Aryl cyanides, addition with

Dehalogenation of monochlorotoluenes can be readily effected with hydrogen and noble metal catalysts (34). Conversion of -chlorotoluene to Ncyanotoluene is accompHshed by reaction with tetraethyl ammonium cyanide and zero-valent Group (VIII) metal complexes, such as those of nickel or palladium (35). The reaction proceeds by initial oxidative addition of the aryl haHde to the zerovalent metal complex, followed by attack of cyanide ion on the metal and reductive elimination of the aryl cyanide. Methylstyrene is prepared from -chlorotoluene by a vinylation reaction using ethylene as the reagent and a catalyst derived from zinc, a triarylphosphine, and a nickel salt (36). 

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. 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

The coupling of cyanides ions with aryl radicals is an interesting example where quantitative kinetic data are available.30 The forming bond is strong, but this favorable factor is counteracted, in terms of driving force, by the fact that °./x- [second term in equation (3.24)] is very positive (in other words, CN is a hard nucleophile). In addition, the large value of Drx r +x is unfavorable in terms of the intrinsic barrier. Overall, the presence of electron-withdrawing substituents is necessary to allow the... 

Addition of a suspected intermediate. If a certain intermediate is suspected, and if it can be obtained by other means, then under the same reaction conditions it should give the same products. This kind of experiment can provide conclusive negative evidence if the correct products are not obtained, the suspected compound is not an intermediate. However, if the correct products are obtained, this is not conclusive since they may arise by coincidence. The von Richter reaction (3-25) provides us with a good example here too. For many years it had been assumed that an aryl cyanide was an intermediate, since cyanides are easily hydrolyzed to carboxylic acids (6-5). In fact, in 1954, p-chlorobenzonitrile was shown to give p-chlorobenzoic acid under normal von Richter conditions.29 However, when the experiment was repeated with 1-cyanonaphthalene, no 1-naphthoic acid was obtained, although... 

The other type of carbamoyllithiums IIIc can also be prepared by reaction of CO with (V-lithioketimines, resulting from the addition of rert-butyllithium to aryl cyanides 10477,102. These intermediates 105 underwent selective cyclization to give 177-isoindole derivatives 10677 and six- (107)102 or seven-membered (108)102 cyclic products (Scheme 27). Compounds 107 result either by insertion of the carbene structure into the benzylic carbon-hydrogen bond, as in the case of carbamoyllithiums96, or by intramolecular protonation. 

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. 

Ni/PCys can catalyse cross-couplings of aryl cyanides with atyl or alkenyl boronic esters in the presence of KOtBu as base and CuFa as additive. The reaction exhibits a wide substrate scope and gives moderate to good product yields (Scheme 14.42). ° ... 

In an effort to move away from precious metal catalysts, various reports in recent years have focused on the use of first-row metal catalysts for direct arylations [57-60]. As a representative example of these new developments, we illustrate in Scheme 23.15 the chelate-assisted ortho-C-H arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)j in conjunction with bidentate pyridine ligands, Zn-aryl reagents as aryl transfer reagents and 1,2-dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An interesting feature of this reaction is the hydrolysis of the imine moiety after work-up. The reaction conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and thiophenes. 

In addition to carbon nucleophiles, nitrogen-based nucleophiles can be used for the nickel-catalyzed cross-coupling with aryl cyanides in the presence of CsF, the role of which is yet to be clarified (Scheme 13) [55]. Silylphosphines are reported to... 

C-CN activation via oxidative addition can be followed by the activation of another C-C bond to develop cycloaddition reactions. The reaction of o-arylcarboxyben-zonitrile with alkynes proceeds in this manner to give coumarins, aryl cyanides, and an alkyne-arylcyanation product in the presence of catalytic amounts of nickel and aluminum-based Lewis acid (Scheme 18) [61]. Likewise, o-cyanophenyl-benzamides undergo the transformation to give quinolones (Scheme 18 [62]. A catalytic cycle involving a five-membered nickelacycle intermediate, generated possibly by the oxidative addition of Ar-CN bonds, and the subsequent C-C bond activation [63] is proposed (Scheme 19). 

In this context, Radius studied the activation of organonitriles with NHC-Ni complex. They showed that [(IiPr)4Ni2(COD)] led to the efficient addition and C-CN cleavage of aromatic and aliphatic nitriles. This reaction irreversibly proceeded via p -coordination of organonitriles, followed by formation of Irons aryl cyanide complexes (Scheme 10.2). They applied this reaction to acetonitrile or trimethylsilylnitrile as well as adiponitrile, but with the latter, some by-reactions were observed. 

Hydrolyse the substance by heating it under reflux with concentrated alkali (alkyl cyanides) or 70 % sulphuric add (aryl cyanides) for about an hour. Liberate the organic add from the cooled hydrolysate by addition of excess of mineral acid (aliphatic acids) or by careful addition to water (aromatic acids), and identify the product. 

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]. 

Treatment of a-(benzotriazol-l-yl)alkyl thioethers 831 with ZnBr2 weakens the bond with benzotriazole, and the obtained complex 832 may partially dissociate to thionium cation 835 that can be trapped by even mild nucleophiles. Thus, trimethylsilyl cyanide added to the reaction mixture causes substitution of the benzotriazole moiety by the CN group to give a-(phenylthio)carbonitrile 834. In a similar manner, treatment with allylsilane leads to y,S-unsaturated thioether 833. Addition of species 835 to the double bond of a trimethylsilyl ot-arylvinyl ether followed by hydrolysis of the silyloxy group furnishes (i-(phenylthio)alkyl aryl ketones 836 (Scheme 132) <1996TL6631>. 

The highest enantioselectivity in the dialkyl-substituted olefines has been obtained with the aryl ethers of DHQD 94a and DHQ 94b. With potassium ferri-cyanide as secondary oxidant, it is possible to carry out the reaction at room temperature, and slow addition of the olefins is not required. Under these conditions, the diols can be obtained in 85-90% yield and excellent enantioselectivity. 

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