Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

Abstract

The regiodivergent palladium-catalyzed C À Ha rylation of pyrazolo [1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. Ap hosphinecontaining palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas ap hosphine-free catalyst targets the most electron-rich position (C3).The direct CÀHa rylation of heterocyclics ubstrates (Scheme 1) is ap owerful synthetic tool for the construction of functionalized heterocycles.I tm aintains the expediency associated with simple cross-coupling reactions,b ut with greater step economy and lower waste production.[1] In heterocycles with multiple C À Hg roups,i tw ould be highly advantageous to be able to choose which CÀHg roup is functionalized, ideally with complete selectivity and with the ability to "switch" regioselectivity at will.[2] Seminal examples of this approach include the vinylation or arylation of pyrroles and indoles at either C2 or C3, where the outcome is driven by achange in substrate derivatization, [3,4] solvent, [5] or oxidant.[6]In these cases,the site selectivity is typically controlled by prohibiting or encouraging migration between positions C3 and C2. By contrast, we were interested to find out whether site selectivity could be engendered in the arylation of remote CÀHg roups,a nd whether catalyst "tuning" could be employed to drive this selectivity. [7] We report herein the catalyst-controlled switching in regioselectivity between the remote positions C3 and C7 of pyrazolo[1,5-a]pyrimidine (1; Figure 1). We chose this motif [8] because it forms the core of ar ange of biologically active compounds.S pecifically,a ryl-substituted pyrazolo[1,5-a]pyrimidines show antitumor [9] and anti-inflammatory properties, [10] have been examined as hepatitis Cvirus inhibitors and estrogen receptor ligands, [11,12] and are found in the approved sedative agents zaleplon and indiplon as well as in the anxiolytic agent ocinaplon.We began our study with the optimization of the coupling of compound 1 with bromobenzene in the presence of av ariety of palladium sources,w ith and without phosphines, changing solvents,bases,additives,and conditions.The results from this survey are summarized in the Supporting Information, and Scheme 2highlights the optimized conditions. Theu se of the monodentate phosphine ligand SPhos proved crucial to achieving site selectivity at C7, giving the desired product 2a in good yield.[13] NMR and UHPLC/ES-MS analyses of the crude reaction mixture showed at race amount (4 %) of the 3,7-diphenylated product (4a)b ut none of the 3-arylated species 3a,t hus indicating that arylation at C3 can only occur (to avery limited extent) after arylation at C7. [14] Conveniently,the reaction works just as well under air as under an inert atmosphere.The relatively high air stability of SPhos is obviously apivotal factor here.

Tuning the Electronic Properties of Piezoresistive Bilayer Films Based on α‐(BEDT‐TTF)2I3

“…Surprisingly, reaction of 3‐phenyl‐[1,2,3]triazolo[1,5‐ a ]pyridine with bromobenzene generates the pyridine derivative 15 in less than 10% yield under the standard conditions. This product presumably arises by secondary reaction of the initially formed 3,7‐diphenyl‐[1,2,3]triazolo[1,5‐ a ]pyridine through a pathway involving ring‐opening and displacement of diazo group by acetate 20,44. Because 10% of Pd(OAc) 2 is used in this process, the theoretical amount of acetate available for reaction is only 20%.…”

“…In terms of atom and step economy, the development of a direct and concise approach via CH activation would be attractive, however, this has remained an elusive goal 19. Very recently, the Bedford group published a Pd‐catalyzed direct C‐7 arylation of pyrazolo[1,5‐ a ]pyrimidines using SPhos ligand 20. Below, we describe Pd‐catalyzed arylation reactions of 1,2‐azolo[1,5‐ a ]pyridines.…”

Reviewing of Synthesis and Computational Studies of Pyrazolo Pyrimidine Derivatives

“…The HOMO orbital has critical electron density at the C3 position, and that this position has by far the highest "electrophile affinity" (Eα) value (Figure 15a) [79], on the other hand, they focused the significantly greater acidity of the C7-H group as detected by comparing the computed relative energies for the removal of each of the protons by acetate (Figure 15b) [80].…”

Palladium‐Catalyzed Divergent Arylation of Triazolopyridines: A Computational Study

“…Solvation calculations were carried out on the optimized gas-phase geometries by using ad ielectric constant of e = 2.379 for toluene. The change in solution-phase free energy, DG(sol), was calculated from Equations (1)- (5).…”

“…[3] Demonstrating the power of this methodology,werecently reported apalladium-catalyzed divergenta rylationf rom triazolopyridines (Scheme 1). [4] This transformation relied on differentiation (C3 vs. C7) between the reactivity at the C7-position, [5] which was the most acidic site in the molecule, and the C3-position, which served as ac arbenep recursor.I na ddition, two concur-rent arylation events were successfully performed in ao ne-pot process with as ingle palladium catalystt oa fford 6-aryl-2-astyrylpyridines of high synthetic utility.W ec oncluded that the choice of base was important for obtaining high yields in these reactions. Interestingly,a lkoxide bases (e.g.,p otassium tert-butoxide) favored reactivity at the C7-position, whereas carbonate bases (e.g.,p otassium carbonate) directed the reaction to the C3-position (Scheme 1).…”