Novel, Practical, and Efficient Process for the Preparation of 4,5-Dichloroindole

Abstract

A novel, practical, and efficient three-step process for the preparation of 4,5-dichloroindole 5, an important starting material for a wide range of fine chemicals and pharmaceuticals has been developed. The process comprises nitration of commercially available 2,3-dichlorobenzaldehyde 1, a telescopic process for the Henry reaction, and subsequently reductive cyclization of resulting o,β-dinitrostyrene intermediate 4 into 4,5-dichloroindole using iron powder in methanol and acetic acid by the Nenitzescu reaction. The large-scale applicability of this novel and improved process has been successfully demonstrated on a multikilogram scale by carrying multiple batches to produce 5 in 67–70% yields and 96–98% purity without column chromatography. The reactions are facile, safe, and easy to scale up.

Nitroarenes and nitroalkenes as potential amino sources for the synthesis of N-heterocycles

“…Based on the Fe-catalyzed intramolecular reductive coupling of nitroarenes with olefins for the preparation of indole derivatives, the group of Pati has developed a practical, friendly, and efficient three-step approach to prepare 4,5-dichloroindole, which is a significant starting material for a series of fine chemicals and pharmaceuticals. 32 As early as 2018, Radosevich et al achieved a novel transition-metal-free intramolecular C(sp 2 )-H amination with the same substrates 38 to generate indoles (Scheme 10b). 33 A smallring phosphacycloalkane (1,2,2,3,4,4-hexamethylphosphetane, methyl phosphetane P-oxide, 3•[O]) was found to be the optimal catalyst, while other exocyclic P-substituent catalysts such as P-phenyl phosphetane 4•[O] and P-pyrrolidino phosphetane 5•[O] showed significantly lower yields.…”

“…Based on the Fe-catalyzed intramolecular reductive coupling of nitroarenes with olefins for the preparation of indole derivatives, the group of Pati has developed a practical, friendly, and efficient three-step approach to prepare 4,5-dichloroindole, which is a significant starting material for a series of fine chemicals and pharmaceuticals. 32…”

Development of Versatile Routes for the Preparation of an Intermediate to Immuno-Oncology Agonist BMS-986299

“…It was known that the tetrahydropyranyl (THP) group is compatible and can be easily removed in the downstream synthetic chemistry. ,, Then, the THP group was introduced by addition to derivative 3 through the well-established N -alkylation process in excellent yield ( 4 , 91% yield). At last, reduction of the nitrogen group in compound 4 in the presence of the Fe/NH 4 Cl system gave the desired product 5 in good yield (86%) by simply filtering with Celite (Scheme ). Much to our disappointment, the ynone derivative 6 bearing a triisopropylsilyl­( tips ) group was not a suitable partner to deliver the desired product 2 or 7 (Scheme ).…”