Palladium cyanates

Cyanuric acid can also be prepared from HNCO (100). Isocyanic acid [75-13-8] can be synthesized directiy by oxidation of HCN over a silver catalyst (101) or by reaction of H2, CO, and NO (60—75% yield) over palladium or iridium catalysts at 280—450°C (102). Ammonium cyanate and urea are by-products of the latter reaction. 

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. 

Vinylic copper reagents react with CICN to give vinyl cyanides, though BrCN and ICN give the vinylic halide instead." Vinylic cyanides have also been prepared by the reaction between vinylic lithium compounds and phenyl cyanate PhOCN." Alkyl cyanides (RCN) have been prepared, in varying yields, by treatment of sodium trialkylcyanoborates with NaCN and lead tetraacetate." Vinyl bromides reacted with KCN, in the presence of a nickel complex and zinc metal to give the vinyl nitrile. Vinyl triflates react with LiCN, in the presence of a palladium catalyst, to give the vinyl nitrile." ... 

Later, a nickel-catalyzed cascade conversion of propargyl halides and propargyl alcohol into a pyrone in water was reported. The reaction involved a carbonylation by CO and a cyanation by KCN (Eq. 4.55).96 Recently, Gabriele et al. explored a facile synthesis of maleic acids by palladium catalyzed-oxidative carbonylation of terminal alkynes in aqueous DME (1,2-dimethoxyethane) (Eq. 4.56).97... 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

Ene-nitrile oxidoisoquinolinium betaine 131 was readily prepared from vinyl triflate aldehyde 79 (Scheme 1.14). Palladium-catalyzed cyanation of vinyl triflate 79 with Zn(CN)2 in DMF at 60 °C produced ene-nitrile aldehyde 129 in 85 % yield [54]. Using the previously developed Staudinger-aza-Wittig reduction sequence, aldehyde 129 was coupled with cyclic ketal azide 121 to afford a 79 % yield of amine 130. The cyclic ketal amine 130 was then treated with 9 1 mixture of CH2CI2/TFA to provide ene-nitrile oxidoisoquinolinium betaine 131 in 93 % yield. 

The same group of authors has recently reported a combination of various palladium- and copper-catalyzed Suzuki, cyanation, and Ullmann condensation reactions for the synthesis of thiophene-based selective angiotensin II AT2 receptor antagonists (Scheme 6.24) [55],... 

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... 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

Our new approach has proven its initial value in both palladium-(Schareina et al. 2004) and copper-catalyzed cyanations (Schareina et al. 2005) and has been adopted by other groups. Very recently, in a joint collaboration with Saltigo GmbH we developed a new and improved copper-based catalyst system, which allows for efficient cyanations of a variety of aromatic and heteroaromatic halides. Importantly, notoriously difficult substrates react in excellent yield and selectivity, making the method applicable on an industrial scale. 

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... 

It is frequently necessary in synthesis to operate on the non-heterocycle portion of a molecule, and palladium technology often succeeds admirably in this regard. For example, N-(4-iodophenyl)pyrrole (200) is cyanated to 201 in excellent yield [146],... 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

The 8-0-trifluoromethanesulfonate substituent on the aromatic B-ring of the duocarmycin derivative DU-86 78 can be replaced in acceptable yields using either palladium(0)-catalyzed reduction or cyanation with tributyltin cyanide (Equation 16) <1996BMC1379>. 

P NMR spectroscopy.53 Steric factors account for the different coordination modes, while the influence of electronic factors is evidenced by the difference in structure between analogous palladium(II) and platinum(II) compounds, for example, the thiocyanates are N- and S-bonded in [Pd(NCS)(SCN)(diars)], but only S-bonded in [Pt(SCN)2(diars)].54 These and other diphosphine or diarsine complexes of palladium(II) with thio- or seleno-cyanate ligands are further discussed in Section 51.8.2.6. 

Scheme 2.20 Palladium-catalysed cyanation of morphinan triflates.

Scheme 17 Palladium-catalyzed cyanation of a heteroaryl bromide into a heteroaryl nitrile...

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. 

Scheme 19 Palladium-catalyzed aryl cyanation using a triaryl phosphine on polymer-support...

Scheme 20 Effective cyanation using aryl triflates and palladium catalysis...

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>. 

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