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Article

Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines

by
Kaikai Wang
1,
Wenwen Zhou
1,
Jun Jia
2,
Junwei Ye
1,
Mengxin Yuan
1,
Jie Yang
3,*,
Yonghua Qi
1 and
Rongxiang Chen
1,*
1
School of Pharmacy, Xinxiang University, Xinxiang 453000, China
2
Jilin Province Product Quality Supervision and Inspection Institute, Changchun 130012, China
3
School of Chemistry & Materials Engineering, Xinxiang University, Xinxiang 453000, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(19), 6761; https://doi.org/10.3390/molecules28196761
Submission received: 21 August 2023 / Revised: 19 September 2023 / Accepted: 20 September 2023 / Published: 22 September 2023
(This article belongs to the Section Organic Chemistry)
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Abstract

:
Substrate-controlled diversity-oriented synthesis of polycyclic frameworks via [4 + 2] and [3 + 2] annulations between ninhydrin-derived Morita–Baylis–Hillman (MBH) adducts and 3,4-dihydroisoquinolines under similar reaction conditions have been developed. The reaction provides diversity-oriented synthesis of a series of novel and structurally complex spiro multi heterocyclic skeletons in good yields (up to 87% and 90%, respectively) with excellent diastereoselectivities (up to >25:1 dr). In particular, the switchable [4 + 2] and [3 + 2] annulation reactions are controlled by tuning the hydroxyl protecting group on the ninhydrin-derived MBH adduct to deliver structural diverse spiro[indene-2,2′-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1′-pyrrolo[2,1-a]isoquinoline], respectively. Furthermore, the relative configuration and chemical structure of two kinds of cycloadducts were confirmed through X-ray diffraction analysis.

1. Introduction

Polycyclic rings are the important frameworks as a core structure widespread throughout most classes of natural and non-natural products with a wide spectrum of pharmacological and biological activities, which makes them arouse ever-increasing attention in organic and medicinal chemistry [1,2,3,4,5,6,7]. The polycyclic compounds containing some privileged structures, such as tetrahydroisoquinoline motifs [8,9,10], tetrahydropyrrole moieties [11,12,13] or indane-1,3-dione units [14,15] and so on, especially play a key role in drug discovery and development. Owing to their usefulness and potential pharmacological activity, a wide array of synthetic methods has been developed to directly construct functional and complex polycyclic scaffolds bearing privileged structures including Diels-Alder reaction [16,17,18,19,20,21], cycloaddition reaction [22,23], cascade reaction [24,25,26,27], etc., from all kinds of reaction partners. Among them, the Morita–Baylis–Hillman (MBH) adducts and their derivatives have been extensively explored due to their multifunctional features, and applied as versatile synthons in diverse annulation reactions, mostly for the construction of polycyclic frameworks via cycloaddition with a large variety dipolarophiles [28,29,30,31,32,33]. In particular, isatins or aldehydes-derived MBH carbonates can act as valuable C1, C2, C3, or C4 synthons, which in situ generated zwitterionic allylic ylide species under Lewis base catalysis [34,35,36,37] or π-allyl metal complexes [38,39,40,41,42,43,44,45], to exhibit universal building blocks for the construction of multifunctional and potentially biologically active ring structures via various [3 + n] [46,47,48,49,50,51,52,53], [2 + n] [54,55,56,57,58], [1 + n] [59,60,61,62,63] annulation reactions. As a result, in the past few years, these annulations of employing the isatin or aldehydes-derived MBH carbonates as substrates have evolved into an extremely vibrant research area and achieved great progress and developments. In sharp contrast, the analogous ninhydrin-derived MBH adducts [46,64,65], including MBH alcohols due to its poor leaving nature, have been less explored compared with classical MBH adducts from isatins or aldehydes. Therefore, it is still of great necessity and importance to develop ninhydrin-derived MBH adducts as substrates to access diverse functional cyclic compounds bearing indane-1,3-dione as promising pharmacophores. Notably, it still is highly desirable to find suitable reaction partners for MBH alcohols [66,67,68], further expanding the chemical space of MBH adducts.
On the other hand, 3,4-dihydroisoquinolines (DHIQ) as an inactivated cyclic imine have been broadly applied as valuable synthons which could react with nucleophilic reagent to fulfill potential active tetrahydroisoquinoline derivatives in organic synthesis [69,70,71,72,73,74,75,76]. In 2017, the Cui and co-workers developed catalyst-free [3 + 2] cyclization of 3,4-dihydroisoquinolines and aldehydes-derived MBH carbonates to provide tetrahydropyrrolo[2,1-a]isoquinolines in good yields (Scheme 1a) [77]. It was noteworthy that no desired product was observed between aldehydes-derived MBH alcohol and 3,4-dihydroisoquinoline under standard conditions, because the hydroxyl group was not a good leaving group. Subsequently, their group realized the tetrahydroisoquinoline-fused spirooxindoles containing tetrahydroisoquinoline and spirooxindole frameworks in good yields from 3,4-dihydroisoquinolines with isatins-derived MBH carbonates under the same strategy (Scheme 1b) [78]. Along these lines, the development of efficient synthetic protocols for integrating other kinds of privileged structures into tetrahydroisoquinoline motifs may enhance their biological activities with latent medicinal value. As part of our continued efforts on cycloaddition reactions of MBH adducts as substrates [79,80,81,82], herein, we would like to report this substrate-controlled diversity-oriented synthesis via [4 + 2] and [3 + 2] annulations of ninhydrin-derived MBH adducts with 3,4-dihydroisoquinolines, efficiently furnishing the diversity-oriented synthesis of novel and structurally diverse spiro[indene-2,2′-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1′-pyrrolo[2,1-a]isoquinoline] derivatives with high molecular complexity in excellent diastereo- and regioselectivity (Scheme 1c). This strategy could offer distinct cycloadducts, especially skeletally diverse frameworks, depending on the switchable elaboration of similar starting materials. The incorporation of tetrahydroisoquinoline and indane-1,3-dione moieties and six- or five-membered heterocycles may provide promising opportunities for tuning their diverse pharmacological properties.

2. Results

We began our study by screening the model reaction conditions between ninhydrin-derived MBH alcohol 1a and 3,4-dihydroisoquinoline 2a. The results are summarized in Table 1. To our delight, the reaction could smoothly proceed via a [4 + 2] cycloaddition reaction and afford the product 3a in 78% yield with high diastereoselectivity and regioselectivity in the presence of DABCO in CH2Cl2 at room temperature (entry 1, in Table 1). Then, in order to improve the yield, the reaction was carried out in the presence of different bases, such as TEA, DIPEA, DBU, Na2CO3, and NaOH (entries 2–6 in Table 1). The results showed that no further improvement in the chemical yield through screening a series of organic and inorganic bases. Subsequently, various solvents were evaluated for the reaction (entries 7–12, in Table 1). Based on the results, with CH3CN as the most suitable solvent, the annulation reaction could furnish product 3a in 85% yield with high >25:1 dr (entry 9, in Table 1). The reaction did not effectively offer the product in dioxane or THF (entries 10–11, in Table 1), while only trace amounts of the desired product 3a were observed even if prolonging the reaction time to 24 h. Other solvents including CHCl3, toluene, and EtOAc resulted in inferior yields (entries 6, 8, and 12, in Table 1). On the other hand, increasing the amount of DABCO, the yield of product 3a has no obvious change (entry 13, in Table 1). Interestingly, as for the MBH adduct, when changed from MBH alcohol 1a to MBH carbonate 4a with 2a in the model reaction, the reaction could switch [3 + 2] annulation, to give product 5a in 75% yield under the same condition (entry 14, in Table 1). It shows that this switch of [4 + 2] and [3 + 2] annulation is controlled by the MBH adducts. Encouraged by the promising result, we then further optimized the [3 + 2] reaction condition between MBH carbonate 4a with 2a. In the absence of DABCO, the [3 + 2] annulation reaction could slightly improve the yield of product 5a from 75% to 78% (entry 14 vs. entry 15, in Table 1). The subsequent evaluation of solvents (entries 15–20, in Table 1) demonstrated that using CH2Cl2 as a solvent could obviously improve the yield in a shorter reaction time compared with other solvents.

3. Discussion

After establishing the optimized conditions in hand, we then examined the scope of the present [4 + 2] annulation reaction of ninhydrin-derived MBH alcohols with dihydroisoquinolines. Firstly, the effect of substituents on the phenyl ring of dihydroisoquinolines 2 was studied and various dihydroisoquinolines 2 bearing diverse substituents with ninhydrin-derived MBH alcohol 1a were investigated in the [4 + 2] annulation reaction under optimal conditions. The results were summarized in Scheme 2. The reaction could process smoothly and efficiently transform into the corresponding cycloadducts 3a–3k in 80–87% yields with an excellent diastereomeric ratio (all > 25:1 dr). The results clearly demonstrate that the different electronic properties or the substitution pattern variation hardly influenced the reaction efficiency and selectivity, regardless of the different positions or electronic properties of the substituents on the phenyl ring of dihydroisoquinoline moieties. In addition, the reaction could successfully provide the desired product 3k in 85% yield when it employed heterocyclic imine. On the other hand, we extended the scope of this reaction to investigate the MBH alcohols with other functional groups, such as MBH alcohols bearing a larger steric hindrance of the tert-butyl ester group or cyano group or the carbonyl group. These cycloaddition reactions also occurred smoothly to afford the corresponding products 3l–3n in 81–86% yields with an excellent diastereomeric ratio (all > 25:1 dr). It is worth noting that all the products could be obtained as a pure diastereomer in >25:1 dr. Furthermore, the relative configuration and chemical structure of product 3n (CCDC 2277407) (see Supplementary Materials) [83] was undoubtedly confirmed by X-ray crystallographic analysis. Unfortunately, the reaction did not effectively provide the desired product 3o when the cyclic imine bearing a methyl group on the α-position of 3,4-dihydroisoquinoline was applied in this [4 + 2] annulation reaction. The possible reason may be that it is difficult for the construction of quaternary carbon stereocenter when increasing steric hindrance at the α-position of 3,4-dihydroisoquinoline.
Subsequently, the substrate scope of [3 + 2] annulations between ninhydrin-derived MBH carbonates 4 and 3,4-dihydroisoquinolines 2 was also explored. The results were shown in Scheme 3. Under the optimized condition, the [3 + 2] annulation reaction could successfully be carried out when employing 3,4-dihydroisoquinolines featuring different substituents at the C5–C8 positions of the phenyl ring and different substitution patterns, resulting in the corresponding products (5a–5i) in high yields (85–90%) with excellent regioselectivities. Moreover, the structure of product 5b (CCDC 2277406) (see Supplementary Materials) [84] was confirmed unambiguously by single-crystal X-ray diffraction analysis. Heterocyclic derived cyclic imine with ninhydrin-derived MBH carbonate 4a was also successfully tested in the reaction, obtaining the expected product 5j with slightly lower yield. Furthermore, as for the EWG group on the MBH carbonates, it could be successfully changed from a methyl ester group to a larger steric hindrance of a tert-butyl ester group or a cyano group; the reactions were hardly affected, to give the corresponding products 5k and 5l in 87% and 89% yields, respectively. It is worth mentioning that the reaction could successfully be extended to 1-methyl-3,4-dihydroisoquinoline, delivering the desired product 5m containing two vicinal tetrasubstituted carbon stereocenters in 86% yield.
Furthermore, in order to exhibit the synthetic practicability of the reaction, a gram-scale experiment of 4.4 mmol 1a or 4a with 4 mmol 2a was conducted under standard conditions (Scheme 4). The larger-scale reaction could smoothly occur, yielding [4 + 2] cycloadduct 3a and [3 + 2] cycloadduct 5a in 82% yield with >25:1 dr and 86% yield, respectively, similar to the results of the small-scale reaction.
Based on our experimental results and the literature reports, [34,35,36,37,46,47,48,49,50,51,52,53,66,67,68,79,80,81,82] a plausible mechanism is described to explain the reaction process in Scheme 5. Under the basic condition, MBH alcohol 1a would be activated or deprotonated to form Michael donor with 3,4-dihydroisoquinoline, to produce the intermediate A via Michael addition. Subsequently, the intermediate A can proceed with intramolecular cyclization to provide the [4 + 2] cycloadduct 3a. In contrast, the MBH carbonate 4a as the substrate could be attacked by dihydroisoquinoline 2a to generate the azomethine ylide B or C following the release of CO2 and tert-BuOH. Finally, the ylide C followed by an intramolecular ring-closure event through γ-site attacking imine to afford the γ-regioselective [3 + 2] cycloadduct 5a.

4. Materials and Methods

NMR data were obtained for 1H at 400 MHz, and for 13C at 100 MHz, and 19F at 376 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution. ESI HRMS was recorded on a Waters SYNAPT G2. Column chromatography was performed on silica gel (200–300 mesh) eluting with ethyl acetate/petroleum ether. TLC was performed on glass-backed silica plates. UV light, I2, and solution of potassium permanganate were used to visualize products. All chemicals were used without purification as commercially available unless otherwise noted. Petroleum ether and ethyl acetate were distilled. THF was freshly distilled from sodium/benzophenone. Unless otherwise noted, experiments involving moisture and/or air-sensitive components were performed under a positive pressure of argon in oven-dried glassware equipped with a rubber septum inlet. Dried solvents and liquid reagents were transferred by oven-dried syringes. Ninhydrin-derived MBH adducts 1 and 4 [46,65,66,67] and 3,4-dihydroisoquinolines 2 [71,72,73,74,75,76,77,78] were prepared according to the literature procedures.
An oven-dried 10 mL flasket charged with a mixture of ninhydrin-derived MBH alcohols 1 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv), DABCO (20 mol%) in CH3CN (1.0 mL) was stirred at room temperature for 12 h. After completion, product 3 was obtained by flash chromatography on silica gel (petroleum ether/ethyl acetate = 3:1 to 2:1).
An oven-dried 10 mL flasket charged with a mixture of ninhydrin-derived MBH carbonates 4 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was stirred at room temperature for 1 h. After completion, product 5 was obtained by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1 to 3:1).
Experimental data of products:
3a: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.31) gave a white solid (32.0 mg, 85% yield), mp 138–139 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.91–7.82 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.00 (s, 1H), 4.31 (t, J = 13.2 Hz, 1H), 3.84 (dd, J = 12.4, 5.2 Hz, 1H), 3.71 (td, J = 11.6, 3.6 Hz, 1H), 3.57–3.52 (m, 4H), 3.10–3.02 (m, 1H), 2.85–2.81 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 194.6, 171.4, 141.7, 140.7, 136.0, 135.8, 135.0, 132.4, 128.8, 128.6, 128.5, 125.9, 124.4, 123.9, 84.3, 75.1, 52.2, 49.8, 42.3, 35.1, 29.1 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H20NO5 378.1336, found 378.1319.
3b: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.34) gave a white solid (35.8 mg, 82% yield), mp 112–113 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.87 (dd, J = 16.4, 7.2 Hz, 2H), 6.59 (s, 1H), 6.45 (s, 1H), 5.96 (s, 1H), 4.31 (t, J = 13.2 Hz, 1H), 3.86–3.82 (m, 4H), 3.74–3.70 (m, 4H), 3.59–3.51 (m, 4H), 3.05–2.96 (m, 1H), 2.84–2.73 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.6, 194.7, 171.4, 149.5, 147.4, 141.7, 140.8, 136.0, 135.9, 127.7, 124.5, 124.4, 123.9, 111.3, 110.8, 84.2, 75.1, 56.0, 55.9, 52.2, 49.9, 42.2, 35.2, 28.8 ppm. IR (KBr):3437, 2925, 2839, 1712, 1602, 1518, 1456, 1355, 1323, 1277, 1229, 1139, 1072, 1012, 905, 843, 780, 727, 677, 634, 564, 521 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C24H24NO7 438.1547, found 438.1540.
3c: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.33) gave a white solid (31.6 mg, 80% yield), mp 145–146 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.91–7.83 (m, 2H), 7.00–6.96 (m, 1H), 6.82–6.74 (m, 2H), 5.98 (s, 1H), 4.29 (t, J = 13.2 Hz, 1H), 3.82 (dd, J = 12.4, 5.2 Hz, 1H), 3.67 (t, J = 11.2 Hz, 1H), 3.59–3.52 (m, 4H), 3.09–3.00 (m, 1H), 2.82 (d, J = 16.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 194.5, 171.3, 162.6 (d, J = 245.9 Hz), 141.7, 140.7, 137.6 (d, J = 8.0 Hz), 136.0, 135.9, 130.6 (d, J = 8.6 Hz), 128.4 (d, J = 2.7 Hz), 124.4, 123.9, 114.8 (d, J = 21.0 Hz), 113.3 (d, J = 21.7 Hz), 83.8, 75.1, 52.2, 49.8, 41.9, 35.1, 29.2 ppm. 19F{1H} NMR (376 MHz, CDCl3) δ 113.3. HRMS (ESI) m/z: [M + H]+ calcd for C22H19FNO5 396.1242, found 396.1237.
3d: Purification by flash chromatography (PE/EA = 2:1 as an eluent, Rf = 0.32) gave a white solid (34.1 mg, 83% yield), mp 129–130 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.92–7.84 (m, 2H), 7.11 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.97 (s, 1H), 4.28 (t, J = 13.2 Hz, 1H), 3.82 (dd, J = 12.0, 4.4 Hz, 1H), 3.70–3.64 (m, 1H), 3.59–3.52 (m, 4H), 3.09–2.99 (m, 1H), 2.81 (d, J = 13.2 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.4, 171.2, 141.7, 140.7, 137.0, 136.1, 135.9, 134.3, 130.9, 130.2, 128.3, 126.3, 124.5, 123.9, 83.7, 75.1, 52.2, 49.7, 42.0, 35.2, 29.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19ClNO5 412.0946, found 412.0938.
3e: Purification by flash chromatography (PE/EA = 2:1 as an eluent, Rf = 0.36) gave a white solid (33.3 mg, 81% yield), mp 131–132 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.94–7.85 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 5.94 (s, 1H), 4.27 (t, J = 13.2 Hz, 1H), 3.82 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (dd, J = 11.6, 7.6 Hz, 1H), 3.56–3.52 (m, 4H), 3.04–2.96 (m, 1H), 2.84–2.77 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.5, 171.2, 141.7, 140.7, 136.1, 136.0, 134.1, 133.6, 131.5, 129.9, 128.8, 128.6, 124.5, 124.0, 83.7, 75.1, 52.3, 49.7, 42.3, 35.3, 28.6 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19ClNO5 412.0946, found 412.0939.
3f: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.36) gave a white solid (39.1 mg, 86% yield), mp 158–159 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.92–7.84 (m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 6.99–6.93 (m, 2H), 5.98 (s, 1H), 4.28 (t, J = 13.2 Hz, 1H), 3.85 (dd, J = 12.4, 5.2 Hz, 1H), 3.72–3.65 (m, 1H), 3.58–3.52 (m, 4H), 3.00–2.96 (m, 1H), 2.91–2.83 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.4, 171.2, 141.7, 140.7, 136.1, 135.9, 135.0, 134.7, 132.5, 128.1, 127.3, 124.7, 124.5, 123.9, 83.9, 75.1, 52.3, 49.6, 42.1, 35.1, 30.1 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19BrNO5 456.0441 (79Br) and 458.0421 (81Br), found 456.0435, 458.0409.
3g: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.35) gave a white solid (38.2 mg, 84% yield), mp 121–122 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.92–7.84 (m, 2H), 7.28 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.95 (s, 1H), 4.28 (t, J = 13.2 Hz, 1H), 3.82 (dd, J = 12.8, 4.8 Hz, 1H), 3.69–3.64 (m, 1H), 3.56–3.52 (m, 4H), 3.08–2.99 (m, 1H), 2.83–2.79 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.4, 171.2, 141.7, 140.7, 137.4, 136.1, 135.9, 131.5, 131.3, 130.4, 129.2, 124.5, 123.9, 122.5, 83.8, 75.1, 52.3, 49.7, 42.0, 35.2, 28.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19BrNO5 456.0441 (79Br) and 458.0421 (81Br), found 456.0433, 458.0411.
3h: Purification by flash chromatography (PE/EA = 2:1 as an eluent, Rf = 0.34) gave a white solid (39.6 mg, 87% yield), mp 131–132 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.92–7.87 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.94 (s, 1H), 4.27 (t, J = 13.2 Hz, 1H), 3.82 (dd, J = 12.0, 4.0 Hz, 1H), 3.65 (t, J = 10.4 Hz, 1H), 3.56–3.52 (m, 4H), 3.00–2.93 (m, 1H), 2.79 (d, J = 16.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.5, 171.2, 141.7, 140.7, 136.2, 136.0, 134.5, 134.1, 131.62, 131.56, 130.2, 124.5, 124.0, 119.4, 83.6, 75.1, 52.3, 49.7, 42.2, 35.3, 28.7 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19BrNO5 456.0441 (79Br) and 458.0421 (81Br), found 456.0437, 458.0414.
3i: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.37) gave a white solid (36.4 mg, 80% yield), mp 154–155 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.89–7.81 (m, 2H), 7.26 (d, J = 5.2 Hz, 1H), 7.06–7.02 (m, 2H), 6.16 (s, 1H), 4.41 (t, J = 13.2 Hz, 1H), 3.87 (dd, J = 12.4, 4.8 Hz, 1H), 3.73 (dd, J = 16.0, 6.8 Hz, 1H), 3.60–3.54 (m, 4H), 3.12–3.03 (m, 1H), 2.84–2.80 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 197.0, 194.2, 171.3, 142.2, 140.6, 137.9, 136.1, 135.6, 131.7, 130.7, 129.9, 127.8, 124.4, 123.7, 83.5, 75.2, 52.2, 49.9, 41.6, 34.3, 29.4 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19BrNO5 456.0441 (79Br) and 458.0421 (81Br), found 456.0436, 458.0413.
3j: Purification by flash chromatography (PE/EA = 2:1 as an eluent, Rf = 0.33) gave a yellow solid (33.8 mg, 80% yield), mp 159–160 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.2 Hz, 1H), 8.06–8.00 (m, 2H), 7.95 (t, J = 7.2 Hz, 1H), 7.90–7.87 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 6.08 (s, 1H), 4.30 (t, J = 13.2 Hz, 1H), 3.83 (dd, J = 12.4, 5.2 Hz, 1H), 3.72–3.66 (m, 1H), 3.59–3.52 (m, 4H), 3.16–3.08 (m, 1H), 2.98–2.87 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 194.4, 170.9, 146.3, 143.1, 141.7, 140.6, 136.3, 136.1, 133.9, 129.6, 124.5, 124.22, 124.18, 123.4, 83.4, 75.0, 52.3, 49.6, 41.8, 35.4, 29.4 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H19N2O7 423.1187, found 423.1180.
3k: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.34) gave a pale yellow solid (32.6 mg, 85% yield), mp 114–115 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.89–7.85 (m, 2H), 6.99 (d, J = 4.4 Hz, 1H), 6.68 (d, J = 4.8 Hz, 1H), 5.97 (s, 1H), 4.30 (t, J = 13.2 Hz, 1H), 3.81 (dd, J = 12.0, 4.4 Hz, 1H), 3.73–3.69 (m, 1H), 3.59–3.51 (m, 4H), 3.04–2.97 (m, 1H), 2.90 (d, J = 12.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.6, 171.2, 141.7, 140.7, 138.1, 136.0, 135.9, 132.6, 125.7, 124.4, 123.9, 123.2, 81.4, 74.8, 52.2, 49.6, 43.1, 35.7, 25.6 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C20H18NO5S 384.0900, found 384.0893.
3l: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.33) gave a white solid (34.8 mg, 83% yield), mp 122–125 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.91–7.82 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 5.93 (s, 1H), 4.24 (t, J = 12.8 Hz, 1H), 3.74–3.65 (m, 2H), 3.50 (dd, J = 14.0, 5.2 Hz, 1H), 3.09–3.01 (m, 1H), 2.84–2.81 (m, 2H), 1.08 (s, 9H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 194.4, 169.3, 141.8, 141.0, 135.9, 135.8, 135.1, 132.5, 128.8, 128.52, 128.50, 125.9, 124.5, 123.9, 84.4, 82.7, 75.4, 49.9, 42.4, 34.9, 29.1, 27.5 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C25H26NO5 420.1805, found 420.1800.
3m: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.34) gave a white solid (27.9 mg, 81% yield), mp 117–118 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.97 (dd, J = 16.4, 7.2 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.11 (dd, J = 15.2, 7.6 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 4.43 (t, J = 13.2 Hz, 1H), 3.68 (dd, J = 12.0, 5.6 Hz, 2H), 3.51 (dd, J = 14.0, 4.4 Hz, 1H), 3.11–3.02 (m, 1H), 2.83 (d, J = 12.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 197.2, 192.9, 141.2, 140.4, 137.3, 137.1, 134.8, 131.8, 128.9, 128.8, 128.6, 126.1, 124.8, 124.4, 116.3, 84.3, 75.5, 50.3, 42.2, 29.0, 21.3 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C21H17N2O3 345.1234, found 345.1227.
3n: Purification by flash chromatography (PE/EA = 2:1 as an eluent, Rf = 0.32) gave a white solid (32.3 mg, 86% yield), mp 127–128 °C, >25:1 dr, determined by 1H NMR (400 MHz, CDCl3) analysis; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 7.2 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.98 (s, 1H), 4.32 (t, J = 13.2 Hz, 1H), 3.89 (dd, J = 12.4, 4.8 Hz, 1H), 3.75 (td, J = 11.2, 3.6 Hz, 1H), 3.59 (dd, J = 13.6, 4.8 Hz, 1H), 3.12–3.04 (m, 1H), 2.88–2.84 (m, 2H), 2.54–2.36 (m, 2H), 0.93 (t, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 209.9, 198.1, 195.0, 141.9, 140.4, 135.9, 135.5, 134.9, 132.5, 128.8, 128.8, 128.6, 128.5, 126.0, 124.3, 123.9, 84.1, 75.4, 50.4, 44.6, 42.6, 33.3, 29.2, 7.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C23H22NO4 376.1543, found 376.1537.
5a: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.32) gave a white solid (31.6 mg, 88% yield), mp 116–117 °C, 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.47 (s, 1H), 7.13–7.05 (m, 2H), 6.80 (t, J = 7.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.67 (s, 1H), 3.77 (dd, J = 12.8, 4.4 Hz, 1H), 3.43–3.34 (m, 4H), 3.24–3.16 (m, 1H), 2.75 (d, J = 15.2 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.9, 198.9, 164.6, 151.9, 142.9, 142.1, 135.8, 135.4, 135.3, 131.4, 129.5, 127.5, 126.5, 125.1, 123.3, 123.2, 102.7, 68.1, 67.3, 50.6, 45.0, 30.2 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H18NO4 360.1230, found 360.1226.
5b: Purification by flash chromatography (PE/EA = 5:1 as an eluent, Rf = 0.35) gave a white solid (36.0 mg, 86% yield), mp 125–126 °C, 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 6.57 (s, 1H), 5.58 (d, J = 4.4 Hz, 2H), 3.80 (s, 3H), 3.75 (dd, J = 13.2, 5.2 Hz, 1H), 3.45 (s, 3H), 3.36 (td, J = 12.4, 2.8 Hz, 1H), 3.14–3.06 (m, 1H), 3.02 (s, 3H), 2.65 (d, J = 14.8 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 203.2, 198.8, 164.7, 151.9, 148.0, 147.4, 142.9, 142.2, 135.9, 135.3, 127.5, 123.4, 123.2, 122.6, 111.8, 107.8, 102.1, 68.4, 67.4, 55.7, 54.9, 50.7, 44.9, 29.6 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C24H22NO6 420.1442, found 420.1433.
5c: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.32) gave a white solid (33.9 mg, 90% yield), mp 109–110 °C, 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.52 (t, J = 8.4 Hz, 1H), 6.22–6.18 (m, 1H), 5.63 (s, 1H), 3.77 (dd, J = 12.8, 4.8 Hz, 1H), 3.43 (s, 3H), 3.35 (t, J = 12.4 Hz, 1H), 3.23–3.15 (m, 1H), 2.73 (d, J = 15.2 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.7, 198.8, 164.5, 161.5 (d, J = 245.9 Hz), 151.8, 142.9, 141.9, 137.9 (d, J = 7.6 Hz), 136.0, 135.6, 127.2 (d, J = 3.1 Hz), 126.7 (d, J = 8.4 Hz), 123.3, 123.2, 116.1 (d, J = 21.1 Hz), 113.8 (d, J = 21.9 Hz), 103.1, 67.6, 67.3, 50.7, 44.7, 30.3 ppm. 19F{1H} NMR (376 MHz, CDCl3) δ 114.1. HRMS (ESI) m/z: [M + H]+ calcd for C22H17FNO4 378.1136, found 378.1130.
5d: Purification by flash chromatography (PE/EA = 4:1 as an eluent, Rf = 0.35) gave a white solid (35.4 mg, 90% yield), mp 137–138 °C, 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.13 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 3.77 (dd, J = 12.8, 4.4 Hz, 1H), 3.43 (s, 3H), 3.34 (t, J = 12.4 Hz, 1H), 3.22–3.14 (m, 1H), 2.73 (d, J = 15.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.5, 198.7, 164.5, 151.7, 142.9, 141.9, 137.3, 136.0, 135.6, 133.2, 130.0, 129.4, 126.8, 126.4, 123.33, 123.29, 103.2, 67.5, 67.2, 50.7, 44.7, 30.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17ClNO4 394.0841, found 394.0834.
5e: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.32) gave a white solid (34.2 mg, 87% yield), mp 131−132 °C, 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.07–7.02 (m, 2H), 6.17 (s, 1H), 5.58 (s, 1H), 3.77 (dd, J = 12.8, 4.8 Hz, 1H), 3.44 (s, 3H), 3.33 (t, J = 10.8 Hz, 1H), 3.17–3.09 (m, 1H), 2.73 (d, J = 15.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.4, 198.6, 164.5, 151.8, 142.8, 142.0, 136.1, 135.7, 133.8, 133.2, 132.2, 130.7, 127.7, 125.2, 123.4, 123.3, 103.1, 67.6, 67.3, 50.7, 44.8, 29.6 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17ClNO4 394.0841, found 394.0841.
5f: Purification by flash chromatography (PE/EA = 4:1 as an eluent, Rf = 0.33) gave a white solid (37.1 mg, 85% yield), mp 128–129 °C, 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 5.60 (s, 1H), 3.77 (dd, J = 12.8, 4.0 Hz, 1H), 3.43 (s, 3H), 3.34 (t, J = 12.4 Hz, 1H), 3.18 (t, J = 10.8 Hz, 1H), 2.72 (d, J = 15.2 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.5, 198.7, 164.5, 151.7, 142.9, 141.9, 137.6, 136.0, 135.6, 132.4, 130.5, 129.7, 126.6, 123.33, 123.32, 121.3, 103.2, 67.6, 67.1, 50.7, 44.7, 29.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17BrNO4 438.0335 (79Br) and 440.0315 (81Br), found 438.0327, 440.0305.
5g: Purification by flash chromatography (PE/EA = 5:1 as an eluent, Rf = 0.36) gave a white solid (38.9 mg, 89% yield), mp 133–134 °C, 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.2 Hz, 1H), 7.89 (t, J = 7.2 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.57 (s, 1H), 3.77 (dd, J = 12.8, 4.8 Hz, 1H), 3.44 (s, 3H), 3.36–3.29 (m, 1H), 3.13–3.05 (m, 1H), 2.71 (d, J = 15.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.4, 198.6, 164.5, 151.8, 142.7, 142.0, 136.1, 135.7, 134.3, 133.6, 131.0, 130.5, 128.3, 123.4, 123.3, 119.9, 103.1, 67.5, 67.4, 50.7, 44.7, 29.6 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17BrNO4 438.0335 (79Br) and 440.0315 (81Br), found 438.0330, 440.0307.
5h: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.32) gave a white solid (37.6 mg, 86% yield), mp 130–131 °C, 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 5.90 (s, 1H), 3.74 (d, J = 12.0 Hz, 1H), 3.41 (s, 3H), 3.21 (t, J = 14.4 Hz, 2H), 2.71 (d, J = 13.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.4, 197.9, 164.1, 153.2, 143.6, 140.9, 140.4, 135.3, 132.0, 131.4, 128.7, 128.5, 122.9, 122.8, 122.7, 106.7, 68.6, 67.5, 50.7, 46.2, 30.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17BrNO4 438.0335 (79Br) and 440.0315 (81Br), found 438.0330, 440.0308.
5i: Purification by flash chromatography (PE/EA = 4:1 as an eluent, Rf = 0.34) gave a white solid (35.1 mg, 87% yield), mp 124–125 °C, 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.82 (t, J = 7.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 5.67 (s, 1H), 3.84 (dd, J = 12.8, 4.8 Hz, 1H), 3.45 (s, 3H), 3.39 (t, J = 12.8 Hz, 1H), 3.29–3.21 (m, 1H), 2.90 (d, J = 15.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 201.9, 198.6, 164.3, 151.6, 146.2, 143.0, 142.7, 141.8, 136.4, 136.1, 133.3, 130.6, 123.7, 123.3, 122.3, 120.3, 103.8, 67.6, 67.3, 50.8, 44.3, 30.3 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C22H17N2O6 405.1081, found 405.1077.
5j: Purification by flash chromatography (PE/EA = 5:1 as an eluent, Rf = 0.33) gave a white solid (30.3 mg, 83% yield), mp 132–133 °C, 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 6.8 Hz, 1H), 7.87–7.84 (m, 3H), 7.51 (s, 1H), 6.89 (d, J = 5.2 Hz, 1H), 5.86 (d, J = 5.2 Hz, 1H), 5.49 (s, 1H), 3.84 (dd, J = 12.8, 5.2 Hz, 1H), 3.44–3.37 (m, 4H), 3.15–3.07 (m, 1H), 2.87 (d, J = 15.6 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 202.5, 198.5, 164.7, 151.6, 142.4, 141.9, 136.0, 135.5, 135.3, 129.7, 123.9, 123.32, 123.25, 102.1, 67.0, 65.9, 50.6, 44.8, 25.7 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C20H16NO4S 366.0795, found 366.0792.
5k: Purification by flash chromatography (PE/EA = 4:1 as an eluent, Rf = 0.34) gave a white solid (34.9 mg, 87% yield), mp 119–120 °C, 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.65 (s, 1H), 3.76 (dd, J = 12.4, 4.9 Hz, 1H), 3.33 (td, J = 12.4, 2.4 Hz, 1H), 3.22–3.14 (m, 1H), 2.73 (d, J = 15.2 Hz, 1H), 1.04 (s, 9H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 203.2, 198.8, 163.4, 152.2, 143.0, 142.3, 135.8, 135.6, 135.3, 131.6, 129.4, 127.4, 126.3, 125.2, 123.3, 123.1, 104.6, 79.3, 68.6, 67.4, 45.0, 30.1, 27.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C25H24NO4 402.1700, found 402.1693.
5l: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.31) gave a yellow solid (29.0 mg, 89% yield), mp 126–127 °C, 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 7.2 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15–7.08 (m, 2H), 6.85 (t, J = 7.6 Hz, 1H), 6.26 (d, J = 7.6 Hz, 1H), 5.73 (s, 1H), 3.79 (dd, J = 12.8, 5.2 Hz, 1H), 3.42–3.35 (m, 1H), 3.25–3.17 (m, 1H), 2.78 (d, J = 15.2 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 199.8, 196.2, 153.4, 142.1, 141.9, 136.8, 136.3, 135.2, 130.8, 129.5, 127.7, 126.8, 125.0, 124.0, 123.9, 116.4, 78.4, 67.3, 66.6, 45.0, 30.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C21H15N2O2 327.1128, found 327.1122.
5m: Purification by flash chromatography (PE/EA = 3:1 as an eluent, Rf = 0.32) gave a yellow solid (32.1 mg, 86% yield), mp 117–118 °C, 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 3.70 (dd, J = 13.2, 5.2 Hz, 1H), 3.46–3.39 (m, 4H), 3.23–3.14 (m, 1H), 2.74 (d, J = 15.2 Hz, 1H), 1.74 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 199.6, 199.5, 164.9, 150.5, 143.1, 142.2, 136.8, 135.5, 135.3, 134.5, 129.6, 127.2, 126.0, 125.7, 123.1, 123.0, 100.5, 72.0, 69.1, 50.6, 42.5, 30.7, 25.4 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C23H20NO4 374.1387, found 374.1379.

5. Conclusions and Future Perspective

In summary, we have developed a substrate-controlled diversity-oriented synthesis via [4 + 2] and [3 + 2] annulation reaction to afford regioselective synthesis of a broad range of bioinspired novel spiro[indene-2,2′-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1′-pyrrolo[2,1-a]isoquinoline] derivatives containing tetrahydroisoquinoline motif and indane-1,3-dione motif, relying on the ninhydrin-derived MBH adducts encountered. The ninhydrin-derived MBH alcohols serves as a four-atom synthon in [4 + 2] annulation with 3,4-dihydroisoquinolines to furnish the spiro[indene-2,2′-[1,3]oxazino[2,3-a]isoquinoline] in good yields (up to 87%) with excellent diastereoselectivity (>25:1 dr), while its carbonates serve as a three-atom synthon in [3 + 2] annulation with the same reaction partners under a similar reaction condition, which leads to γ-regioselective formation of spiro[indene-2,1′-pyrrolo[2,1-a]isoquinoline] derivatives in high yields (up to 90%). In addition, a proposed mechanism for the switchable reactions is provided. This method exhibits the synthetic efficacy to synthesize polyheterocycles with highly valuable complex structures and stereogenic complexity from easily available starting materials. The further challenging application of this method is presently under antibacterial bioactive investigation in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28196761/s1, Figure S1: Crystal data and structural refinement for 3n and 5b, Figure S2: NMR spectra.

Author Contributions

K.W., W.Z., J.J., J.Y. (Junwei Ye), Y.Q. and M.Y. participated in the synthesis, purification, and characterization of the new compound. K.W., R.C. and J.Y. (Jie Yang) participated in the interpretation of spectroscopy of new compounds and the review of the manuscript. K.W., R.C. and J.Y. (Jie Yang) participated in the interpretation of the results, writing, revision, and correspondence to the journal of molecules until the manuscript was accepted. All authors have read and agreed to the published version of the manuscript.

Funding

The authors are grateful for the financial support from the National Natural Science Foundation of China (21801214, K.W.), the Program for Youth Backbone Teacher Training in University of Henan Province (2021GGJS163, K.W.), the Higher Education Institution Key Research Project Plan of Henan Province (23A150044, K.W.), Science and Technology Research Program of Henan Province (202102210232, J.Y.), and the Henan Province professional degree graduate excellent teaching case project (YJS2023AL094, Y.Q.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article or Supplementary Material.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Lin, W.-B.; Mou, Y.; Lu, H.-Y.; Hu, Z.-Q.; Chen, C.-F. Metal-free construction of contiguous quaternary stereocentres with a polycyclic framework. Chem. Commun. 2019, 55, 4631–4634. [Google Scholar] [CrossRef]
  2. Kallepu, S.; Sanjeev, K.; Chegondi, R.; Mainkar, P.S.; Chandrasekhar, S. Benzyne Insertion onto β-Keto Esters of Polycyclic Natural Products: Synthesis of Benzo Octacyclo Scaffolds. Org. Lett. 2018, 20, 7121–7124. [Google Scholar] [CrossRef] [PubMed]
  3. Galliford, C.V.; Scheidt, K.A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. [Google Scholar] [CrossRef]
  4. Kandimalla, S.R.; Sabitha, G. Diversity-Oriented Synthesis of Oxacyclic Spirooxindole Derivatives through Ring-Closing Enyne Metathesis and Intramolecular Pauson–Khand [2 + 2 + 1] Cyclization of Oxindole Enynes. Adv. Synth. Catal. 2017, 359, 3444–3453. [Google Scholar] [CrossRef]
  5. Bietsch, J.; Chen, A.; Wang, D.; Wang, G. Synthesis of a Series of Trimeric Branched Glycoconjugates and Their Applications for Supramolecular Gels and Catalysis. Molecules 2023, 28, 6056. [Google Scholar] [CrossRef]
  6. Kula, K.; Łapczuk, A.; Sadowski, M.; Kras, J.; Zawadzińska, K.; Demchuk, O.M.; Gaurav, G.K.; Wróblewska, A.; Jasiński, R. On the Question of the Formation of Nitro-Functionalized 2,4-Pyrazole Analogs on the Basis of Nitrylimine Molecular Systems and 3,3,3-Trichloro-1-Nitroprop-1-Ene. Molecules 2022, 27, 8409. [Google Scholar] [CrossRef] [PubMed]
  7. Li, L.-Q.; Zhao, J.-Q.; Zhang, Y.-P.; You, Y.; Wang, Z.-H.; Ge, Z.-Z.; Zhou, M.-Q.; Yuan, W.-C. Diastereoselective Formal 1,3-Dipolar Cycloaddition of Trifluoroethyl Amine-Derived Ketimines Enables the Desymmetrization of Cyclopentenediones. Molecules 2023, 28, 5372. [Google Scholar] [CrossRef] [PubMed]
  8. Kulagina, N.; Papon, N.; Courdavault, V. Microbial Cell Factories for Tetrahydroisoquinoline Alkaloid Production. Chembiochem 2021, 22, 639–641. [Google Scholar] [CrossRef]
  9. Gao, Y.; Tu, N.; Liu, X.T.; Lu, K.K.; Chen, S.Y.; Guo, J. Progress in the Total Synthesis of Antitumor Tetrahydroisoquinoline Alkaloids. Chem. Biodivers. 2023, 20, e202300172. [Google Scholar] [CrossRef]
  10. Le, V.H.; Inai, M.; Williams, R.M.; Kan, T. Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. Nat. Prod. Rep. 2015, 32, 328–347. [Google Scholar] [CrossRef] [PubMed]
  11. Estevez, V.; Villacampa, M.; Menendez, J.C. Recent advances in the synthesis of pyrroles by multicomponent reactions. Chem. Soc. Rev. 2014, 43, 4633–4657. [Google Scholar] [CrossRef]
  12. Gumus, M.; Babacan, S.N.; Demir, Y.; Sert, Y.; Koca, I.; Gulcin, I. Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors. Arch. Pharm. 2022, 355, e2100242. [Google Scholar] [CrossRef] [PubMed]
  13. Basha, N.J.; Basavarajaiah, S.M.; Shyamsunder, K. Therapeutic potential of pyrrole and pyrrolidine analogs: An update. Mol. Divers. 2022, 26, 2915–2937. [Google Scholar] [CrossRef] [PubMed]
  14. Pigot, C.; Brunel, D.; Dumur, F. Indane-1,3-Dione: From Synthetic Strategies to Applications. Molecules 2022, 27, 5976. [Google Scholar] [CrossRef]
  15. Chen, G.; Zhang, J.; Wu, Y. Synthesis and regiochemistry of spiro indane-1,3-dione compounds. Res. Chem. Intermed. 2012, 38, 413–420. [Google Scholar] [CrossRef]
  16. Bhojgude, S.S.; Bhunia, A.; Biju, A.T. Employing Arynes in Diels-Alder Reactions and Transition-Metal-Free Multicomponent Coupling and Arylation Reactions. Acc. Chem. Res. 2016, 49, 1658–1670. [Google Scholar] [CrossRef]
  17. Jiang, X.; Wang, R. Recent Developments in Catalytic Asymmetric Inverse-Electron-Demand Diels-Alder Reaction. Chem. Rev. 2013, 113, 5515–5546. [Google Scholar] [CrossRef]
  18. Knall, A.-C.; Slugovc, C. Inverse electron demand Diels-Alder (iEDDA)-initiated conjugation: A (high) potential click chemistry scheme. Chem. Soc. Rev. 2013, 42, 5131–5142. [Google Scholar] [CrossRef]
  19. Yang, B.; Gao, S. Recent advances in the application of Diels-Alder reactions involving o-quinodimethanes, aza-o-quinone methides and o-quinone methides in natural product total synthesis. Chem. Soc. Rev. 2018, 47, 7926–7953. [Google Scholar] [CrossRef]
  20. Gaso-Sokac, D.; Stivojevic, M. Diels-Alder “Click” Reactions. Curr. Org. Chem. 2016, 20, 2211–2221. [Google Scholar] [CrossRef]
  21. Cao, M.-H.; Green, N.J.; Xu, S.-Z. Application of the aza-Diels-Alder reaction in the synthesis of natural products. Org. Biomol. Chem. 2017, 15, 3105–3129. [Google Scholar] [CrossRef]
  22. Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Formal [4 + 1] Annulation Reactions in the Synthesis of Carbocyclic and Heterocyclic Systems. Chem. Rev. 2015, 115, 5301–5365. [Google Scholar] [CrossRef] [PubMed]
  23. Ylijoki, K.E.O.; Stryker, J.M. [5 + 2] Cycloaddition Reactions in Organic and Natural Product Synthesis. Chem. Rev. 2013, 113, 2244–2266. [Google Scholar] [CrossRef]
  24. Biemolt, J.; Ruijter, E. Advances in Palladium-Catalyzed Cascade Cyclizations. Adv. Synth. Catal. 2018, 360, 3821–3871. [Google Scholar] [CrossRef]
  25. Li, J.; Yang, S.; Wu, W.; Jiang, H. Palladium-Catalyzed Cascade Cyclization/Alkynylation Reactions. Chem. Asian J. 2019, 14, 4114–4128. [Google Scholar] [CrossRef]
  26. Ohno, H. Gold-Catalyzed Cascade Reactions of Alkynes for Construction of Polycyclic Compounds. Israel J. Chem. 2013, 53, 869–882. [Google Scholar] [CrossRef]
  27. Du, G.; Wang, G.; Ma, W.; Yang, Q.; Bao, W.; Liang, X.; Zhu, L.; Lee, C.-S. Syntheses of Diverse Natural Products via Dual-Mode Lewis Acid Induced Cascade Cyclization Reactions. Synlett 2017, 28, 1394–1406. [Google Scholar]
  28. Liu, T.-Y.; Xie, M.; Chen, Y.-C. Organocatalytic asymmetric transformations of modified Morita-Baylis-Hillman adducts. Chem. Soc. Rev. 2012, 41, 4101–4112. [Google Scholar] [CrossRef]
  29. Huang, W.-Y.; Anwar, S.; Chen, K. Morita-Baylis-Hillman (MBH) Reaction Derived Nitroallylic Alcohols, Acetates and Amines as Synthons in Organocatalysis and Heterocycle Synthesis. Chem. Rec. 2017, 17, 363–381. [Google Scholar] [CrossRef]
  30. Elleuch, H.; Mihoubi, W.; Mihoubi, M.; Ketata, E.; Gargouri, A.; Rezgui, F. Potential antioxidant activity of Morita-Baylis-Hillman adducts. Bioorg. Chem. 2018, 78, 24–28. [Google Scholar] [CrossRef]
  31. Zhong, N.-J.; Wang, Y.-Z.; Cheng, L.; Wang, D.; Liu, L. Recent advances in the annulation of Morita-Baylis-Hillman adducts. Org. Biomol. Chem. 2018, 16, 5214–5227. [Google Scholar] [CrossRef]
  32. Calcatelli, A.; Cherubini-Celli, A.; Carletti, E.; Companyo, X. Unconventional Transformations of Morita-Baylis-Hillman Adducts. Synthesis 2020, 52, 2922–2939. [Google Scholar]
  33. Juma, W.P.; Nyoni, D.; Brady, D.; Bode, M.L. The Application of Biocatalysis in the Preparation and Resolution of Morita-Baylis-Hillman Adducts and Their Derivatives. Chembiochem 2022, 23, e202100527. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, Z.-C.; Chen, Z.; Du, W.; Chen, Y.-C. Transformations of Modified Morita-Baylis-Hillman Adducts from Isatins Catalyzed by Lewis Bases. Chem. Rec. 2020, 20, 541–555. [Google Scholar] [CrossRef]
  35. Meng, Y.; Chen, L.; Li, E.-Q. Recent Advances in Lewis Base-Catalysed Chemo-, Diastereo- and Enantiodivergent Reactions of Electron-deficient Olefins and Alkynes. Chem. Rec. 2022, 22, e202100276. [Google Scholar] [CrossRef]
  36. Zhou, R.; Liu, R.; Li, R.; He, Z. Progress in Phosphine-Promoted Annulations between Two Electrophiles. Chin. J. Org. Chem. 2014, 34, 2385–2405. [Google Scholar] [CrossRef]
  37. Xie, P.; Huang, Y. Morita-Baylis-Hillman adduct derivatives (MBHADs): Versatile reactivity in Lewis base-promoted annulation. Org. Biomol. Chem. 2015, 13, 8578–8595. [Google Scholar] [CrossRef]
  38. Yang, Z.-H.; Chen, P.; Chen, Z.-C.; Chen, Z.; Du, W.; Chen, Y.-C. A Double Deprotonation Strategy for Cascade Annulations of Palladium-Trimethylenemethanes and Morita-Baylis-Hillman Carbonates to Construct Bicyclo 3.1.0 hexane Frameworks. Angew. Chem. Int. Ed. 2021, 60, 13913–13917. [Google Scholar] [CrossRef]
  39. Song, X.; Zhang, J.; Wu, Y.-X.; Ouyang, Q.; Du, W.; Chen, Y.-C. Asymmetric Formal Nucleophilic o-Cresolylation with Morita-Baylis-Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis. J. Am. Chem. Soc. 2022, 144, 9564–9569. [Google Scholar] [CrossRef]
  40. Li, Y.; Chen, P.; Chen, Z.-C.; Du, W.; Chen, Y.-C. Cooperative Tertiary Phosphine/Palladium Catalyzed Nucleophilic Allylation between Morita-Baylis-Hillman Carbonates and Alkenes. Eur. J. Org. Chem. 2022, 2022, e202200218. [Google Scholar] [CrossRef]
  41. He, Z.-L.; Chen, P.; Chen, Z.-C.; Du, W.; Chen, Y.-C. Construction of Hydrodibenzo b,d furan Frameworks from Morita-Baylis-Hillman Carbonates of Isatins and o-Hydroxy Enones via Palladium and Bronsted Base Relay Catalysis. Org. Lett. 2022, 24, 100–104. [Google Scholar] [CrossRef] [PubMed]
  42. Yang, Y.; Zhu, B.; Zhu, L.; Jiang, Y.; Guo, C.-L.; Gu, J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Combining palladium and ammonium halide catalysts for Morita-Baylis-Hillman carbonates of methyl vinyl ketone: From 1,4-carbodipoles to ion pairs. Chem. Sci. 2021, 12, 11399–11405. [Google Scholar] [CrossRef] [PubMed]
  43. Yang, X.-X.; Yan, R.-J.; Ran, G.-Y.; Chen, C.; Yue, J.-F.; Yan, X.; Ouyang, Q.; Du, W.; Chen, Y.-C. pi-Lewis-Base-Catalyzed Asymmetric Vinylogous Umpolung Reactions of Cyclopentadienones and Tropone. Angew. Chem. Int. Ed. 2021, 60, 26762–26768. [Google Scholar] [CrossRef] [PubMed]
  44. Yan, R.-J.; Liu, B.-X.; Hu, Y.; Du, W.; Chen, Y.-C. Generation of zwitterionic trifluoromethyl N-allylic ylides and their use in switchable divergent annulations. Chem. Commun. 2021, 57, 9056–9059. [Google Scholar] [CrossRef]
  45. Chen, Z.; Chen, Z.-C.; Du, W.; Chen, Y.-C. Asymmetric [4+3] Annulations for Constructing Divergent Oxepane Frameworks via Cooperative Tertiary Amine/Transition Metal Catalysis. Org. Lett. 2021, 23, 8559–8564. [Google Scholar] [CrossRef]
  46. Tian, Z.; Jiang, J.; Yan, Z.-H.; Luo, Q.-Q.; Zhan, G.; Huang, W.; Li, X.; Han, B. Catalytic asymmetric [3+2] cycloaddition of pyrazolone-derived MBH carbonate: Highly stereoselective construction of the bispiro-[pyrazolone-dihydropyrrole-oxindole] skeleton. Chem. Commun. 2022, 58, 5363–5366. [Google Scholar] [CrossRef] [PubMed]
  47. Lu, Z.; Jia, Y.; Chen, X.; Li, P. Organocatalytic Regio-and Enantioselective [3 + 2]-Annulations of Ninhydrin-Derived Morita-Baylis-Hillman Carbonates with 3-Methyleneoxindoles. J. Org. Chem. 2022, 87, 3184–3194. [Google Scholar] [CrossRef]
  48. He, X.-H.; Fu, X.-J.; Zhan, G.; Zhang, N.; Li, X.; Zhu, H.-P.; Peng, C.; He, G.; Han, B. Organocatalytic asymmetric synthesis of multifunctionalized alpha-carboline-spirooxindole hybrids that suppressed proliferation in colorectal cancer cells. Org. Chem. Front. 2022, 9, 1048–1055. [Google Scholar] [CrossRef]
  49. Mei, M.-S.; Wang, Y.-J.; Zhang, G.-S.; Tang, J.-Y.; Tian, P.; Wang, Y.-H. Catalyst-Controlled Diastereoselectivity Switch in the Asymmetric [3 + 2] Annulation of Isatin-Derived MBH Carbonates and 5-Alkenylthiazol-4(5H)-ones. Org. Lett. 2021, 23, 7336–7341. [Google Scholar] [CrossRef]
  50. Yadav, A.; Banerjee, J.; Arupula, S.K.; Mobin, S.M.; Samanta, S. Lewis-Base-Catalyzed Domino Reaction of Morita-Baylis-Hillman Carbonates of Isatins with Enolizable Cyclic Carbonyl Compounds: Stereoselective Access to Spirooxindole-Pyrans. Asian J. Org. Chem. 2018, 7, 1595–1599. [Google Scholar] [CrossRef]
  51. Yan, R.-J.; Liu, B.-X.; Xiao, B.-X.; Du, W.; Chen, Y.-C. Asymmetric (4 + 3) and (4 + 1) Annulations of Isatin-derived Morita-Baylis-Hillman Carbonates to Construct Diverse Chiral Heterocyclic Frameworks. Org. Lett. 2020, 22, 4240–4244. [Google Scholar] [CrossRef] [PubMed]
  52. Du, J.-Y.; Ma, Y.-H.; Meng, F.-X.; Zhang, R.-R.; Wang, R.-N.; Shi, H.-L.; Wang, Q.; Fan, Y.-X.; Huang, H.-L.; Cui, J.-C.; et al. Lewis Base-Catalyzed [4 + 3] Annulation of ortho-Quinone Methides and MBH Carbonates: Synthesis of Functionalized Benzo b oxepines Bearing Oxindole Scaffolds. Org. Lett. 2019, 21, 465–468. [Google Scholar] [CrossRef] [PubMed]
  53. Jia, R.-L.; Liu, Q.-L.; Yang, L.-W.; Deng, S.; Song, Y. [6+3] Annulations of Morita-Baylis-Hillman carbonates and dicyanoheptafulvene. Org. Biomol. Chem. 2021, 19, 9867–9871. [Google Scholar] [CrossRef] [PubMed]
  54. Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Catalyst-Controlled Switch in Chemo- and Diastereoselectivities: Annulations of Morita-Baylis-Hillman Carbonates from Isatins. Angew. Chem. Int. Ed. 2016, 55, 2147–2151. [Google Scholar] [CrossRef]
  55. Zheng, J.; Huang, Y.; Li, Z.M. Phosphine-catalyzed sequential annulation domino reaction: Rapid construction of bicyclo [4.1.0] heptene skeletons. Chem. Commun. 2014, 50, 5710–5713. [Google Scholar] [CrossRef] [PubMed]
  56. Warghude, P.K.; Dharpure, P.D.; Bhat, R.G. Cycloaddition of isatin-derived MBH carbonates and 3-methyleneoxindoles to construct diastereoselective cyclopentenyl bis-spirooxindoles and cyclopropyl spirooxindoles: Catalyst controlled [3 + 2] and [2 + 1] annulations. Tetrahedron Lett. 2018, 59, 4076–4079. [Google Scholar] [CrossRef]
  57. Chen, R.; Xu, S.; Fan, X.; Li, H.; Tang, Y.; He, Z. Construction of dispirocyclohexanes via amine-catalyzed [2 + 2 + 2] annulations of Morita-Baylis-Hillman acetates with exocyclic alkenes. Org. Biomol. Chem. 2015, 13, 398–408. [Google Scholar] [CrossRef]
  58. Xie, P.Z.; Huang, Y.; Chen, R.Y. Phosphine-Mediated Domino Benzannulation Strategy for the Construction of Highly Functionalized Multiaryl Skeletons. Chem. Eur. J. 2012, 18, 7362–7366. [Google Scholar] [CrossRef]
  59. Cheng, Y.; Fang, Z.; Li, W.; Li, P. Phosphine-mediated enantioselective [4 + 1] annulations between ortho-quinone methides and Morita-Baylis-Hillman carbonates. Org. Chem. Front. 2018, 5, 2728–2733. [Google Scholar] [CrossRef]
  60. Sekiguchi, Y.; Yoshikai, N. Zinc-Catalyzed beta-Functionalization of Cyclopropanols via Enolized Homoenolate. J. Am. Chem. Soc. 2021, 143, 18400–18405. [Google Scholar] [CrossRef]
  61. Cheng, Y.; Han, Y.; Li, P. Organocatalytic Enantioselective [1 + 4] Annulation of Morita-Baylis Hillman Carbonates with Electron-Deficient Olefins: Access to Chiral 2,3-Dihydrofuran Derivatives. Org. Lett. 2017, 19, 4774–4777. [Google Scholar] [CrossRef] [PubMed]
  62. Hu, F.-L.; Wei, Y.; Shi, M. Phosphine-catalyzed asymmetric [4 + 1] annulation of activated alpha,beta-unsaturated ketones with Morita-Baylis-Hillman carbonates: Enantioselective synthesis of spirooxindoles containing two adjacent quaternary stereocenters. Chem. Commun. 2014, 50, 8912–8914. [Google Scholar] [CrossRef]
  63. Han, X.Y.; Yao, W.J.; Wang, T.L.; Tan, Y.R.; Yan, Z.Y.; Kwiatkowski, J.; Lu, Y.X. Asymmetric Synthesis of Spiropyrazolones through Phosphine-Catalyzed [4 + 1] Annulation. Angew. Chem. Int. Ed. 2014, 53, 5643–5647. [Google Scholar] [CrossRef]
  64. Wang, K.-K.; Li, Y.-L.; Jing, J.; Chen, R.; Zhao, N.-N.; Li, Z.-H.; Wang, M.-Y.; Ji, S.-K. Synthesis of 1,3,5-trisubstituted pyrazoles via 1,3-dipolar cycloaddition of nitrile imines with ninhydrin-derived Morita–Baylis–Hillman carbonates. Org. Biomol. Chem. 2022, 20, 6923–6930. [Google Scholar] [CrossRef] [PubMed]
  65. Tang, X.; Wu, Y.; Jiang, J.; Fang, H.; Zhou, W.-J.; Huang, W.; Zhan, G. Formal [3 + 1 + 1] Carboannulation of Morita-Baylis-Hillman Carbonates with Pyridinium Ylides: Access to Spiro-Cyclopentadiene Oxindoles. Org. Lett. 2021, 23, 8937–8941. [Google Scholar] [CrossRef] [PubMed]
  66. Zhou, L.; Yuan, C.; Zeng, Y.; Wang, Q.; Wang, C.; Liu, M.; Wang, W.; Wu, Y.; Zheng, B.; Guo, H. Direct Activation of Unmodified Morita–Baylis–Hillman Alcohols through Phosphine Catalysis for Rapid Construction of Three-Dimensional Heterocyclic Compounds. Org. Lett. 2019, 21, 4882–4886. [Google Scholar] [CrossRef] [PubMed]
  67. Zhou, L.; Zeng, Y.; Gao, X.; Wang, Q.; Wang, C.; Wang, B.; Wang, W.; Wu, Y.; Zheng, B.; Guo, H. A chiral squaramide-catalyzed asymmetric dearomative tandem annulation reaction through a kinetic resolution of MBH alcohols: Highly enantioselective synthesis of three-dimensional heterocyclic compounds. Chem. Commun. 2019, 55, 10464–10467. [Google Scholar] [CrossRef]
  68. Lokesh, K.; Kumarswamyreddy, N.; Kesavan, V. Diastereoselective Construction of Tetrahydro-Dispiro[indolinone-3,2′-pyran-5′,4″-pyrazolone] Scaffolds via an Oxa-Michael Cascade [4 + 2] Annulation Reaction. J. Org. Chem. 2022. [Google Scholar] [CrossRef] [PubMed]
  69. Zhang, X.; Ouyang, X.-H.; Li, Y.; Chen, B.; Li, J.-H. Rhodium-Catalysed [4 + 2] Annulation of Aromatic Oximes with Terminal Alkenes by C-H/N-O Functionalization towards 3,4-Dihydroisoquinolines. Adv. Synth. Catal. 2019, 361, 4955–4960. [Google Scholar] [CrossRef]
  70. Sosnovskikh, V.Y.; Usachev, B.I.; Shklyaev, Y.V. Reactions of 1,3,3-trimethyl-3,4-dihydroisoquinolines with polyhaloalkanonitriles. Russ. Chem. B. 2004, 53, 1248–1252. [Google Scholar] [CrossRef]
  71. Jarvis, C.L.; Jemal, N.M.; Knapp, S.; Seidel, D. Formal [4 + 2] cycloaddition of imines with alkoxyisocoumarins. Org. Biomol. Chem. 2018, 16, 4231–4235. [Google Scholar] [CrossRef]
  72. Pramthaisong, C.; Worayuthakarn, R.; Pharikronburee, V.; Duangthongyou, T.; Rattanakam, R.; Ruchirawat, S.; Thasana, N. Base-Mediated Cascade Cyclization: Stereoselective Synthesis of Benzooxazocinone. Org. Lett. 2018, 20, 4015–4019. [Google Scholar] [CrossRef]
  73. Wang, K.-K.; Li, Y.; Zhang, W.; Chen, R.; Ma, X.; Wang, M.; Zhou, N. Facile Synthesis of Tricyclic 1,2,4-Oxadiazolines-Fused Tetrahydro-Isoquinolines from Oxime Chlorides with 3,4-Dihydroisoquinoline Imines. Molecules 2022, 27, 3064. [Google Scholar] [CrossRef]
  74. Wang, K.-K.; Li, Y.-L.; Wang, Z.-Y.; Ma, X.; Mei, Y.-L.; Zhang, S.-S.; Chen, R. Formal [3 + 2] cycloaddition of azomethine ylides generated in situ with unactivated cyclic imines: A facile approach to tricyclic imidazolines derivatives. J. Heterocycl. Chem. 2020, 57, 1456–1463. [Google Scholar] [CrossRef]
  75. Elliott, M.C.; Williams, E. Synthesis and reactions of partially reduced biisoquinolines. Org. Biomol. Chem. 2003, 1, 3038–3047. [Google Scholar] [CrossRef]
  76. Mbere, J.M.; Bremner, J.B.; Skelton, B.W.; White, A.H. Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations. Tetrahedron 2011, 67, 6895–6900. [Google Scholar] [CrossRef]
  77. Tang, X.; Yang, M.-C.; Ye, C.; Liu, L.; Zhou, H.-L.; Jiang, X.-J.; You, X.-L.; Han, B.; Cui, H.-L. Catalyst-free [3 + 2] cyclization of imines and Morita-Baylis-Hillman carbonates: A general route to tetrahydropyrrolo [2,1-a] isoquinolines and dihydropyrrolo [2,1-a] isoquinolines. Org. Chem. Front. 2017, 4, 2128–2133. [Google Scholar] [CrossRef]
  78. Tang, X.; Gao, Y.-J.; Deng, H.-Q.; Lei, J.-J.; Liu, S.-W.; Zhou, L.; Shi, Y.; Liang, H.; Qiao, J.; Guo, L.; et al. Catalyst-free [3 + 2] cyclization of dihydroisoquinoline imines and isatin-derived Morita-Baylis-Hillman carbonates via 1,5-electrocyclization: Synthesis of tetrahydroisoquinoline-fused spirooxindoles. Org. Biomol. Chem. 2018, 16, 3362–3366. [Google Scholar] [CrossRef] [PubMed]
  79. Wang, K.-K.; Jing, J.; Zhou, W.-W.; Wang, C.; Ye, J.-W.; Zhou, R.; Wang, T.-T.; Wang, Z.-Y.; Chen, R. Divergent Synthesis of Highly Substituted Tetrahydroquinolines and Cyclopentenes via Lewis Base Catalyzed Switchable [4 + 2] and [3 + 2] Annulations of MBH-Carbonates with Activated Olefins. J. Org. Chem. 2023, 88, 5982–5996. [Google Scholar] [CrossRef]
  80. Wang, K.-K.; Du, W.; Zhu, J.; Chen, Y.-C. Construction of polycyclic spirooxindoles through [3 + 2] annulations of Morita-Baylis-Hillman carbonates and 3-nitro-7-azaindoles. Chin. Chem. Lett. 2017, 28, 512–516. [Google Scholar] [CrossRef]
  81. Wang, K.-K.; Wang, P.; Ouyang, Q.; Du, W.; Chen, Y.-C. Substrate-controlled switchable asymmetric annulations to access polyheterocyclic skeletons. Chem. Commun. 2016, 52, 11104–11107. [Google Scholar] [CrossRef] [PubMed]
  82. Wang, K.-K.; Jin, T.; Huang, X.; Ouyang, Q.; Du, W.; Chen, Y.-C. alpha-Regioselective Asymmetric [3 + 2] Annulations of Morita-Baylis-Hillman Carbonates with Cyclic 1-Azadienes and Mechanism Elucidation. Org. Lett. 2016, 18, 872–875. [Google Scholar] [CrossRef] [PubMed]
  83. CCDC 2277407 Contains the Supplementary Crystallographic Data for This Paper. Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 31 August 2023).
  84. CCDC 2277406 Contains the Supplementary Crystallographic Data for This Paper. Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 30 August 2023).
Molecules 28 06761 sch001
Scheme 1. Previous reports of aldehydes or isatins-derived MBH adducts with 3,4-dihydroisoquinolines (a,b) and our protocol (c).
Scheme 1. Previous reports of aldehydes or isatins-derived MBH adducts with 3,4-dihydroisoquinolines (a,b) and our protocol (c).
Molecules 28 06761 sch001
Molecules 28 06761 sch002
Scheme 2. Substrate scopes for [4 + 2] annulations a. a Reactions were performed with ninhydrin-derived MBH alcohols 1 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv), DABCO (20 mol%) in CH3CN (1.0 mL) at room temperature for 12 h. Isolated yield and dr > 25:1 by 1H NMR analysis. b The thermal ellipsoids in the ORTEP diagram (CCDC 2231641) are shown at a 50% probability level.
Scheme 2. Substrate scopes for [4 + 2] annulations a. a Reactions were performed with ninhydrin-derived MBH alcohols 1 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv), DABCO (20 mol%) in CH3CN (1.0 mL) at room temperature for 12 h. Isolated yield and dr > 25:1 by 1H NMR analysis. b The thermal ellipsoids in the ORTEP diagram (CCDC 2231641) are shown at a 50% probability level.
Molecules 28 06761 sch002
Molecules 28 06761 sch003
Scheme 3. Substrate scopes for [3 + 2] annulations a. a Reactions were performed with ninhydrin-derived MBH carbonates 4 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) at room temperature for 1 h. Isolated yield. b The thermal ellipsoids in the ORTEP diagram (CCDC 2231641) are shown at a 50% probability level.
Scheme 3. Substrate scopes for [3 + 2] annulations a. a Reactions were performed with ninhydrin-derived MBH carbonates 4 (0.11 mmol, 1.1 equiv), 3,4-dihydroisoquinolines 2 (0.1 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) at room temperature for 1 h. Isolated yield. b The thermal ellipsoids in the ORTEP diagram (CCDC 2231641) are shown at a 50% probability level.
Molecules 28 06761 sch003
Molecules 28 06761 sch004
Scheme 4. Gram-scale reaction for [4 + 2] cycloadduct 3a and [3 + 2] cycloadduct 5a.
Scheme 4. Gram-scale reaction for [4 + 2] cycloadduct 3a and [3 + 2] cycloadduct 5a.
Molecules 28 06761 sch004
Molecules 28 06761 sch005
Scheme 5. Proposed mechanism to explain the reaction process via these intermediate A–C.
Scheme 5. Proposed mechanism to explain the reaction process via these intermediate A–C.
Molecules 28 06761 sch005
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 06761 i001
EntrySubstrateCatalystSolventTime (h)Yield (%) b
11aDABCOCH2Cl2123a, 78
21aTEACH2Cl2123a, 73
31aDIPEACH2Cl2123a, 69
41aDBUCH2Cl2123a, trace
51aNa2CO3CH2Cl2123a, trace
61aNaOHCH2Cl2123a, trace
71aDABCOCHCl3243a, 72
81aDABCOtoluene243a, 36
91aDABCOCH3CN123a, 85
101aDABCOdioxane243a, trace
111aDABCOTHF243a, trace
121aDABCOEtOAc123a, 81
13 c1aDABCOCH3CN123a, 86
144aDABCOCH3CN65a, 75
154a/CH3CN65a, 78
164a/CH2Cl215a, 88
174a/CHCl315a, 85
184a/EtOAc125a, 80
194a/Toluene125a, 69
204a/THF65a, 58
a Unless noted otherwise, reactions were performed with ninhydrin-derived MBH adduct 1a or 4a (0.11 mmol, 1.1 equiv) and 3,4-dihydroisoquinoline 2a (0.1 mmol, 1.0 equiv), catalyst (20 mol%) in solvent (1.0 mL). b Yield of the isolated product and dr > 25:1 by 1H NMR analysis. c DABCO (50 mol%).
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Wang, K.; Zhou, W.; Jia, J.; Ye, J.; Yuan, M.; Yang, J.; Qi, Y.; Chen, R. Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines. Molecules 2023, 28, 6761. https://doi.org/10.3390/molecules28196761

AMA Style

Wang K, Zhou W, Jia J, Ye J, Yuan M, Yang J, Qi Y, Chen R. Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines. Molecules. 2023; 28(19):6761. https://doi.org/10.3390/molecules28196761

Chicago/Turabian Style

Wang, Kaikai, Wenwen Zhou, Jun Jia, Junwei Ye, Mengxin Yuan, Jie Yang, Yonghua Qi, and Rongxiang Chen. 2023. "Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines" Molecules 28, no. 19: 6761. https://doi.org/10.3390/molecules28196761

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