In numerous variants that have been developed, other transition metal salts, including copper(II), iron(III) and cobalt(III) have also been employed. Daniel L. Comins, Sajan P. Joseph, in Comprehensive Heterocyclic Chemistry II, 1996. If a cyclic ketone is used in place of an acyl chloride, spiro derivatives are formed. It is an example of a radical-nucleophilic aromatic substitution. Careful control of reaction time and temperature and exclusion of moisture eliminated the formation of 3-H and 3-OH by-products. Hay, ... W.R. Wilson, in Comprehensive Medicinal Chemistry III, 2017. The photolysis products were shown to be less cytotoxic in vitro and less toxic to mice than SN30000.230 The practical resolution of this problem was to store and formulate SN30000 and solutions in amber vials, and this has proved to be satisfactory. Halogen exchange on 5-chloro-8-hydroxy-7-iodoquinoline with cross linked polystyrene-4-vinyl-pyridinium dichloroiodate gave the 5,7-diiodo derivative 〈89JCS(P1)2279〉. [5] Typical reaction conditions are as follows:[7][8]. <> These reactions typically proceed through the formation of an aryl diazonium salt followed by a reaction with a copper(I) salt to yield a substituted arene according to the scheme below. See also Section 4.06.7.2. Iodobenzene can also serve as a substrate for the Sonogashira coupling, Heck reaction, and other metal-catalyzed couplings. The first of these was to use the reductive amination of aldehyde 75 with NaBH(OAc)3 that provided 77 directly in 80% yield. Table of Contents. (Due to the low cost of copper salts, a stoichiometric amount is often employed for better reactivity even when catalysis is possible.) [13][14][15] However, evidence for such an organocopper intermediate is weak and mostly circumstantial,[16][17] and the exact pathway may depend on the substrate and reaction conditions. N-Methylbenzimidazole 407 was arylated by various aryl iodides at the 2-position when catalyzed by copper(i) iodide to give excellent yields (Scheme 98) <1998BCJ467>.

This iodoimidazole was also cross-coupled with styrene under similar conditions.

The anhydrous Sandmeyer reaction was initially carried out with diiodomethane, but this was replaced with iodine when we scaled this reaction up. Optimization of the nitration conditions identified milder conditions as a viable alternative. This was followed by selective bromination at C-5 by lithiation and reaction with CBr4 <2000JOM(601)233>. 1 Nucleophilic Aromatic Substitution Reactions in which the Substituents of the Benzene Ring are Replaced.

Fig.

The reaction takes place with excellent yields (86–93%). The Sandmeyer reaction is an extremely useful reaction for the functionalization of aromatic rings through a diazonium intermediate. Depending on the choice of catalyst, 1-methylimidazole coupled with solid phase bound aryl iodide in 67% yield at the 5-position when Pd(OAc)2 and PPh3 were used as the catalyst system. The use of cHNO3 in acetic acid with careful temperature control gave an excellent yield of 70 with only ∼ 9% of 71 after an aqueous workup.

However, several key modifications were made in the pilot plant to achieve a robust, scalable Good Manufacturing Practice (GMP) synthesis. It is a volatile colorless liquid, although aged samples appear yellowish.

The diazonium salt is then intercepted by an alkene in a Heck–Matsuda coupling reaction to form the desired trans stilbene products. In the first step, the amine … OEt2 in dichloromethane at low temperature (see Section 2.15.8.4, Scheme 60) <1996JOC8160, 1999TL2105, 2000AG(E)3681, 2002BMCL1845, 2002TL9717>. Compare for example, Diminazene (Berenil), and Isometamidium chloride. The initially formed allylic azo products, which were produced by the normal SE2′ route, would undergo a 1,3-tautomerization to form hydrazone derivatives on warming to room temperature, so long as there was an allylic hydrogen adjacent to the diazo group (X=H).420. Imidazole zinc reagent 372 was made from 2-iodoimidazole 371 with activated zinc dust. Chlorination of thiazole at C-2 has been reported in 90% yield after activation with lithium and treatment with CCl4. Rhodium-catalyzed C-2 arylation of benzimidazole and a number of other azoles with aryl iodides was reported <2004OL35>. The aniline stream is thereby segmented by an inert phase before combination with t-BuONO for diazotation. The direct reductive amination of 75 using NaCNBH3 was accomplished in poor to low yields (15–52%) on a small scale, and we elected not to pursue this reaction for scale-up. This resin bound imidazolylzinc reagent was cross-coupled with aryl iodides under palladium catalysis to give 2-arylimidazoles (upon cleavage from resin) in moderate yields <2001S909>. When both palladium and copper were used, a mixture of 2-phenylimidazole and 2,5-diphenylimidazole were obtained in a nearly 1:1 ratio.

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