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

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.


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 sp 3 -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.
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(sp 3 )−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(sp 3 )−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.

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][16][17][18][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][21][22].At last, the optimal reaction conditions were determined to be those described in entry 21 of Table 1.

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/aromatizationdearomatization 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][16][17][18][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][21][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 electronwithdrawing 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.propanol.2 Isolated yield after column chromatography; dr > 20:1, dr was determined by 1 H NMR.
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 gemdimethyl-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 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.
Molecules 2024, 29, x FOR PEER REVIEW 5 of 16 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 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 H 2 /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(sp 3 )−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.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(sp 3 )−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. Scheme 6. Proposed mechanism.

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 ( 1 H NMR) were recorded on a Bruker Scheme 6. Proposed mechanism.

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 ( 1 H NMR) were recorded on a Bruker 500 MHz or 400 MHz NMR spectrometer (CDCl 3 , DMSO-d 6 or Methanol-d 4 solvent).The chemical shifts were reported in parts per million (ppm), downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet), dimethyl sulfoxide-d 6 (δ 2.54, singlet) or methanol-d 4 (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 ( 13 C 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].
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 H 2 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.

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.

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.

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(sp 3 )−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.

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.

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

3 .
Scheme 5.The investigation into the influence factor for the hydride transfer process.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 imme-

Table 1 .
Optimization of the reaction conditions 1 .

Table 1 .
Optimization of the reaction conditions 1 .