Investigation of reaction conditions. To validate the hypothesis, we commenced our studies by evaluating the reaction between 1-methyl-2-(phenylethynyl)benzene (1a) and benzonitrile (2a) in THF at 100 oC in the presence of different alkali metal salts (Table 1). Several metal amides in combination with t-BuOK were initially tested (entries 1−3), and LiN(SiMe3)2 turned out to be the best choice to give product 3a in 35% yield. Subsequently, screening of the reaction temperatures identified the optimal 120 oC (entries 4−6). The examination of other parameters including additive, solvent, and reaction time (entries 7−15) revealed that the reaction proceeded well with t-BuOK as additive in CPME for 24 h, improving the yield of 3a to 65%. Next, investigation of detailed molar ratios of all components indicated that excess nitrile was required due to the consumption of self-cyclotrimerization, and the well-balanced interaction between LiN(SiMe3)2 and t-BuOK is the key to the success of reaction (entries 16 and 17, see the Supporting Information for details). Finally, the reaction of 1a: 2a: LiN(SiMe3)2: t-BuOK in a molar ratio of 1: 3: 2: 1.5 gave 3a in 80% isolated yield (entry 17).
Substrate scope. Having established the optimal reaction conditions, the scope of this [4+2] cycloaddition reaction was then explored (Table 2). Pleasingly, o-substituted aryl alkynes 1 with electron-donating substituents, such as -Me, -t-Bu, and -OMe at the 4-position of aromatic ring Ar1, were well compatible in this reaction, and the desired products (3b–3d) were isolated in 60-78% yields. o-Substituted aryl alkyne bearing 3-Me substituted Ar1 also reacted with 2a to afford 3e in a slightly descending yield, while the substrates containing halogens were relatively limited (e.g., 3f). The reaction proceeded as well with a larger aromatic Ar1, 2-naphthyl, providing the corresponding adduct 3g in 65% yield. Moreover, when using a series of functionalized nitriles 2 as reactants, including p-Me, p-t-Bu, p-OMe, p-Ph, and m-t-Bu substituted benzonitriles, isoquinoline derivatives (3h-3l) with moderate to good yields (48-82%) were obtained The structure of 3i was confirmed unambiguously by X-ray diffraction. The substituent R1 on arylmethane ring could be varied as well (3m-3p) under the standard conditions. When R2 was replaced by a cyano group, contributing to relatively acidic benzyl protons, the cycloadditions occurred smoothly in the absence of lithium amide (3q-3r). In addition, the introduction of a sterically demanding phenyl at the benzylic position enabled the release of larger conjugated isoquinoline derivative in 45% yield (3s). Benzylic C-H bond with a methyl group at the benzylic position could also be functionalized in this reaction albeit in 28% yield (3t). However, the substrate with a phenoxy group R2 failed to undergo the desired [4 + 2] cycloaddition reaction (3u).
To further expand the generality of this method, a series of functionalized heteroaromatic substrates were utilized to test the reactivity (Table 3). The result indicated 3-alkynyl-2-methylbenzo[b]thiophene (4) with different substituents (H, OMe, N,N-2Me) on the aromatic ring Ar1 were well tolerated, converting to the fused heterocycle benzothienopyridine derivatives 5a-5c in 71-90% yields. Gratifyingly, halogens, such as 4-F, 4-Cl, 4-Br, 3-Cl and 3,5-2F, could also be installed on the same aromatic ring Ar1, and the corresponding products 5d-5h were obtained in acceptable to good yields. The generated heteroaryl halides provided versatile synthetic handles for further derivatization. Moreover, the synthesis of compounds 5j-5n with 53-71% yields suggested that the compatibility of substituents on nitrile has been extended to -Cl, -CF3, -OMOM, and -1,3-dioxolane derived fromaldehyde group, thus providing a platform for additional functionalization. 3,5-Disubstituted benzonitrile and 2-naphthonitrile were also applicable in this system, and the desired products 5o and 5p were delivered in 72% and 66% yields, respectively. It should be noted that the pincer-type or dipyridyl-type nitrogen ligands 5i, 5q and 5r could be constructed in good yields. More importantly, this protocol was also applied to the late-stage functionalization of drug molecule citalopram, which is a selective serotonin-uptake inhibitor, and the compound 5s was provided in 67% yield, exhibiting the potential in pharmaceutical research.
Specifically, this method also applied to the substrates bearing less acidic C(sp3)-H bonds. For instance, the desired reaction of (Z)-pent-3-en-1-yn-1-ylbenzene (6) and 2a was carried out successfully after simply adjusting the reaction conditions to afford the product 2-benzyl-6-phenylpyridine (7a) in 60% yield (Table 4). Then substituted nitriles with 4-t-Bu, 4-OMe, -Ph, 3-Me and 3,5-2Me were further examined, and a series of 2,6-disubstituted pyridines were isolated in 35-58% yields (7b-7f). To our knowledge, this is the rare example of demonstrating possibility of formal allylic C-H bond addition to nitrile.
To further illustrate the value of this method, gram-scale experiments and postderivatizations of the newly formed products were conducted (Fig. 3). When the reaction proceeded at a 5 mmol scale, the desired products 3c and 5a were obtained in almost unaffected yields even with reduced amount of nitrile. Additionally, inspired by the importance of organic fluorophores in a number of fields including materials science and biology, two new solid-state-emitting organic molecules 8 and 9 were synthesized. Tetraarylethylene 8 was obtained by a single Suzuki–Miyaura coupling of 5f with 60% yield, while the successive hydrolysis and condensation reaction of 5n gave compound 9 in 95% total yield. Studies on the photophysical propertie showed the absorption maxima of 8 and 9 were about 336 nm and 385 nm in DMSO solution, respectively, and the corresponding intense emission peaks were at 404 nm and 587 nm in powder, which might find applications in construction of functional materials.
Mechanistic investigations. To shed light on the reaction mechanism, several control experiments were performed. Firstly, when 15N-labeled benzonitrile was emplyed under the standard reaction conditions, 3c(15N) and 3c(14N) were detected respectively with the ratio of 49: 51 by HRMS analysis, elucidating that the nitrogen atom in the pyridine framework came not only from nitrile but also LiN(SiMe3)2 (Fig. 4a). Then, the studies of introducing exogenous halogens PhX (X = F, Cl, or Br) to the reaction system showed that fluorobenzene slightly reduced the yield of 3c, while chlorobenzene and bromobenzene greatly suppressed the transformation, indicating that the coordination of PhX to the alkali metals might account for the inhibitory effect (Fig. 4b).83 Next, a Hammett study was carried out using various substituted benzonitriles to investigate a rate dependence on the electronic effect of nitrile (Fig. 4c). A linear
relationship with negative ρ value of -2.95 was observed when relative rates with -OMe, -Me, -H, -Cl, and -CF3 substituted benzonitriles [log(kX/kH)] were plotted against the substituent constant (σ). These results suggested that the electron-donating group should facilitate the intermolecular addition step, which was consistent with the reactivity of the nitrile substrates reported in Tables 2-4. Finally, the kinetic order experiments (Fig. 4d) showed a first-order dependence on concentrations of 2a, which indicated that the formation of metalated imine by quickly capturing benzylic−metal species with nitrile should be the rate-limiting step. However, the benzyl substrate 1c, theoretically accelerating an equilibrium formation of benzylic−metal species, exhibited the negative-order kinetic effect in the reaction. Moreover, the rates of both t-BuOK and LiN(SiMe3)2 could not be described by a single power function. These observations aligned with the optimization data possibly portend the well-balanced interactions between base and additive for benzylic or allylic C(sp3)-H activation. This cooperative interaction was further proved with hydrogen/deuterium exchange experiment of 1c-d (Fig. S1).
Based on the above investigation and literature reports,82-90 a possible mechanism is proposed in Fig. 5. Initially, the C(sp3)-H bond of 1a is activated by the interaction of LiN(SiMe3)2 and t-BuOK to afford a nucleophilic benzylic−metal species A, which is quickly trapped by nitrile 2a to form the metalated imine intermediate B. Next, subsequent addition of intermediate B to the alkyne achieves the cyclization. The resulting alkenyl-metal species C undergoes protonation and 1,5-hydrogen shift process to deliver the desired 3a. Alternatively, the reaction could proceed by either protonation or silylation of intermediate B with HN(SiMe3)2 from the initial deprotonation equilibrium, generating imine D.82 In the presence of Li/KN(SiMe3)2, the imine D would undergo a reversible addition, silyl migration, and elimination pathway to release nitrogen-exchanged intermediate F,91,92 followed by the further silyl transfer and cyclization to give nitrogen-exchanged intermediate G.