Light-Promoted Dearomative Cross-Coupling of Heteroarenium Salts and Aryl Iodides via Nickel Catalysis

Abstract

Partially saturated nitrogen heterocycles are versatile building blocks for the preparation of other nitrogen heterocycles. For example, dihydropyridines can be converted to pyridines, tetrahydropyridines, and piperidines through oxidation, reduction, and functionalization reactions, respectively. Dearomatization of heteroarenes is an attractive approach for the synthesis of partially saturated heterocycles such as dihydropyridines due to the wide availability of heteroarenes. Significant research efforts have been dedicated to the addition of nucleophiles to various heteroarenium salts in this direction using organoboron or organometallic reagents. The availability of organoboron and organometallic coupling partners has been an important limitation to this chemistry. Direct coupling of electrophiles with heteroareniums could significantly improve the scope of these dearomatization reactions due to the wider availability of electrophiles compared to nucleophiles such as organoboron and organometallic reagents. Herein, we report the coupling of aryl iodides with pyridinium and related heteroarenium salts catalyzed by Ni/bpp and an Ir photocatalyst using Zn as a terminal reductant. This methodology tolerates a wide range of functional groups and allows the coupling of aryl and heteroaryl iodides, thus significantly expanding the scope of nitrogen heterocycle scaffolds that could be prepared through dearomatization of heteroarenes. The reaction products have been further functionalized to prepare various nitrogen heterocycles. Initial mechanistic studies indicate that the reaction described herein goes through a unique mechanism involving dimers of dihydroheteroarenes.

Interrogating the Mechanistic Features of Ni(I)-Mediated Aryl Iodide Oxidative Addition Using Electroanalytical and Statistical Modeling Techniques

“…As bidentate and tridentate nitrogenous ligands are the most commonly used in modern variants of Ni-catalyzed coupling reactions of aryl electrophiles, we selected representative achiral examples 39 for evaluation, including bipyridine (BPy)-, 15,16,40−44 phenanthroline (Phen)-, 17,24,45−47 terpyridine (Terpy)-, 48−50 and 2,6-bis((1H-pyrazol-1-yl)methyl)pyridine (BPP)-type ligands. 51,52 We began our study by conducting cyclic voltammetry (CV) measurements of the Ni(II)/Ni(I) redox couple of prepared Ni(II) complexes containing BPy, Phen, Terpy, and BPP ligands. However, Ni complexes bearing the parent bidentate ligands, bipyridine, and phenanthroline resulted in uninterpretable CVs with overlapping peak responses, consistent with literature precedent.…”

“…We selected a Ni(BPP)catalyzed cross-coupling reaction between pyridinium salts and aryl iodides, reported by Karimov et al, as a case study. 52 This reaction was analyzed for two reasons: first, it is proposed to proceed via a Ni(I) oxidative addition to aryl iodides and, second, because the reported substrate scope includes reaction yields ranging from 14 to 85% that would potentially enable statistical modeling. Indeed, using MLR, we found that the yields of this reaction correlated with predicted oxidative addition rates (k pred ) and the buried volume of the aryl iodide substrate (% VBur 2.0 ) (Figure 7B).…”

Mechanistic views and computational studies on transition-metal-catalyzed reductive coupling reactions

“…40,[51][52][53][54][55][56][57][58][59][60] The introduction of transition metal catalysis via selectively activating the corresponding electrophiles or stabilizing certain intermediates can effectively improve the yields and selectivity of reductive coupling reactions. [61][62][63][64][65][66][67][68] Semmelhack, Kende, and Kumada demonstrated the ability of Ni to mediate the reductive homocoupling of C(sp 2 ) halide electrophiles to construct biaryl products (Scheme 2(a)). [69][70][71] Many new reactions have been discovered based on different kinds of transition-metal insertions into various C-X (X: F, Cl, Br, I, OTf, etc.)…”

Dearomatization of Heteroarenium Salts with ArBpin Reagents. Application to the Total Synthesis of a Nuphar Alkaloid

“…Dearomatization of nitrogen heteroarenes for the synthesis of saturated azaheterocycles is an attractive approach as it uses commonly available heteroarenes as starting materials and the reaction products, dihydropyridines, can be further functionalized for the synthesis of pyridines, tetrahydropyridines, and piperidines. − The addition of various nucleophiles has been achieved, including asymmetric additions for the synthesis of enantiopure dihydropyridines. With regard to asymmetric dearomative arylation of pyridiniums and related heteroarenium salts, recently our group and others have reported that N -alkyl- and N -acylpyridinium salts can undergo asymmetric dearomatization using aryl boronic acids, aryl zinc, and electron rich aryl nucleophiles. ,,,, …”