Fast Halogenation of Some N‐Heterocycles by Means of N,N′‐Dihalo‐5,5‐dimethylhydantoin

Abstract

An instantaneous, selective and high-yielding halogenation process is reported. The method operates with imidazoles, pyrazoles, and indoles under benign reaction conditions. The developed process involves the use of N,N'-dihalo-5,5-dimethylhydantoins (halo = chlorine, bromine, iodine) as halogenation reagents that are activated by catalytic quantities of a strong Brønsted acid. Moreover, the halogenation process is switchable to produce either the mono-or di-halogenated products. Issues related to the reaction mechanism are investigated and a proposal for a reaction mechanism is disclosed.

Use of Bromine and Bromo-Organic Compounds in Organic Synthesis

“…948 Aromatic heterocycles are also successfully brominated using DBH. 949,950 Dehydrogenation (bromination−dehydrobromination) reactions using a 3-bromo derivative and DBH as the brominating agents was carried out in CCl 4 to produce an 84.7% yield of naphthalene from tetrahydronaphthalene. 951 The reaction was performed without using any catalyst.…”

“… They also studied the regioselective bromination of pyrogallol derivatives by DBH, which gave single monobromides in 1.5 h at room temperature . Aromatic heterocycles are also successfully brominated using DBH. , …”

Design and identification of a novel, functionally subtype selective GABAApositive allosteric modulator (PF-06372865).

“…In contrast, sulfone 28 was synthesized from aryl bromide 53; here, the use of Pd(PPh 3 ) 4 in the Suzuki coupling gave an excellent yield of desired product. Bromide 53 was synthesized from fluorophenyl imidazopyridazine 1 using the strongly electrophilic bromination conditions of 1,3-dibromo-5,5dimethylhydantoin and concentrated sulfuric acid 41 (Scheme 5).…”

C3-selective C–H thiolation of quinolines via an N-arylmethyl activation strategy

“…To our delight, the N -naphtha-1-ylmethyl ( 1aj ) group (denoted as Nptm) as the activator increased the yield of the desired product to 53%. Considering that Brønsted acids or Lewis acids can activate electrophiles by coordinating with the O atom of succinimide, 15 we subsequently investigated the effect of various acidic additives on the reaction with 1aj as the substrate. Retinoic acid was proved to be the most effective promotor, giving rise to the desired product in 75% yield (Table 1, entries 1–7).…”

“…Based on the above results, a plausible mechanism for the current transformation is proposed, as shown in Scheme 4. First, the homolytic cleavage of Phth–SCF 3 with heat generates an electrophilic trifluoromethylthio radical with the promotion of an acid, 15 which then undergoes a regioselective radical addition to the quinolinium ring to form the unstable radical cation I . Subsequently, deprotonation of the radical cation I with the counter anion Br − , followed by single-electron oxidation with 2a 18 affords the quinolinium salt II (detected by HRMS), upon which a heterolytic cleavage of the N–C bond occurs with the assistance of the bromide anion to give the product.…”