Facile Access to 3,5‐Dihalogenated Pyrazoles by Sydnone Cycloaddition and their Versatile Functionalization by Pd‐Catalyzed Cross‐Coupling Processes

Abstract

The 1,3-dipolar cycloaddition of diversely N-substituted 4iodosydnones with 3-halopropiolates produces easily separable mixtures of dihalogenated pyrazolylcarboxylic esters at a preparative scale level, with the 3,5-dihalogenopyrazole regioisomers always predominating. Further decarboxylation of the major isomers provided the corresponding 3,5-dihalogenopyrazoles with a free C-4 position. These were found to be valuable scaffolds for the elaboration of unsymmetrically 1,3,5-trisubstituted pyrazole derivatives by site-selective Pd- [a] Results and Discussion Preparation of 4-Halosydnones and 1-HaloalkynesN-Substituted 4-halosydnones 1a-f [10] and ethyl halopropiolates 2a-c [13] were easily prepared following prewww.eurjoc.org

Preparation and Chemistry of 3/5-Halogenopyrazoles

“…In the case of asymmetric dipoles, the 3-halogeno regioisomers of general formula B that are sometimes occurring as electronic factors rather than steric ones are then governing the regioselectivity of the 1,3-dipolar cycloaddition. , As shown in Table , entries 11–16 and 22, by reacting 4-halogenosydnones and halogen-bearing dipolarophiles, many remarkable 3,5-dihalogenopyrazoles were prepared. Unexpectedly, the 3-iodo-5-bromopyrazole, isomer to the main product described in Table , entry 14, could not be obtained because of the instability of the corresponding 4-bromosydnone under the reaction conditions used . The size of the ester moiety had little influence on the regioselectivity of this cycloaddition (compare Table , entries 14 and 15).…”

“…The recent report describing the regioselective Suzuki–Miyaura coupling of an array of arylboronic acids on carbon 5 of the 3,5-bishalogenated pyrazole 263 to give 3-bromopyrazoles 264 , fully susceptible to a second round of coupling, illustrates again the reactivity difference of these two positions (for more on the regioselectivity of these palladium-catalyzed coupling, see section 7). , …”

1,3-Dipolar cycloaddition between acetylenic dipolarophiles and sydnone-N-ylides as bis(1,3-dipoles)

“…14 The most important chemical reaction of sydnones is 1,3-dipolar cycloaddition with alkynes to give pyrazoles that have numerous applications as pharmaceuticals and agrochemicals. [15][16][17][18][19][20][21] Also, the sydnones served as a key intermediate in the synthesis of the alkaloid withasomnine 22 As a result of their interesting chemistry, biological and physicochemical properties, sydnones have already been the subject of various reviews. 10,23,24 On the other hand, the pyrroloazines, pyrrolo[2,1-a]phthalazines and pyrrolo[2,1-a]isoquinolines have attracted more attention due to their biological [25][26][27][28][29][30] and optical 31,32 properties.…”

Introducing chirality in halogenated 3-arylsydnones and their corresponding 1-arylpyrazoles obtained by 1,3-dipolar cycloaddition

“…[6][7][8][9][10][11] Sydnones 12,13 in particular, have been employed as 1,3-dipoles in obtaining N-arylpyrazoles by 1,3-dipolar cycloaddition reaction. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] N-Arylpyrazole derivatives have been shown to possess antithrombotic, 29 anticancer, 30 parathyroid dysfunction, 31 anti-biolm, 32 and antipain 33 activity which makes them valuable targets for the pharmaceutical eld.…”