A one-pot process for synthesis of eight-membered cyclopalladated amidines via cascade Csingle bondH activation and insertion

https://doi.org/10.1016/j.jorganchem.2020.121461Get rights and content

Highlights

  • Synthesis of eight-membered cyclopalladated amidines.

  • Without isolation of the intermediates.

  • Superb functional group compatibility.

  • Satisfactory overall yields.

Abstract

A one-pot process involving cascade Csingle bondH activation and insertion between amidines and alkynes in the presence of palladium salt is described. With this methodology, various novel eight-membered cyclopalladated amidines were efficiently constructed. Notably, a series of functionalities with potential application were readily accommodated under the reaction conditions. Isotope effects and H/D exchange suggested that this cascade is initiated by the cleavage of the ortho Csingle bondH bond in the N-phenyl ring of amidines.

Introduction

Organopalladium compounds have significantly enriched organo-transition-metal chemistry and attracted considerable attention in recent years [1], [2], [3], [4], [5]. Among them, palladacycle [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17] equipped with at least one metal-carbon bond and at least one donor atom, [18] has been of particular interest due to the advantages of easy preparation and separation, [19] good compatibility with functional groups, stability, and extensive participation in organic synthesis [20], [21], [22], [23], [24]. Thus, the development of new approaches to palladacycle is highly desirable.

Since pioneering work by Cope demonstrated the cyclopalladation of azobenzene derivatives, [25], [26], [27] classical methodologies for the formation of palladacycles have been achieved, such as oxidative addition, [28], [29], [30], [31], [32] transmetalation, [33] and nucleophilic addition onto an unsaturated bond [34], [35] (Scheme 1, Eq. 1). Moreover, the directed chelation-assisted palladation of Csingle bondH bonds [36], [37], [38], [39], [40] has been realized as the most concise and practical strategy for the formation of palladacycles, as the precoordination of a given donor atom (N, [41], [42] P, O, [43], [44], [45], [46] S45, and others) to palladium metal enables effectively stabilizing Pd-C bond. Na2PdCl4, [3] Pd(OAc)2 or Pd(COD)X246 can be employed as palladating reagents, usually giving access to five- [47], [48], [49] or six membered palladacycles [50], [51], [52], [53]. Nevertheless, the construction of eight-membered palladacycles by Csingle bondH activation is an attractive but less explored approach [54]. The Pdsingle bondC bond exhibits a rich reactivity toward unsaturated molecules that has been widely exploited for the construction of ring-enlarged palladacycles [55], [56]. In this context, mono- and dialkyne insertion reactions of palladacycles, [57] in many cases, containing amino, imino, pyridyl, and azo functionalities, have been studied to afford eight-membered palladacycles over the past few decades (Scheme 1, Eq. 2). For example, Vicente's group has disclosed the synthesis of eight-membered palladacycles by insertion of olefins into the Pdsingle bondC bond of ortho-palladated arylalkylamines [58] or phenethyl-amines, [59] as well as by alkyne mono insertions into the Pdsingle bondC bond of cyclopalladated phenylacetamides [43], homoveratryl- amine, [60] and phenethylamines [61]. Meanwhile, Thirupathi's group has investigated alkyne insertion reactions of cyclopalladated guanidines, delivering eight-membered palladacycles in high yield [62], [63], [64]. Unfortunately, these methods typically require multistep sequences, isolation of the intermediates, and also suffer from limited type of eight-membered palladacycles and unsatisfactory low overall yields. Therefore, it is highly desirable to develop an efficient one-pot process to construct novel eight-membered palladacycles in one pot.

Imine nitrogen atom of amidine has been used as an assisted donor group for the stabilization of six-membered cyclopalladated complexes. However, to the best of our knowledge, eight-membered palladacycles, derived from amidines and alkynes, have not been reported. Herein, we report a unique and convergent method for high-yield cyclopalladation of amidines to afford eight-membered palladacycles. This method undergoes a cascade Csingle bondH bond activation and two-fold alkyne insertion into Pdsingle bondC bond in one pot.

The optimization of the cascade protocol is detailed in Table 1. We selected N-phenylbenzimidamide 1a and 1,2-diphenylethyne 2a as the model substrates, and the isolated yield was calculated based on Pd source. Metal sources, additives and other reaction conditions were systematically varied when an excess of 1a was employed. A series of additives typically employed for C-H activation reactions were examined, and a significant yield was observed with iPrOH (entries 1-3). Detailed examination of several additives of this family showed MeOH, EtOH and butyl alcohol to be the competent additives, whereas the yield of 3aa decreased significantly (51%) when HFIP was used (entries 4-7). A variety of Pd sources were also screened, with Pd(OAc)2 providing the best reactivity (entry 3). The use of PdCl2(PPh3)2 as reactant failed to promote the reaction, while other Pd salts were also competent, albeit with lower yields (entries 9-12). Further screening of solvents showed that the mixture of toluene and DCE (v/v =1:4) was found to give the highest yield (entry 3). However, the use of toluene, dioxane or PhCl as the solvent failed to provide the desired product 3aa (entries 13-16). Altering the reaction temperature to 110 °C or 40 °C was not beneficial for this reaction, as 3aa was obtained in 60% and 0% yields, respectively (entries 17 and 18). In addition, some carboxylic acids such as CH3COOH and nicotinic acid have been added to the reaction mixture, which have led to a decrease in the yield of 3aa (entries 19 and 20). When the ratio of 2a and 1a was changed to 2:1, the desired product was obtained in 67% yield (entry 21).

With the optimized Csingle bondH activation/insertion manifold in hand, we explored the scope of the reaction with regard to amidines to survey the generality of the reaction, and the results are summarized in Scheme 2. The transformations were compatible with both electron-donating and electron-withdrawing substitutions in general, thus leading to eight-membered cyclopalladated amidines in low to good yields (22–89%, 22 examples). A variety of valuable functional groups were tolerated in this protocol, including: halogen (1b-1c, 1j-1l, 1q), aryl (1i), methoxy (1f, 1p, 1t), or even -OCF3 (1g) and CF3 (1d) groups. The most convincing example was the synthesis of product 3ba with the yield up to 87%. The structures of 3ia and 3pa were unambiguously confirmed by single-crystal X-ray crystallography (see SI). The substrates 1c-1l, regardless of the electronic nature and different positions of substituent located on ring A of amidines, result in the expected products 3ca-3la in 36-57% yields. Amidines featuring a para- or meta-substituent on ring B, were efficiently converted into the desired products (3ma-3ta) with good efficiency, whereas para- halide groups proved to be problematic. When N-phenyl-1-naphthimidamide 1u and N- (naphthalen-1-yl) benzimidamide 1v were used as substrates, products 3ua and 3va were obtained, albeit with lower yields due to the incomplete conversions of amidines (39% and 33% yields, respectively). It is noteworthy that thiophene-based amidine was also identified as viable substrate, furnishing the desired product 3wa in 51% yield. However, pyridine-based amidines completely shut down the transformation. It is probably attributed to direct coordination of palladium complex by the nitrogen atom of pyridine ring.

The scope of the alkyne partners was also investigated, and the results are shown in Scheme 3. The reactions of either symmetrical- or unsymmetrical diaryl alkyne substrates (2a2m) with 1a and Pd(OAc)2 proceeded smoothly to provide the eight-membered palladacycles 3aa-3am in moderate to good yields. Specifically, halide (F, Cl, Br), alkyl (Me), and alkoxy (MeO, EtO) were well tolerated under the reaction conditions. Importantly, the chloride or bromide on the aromatic ring offers an opportunity for further transformations. The substrates possessing para- and meta- substituents on the benzene ring could be converted to the desired products 3ab-3ah in similar yields range from 56% to 72%. When the chloro group on the phenyl ring was changed from meta to para-position, the yield of the corresponding products increased from 62% to 72% yield (3af and 3ad). Notably, the unsymmetrically substituted alkyne served as suitable substrates, however, a mixture of isomers 3ai-3am were isolated (Supporting Information (SI)).

To further validate the synthetic potentiality of eight-membered cyclopalladated amidines, the Suzuki-Miyaura coupling reactions involving iodine benzene and PhB(OH)2 was carried out in the presence of 5 mol% 3aa and 2 equiv of K2CO3 in DMF, delivering the desired 1,1′-biphenyl 4aa in 71% yield. The result demonstrated that 3aa was deemed to be a good catalyst for Suzuki cross-coupling reaction (Scheme 4). Treatment of 3aa with pyridine under reflux conditions failed to generate depalladated product [65].

To shed light on the mechanism of this cascade reaction, a series of control experiments and deuterium-labeling experiments were conducted (Scheme 5). An intermolecular competition experiment between 1a and [D5]-1a revealed a 3.6:1 KIE. This observation suggested that C-H bond cleavage might be involved in the rate-determining step. After that, reaction of [D5]-1a and 2a under the standard conditions delivered [D5]-3aa in 43% yield, wherein 9% H/D exchange was observed at the ortho-position of amidine (SI). This result indicates that the C-H activation forms a Pd-C species and the process is reversible. In addition, the reaction of 1a and 2a in the presence of 4 equiv of D2O at 80°C gave the desired product 3aa in 26% yield, and 1H NMR analysis of the isolated product revealed that H/D exchange (20%) was observed at the ortho position of the ring B. Meanwhile, [D]-1a was recovered and deuterium incorporations at the ortho position of aryl group attached to nitrogen atom (32%) were detected. These results indicate that Csingle bondH cleavage is probably reversible. After that, we probed the electronic preference of this reaction via amidines competition experiments. First, the reaction between 1d and 1e differing in electronic effects on ring A of amidines was conducted with 2a for 4 h, and then 3ea and 3da (7% yield, 1.3:1) were isolated. Second, subjecting 1q and 1s to the reaction, this process provided the mixture of 3qa, 3ra, and the corresponding 3sa in 0.45:1 ratio (R=Cl or Me). This phenomenon reveals that the reaction is more favorable for amidines bearing electron-donating substituents on ring B.

Based on the aforementioned results and the literature precedents, a plausible mechanism is proposed using N-phenylbenzimidamide 1a and 1,2-diphenylethyne 2a as an example (Scheme 6). Initially, Csingle bondH activation at the ortho-H of N-phenyl ring of amidine gives rise to six-membered palladacycle I, as previously suggested in the formation of 3aa containing partial H-D exchange (Scheme 5, Eq. 2). The intermediate I undergoes an insertion reaction with 2a to afford the eight-membered palladacyclic intermediate II. Subsequent amine-imine tautomerization and E/Z isomerization can lead to the intermediate III, which can be transformed to desired product 3aa via insertion with a second alkyne.

Section snippets

Conclusions

In conclusion, a cascade Csingle bondH bond activation and dialkyne insertion reaction between amidines and alkynes in the presence of Pd(OAc)2 has been described. This one-pot synthesis enables the rapid fabrication of novel eight-membered palladacycles in good to excellent yield without separation of six-membered cyclopalladated intermediate. Notably, the developed reaction tolerates various valuable functional groups, including Br, Cl, F, and CF3, thus providing potential application in organic and

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We are grateful to the support from the National Natural Science Foundation of China (21701148), the Program for Innovative Research Team in Science and Technology in University of Henan Province (20IRTSTHN003), Key Projects of Colleges and Universities in Henan Province (17A150053), and the Natural Science Foundation of Henan Province (NO. 162300410318).

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