Nitriles with copper cyanide

The alpha-chloromethyl ethers app ai ently do not react with alkali-metal cr"anides, but give good yields of nitriles with copper cyanide ... 

Iodo-7-methylbenzo[l,2-/ 4,3- ]dithiophene 65 undergoes nucleophilic substitution on reaction with copper cyanide in DMF to produce the nitrile derivative 66 (Equation 10) <1997TL457>. 

Under more forcing conditions, substitution of halogen at less reactive sites can be achieved both 3-bromo-79 and 5-bromothieno[2,3-6]-pyridineR6 gave the corresponding nitrile with copper(I) cyanide in refluxing dimethylformamide. 

For the preparation of aromatic cyanides from aromatic halides Rosenmund and von Braun introduced copper cyanide in place of the alkali cyanide the halide is warmed with copper cyanide, if necessary with addition of a little pyridine, at 150-250°. The reaction can be accelerated by small amounts of a nitrile or of copper sulfate.444... 

In the first method a secondary acetylenic bromide is warmed in THF with an equivalent amount of copper(I) cyanide. We found that a small amount of anhydrous lithium bromide is necessary to effect solubilization of the copper cyanide. Primary acetylenic bromides, RCECCH Br, under these conditions afford mainly the acetylenic nitriles, RCsCCHjCsN (see Chapter VIII). The aqueous procedure for the allenic nitriles is more attractive, in our opinion, because only a catalytic amount of copper cyanide is required the reaction of the acetylenic bromide with the KClV.CuCN complex is faster than the reaction with KCN. Excellent yields of allenic nitriles can be obtained if the potassium cyanide is added at a moderate rate during the reaction. Excess of KCN has to be avoided, as it causes resinifi-cation of the allenic nitrile. In the case of propargyl bromide 1,1-substitution may also occur, but the propargyl cyanide immediately isomerizes under the influence of the potassium cyanide. 

Arylthallium bis(trifluoroacetates) (see 12-21) can be converted to aryl nitriles by treatment with copper(I) cyanide in acetonitrile. Another procedure uses excess aqueous KCN followed by photolysis of the resulting complex ion ArTl(CN)3 in the presence of excess KCN. Alternatively, arylthallium acetates react with Cu(CN)2 or CuCN to give aryl nitriles. Yields from this procedure are variable, ranging from almost nothing to 90 or 100%. 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

The cyanide ion is an ambident nucleophile and isocyanides may be side products. If the preparation of isocyanides is desired, they can be made the main products by the use of silver or copper(I) cyanide1577 (p. 368). Vinylic bromides can be converted to vinylic cyanides with CuCN,1578 with KCN, a crown ether, and a Pd(0) complex,1579 with KCN and a Ni(0) catalyst,15 1 or with K4Ni2(CN)6.1581 Tertiary halides can be converted to the corresponding nitriles by treatment with trimethylsilyl cyanide in the presence of catalytic amounts of SnCl4 RjCCl + Me3SiCN — R3CCN.1582... 

The ready replacement of the halogen in an alkyl or an aralkyl halide illustrated in Expt 5.157 by reaction with sodium or potassium cyanide is inapplicable in the case of aryl halides wherein the halogen is relatively inert. However, aryl bromides can be converted into nitriles in good yield by heating them for several hours at about 200 °C with copper(i) cyanide in the presence of pyridine (e.g. 1-naphthonitrile, Expt 6.168). This displacement may be achieved more readily by using dimethylformamide as the solvent, when reaction is usually completed in a few hours at reflux temperature.63... 

The palladium-catalyzed, microwave-assisted conversion of 3-bromopyridine to 3-cyanopyridine using zinc cyanide in dimethylformamide (DMF) has been reported <2000JOC7984>. Substoichiometric quantities of copper or zinc species improve both conversion rate and efficiency of Pd-catalyzed cyanation reactions <1998JOC8224>. A modification of this procedure uses a heterogeneous catalyst prepared from a polymer-supported triphenylphosphine resin and Pd(OAc)2 the nitriles were obtained from halopyridines in high yields <2004TL8895>. The successful cyanation of 3-chloropyridine is observed with potassium cyanide in the presence of palladium catalysts and tetramethylethylenediamine (TMEDA) as a co-catalyst <2001TL6707>. 

Normally tosyl cyanide reacts with the functionalized zinc reagents, such as 44, to provide the expected nitrile 45 (0°C to 25 °C, 2 h). However, the benzylic zinc reagent 46 and the corresponding copper-zinc reagent 47 react with tosyl cyanide differently. Whilst the zinc reagent furnishes the SE2 substitution product 48 (functionalization at the ortho position of the phenyl ring), the zinc-copper compound leads to the direct (SE2) substitution product 49 (Scheme 1.14).51... 

The first mechanism is. in fact, reminiscent of the well-known copper-catalyzed dimerization of acetylene viny(acetylene being the main by-product of this process. This side reaction can, however, be inhibited to some extent by the use of cobalt salts as additives [IS]. The cyanation of acetylene and of alkenyl halides is also promoted by Co and Ni cyanides and Pd catalysis. A reducing reagent, such as Zn or NaBll4, has been used in conjunction with cobalt cyanide complexes, and the formation of. succinonitrile has been reported to result from the basebase-catalyzed hydrocyanation of acrylonitrile. 

Hydrolysis of acid chlorides, acid anhydrides, esters and carboxamides leads to the carboxylic acid, although these compounds are often derived from a carboxylic acid group in the first place (Scheme 5.5). Nitriles are usually derived from amines via diazotization and reaction with copper(I) cyanide (see Chapter 8) and so the hydrolysis of a nitrile group is of more value. In all cases, alkaline hydrolysis gives the salt of the acid, from which the free acid is obtained by addition of mineral acid. 

The replacement of an aryl halogen atom by the cyano group can be accomplished by the action of anhydrous cuprous cyanide at 150-250° with or without an organic base (usually pyridine) as a promoter or solvent (Rosenmund-von Braun nitrile synthesis). The reaction is autocatalytic and may be accelerated by the addition of small amounts of a nitrile and Copper sulfate. Typical laboratory procedures are found in the syntheses of a-naphthonitrile (90%) and 9-cyanophenanthrene (87%). The adaptation of the process to commercial practice has been discussed. ... 

Many aryl nitriles are obtained from diazonium salts by treatment with copper(l) cyanide. Hydroxy and amino nitriles are obtained from addition reactions to carbonyl compounds. 

Nitriles from Iso-thio-cyanates.— The nitriles may also be made from iso-thio-cyanates (p. 73). When these are heated with copper the sulphur is eliminated and the iso-cyanides ox iso-nitriles are obtained and these iso-cyanides are transformed into the cyanide or nitrile. 

Aryl halides reaction with metal cyanides, often with another transition metal catalyst, to give aryl nitriles (aryl cyanides). Aryl halides react with Zn(CN)2 and a palladium catalyst, for example, to give the aryl nitrile. Similarly, aryl iodides react with CuCN and a palladium catalyst to give the aryl nitrile. Potassium cyanide (KCN) reacts in a similar manner with a palladium catalyst. " Sodium cyanide has been used with a copper catalyst and 20% The reaction of aryl iodides... 

For work-up of the reaction mixtures, reagents which destroy the nitrile-copper cyanide complexes, for instance Fe /HCl (oxidation of Cu to Cu , followed by extraction of the nitrile), ethylenediamine (complexation of Cu ions) or an excess of aqueous NaCN (formation of the soluble NaCu(CN)2), proved to be particularly useful. With appropriate ortho substituents, such as carboxy groups, cyclization reactions may be observed under the reaction conditions. If treated at higher temperatures with CuCN, o-dihalides often provide phthalocyanines. 

Finally, it should be noted that Vilsmeier intermediates can be used to generate nitriles. Thus, the nitrile compounds MejNCRCCN) (R = H, Me, Ph, SMe or NMe ) were prepared by the reaction of a tertiary carboxamide with phosgene to form the [Me 2N=CRC1]C1 salt, followed by treatment with copper(I) cyanide suspended in MeCN [81]. 

In the first, a previously dried mixture of butadiene and hydrochloric acid is sent to the reactor with hydrogen cyanide entrained by nitrogen. The butadiene/HCN/N HC1 molar ratio is 1/1/1/0.2. Residence time remains less than one hour, at between 210 and 220 C, in the presence of copper chromite and magnesium as catalyst. A mixture of 3- and 4-pentene nitriles (88 per cent) and branched 3-methyl 1- and 2-butene nitriles (12 per cent) is obtained with virtually total once-througb conversion ... 

Both 6-(4-(l-imidazolyl)phenyl)-3(2//)-pyridazinone (64) and its 4-chloro analogue (65) reacted with potassium cyanide in DMSO to give the 4,5-dicyano derivative (66) (Scheme 21). The 5-cyano-3(2//)-pyridazinone (67) was isolated from reaction of the des-chloropyridazine, but the 4-cyano analogue was not observed from either substrate. This unusual reaction proceeds faster in an oxygen atmosphere and more slowly under an inert atmosphere the nitriles were not produced in other solvents or when copper cyanide was used <86JHC1515>. 

It is preferable to use copper cyanide rather than alkali cyanide also for the preparation of unsaturated nitriles, e.g., of allyl cyanide from allyl chloride seven hours refluxing in the presence of potassium iodide, with exclusion of water, affords a 79-84% yield of allyl cyanide.449... 

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