Aryl halides, cyanation

In the last few years numerous reports have been published in the field of microwave-promoted aryl halide cyanation, utilizing nickel [71], palladium [72,73] and copper [74,75] catalysis. Even water [75] and ionic liquids [76] have proven useful as solvents in these processes. Srivastava and Collibee have exemplified a swift and dynamic procedure using polymer-supported triphenyl phosphine to enable easy subsequent removal through filtration [72]. As shown in Scheme 19, both bromides and iodides could be activated using palladium catalysis in DMF. Even without optimization of the individual reaction times, the overall process time involving simple filtration and extraction for compound isolation appears to be short. 

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 synthesis of (hetero)aryl cyanides from (hetero)aryl halides via transition-metal catalysis is a very valuable reaction since a nitrile can be easily transformed into several other functional groups. Not until 2000 were the first examples on microwave-assisted cyanation reported in the literature. Alter-man and Hallberg found that 3-bromopyridine and 3-bromothiophene were... 

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... 

Schareina T, Zapf A, Beller M (2004a) Potassium hexacyanoferrate(II)—a new cyanating agent for the palladium-catalyzed cyanation of aryl halides. Chem Commun 1388-1389... 

The concept of CPTC has been applied in a large number of catalytic reactions such as reduction of allyl chlorides with HCOONa, carbonylation of aryl and allyl halides, allylation of aldehydes, cyanation of aryl halides etc.214 For example, Okano et a/.215 reduced l-chloro-2-nonene to afford 1-nonene and... 

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. 

Cyanation Catalyzed by trans-CHLORO ( aryl ) bis ( triphenylphos-phine) nickel (II) Complexes. In Table III cyanation of aryl halides catalyzed by the Ni(II) complexes obtained by reaction between aryl halides and Ni[P(C6H5)3]3 (Reaction 2) is shown. In general the trans-chloro (1-naphthyl) bis (triphenylphosphine) nickel (II) complex was used. Ortho substituted aryl halides were allowed to react in dimethylformamide... 

By using this source of cyanide ions the reaction occurred in a variety of solvents and at very mild conditions. For example in acetone it was possible to observe a rapid reaction even at 30 °C. A strong base, such as triethylamine, was necessary to induce the formation of cyanide ion (15). In the presence of weak bases such as pyridine, cyanation does not occur under the same reaction conditions. Ortho substituted aryl halides were... 

As reported before, the reaction can be carried out in ethanol by adding quickly a stoichiometric quantity of NaCN after the catalyst and aryl halide additions. In methanol or in dimethylformamide the catalytic cyanation occurs only if the sodium cyanide is added slowly. In benzene, always in the presence of NaCN, the reaction does not occur and complexes 1 can be isolated. 

Therefore it seems reasonable to assume that cyanation of aryl halides involves two fundamental processes oxidative addition of the tris(triphenylphosphine)nickel complex on the aromatic halide (Reaction 2) and cyanation of the arylnickel(II) complex 1 (Reaction 8). A further proof of the validity of this scheme is that both Ni[P(C6H5)3]3 and arylnickel (II) complexes 1 have an equal catalytic activity, these latter being intermediates of the catalytic process. Recent studies (22) on the influence of substituents on the aromatic halide in the oxidative addition reaction with Ni[P(C6H5)3]3 have given the results shown in Figure 4. 

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. 

Sundermeier, M. Zapf, A. Beller, M. A convenient procedure for the Pd-catalyzed cyanation of aryl halides. Angew. Chem. Int. Ed. 2003, 42, 1661-1664. 

The hydrocyanation of alkenes [1] has great potential in catalytic carbon-carbon bond-formation because the nitriles obtained can be converted into a variety of products [2]. Although the cyanation of aryl halides [3] and carbon-hetero double bonds (aldehydes, ketones, and imines) [4] is well studied, the hydrocyanation of alkenes has mainly focused on the DuPont adiponitrile process [5]. Adiponitrile is produced from butadiene in a three-step process via hydrocyanation, isomerization, and a second hydrocyanation step, as displayed in Figure 1. This process was developed in the 1970s with a monodentate phosphite-based zerovalent nickel catalyst [6],... 

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. 

Cyanation of aryl halides to form nitriles is generally robust unless catalyzed by Co, Ni or Pd complexes [167 —171], A useful catalytic mixture comprises NiBr2/Zn/ phosphine/KCN. The use of PPh3 is sufficient to achieve good conversion of chlorobenzene to benzonitrile. But for the more resistant o-dichlorobenzene and o-chlorobenzonitrile, dppf is reported to show better conversion and selectivity [172], The choice of phosphine is obviously crucial as P(o-Tol)3 and dppe are distinctly ineffective. The superiority of dppf over many other phosphines is remarkably evident in the cyanation of aryl triflates and halides when catalyzed by phosphine-doped Pd2(dba)3 [173]. 

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... 

Nitriles are versatile and important components of a range of dyes, natural products, and pharmaceuticals. Aryl nitriles can be synthesized from aryl halides by direct reaction between aryl halides and copper cyanide, known as the Rosemund von Braun reaction [36]. These cyanation reactions can have several disadvantages, in particular the long reaction times required. Ren and coworkers showed that 1,3-dialkylimidazolium halide-based ionic liquids can be used as solvents in the Rosemund von Braun reaction [37]. Complete conversion, based on GC-MS analysis, was achieved after 24 h at 90 °C. When using microwave irradiation and ionic liquid as a solvent, Leadbeater and coworkers showed the reaction times could be reduced to between 3 and 10 min [38]. Under the optimized reaction conditions, 2 equiv. CuCN and 1 equiv. aryl halide were rapidly heated to 200 °C in [i-PrMIM]Br as solvent. Representative results are collected in Table 7.3. The microwave method works as well as the conventional method for a range of aryl iodide and aryl bro-... 

In contrast to traditional methods for preparing nitriles such as the Sandmeyer [12] and Rosenmund-von Braun [13] reactions, the Pd-catalyzed cyanation provides an opportunity to convert an aryl halide or pseudohalide to a nitrile under relatively mild conditions. 

The first example of an enantioselective intramolecular cascade Mizoroki-Heck-cyanation sequence was recently reported which included the reaction of amide 104 (Scheme 12.24) [33], The cyanide source employed was potassium ferro(II)cyanide, which has been utilized for the palladium-catalysed cyanation of aryl halides. The proposed reaction pathway for the Mizoroki-Heck-cyanation involves capture of a a-alkylpalladium intermediate. Previous examples of enantioselective Mizoroki-Heck cyclization-anion capture most often involve trapping of the 7r-allylpalladium complexes in group-selective reactions. Reaction conditions were surveyed for the Mizoroki-Heck cyanation sequence. It was found that Pd(dba)2 afforded better enantioselectivities than Pd(OAc)2 with Ag3P04 as the additive. Using PMP under neutral conditions led to racemic product. To improve the enantioselectivity, several bidentate ligands were screened, and the ligand DIFLUORPHOS 54a was found to give the best enantioselectivity. 

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

The exceptional strength of the metal-cyanide linkage makes it challenging to develop catalytic processes that involve excess CN" as reagent. The Pd-catalyzed cyanation of aryl halides discussed in Chapter 19 to form aryl nitriles initially suffered from the formation of catalytically inactive cyanide complexes containing multiple CN" ligands the reaction has been improved by the use of ZnfCN) or Kj[Fe(CN)J as the CN" source. ... 

Pd(II) complexes formed by oxidative addition of organic electrophiles to Pd(0) may react with amines, alcohols, or thiols in the presence of a base to give the corresponding key amido, aUcoxide, or sulfide complexes. These complexes undergo reductive ehmination to afford the new C-X (X = O, N, S) bond in the final organic product [104, 387] and the paUadium(O) species is regenerated. The palladium-catalyzed cyanation of aryl halides [388] is probably mechanistically related to these reactions. 

A Pd-catalyzed cyanation procedure using aryl halides and potassium cyanide was reported in 1973 (Scheme 3.79) [258, 259]. Many studies investigated effective Pd catalysts, metal cyanides, solvents, or additives, intending to provide the efficient catalytic reactions of a variety of carbon electrophiles including aryl halides under rrald conditions. In addition to Zn(CN)2, KCN, and NaCN, several other cyanide sources including NaCN, K4[Fe(CN),5], cyanohydrines, and trimethylsilyl cyanide (TMSCN) have been shown to participate in Pd-catalyzed cyanations [258b]. 

Scheme 3.79 Pd-catalyzed cyanation of aryl halides with KCN in DMF [258, 259].

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