Catalytic atroposelective electrophilic amination of diaryl anilines and diaryl phenols for the synthesis of axially chiral diaryl compounds

Abstract

Disclosed here is a chiral phosphoric acid-catalyzed atroposelective electrophilic amination reaction, which provides access to a series of axially chiral diaryl compounds through the desymmetric amination reactions of diaryl anilines and diaryl phenols with azodiformates as electrophilic reagents. The reaction could be carried out at room temperature and provide the products with excellent yield and enantioselectivity.

---

1. Introduction

Molecular chirality is an important feature of many functional materials.¹ There are different types of molecular chirality, including point chirality, axial chirality,² planar chirality,³ helical chirality,⁴ inherent chirality,⁵etc. Among them, axially chiral molecules are not only widely present in natural products but have also become a prominent focus of investigation in the fields of drug development and asymmetric synthesis in recent years (Fig. 1).² Therefore, there has been increasing interest in the development of synthetic strategies for axially chiral compounds. The well-established methods include asymmetric coupling reactions,⁶ atroposelective cycloaddition reactions,⁷ desymmetrization reactions⁸ and others.⁹ However, in view of the expanding utility of these molecules, there remains a high demand for developing new alternative methods.

Fig. 1 Selected axially chiral diaryl natural compounds and useful ligand backbones.

Asymmetric desymmetrization allows for selective functionalization of simple symmetric molecules in a chiral environment, which has become an important strategy for the construction of axially chiral compounds.⁸ In 2022, Chen and co-workers¹⁰ reported a chiral selenide-catalyzed atroposelective sulfenylation reaction, achieving the desymmetrization of diaryl phenols to provide access to a series of axially chiral sulfur-containing diaryl phenols. Subsequently, Chen¹¹ expanded this strategy to diaryl anilines, providing access to axially chiral sulfur-containing diaryl anilines. However, in order to enhance enantioselectivity, these reactions generally require extremely low temperatures. A similar desymmetrization process that can proceed at ambient temperature would be complementary to access such axially chiral molecules (Scheme 1).

Scheme 1 Atroposelective electrophilic sulfenylation and amination of diaryl anilines and diaryl phenols.

Azodicarboxylates are common electrophilic amination reagents that have played an important role in organic synthesis, most notably in the Mitsunobu reaction.¹² Recently, they have also received widespread attention for asymmetric synthesis, enabling the synthesis of various types of chiral compounds, including axially chiral,¹³ planar chiral¹⁴ and central chiral¹⁵ compounds. For example, Yang and coworkers¹⁶ achieved the synthesis of axially chiral ether compounds through desymmetrizative amination of the benzene-1,3-diamine fragment of diaryl ethers, but structurally, the amine groups need to be protected. Inspired by these works, we propose to use azodicarboxylates to achieve desymmetrization of both diaryl anilines and diaryl phenols through asymmetric electrophilic amination reactions for the construction of axially chiral diaryl compounds.

2. Results and discussion

To test our hypothesis, we utilized diaryl aniline 1a and diethyl diazene-1,2-dicarboxylate (DEAD) 2a as the model substrates. Initially, in the presence of a catalytic amount of chiral phosphoric acid CPA-1, substrates 1a and 2a reacted expectedly to form the axially chiral product 3a with 71% ee (Table 1, entry 1). Subsequently, we compared the performance of different chiral backbones of the chiral phosphoric acids, including [H₈]BINOL and SPINOL, which indicated that the BINOL backbone provided the best outcome (Table 1, entries 1–3). Next, we investigated the effect of substituents on the 3,3′-positions of the BINOL-based CPAs. It was gratifying to find that the use of 2,6-(ⁱPr)₂–4-admantylphenyl group could increase the enantioselectivity to 82% (Table 1, entry 7). Further screening of solvents and additives indicated that DCM was the best and the use of 3 Å molecular sieves (MS) could further enhance the enantioselectivity (Table 1, entries 8–15). Finally, by reducing the reaction concentration, the enantioselectivity could be further improved to 88% (Table 1, entry 16).

Table 1 Optimization of the reaction conditions^a

Entry	CPA	Solvent	Additive	Yield	ee
a Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), CPA (0.005 mmol, 10.0 mol%) and additive (15 mg) in solvent (0.5 mL) at rt for 3 h. b DCM (2.0 mL) was used.
1	CPA-1	DCM	—	>95%	71%
2	CPA-2	DCM	—	>95%	55%
3	CPA-3	DCM	—	>95%	−17%
4	CPA-4	DCM	—	>95%	Rac
5	CPA-5	DCM	—	>95%	6%
6	CPA-6	DCM	—	>95%	54%
7	CPA-7	DCM	—	>95%	82%
8	CPA-7	DCE	—	>95%	78%
9	CPA-7	CHCl3	—	93%	75%
10	CPA-7	PhCl	—	92%	64%
11	CPA-7	Toluene	—	88%	60%
12	CPA-7	Et2O	—	89%	42%
13	CPA-7	DCM	3 Å MS	>95%	85%
14	CPA-7	DCM	4 Å MS	>95%	80%
15	CPA-7	DCM	5 Å MS	>95%	81%
16^b	CPA-7	DCM	3 Å MS	>95%	88%

---

After condition optimization, we next examined the reaction with different azodicarboxylates. Initially, when DEAD was used as the electrophilic reagent, the standard product 3a could be obtained in 95% yield with 88% ee. Increasing the steric hindrance of azodicarboxylates could further enhance the enantioselectivity. For example, when di-tert-butyl azodicarboxylate (DBAD) was employed, the ee value of the product 3c was increased to 93%. In addition, we also investigated the reactions of dibenzyl and di(methoxymethyl) azodicarboxylates, which led to the corresponding products 3d and 3e, albeit with a slightly reduced enantioselectivity. Azodicarbonamides were also evaluated, but unfortunately, the desired products were not formed in these cases (Scheme 2).

Scheme 2 Scope of azodicarboxylates. Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), CPA-7 (0.02 mmol, 10.0 mol%) and 3 Å MS (60 mg) in DCM (8.0 mL) at rt for 3 h.

With DBAD as the optimal azodicarboxylate reaction partner, we next investigated the functional group tolerance of diaryl anilines (Scheme 3). Generally, all the examined substrates provided the corresponding products with excellent yield and enantioselectivity. The efficiency of the reaction was not affected by the presence of an OMOM substituent on the naphthyl group. Furthermore, the substrate containing a dibenzo[b,d]furan group could also form the optically pure product 3g with 93% yield and 92% ee. Subsequently, we synthesized a series of biphenyl-type diaryl anilines by replacing the naphthyl group with a phenyl group and investigated their reactivity. We were pleased to find that OMOM, OMe, SMe and halogen substituents at the ortho position of the phenyl group could serve as blocking groups, providing the corresponding products 3h–3n with excellent yield and enantioselectivity. Among them, products 3i and 3j have NOBIN skeleton structures, which hold promising potential as chiral backbones for catalyst design. A substrate with a 2-methoxynaphthalen-1-yl substituent was also capable of providing the corresponding product 3o, but unfortunately, a significant decrease in enantioselectivity (only 27% ee) was observed, which might be a result of a significant increase of steric hindrance in proximity to the reaction center.

Scheme 3 Scope of diaryl anilines. Reaction conditions: 1 (0.2 mmol), 2c (0.24 mmol), CPA-7 (0.02 mmol, 10.0 mol%) and 3 Å MS (60 mg) in DCM (8.0 mL) at rt for 5 h–5 d.

After successfully achieving the desymmetrization of diaryl anilines, we envisioned the possibility of extending this protocol to the desymmetrization of diaryl phenols. To our delight, diaryl phenol 4a could selectively undergo electrophilic amination with DEAD as an electrophilic reagent under the standard conditions, leading to the construction of axially chiral compound 5a in 98% yield with 99% ee (eqn (1), 5a). Additionally, diisopropyl azodicarboxylate (DIAD) maintained good reaction efficiency to afford product 5b with excellent yield and enantioselectivity (eqn (1), 5b). Unfortunately, DBAD was not compatible, resulting in a mixture (eqn (1), 5c).

Subsequently, we utilized DEAD as an electrophilic reagent to explore the generality of the diaryl phenol structures. Initially, substrates with different substituents on the naphthyl group, including OMe, halogen, and cyano groups, could undergo the desymmetrization smoothly to afford products 5d–5h with 78–98% yields and excellent enantioselectivity. Similarly, the desymmetrization was also applicable for constructing axially chiral biphenyl-type compounds. The results indicated that the alkyl or halogen substituents on the phenyl group could also serve as effective bulky groups for restricting rotation, resulting in products 5i–5l with excellent ee. Furthermore, the desymmetrization reaction of 1-phenanthryl-substituted diaryl phenol was also successfully achieved, leading to the formation of the axially chiral product 5m with 92% yield and 99% ee. The absolute configuration of the products was confirmed through X-ray single crystal diffraction analysis of 5k (CCDC 2368440†) (Scheme 4).

Scheme 4 Scope of diaryl phenols. Reaction conditions: 4 (0.2 mmol), 2a (0.24 mmol), CPA-7 (0.02 mmol, 10.0 mol%) and 3 Å MS (60 mg) in DCM (8.0 mL) at rt for 24–48 h.

A linear relationship between the ee values of the product and the CPA catalyst was observed, consistent with the involvement of only one CPA molecule in the stereo-determining transition state. It was believed that the CPA catalyst might work as a bifunctional catalyst, activating both reactants in its chiral pocket through hydrogen bonding. A possible enantiodetermining transition state is proposed in Scheme 5, in which the bulky aryl substituents on the catalyst might direct the substrate to approach from the back face due to steric hindrance.

Scheme 5 The proposed stereo-determining transition state.

Next, we demonstrated potential synthetic applications of the products. Product 3c could undergo amidation with isocyanate to synthesize chiral urea 6. Notably, the enantiopurity of product 6 could be improved to 99% after simple recrystallization, thereby permitting further potential utilization as a chiral catalyst. Bromination of product 5a could lead to selective bromination of product 7 in an excellent yield (Scheme 6).

Scheme 6 The synthetic applications.

3. Conclusions

In summary, we have developed an atroposelective electrophilic amination reaction of diaryl anilines and diaryl phenols using azodicarboxylates as electrophilic reagents for the synthesis of a series of axially chiral diaryl compounds. Catalyzed by chiral phosphoric acid, this highly enantioselective process allowed the efficient construction of axially chiral compounds by a desymmetrization strategy, which features mild reaction conditions and good functional group tolerance. In particular, the free diamine functionality can react directly without protection, demonstrating advantages for synthetic applications.

Author contributions

H. Zhu performed the experiments. L. Cheng and J. Wang participated in the synthesis of substrates and CPAs. H. Huang and Z. Han supervised the project. J. Sun and H. Huang wrote the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data for 5k have been deposited at the Cambridge Structural Database under CCDC 2368440.†

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

This work was supported by the NSFC (22071210, 22101033, 22201023, and 22271242), the Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110), the Natural Science Foundation of Jiangsu Province (BK20210849), and the Innovation & Entrepreneurship Talents Plan of Jiangsu Province (JSSCRC2021536).

References

1. (a) W. A. Bonner, The Origin and Amplification of Biomolecular Chirality, Origins Life Evol. Biospheres, 1991, 21, 59–111; (b) P. Xing and Y. Zhao, Controlling Supramolecular Chirality in Multicomponent Self-assembled Systems, Acc. Chem. Res., 2018, 51, 2324–2334; (c) L. D. Barron, From Cosmic Chirality to Protein Structure: Lord Kelvin's Legacy, Chirality, 2012, 24, 879–893.
2. (a) G. Bringmann, T. Gulder, T. A. M. Gulder and M. Breuning, Atroposelective Total Synthesis of Axially Chiral Biaryl Natural Products, Chem. Rev., 2011, 111, 563–639; (b) S. T. Toenjes and J. L. Gustafson, Atropisomerism in Medicinal Chemistry: Challenges and Opportunities, Future Med. Chem., 2018, 10, 409–422; (c) L. Pu, Enantioselective Fluorescent Sensors: A Tale of BINOL, Acc. Chem. Res., 2012, 45, 150–163; (d) S. Schenker, A. Zamfir, M. Freund and S. B. Tsogoeva, Developments in Chiral Binaphthyl-Derived Bronsted/Lewis Acids and Hydrogen-Bond-Donor Organocatalysis, Eur. J. Org. Chem., 2011, 2209–2222; (e) N. Tajuddeen, D. Feineis, H. Ihmels and G. Bringmann, The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids, Acc. Chem. Res., 2022, 55, 2370–2383; (f) J. M. Brunel, BINOL: A Versatile Chiral Reagent, Chem. Rev., 2005, 105, 857–897; (g) K. Ding, H. Guo, X. Li, Y. Yuan and Y. Wang, Synthesis of NOBIN derivatives for asymmetric catalysis, Top. Catal., 2005, 35, 105–116.
3. R. Lopez and C. Palomo, Planar Chirality: A Mine for Catalysis and Structure Discovery, Angew. Chem., Int. Ed., 2022, 61, e202113504.
4. M. Rickhaus, M. Mayor and M. Juricek, Strain-induced Helical Chirality in Polyaromatic Systems, Chem. Soc. Rev., 2016, 45, 1542–1556.
5. M. Tang and X. Yang, Catalytic Enantioselective Synthesis of Inherently Chiral Molecules: Recent Advances, Eur. J. Org. Chem., 2023, 2023, e202300738.
6. (a) Y.-B. Wang and B. Tan, Construction of Axially Chiral Compounds via Asymmetric Organocatalysis, Acc. Chem. Res., 2018, 51, 534–547; (b) F. Zhou, J. Liu and Q. Cai, Transition Metal Catalyzed Asymmetric Aryl Carbon-Heteroatom Bond Coupling Reactions, Synlett, 2016, 27, 664–675; (c) H.-H. Zhang and F. Shi, Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications, Acc. Chem. Res., 2022, 55, 2562–2580.
7. (a) W. Qin, Y. Liu and H. Yan, Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs), Acc. Chem. Res., 2022, 55, 2780–2795; (b) Q. Zhao, C. Peng, Y.-T. Wang, G. Zhan and B. Han, Recent Progress on the Construction of Axial Chirality through Transition-metal-catalyzed Benzannulation, Org. Chem. Front., 2021, 8, 2772–2785; (c) K. Tanaka, Transition-metal-catalyzed Enantioselective [2 + 2 + 2] Cycloadditions for the Synthesis of Axially Chiral Biaryls, Chem. – Asian J., 2009, 4, 508–518; (d) J. Wang, C. Zhao and J. Wang, Recent Progress toward the Construction of Axially Chiral Molecules Catalyzed by an N-heterocyclic Carbene, ACS Catal., 2021, 11, 12520–12531.
8. (a) J. Wencel-Delord, A. Panossian, F. R. Leroux and F. Colobert, Recent Advances and New Concepts for the Synthesis of Axially Stereoenriched Biaryls, Chem. Soc. Rev., 2015, 44, 3418–3430; (b) G.-J. Mei, W. L. Koay, C.-Y. Guan and Y. Lu, Atropisomers beyond the C-C Axial Chirality: Advances in Catalytic Asymmetric Synthesis, Chem, 2022, 8, 1855–1893.
9. (a) J. K. Cheng, S.-H. Xiang and B. Tan, Organocatalytic Enantioselective Synthesis of Axially Chiral Molecules: Development of Strategies and Skeletons, Acc. Chem. Res., 2022, 55, 2920–2937; (b) B.-C. Da, S.-H. Xiang, S. Li and B. Tan, Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of Axially Chiral Compounds, Chin. J. Chem., 2021, 39, 1787–1796.
10. H.-Y. Luo, Z.-H. Li, D. Zhu, Q. Yang, R.-F. Cao, T.-M. Ding and Z.-M. Chen, Chiral Selenide/Achiral Sulfonic Acid Co-catalyzed Atroposelective Sulfenylation of Biaryl Phenols via a Desymmetrization/Kinetic Resolution Sequence, J. Am. Chem. Soc., 2022, 144, 2943–2952.
11. X.-Y. Zhang, D. Zhu, Y.-X. Huo, L.-L. Chen and Z.-M. Chen, Atroposelective Sulfenylation of Biaryl Anilines Catalyzed by Chiral SPINOL-Derived Selenide, Org. Lett., 2023, 25, 3445–3450.
12. (a) P. Singh and Mritunjay, Progress of Dialkyl Azodicarboxylates in Organic Transformations, Asian J. Org. Chem., 2021, 10, 964–979; (b) A. Vallribera, R. M. Sebastian and A. Shafir, Azodicarboxylates as Electrophilic Aminating Reagents, Curr. Org. Chem., 2011, 15, 1539–1577; (c) M. Usman, X.-W. Zhang, D. Wu, Z.-H. Guan and W.-B. Liu, Application of Dialkyl Azodicarboxylate Frameworks Featuring Multi-functional Properties, Org. Chem. Front., 2019, 6, 1905–1928; (d) V. Nair, A. T. Biju, S. C. Mathew and B. P. Babu, Carbon-nitrogen Bond-forming Reactions of Dialkyl Azodicarboxylate. A Promising Synthetic Strategy, Chem. – Asian J., 2008, 3, 810–820.
13. (a) C. Portolani, G. Centonze, S. Luciani, A. Pellegrini, P. Righi, A. Mazzanti, A. Ciogli, A. Sorato and G. Bencivenni, Synthesis of Atropisomeric Hydrazides by One-Pot Sequential Enantio- and Diastereoselective Catalysis, Angew. Chem., Int. Ed., 2022, 61, e202209895; (b) F. Jiang, K.-W. Chen, P. Wu, Y.-C. Zhang, Y. Jiao and F. Shi, A Strategy for Synthesizing Axially Chiral Naphthyl-Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates, Angew. Chem., Int. Ed., 2019, 58, 15104–15110; (c) W. Liu, Q. Jiang and X. Yang, Versatile Method for Kinetic Resolution of Protecting-Group-Free BINAMs and NOBINs through Chiral Phosphoric Acid Catalyzed Triazane Formation, Angew. Chem., Int. Ed., 2020, 59, 23598–23602; (d) D. Wang, Q. Jiang and X. Yang, Atroposelective Aynthesis of Configurationally Stable Nonbiaryl N-C Atropisomers through Direct Asymmetric Aminations of 1,3-Benzenediamines, Chem. Commun., 2020, 56, 6201–6204; (e) D. Wang, W. Liu, M. Tang, N. Yu and X. Yang, Atroposelective Synthesis of Biaryl Diamines and Amino Alcohols via Chiral Phosphoric Acid Catalysed para-Aminations of Anilines and Phenols, iScience, 2019, 22, 195–205; (f) Z. Ye, W. Xie, D. Wang, H. Liu and X. Yang, Atroposelective Synthesis of Diarylamines via, Organocatalyzed Electrophilic Amination, ACS Catal., 2024, 14, 4958–4967.
14. (a) S. Yu, H. Bao, D. Zhang and X. Yang, Kinetic Resolution of Substituted Amido[2.2]paracyclophanes via Asymmetric Electrophilic Amination, Nat. Commun., 2023, 14, 5239; (b) D. Wang, Y.-B. Shao, Y. Chen, X.-S. Xue and X. Yang, Enantioselective Synthesis of Planar-Chiral Macrocycles through Asymmetric Electrophilic Aromatic Amination, Angew. Chem., Int. Ed., 2022, 61, e2022010.
15. (a) Z. Ye, W. Liu, H. Gu and X. Yang, Enantioselective Dearomatization of Substituted Phenols via Organocatalyzed Electrophilic Amination, Org. Lett., 2023, 25, 5838–5843; (b) Q. Jiang, W. Xie and X. Yang, Asymmetric Synthesis of Highly Sterically Congested α-Tertiary Amines via Organocatalyzed Kinetic Resolution, Chem. Commun., 2023, 59, 4762–4765; (c) D. Zhang, Y.-B. Shao, W. Xie, Y. Chen, W. Liu, H. Bao, F. He, X.-S. Xue and X. Yang, Remote Enantioselective Desymmetrization of 9,9-Disubstituted 9,10-Dihydroacridines through Asymmetric Aromatic Aminations, ACS Catal., 2022, 12, 14609–14618; (d) J. Xie, Z. Guo, W. Liu, D. Zhang, Y.-P. He and X. Yang, Kinetic Resolution of 1,2-Diamines via Organocatalyzed Asymmetric Electrophilic Aminations of Anilines, Chin. J. Chem., 2022, 40, 1674–1680; (e) F. He, G. Shen and X. Yang, Asymmetric Aminations and Kinetic Resolution of Acyclic α-Branched Ynones, Chin. J. Chem., 2022, 40, 15–21; (f) Y. Pan, D. Wang, Y. Chen, D. K. Zhang, W. Liu and X. Yang, Kinetic Resolution of α-Tertiary Propargylic Amines through Asymmetric Remote Aminations of Anilines, ACS Catal., 2021, 11, 8843–8848; (g) Z. Wu, S. Krishnamurthy, K. S. S. Tummalapalli and J. C. Antilla, Chiral Calcium Phosphate-Catalyzed Enantioselective Amination of 3-Aryl-2-oxindoles with Dibenzyl Azodicarboxylate, J. Org. Chem., 2022, 87, 8203–8212; (h) X. Fu, Y. Hao, H.-Y. Bai, A. Duan and S.-Y. Zhang, Co-Catalyzed Direct Regio- and Enantioselective Intermolecular γ-Amination of N-Acylpyrazoles, Org. Lett., 2021, 23, 25–30; (i) R. Liu, S. Krishnamurthy, Z. Wu, K. S. S. Tummalapalli and J. C. Antilla, Chiral Calcium Phosphate Catalyzed Enantioselective Amination of 3-Aryl-2-benzofuranones, Org. Lett., 2020, 22, 8101–8105; (j) X.-Y. Huang, P.-P. Xie, L.-M. Zou, C. Zheng and S.-L. You, Asymmetric Dearomatization of Indoles with Azodicarboxylates via Cascade Electrophilic Amination/Aza-Prins Cyclization/Phenonium-like Rearrangement, J. Am. Chem. Soc., 2023, 145, 11745–11753.
16. H. Bao, Y. Chen and X. Yang, Catalytic Asymmetric Synthesis of Axially Chiral Diaryl Ethers through Enantioselective Desymmetrization, Angew. Chem., Int. Ed., 2023, 62, e202300481.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 2368440. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01413h

---