Tandem C–S Coupling and Debrominative Cyclization Enables an Easy Access to β‑Thiazole-Fused Porphyrins

A catalyst-free synthetic approach to β-thiazole-fused 5,10,15,20-tetraarylporphyrins via a cascade reaction of nickel(II) or copper(II) 2-amido-3-bromo-5,10,15,20-tetraarylporphyrins and Lawesson’s reagent is described. During the course of the reaction, 3-bromo-2-thioamido-5,10,15,20-tetraarylporphyrins formed in situ undergo debrominative cyclization in refluxing toluene to provide novel β-thiazole-fused porphyrin macrocycles in good yields. Furthermore, free-base and zinc(II) β-thiazole-fused porphyrins have also been constructed in excellent yields by using standard demetalation and zinc metal insertion procedures. The preliminary photophysical studies revealed a significant bathochromic shift in the electronic absorption and emission spectra of new porphyrins as compared to meso-tetraarylporphyrin precursors

Cascade Amination and Aza-6π-Annulation-Aromatization Strategy for the Synthesis of β‑Pyrimidine-Fused Porphyrins

Novel nickel(II) and copper(II) complexes of 2-(N,N-dimethylformamidine)-3-formyl-5,10,15,20-tetraarylporphyrins have been synthesized for the first time from 2-aminoporphyrins under Vilsmeier–Haack conditions. These porphyrins are utilized as new building blocks to construct diverse β-pyrimidine-fused 5,10,15,20-tetraarylporphyrins in good yields via a cascade ammonia-mediated condensation and intramolecular aza-6π-annulation/aromatization in 1,2-dichloroethane at 80 °C. Furthermore, copper(II) β-pyrimidine-fused porphyrins underwent demetallation in the presence of conc. H2SO4 to afford free-base porphyrins, which on zinc insertion using Zn(OAc)2 in CHCl3–MeOH provided zinc(II) β-pyrimidine-fused porphyrins in appreciable yields. Notably, these newly synthesized π-extended porphyrins displayed a modest bathochromic shift in their electronic absorption and emission spectra as compared to the traditional meso-tetraarylporphyrins. However, the protonated porphyrins (2a) and (3g) displayed a significant red-shifted absorption

Sulfur-Directed α‑C(sp³)–H Amidation of Pyrrolidines with Dioxazolones under Rhodium Catalysis

Site-selective functionalization of saturated N-heterocycles such as pyrrolidines is a central topic in organic synthesis and drug discovery. We herein report the sulfur-assisted rhodium­(III)-catalyzed sp3 C–H amidation of pyrrolidines with dioxazolones as amidating agents. The amenability of the thioamide directing group is elucidated by a series of control experiments

Rh(III)-Catalyzed C8-Spiroannulation of 1‑Aminonaphthalenes with Maleimides

The rhodium(III)-catalyzed C8-spiroannulation of 1-aminonaphthalenes with maleimides is described herein. Initially formed C8-alkenylated 1-aminonaphthalenes can intercept nucleophilic 1-amino groups through the intramolecular aza-Michael reaction, resulting in the formation of spirofused tetracyclic frameworks. This protocol displayed a wide substrate scope and a broad functional group compatibility. The synthetic utility of this process is demonstrated by the gram-scale synthesis, late-stage modification, and synthetic transformations

Sulfur-Directed α‑C(sp³)–H Amidation of Pyrrolidines with Dioxazolones under Rhodium Catalysis

Site-selective functionalization of saturated N-heterocycles such as pyrrolidines is a central topic in organic synthesis and drug discovery. We herein report the sulfur-assisted rhodium­(III)-catalyzed sp3 C–H amidation of pyrrolidines with dioxazolones as amidating agents. The amenability of the thioamide directing group is elucidated by a series of control experiments

Rh(III)-Catalyzed C8-Spiroannulation of 1‑Aminonaphthalenes with Maleimides

The rhodium(III)-catalyzed C8-spiroannulation of 1-aminonaphthalenes with maleimides is described herein. Initially formed C8-alkenylated 1-aminonaphthalenes can intercept nucleophilic 1-amino groups through the intramolecular aza-Michael reaction, resulting in the formation of spirofused tetracyclic frameworks. This protocol displayed a wide substrate scope and a broad functional group compatibility. The synthetic utility of this process is demonstrated by the gram-scale synthesis, late-stage modification, and synthetic transformations

Manufacturing Process Development of Tegoprazan as a Potassium-Competitive Acid Blocker (P-CAB)

Tegoprazan, a selective potassium-competitive acid blocker, was approved in 2018 in the Republic of Korea for the treatment of gastroesophageal reflux disease (GERD), erosive esophagitis (EE), and nonerosive reflux disease (NERD). The complexity of tegoprazan, which contains a 4,6-disubstituted 1H-benzo[d]imidazole core and a chiral chromanol moiety, makes it a challenging molecule to prepare on a commercial scale. An efficient and economical route of the key intermediates and a much improved end-game for tegoprazan were developed

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)–fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1–3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)–fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1–3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC

Catalyst-Controlled C–H Allylation and Annulation of 2‑Aryl Quinazolinones with 2‑Methylidene Cyclic Carbonate

The site-selective modification of quinazolinone as a privileged bicyclic N-heterocycle is an attractive topic in medicinal chemistry and material science. We herein report the ruthenium­(II)-catalyzed C–H allylation of 2-aryl quinazolinones with 2-methylidene cyclic carbonate. In addition, tandem C–H allylation and annulation are achieved under rhodium­(III) catalysis, resulting in the formation of tetracyclic quinazolinones including a tertiary carbon center. Post-transformations of the synthesized products demonstrate the potential of the developed methodology. A series of mechanistic investigations were also performed