Enantioselective Syntheses of Tricyclic Benzimidazoles via

Letter Cite This: Org. Lett. 2019, 21, 608−613

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Enantioselective Syntheses of Tricyclic Benzimidazoles via Intramolecular Allylic Aminations with Chiral-Bridged Biphenyl Phosphoramidite Ligands Xiaoding Jiang,† Xiangmeng Chen,† Yongsu Li,† Hao Liang,† Yaqi Zhang,† Xiaobo He,† Bin Chen,† Wesley Ting Kwok Chan,‡ Albert S. C. Chan,† and Liqin Qiu*,†

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†

School of Chemistry, The Key Laboratory of Low-Carbon Chemistry & Energy Conservation of Guangdong Province, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China ‡ Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, People’s Republic of China S Supporting Information *

ABSTRACT: The first iridium-catalyzed enantioselective intramolecular allylic aminations of benzimidazole-tethered allylic carbonates were developed, providing three classes of tricyclic benzimidazoles bearing a tertiary carbon stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, 99% ee). Wide substrate scope, excellent catalytic efficiency and mild conditions rendered this protocol particularly superior and practical. Impressively, the chiral bridge with a tunable structure was shown to provide a very good adjustment space for the chiral environment. The excellent catalytic performance of the ligands manifested their advantages over the bisphenol-based and BINOL-derived counterparts in these transformations. It also highlighted the potential application value of the chiral-bridged ligands.

B

enantioselectivities were dissatisfactory.9 In view of the importance of chiral molecule’s interaction modes in medicinal chemistry,10 successful construction of these chiral frameworks will undoubtedly contribute to the establishment of relevant bioactive molecules and their intermediate libraries for biological evaluations. Consequently, the development of catalytic asymmetric protocols to efficiently access these enantiomeric frameworks is highly desired in drug discovery. Recently, iridium-catalyzed asymmetric allylic aminations have received increased attention from scientists in enantioselective syntheses of bioactive compounds.11 Related studies have also brought about remarkable advances in catalyst design.12 At present, the most representative ligands for the iridiumcatalyzed allylations are chiral phosphoramidites, such as Feringa’s13/Alexakis’s14 P,C ligands, Carreira’s P,olefin ligand,15 and You’s Me-THQphos ligand.16 All of these were derived from 1,1′-bi-2-naphthol (BINOL) (Figure 2). Despite the impressive progress, challenges remain for the fact that highly effective catalysts and ligands suitable for a wide range of substrates are still limited. Since Chan and co-workers introduced the diastereoselective syntheses of biphenyl diphosphine ligands bearing additional sp3 chiral centers on the backbone,17 several types of chiral-bridged

enzimidazole-fused piperazinone, piperazine, and diazepanone derivatives are of high value, because of their diverse biological properties including antiviral,1 anti-inflammatory,2 anticoagulant,3 anticancer,4 and antimicrobial5 activities, as well as the capability of serving as liver X receptor (LXR) agonists,6 and poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors7(Figure 1). Accordingly, considerable effort has been directed toward the syntheses of these tricyclic benzimidazoles.8 Nevertheless, direct asymmetric catalytic approaches to such chiral scaffold of nitrogen-containing tricyclic system are scarce. So far, only one publication involved the preparation of benzimidazole-fused piperazines with a tertiary carbon stereogenic center, but the synthetic pathway was quite tedious and the

Figure 1. Representative bioactive molecules containing relevant scaffolds. © 2019 American Chemical Society

Received: November 14, 2018 Published: January 15, 2019 608

DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613

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Organic Letters

Table 1. Ligand Optimization for Allylic Amination of Sa-1a

Figure 2. Representative (a) binaphthyl phosphoramidites and (b) chiral-bridged biphenyl phosphoramidites.

atropisomeric phosphine ligands, such as P,N or P,O ligands, were developed and successfully applied in transition-metalcatalyzed asymmetric reactions.18 Very recently, we developed an array of chiral-bridged phosphoramidite ligands that showed better catalytic performance than their BINOL-derived counterparts in the iridium-catalyzed asymmetric addition of arylboronic acids to N-protected isatins (Figure 2).19 Introduction of a chiral bridge with variable chain length not only offered a great potential in fine-tuning of the ligand dihedral angle but also provided extra ligand rigidity and chiral control.20 On this basis, we herein report the interesting results of enantioselective syntheses of tricyclic benzimidazoles via intramolecular allylic aminations with chiral-bridged biphenyl phosphoramidite ligands. According to Marco Bandini’s works,21 regardless of the allylic carbonate CC configuration, it made no difference to the absolute configuration of allylation product, except for yield and enantioselectivity. Therefore, readily available (E)-configurated allylic carbonates were designed for intramolecular allylic alkylation in our research. Initially, with the iridium catalyst generated from [Ir(cod)Cl]2 (2 mol %), L1 (4 mol %),22 reaction of Sa-1 proceeded smoothly in the presence of KF (1.1 equiv) as a base in THF at 50 °C, affording product I-1 with 92% yield and 85% enantiomeric excess (ee). Careful examination of bases showed that K3PO4 was optimal. No improvement in enantioselectivity was observed by using more or lower catalyst loading. Temperature variation made some difference in the outcome, and the best result was obtained at 30 °C (99% yield, 95% ee). The use of solvents other than THF did not lead to any improvement (see Table S1 in the Supporting Information for details). As shown in Table 1, the use of ligand L2, a diastereoisomer of L1, resulted in a sharp decrease in yield and enantioselectivity (50% vs 99% yield, 31% vs 95% ee; see Table 1, entries 1 vs 2). Similar observation could be made in the reactions with ligands L7 and L8 (Table 1, entries 7 vs 8). Thus, it is easy to infer that the consistency of axial chirality and central chiralities of the amine is the preferential configuration in this case. Moreover, the enantioselectivity decreased with the increase of the bridge fragment flexibility (entries 1, 2 vs 7, 8), and shorter bridge linker also had negative influence (Table 1, entries 4 vs 6), which indicated that an appropriate dihedral angle of the bridged ligands was essential for better catalytic results. Ligands L3−L5 only provided moderate yields and very low ee values (Table 1, entries 3−5), suggesting that small steric hindrance in the amine moiety was not beneficial to the yield and enantioselectivity. Inspired by these findings, we further modified the amine moiety and synthesized new ligands L9− L10 with a more bulky amine from (R)-[6,6′-(2S,4Sbutanedioxy)]-(2,2’)-dihydroxy-(1,1’)-biphenyl and enantiopure 2-methyl-1,2,3,4-tetrahydroquinoline.23 As expected,

entry

ligand

time

yieldb [%]

eec [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14

L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L13 L14

20 min 48 h 24 h 24 h 24 h 24 h 24 h 24 h 20 min 2h 4h 1h 40 min 8h

99 50 38 78 82 67 86 36 99 82 76 98 99 86

95 (R) 31 (R) 0 37 (R) 48 (R) 25 (R) 78 (S) 55 (S) 99 (S) 61 (S) 65 (R) 84 (R) 90 (S) 72 (S)

a

Conditions: [Ir(cod)Cl]2 (2 mol %), ligand (4 mol %), K3PO4 (0.22 mmol), and Sa-1, (0.2 mmol) in THF (2.0 mL) at 30 °C. bIsolated yields. cDetermined by HPLC analysis.

(S,S,Ra,R)-L9 was highly effective, giving the corresponding product of reverse configuration with 99% yield and 99% ee in 20 min (Table 1, entry 9), whereas (S,S,Ra,S)-L10 with the opposite stereocenter of the chiral amine subunit led to remarkably decreased efficiency (2 h, 82% yield and 61% ee; see Table 1, entry 10). Again, this demonstrated the considerable effects of consistency/inconsistency between stereochemical elements of the chiral amine and axial chirality in the ligands.24 Impressively, bisphenol-based ligand L11 and Feringa’s (R)-BINOL-derived ligands L12 and L13 all gave significantly inferior results compared with the corresponding chiral-bridged ligands under similar conditions (Table 1, entries 11−13). This provides further evidence of necessity and effectiveness of the chiral bridge regulation on the asymmetric catalytic performance of the ligand.18 The scope of the reaction under the optimized conditions is shown in Scheme 1. Importantly, regardless of the electronic properties of the protecting group on the linking N atom, various benzimidazole-fused piperazinones (I-1−I-5) could be constructed in consistently good yields and high enantioselectivities. Furthermore, both electron-donating group (5-MeO) and electron-withdrawing group (5,6-F2, 5,6-Cl2, 5-NO2) were compatible with the procedure. Notably, the substrate 609

DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613

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Organic Letters Scheme 1. Substrate Scope of Saa−c

Scheme 2. Substrate Scope of Sba−c

a

Conditions: [Ir(cod)Cl]2 (2 mol %), L9 (4 mol %), K3PO4 (0.22 mmol) and substrate (0.2 mmol) in THF (2.0 mL) at 30 °C for 20 min. bIsolated yields. cDetermined by HPLC analysis.

containing a MeO or NO2 group on the benzimidazoles core afforded two products with excellent ee values in 65:35 and 95:5 yields, respectively. This could be attributed to the existence of tautomerism of the corresponding substrates. The absolute configuration of product (R)-I-1 was determined by X-ray crystallography (see the Supporting Information for details). Subsequently, another class of benzimidazole-tethered allylic carbonates Sb were probed as substrates for preparing benzimidazole-fused piperazines. Model reaction of Sb-1a was set up and explored to obtain the optimal conditions. Satisfactorily, ligand L9 still exhibited the best catalytic performance. Especially, shorter reaction time highlighted an obvious advantage of ligand L9 over other ligands. Other leaving groups such as OAc, OBoc, or OTroc all led to significantly lower yields and enantioselectivities (see Table S2 for details). As shown in Table S3, the addition of DBU (2.0 equiv) as the base was beneficial to full conversion of the substrate and higher enantioselectivity. Further temperature tests showed that 50 °C was appropriate for the reaction. In addition, MTBE was identified as the crucial solvent for higher enantioselectivity. As summarized in Scheme 2, all studied substrates containing different protecting groups on the amine moiety in the tether produced the corresponding products with very good yields and excellent enantioselectivities (92%−99% ee). The electronic effect of substituents on the benzimidazole core was also investigated. Obviously, both electron-donating groups (5,6Me2) or electron-withdrawing groups (5,6-F2, 5,6-Cl2) served well in the transformation, furnishing the desired products in high yields and excellent enantioselectivities. The absolute configuration of these products was deduced from the configuration of their analogues I-1−I-12. Concurrent with these studies, we prepared another substrates Sc for constructing novel chiral benzimidazole-fused diazepanone derivatives. Through the reaction of Sc-1 with the catalyst composed of [Ir(cod)Cl]2 (2 mol %), ligand L1 (4 mol %), and K3PO4 (1.0 equiv), product III-1 was successfully obtained in 99% yield albeit with 74% ee. Exploration of various bases revealed that DABCO was the best choice. Systematic screening of solvents revealed that DME afforded optimal selectivity (see Table S4 for details). The reaction conducted at 30 °C can provide the corresponding product in 99% yield and 88% ee (Table 2, entry 2). Finally, several ligands with relatively

a

Conditions: [Ir(cod)Cl]2 (2 mol %), L9 (4 mol %), DBU (0.4 mmol) and substrate (0.2 mmol) in MTBE (2.0 mL) at 50 °C for 4 h. b Isolated yields. cDetermined by HPLC analysis.

Table 2. Selected Optimization of the Reaction Conditions toward III-1a

entry

ligand

t [°C]

time [h]

yieldb [%]

eec [%]

1 2 3 4 5 6 7 8 9 10

L1 L1 L1 L1 L1 L8 L9 L11 L12 L13

50 30 20 0 reflux 30 30 30 30 30

0.5 0.5 0.5 12 0.5 10 0.5 12 4 2

99 99 99 97 99 78 99 75 85 92

83 (R) 88 (R) 81 (R) 71 (R) 76 (R) 58 (S) 99 (S) 46 (R) 63 (R) 84 (S)

a

Conditions: [Ir(cod)Cl]2 (2 mol %), ligand (4 mol %), Sc-1 (0.2 mmol), and base (0.2 mmol) in DME (2.0 mL) at 50 °C. bIsolated yields. cDetermined by HPLC analysis.

good performance in the aforementioned reactions were further investigated. Interestingly, L9 was still the optimum ligand, affording full conversion and 99% ee in only 30 min (Table 2, entry 8). For comparison, L11−L13 were also examined but all were inferior to L9 for the lower enantioselectivity, catalytic activity, and extended reaction time (Table 2, entries 9−11). The significant differences in the catalytic performance reconfirmed the unique importance of the chiral bridges and their structural fine-tuning. Scheme 3 summarizes the scope of Sc under the optimized conditions. Altering the skeleton structure had no deleterious effect and seven-membered rings can also be assembled in this 610

DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613

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Organic Letters Scheme 3. Substrate Scope of Sca−c

To further verify the robustness of this method, gram-scale reactions of Sa-1, Sb-1a, and Sc-7 were performed, respectively. Apparently, the reactions still generated the corresponding products without much detriment to yields and enantioselectivities (Scheme 4). Scheme 4. Gram-Scale Reactions

a

Conditions: [Ir(cod)Cl]2 (2 mol %), L9 (4 mol %), base (0.2 mmol) and substrate (0.2 mmol) in DME (2.0 mL) at 30 °C for 30 min. b Isolated yields. cDetermined by HPLC analysis. d1.0 equiv of DABCO was used. e2.0 equiv of DBU was used.

In summary, we have developed a highly efficient, enantioselective iridium-catalyzed intramolecular allylation of benzimidazole-tethered allylic carbonates. The methods enables access to synthetically valuable tricyclic benzimidazoles with a tertiary carbon stereogenic center in high yields (up to 99%) and excellent enantioselectivities (up to 99% ee). Wide substrate scope, excellent catalytic efficiency, and mild conditions demonstrated the superiority and practicability of this methodology. In comparison with classical ligands, the employment of chiral-bridged biphenyl phosphoramidite ligands greatly improved the enantioselectivity and reactivity of the process, which contributed crucially to the success of these asymmetric transformations. The chiral-bridged ligand with a tunable structure was shown to provide a very good adjustment space for the chiral environment. Besides, the results highlighted the potential application value of the chiral-bridged ligands. Further studies regarding the mechanistic details and the applications of the resulting chiral compounds are currently underway in our laboratory.

manner. Substrates bearing varying substituents at R4 including H, straight-chain, or branched alkyl groups (CH3, CF3, isopropyl) and cycloalkyl groups (cyclopropyl, cyclohexyl) underwent the desired reactions smoothly, providing products III-1−III-6 in high yields with excellent enantioselectivities (93%−99% ee). Thereinto, the electron-rich group CH3 was slightly better than the electron-deficient group CF3 for stereoselectivity. Interestingly, when R4 became aryl groups, DABCO as the base was not good enough to maintain high enantioselectivity, despite still affording nice yields. This may be largely ascribed to the different steric effect of R4. Delightfully, however, just replacing 1.0 equiv of DABCO with 2.0 equiv of DBU, reactions of these substrates could also be realized perfectly, thus affording products III-7−III-26 in excellent yields and ee values. The influence of electronic nature of substituents on the reaction efficiency was relatively small. Both electron-rich substituents (CH3, OCH3, isopropyl) and electron-deficient substituents (F, Cl, Br, CF3, NO2, CN) at para-position of the aromatic ring showed no significant difference, all furnishing the corresponding products excellently. Remarkably, hydroxyl group was also tolerated, giving product III-19 in 90% yield with 95% ee. The installation of substituents at the ortho-, meta-, or para-position of the phenyl ring did not affect the catalytic efficiency. Similarly, reactions of substrates bearing double (3,4-Me2, 3,5-Cl2) or triple (3,4,5-(OMe)3 substituents all gave excellent enantioselectivities as well. The introduction of bulky 1-naphthyl group at R4 was also feasible. Even for substrates possessing a heteroaryl group such as furyl or thienyl ring, the reactions still proceeded smoothly. All these results demonstrated the versatility of this synthetic methodology. The absolute configuration of product (R)-III-7 was also confirmed by X-ray crystallographic analysis (see the Supporting Information for details).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03640. Experimental details, characterization data, NMR spectra of new compounds, and HPLC traces (PDF) Accession Codes

CCDC 1879975 and 1879976 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 611

DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613

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Organic Letters

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiaoding Jiang: 0000-0002-4288-476X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant No. 21772238), Special Financial Fund of Innovative Development of Marine Economic Demonstration Project (No. GD2012-D01-001) and Natural Science Foundation of Guangdong Province (No. S2011010001305). We also appreciate Prof. Qing-Hua Fan (Institute of Chemistry, Chinese Academy of Sciences) and Prof. Yong-Gui Zhou (Dalian Institute of Chemical Physics, Chinese Academy of Sciences) for the very generous support of enantiopure 2-methyl-1,2,3,4-tetrahydroquinoline.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613

Letter

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DOI: 10.1021/acs.orglett.8b03640 Org. Lett. 2019, 21, 608−613