As a part of a vast project aimed at finding novel Farnesoid X Receptor (FXR) ligands, we recently reported the discovery of pyrazolo[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of non steroidal FXR agonists.1 The general synthetic strategy for the preparation of pyrazolo[3,4-e][1,4]thiazepin-7-one core involved the condensation of an 1-substituted-3-methyl-5-aminopyrazole 3, an aryl aldehyde and 2-mercaptopropanoic acid. The preparation of 3 appeared to be the limiting step towards a quick development of a structure-activity relationship scheme. Indeed, the known procedure required three steps (Scheme 1) and suffered from the burden of some drawbacks. First, the tin reduction required an excess of reducing agent and tin wastes were produced in significant quantity working in gram scale; second, the isolation of the arylhydrazine 2 was a tedious process and in most cases 2 was unstable and required immediate use for the next step; last, but not least, the isolation of 2 appeared redundant considering that both the reduction and the condensation step required acidic conditions. With the aim to address these issues, we will report a practical one-pot protocol allowing us to obtain N-aryl-5-aminopyrazoles 3 from anilines 1 by using a natural organic reducing agent, such as L-ascorbic acid, in entirely aqueous conditions.
ENVIRONMENTALLY FRIENDLY, SEQUENTIAL, ONE-POT SYNTHESIS OF N-ARYL-5-AMINOPYRAZOLES FROM ANILINES
MARCELLI, GLORIA;CAROTTI, Andrea;NATALINI, Benedetto;MARINOZZI, Maura
2013
Abstract
As a part of a vast project aimed at finding novel Farnesoid X Receptor (FXR) ligands, we recently reported the discovery of pyrazolo[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of non steroidal FXR agonists.1 The general synthetic strategy for the preparation of pyrazolo[3,4-e][1,4]thiazepin-7-one core involved the condensation of an 1-substituted-3-methyl-5-aminopyrazole 3, an aryl aldehyde and 2-mercaptopropanoic acid. The preparation of 3 appeared to be the limiting step towards a quick development of a structure-activity relationship scheme. Indeed, the known procedure required three steps (Scheme 1) and suffered from the burden of some drawbacks. First, the tin reduction required an excess of reducing agent and tin wastes were produced in significant quantity working in gram scale; second, the isolation of the arylhydrazine 2 was a tedious process and in most cases 2 was unstable and required immediate use for the next step; last, but not least, the isolation of 2 appeared redundant considering that both the reduction and the condensation step required acidic conditions. With the aim to address these issues, we will report a practical one-pot protocol allowing us to obtain N-aryl-5-aminopyrazoles 3 from anilines 1 by using a natural organic reducing agent, such as L-ascorbic acid, in entirely aqueous conditions.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
