One-pot regioselective C–H activation iodination–cyanation of 2,4-diarylquinazolines using malononitrile as a cyano source

A one-pot cyanation of 2,4-arylquinazoline with NIS and malononitrile has been developed. The one-pot reaction includes two steps. The Rh-catalyzed selective C–H activation/iodization of 2,4-diarylquinazoline with NIS, and then Cu-catalyzed cyanation of the corresponding iodinated intermediate with malononitrile to selectively give 2-(2-cyanoaryl)-4-arylquinazolines or 2-(2,6-dicyanoaryl)-4-arylquinazolines in good to excellent yields.

Recent, malononitrile, being more inexpensive, readily industry available, less toxic, stable and easy-to-handle, had been used as an alternative organic cyano-group source. 23 Although attempts have been made to utilize malononitrile as the cyano-group source in several aryl halogens cyanation reactions (Scheme 1a), 23 there is no report about utilizing it as Scheme 1 Some previous works and this work. a cyano-group source in one-pot C-H bond activation/ cyanation.
On the other hand, quinazoline core structure exhibits a wide range of important potential biological activities. 24,25 For example, Erlotinib and Getinib are well-known lung cancer drugs. 26 Prazosin is used for curing high blood pressure 27 and Trimetrexate has been used in the treatment of pneumocystis pneumonia 28 (Fig. 1). Thus tremendous efforts have been devoted to develop new synthetic methods for the construction of diverse quinazoline architectures and evaluate their bioactivities. 29 In the past few years, our group has focused extensively on the development methods for the synthesis of quinazoline skeletons and the late-stage functionalization of the quinazoline core with a wish to construct a quinazolinebased molecular library for bioactivity assay. 30 However, the construction of quinazoline core coupling-nitrile moiety had been rarely reported. In 2013, we reported palladium catalyzed cyanation of quinazoline-4-tosylates with CuCN for access to quinazoline-4-nitriles (Scheme 1b). 31 In 2017, we disclosed quinazoline-directed selective ortho-iodination of 2,4-diarylquinazolines for the synthesis of 2-(2-iodoaryl)-4arylquinazolines (Scheme 1c). 32 Very recently, iodination of 2,4diarylquinazoline with NIS catalyzed by rhodium, and then tri-uoromethylthiolation of the corresponding iodides for the synthesis of SCF 3 -substituted 2,4-diarylquinazolines was reported in our group (Scheme 1d). 33 Base on these, we here reported selective synthesis of 2-(2-cyanophenyl)-4-phenylquinazolines and 2-(2,4-dicyanophenyl)-4-phenylquinazolines by one-pot C-H activation iodination/cyanation using malononitrile as a cyanogroup source (Scheme 1e).

Results and discussion
Our interest in this particular on the regioselective C-H activation/cyanation of 2,4-diarylquinazolines originated from our recent studies that [RhCp*Cl 2 ] 2 /AgSbF 6 catalyzed iodination of 2,4-arylquinazoline. 33 Here, we rst optimize the reaction conditions of one-pot C-H iodination/cyanation of 2,4-phenylquinazoline. To avoid produce mixture of mono-and bisfunctionalization products, 2-(o-methyl)phenyl-4-(p-methyl) phenyl quinazoline 1a, which one of ortho position was blocked by a methyl, was chosen as the model substrate for the optimization of the one-pot cyanation conditions. According to our previous work, 33 the standard iodination protocol was carried out by using 1a (1.0 eq.), NIS (N-iodosuccinimide, 1.5 eq.), [RhCp*Cl 2 ] 2 (1.0 mol%) and AgSbF 6 (8.0 mol%) in DCE at 85 C for 30 min. When the iodination reaction was nished, the DCE solvent was removed under reduced pressure, and the mixture of malononitrile (2.0 eq.), catalyst-system Cu 2 O (10 mol%)-L (20 mol%), t-BuOK (2.0 eq.) and DMF (2.0 mL) as the solvent were added and then reacted at 120 C. To our delight, the target product 3a was isolated in a yield of 25% (Table 1, entry 1). Various of bases, such as K 2 CO 3 , KOH, Cs 2 CO 3 , and NaOH, were screened, and t-BuOK was found to be the best one (entries 1-5). Different copper salts were then examined, and Cu 2 O was proved to be the best selected, which resulted in a yield of 58% (entries [6][7][8][9][10][11][12]. The results of solvents tested indicated that trace amount of product was detected in H 2 O or acetone (not listed in Table 1); low yield of 47% and 49% were obtained in DMAC or DMSO (entries 13 and 14). Additive KF found to be benecial to the reaction, and gave a yield up to 63% (entry 15). Among the ligands used, L 4 (Bathocuproine) was found to be more facilitating to the reaction than the others (entries 16-18). Excitingly, Fig. 1 The quinazoline core structure of drugs. CuBr CuI adding 50 v% of water in DMF can improve the yield to 84% (entries 19-21) and short the reaction time from 18 h to 3 h. Finally, when NBS (N-bromosuccinimide) was used as the reactant instead of NIS under the standard reaction conditions, only trace amount of the desired product was detected.
As shown in Table 2, a variety of 2-(o-canyophenyl)-4arylquinazolines were generated under the standard experimental conditions. In general, the electron-donating R 1 , R 2 , R 3 group substituent fascinated the reactions, and gave higher yields than that of electron-withdrawing ones. For examples, when R 2 is a methyl, and R 1 is p-methyl or p-methoxyl, the corresponding products 3a and 3b were obtained in excellent of yields of 84% and 85%. The reaction of electron-withdrawing uorinated substrate 1d gave good yield of 59%. The substituent group at the meta or ortho position of 4-phenyl, due to the steric hindrance, nished the corresponding products 3e, 3f and 3g in a yield of 63%, 48% and 67%, respectively. When R 2 is chloro, the reactions gave the corresponding products 3h-3j in good yields 79-49%.
Subsequently, the effects of substituent on the phenyl moiety of quinazoline mother ring were then examined. Pleasingly, methoxy and chloro functionalities were all tolerated, providing the desired products 3k-3q in good to excellent yields. 3r was obtained in a low yield due to double electron-withdrawing substituent effect.
As we seen, when R 2 is H, the reaction may produce monocyanation and bis-cyanation selectivity. In our previous work, exclusively generate mono-iodination on the 2-aryl group was obtained catalyzed by PbCl 2 -PPh 3 , and then cyanation of the corresponding 2-(2-iodoaryl)quinazolines using conventional procedure 1e could selective giving 2-(2-mono-nitrile) quinazolines. Thus, here we focus our attention on selective to produce bis-cyanation quinazolines in one-pot reaction. The results are listed in Table 3.  When 2,4-di-(p-methyl)phenylquinazoline 1aa was selected as the model substrate, and the corresponding regents were adding double of the standard protocol above, the corresponding bis-cyanation product 4a was obtained in a yield of 65% (Table 3). The electron-donating R 1 , R 2 , R 3 group substituent also fascinating the reactions, and gave higher yields (4a, 4b, 4f and 4i) than that of electron-withdrawing ones (4d, 4e, 4g and 4h). Interestingly, dicyano-compounds were obtained in reasonable yields (4j and 4k) when m-substituted of 2,4-diarylquinazolines were used.
In order to further explore the substrate scope, 2-phenylpyridine was then investigated under the standard conditions, however, the corresponding product 4l was obtained in 23% yield. This result again disclosed that the directing properties of diazine in quinazoline are distinctive from that of pyridine.
To demonstrate the potential synthetic utility of this transformation, a gram-scale reaction of 2-(o-methyl)phenyl-4-(pmethyl)phenylquinazoline (1a) was carried out. As shown in Scheme 2a, the cyanation product (3a) was isolated in an 71% yield.
In view of the above results, a plausible mechanism was disclosed in Scheme 3. The one-pot iodination/cyanation reaction include two catalytic cycles. In the rst catalytic cycle I, the reaction of [Cp*RhCl 2 ] 2 and AgSbF 6 forms [Cp*Rh(SbF 6 ) 2 ] 2 , which reacted with 1 through C-H activation to give vemembered rhodacycle A, and then was oxidation adduction with NIS to provide the Rh(IV) intermediate B, followed reductive eliminated to give iodide intermediate product 2 along with the Rh(III) C, which was acidized to regenerate catalyst [Cp*Rh(SbF 6 ) 2 ] 2 and nish catalytic cycle I.
In the second catalytic cycle II, the ligand was incorporated with Cu I X to form the catalyst LCuX, and then incorporate with malononitrile to provide the complex D, which was reacted with t-BuOK to give intermediate E, and then undergoes transmetalation to generate the active species LCu I CN. The LCu I CN subjected to oxidative adduction with 2 to form vemembered cyclic Cu(III) G, and followed reductive eliminated to give product 3, and release the LCu I X catalyst and nish the catalytic cycle.

Experimental section
Unless otherwise noted, commercial reagents were purchased from Aldrich, Alfa, or other commercial suppliers. All solvents were dried and distilled according to standard procedures before use. Reactions were conducted in standard techniques on vacuum line. Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a uorescent indicator (254 nm). Flash column chromatography was performed using silica gel (60Å pore size, 32-63 mm, standard grade). Organic solutions were concentrated on rotary evaporators at 20 torr (house vacuum) at 25-35 C. Nuclear magnetic resonance (NMR) spectra are recorded in parts per million (ppm) from internal standard tetramethylsilane (TMS) on the d scale.

Conflicts of interest
There are no conicts to declare.