Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE6 Jun 2022Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction Guihua Pan, Changli He, Min Chen, Qian Xiong, Weidi Cao and Xiaoming Feng Guihua Pan Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Changli He Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Min Chen Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Qian Xiong Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Weidi Cao *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author and Xiaoming Feng *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101060 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report the first asymmetric three-component nucleophilic addition/dearomative [4+2] cycloaddition/isomerization cascade of transient dipoles generated from N-heteroarenes and allenoates with methyleneindolinones in the presence of chiral N,N′-dioxide/metal complexes. This tandem reaction enabled rapid access to versatile chiral polycyclic N-heterocycles with good to excellent enantioselectivities under mild reaction conditions in spite of the strong background reaction, including 1,2-dihydroisoquinoline, 1,2-dihydropyridine derivatives, and others. Meanwhile, a series of control experiments were conducted to elucidate the reaction mechanism and the roles of additives. Download figure Download PowerPoint Introduction Nitrogen-containing heterocyclic compounds represent the largest and most diverse family of organic compounds, which play a crucial role in numerous pharmaceuticals and agrochemicals.1–4 A recent analysis of U.S. Food and Drug Administration (U.S. FDA) approved drugs reveals that 59% of small-molecule drugs contain at least one N-heterocycle.2 As a significant subset of such compounds, hydroisoquinoline and hydropyridine motifs are particularly interesting.1 For instance, hydroisoquinoline skeletons are prevalent in bioactive alkaloids and drug molecules, such as crystamidine ( A), jamtine ( B), haiderine ( C), and emetine ( D) (Scheme 1a).5–11 Note also that hydropyridines are useful synthetic intermediates for the synthesis of complex nitrogenous natural products and pharmaceutical targets12–15 as exemplified by the practical asymmetric synthesis of the influenza drug (–)-oseltamivir (Tamiflu, E).13 Therefore, the development of expeditious entries to hydroisoquinoline and hydropyridine derivatives, especially enantioenriched ones containing diverse peripheral functional groups, would make a great contribution to the discovery of new bioactive molecules or drugs. Scheme 1 | (a and b) Representative biologically active N-heterocyclic compounds and catalytic asymmetric dearomative three-component reaction. Download figure Download PowerPoint Dearomatization strategy in a multicomponent fashion represents one of the most efficient methods for the construction of natural-product-like structures,16–21 which can easily achieve extended molecular complexity and diversity from simple starting materials with high atomic economy. Huisgen 1,4-dipoles generated from heteroarenes (such as pyridine, quinolone, and isoquinoline) and electrophilic π-systems (such as acetylenic esters, allenoates, and diazoesters) are a broadly explored topic in dearomatization chemistry for the construction of (poly)cyclic N-heterocycles.22–26 Among these activated π-systems, allenoates27–29 as an important electrophilic reagent have been less explored. Only the Nair’s30,31 and Shi’s32 groups have reported multicomponent reactions of isoquinoline, allenoate, and α,β-unsaturated compound or activated ketone, respectively. A key transient 1,4-dipole was involved through the nucleophilic addition of isoquinoline to 1,3-diester substituted allene, and subsequently intercepted by the trapping component through [4+2] cycloaddition, affording the isoquinoline derivatives with low to moderate yields and diastereoselectivities. To the best of our knowledge, the enantioselective version of such a dearomative multicomponent reaction in this field is still a great challenge, which may be attributed to the highly reactive and short-lived zwitterions, giving rise to strong background reactions and great difficulty for the stereocontrol.33–35 Inspired by the good performance that N,N′-dioxide-based chiral Lewis acid catalysts showed in activation and stereocontrol of methyleneindolinone compounds via bidentate coordination,36–39 we proposed that the stereoselective control of a sequential dearomative multicomponent reaction involving allenoate could be realized through the careful choice of this type of ligand and metal salt. Herein, we present the first asymmetric three-component nucleophilic addition/dearomative [4+2] cycloaddition/isomerization cascade of N-heteroarenes, allenoates, and methyleneindolinones in the presence of chiral N,N′-dioxide-Mg(II) complexes (Scheme 1b). The nucleophilic component of the multicomponent reaction, including bicyclic aromatic (isoquinoline, quinoline, phthalazine, and phenanthridine), was successfully varied, as well as the more challenging monocyclic aromatic pyridine because of its increased resonance stabilization and possibility of poisoning the catalytic system.20,26 As a result, a wide range of chiral N-heterocyclic compounds could be afforded in good to excellent results under mild reaction conditions. Experimental Methods General procedure for asymmetric reaction with 2a To an oven-dried tube was added Mg(OTf)2 (3.2 mg, 0.01 mmol, 10 mol %), L3-Pi c H (4.9 mg, 0.01 mmol, 10 mol %), and methyleneindolinone 1b (33.1 mg, 0.10 mmol) under N2 atmosphere. Tetrahydrofuran (THF; 0.5 mL) was added, and the mixture was stirred at 35 °C for 30 min. Then the mixture was concentrated in vacuo, and CH2Cl2 (1.0 mL) and H2O (0.5 μL) were added. Subsequently, the isoquinoline 2a (12.9 mg, 0.10 mmol) and allenoate 3a (22.1 mg, 0.12 mmol) were added at 20 °C under air atmosphere. The reaction mixture was stirred at 20 °C for 2 h, then Et3N (0.05 mmol, 50 mol %) was added and stirred for another 2 h. The reaction was directly subjected to flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane/diethyl ether = 7∶1∶1) to afford the product 4b. General procedure for asymmetric reaction with 5a To an oven-dried tube was added Mg(OTf)2 (3.2 mg, 0.01 mmol, 10 mol %), L3-PrEt2Me (4.7 mg, 0.01 mmol, 10 mol %), and methyleneindolinone 1b (33.1 mg, 0.10 mmol) under N2 atmosphere. THF (0.5 mL) was added, and the mixture was stirred at 35 °C for 30 min. Then the mixture was concentrated in vacuo, and CH2Cl2 (1.0 mL) and H2O (0.5 μL) were added. Subsequently, the 4-phenylpyridine 5a (15.5 mg, 0.10 mmol) and allenoate 3b (18.7 mg, 0.12 mmol) were added at 20 °C under air atmosphere. The reaction mixture was stirred at 20 °C for 36 h. Then the reaction was directly subjected to flash column chromatography on silica gel (petroleum ether/dichlorometane/ethyl acetate = 6:1:1 = 4∶1) to afford the product 6a. Results and Discussion In the initial study, we employed methyleneindolinone 1a as the electrophile to trap the transient intermediate, which formed from isoquinoline 2a and diethyl allenedicarboxylate 3a, to optimize the reaction conditions (Table 1). In the preliminary screening, when the reaction was carried out without chiral ligand/metal salt complex, the desired product 4a was obtained in 63% yield with low diastereoselectivity (2.6∶1 dr), revealing the existence of a strong background reaction (Table 1, entry 1). Next, several metal salts coordinating with chiral N,N′-dioxide L3-PiPr2 were tested in CH2Cl2 at 35 °C. L3-PiPr2/Mg(OTf)2 could promote the reaction to give the desired product 4a in 60% yield, >19∶1 diastereomeric ratio (dr), and 38% enantiomeric excess (ee) along with a small amount of exocyclic alkene product Int-4a (entry 2). When Mg(OTf)2 changed into Ni(OTf)2 or Zn(OTf)2, the product 4a could be obtained in moderate yield but as a racemic version (entries 3 and 4). To our surprise, when rare-earth metal salts were used, such as Y(OTf)3 and Yb(OTf)3, nearly optically pure product with the opposite configuration was obtained (entries 5 and 6). Combined with our previous work40 and the control experiments (see Supporting Information), we thought that YIII or YbIII led to the deprotection (N-Boc) of 4a through a kinetic resolution process in the presence of N,N′-dioxide. Subsequent investigation of the ligands showed that L3-Pi c H gave better results than L3-Pr c H and L3-Ra c H (entries 7–9). Lowering the reaction temperature to 20 °C slightly improved the enantioselectivity but with lower yield (entry 10). When 1b was used instead of 1a as the trapping dipolarophile as well as reducing the reaction concentration, the desired product 4b was obtained in 73% yield with >19:1 dr and 94% ee (entry 12). It should be noted that Et3N could accelerate the transformation of Int-4b into 4b to give a higher yield (entry 13 and see Supporting Information). The addition of H2O reduced the reactivity and may have precluded the background reaction, which slightly improved the enantioselectivity (see Supporting Information). Thus, the optimized reaction conditions were established (entry 14, 92% yield, >19∶1 dr, and 94% ee). Table 1 | Optimization of the Reaction Conditions for the Construction of Chiral 1,2-Dihydroisoquinolinesa Entry 1 Metal Salt Ligand T (°C) Yield (%)b drc ee (%)c 1 1a — — 35 63 2.6∶1 0 2 1a Mg(OTf)2 L3-PiPr2 35 60 >19∶1 38 3 1a Ni(OTf)2 L3-PiPr2 35 82 11∶1 0 4 1a Zn(OTf)2 L3-PiPr2 35 54 >19∶1 0 5 1a Y(OTf)3 L3-PiPr2 35 30 >19∶1 −99 6 1a Yb(OTf)3 L3-PiPr2 35 31 >19∶1 −99 7 1a Mg(OTf)2 L3-Pi c H 35 81 >19∶1 86 8 1a Mg(OTf)2 L3-Pr c H 35 77 >19∶1 57 9 1a Mg(OTf)2 L3-Ra c H 35 64 >19∶1 75 10 1a Mg(OTf)2 L3-Pi c H 20 69 18∶1 90 11d 1b Mg(OTf)2 L3-Pi c H 20 71 >19∶1 91 12d–e 1b Mg(OTf)2 L3-Pi c H 20 73 >19∶1 94 13d–f 1b Mg(OTf)2 L3-Pi c H 20 88 >19∶1 90 14d–g 1b Mg(OTf)2 L3-Pi c H 20 92 >19∶1 94 aUnless otherwise noted, all reactions were carried out with 1 (0.10 mmol), 2a (0.10 mmol), 3a (0.10 mmol), Ligand/metal salt (1:1, 10 mol %) in CH2Cl2 (0.5 mL) for 10 h. bIsolated yield. cDetermined by high-performance liquid chromatography (HPLC) or supercritical-fluid chromatography (SFC) analysis using a chiral stationary phase. dPerformed with 3a (0.12 mmol). eIn CH2Cl2 (1.0 mL). fAt 20 °C for 2 h, then Et3N (50 mol %) was added and stirred for another 2 h. gH2O (0.5 μL) was added. With the optimized reaction conditions in hand, the substrate scope of asymmetric synthesizing 1,2-dihydroisoquinoline derivatives was examined (Table 2). Changing the ester group of methyleneindolinone from iso-propyl to less steric methyl, ethyl, benzyl, or bulkier tert-butyl and 2-adamantyl group, the enantioselectivities and diastereoselectivities could basically be maintained ( 4a– 4f, 65–92% yield, 10:1–>19:1 dr, 85–95% ee). The 3-ethylthioester, 3-heteroaromatic ring, or 3-benzoyl group-substituted methyleneindolinones were also tolerated in this three-component reaction, delivering the product 4g– 4l with good to excellent results (63–80% yield, >19:1 dr, 71–99% ee). The methyleneindolinones with electron-donating substituents (R2) on the phenyl ring of the oxindole could be smoothly converted into the corresponding cycloaddition products 4m– 4q in 64–77% yield with >19:1 dr and 73–99% ee. By comparison, the substrates bearing electron-withdrawing substituents (R2) yielded moderate results with using 3b as the activated π-system ( 4r– 4t, 54–75% yield, >19:1 dr, 82–84% ee). Subsequently, variations of the isoquinolines and allenoates were studied. Generally, the isoquinoline 2 with different substituents (both electron-donating and -withdrawing groups at C4, C5, C6, or C8 positions) reacted with 1b and 3a well to form the corresponding chiral dihydroisoquinoline derivatives ( 4u– 4ad) in 52–86% yield with moderate to excellent diastereoselectivities (10:1–>19:1 dr) and enantioselectivities (78–96% ee). Functional groups (cyano, nitro) attached to the isoquinoline were also tolerated in this reaction, which were useful precursors of amides or amines ( 4w and 4ab). We then investigated the steric effect of ester substituents on allenoates, and the product 4ag bearing isopropyl ester group was obtained with a lower yield and ee value ( 4ag, 63% yield, 86% ee). The absolute configuration of 4x was determined to be (2′S, 3R, 11b′R) by using single-crystal X-ray diffraction analysis.a Table 2 | Substrate Scope for the Construction of Chiral 1,2-Dihydroisoquinolinesa aUnless otherwise noted, all reactions were carried out with 1 (0.10 mmol), 2 (0.10 mmol), 3 (0.12 mmol), H2O (0.5 μL), L3-Pi c H/Mg(OTf)2 (1:1, 10 mol %) in CH2Cl2 (1.0 mL) at 20 °C for 2 h. Then Et3N (50 mol %) was added and stirred for another 2 h. The dr was determined by 1H NMR spectroscopy, and the ee value was determined by HPLC or SFC analysis using a chiral stationary phase. bPerformed for 6 h. Next, we turned our attention to the more challenging nitrogen-containing aromatic heterocycles, such as pyridine, which can also form transient 1,4-dipoles by the addition to allenoate.31 Under the aforementioned optimized reaction conditions, 1b reacted with 3b and 4-phenyl pyridine 5a smoothly to afford the desired product 6a but with moderate results. Upon switching the chiral N,N′-dioxide ligand to L3-PrEt2Me and prolonging the reaction time to 36 h without adding base, 6a could be formed in 77% yield with 92% ee as a single diastereomer ( Supporting Information Table S7). The substrate scope of pyridines for synthesizing 1,2-dihydropyridine derivatives was investigated (Table 3). A range of pyridines bearing different substituents at C4 positions delivered the corresponding products, and the electron-withdrawing group substituted substrates exhibited higher enantioselectivities than the electron-donating one ( 6b and 6c vs 6d). For 3-substituted pyridines, excellent diastereo- and enantioselectivities were preserved. However, a regioselective situation was observed in the annulation step which was significantly affected by the steric hindrance and electronic effect. With 3-methyl, 3-chloro, 3-bromo, and 3-iodo-substituted pyridines, the annulation took place preferentially at the less steric hindered C6 position ( 6e– 6h). Nonetheless, the regioselectivity was lower when 3-chloride or 3-bromo-pyridine was used ( 6f/ 6f′ = 1.7:1, 6g/ 6g′ = 4.8:1). For strong electron-donating group (3-OMe) substituted pyridine, the reaction preferentially occurred at the C2 position, while 6j at the C6 position was obtained with bearing the strong electron-withdrawing group (3-CN). For 3,5-disubstituted pyridines, the regioselectivity may lie on the steric hindrance of the substituents. Thus, when 3-bromo-5-fluoropyridine ( 5k) was employed, the normal C6 selective product 6k was obtained in 78% yield, >19:1 dr with 96% ee, while low regioselectivity was obtained for 3-bromo-5-methylpyridine ( 5l). It is worth noting that such a special selectivity has rarely been reported with respect to the addition of pyridinium salts, especially for the pyridine-bearing electron-donating groups.41–43 Table 3 | Substrate Scope for the Construction of Chiral 1,2-Dihydropyridine Derivativesa aUnless otherwise noted, all reactions were carried out with 1b (0.10 mmol), 5 (0.10 mmol), 3b (0.12 mmol), H2O (0.5 μL), L3-PrEt2Me/Mg(OTf)2 (1∶1, 10 mol %) in CH2Cl2 (1.0 mL) at 20 °C for 36 h. The dr was determined by 1H NMR spectroscopy, and the ee value was determined by HPLC or SFC analysis using a chiral stationary phase. The regioselectivity ratio (rr) was determined by 1H NMR spectroscopy of the crude product. In view of the high utility of polycyclic N-heterocycles, several other kinds of N-heteroaromatic substrates were explored (Table 4). 3-Methoxy and 6-bromoquinolines could be transformed into the corresponding products 8a and 8b, excellent diastereo- and enantioselectivitivities were obtained, albeit with lower yields. Phthalazine was also tolerated and gave the desired product 8c in 35% yield with >19∶1 dr and 91% ee. Phenanthridine was examined as well, but the desired product 8d was obtained with poor results (26% yield, >19∶1 dr, 47% ee). Benzimidazole, benzothiazole, and benzoxazole were also tested but did not proceed well (see Supporting Information). Table 4 | Investigation of Other Heteroaromatic Compoundsa aUnless otherwise noted, all reactions were carried out with 1b (0.10 mmol), 7 (0.10 mmol), 3a (0.12 mmol), H2O (0.5 μL), L3-Pi c H/Mg(OTf)2 (1:1, 10 mol %) in CH2Cl2 (1.0 mL) at 20 °C for 24 h. Then Et3N (50 mol %) was added and stirred for another 2 h. The yield was determined by 1H NMR spectroscopy using acetanilide as the internal standard. The dr was determined by 1H NMR spectroscopy, and the ee value was determined by HPLC analysis using a chiral stationary phase. bIsolated yield. cPerformed for 48 h. To show the synthetic utility of the current catalytic system, a scale-up synthesis of 4d was performed. As shown in Scheme 2a, 1d (2.5 mmol) reacted with 2a (2.5 mmol) and 3a (3.0 mmol) smoothly under the optimized reaction conditions, delivering 4d in 83% yield with >19∶1 dr and 93% ee. Moreover, derivatizations of products were conducted. The dihydroisoquinoline 4d could be oxidized by m-CPBA to generate the expected epoxide 9a as a single diastereomer with 91% ee. Treatment of 6a with Pd/C under 60-bar hydrogen pressures, the hexahydropyridine derivative 9b was obtained in 62% yield with 92% ee (Scheme 2b). The absolute configuration of 9b was determined to be (2′S, 3R, 8′S, 9a′R) by using single-crystal X-ray diffraction analysis for its N-Ts protected derivative hexahydropyridine 9b′ (see Supporting Information).b The 1,2-dihydropyridine ring system is capable of behaving as a diene component in Diels–Alder reactions.12,13 For example, the dearomative product 6a could react with dimethyl but-2-ynedioate smoothly and afford the bridged heterocyclic compound 9d with high stereoselectivity but in a low yield ( 9d, 23% yield, >19∶1 dr, 92% ee, see Supporting Information). Scheme 2 | (a and b) Gram-scale synthesis and derivatization. Download figure Download PowerPoint To get insight into the reaction mechanism, several control experiments were carried out. First, deuterium-labelling experiments were performed to clarify the 1,3-H shift process. As shown in Scheme 3a, when 10 equiv of D2O were added, product 4a was obtained in 75% yield without deuterated [D]- 4a being observed. Furthermore, deuterium-labeled diethyl allenedicarboxylate [D2]-3a (88% D) reacted with equivalent amounts of 1a and 2a, affording the product [D2]-4a with 80.5% D. Even by prolonging the reaction time to 3 days, the starting materials could not be completely converted into final products. These two deuterium experiment results were consistent with an intramolecular 1,3-H shift process in this reaction. Next, we analyzed the reaction system along with reaction time in the construction of 6a (Scheme 3b). It was obvious that the exocyclic alkene Int-6a was transferred into final product as the reaction time went on (see Supporting Information). Scheme 3 | (a–c) Control experiments and proposed mechanism. Download figure Download PowerPoint Based on the control experiments as well as previous work,30–32,44–46,c a possible reaction pathway was proposed (Scheme 3c). Initially, the zwitterion Int-1 was generated in situ from isoquinoline ( 2a) and diethylallenedicarboxylate ( 3a). As the β-Si face of the methyleneindolinone 1b coordinating with L3-Pi c H/Mg(II) complex was shielded by the neighboring cyclohexyl group of the ligand, the dearomative [4+2] cycloaddition of 1b with Int-1 occurred through a simultaneous Si/β-Re face attack preferentially based on the observed high diastereoselectivities, affording the exocyclic alkene Int-4b. Nevertheless, the possibility of a step-wise nucleophilic addition/ring closure process cannot be completely ruled out.25 Finally, the base accelerated the intramolecular [1,3]-hydrogen shift of Int-4b to furnish the isomerized product 4b. Conclusion We have described the first highly efficient catalytic asymmetric sequential dearomatizing three-component reactions of methyleneindolinones with transient zwitterions formed by N-heteroaromatic compounds and allenoates in the presence of a chiral N,N′-dioxide/Mg(OTf)2 catalyst. A wide range of chiral polycyclic N-heteroaromatic compounds were obtained with good to excellent results (up to 92% yield, >19:1 dr, 99% ee), including 1,2-dihydroquinolines, 1,2-dihydropyridines, and so on. The roles of additives were elucidated based on the control experiments. A possible reaction cycle was proposed to explain the reaction process and the origin of the stereoinduction. Footnotes a CCDC 2032911 ( 4x) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. b CCDC 2051882 ( 9b′) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. c CCDC 2023083 [(S)- L3-PicH/Mg(II)] contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. Supporting Information Supporting Information is available and includes general information, substrates synthesis, experimental procedures, optimization details, control experiments, synthesis transformations, X-ray crystallographic data, product characterization data, and copies of SFC, HPLC, CD, and NMR spectra. Conflict of Interest There is no conflict of interest to report. Funding Information The authors appreciate financial support from the National Natural Science Foundation of China (grant no. 21772127). Acknowledgments The authors wish to acknowledge Dr. Yuqiao Zhou (Sichuan University) for his assistance in X-ray crystallographic analysis.