Cyanation, palladium catalyzed

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. 

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. 

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... 

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>. 

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

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

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>. 

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. 

An indirect method involves the reaction of an aromatic ring with tert-butyl-lithium, particularly when there is a directing group (see 13-17), followed by reaction with PhOCN (phenyl cyanate) to give the aryl nitrile. another indirect method involve the palladium catalyzed reaction of aryl bromides with the cyanohydrin of acetone [Me2C(OH)CN] to give ArCN. ... 

Palladium catalyzed cyanation [71] has recently received a lot of attention in the literature as a cross-coupling which employs cheap, commercially available metal cyanides and incorporates the versatile and synthetically useful cyano group. The development of a domino ort/ o-functionalization/cyanation reaction represents an advance in palladium catalysis as there are very few, if any palladium-catalyzed domino cyanation reactions. The development of the domino ortfto-functionalization/ cyanation [72, 73] by Lautens has led to some of the most significant discoveries of highly functionalized alkyl halides as coupling partners, as well as further development in the selectivity and scope of o/t/to-arylation chemistry. 

Cyanopyrazines were previously prepared by treatment of bromopyrazines with copper(I) cyanide in refluxing 4-picoline <56JA2i4i>. These compounds can also be synthesized by palladium-catalyzed cyanation of the less reactive chloropyrazines with potassimn cyanide (Section 6.03.5.4.2). Sodium dicyanocuprate is similarly effective for the cyanation of 2-amino-3-bromopyrazine, the halogen of which is almost inert to copper(I) cyanide. Dehydration of pyrazinecarboxamides with phosphoryl chloride, acetic anhydride or phosphorus pentoxide gives the carbonitriles. 

A process for palladium-catalyzed cyanation of thiophene halides has been developed. Thus for example, 3,4-dibromothiophene 69 underwent efficient cyanation to the corresponding 3,4-dicyanothiophene 70 (91% conversion) <04S23>. 

Palladium-catalyzed carbonylation of aryl triflates in the presence of an alcohol141 or amine1423 provides a good method for preparation of arenecarboxylic esters and amides from phenols (equation 121). However, palladium-catalyzed cyanation of 5,6,7,8-tetrahydro-2-naphthyl triflate with potassium cyanide failed completely whereas the more reactive tetrakis(triphenylphosphine)nickel(0) could catalyze the same reaction which gives the nitrile in a good yield142b (equation 122). 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

Scheme 16.89. Palladium-catalyzed cyanations utilizing polymer-bound triphenyl phosphine.

Development of a Mild and Robust Method for Palladium Catalyzed Cyanation on Large Scale... 

Despite the importance of nitriles as synthetic intermediates and structural motifs in drugs, relatively few large scale applications of the palladium-catalyzed cyanation have been reported [14-20]. The primary reason behind this has been the lack of robust and scalable conditions, and for a long time the reaction had a reputation of being capricious and particularly difficult to scale up. 

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