Copper-catalyzed, oxidative sp 2 C-H cyanation: facile synthesis of aromatic carbonitriles

Cu(OAc) 2 -catalyzed regioselective oxidative C-H cyanation of two different types of aromatics was described, providing facile access to functionalized heterocycles in good yields. Control experiments suggest the copper chelation-assisted oxidative C-H activation mechanism


Introduction
Aryl carbonitriles are versatile building blocks in organic synthesis for pharmaceuticals, natural products, dyes, agrochemicals and materials.Moreover, the nitrile moiety also serves as a key role during the transformations into the formation of amines, amides, acids/ester, ketones, aldehydes and heterocycles. 1Typical strategies for the synthesis of aryl nitriles involve the Rosenmund-von Braun, [2][3] Sandmeyer, 4 and Schmidt 5 reactions.Recent advances show that the cross-coupling between aryl (pseudo)halides and various cyanide sources such as NaCN, 6 KCN, 7 CuCN, 8 TMSCN, 9 Zn(CN) 2 , 10 ethyl cyanoacetate, 11 DMF, 12 CH 3 CN, 13 HCONH 2 , 14 benzyl cyanide, 15 alcohols, 16 MeNO 2 17 and acetone cyanohydrin 18 is also an alternative way to aryl nitriles.Furthermore, metal-catalyzed direct cyanation of aromatic C-H bonds has emerged as a useful alternative, owing to its potential atom-and step-efficient advance.Yu et al. first disclosed the cyanation of C-H bonds of 2-arylpyridine with Cu(OAc) 2 /TMSCN(MeNO 2 )/O 2 . 17ollowing this pioneering report, there has been an increase of activity in this area with various catalytic systems.Cheng reported Pd-catalyzed cyanation of 2-arylpyridine C-H bond with CuCN 19 and a cascade bromination/cyanation reaction using K 3 [Fe(CN) 6 ]. 20 K 4 [Fe(CN) 6 ] also proved to be a useful CN source in Pd catalyzed cyanation reactions. 21Recently, the research groups of Chang 22 and Jiao 23 found Pd/DMF with/without NH 3 was efficient system for C-H cyanation.Meanwhile, Cheng found DMSO contributes to the formation of final nitrile. 24Very recently, Zhu 25 and Xu 26 communicated the cyanation of C-H using a Pd/isocyanide system.Pdfree examples of C-H cyanation are comparatively few.In particular, the less expensive coppercatalyzed examples are limited.After Yu's report mentioned above, recently Wang et al. communicated the CuBr/benzyl nitrile/DMF system for cyanation of 2-phenylpyridines. 27augulis et al. investigated the direct cyanation of benzothiazole. 28Chang's group disclosed copper-mediated cyanation of electron-rich benzenes, 29 indoles 30 and 2-phenylpyridines 30 with NH 4 I and DMF.Very recently, Fan et al. have found that Cu(OAc) 2 /AIBN is also an efficient system for the cyanation of aromatics. 31These copper-catalyzed approaches on cyanation still leave much scope to develop for the direct cyanation of other important structures.Herein, we report a straight Cu-catalyzed regioselective C(sp 2 )-H cyanation of 2-arylpyridines as well as pyrazoles, which are important units and blocks due to their pharmaceutical or biological activity and facile derivatization. 32

Results and Discussion
Initially, we examined whether 2-phenylpyridine (1a) could undergo cyanation under CuCN/air/DMF system at 120 o C (similar to Wang's procedure 27 ).However, no conversion of the starting substrates 1a was observed (Table 1, entry 1).Yu demonstrated that Cu(OAc) 2 /O 2 worked in the oxidative C-H functionalization. 17We envisioned that one of the oxidants could work.To test our hypothesis, we employed O 2 as the sole oxidant for the cyanation.However, O 2 alone gave no conversion of raw materials (Table 1, entry 2), and the same situation was true for Cu(OAc) 2 (Table 1, entry 3) while trace product was seen with combined Cu(OAc) 2 and O 2 (Table 1, entry 4).Further improvement with the introduction of anhydrous CuBr (0.2 equiv.) was achieved with an increased yield to 8% (Table 1, entry 5), which meant that in situ bromination might occur during the reaction, albeit relative low yield.To test our hypothesis, we introduced water (5.0 equiv.)into the reaction and the result showed that no conversion of 1a was found (Table 1, entry 6), which meant that water could sharply inhibit the reaction.However, without Cu(OAc) 2 , CuBr alone could not catalyze the reaction (Table 1, entry 7).Replacing CuBr with KI led to an accelerated reaction and resulted in a significantly improved yield. 33Our experiments confirmed the catalysis by KI (Table 1, entry 8).Finally, the combination of Cu(OAc) 2 and KI (0.1 equiv.)gave the desired 2a in moderate yield and chemoselectivity (Table 1, entry 8).There was no difference between iodide ion sources (Table 1, entries 8, 9).Further addition of 10 equiv.AcOH made a great improvement and gave the desired product in good yield and chemoselectivity (   Further experiments with other cyano sources such as TMSCN, K 4 [Fe(CN) 6 ] and Zn(CN) 2 , even with Cu(OAc) 2 and KI, confirmed our choice of CuCN (Table 2, entries 1-4).Subsequently, several other oxidants (CuBr 2 , Cu(NO 3 ) 2 , CuO, CuSO 4 , Oxone, Fe(NO 3 ) 3 ) were also tested (Table 2, entries 5-10).None of them was effective in the cyanation of compound 1a.Finally, the solvent was screened and the results showed that the reaction in DMSO, NMP and DMA gave results competitive with DMF, while other solvents such as CH 3 CN, toluene, AcOH and octanol proved to be ineffective (Table 2, entries 11-17).DMF was chosen for its facile handling and commercial availability.Herein, Cu(OAc) 2 /CuCN /DMF system was confirmed as the optimal conditions for cyanation of 2-phenylpyridines, which could gave a higher yield than reported results. 17ith the optimal conditions in hand, the scope and limitation of the reaction were investigated and the results were collected in Scheme 1.As to four reported products (2a-2d), our cyanation condition gave comparable (2c) or higher yields (2a, 2b and 2d).Replacing the directing group with 5-methylpyrimidine, 2-(5-methylpyrimidin-2-yl)benzonitrile (2e) could be generated in good yield and the more electron-deficient product 2f could be obtained in moderate yield.Finally, methyl 6-(furan-3-yl)nicotinate could be applied in this reaction producing the corresponding 2g in good yield.Due to the wide usage of pyrazoles in pharmaceuticals, N-(1-methyl-1H-pyrazol-4yl)pyrimidin-2-amine 1′a was tried as a model substrate.Under standard conditions, the desired cyanated product 3a was obtained in 82% yield during 12 hrs, which meant a rapid reaction under these conditions.It is worthy of mention that, in the absence of acetic acid, 1′a afforded the desired cyanated product 3a with intermolecular coupling product 4a and amination product 6a.Fortunately, the byproducts could be inhibited with the addition of 10 equivalents of AcOH (Scheme 2).Scheme 2. Cyanation of 1′a under different conditions: without acetic acid: 3a:4a:6a=56:25:10; with acetic acid 3a:4a:6a=92:1:0.Under these conditions, we explored the scope and limitation the cyanation of different pyrazoles (Scheme 3).Pyrazoles with Me, CH 2 CF 3 and Ph at the 1 position were cyanated smoothly in 82%, 82% and 84% yields, respectively (3a, 3b and 3c, Scheme 3).These results suggested that the cyanation was not sensitive to the electronic character of the substituent at the 1 position of pyrazole, while 4-and 5-methylpyrimidines led to similar results, producing 3i and 3j in 81% and 82% yields.Substituents with varied electronic properties, such as H (3d), methyl (3e), fluoro (3g), cyano (3f) and nitro (3h), on the 5-position of the pyridine ring were tolerated under the reaction conditions, giving comparable or slightly lower yields.Other heterocyclesubstituted 4-aminopyrazoles including 5-methylpyrazin-2-yl (3k), quinazolin-2-yl (3l and 3m) were successfully applied in this reaction with comparable yields.Interestingly, the formation of 1-methyl-4-pyrimidin-2-yl-5-cyanopyrazole (3n) demonstrated that the 4-amino in the pyrazoles was not crucial.This result was further verified by the methyl substitution of the 4-amino group (3o).Compounds 3d and 3o were obtained in the same yield.However, the 4-(N-phenylamino) substituted pyrazole (3p) failed to yield the desired product, which meant that the directing group was crucial.
The regioselectivity of the C-H cyanation was confirmed by Noesy analysis of 3b and X-ray analysis of 3e (Figure 1). 34The results confirmed that the cyanation occurred at the 5 position of the pyrazole.To further understand the reaction, mechanistic studies were also carried out (Scheme 4).First, control experiments were performed.Under the optimal conditions, the relative higher nucleophile 4-phenylaminopyrazole 1′p produced the corresponding double C-H amination product 4p in 75% yield (eq 1), whereas 1′q gave the mono C-H amination product 5q in 60% yield (eq 2).These results demonstrated that amination and cyanation at the 5-position of pyrazole were competitive reactions.Inserting a methylene into the 4-position of pyrazole and pyrimidine, 1′r did not yield any corresponding product.The same situation was found in the amide group 1′s.A directing group effect was further confirmed with 4-(2-chloropyrimidine-5yl)pyrazole 1′t, which afforded no desired product.Reactions of nitro-substituted pyrazoles, either 1′u or 1′v, which are highly electron-deficient aromatics, were sluggish, and no product was obtained.
Based on the reactions above and the substrates, conclusions could be drawn as follows: 1) the Cu(OAc) 2 is essential to the reaction and the OAc anion should participate in the reaction; 2) the copper(II) ion participates in the reaction through chelation with the N-amino Nheterocycle; 3) KI participates in the reaction and accelerates the reaction.
Zhou et al. have demonstrated that the chelation of copper with N-heterocycles was the initial reaction. 35Single electron transfer (SET) is thought to be the reasonable mechanism with literatures.Thus, we envisioned the cyanation reaction proceeded with copper chelation-assisted six-membered cyclic process as shown in Scheme 5. Oxidative addition of compound

Conclusions
In conclusion, we have described the direct C-H cyanation with CuCN/Cu(OAc) 2 to form aromatic carbonitriles.The present approach is convenient with easy operation, inexpensive catalytic system and broad substrate scope.In addition, a plausible mechanism is proposed to account for the formation of products.Further experiments are currently underway in our lab.

Experimental Section
General.Organic solutions were concentrated by rotary evaporation (house vacuum, ~25 Torr) at 23-30 °C.Flash column chromatography was performed by employing silica gel (60 Å pore size, 230-400 mesh, standard grade).Analytical thin layer chromatography (TLC) was performed using aluminum plates pre-coated with silica gel (0.25 mm, 60 Å pore size, 230-400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 mm).TLC plates were visualized by exposure to ultraviolet light (UV) and/or exposure to phosphmolybdic acid (PMA) followed by heating on a hot plate.Proton and carbon nuclear magnetic resonance spectra ( 1 H NMR and 13 C NMR) were recorded with Varian Mercury 400 (400 MHz/ 100 MHz) NMR spectrometers.Chemical shifts for protons are reported in parts per million (δ scale) and internally referenced to the tetramethylsilane signal.Chemical shifts for carbon are reported in parts per million (δ scale) and referenced to the carbon resonances of the solvent (CDCl 3 : δ 77.36, the middle peak).Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, td = triple doublet), coupling constant in Hz, and integration.Liquid chromatography mass spectra were obtained using an Agilent Technologies 6120MSD mass spectrometer.

Preparation of substrates
Typical procedure A. Aminopyrazole (3.0 mmol, 1.0 equiv), halide (3.15mmol, 1.05 equiv) and TsOH (3.0 mmol, 1.0 equiv) were added to 2-propanol (10 mL).The resultant mixture was reacted under microwave radiation at 145 o C for 1hrs.On the completion of the reaction, the solvent was removed under reduced pressure.To the residue was added water (50 mL), neutralized with saturated aqueous NaHCO 3 , extracted with ethyl acetate.The combined organic phase was successively washed with water, brine for three times and dried over Na 2 SO 4 .After the removal of the solvent, purification of the residue with flash chromatography (MeOH/H 2 O = 0:1~10:1) gave the desired product.Typical procedure B. To 1,4-dioxane (15 mL) and water (1 mL) was added bromopyrimidine (3 mmol, 1.0 equiv), pyrazole boric acid ester (3.6 mmol, 1.2 equiv), Pd(PPh 3 ) 4 (0.3 mmol, 1.0 eq) and K 2 CO 3 (6 mmol, 2.0 eq) under N 2 atmosphere.The reaction mixture was warmed to 110 o C and kept overnight.After the completion of the reaction, the content was poured into water (100 mL) and extracted with ethyl acetate.The combined organic phase was dried over Na 2 SO 4 and the solvent was removed under reduced pressure.Desired product was obtained after purification with flash chromatography (Petro-Ester (PE)/EtOAc = 1:0~1:1).Typical procedure C. To dichloromethane (15 mL) was added aminopyrazole (5 mmol, 1.0 equiv), phenyl boric acid (7.5 mmol, 1.5 equiv), Cu(OAc) 2 (10 mmol, 2.0 equiv) and anhydrous pyridine (50 mmol, 10.0 equiv) under O 2 atmosphere.The reaction mixture was heated to reflux and kept for 48 hrs.After the completion of the reaction, the solvent was evaporated under reduced pressure.The residue was purified with flash chromatography (PE/EtOAc = 1:0~3:1) to generate the desired product.Typical procedure D. To 1,4-dioxane (15 mL) and water (1 mL) mixture were added bromopyridine (3 mmol, 1.0 equiv), substituted pyrazole (3.6 mmol, 1.2 equiv), Pd(dppf)Cl 2 (0.3 mmol, 1.0 equiv) and Cs 2 CO 3 (6 mmol, 2.0 equiv) under N 2 atmosphere.The reaction mixture was warmed to 110 o C and kept overnight.After the completion of the reaction, the content was poured into water (100 mL) and extracted with ethyl acetate.The combined organic phase was dried over Na 2 SO 4 and the solvent was removed under reduced pressure.Desired product was obtained after purification with flash chromatography (PE/EtOAc = 1:0~1:1).
Typical procedure E.To pyrazole (3 mmol, 1.0 equiv) and Et 3 N (4.5 mmol, 1.5 equiv) dissolved in dichloromethane (15 mL) was added acyl chloride (3.15 mmol, 1.05 equiv) in an ice-water bath.After the completion of addition, the resultant reaction mixture was warmed to room temperature and kept for 2hrs.On the completion of the reaction, the solvent of the reaction mixture was removed under reduced pressure.The residue was poured into water (50 mL) and the desired product was obtained.
For the synthesis of N-aryl substituted pyrazoles, procedure F. Nitropyrazoles (10 mmol, 1.1 equiv), aryl halide (9.1 mmol, 1.0 equiv), CuI (1.0 mmol, 0.1 equiv) and K 2 CO 3 (18.2mmol, 2.0 equiv) were added to DMF (20 mL) under N 2 atmosphere.The resultant mixture was heated to 110 o C and kept overnight.On the completion of the reaction, the reaction mixture was poured into water, and extracted with ethyl acetate.The combined organic phase was successively washed with water, brine for three times and dried over Na 2 SO 4 .After the removal of the solvent, purification of the residue with flash chromatography (PE/EtOAc = 40:1~1:1) gave the desired product.Typical procedure G.To 1,4-dioxane (15 mL) were added chloro-substituted N-heterocycles (10.0 mmol), aromatic boronic acid (or pinacol ester, 12.0 mmol), Pd(dppf)Cl 2 (0.73 g, 1.0 mmol) and aqueous Cs 2 CO 3 (2 N, 10 mL, 20.0 mmol) under N 2 atmosphere.The content was heated and kept at 110 o C overnight.The reaction mixture was cooled to room temperature after the completion of the reaction.Dioxane was removed under reduced pressure.The resultant aqueous solution was extracted with EtOAc.The combined organic phase was washed with water and saturated brine for three times, and dried over Na 2 SO 4 .After the removal of the solvent under reduced pressure, the residue was charged to flash chromatography, which gave the pure product.

N-Methyl-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-2-amine (1′o)
was obtained from the methylation of 1′d.To anhydrous THF (10mL) was added 1′d (0.24 g, 1.0 mmol) and NaH (0.05 g, 1.2 mmol) under ice-water bath.The reaction mixture was kept for 0.5 hr, and then methyl iodide (0.17 g, 1.2 mmol) was added.The resultant reaction mixture was warmed to room temperature and kept overnight.The reaction mixture was poured into ice-water, and extracted with ethyl acetate.The combined organic phase was successfully washed with water and brine for three times and dried over Na 2 SO 4 .After the removal of the solvent, the desired product 1′o was obtained as light yellow oil with 94% yield.
Scope of the cyanation of substituted pyrazoles.