Best reaction conditions for the cyanation of 4-methoxyaryldiazoniumborotetraflouride were elaborated (Table 1). The Cu based catalysts such as CuI, CuBr, CuCl, Cu(OAc)2, Cu(OTf)2 and Cu(ClO4)2 were screened in the presence of stoichiometric amount of (Me3Si)2 with 2 equivalents of PrOH in THF (1 mL) as solvent (Table 1, entry 1-6). Although, these Cu catalysts were unable to elaborate the cyanated product in our proposed reaction (Table 1, entry 1-6). Consequently, Pd catalysts, namely, (Pd(OAc)2, PdCl2 , Pd2(dba)3 and Pd(acac)2) were tested and cyanation product yields of 65%, 51%, 54% and 58% respectively were observed (Table 1, entry 7-10). Addition of different alcohols such as t-BuOH, MeOH, EtOH and week acid (CH3CO2H) varied the reactivity with the yields of 78%, 29%, 38% and 45% respectively (Table.1, entry 11-14).
As shown in table 1, t-BuOH shows excellent performance leading to higher yield (78%) of cyanated product (Table 1, entry 11). Various other solvents such as 1,4-dioxane, dimethyl ether (DME) and dichloroethane (DCE) were examined (Table1, entry 15-17). However, only the DME solvent proved to be pertinent facilitating solvent (52% yield of cyanated product (4a)) compared to DCE and 1,4-dioxane which afforded only a trace yield of 4a product (Table.1, entry 15-17). Changing the additive (Me3Si)2 to (PhMe2Si)2 or Ph6Si2 or Me3SiH reduced the reactivity and formed the cyanated product (4a) in 35%, 58% and 22% yields (Table1, entry 18-20) respectively. Moreover, we conducted an experiment in the absence of t-BuOH, which showed low efficiency and gave 47% yield of cyanated product (4a) (Table.1, entry 21). Similarly, 43% yield of 4a was obtained in the absence of additive (Me3Si)2 (Table.1, entry 22). Although, significant effect was observed by addition of Pd(OAc)2 catalyst in the absence of (Me3Si)2 and t-BuOH resulted no product (4a) (Table 1, entry 23). Moreover, we decreased the time of reaction to 24 h with 10 mol% Pd(OAc)2 catalyst in the presence of t-butanol (2 eq.) and stoichiometric equivalent of ((CH3)3Si)2 as additive in THF at 55 oC gave 51% yield of cyanated product (4a) (Table. 1, entry 24). After optimizing the reaction conditions, the developed protocol was used for the cyanation of variety of functionalized aryldiazonium tetrafluoroborates (Scheme 2). The substrate scope was examined with 10 mol% Pd(OAc)2 catalyst in the presence of t-butanol (2 eq.) and stoichiometric equivalent of ((CH3)3Si)2 as additive in THF at 55 oC for 48 h (Scheme 2).
Gratifyingly, electron donating groups attached to aryl ring of diazonium tetrafluoroborate such as methoxy (2a) ethoxy (2b), dimethoxy (2c), trimethoxy (2d), methylthio (2e), phenoxy (2f), and simple methyl group (2g), which stabilized the arenes and reacted well with good to excellent yields (58% _ 88%) of cyanated products (4a _ 4g) (Scheme 2).
Moreover, electron withdrawing functional groups such as cyano group at para and meta positions of aryl ring of diazonium tetrafluoroborate has led to excellent yields (54% and 50%) of terephthalonitrile (4h) and isophthalonitrile (4i) products (Scheme 2) respectively. Similarly, electron sensitive groups (CO2Me, COPh and NO2) attached at different positions to aromatic diazonium tetrafluoroborate ring accelerated well the reaction and transformed into methyl 4-cyanobenzoate (4j), 4-acetylbenzonitrile (4k), 4-nitrobenzonitrile (4l), 3-nitrobenzonitrile (4m) and 4-methyl-3-nitrobenzonitrile (4n) products with good yields (52% to 60%) (Scheme 2). Heterocyclic compounds such as 1-methyl-1H-indole-5-carbonitrile (4o) and benzofuran-5-carbonitrile (4p) are mainly found in biologically active products could be synthesized with 71% and 67% yields (Scheme 2) respectively.
Next, we tried to prepare etravirine which is used as anti-AIDS drug with high potential against mutant HIV strains.[9] It is necessary to mention that unprotected alcohol and amine groups are compatible in our deazoniumcyanation system (Scheme 3). Therefore, we commenced our synthesis by evaluating 4-diazoniumtetrafluoroborate-2,6-dimethylphenol (2q) and 4-diazoniumtetrafluoroborateaniline (2r) under the standard conditions and resulted in 4-hydroxy-3,5-dimethylbenzonitrile (4q) in 67% yield and 4-aminobenzonitrile (4r) in 60% yield (Scheme 3). Moreover, 4-hydroxy-3,5-dimethylbenzonitrile (4q) was used to react with 5-bromo-2,4-dichloropyrimidine through ordinal coupling reactions in one step and furnished 4-((5-bromo-2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (5a) in 93% yields (Scheme 3). Similarly, 4-((5-bromo-2-((4-cyanophenyl)(pivaloyloxy)amino)pyrimidin-4-yl)oxy)benzonitrile (5b) could be synthesized by the reaction of 4-((5-bromo-2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (5a) and 4-aminobenzonitrile (4r) in two steps with total 82% yield, which was transferred into etravirine (5c) in 63% yield based on the modification of reported strategy (Scheme 3).[10]
Conditions: products (4q and 4r) obtained by our general procedure of aromatic diazonium compound at 0.2 mmol scale. For product 5a; 4q (2.5 mmol), K2CO3 (1.1 equiv.), DMF and stirring for 1 h at 30 oC. For product 5b;i) stirring and heating of 4r (2.0 mmol scale), and 5a (1.0 mmol scale), at 150 oC ii) Boc2O (2.1 equiv.), DMAP (10 mol%), Pr2NH (2 equiv.) THF, 30 oC for 1 h. For product 5c; i) (0.1 mmol), AgF2 (1.5 equiv.), MeCN, r.t, 3 h. ii) NH3 (aq.), DMSO (50 equiv.), iPrOH, 80 oC for 2 h. iii) HCl, r.t, 40 min. [b] Isolated yield.
Nitrile (CN) group also serve as carboxylic acid, amide, amine, carbonyl and heterocycle equivalents concluded with various types of conversions.[1d] 2-diazoniumtetrafluoroborate-N-pyrimidine-indole (2s) was subjected to cyanation conditions to form 1H-indole-2-carbonitrile (4s) in two steps with good yields (Cyanation with 59%, and demethylation with 90% yields) (Scheme 4). For typical conversions of 4s into an oxazole (6a), thiazole (6b), amino.hydrochloride (6c), tetrazole (6d), and imidazole (6e). These reactions were repeated as demonstrated in Scheme 4 based on different reports to highlight the importance of 2-cyanoindole (4s).[11] A unique bioactive compound NR2B (6c), a NMDA receptor antagonist, was easily constructed from 4s in two steps with good yield (70%) (Scheme 4).[11]
The mechanistic study for Pd-catalyzed cyanation of aryldiazonium tetrafluoroborate involved similar pathways as that of the other transition metal catalyzed cyanation of substituted aryldiazonium tetrafluoroborate.[7] However, It is assumed that the CN unit (7a) could be produced using Pd/(Me3Si)2 in our reaction system (Scheme 5). The Pd catalyst cycle involve the oxidative addition of Pd to aryldiazonium tertaborate (2) compound and transformation to intermediate (8a) as shown in scheme 5. Subsequently, N2 was released from intermediate 8a (NΞN-Pd(II)-Ar) to the intermediate 8b (NC-Pd(II)-Ar) in anion exchange step (Scheme 5). Finally, Pd(II) was reduced to Pd(0) yielding nitrile product (4) in the reductive elimination step (Scheme 5). Moreover, the C-CN bond cleavage was considered and experiments were performed to mark CN ions in the reaction mixture by paper indicator followed by Cheng’s method (Figure S1).[12] Further, mechanistic study is to find the role of the t-BuOH and (Me3Si)2 is in progress in our laborites.