as diaryldiynes bearing a methoxy-or a thiomethyl substituent on the ortho position underwent a regioselective 5-endo-dig-cyclization to give a variety of 2-aryl-and 2-styrylbenzofuran or benzothiphene derivatives. We believe that, this new environmentally metal-free procedure combined to microwave irradiation would be in importance in the search of green laboratory-scale synthesis

Synthèse et évaluation biologique d'analogues structuraux du 2-méthoxyestradiol (nouvelle voie d'accès aux benzofuranes et benzothiophènes par une méthode éco-compatible)

L angiogenèse est un processus fondamental du développement embryonnaire et adulte qui induit la formation de vaisseaux sanguins à partir du réseau existant. Il est alors appelé angiogenèse physiologique . Un dysfonctionnement de ce processus est observé dans de nombreuses pathologies notamment dans les maladies inflammatoires, ischémiques, infectieuses, immunologiques et dans les cancers. Dans ce cas, on parle alors d angiogenèse tumorale . Trois types d approche thérapeutique ciblent la vascularisation tumorale : l une vise à la désorganisation rapide des néovaisseaux existants par l utilisation d agents anti-vasculaires (VDA), la deuxième consiste à anormaliser les vaisseaux tumoraux en bloquant le ligand des récepteurs membranaires Notch, le facteur DLL-4 et la troisième consiste à inhiber la formation des néovaisseaux par le recours à des agents anti-angiogéniques (AIA). Parmi les AIA, le 2-méthoxyestradiol (2-ME2), un métabolite de l estrogène inhibant la prolifération tumorale via ses activités anti-angiogéniques et pro-apoptotiques, est actuellement en développement clinique de phase II. L objectif de cette thèse a été de synthétiser puis d évaluer in vitro de nouveaux analogues structuraux du 2-ME2. Pour cela, nous avons choisi de préparer des analogues comportant en position C2 divers substituants carbonés d hybridations sp, sp2 et sp3. Les résultats obtenus nous ont décidés à nous intéresser également au développement d une méthodologie permettant la synthèse d hétérocycles, benzofuranes et benzothiophènes, constituant les pharmacophores de molécules d intérêt thérapeutique.Angiogenesis is a key process of the embryonal and adult growth that induces the formation of blood vessels from the existing network. It is called physiological angiogenesis . A modification of this process can be observed in numerous pathologies, in particular in inflammatory, ischemic, infectious and immunologic diseases and in cancers. In this case, this is called tumoral angiogenesis . Three kinds of approach target the tumoral vascularization: the first one aims at the rapid disorganization of the existing neovessels by using antivascular agents (VDA), the second one consists in abnormalizing the tumoral vessels by blocking the ligand of the membranous receptors Notch, the factor DLL-4 and the third one consists in inhibiting the formation of neovessels thanks to anti-angiogenic agents (AIA). Among the AIA, the 2-methoxyestradiol (2-ME2), an estrogen metabolite inhibiting the tumoral proliferation by its anti-angiogenic and pro-apoptotic activities, is currently in clinical development phase II. The goal of this thesis has been to synthesize and then evaluate in vitro some new analogues of 2-ME2. To fulfill it, we aimed at preparing some analogues which included miscellaneous carbonated substitutes of hybridation sp, sp2 and sp3 in C2 position. Following some of the results obtained during these experiences, we decided then to focus also on the development of a methodology enabling the synthesis of heterocycles, benzofuranes and benzothiophenes, found as pharmacophoric scaffold in molecules of therapeutic interest.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF