Aryl halides with cyanide

The palladium-catalyzed reaction of aryl halides with cyanides to give cyanobenzenes takes place under relatively mild conditions compared to the conventional method using a stoichiometric amount of CuCN [74]. Thus, palladium catalysis has been often employed. Recently, a number of effective methods for the cyanation have been reported. The reaction of aryl iodides with NaCN under two-phase conditions [75] and those of aryl triflates [76, 77] and aryl chlorides [78] with Zn(CN)2 occur with good efficiency, while these are considered to proceed via mechanism B. 

It is well known that the normal PTCs are effective for the biphasic cyanation of aryl halides with cyanide salts using hydrophobic catalysts [25]. However, a simple application of hydrophilic catalysts results in failure. The cyanation with 2 requires... 

For a list of reagents that convert aryl halides to cyanides, with references, see Ref. 138,... 

Aryl nitriles can be prepared by the cyanation of aryl halides with an excess of copper(I) cyanide in a polar high-boiling solvent such as DMF, nitrobenzene, or pyridine at reflux temperature. 

By far one of the most important reactions through the S l mechanism is formation of a C—C bond by the reaction of aryl halides with carbanions derived from hydrocarbons, ketones, esters, amides, nitriles and even, with some limitations, from aldehydes. The reactions of cyanide ions and carbonyl complexes of Co and Fe also form a new C—C bond. 

Th synthesis of the acid from the nitrile thus becomes in reality a synthesis from sulphonic acids. An exactly analogous reaction takes place when an aryl halide, with the halogen in the side chain, is distilled with potassium cyanide, as discussed later (p. 678). 

After the reaction of an aryl halide with cuprous cyanide to form a nitrile, added ethylenediamine complexes with cuprous and cupric ions and facilitates isolation of the nitrile (see Ferric chloride). 

Special solvent. Newman - recommends N-methyl-2-pyrrolidone as solvent for the reaction of an aryl halide with cuprous cyanide to produce the corresponding nitrile. Dimethylformamide (b.p. 153°) has been suggested as a better solvent than originally used pyridine (b.p. 115°), but l-methyl-2-pyrrolidone has an even higher boiling point and seems still more satisfactory. An example is the synthesis of... 

Palladium-catalyzed coaddition of vinyl or aryl halides and cyanides is achieved stereose-lectively (cis-exo) when potassium or sodium cyanide in the presence of palladium(II) acetate and triphenylphosphane in tetrahydrofuran or dimethylformamide is used3173. Palladium-catalyzed addition with copper cyanide, which gives excellent yields in a stoichiometric version15, leads to only small yields of the adduct31, while addition of tributyltin cyanide fails7. 

The most important member of the group is an effective synthesis of aryl nitriles that involves heating the aryl halide with cuprous cyanide. Some examples of the reaction are given in Scheme 7.9. 

Catalysts containing chelating ligands and conditions that limit the concentration of cyanide have allowed the development of the coupling of cyanide with aryl halides with improved catalyst lifetimes. Recent procedures have been devised that slowly release cyanide from a cyanohydrin or trimethylsilylcyanide or that include less reactive cyanide reagents, such as zinc cyanides. High-yield reactions have also been reported with potassium hexacyanoferrate(II) as a safe cyanide source (Equation 19.19). " This reagent releases little free cyanide, but does transfer cyanide in the catalytic process. It has such little toxicity that it is even used as a food additive. 

The reaction begins with conversion of the aniline (1) to the diazo compoimd (2). Usually in the same pot, 2 is then treated with the cuprous halide or cyanide to form the aryl halide or cyanide (3). 

Similarly, a copper-mediated cyanation of aryl halide with the combination of ammonium bicarbonate and DMF as a cyanide source was reported by Zhang et al. (Scheme 5.83) [84]. This approach provided aryl nitriles in moderate to good yields. 

The nucleophilic displacement reaction of both alkyl and aryl halides by cyanide ions in dipolar aprotic solvents has been studied extensively [1,6,11]. This reaction can be visualized as a condensation of NaCN with RX to give RCN. In the alkyl series, sodium cyanide is usually used with dimethyl sulfoxide or dimethylformamide as the solvent [12-20]. Some examples from Friedman and Shechter [1] are reproduced in Table II. 

R—N=N Aryl diazonium 10ns are formed by treatment of primary aromatic amines with nitrous acid They are ex tremely useful in the preparation of aryl halides phenols and aryl cyanides... 

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

The reaction between aryl halides and cuprous cyanide is called the Rosenmund-von Braun reactionP Reactivity is in the order I > Br > Cl > F, indicating that the SnAt mechanism does not apply.Other cyanides (e.g., KCN and NaCN), do not react with aryl halides, even activated ones. However, alkali cyanides do convert aryl halides to nitrilesin dipolar aprotic solvents in the presence of Pd(II) salts or copper or nickel complexes. A nickel complex also catalyzes the reaction between aryl triflates and KCN to give aryl nitriles. Aromatic ethers ArOR have been photochemically converted to ArCN. 

In a related study, Srivastava and Collibee employed polymer-supported triphenyl-phosphine in palladium-catalyzed cyanations [142]. Commercially available resin-bound triphenylphosphine was admixed with palladium(II) acetate in N,N-dimethyl-formamide in order to generate the heterogeneous catalytic system. The mixture was stirred for 2 h under nitrogen atmosphere in a sealed microwave reaction vessel, to achieve complete formation of the active palladium-phosphine complex. The septum was then removed and equimolar amounts of zinc(II) cyanide and the requisite aryl halide were added. After purging with nitrogen and resealing, the vessel was transferred to the microwave reactor and irradiated at 140 °C for 30-50 min... 

Aryldiazonium salts, usually obtained from arylamines, undergo replacement of the diazonium group with a variety of nucleophiles to provide advantageous methods for producing aryl halides, cyanides, phenols and arenes by reductive removal of the diazo group. Coupling reaction of aryldiazonium salts with phenols or arylamines give rise to the formation of azo dyes. 

Generation of aryl radicals by reduction of aryl halides in the presence of some nucleophiles, particularly alkyl or aryl sulphide ions and cyanide ions, leads to bond formation with the generation of a new radical-anion. Overall, a reaction between the initial aryl halide and a nucleophile is triggered at the cathode and is an equivalent of the Sr I process. It proceeds in stages according to Scheme 4.6 [156] and requires only a catalytic concentration of radical-anion. The reaction can... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Acyl cyanides1708 can be prepared by treatment of acyl halides with copper cyanide. The mechanism is not known and might be free-radical or nucleophilic substitution. The reaction has also been accomplished with thallium(I) cyanide,1709 with MejSiCN and an SnCl4 catalyst,1710 and with Bu3SnCN,1711 but these reagents are successful only when R = aryl or tertiary alkyl. KCN has also been used, along with ultrasound,1712 as has NaCN with phase transfer catalysts.1713 OS III, 119. 

The reaction of the cyanide ion with alkyl halides, using PTC, has been widely studied since the first example was reported by Starks.167 However, with unactivated aryl halides (e.g., chlorobenzene and dichlorobenzene) the reaction fails.229 On the other hand, chloropyrimidine reacts with tetra-ethylammonium cyanide in acetonitrile.230 Hermann and Simchen231 have described more generally the synthesis of cyano heterocycles, using tetra-ethylammonium cyanide. 

The nickel-catalyzed transformation of aromatic halides into the corresponding nitriles by reaction with cyanide ions is reported. Both tris(triarylphosphine)nickel(0) complexes and tY2ins-chloro( aryl )bis( triarylphosphine )nickel(II) complexes catalyze the reaction. The influence of solvents, organophos-phines, and substituents on the aromatic nucleus on catalytic cyanation is studied. A mechanism of the catalytic process is suggested based on the study of stoichiometric cyanation of ti3ins-chloro(aryl)bis(triphenylphosphine)nickel-(II) complexes with NaCN and the oxidative addition reaction of Ni[P(C6H5)3]s with substituted aryl halides. 

In this context it is interesting to note that benzonitrile, Ph—C=N, trimerizes to a triazine on a Raney nickel surface. It was assumed that Jt-bonded nitriles were involved in the reaction mechanism.10 This reaction resembles the well-known template synthesis of phthalocyanine complexes from phthalodinitrile. Formation of linear polymers [—C(R)—N—] occurs on heating aryl or alkyl cyanides with metal halides.11... 

---