Palladium-catalyzed cyanations

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... 

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

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. 

At the time of the work, only two large scale examples of the palladium-catalyzed cyanation had been reported [14, 15], and the standard method consisted of heating an aryl iodide or bromide with Pd(OAc)2, dppf, Zn(CN)2 and Zn (dust) in DMF at 80-120°C [23]. Application of these conditions on 1 g scale in the lab gave high conversion to 2, but during the 50 g scale manufacture, the reaction stopped at incomplete conversion. Even after forced conditions (>10 h at 120°C), only a 35% conversion to product was observed, together with a mixture of equal amounts of unreacted starting material and by-products. 

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. 

Tschaen et al. [260] have used zinc cyanide in palladium-catalyzed cyanations of aryl bromides and iodides. As a result, a tetrakis(triphenylphosphine)palladium-catalyzed cyanation of aryl bromides and iodides with Zn(CN)2 evolved (Scheme 3.80). 

Application of Transition Metal Catalysts in Organic Synthesis, Springer, Berlin, 1998, 149-178. Nickel- and Palladium-Catalyzed Cyanation of sp -Halides and sp -Trillates. 

Sundermeier M, Zapf A, Mutyala S, Baumann W, Sans J, Weissand S, Beller M (2003) Progress in the palladium-catalyzed cyanation of aryl chlorides. Chem Eur J 9 1828-1936. doi 10.1002/chem.200390210... 

Erhardt, S., Grushin, W, Kilpatrick, A.H., Macgregor, S.A., Marshall, W.J. and Roe, D.C., Mechanisms of catalyst poisoning in palladium-catalyzed cyanation of haloarenes. 

Palladium complexes have also been reported to catalyze the cyanation of aryl halides via C-CN activation of nitriles, such as phenylacetonitrile [69] and ethyl cyanoacetate [70] (Scheme 21). An excess amount of acetonitrile can also be activated to serve as a cyanating agent in the presence of palladiiun catalyst [71]. The mechanism of C-CN activation in these palladium-catalyzed cyanation reactions is also yet to be understood. 

Yang, C. Williams, J. M. Palladium catalyzed cyanation of aryl bromides promoted by low-level organotin compounds. Org. Lett. 2004, 6, 2837-2840. 

Buono, F. G. Chidambaram, R. Mueller, R. H. Waltermire, R. E. Insights into palladium-catalyzed cyanation of bromobenzene Additive effects on the rate-limiting step. Org. Lett. 2008, 10, 5325-5328. 

Kim J, Chang S (2010) A new combined source of CN from AAf-dimethylformamide and ammonia in the palladium-catalyzed cyanation of aryl C-H bonds. J Am Chem Soc 132 (30) 10272-10274... 

Ren X, Chen J, Chen F, Cheng J (2011) The palladium-catalyzed cyanation of indole C-H bonds with the combination of NH4HCO3 and DMSO as a safe cyanide source. Chem Commun 47 6725-6727... 

Sakamoto, T. and K. Ohsawa. 1999. Palladium-catalyzed cyanation of aryl and heteroaryl iodides with copper(I) cyanide. J Chem Soc Perkin Trans 1 16 2323-2326. 

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