Copper-Catalyzed Cyanation of Heterocycle Carbon−Hydrogen Bonds

Abstract

A method for regioselective cyanation of heterocycles has been developed. A number of aromatic heterocycles as well as azulene can be cyanated in reasonable to good yields by using a copper cyanide catalyst and an iodine oxidant.The nitrile functional group is found in many pharmaceuticals and agrochemicals. 1,2 Sandmeyer and Rosenmund-von Braun reactions are classic methods for the synthesis of aromatic nitriles (scheme 1A). 3 However, both procedures employ a stoichiometric copper(I) cyanide reagent and prefunctionalized starting materials. Cyanation of aryl halides by employing catalytic copper or palladium is also well-known. 4 In contrast, direct cyanation through C-H bond functionalization is more attractive due to use of readily available reactants. 5 Direct cyanation can be achieved by employing an appropriate oxidant in combination with a cyanide source (scheme 1B). 6 Methods for direct cyanation of pyridines, 6b thiophenes,6c,e substituted indoles,6c,e,h pyrroles,6c,e and 2-phenylpyridines6d,f,g have been reported in the literature. However, direct transitionmetal catalyzed cyanation of acidic heterocycles such as azoles, imidazoles, and triazoles has not been described yet.6j,k We report here a method for regioselective, direct cyanation of aromatic heterocycles as well as azulene by employing copper catalysis and an iodine oxidant.Several key issues need to be addressed for achieving a general cyanation procedure. First, high regioselectivity is required for the procedure to be synthetically relevant. High regioselectivity observed in direct arylation 7 and halogenation reactions 8 (scheme 2A) is imparted by the initial deprotonation step. This protocol rules out the use of positive cyanide sources due to their incompatibility with strong bases. Consequently, simple cyanide salts such as NaCN or KCN must be employed. Second, choice of base is important. As described earlier, 7,8 tBuOLi allows for functionalization of a wide range of substrates possessing DMSO pKa's below 35-37. Third, the oxidant has to be compatible with all other reagents. It should not react with the organolithium intermediate producing byproducts that can not be converted to the * olafs@uh.edu.

Rapid, microwave accelerated synthesis of [1,2,4]triazolo[3,4- b ][1,3,4]oxadiazoles from 4-acylamino-1,2,4-triazoles

“…Direct heterocycle cyanation conditions with CuCN, NaCN, I 2 , t BuOLi, and 1,10-phenanthroline in m -xylene and 1,4-dioxane at 110 °C have been reported 38 and similar conditions were attempted with our system. However, the presence of the pendant amide carbonyl instead promoted cyclization into the triazole to yield the [1,2,4]triazolo[3,4- b ][1,3,4]oxadiazole 16 , as opposed to target compound 15 (Scheme 1).…”

Copper-catalyzed, oxidative sp2 C-H cyanation: facile synthesis of aromatic carbonitriles

“…27 Daugulis et al investigated the direct cyanation of benzothiazole. 28 Chang's group disclosed copper-mediated cyanation of electron-rich benzenes, 2 /AIBN is also an efficient system for the cyanation of aromatics. 31 These copper-catalyzed approaches on cyanation still leave much scope to develop for the direct cyanation of other important structures.…”

Azulene-based organic functional molecules for optoelectronics

“…15 Azulene was firstly discovered from oil extraction [2]. Because 16 of its low concentration in nature source and difficulty in synthesis, 17 the development of azulene-based functional molecules has 18 lagged far behind its isomer naphthalene. 19 Despite the difficulty to access azulene derivatives, their unique 20 electronic structures have intrigued lots of interest in the fields of 21 optical and electronic investigations.…”

“…Many simple azulene derivatives have been synthesized by 56 attaching various functionalized groups (6-13) [4, [16][17][18][19][20][21][22][23][24][25]. Fig.…”

“…3 57 summarizes the typical synthesis methods to obtain different 58 azulene derivatives. Azulene can easily interact with electrophilic 59 reactants at its electron-rich 1-and 3-positions resulting in 60 structures like compounds 6 [16] and 7 [17]. To attain biaryl 61 compounds, Suzuki [26] and Stille coupling [25] reactions are the 62 most popular synthesis methods.…”