Acid-Mediated Halogen Exchange in Heterocyclic Arenes: A Highly Effective Iodination Method

Abstract

Heterocyclic arenes including pyridyl, quinolyl, and isoquinolyl chlorides have been converted to their corresponding iodides in good to high yields via acid-mediated nucleophilic halogen exchange with sodium iodide. This procedure avoids the use of transition metals, harsh reaction conditions, and affords highly regioselective halide exchange. Chloride substituents in position 2 and 4 of pyridines and quinolines are readily substituted by iodide in 75-91% and conversion of 1-chloroisoquinoline to its iodide derivative was found to proceed with 90% yield. Positions that are not activated for nucleophilic aromatic substitution proved to be inert to halide exchange. Regioselective chloride/iodide exchange in 4,7-dichloroquinoline hydrochloride gave 7-chloro-4-iodoquinoline, an important precursor of anti-malaria drugs, in almost 90% yield.Aryl iodides are frequently used starting materials for a variety of organic transformations. Through metal/halide exchange the iodide can easily be reductively replaced or transformed to a nucleophilic Grignard or organolithium reagent for reaction with a suitable electrophile. Furthermore, aryl iodides are excellent starting materials for transition metal catalyzed Suzuki, Negishi, Hiyama, Kumada, Stille, and Heck reactions. 1 Unlike aryl chlorides, iodides are usually quite expensive or not commercially available. This can partly be attributed to the reduced stability and shelf life of aryl iodides. The low availability of aryl iodides also stems from the lack of effective methods for their preparation, which is an important limitation to some of the reactions mentioned above. Accordingly, highly active transition metal complexes that catalyze aryl-aryl coupling reactions utilizing readily available but less reactive chlorides have been developed. 2 The remaining problem is that some of these catalysts are expensive and need to be prepared prior to use. In addition to their synthetic use, aryl iodides play an important role in radiopharmaceutical chemistry. Radioactive 125 I-labeled arenes have been employed in radioimmunoassay and nuclear imaging studies. 3 The development of effective methods for the synthesis of aryl iodides thus continues to be highly desirable.Common strategies for the synthesis of aryl iodides are limited to metal-promoted halide exchange or electrophilic aromatic substitution reactions using iodonium salts. 4 Recently, Buchwald et al. reported high yields for the 1,2-diamine-accelerated copper-catalyzed conversion of aryl bromides to aryl iodides. 5 This elegant approach is also applicable to the formation of aryl cyanides. 6 However, it is limited to aryl bromides as starting materials and requires the use of a transition metal catalyst. Schlosser et al. introduced iodotrimethylsilane for the preparation of heterocyclic aryl iodides from their corresponding chlorides. 7 A drawback of this silyl-mediated transformation is that corrosive chlorotrimethylsilane is formed as a volatile by-product reducing the applicability of this approach to industrial sca...

Reactivity of the 4,5‐Didehydroisoquinolinium Cation

“…The structure was verified by x‐ray crystallography. The precursors for biradical 12 , 4,6‐dinitroisoquinoline,22 and biradical 11 , 1‐iodoisoquinoline,23 were synthesized by known methods.…”

Stereoselective Sensing by Substrate‐Controlled syn/anti Interconversion of a Stereodynamic Fluorosensor

“…4-Iodo-2-isopropylquinoline was prepared as described previously. [20] 1,8-Dibromonaphthalene was prepared from 1,8-diaminonaphthalene as described in the literature. [21] All reactions were carried out under nitrogen and under anhydrous conditions.…”

Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition

“…A series of experiments were carried out to find an optimal catalyst for this reaction. Treatment of 11 with sodium iodide in acetonitrile at 60°C for 2 h in the presence of either acetyl chloride, [27] trimethylsilyl chloride (TMSCl), [28] or hydrochloric acid, common catalysts for halogen exchange in 2-or 4-chloropyridines, afforded iodoquinoline 12 in excellent yields (Table 1, Entries 1-3, 87-93 %). Remarkably, the use of acid-free acetyl chloride (distilled from PCl 5 followed by distillation from quinoline) under the same conditions led to only 10 % conversion after 24 h (Entry 4), which shows for this reaction the importance of an initially formed protonated species.…”