Cyanide, cuprous reagents

Another type of o-aminobenzyl synthon is based on o-(bis-trimethylsilylaminobenzyl)copper-zinc reagents <89TL4795>. These are prepared from the corresponding benzylic bromides by reaction with zinc, followed by addition of cuprous cyanide. These reagents react with acid chlorides to give 2-substituted indoles. Since the reactions proceed by C-acylation rather than iV-acylation, the conditions required for cyclization are mild and typically the C-acylated intermediates are not isolated. 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Propargyl alcohols may be converted to allenes by several methods, for example, (a) through the intermediate formation of propargyl halides which are not isolated but react directly with cuprous salts and hydrogen halide [60, 72-73] or cyanide [71] (b) typical alcohol reactions with thionyl chloride [74a-d] phosphorus halides [75-77], and miscellaneous reagents (see Scheme 3). 

The yields vary with the quality of the cuprous cyanide. One lot of this reagent gave yields of only 60 to 75 per cent. Larger amounts may be run, but the amount of pyridine used should be reduced to decrease the reflux. For a 2-mole run, 160 cc. of pyridine was satisfactory. The yield of the large runs was 81 per cent. 

Other typical reagents generated for coulometric titrations are hydrogen and hydroxyl ions, redox reagents such as ceric, cuprous, ferrous, chromate, ferric, manganic, stannous, and titanous ions, precipitation reagents such as silver, mercurous, mercuric, and sulfate ions, and complex-formation reagents such as cyanide ion and EDTA [8-10]. 

One general method for acyl silane synthesis particularly successful for a-cyclopropyl examples (and even an a-cyclobutyl example) involves treatment of acid chlorides with lithium tetrakis(trimethylsilyl) aluminum or lithium methyl tris(trimethylsilyl) aluminium and cuprous cyanide (vide supra, Section III.A.3)77. For example, cyclopropyl acyl silane (23) was obtained in 89% yield by this process. Improved procedures use lithium t-butyldimethylsilyl cuprate78 and a dimethylphenylsilyl zinc cuprate species79,80 as reagents. 

In the preparation of a-naphrhonitrile, somewhat better yields are obtained by substituting nickel cyanide for the usual cuprous cyanide reagent (55% vs. 78%). 5-Cyanoquinoline is prepared satisfactorily by the Sandmeyer reaction, but the 8-isomer could not be obtained by this procedure. ... 

Treatment of a-halo ethers with metallic cyanides such as cuprous, mercuric, or silver cyanides gives the corresponding cyano ethers the alkali cyanides are without effect. Very little of the corresponding isonitriles are encountered despite the fact that these compounds often result from the interaction of heavy-metal cyanides and alkyl halides. Generally, cuprous cyanide, the most commonly used reagent, is suspended in dry anhydrous ether or dry benzene and treated with the halo ether under gentle reflux (55-80%). 

Replacement of the hydroxyl group in 2-methoxyphenol by an n-butyl group was achieved in the following way. To Li2Cu(CN)Bu2, prepared by dropwise addition of n-butyllithium in tetrahydrofuran at -78 C to cuprous cyanide in tetrahydrofuran and warming of the mixture to -20°C, 2-methoxyphenyl trifluoromethanesulphonate in tetrahydrofuran was gradually added after the reagent mixture had been recooled to -70°C. Reaction was completed over 40 hours at -20 C to afford 2-n-butylanisole in 50% yield (ref.68). 

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. 

Cuprates are very useful but there are a few problems associated with them. In an attempt to circumvent these problems, Lipshutz developed the so-called higher order mixed cuprates (R2Cu(CN)Li2), prepared by reaction of 2 equivalents of organolithium reagent with cuprous cyanide (CuCN). 35 Mixed cuprates react... 

Early reports from the Bradsher group highlighted new routes to anthracene derivatives iP In the event, conversion of chloride 49 to ketone 6 was accomplished by treatment with cuprous cyanide followed by 1,2-addition of a Grignard reagent. The cyclized product 7 was obtained by heating with hydrobromic acid. It was reported later that liquid sulfur dioxide as solvent was effective in facilitating the aromatic cyclodehydration. " ... 

Procedure II. A drop of the test solution is precipitated with the reagent, either on a spot plate or on filter paper, and then a few drops of dilute hydrochloric acid or ammonium chloride are added. The mercury compound dissolves while the red silver precipitate remains. Procedure II is recommended when copper as well as mercury is present, since the cuprous cyanide is sufficiently dissociated (when potassium cyanide is used) to react with the reagent to give a red insoluble cuprous salt, which resembles the silver compound. 

During an unsuccessful attempt to prepare phenylacetylene (5) from diazobenzene (4), Sandmeyer discovered that chlorobenzene (6) could be efficiently prepared from 4 under these reaction conditions. While investigating the formation of this unexpected product, he discovered that the active reagent was cuprous chloride, formed in hydrochloric acid solution. He further postulated that this particular reaction was unique to cuprous chloride, since cupric and ferrous chloride did not exhibit a similar behavior. It would be many years, however, before a more complete understanding of this process could be secured. Sandmeyer s subsequent studies demonstrated that, when reacted with diazobenzene (4), cuprous bromide produced bromobenzene (8) and cuprous cyanide produced cyanobenzene (7). Strictly... 

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