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Communication

Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations

by
Jia-Cheng Ge
1,2,†,
Yufeng Wang
1,†,
Feng-Wei Guo
1,
Xiangyun Kong
1,
Fangzhi Hu
1,* and
Shuai-Shuai Li
1,2,*
1
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
2
Hailir Pesticides and Chemicals Group Co., Ltd., Qingdao 266109, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(5), 1012; https://doi.org/10.3390/molecules29051012
Submission received: 25 January 2024 / Revised: 16 February 2024 / Accepted: 21 February 2024 / Published: 26 February 2024
(This article belongs to the Special Issue Synthesis and Properties of Heterocyclic Compounds: Recent Advances)
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Abstract

:
The Sc(OTf)3-catalyzed dearomative [5+1] annulations between readily available 3-aminophenols and O-alkyl ortho-oxybenzaldehydes were developed for synthesis of spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones. The “two-birds-with-one-stone” strategy was disclosed by the dearomatization of phenols and direct α-C(sp3)–H bond functionalization of oxygen through cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process. In addition, the antifungal activity assay and derivatizations of products were conducted to further enrich the utility of the structure.

Graphical Abstract

1. Introduction

Aromatic compounds as bulk and fundamental chemical feedstocks play a prominent role in organic synthesis [1,2,3]. Dearomatization is the high-value-added transformation of aromatic compounds to generate structurally diverse three-dimensional polycyclic molecules [4,5,6,7]. Due to the high significance of dearomatization in assembling sophisticated polycyclic architectures with enhanced sp3-character, much more attention has been paid to dearomatization chemistry [4,5,6,7,8,9,10,11,12,13,14,15,16]. Among the dearomatization reactions, phenol is one of the most studied structures which could be facilely converted into cyclohexadienone, and many strategies have been developed to achieve dearomatization of phenols [13,14,15,16]. For example, ortho-substituted phenols were commonly used to undergo oxidant-promoted oxidative dearomatization or transition-metal-catalyzed allylation, alkylation, amination to generate cyclohexadienones (Scheme 1a) [17,18,19]. Although great progress has been made in these transformations, the ortho-substituted phenols have to be prefabricated, which brings limitations in practical production. Notably, the employment of phenols and dielectrophiles as starting materials for direct dearomatization of phenols was a highly atom- and step-economic strategy (Scheme 1b). Until now, the dearomatization of phenols by employment of the phenols without pre-installed substituents at the dearomatization site via direct formation of two chemical bonds was a huge challenge.
Hydride transfer/cyclization has attracted intense interest as an efficient strategy with the breaking and formation of a number of bonds in one operation for construction of privileged molecules [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Among the diverse transformations, the α-C(sp3)−H bond functionalization of amine occupied the majority (Scheme 1c) [23,24,25,26,27,28,29,30,31,32,33,34,35], while the application of an α-C(sp3)−H bond of oxygen as hydride donor was relatively challenging, which might be attributed to (1) lower reactivity of the α-C(sp3)−H bond of oxygen than that of tert-amine; (2) the in situ-formed acyclic oxocarbenium intermediate tends to hydrolyze [36,37,38]. This disadvantage led to few acceptors being available for initiating the α-C(sp3)−H bond functionalization of oxygen (Scheme 1d).
Aromatization is an important thermodynamic driving force for organic transformation [39,40,41,42]. Inspired by the above-mentioned challenge, we designed to utilize the in situ-assembled ortho-quinone methides (o-QMs) from phenols and aldehydes as hydride acceptors for driving hydride transfer with the potent propensity of aromatization. In addition, the formal [5+1] annulation that undergo dearomatization/rearomatization/dearomatization process would achieve the direct dearomatization of phenols and α-C(sp3)−H bond functionalization of oxygen (Scheme 1e).
As a continuation of our interest in developing hydride transfer-involved reactions for the rapid construction of privileged heterocyclic skeletons [7,22,34,35,42], herein we report the “two-birds-with-one-stone” strategy to dearomatize phenols and functionalize α-C(sp3)−H bond of oxygen. This dearomative [5+1] annulation provided a variety of cy spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones from 3-aminophenols and O-alkyl ortho-oxybenzaldehydes through Sc(OTf)3-catalyzed cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process (Scheme 1f). It is worth mentioning that the direct dearomatization of phenols combined with the functionalization of an α-C(sp3)−H bond of oxygen via a hydride transfer strategy was achieved unprecedentedly. In addition, the antifungal activity assay preliminarily showed the potential of these products in the prevention and control of agricultural pathogens.

2. Results and Discussion

At the outset of the reaction, the O-benzyl salicylaldehyde-derived substrate 1a and phenol 2a were selected as model substrates to examine the reaction (Table 1). Firstly, Lewis acids Sc(OTf)3, Mg(OTf)2, and Zn(OTf)2 were applied as catalysts in DCE to promote the desired transformation. To our delight, the expected cyclohexadienone-fused spirochromane 3a was obtained through the Lewis acids-catalyzed cascade condensation/[1,5]-hydride transfer/dearomative-cyclization, and a 52% yield was isolated with Sc(OTf)3 as catalyst (entry 1). Next, various Brønsted acids were also applied to evaluate the reaction. As shown, Brønsted acids showed slightly weaker catalytic activity than Lewis acids (entries 4–7). Subsequently, diverse solvents were investigated with Sc(OTf)3 as catalyst to further improve the yield of the product. Delightedly, fluorinated alcohol TFE (2,2,2-trifluoroethanol) was efficient in mediating the dearomatization/aromatization-dearomatization process to afford the product 3a in 84% yield and excellent diastereoselectivity (entries 8–13). Moreover, HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol) was also a good reaction medium for the transformation (entry 14). Then, the ratios of substrates, reaction temperature, and the loading of catalyst were meticulously screened. The results showed that the adjustment of the ratio of 1a and 2a and reaction temperature was unavailing for improving the reaction efficiency (entries 15–19). The examination of the loading of catalyst indicated that 20 mol% of Sc(OTf)3 was the suitable dosage for the reaction (entries 20–22). At last, the optimal reaction conditions were determined to be those described in entry 21 of Table 1.
With the optimal reaction conditions in hand, the generality of the dearomative [5+1] annulation with respect to diverse O-alkyl ortho-oxybenzaldehydes 1 was investigated (Scheme 2). Notably, substrates 1 carrying electron-withdrawing or -donating groups on the phenyl ring of the benzyl moiety were applicable for the [5+1] annulation with phenol 2a to afford the corresponding products 3a–g in moderate to excellent yields and excellent diastereoselectivities. Moreover, among the diverse substituents, the electron-withdrawing group had some effect on the reaction efficiency, delivering slightly lower yields of products (3b, 3c, 3f, 3g). Apart from 2-phenyl spirochromane, the 2-naphthyl spirochromane 3h could also be obtained in 90%. Moreover, isopropyl could act as hydride donor to conduct the hydride transfer-involved dearomative [5+1] annulation to provide the gem-dimethyl-substituted spirochromane 3i. In addition, the methyl-substituted benzyl and allyl-derived ortho-oxybenzaldehydes 1 were good reaction partners with phenol to perform the dearomative [5+1] annulation for giving the diversity-enriched spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3j and 3k in 70% and 90% yields, respectively.
Next, further investigation of the substrate scope with regard to phenols was performed for dearomatization of diverse phenols (Scheme 3). Various types of phenols were applied to react with O-alkyl ortho-oxybenzaldehydes 1. For example, non-substituted phenol was unavailable for the transformation, and electron-rich sesamol gave several unascertained products. Moreover, m-aminophenols showed excellent activity for reacting with O-alkyl ortho-oxybenzaldehydes. For instance, dimethylamine, pyrrolidine, piperidine, and azepine-substituted phenols were applicable for the transformation, affording the corresponding spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3l-o in moderate to excellent yields. In addition, dibenzylamine- and diallylamine-substituted phenols were also available for the reaction which further enriched the diversity of the substituents of products. The wide tolerance of the substituents on the phenols made the product more feasible for late-stage functionalization. On the other hand, the ortho tert-butyl could be replaced by iso-propyl or sec-butyl, delivering the corresponding products 3t or 3u in slightly lower yields than product 3a.
Then, the practicality of this protocol was demonstrated by the gram-scale synthesis of products 3. As shown in Scheme 4a, the reaction efficiency was almost unaffected in a 4 mmol scale to give the corresponding products 3a and 3k in 67% and 74% yields, respectively (Scheme 4a). In addition, in order to illustrate the biological activity of the product, the antifungal activity assay was performed (See Supporting Information). Compounds 3a, 3j, 3k, 3q, 3t and 3u were evaluated for their antifungal activities against four economically important phytopathogenic fungi: Rhizoctonia solani, Alternaria solani, Alternaria mali, and Sclerotium rolfsii. The results showed that most of the tested compounds possessed in vitro antifungal activity at a concentration of 200 mg/L. Especially, compound 3a exhibited remarkable antifungal potency among all target compounds, with inhibition rates of 40.21, 60.35, 53.56 and 29.09% at a concentration of 200 mg/L, respectively, against Rhizoctonia solani, Alternaria solani, Alternaria mali, and Sclerotium rolfsii. The results preliminarily showed the potential of these products in the prevention and control of agricultural pathogens. Moreover, the selective reduction in the terminal alkene by H2/Pd/C was performed to provide the 2-ethyl spirochromane 4k in 82% yield (Scheme 4b). This transformation remedied the deficiency that was unable to furnish 2-ethyl spirochromane by the direct dearomative [5+1] annulation. Apart from spirochromanes, polyarylated methane 5a could also be provided by twice nucleophilic addition with the employment of the O-alkyl ortho-oxybenzaldehyde 1v (Scheme 4c). This transformation indicated that the latter nucleophilic addition and hydride transfer were competitive reaction pathways.
Subsequently, the key factor for the hydride transfer/dearomative-cyclization was investigated (Scheme 5). In a hydride transfer reaction, the distance between hydride donor and hydride acceptor was decisive for the occurrence, and the conclusion was verified by the investigation on the “buttressing effect”. As shown in Scheme 5a, remarkable enhancement of the reactivity by the bulky group ortho to the alkoxy group could be clearly observed, which might be due to the steric repulsion between the ortho group and the alkoxy group shortening the distance between hydride donor and hydride acceptor. Then, the investigation into the effect of hydride donors demonstrated that the transfer ability of the hydride donors was a key factor as well (Scheme 5b). The examination of the α-C(sp3)−H bond of ethyl, iso-propyl, and benzyl adjacent to oxygen showed the difference in the activity, which might be dependent on the transfer ability of the hydride donors and the stability of the cations generated upon hydride transfer.
Based on the above experiments and precedent reports [37,38], a plausible mechanism was proposed to rationalize the dearomative [5+1] annulation (Scheme 6). First, the catalyst scandium-aggregated O-alkyl ortho-oxybenzaldehyde 1 and phenol 2 to mediate the Friedel–Crafts hydroxyalkylation condensation. Then, the adduct dehydrated immediately to generate an o-QM intermediate II. The propensity for aromatization of o-QM as a driving force initiated the α-hydride of oxygen transfer to yield the zwitterionic intermediate III. Next, the dearomative cyclization of III took place to furnish the cyclohexadienone-fused spirochromane 3.

3. Materials and Methods

3.1. General Information

Unless otherwise noted, all reagents and solvents were purchased from the commercial sources (from Adamas-beta, Shanghai, China) and used as received. Thin layer chromatography (TLC) was used to monitor the reaction on a Merck 60 F254 precoated silica gel plate (0.2 mm thickness). TLC spots were visualized by UV-light irradiation on a Spectroline Model ENF-24061/F 254 nm. The products were purified by flash column chromatography (200–300 mesh silica gel) eluted with the gradient of petroleum ether and ethyl acetate. Proton nuclear magnetic resonance spectra (1H NMR) were recorded on a Bruker 500 MHz or 400 MHz NMR spectrometer (CDCl3, DMSO-d6 or Methanol-d4 solvent). The chemical shifts were reported in parts per million (ppm), downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet), dimethyl sulfoxide-d6 (δ 2.54, singlet) or methanol-d4 (δ 3.31, quintuplet). Multiplicities were afforded as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet) or m (multiplets). The number of protons for a given resonance is indicated by nH. Coupling constants were reported as a J value in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) were referenced to the appropriate residual solvent peak. High-resolution mass spectral analysis (HRMS) was performed on Waters XEVO G2 Q-TOF. The ortho-substituted benzaldehydes were prepared according to the literature [43].

3.2. General Procedure for the Dearomative [5+1] Annulation

A sealed tube was charged with O-alkyl ortho-oxybenzaldehyde 1 (0.1 mmol), phenol 2 (0.15 mmol), Sc(OTf)3 (20 mol%), and TFE (1.0 mL). The mixture was stirred at 120 °C for 5 h. Upon completion of the reaction, as indicated by TLC analysis, the mixture was concentrated in vacuum and the residue was directly purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:3) to afford the desired spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3a–u.

3.3. Gram-Scale Synthesis and Derivatization of Products 3

A round-bottom flask was charged with O-alkyl ortho-oxybenzaldehydes 1a (4.0 mmol, 1.07 g) or 1k (4.0 mmol, 0.87 g), phenol 2a (6.0 mmol, 0.99 g), Sc(OTf)3 (20 mol%), and TFE (40.0 mL). The mixture was stirred at 120 °C for 5 h. Upon completion of the reaction, as indicated by TLC analysis, the mixture was concentrated in vacuum and the residue was directly purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:3) to afford the desired spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3a in 67% yield or 3k in 74% yield, respectively.
A reaction tube was charged with cyclohexadienone-fused spirochromane 3k (0.1 mmol, 36.6 mg) and 30% by wt Pd/C (10% by wt relative to 3k) in 1.0 mL of MeOH. The tube was equipped with a magnetic stir bar, and the suspension was sealed with a septum under an atmosphere of H2 supplied via a balloon for 6 h. Upon completion of the reaction, as indicated by TLC analysis, the suspension was filtered through a pad of Celite. The filtrate was concentrated in vacuum. The residue was directly purified by flash column chromatography on silica gel (ethyl acetate: petroleum ether, 1:3) to give the desired product 4k in 82% yield and 1:1 diastereoselectivity.

3.4. The Procedure for Synthesis of Product 5a

A tube was charged with O-alkyl ortho-oxybenzaldehyde 1v (0.1 mmol, 32.8 mg), phenol 2a (0.22 mmol, 36.4 mg), Sc(OTf)3 (20 mol%), and TFE (1.0 mL). The mixture was stirred at room temperature for 5 h. Upon completion of the reaction, as indicated by TLC analysis, the mixture was concentrated in vacuum and the residue was directly purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:15) to afford the polyarylated methane 5a in 81% yield.

3.5. Investigation on the “Buttressing Effect”

A tube was charged with O-alkyl ortho-oxybenzaldehydes 1 bearing methyl, isopropyl, or tertbutyl (0.1 mmol), phenol 2 (0.15 mmol), Sc(OTf)3 (20 mol%), and TFE (1.0 mL). The mixture was stirred at 120 °C for 5 h. Upon completion of the reaction, as indicated by TLC analysis, the mixture was concentrated in vacuum and the residue was directly purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:3) to afford the desired spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3v, 3t, or 3a. A remarkable enhancement of the reactivity by the bulky group ortho to the alkoxy group could be clearly observed, which might be due to the steric repulsion between ortho group and alkoxy group shortening the distance between hydride donor and hydride acceptor.

3.6. Investigation on the Effect of Hydride Donors

A tube was charged with O-ethyl, O-isopropyl, or O-benzyl ortho-oxybenzaldehydes 1 (0.1 mmol), phenol 2 (0.15 mmol), Sc(OTf)3 (20 mol%), and TFE (1.0 mL). The mixture was stirred at 120 °C for 5 h. Upon completion of the reaction, as indicated by TLC analysis, the mixture was concentrated in vacuum and the residue was directly purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:3) to afford the desired spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones 3w, 3i, or 3a. A remarkable enhancement of the reactivity by the bulky group ortho to the alkoxy group could be clearly observed, which might be due to the steric repulsion between ortho group and alkoxy group shortening the distance between hydride donor and hydride acceptor. The examination of the α-C(sp3)−H bond of ethyl, iso-propyl, and benzyl adjacent to oxygen showed the difference in the activity, which might be dependent on the transfer ability of the hydride donors and the stability of the cations generated upon hydride transfer.

3.7. Characterization of Products

8-(tert-butyl)-4′-(diethylamino)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3a). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (35.3 mg, 85% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.30 (m, 2H), 7.17–7.08 (m, 4H), 6.95 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 6.26 (dd, J = 10.4, 2.1 Hz, 1H), 5.24 (s, 1H), 4.93 (d, J = 2.0 Hz, 1H), 3.85 (d, J = 16.5 Hz, 1H), 3.16–3.01 (m, 4H), 2.62 (d, J = 16.6 Hz, 1H), 1.30 (s, 9H), 0.93 (t, J = 7.0 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.4, 156.2, 152.6, 142.2, 137.9, 137.1, 127.9, 127.6, 127.1, 124.4, 121.0, 120.4, 119.0, 97.4, 83.5, 49.9, 45.0, 36.9, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C28H33NNaO2+: 438.2404, found: 438.2408.
8-(tert-butyl)-4′-(diethylamino)-2-(2-fluorophenyl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3b). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (20.4 mg, 47% yield) as a yellow solid.
1H NMR (500 MHz, CDCl3) δ 7.41 (t, J = 6.9 Hz, 1H), 7.21 (d, J = 6.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.02 (m, 2H), 6.99–6.94 (m, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 10.4 Hz, 1H), 6.43 (dd, J = 10.4, 1.8 Hz, 1H), 5.61 (s, 1H), 5.05 (d, J = 1.4 Hz, 1H), 3.97 (d, J = 16.6 Hz, 1H), 3.21 (d, J = 6.2 Hz, 4H), 2.70 (d, J = 16.6 Hz, 1H), 1.34 (s, 9H), 1.04 (t, J = 6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 194.5, 160.2 (d, J = 248.7 Hz), 156.0, 152.5, 142.2, 137.8, 129.5 (d, J = 3.8 Hz), 129.3 (d, J = 8.8 Hz), 127.9, 124.5 (d, J = 12.5 Hz), 124.4, 122.6 (d, J = 3.8 Hz), 120.8, 120.5, 119.0, 115.3, 115.2, 96.7, 77.6, 49.2, 44.9, 36.8, 34.7, 29.7. HRMS (ESI): [M+Na]+calcd. for C28H32FNNaO2+: 456.2309, found: 456.2311.
8-(tert-butyl)-2-(3-chlorophenyl)-4′-(diethylamino)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3c). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (25.6 mg, 57% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.40 (s, 1H), 7.28 (s, 1H), 7.23–7.19 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 10.4 Hz, 1H), 6.40 (dd, J = 10.4, 2.2 Hz, 1H), 5.28 (s, 1H), 5.05 (d, J = 2.1 Hz, 1H), 3.92 (d, J = 16.6 Hz, 1H), 3.22 (d, J = 6.4 Hz, 4H), 2.71 (d, J = 16.7 Hz, 1H), 1.39 (s, 9H), 1.05 (t, J = 7.0 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 194.8, 156.1, 152.3, 141.7, 139.1, 137.9, 132.8, 128.4, 127.9, 127.7, 127.3, 126.1, 124.5, 120.8, 120.6, 119.3, 97.3, 82.7, 49.7, 45.0, 36.5, 34.7, 29.8. HRMS (ESI): [M+Na]+ calcd. for C28H32ClNaNO2+: 472.2014, found: 472.2010.
8-(tert-butyl)-4′-(diethylamino)-2-(m-tolyl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3d). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (38.2 mg, 89% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.16 (m, 3H), 7.08 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.3 Hz, 2H), 6.86 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 10.4 Hz, 1H), 6.32 (dd, J = 10.4, 2.2 Hz, 1H), 5.25 (s, 1H), 4.99 (d, J = 2.2 Hz, 1H), 3.90 (d, J = 16.6 Hz, 1H), 3.28–3.01 (m, 4H), 2.67 (d, J = 16.6 Hz, 1H), 2.27 (s, 3H), 1.36 (s, 9H), 0.99 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.2, 156.1, 152.5, 142.1, 137.7, 136.9, 136.2, 128.2, 128.2, 127.8, 126.8, 124.5, 124.3, 120.8, 120.2, 118.8, 97.3, 83.4, 49.7, 44.9, 36.8, 34.7, 29.7, 21.4. HRMS (ESI): [M+Na]+ calcd. for C29H35NNaO2+: 452.2560, found: 452.2558.
8-(tert-butyl)-4′-(diethylamino)-2-(p-tolyl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3e). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (39.1 mg, 91% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 1.9 Hz, 1H), 7.27 (s, 1H), 7.22–7.16 (m, 1H), 7.04 (m, 3H), 6.89 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 10.4 Hz, 1H), 6.36 (dd, J = 10.4, 2.2 Hz, 1H), 5.30 (s, 1H), 5.02 (d, J = 2.2 Hz, 1H), 3.93 (d, J = 16.6 Hz, 1H), 3.20 (d, J = 6.7 Hz, 4H), 2.70 (d, J = 16.6 Hz, 1H), 2.30 (s, 3H), 1.40 (s, 9H), 1.03 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.3, 156.1, 152.6, 142.2, 137.7, 137.0, 134.1, 127.8, 127.6, 127.3, 124.3, 120.8, 120.2, 118.9, 97.3, 83.3, 49.8, 44.85, 36.8, 34.7, 29.7, 21.1. HRMS (ESI): [M+Na]+ calcd. for C29H35NNaO2+: 452.2560, found: 452.2556.
8-(tert-butyl)-4′-(diethylamino)-2-(4-fluorophenyl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3f). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (34.6 mg, 80% yield) as a yellow solid.
1H NMR (500 MHz, CDCl3) δ 7.40–7.31 (m, 2H), 7.18 (dd, J = 7.9, 1.7 Hz, 1H), 7.02 (dd, J = 7.5, 1.6 Hz, 1H), 6.95–6.85 (m, 3H), 6.62 (d, J = 10.5 Hz, 1H), 6.36 (dd, J = 10.5, 2.3 Hz, 1H), 5.30 (s, 1H), 5.02 (s, 1H), 3.89 (dt, J = 16.5, 1.1 Hz, 1H), 3.20 (q, J = 7.2 Hz, 4H), 2.69 (d, J = 16.6 Hz, 1H), 1.37 (s, 9H), 1.03 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 195.2, 162.3 (d, J = 244.0 Hz, 1H), 156.2, 152.5, 142.1, 137.9, 129.2 (d, J = 8.0 Hz, 1H), 127.9, 124.5, 120.9, 120.6, 119.2, 113.9 (d, J = 21.0 Hz, 1H), 97.3, 82.8, 49.8, 45.0, 36.9, 34.8, 29.8. HRMS (ESI): [M+Na]+calcd. for C28H32FNNaO2+: 456.2309, found: 456.2311.
2-(4-bromophenyl)-8-(tert-butyl)-4′-(diethylamino)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3g). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (25.6 mg, 52% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 2H), 7.20 (s, 1H), 7.18 (s, 1H), 7.11 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 10.4 Hz, 1H), 6.28 (dd, J = 10.4, 2.2 Hz, 1H), 5.20 (s, 1H), 4.95 (d, J = 2.1 Hz, 1H), 3.82 (d, J = 16.6 Hz, 1H), 3.14 (d, J = 5.4 Hz, 4H), 2.62 (d, J = 16.7 Hz, 1H), 1.29 (s, 9H), 0.97 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.7, 156.9, 153.1, 142.6, 138.6, 137.0, 131.0, 130.0, 128.6, 125.3, 122.3, 121.6, 121.4, 120.0, 98.1, 83.5, 50.5, 45.8, 37.5, 35.5, 30.6. HRMS (ESI): [M+Na]+ calcd. for C28H32BrNNaO2+: 516.1509, found: 516.1496.
8-(tert-butyl)-4′-(diethylamino)-2-(naphthalen-2-yl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3h). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (41.8 mg, 90% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.84–7.80 (m, 1H), 7.80–7.76 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.5, 1.7 Hz, 1H), 7.45–7.41 (m, 2H), 7.22 (d, J = 7.0 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 10.4 Hz, 1H), 6.34 (dd, J = 10.5, 2.2 Hz, 1H), 5.50 (s, 1H), 4.98 (d, J = 2.2 Hz, 1H), 3.98 (d, J = 16.6 Hz, 1H), 3.05 (s, 4H), 2.75 (d, J = 16.6 Hz, 1H), 1.41 (s, 9H), 0.83 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 195.2, 156.1, 152.6, 142.1, 137.9, 134.8, 133.0, 132.5, 128.3, 127.9, 127.3, 126.6, 126.4, 125.8, 125.6, 125.5, 124.4, 120.9, 120.4, 119.1, 97.2, 83.43, 49.94, 44.8, 37.0, 34.8, 29.8. HRMS (ESI): [M+Na]+ calcd. for C32H35NNaO2+: 488.2560, found: 488.2550.
8-(tert-butyl)-4′-(diethylamino)-2,2-dimethylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3i). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (22.8 mg, 62% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.15 (dd, J = 7.8, 1.7 Hz, 1H), 7.00–6.92 (m, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 10.5 Hz, 1H), 6.42 (dd, J = 10.5, 2.3 Hz, 1H), 5.31 (d, J = 2.3 Hz, 1H), 3.69–3.58 (m, 1H), 3.39 (q, J = 7.1 Hz, 4H), 2.46 (d, J = 16.9 Hz, 1H), 1.47 (s, 3H), 1.39 (s, 9H), 1.33 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.9, 156.4, 151.1, 146.1, 138.1, 127.7, 124.3, 120.9, 119.6, 117.8, 97.4, 79.1, 77.2, 50.2, 44.9, 34.8, 33.8, 30.4, 29.7, 24.6, 21.6. HRMS (ESI): [M+Na]+ calcd. for C24H33NNaO2+: 390.2404, found: 390.2409.
8-(tert-butyl)-4′-(diethylamino)-2-methyl-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3j). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (30.0 mg, 70% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.54–7.46 (m, 2H), 7.23 (dd, J = 7.9, 1.7 Hz, 1H), 7.20–7.12 (m, 3H), 7.03 (dd, J = 7.5, 1.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 10.5 Hz, 1H), 6.08 (dd, J = 10.5, 2.3 Hz, 1H), 5.08 (d, J = 2.3 Hz, 1H), 3.83 (d, J = 17.1 Hz, 1H), 3.09 (d, J = 7.4 Hz, 4H), 2.58 (d, J = 17.2 Hz, 1H), 1.86 (s, 3H), 1.45 (s, 9H), 0.93 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.2, 156.1, 150.7, 144.6, 142.3, 138.9, 127.9, 126.7, 126.7, 126.4, 124.7, 121.3, 120.4, 118.1, 98.5, 83.3, 50.9, 44.9, 34.9, 33.4, 30.2, 29.7, 20.1. HRMS (ESI): [M+Na]+ calcd. for C29H35NNaO2+: 452.2560, found: 452.2563.
8-(tert-butyl)-4′-(diethylamino)-2-vinylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3k). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:5) afforded the product (32.9 mg, 90% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.16 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.58–6.42 (m, 2H), 5.86–5.71 (m, 1H), 5.51 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 2.0 Hz, 1H), 5.19 (d, J = 10.8 Hz, 1H), 4.81 (d, J = 5.2 Hz, 1H), 3.67 (d, J = 16.4 Hz, 1H), 3.39 (dd, J = 14.1, 7.0 Hz, 4H), 2.61 (d, J = 16.4 Hz, 1H), 1.42 (s, 9H), 1.23 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.9, 156.6, 152.0, 143.1, 137.6, 133.3, 127.6, 124.4, 120.8, 120.1, 118.3, 117.2, 96.6, 80.8, 48.1, 44.9, 37.6, 34.7, 29.6. HRMS (ESI): [M+Na]+ calcd. for C24H31NNaO2+: 388.2247, found: 388.2244.
8-(tert-butyl)-4′-(dimethylamino)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3l). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (34.8 mg, 90% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.31 (dd, J = 7.3, 2.4 Hz, 2H), 7.18–7.13 (m, 3H), 7.12–7.07 (m, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 10.5 Hz, 1H), 6.32 (dd, J = 10.4, 2.3 Hz, 1H), 5.30 (s, 1H), 4.92 (d, J = 2.3 Hz, 1H), 3.77 (d, J = 16.5 Hz, 1H), 2.79 (s, 6H), 2.59 (d, J = 16.5 Hz, 1H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 195.9, 158.1, 152.6, 142.4, 137.9, 137.5, 127.7, 127.7, 127.6, 127.3, 124.5, 120.9, 120.4, 118.7, 97.6, 82.9, 50.0, 39.9, 38.3, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C26H29NNaO2+: 410.2091, found: 410.2094.
8-(tert-butyl)-2-phenyl-4′-(pyrrolidin-1-yl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3m). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (17.7 mg, 43% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.34 (dd, J = 7.5, 1.7 Hz, 2H), 7.20–7.15 (m, 3H), 7.11 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 10.3 Hz, 1H), 6.23 (dd, J = 10.3, 1.9 Hz, 1H), 5.35 (s, 1H), 4.87 (d, J = 1.8 Hz, 1H), 3.78 (d, J = 16.5 Hz, 1H), 3.32 (m, 2H), 3.03 (m, 2H), 2.60 (d, J = 16.5 Hz, 1H), 1.82 (s, 4H), 1.31 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 195.3, 155.7, 152.6, 142.7, 137.9, 137.7, 127.7, 127.7, 127.6, 127.3, 124.5, 121.0, 120.3, 119.9, 97.3, 82.8, 50.3, 48.0, 47.8, 38.6, 34.8, 29.9, 25.3, 24.6. HRMS (ESI): [M+Na]+ calcd. for C28H31NNaO2+: 436.2247, found: 436.2251.
8-(tert-butyl)-2-phenyl-4′-(piperidin-1-yl)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3n). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:5) afforded the product (27.3 mg, 64% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.42–7.36 (m, 2H), 7.24 (m, 3H), 7.19 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 10.4 Hz, 1H), 6.40 (d, J = 10.4 Hz, 1H), 5.32 (s, 1H), 5.13 (s, 1H), 3.91 (d, J = 16.5 Hz, 1H), 3.24 (t, J = 5.2 Hz, 4H), 2.71 (d, J = 16.6 Hz, 1H), 1.63–1.54 (m, 2H), 1.44–1.32 (m, 13H). 13C NMR (125 MHz, CDCl3) δ 196.2, 157.4, 152.6, 141.6, 137.8, 137.1, 127.8, 127.6, 127.5, 127.1, 124.4, 120.8, 120.4, 119.1, 99.1, 83.4, 49.9, 48.2, 36.9, 34.7, 29.8, 25.2, 24.3. HRMS (ESI): calcd. for C29H33NO2 [M+Na]+: 450.2404, found: 450.2404. HRMS (ESI): [M+Na]+ calcd. for C29H33NNaO2+: 450.2404, found: 450.2408.
4′-(azepan-1-yl)-8-(tert-butyl)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3o). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (26.9 mg, 61% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.46–7.37 (m, 2H), 7.28–7.16 (m, 4H), 7.05 (dd, J = 7.5, 1.5 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 10.4 Hz, 1H), 6.41 (dd, J = 10.5, 2.3 Hz, 1H), 5.34 (s, 1H), 5.07 (d, J = 2.2 Hz, 1H), 3.95 (d, J = 16.5 Hz, 1H), 3.67–3.07 (m, 4H), 2.71 (d, J = 16.6 Hz, 1H), 1.58 (s, 4H), 1.40 (s, 9H), 1.28 (s, 4H). 13C NMR (125 MHz, CDCl3) δ 195.5, 157.2, 152.6, 142.2, 137.9, 137.2, 127.9, 127.7, 127.6, 127.1, 124.4, 120.9, 120.4, 118.8, 97.6, 83.5, 49.9, 36.9, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C30H35NNaO2+: 464.2560, found: 464.2566.
8-(tert-butyl)-4′-(dibenzylamino)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3p). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (38.3 mg, 71% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.42 (m, 3H), 7.37–7.27 (m, 8H), 7.21 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.91 (m, 5H), 6.67 (d, J = 10.4 Hz, 1H), 6.43 (dd, J = 10.4, 2.1 Hz, 1H), 5.32 (s, 1H), 5.24 (d, J = 2.1 Hz, 1H), 4.41 (s, 4H), 3.96 (d, J = 16.6 Hz, 1H), 2.77 (d, J = 16.7 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 196.4, 158.3, 152.6, 142.9, 137.9, 137.1, 128.9, 127.9, 127.7, 127.6, 127.3, 126.3, 124.5, 120.7, 120.6, 119.2, 98.7, 83.8, 50.4, 36.4, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C38H37NNaO2+: 562.2717, found: 562.2724.
8-(tert-butyl)-4′-(diallylamino)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3q). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (36.4 mg, 83% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.36 (m, 2H), 7.23 (m, 3H), 7.19 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 10.4 Hz, 1H), 6.28 (dd, J = 10.4, 2.3 Hz, 1H), 5.73–5.51 (m, 2H), 5.29 (s, 1H), 5.11 (d, J = 10.4 Hz, 2H), 5.07 (d, J = 2.2 Hz, 1H), 4.81 (d, J = 17.2 Hz, 2H), 3.91 (d, J = 16.6 Hz, 1H), 3.72 (s, 4H), 2.70 (d, J = 16.7 Hz, 1H), 1.38 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 196.1, 157.6, 152.5, 142.1, 137.8, 136.9, 127.8, 127.5, 127.4, 127.0, 124.4, 120.7, 120.4, 119.2, 117.1, 98.1, 83.5, 52.2, 50.0, 36.6, 34.7, 29.8. HRMS (ESI): [M+Na]+ calcd. for C30H33NO2+: 462.2404, found: 462.2409.
2-([1,1′-biphenyl]-4-yl)-8-(tert-butyl)-4′-(diallylamino)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3r). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (43.3 mg, 84% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.64–7.53 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.50–7.39 (m, 4H), 7.37–7.31 (m, 1H), 7.20 (dd, J = 7.8, 1.7 Hz, 1H), 7.04 (dd, J = 7.6, 1.5 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 10.4 Hz, 1H), 6.30 (dd, J = 10.4, 2.3 Hz, 1H), 5.59 (s, 2H), 5.33 (s, 1H), 5.12–5.01 (m, 3H), 4.81– 4.77 (m, 2H), 3.93 (d, J = 16.4 Hz, 1H), 3.71 (s, 4H), 2.71 (d, J = 16.6 Hz, 1H), 1.39 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 196.1, 157.7, 152.6, 142.2, 140.9, 140.3, 137.9, 136.2, 128.8, 127.9, 127.9, 127.2, 126.9, 125.8, 124.5, 120.8, 120.5, 119.4, 98.3, 83.4, 77.3, 50.2, 36.7, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C36H37NNaO2+: 538.2717, found: 538.2715.
2-([1,1′-biphenyl]-4-yl)-8-(tert-butyl)-4′-(diethylamino)spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3s). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (40.7 mg, 83% yield) as a white oil.
1H NMR (500 MHz, CDCl3) δ 7.63–7.55 (m, 2H), 7.52–7.41 (m, 6H), 7.39–7.32 (m, 1H), 7.23 (dd, J = 7.7, 1.7 Hz, 1H), 7.07 (dd, J = 7.5, 1.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 10.4 Hz, 1H), 6.39 (dd, J = 10.5, 2.3 Hz, 1H), 5.39 (s, 1H), 5.07 (d, J = 2.3 Hz, 1H), 3.98 (dd, J = 16.5, 1.0 Hz, 1H), 3.19 (q, J = 7.0 Hz, 4H), 2.74 (d, J = 16.6 Hz, 1H), 1.43 (s, 9H), 1.01 (t, J = 7.0 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 195.3, 156.3, 152.6, 142.2, 141.0, 140.3, 137.9, 136.3, 128.8, 128.0, 127.9, 127.2, 126.9, 125.8, 124.5, 120.9, 120.5, 119.1, 97.5, 83.3, 49.9, 45.0, 36.8, 34.8, 29.9. HRMS (ESI): [M+Na]+ calcd. for C34H37NNaO2+: 514.2717, found: 514.2719.
4′-(dibenzylamino)-8-isopropyl-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3t). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:5) afforded the product (25.7 mg, 49% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.41–7.35 (m, 3H), 7.34–7.25 (m, 8H), 7.13–7.08 (m, 1H), 6.99 (dd, J = 8.0, 1.3 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.88–6.83 (m, 4H), 6.56 (d, J = 10.5 Hz, 1H), 6.36 (dd, J = 10.5, 2.3 Hz, 1H), 5.31 (s, 1H), 5.23 (d, J = 2.3 Hz, 1H), 4.36 (d, J = 13.0 Hz, 4H), 3.90 (dd, J = 16.5, 1.2 Hz, 1H), 3.38–3.30 (m, 1H), 2.71 (d, J = 16.6 Hz, 1H), 1.22 (dd, J = 14.5, 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 196.5, 158.3, 150.8, 142.7, 137.3, 136.4, 128.9, 127.7, 127.6, 127.5, 127.3, 127.2, 126.3, 124.0, 120.7, 119.8, 119.2, 98.7, 83.5, 77.3, 50.3, 36.3, 26.9, 23.1, 22.3. HRMS (ESI): [M+Na]+ calcd. for C37H35NNaO2+: 548.2560, found: 548.2568.
8-(sec-butyl)-4′-(dibenzylamino)-2-phenylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (3u). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:5) afforded the product (36.1 mg, 67% yield, dr 2:1) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.41–7.34 (m, 3H), 7.35–7.20 (m, 8H), 7.09–7.04 (m, 1H), 7.02–6.94 (m, 1H), 6.98–6.89 (m, 1H), 6.87–6.80 (m, 4H), 6.55 (m, 1H), 6.39–6.30 (m, 1H), 5.31 (d, J = 3.1 Hz, 1H), 5.23 (t, J = 2.8 Hz, 1H), 4.58–4.23 (m, 4H), 3.96–3.84 (m, 1H), 3.16–3.09 (m, 1H), 2.71 (d, J = 16.6 Hz, 1H), 1.66–1.48 (m, 2H), 1.20 (m, 3H), 0.86 (t, J = 7.4 Hz, 2H), 0.79 (t, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 196.6, 196.6, 158.4, 158.4, 151.2, 151.2, 142.9, 142.8, 137.3, 135.2, 135.2, 128.9, 128.6, 127.7, 127.6, 127.6, 127.5, 127.5, 127.3, 127.3, 127.1, 126.3, 124.8, 120.7, 119.8, 119.7, 119.2, 119.1, 98.7, 98.7, 83.6, 83.4, 77.3, 50.3, 36.3, 33.9, 33.3, 30.7, 29.5, 20.9, 20.3, 12.4, 12.2. HRMS (ESI): [M+Na]+ calcd. for C38H37NNaO2+: 562.2717, found: 562.2723.
8-(tert-butyl)-4′-(diethylamino)-2-ethylspiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-one (4k). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:3) afforded the product (30.1 mg, 82% yield, dr 1:1) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.13 (m, 2H), 6.93 (m, 2H), 6.79 (m, 2H), 6.02 (m, 1H), 5.64 (m, 1H), 5.30 (m, 1H), 5.21 (m, 2H), 5.04 (m, 1H), 4.37 (m, 1H), 3.44–3.21 (m, 7H), 3.19–3.02 (m, 2H), 2.75 (m, 2H), 2.42 (m, 4H), 2.01–1.93 (m, 2H), 1.78–1.59 (m, 4H), 1.41 (m, 16H), 1.18 (m, 13H). 13C NMR (100 MHz, CDCl3) δ 198.7, 163.1, 162.9, 137.1, 134.4, 128.1, 127.9, 124.3, 121.5, 121.3, 119.9, 119.3, 116.4, 98.5, 98.3, 82.3, 79.4, 44.2, 42.3, 42.0, 34.8, 34.7, 34.5, 34.0, 29.7, 29.6, 23.5, 22.8, 22.6, 22.6, 12.2. HRMS (ESI): [M+Na]+ calcd. for C24H33NNaO2+: 390.2404, found: 390.2411.
6,6′-((3-(tert-butyl)-2-((3,5-dimethoxybenzyl)oxy)phenyl)methylene)bis(3-(diethylamino)phenol) (5a). Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1:15) afforded the product (51.8 mg, 81% yield) as a white solid.
1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1H), 7.14 (dd, J = 7.7, 1.8 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.56 (d, J = 2.4 Hz, 2H), 6.44 (t, J = 2.3 Hz, 1H), 6.22 (d, J = 7.9 Hz, 4H), 5.76 (s, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 3.81 (s, 6H), 3.31 (q, J = 7.1 Hz, 8H), 1.50 (s, 9H), 1.15 (t, J = 7.0 Hz, 12H). 13C NMR (100 MHz, CDCl3) δ 160.9, 155.5, 148.6, 139.3, 135.4, 130.7, 129.4, 125.7, 124.4, 114.3, 105.2, 104.6, 100.3, 100.0, 76.6, 55.3, 44.3, 37.4, 35.4, 31.3, 12.7. HRMS (ESI): [M+Na]+ calcd. for C40H52N2NaO5+: 663.3768, found: 663.3778.

3.8. In Vitro Antifungal Activities

Each target compound was dissolved in acetone to prepare the stock solution (2.5 g/L). The stock solution was added into the PDA medium, and the concentration of target compound in the medium was 200.0 mg/L. Pure acetone without the target compound was utilized as the blank control, and difenoconazole and thifluzamide were co-assayed as the reference compound. Fresh dishes with a diameter of 6 mm were taken from the edge of the PDA-cultured fungi colonies and inoculated on the above three PDA media. Each treatment was tested for three replicates, and the antifungal effect was averaged. The relative inhibitory rate I (%) of all the tested compounds was calculated through the equation: I (%) = [(C − T)/(C − 5)] × 100. In this equation, I is the inhibitory rate and C and T are the colony diameter of the blank control (mm) and treatment (mm), respectively. Mycelia growth of four crop pathogenic fungi after treatment with the target compounds on PDA medium is illustrated in the Supplementary Materials Figure S1.

4. Conclusions

In conclusion, we have developed the Sc(OTf)3-catalyzed dearomative [5+1] annulation between readily available 3-aminophenols and O-alkyl ortho-oxybenzaldehydes for synthesis of spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones. The “two-birds-with-one-stone” strategy was disclosed by the dearomatization of phenols and direct α-C(sp3)–H bond functionalization of oxygen for providing a variety of spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones through cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process. The antifungal activity assay and derivatizations of products were conducted to further enrich the utility of the structure. This work offers aromatization of the in situ-formed o-QM as hydride acceptor for initiating the hydride transfer-involved dearomatization, which would further enhance the utility of hydride transfer strategy in dearomatization chemistry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29051012/s1. Online supplementary information contains 1H and 13C NMR spectra for all compounds prepared in this study. CCDC 2310751 contains supplementary crystallographic data for this paper.

Author Contributions

Conceptualization, J.-C.G., Y.W., F.H. and S.-S.L.; methodology, J.-C.G., Y.W., F.H. and S.-S.L.; validation, J.-C.G., Y.W., F.H. and S.-S.L.; formal analysis, J.-C.G., Y.W., F.-W.G. and X.K.; investigation, J.-C.G. and Y.W.; resources, F.H. and S.-S.L.; writing—original draft preparation, J.-C.G. and S.-S.L.; writing—review and editing, Y.W., F.H. and S.-S.L.; supervision, F.H. and S.-S.L.; project administration, F.H. and S.-S.L.; funding acquisition, F.H. and S.-S.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (22208184, 21978144), the Support Plan on Science and Technology for Youth Innovation of Universities in Shandong Province (2019KJM002). The Financial support from the Talents of High Level Scientific Research Foundation (6651118009, 6631115015) and Instrumental Analysis Center of Qingdao Agricultural University for NMR determination are also gratefully acknowledged.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding authors.

Conflicts of Interest

Jia-Cheng Ge and Shuai-Shuai Li were employed by the company Hailir Pesticides and Chemicals Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Molecules 29 01012 sch001
Scheme 1. (a) Dearomatization of phenols. (b) Direct dearomatization of phenols. (c) The α-C(sp3)− H bond functionalization of amine. (d) The α-C(sp3)− H bond functionalization of oxygen. (e) In situ formed o-QM as hydride acceptor for achieving dearomatization of phenols and a-C(sp3)−H bond functionalization of oxygen. (f) Dearomative [5 + 1] annulation with O-alkyl ortho-oxybenzaldehyde as five-atom synthon.
Scheme 1. (a) Dearomatization of phenols. (b) Direct dearomatization of phenols. (c) The α-C(sp3)− H bond functionalization of amine. (d) The α-C(sp3)− H bond functionalization of oxygen. (e) In situ formed o-QM as hydride acceptor for achieving dearomatization of phenols and a-C(sp3)−H bond functionalization of oxygen. (f) Dearomative [5 + 1] annulation with O-alkyl ortho-oxybenzaldehyde as five-atom synthon.
Molecules 29 01012 sch001
Molecules 29 01012 sch002
Scheme 2. The scope of O-alkyl ortho-oxybenzaldehydes for the dearomative [5+1] annulations. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Sc(OTf)3 (20 mol%), TFE (1 mL), at 120 °C under air for 5 h; isolated yield after column chromatography; dr > 20:1, dr was determined by 1H NMR.
Scheme 2. The scope of O-alkyl ortho-oxybenzaldehydes for the dearomative [5+1] annulations. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Sc(OTf)3 (20 mol%), TFE (1 mL), at 120 °C under air for 5 h; isolated yield after column chromatography; dr > 20:1, dr was determined by 1H NMR.
Molecules 29 01012 sch002
Molecules 29 01012 sch003
Scheme 3. The substrate scope of the dearomative [5+1] annulations. Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), Sc(OTf)3 (20 mol%), TFE (1 mL), at 120 °C under air for 5 h; isolated yield after column chromatography; dr > 20:1, dr was determined by 1H NMR.
Scheme 3. The substrate scope of the dearomative [5+1] annulations. Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), Sc(OTf)3 (20 mol%), TFE (1 mL), at 120 °C under air for 5 h; isolated yield after column chromatography; dr > 20:1, dr was determined by 1H NMR.
Molecules 29 01012 sch003
Molecules 29 01012 sch004
Scheme 4. (a) Gram-scale synthesis of products 3a and 3k. (b) Derivatization of Product 3k. (c) Synthesis of polyarylated methane 5a.
Scheme 4. (a) Gram-scale synthesis of products 3a and 3k. (b) Derivatization of Product 3k. (c) Synthesis of polyarylated methane 5a.
Molecules 29 01012 sch004
Molecules 29 01012 sch005
Scheme 5. The investigation into the influence factor for the hydride transfer process.
Scheme 5. The investigation into the influence factor for the hydride transfer process.
Molecules 29 01012 sch005
Molecules 29 01012 sch006
Scheme 6. Proposed mechanism.
Scheme 6. Proposed mechanism.
Molecules 29 01012 sch006
Table 1. Optimization of the reaction conditions 1.
Table 1. Optimization of the reaction conditions 1.
Molecules 29 01012 i001
EntryCatalystRatio (1a:2a)SolventTemp. (°C)Time (h)Yield (%) 2
1Sc(OTf)31:1.5DCE120552
2Mg(OTf)21:1.5DCE120522
3Zn(OTf)21:1.5DCE120540
4TfOH1:1.5DCE1205No
5TsOH1:1.5DCE120522
6CSA1:1.5DCE120520
7TFA1:1.5DCE120516
8Sc(OTf)31:1.5TFE120584
9Sc(OTf)31:1.5MeOH12012Trace
10Sc(OTf)31:1.5EtOH120520
11Sc(OTf)31:1.5n-BuOH12012No
12Sc(OTf)31:1.5Toluene12012No
13Sc(OTf)31:1.5EA12012No
14Sc(OTf)31:1.5HFIP120565
15Sc(OTf)31:1TFE120571
16Sc(OTf)31:1.2TFE120582
17Sc(OTf)31:2TFE120577
18Sc(OTf)31:1.5TFE80570
19Sc(OTf)31:1.5TFE100571
20 3Sc(OTf)31:1.5TFE120578
21 4Sc(OTf)31:1.5TFE120585
22 5Sc(OTf)31:1.5TFE120582
1 Reaction conditions (unless otherwise noted): 1a (0.1 mmol, 26.8 mg), 2a (x mmol), catalyst (30 mol%), solvent (1 mL), under air; TFE = 2,2,2-Trifluoroethanol, HFIP = 1,1,1,3,3,3-Hexafluoro-2-propanol. 2 Isolated yield after column chromatography; dr > 20:1, dr was determined by 1H NMR. 3 Sc(OTf)3 (10 mol%). 4 Sc(OTf)3 (20 mol%). 5 Sc(OTf)3 (40 mol%).
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Ge, J.-C.; Wang, Y.; Guo, F.-W.; Kong, X.; Hu, F.; Li, S.-S. Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations. Molecules 2024, 29, 1012. https://doi.org/10.3390/molecules29051012

AMA Style

Ge J-C, Wang Y, Guo F-W, Kong X, Hu F, Li S-S. Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations. Molecules. 2024; 29(5):1012. https://doi.org/10.3390/molecules29051012

Chicago/Turabian Style

Ge, Jia-Cheng, Yufeng Wang, Feng-Wei Guo, Xiangyun Kong, Fangzhi Hu, and Shuai-Shuai Li. 2024. "Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations" Molecules 29, no. 5: 1012. https://doi.org/10.3390/molecules29051012

APA Style

Ge, J. -C., Wang, Y., Guo, F. -W., Kong, X., Hu, F., & Li, S. -S. (2024). Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1′-cyclohexane]-2′,4′-dien-6′-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations. Molecules, 29(5), 1012. https://doi.org/10.3390/molecules29051012

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