Highly Chemo- and Diastereoselective Dearomative [3 + 2

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Highly Chemo- and Diastereoselective Dearomative [3 + 2] Cycloaddition Reactions of Benzazoles with Donor−Acceptor Oxiranes Shan-Shan Zhang, Dong-Chao Wang,* Ming-Sheng Xie, Gui-Rong Qu, and Hai-Ming Guo*

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Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China S Supporting Information *

ABSTRACT: A Sc(OTf)3-catalyzed dearomative [3 + 2] cycloaddition of benzazoles with donor−acceptor oxiranes through chemoselective C−C bond cleavage of oxiranes was developed under mild conditions. This reaction provides an efficient method to construct benzazolo[3,2-c]oxazole compounds in good yields and with high diastereoselectivity. The reaction has a general substrate scope, and the donor−acceptor oxiranes with electron-donating and electron-withdrawing groups on the aromatic ring afforded the desired cycloadducts.

B

Recently, we developed a novel strategy to synthesize complex polyheterocyclic compounds by direct dearomative [3 + 2] cycloaddition reactions of benzothiazoles and D−A cyclopropanes (Scheme 1a).14 As a part of our ongoing efforts on dearomative reactions of benzazole compounds, herein, we report an efficient Lewis acid-catalyzed [3 + 2] cycloaddition of D−A oxiranes and benzazoles via C−C bond cleavage of oxiranes for the preparations of benzazolo[3,2-c]oxazole derivatives in excellent yields and with high chemo- and diastereoselectivities (Scheme 1b).

enzazoles are an indispensable structural motif in drug discovery and found to have a broad spectrum of therapeutic applications such as anticancer, antihypertensive, anticoagulant, antibacterial, antifungal, antimalarial, anticonvulsant, antiviral, and analgesic.1,2 In particular, 10 drugs in the top 200 pharmaceutical products are benzazole derivatives.3 Dearomatized benzazole motifs are found as core skeletons in natural and unnatural polycyclic molecules.4 Recently, dearomatization reactions of benzazoles for the rapid preparation of three-dimensional fused heterocyclic compounds have attracted much attention.2,5 Therefore, development of efficient methods to construct complex benzazole derivatives is highly desirable. Carbonyl ylides, a useful class of 1,3-dipoles in [3 + 2] cycloaddition reactions, have been often used to construct oxaheterocyclic skeletons such as 1,3-dioxolane, oxazolidine, and tetrahydrofuran.6,7 Donor−acceptor (D−A) oxiranes received remarkable attention as an economical and mild source of carbonyl ylide. Various [3 + 2] cycloaddition reactions of D−A oxiranes with different unsaturated double bonds such as C C,8,9 CO,10 CN,11 CS,12 and CN13 have been reported in the literature. Among them, Zhang and co-workers8a developed a dearomative [3 + 2] cycloaddition of D−A oxiranes and indoles via selective C−C bond cleavage of oxirane for the synthesis of furo[3,4-b]indole compounds for the first time. Subsequently, Feng and co-workers8b demonstrated an efficient catalytic asymmetric system for dearomative [3 + 2] cycloaddition of D−A oxiranes and indoles. To the best of our knowledge, dearomative [3 + 2] cycloadditions of D−A oxiranes with other aromatic compounds have not been reported. © XXXX American Chemical Society

Scheme 1. Dearomative [3 + 2] Cycloaddition Reactions of Benzazoles

Received: November 13, 2018

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DOI: 10.1021/acs.orglett.8b03615 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(Table 1, entry 15). When the dearomative cycloaddition reaction was conducted on gram scale, cycloadduct 3aa was isolated in 87% yield (see Scheme S1). After optimizing the reaction conditions, we explored the scope of this dearomative cycloaddition reaction by varying substituent R1 of benzothiazole substrates. As shown in Scheme 2, benzothiazoles bearing electron-donating or electron-with-

Our investigation began with the 1,3-dipolar cycloaddition of oxirane 2a with benzothiazole 1a. We initially carried out the screening of Lewis acids at room temperature in the presence of 4 Å molecular sieves (MS) using DCE as a solvent. As shown in Table 1, Ni(ClO4)2·6H2O, Yb(OTf)3, and Sc(OTf)3 successTable 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope of Benzothiazoles for the Dearomative [3 + 2] Cycloadditiona

entry

catalyst (mol %)

tempb (°C)

solvent

yieldc (%)

1 2 3 4 5 7 8 9 10 11 12 13 14 15d 16d 17e

Ni(ClO4)2·6H2O (20) Yb(OTf)3 (20) Sc(OTf)3 (20) Zn(OTf)2 (20) Cu(OTf)2 (20) MgI2 (20) Ni(OTf)2 (20) Sc(OTf)3 (20) Sc(OTf)3 (20) Sc(OTf)3 (20) Sc(OTf)3 (20) Sc(OTf)3 (20) Sc(OTf)3 (10) Sc(OTf)3 (10) Sc(OTf)3 (5) Sc(OTf)3 (10)

rt rt rt rt rt rt rt rt rt rt rt rt rt rt 60 rt

DCE DCE DCE DCE DCE DCE DCE DCM toluene CHCl3 MeCN 1,4-dioxane DCE DCE DCE DCE

86 79 92 17 20:1) and excellent chemoselectivity (only C−C bond cleavage of oxirane) in satisfactory yields using 20 mol % catalyst loading (Table 1, entries 1−3). Among them, Sc(OTf)3 showed the highest efficiency and gave the product 3aa in 92% yield (Table 1, entry 3). However, the other Lewis acids showed a lower catalytic activity (Table 1, entries 4−8). DCE was found to be the best solvent among the screened solvents. Then we optimized other conditions such as catalyst amount, reaction time, and temperature. When the reaction was carried out with 10 mol % of Sc(OTf)3 for 16 h, the isolated yield of desired cycloadduct 3aa was only 47% (Table 1, entry 14). On the other hand, when the reaction was carried out for 3 days with 10 mol % of Sc(OTf)3, the cycloadduct 3aa was obtained in 93% yield (Table 1, entry 15). When 5 mol % of Sc(OTf)3 was used, the conversion rate was still low even after the reaction was carried out at 60 °C for 3 days, and the isolated yield of cycloadduct 3aa was only 62% (Table 1, entry 16). Considering the efficiency of reaction, 10 mol % catalyst loading at room temperature was selected as the optimized reaction condition. In addition, the dearomatized cycloadduct was not observed in the absence of MS (Table 1, entry 17). Thus, the optimized reaction conditions are as follows: 10 mol % of Sc(OTf)3, 1.0 equiv of 1a, and 2.0 equiv of 2a in 1.0 mL of DCE at room temperature for 3 days

drawing substituents reacted smoothly with oxirane 2a and led to the corresponding cycloadducts (3aa−la) in good yields and with excellent diastereoselectivities. We next examined the scope of this dearomative cycloaddition by varying R2 and Ar of oxiranes under the optimized conditions. In general, compared with the substrate scope in the dearomative cycloaddition of indoles with epoxides, the current dearomative cycloaddition has a more general scope for the oxiranes. As shown in Scheme 3, the D−A oxiranes with electron-donating and electron-withdrawing groups on the aromatic ring were able to afford the desired cycloadducts. Obviously, D−A oxiranes with electron-rich aryl groups exhibited a higher reactivity than those with electron-deficient aryl groups (Scheme 3, 3ab−ao). Furthermore, the reactivity of oxiranes varied depending on the position of halogen on the aryl groups. For example, using oxiranes with 4-halogen substituted aryl group under the optimal conditions, the desired cycloadducts were obtained in 62−78% yields (Scheme 3, 3ab−ad). 3-Halogen-substituted oxiranes afforded products in 67−72% yields using 20 mol % catalyst loading (Scheme 3, 3ae, 3af). The structure of product 3af was confirmed by single-crystal X-ray diffraction analysis. On the B

DOI: 10.1021/acs.orglett.8b03615 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Substrate Scope of Oxiranes for Dearomative [3 + 2] Cycloadditiona

Scheme 4. Dearomative [3 + 2] Cycloaddition of Benzimidazoles 4a−d with Oxirane 2aa

a

Unless otherwise noted, the reaction conditions are as follows: Sc(OTf)3 (20 mol %), 4 (0.1 mmol), 2a (0.2 mmol), and activated 4 Å MS (60 mg) in DCE (1.0 mL) under N2 at 60 °C for 48 h. b10 mol % of Sc(OTf)3 at at room temperature for 3 days. Product 7 was purified by neutral alumina column chromatography.

by single-crystal X-ray diffraction analysis. The other substituents such as acetyl, tert-butyloxyformyl, and vinyl gave a relatively low yield (Scheme 3, 5ba−da). However, dearomatized cycloadducts were not observed with N1-methyl and -benzyl benzimidazoles, perhaps due to the effect of electron-donating alkyl groups. However, the desired reaction of benzoxazole with oxirane 2a proceeded smoothly, and the corresponding cycloadduct 7 was obtained in 86% yield. It should be noted that the product 7 is easily decomposed on a silica gel column. Finally, the conversion of products into other products with useful functional groups was also studied. As shown in Scheme 5,

a

Reaction conditions: Sc(OTf)3 (10 mol %), 1a (0.1 mmol), 2 (0.2 mmol), and activated 4 Å MS (60 mg) in DCE (1.0 mL) under N2 at room temperature for 3 days. b20 mol % of Sc(OTf)3 at 60 °C for 6 days, c20 mol % of Sc(OTf)3.

Scheme 5. Further Transformation of the Cycloadduct 3aa

other hand, the reactions of 2-chlorophenyl oxirane 2g required 20 mol % catalyst loading, higher reaction temperature, and longer reaction time to afford the desired product 3ag (Scheme 3, 57% yield). In addition, 3,4-dichlorophenyl oxirane 2h with 20 mol % catalyst loading afforded the adduct in 53% yield (Scheme 3, 3ah). In contrast, all of the D−A oxiranes with electrondonating groups gave the corresponding products in 89−94% yields (Scheme 3, 3ai−ao). Moreover, the 1-naphthylsubstituted oxirane furnished the corresponding product in 94% yield (Scheme 3, 3ap). In the end, the oxiranes with various R2 showed a slight effect on the reactivity and afforded the desired dearomatized products in 96% and 92% yields (Scheme 3, 3aq, 3ar). In addition, 3-(thiophene-3-yl)oxirane 2s gave the desired product 3as (Scheme 3) in 86% yield. As shown in Scheme 4, we also examined the reactivity of benzimidazoles and benzoxazole under the optimal conditions. Obviously, benzimidazoles are less reactive than benzothiazoles, and the dearomative [3 + 2] cycloaddition of benzimidazoles required 20 mol % catalyst loading at 60 °C. Effect of various N1 substituent groups of benzimidazoles on their reactivity was also explored. When N1-tosyl (Ts) benzimidazole was employed, the dearomatized cycloadduct 5aa was obtained in 81% yield (Scheme 4). The structure of compound 5aa was also confirmed

selective reduction of ester groups of 3aa was achieved with NaBH4 in CH3OH by varying temperature and time. The reduction of monoester was achieved at 0 °C in 6 h, affording 8 in 64% yield (Scheme 5a), whereas the reduction of both the ester groups to the corresponding alcohols (9, Scheme 5b) was observed at 60 °C in 12 h. In summary, we have successfully developed an efficient dearomative [3 + 2] cycloaddition of benzazoles with donor− acceptor oxiranes through chemoselective C−C bond cleavage of oxiranes under mild conditions. In the presence of Sc(OTf)3 catalyst, a series of benzazolo[3,2-c]oxazoles were synthesized in good yields and with high diastereoselectivities. The reaction has a general substrate scope for oxiranes with electron-donating and electron-withdrawing groups on the aromatic ring. C

DOI: 10.1021/acs.orglett.8b03615 Org. Lett. XXXX, XXX, XXX−XXX

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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.8b03615. Experimental procedures and compound characterization data (PDF) Accession Codes

CCDC 1873311 (3af), 1873309 (5aa) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Dong-Chao Wang: 0000-0002-5037-4727 Ming-Sheng Xie: 0000-0003-4113-2168 Hai-Ming Guo: 0000-0003-0629-4524 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. 2167255 and U1604283), Program for Youth Backbone Teacher Training in University of Henan Province (2017GGJS042), and the 111 Project (No. D17007).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03615 Org. Lett. XXXX, XXX, XXX−XXX