Palladium-catalyzed diastereoselective cross-coupling of two aryl halides via C–H activation: synthesis of chiral eight-membered nitrogen heterocycles

Cang Cheng , Xiang Zuo , Dongdong Tu , Bin Wan and Yanghui Zhang *
School of Chemical Science and Engineering, Shanghai Key Laboratory of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road, Shanghai 200092, China. E-mail: zhangyanghui@tongji.edu.cn

Received 25th January 2021 , Accepted 11th February 2021

First published on 12th February 2021


Abstract

A method for the synthesis of enantiopure eight-membered nitrogen heterocycles has been developed through diastereoselective cross-coupling of 2-iodobiphenyls with 2-bromobenzylamines. The products represent a novel type of chiral scaffold, which feature easy modification and high configurative stability and have the potential to be applied in asymmetric synthesis. Palladacycles that were formed via the C–H activation of 2-iodobiphenyls should act as the intermediates. The reaction provides a new strategy for the synthesis of medium-sized ring compounds.


Chirality is a fundamental property of molecules, and it is of prime significance in chemistry, medicine, and biology. Chirality can be factorized into three elements, namely stereogenic centers, axes of chirality, and planes of chirality.1 Central chirality has been the topic of extensive research in asymmetric synthesis, and axial chirality has gained considerable interest and made noticeable progress recently.2 As a comparison, planar chirality is underexploited and its studies are primarily limited to ferrocenes.3

Tetraphenylene (tetrabenzo[a,c,e,g]cyclooctatetraene) possesses a very intriguing saddle-shaped structure. Owing to their unique geometry, tetraphenylene and its derivatives are not only of great theoretical interest, but also can find numerous applications in materials science and supramolecular chemistry.4 More importantly, although tetraphenylene is achiral, the introduction of substituents may create chirality. The privileged planarly chiral skeleton of substituted tetraphenylenes provides great opportunities for designing novel ligands for asymmetric synthesis.5 However, the construction of the chiral tetraphenylene core is very challenging, and very rare reactions are available, which restricts the applications of tetraphenylenes in asymmetric synthesis.6 All the chiral tetraphenylene derivatives for use in asymmetric catalysis and materials science were obtained by resolution. Furthermore, the current research on the application of chiral tetraphenylenes is limited to the derivatization of the benzene rings of tetraphenylenes. We envisioned that replacing one of the phenyl groups of tetraphenylene with an N-containing functional group would give a new chiral scaffold (Fig. 1a). The nitrogen atom could act as a coordinating site. Moreover, the functional group would allow for the ready modification of the scaffold, which is essential to search for optimal chiral ligands in asymmetric synthesis.


image file: d1cc00398d-f1.tif
Fig. 1 Synthesis of chiral eight-membered nitrogen heterocycles through diastereoselective cross-coupling of palladacycles.

To obtain the nitrogen-incorporated analogues of tetraphenylene, we first needed to develop a protocol for the construction of eight-membered nitrogen heterocycles. Medium-ring structures (8–11-membered rings), in particular N-heterocycles, exist in a variety of bioactive natural products,7 and are desirable scaffolds in drug discovery.8 However, the construction of medium-sized rings remains a challenging goal in organic synthesis due to the unfavorable entropy effect and transannular interactions.9 Although diverse methods have been developed, including intramolecular cyclization, ring-expansion, and cycloaddition,10 it is still highly desirable to develop facile and efficient strategies to gain access to these intriguing structures.

C,C-Palladacycles have a cyclic structure containing two C–Pd bonds (Fig. 1b). These two C–Pd bonds can be functionalized to develop organic reactions, in particular, those for the synthesis of cyclic molecules.11 We envisioned that the unique complex could be utilized to develop new strategies for the construction of medium-ring structures. It should be mentioned that C,C-palladacycles can be obtained by the intramolecular C–H activation of aryl halides, and therefore the reactions have advantages such as high atom- and step-economy.12

Herein, we report a facile method for the construction of eight-membered N-heterocycles via the coupling of C,C-palladacycles with 2-bromobenzylamines. The reaction proceeded diastereoselectively to afford enantiopure products, which represent a novel type of chiral scaffold.

We commenced the studies by investigating the Pd-catalyzed coupling reaction of model substrates 2-iodobiphenyl 1a and 2-bromobenzylamine 2a. The major challenge to form the desired eight-membered ring is to overcome the potential double N-arylation of the benzylamine, which would form a carbazole product.13 The carbazole-forming reaction involves a five-membered ring closing process, so it is much more favorable than the formation of the eight-membered heterocycle. Gratefully, after an extensive survey of the reaction conditions, product 3aa was obtained in 91% yield under the conditions as shown in eqn (1) (for the detailed condition survey, see the ESI).

image file: d1cc00398d-u1.tif

Having developed an efficient protocol for the construction of eight-membered rings, we then investigated its substrate scope. The performance of substituted 2-bromobenzylamines was first probed. As shown in Scheme 1, a range of 2-bromobenzylamines bearing a substituent at the 5-positions underwent the coupling reaction to afford the corresponding nitrogen heterocycles (3ab-3af). While electron-donating groups gave high yields, the presence of electron-withdrawing groups resulted in lower yields. In the low-yielding reactions, carbazoles were formed as the major side products by double N-arylation of the benzylamine. Halo groups, including F, Cl and Br, were well tolerated (3ag-3ai). An ortho-substituent had little influence on the yields (3aj-3al). Notably, the reaction was also compatible with heteroarenes, including pyridine and thiophene, albeit in a low yield, and the analogue derived from naphthalene was also suitable (3am-3ao). The reactions of secondary amines were also investigated. Methyl- and benzyl-substituted benzylamines coupled with 1a effectively (3ap and 3aq). Moreover, the reaction was also compatible with the benzylamine bearing two benzylic methyl groups (3ar).


image file: d1cc00398d-s1.tif
Scheme 1 Substrate scope with respect to 2-bromobenzylamines.

The substrate scope with respect to 2-iodobiphenyls was also probed (Scheme 2). The reactions of symmetrically substituted 2-iodobiphenyls were first examined. A variety of substrates bearing two electron-donating, electron-withdrawing, or halo groups, could react with 2a to afford the corresponding eight-membered products (3ba-3fa). However, the yields were lower than those obtained in the reactions of 2-iodobiphenyl. Lower yields were also caused by the side carbazole-forming reactions. For a substrate bearing one substituent, the reaction produced two isomeric products in a ratio of 1 to 1 (3ga-1 and 3ga-2).


image file: d1cc00398d-s2.tif
Scheme 2 Substrate scope with respect to 2-iodobiphenyls.

It is noted that the eight-membered cyclic products are chiral. For example, 3aa was separable by chiral HPLC. The eight-membered ring represents a novel chiral skeleton, which has great application potential in asymmetric synthesis. Therefore, we set out to study the synthesis of the enantiopure products. Notably, enantiopure 2-bromobenzylamine derivatives bearing a benzylic substituent are commercially available or can be readily synthesized via diastereoselective Grignard addition reaction of chiral N-sulfinyl imines.14 We envisioned that the enantiopure products could be obtained by using chiral 2-bromobenzylamine derivatives if the reactions were diastereoselective. We first investigated the reaction of methyl-substituted 2-bromobenzylamine (Scheme 3). Gratefully, the chirality of the benzylamine was completely transferred to the eight-membered ring. No diastereomers were observed and almost a single enantiomer was obtained (5aa). Encouraged by this result, we examined the reactions of other chiral 2-bromobenzylamines. The benzylamines bearing a cyclopropyl or n-heptyl underwent the coupling reaction with 1a in excellent diastereoselectivity (5ab and 5ac). A TBS-protected γ-aminoalcohol was also suitable (5ad). This outcome is significant because the TBS protecting group can be removed readily and the resulting γ-aminoalcohol allows easy access to bidentate ligands. The reactions of chiral 2-bromobenzylamines derivatives bearing substituents on the benzene rings were then studied. A range of substituents were compatible, and the corresponding products were obtained with very high enantiopurity and in moderate to good yields (5ae-5ak). Remarkably, although the reactions proceeded at 130 °C for 12 hours, excellent enantiomeric excesses were still obtained, which indicated that racemization did not occur even under harsh conditions and the chiral products are highly stable.


image file: d1cc00398d-s3.tif
Scheme 3 Substrate scope with respect to 2-bromobenzylamines in the synthesis of enantiopure eight-membered cyclic products. [a] (R)-2-bromoaniline derivatives were used. [b] (S)-2-bromoaniline derivatives were used.

Next, we investigated the diastereoselective reactions of 2-iodobiphenyl derivatives. As outlined in Scheme 4, a variety of symmetrically substituted 2-iodobiphenyls reacted with 4a diastereoselectively, affording the desired enantiopure products.


image file: d1cc00398d-s4.tif
Scheme 4 Substrate scope with respect to 2-iodobiphenyls in the synthesis of enantiopure eight-membered cyclic products.

To gain insight into the mechanism of the coupling reaction, we prepared palladacycle 1a-C (Scheme 5). 1a-C was allowed to react with 2a under the analogous conditions. Product 3aa was obtained in a 40% yield. Furthermore, two isomers were formed in a ratio of 1 to 1 in the reaction of 1g. These outcomes indicate that the reactions should involve palladacycles as the intermediates (for the detailed mechanism, see the ESI). To determine the absolute configuration of the chiral products, 5aa was brominated to give compound 5aa-B. The structure of 5aa-B was identified by single-crystal X-ray crystallography. Remarkably, the molecule still has a saddle-shaped structure. The two opposite benzene rings are oriented above the average plane of the molecule, and the other benzene ring is below the plane.


image file: d1cc00398d-s5.tif
Scheme 5 Preliminary mechanistic studies and determination of the absolute configuration.

The products have a unique chiral structure and provide opportunities for designing chiral ligands. In particular, the amino group in the products can be readily derivatized and allows easy access to various ligands. On the other hand, chiral phosphoramidite ligands are a class of robust ligands for asymmetric catalysis and have found wide applications in diverse catalytic asymmetric reactions.15 Therefore, we transformed product 5aa to phosphoramidite ligand 6 (Scheme 6). It should be mentioned that the ee value of 6 remains unchanged. Next, ligand 6 was applied to copper-catalyzed conjugate addition of diethylzinc to chalcone.16 The desired product 7 was obtained with 26% ee. Although the enantioselectivity was low, it indicates that the eight-membered skeleton has application potential in asymmetric catalysis.


image file: d1cc00398d-s6.tif
Scheme 6 Synthesis of chiral phosphoramidite ligands and application in the asymmetric reactions.

In conclusion, we have developed a facile method for the synthesis of eight-membered nitrogen heterocycles through Pd-catalyzed cross-coupling of 2-iodobiphenyls with 2-bromobenzylamines. C,C-Palladacycles that are formed via the C–H activation of 2-iodobiphenyls should act as the intermediates. This reaction provides a new strategy for the construction of medium-sized rings. The coupling reaction proceeded with high diastereoselectivity to form enantiopure products. The resulting eight-membered nitrogen heterocycles represent a novel type of chiral scaffold, which has great potential to be applied in asymmetric synthesis. Studies towards the synthesis of other medium-sized rings and applications of the chiral products are underway in our lab.

The authors acknowledge financial support from the National Natural Science Foundation of China (No. 21672162 and 21971196).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

Electronic supplementary information (ESI) available: Optimization of the reaction conditions, experimental procedures, characterization data of all new compounds, NMR spectra and single-crystal X-ray diffraction data of compound. CCDC 5aa2044586 and 5aa-B2044587. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1cc00398d

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