C−H Bond Arylation of Pyrazoles at the β‐Position: General Conditions and Computational Elucidation for a High Regioselectivity

Abstract

Direct arylation of most five-membered ring heterocycles are generally easily accessible ands trongly favored at the a-position using classical palladium-catalysis. Conversely,r egioselective functionalization of such heterocycles at the concurrent b-position remains currently very challenging. Herein, we reportg eneral conditions for regioselective direct arylation at the b-position of pyrazoles, while CÀH apositioni sf ree. By using aryl bromides as the aryl source and aj udiciousc hoice of solvent, the arylation reactiono f variously N-substituted pyrazoless imply proceeds via b-CÀH bond functionalization. The b-regioselectivityi sp romoted by al igand-free palladium catalyst and as imple base without oxidanto rf urther additive, and tolerates av ariety of substituents on the bromoarene. DFT calculations revealed that ap rotic solvent such as 2-ethoxyethan-1-ols ignificantly enhances the acidity of the proton at b-position of the pyrazolesa nd thus favors this direct b-CÀHb ond arylation.T his selectivep yrazoles b-CÀHb onda rylation was successfully applied fort he straightforward building of p-extended poly-(hetero)aromatic structures via furtherP d-catalyzed combined a-CÀHi ntermolecular and intramolecular CÀHb ond arylation in an overallhighlyatom-economical process.

Regioselective Direct C−H Bond (Hetero)arylation of Thiazoles Enabled by a Novel Iminopyridine-Based α‐Diimine Nickel(II) Complex Evaluated by DFT Studies.

“…1 H NMR (500 MHz, CDCl3, 300 K): δ (ppm): 8.73 (s, 1H), 7.91 -7.86 (m, 4H), 7.56 -7.51 (m, 3H), 2,61 (s, 3H). 13 13 C NMR spectra are consistent with previous reports. 47…”

“…Experimental methods: All reagents were purchased from Sigma-Aldrich or Fisher Scientific and employed without additional purification unless otherwise specified. 1 H NMR and 13 C NMR spectra were collected using a 500 MHz Bruker AVANCE III spectrometer with chloroform as the reference solvent. Synthesized α-diimine complexes were characterized by elemental analysis using a Thermo FLASH 2000 CHN elemental analyzer.…”

“…[1][2][3][4][5] Direct C−H bond arylation of heteroaromatics through transition metal catalytic systems has recently drawn significant attention. [2][3][6][7][8][9][10][11][12][13][14][15][16][17] Compared to traditional Negishi, Suzuki, or Stille cross-coupling for making (hetero)aryl compounds, direct arylation offers atom-economical and facile synthetic methods. 3,8,[18][19] Consequently, this synthetic tool has emerged as the most desirable technique for synthesizing small molecules, and building blocks containing five-membered heteroaromatics including thiazoles.…”

Transition Metal‐Catalyzed Regiodivergent C−H Arylations of Aryl‐Substituted Azoles

“…The direct arylations of pyrazole rings which have a free C5 position generally occurred preferentially at the C5‐position using palladium‐catalysis (See Scheme 6). However, very recently our group reported general conditions for regioselective direct arylation at the C4‐position of pyrazoles, while C−H 5‐position was free (Scheme 7b) [22] . This regioselectivity was highly dependent on the nature of the solvent and the base.…”

“…However, very recently our group reported general conditions for regioselective direct arylation at the C4-position of pyrazoles, while CÀ H 5position was free (Scheme 7b). [22] This regioselectivity was highly dependent on the nature of the solvent and the base. With Pd(OAc)2 catalyst and AgOAc as base in 2-ethoxyethan-1ol, the C4-arylated pyrazoles were obtained in 70-98 % regioselectivity with pyrazoles bearing isopropyl, cyclohexyl, benzyl, or 1-phenylethyl substituents on the nitrogen atom.…”