Cyanation of aryl bromides

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

Although the Pd(PPh3)4-catalyzed cyanation of aryl bromides with KCN or NaCN does not take place under ordinary conditions, Zn(CN)2 as the cyanide source enables the reaction in DMF at 80 °C. The solubility of Zn(CN)2 is lower than that of KCN or NaCN and the covalency of the Zn-CN bond is higher than that of K-CN or Na-CN. Therefore, the concentration of free CN must be a minimum in the reaction solution using Zn(CN)2 as the metal cyanide. Thus, Zn(CN)2 is probably able to maintain the active form of the Pd° catalyst over a longer period of time than KCN or NaCN (Scheme Zn(CN)2 is also an effective cyanide source for the Pd°-catalyzed reac-... 

There has been a review of palladium-catalysed cyanation reactions of aryl halides, and efficient routes for the cyanation of aryl bromides have been... 

Tschaen et al. [260] have used zinc cyanide in palladium-catalyzed cyanations of aryl bromides and iodides. As a result, a tetrakis(triphenylphosphine)palladium-catalyzed cyanation of aryl bromides and iodides with Zn(CN)2 evolved (Scheme 3.80). 

Copper has been demonstrated to mediate cyanation of aryl bromides and iodides through the activation of C-CN bonds (Scheme 20). Phenylacetonitrile [64], malononitrUe [65], and even acetonitrile as a reaction solvent [66] have been reported to serve as cyanating agents. 2-Phenylpyridines [67] and indoles [68] are directly cyanated by copper-mediated cyanation reaction using phenylacetonitrile, which is supposedly oxidized first at its benzylic position to give benzoyl cyanide, which further reacts with copper complexes to generate a cyanocopper species responsible for the cyanation event. Nevertheless, detailed mechanisms of these cyanation reactions remain elusive. 

Yang, C. Williams, J. M. Palladium catalyzed cyanation of aryl bromides promoted by low-level organotin compounds. Org. Lett. 2004, 6, 2837-2840. 

Ushkov, A. V. Grushin, V. V. Rational catalysis design on the basis of mechanistic understanding Highly efficent Pd-catalyzed cyanation of aryl bromides with NaCN in recyclable solvents. J. Am. Chem. Soc. 2011, 133, 10999-11005. 

Scheme 6.24 Acetonitrile as a cyano source in catalytic cyanation of aryl bromides.

An indirect method involves the reaction of an aromatic ring with tert-butyl-lithium, particularly when there is a directing group (see 13-17), followed by reaction with PhOCN (phenyl cyanate) to give the aryl nitrile. another indirect method involve the palladium catalyzed reaction of aryl bromides with the cyanohydrin of acetone [Me2C(OH)CN] to give ArCN. ... 

This reaction was modified by the replacement of CuCN with cheaper NaCN in the presence of palladium or nickel catalyst, as exemplified by the 5% Pd(PPh3)4/10% Cul catalyzed reaction and the Ni(CN)2 or NaCN/NiBr2 based reaction under microwave irradiation for aryl bromide. The latter condition is also used for the cyanation of aryl chloride with NaCN and NiBr2. In addition, this reaction has also been extended to the preparation of some Qf,)0-unsaturated nitriles. Further modifications include the copper-catalyzed domino halogen exchange-cyanation and the application of ionic liquid as reaction media. ... 

A method for the electrophilic cyanation of aryl- and heteroaryl-bromides has been developed using A-cyano-(V-phenyl-p-toluenesulfonamide as the cyanide source. The procedure involves generation of Grignard reagents from the aryl bromides prior to... 

It was reported that a palladium-catalyzed reaction of aryl bromide 105 in the presence of zinc metal powder afforded a cyanated product 106 when acetonitrile was used as the solvent (Scheme 6.24) [77]. On the basis of some mechanistic studies, it is proposed that addition of arylpalladium 107 to acetonitrile initially occurs to form iminylpalladium 108. The subsequent C-C bond cleavage is suggested to proceed via P-carbon elimination of iminylzinc 109. There have been several other reports that organic nitriles, such as malononitrile [78], benzyl... 

Cyanation of aryl halides (aryl iodides and aryl bromides) was completed within 20 min using K [Fe(CN)g] as a cyanide source, water as the solvent and tetrabutylam-monium bromide (TBAB) in presence of palladium catalyst using microwave heating (Velmathi and Leadbeater, 2008). 

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of halides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsiiyl cyanide in EtiN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

Leadbeater described the use of Ni(CN)2 for the microwave-assisted cyanation of (hetero)aryl bromides [81]. The use of 0.6equiv of Ni(CN)2 was found to be optimal. Unfortunately, the heteroaryl bromides reported in the study gave relatively low yields due to significant decomposition (Scheme 70). 

This is a problem that has been reported by several researchers in other cya-nation methods on heteroaromatic halides. (Hetero)aryl chlorides have also been tackled via in situ halogen exchange to (hetero)aryl bromides followed by sequential cyanation (Scheme 71). For this microwave-assisted process an equimolar amount of NiBr2 and a two-fold excess of NaCN were used. The only heteroaromatic chloride tested was 2-chloropyridine. Although the procedures described involve the use of significant amounts of nickel salts, a clear advantage is that the reactions can be performed in air. Moreover, the cyanat-ing reagents are easily removed since they are water soluble. 

The excess of copper cyanide and the use of a polar, high-boiling point solvent makes the purification of the products difficult. In addition, elevated temperatures (up to 200°C) lower the functional group tolerance. The use of alkali metal cyanides or cyanation reagents such as cyanohydrins, a catalytic amount of copper(I) iodide and kalium iodide, allows a mild, catalytic cyanation of various aryl bromides. 

Aryl cyanation. Reaction of iodobenzene with sodium cyanide in the presence of 10 mole % of Pd(0) affords only a 5% yield of benzonitrile. If the sodium cyanide is impregnated on alumina the reaction proceeds in quantitative yield. In the same reaction with aryl bromides higher yields obtain when alumina is present as a co-catalyst rather than as a support. 

Martin et al report investigations on the kinetics and the mechanism of aryl cyanate formation frx>m cyanogen bromide and phenols in the presence of different tertiary aliphatic amines. According to Vo-winkel," the use of diethyl ether as the solvent at -10 C raises the yields and various patents describe how the amines can be replaced by sodium hydroxide. There are even reports on work in aqueous solution under phase transfer conditions. With all synthetic variants it is crucial to avoid a surplus of the phenolate as only under these conditions can the often quite fast formation of imino carbonates be prevented (equation 28). 

Using electron-deficient aryl bromides as reagents for ort/zo-arylation, Lautens then expanded the scope of the cyanation reaction to synthesize biaryl cyanides (Scheme 31). As an extension of Catcllam s findings that electron-deficient aryl... 

The preparation of alkyl, alkenyl, and aryl derivatives of cyanoacetylene (1) poses no particular problems. In most cases a terminal acetylene is metalated or converted into an alkynyl Grignard reagent, and these intermediates are subsequently intercepted by a cyano source , which in most cases is either cyanogen chloride or bromide and sometimes cuprous cyanide or phenyl cyanate. Of course, dehydration of an acetylenic amide as described for the parent molecules is also possible and has occasionally been employed. 

The reaction of aryl cyanates with hydrogen chloride or hydrogen bromide in an inert solvent produces the haloformimidinium halides XL ( ). 

The order of reactivity of the aryl electrophiles in Pd-catalyzed cyanation is as follows aryl iodides > aryl triflates > aryl bromides > aryl chlorides. The lower the reactivity of the... 

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