A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical Knoevenagel condensation

Tetrahedron xxx (2017) 1e6

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A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical Knoevenagel condensation De-Suo Yang*, Sen Ke, Xin Du, Peng Gao, Hai-Tao Zhu, Ming-Jin Fan** Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, 721013, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 May 2017 Received in revised form 26 July 2017 Accepted 28 July 2017 Available online xxx

Utilizing simple and readily available 2-hydroxy benzaldehydes and 1,3-diketones or 1,3cyclohexanediones as raw materials, complex 2,8-dioxabicyclo [3.3.1] nonane derivatives were synthesized in one-step via classical Knoevenagel condensation. The reaction was simply conducted under solvent-free and mild conditions, which showed good tolerance to a variety of functional groups. This atom-economical approach delivers an attractive synthetic protocol for 2,8-dioxabicyclo [3.3.1] nonane derivatives. © 2017 Published by Elsevier Ltd.

Keywords: 2,8-Dioxabicyclo [3.3.1] nonane Knoevenagel condensation V-shaped rigid framework

1. Introduction 2,8-Dioxabicyclo [3.3.1] nonane skeletons are precious in natural compounds because of their elaborate V-shaped rigid frameworks and structural complexities.1 These skeletons have been shown to possess a number of biological and pharmacological activities.2,3 For example, the flavonoid proanthocyanidin A1 and A2,4 dracoflavan C and D,5 ephedrannin A and B,6 diinsininol (5) and (4) isolated from natural compounds,7 all exhibit a wide range of biological and pharmacological properties including anti-inflammatory,8 antimicrobial,9 antiviral activities,10 anticoagulant and so on (Fig. 1). Therefore, they have drawn enormous attention and stimulated organic chemists to design strategies for assembling these challenging structures in recent years.11e13 Manolov and coworkers illustrated a base-catalyzed condensation between 3benzoylcoumarin and 4-hydroxycoumarin to afford the corresponding 1-phenyl 2,8-dioxabicyclo [3.3.1] nonanes.14 Yang reported that these molecules could be achieved through the reaction of 2-phenylchroman-4-ol with 4-hydroxycoumarin in the presence of aluminum chloride.15 Wu and Ganguly described the synthesis of 2,8-dioxabicyclo [3.3.1] nonanes derivatives from 2hydroxychalcone-a,b-enones and 4-hydroxycoumarin respectively.16 Aldehyde-substituted vinylogous carbonates and 1,3-

diketones/1,3-cyclohexanediones could also be used as raw materials to construct 2,8-dioxabicyclo [3.3.1] nonane derivatives via cascade Knoevenagel/hetero-Dielse-Alder reactions catalyzed by AuBr3 and D-proline.17 In fact, all these strategies possess shortcomings of harsh reaction conditions, expensive catalysts or complicated starting materials. The development of efficient and metal free catalytic methods toward 2,8-dioxabicyclo [3.3.1] nonanes from simple starting materials is still of significant interest and also represents one of the most challenging goals in organic synthesis.18 As we all know that benzaldehyde can react with 1,3-diketones to afford condensation products in the presence of piperidine/ acetic acid and this reaction was called Knoevenagel condensation reaction. It is a versatile, convenient and extensively used reaction, which represents one of the most fundamental bond-forming protocol in organic synthesis.19 However, during our research, we are surprised to find that 2,8-dioxabicyclo [3.3.1] nonanes can be produced by the reaction of 2-hydroxybenzaldehyde with 1,3diketones under classical Knoevenagel condensation conditions. Herein, we report this efficient synthesis of diverse 1-arylsubstituted 2,8-dioxabicyclo [3.3.1] nonane derivatives from cheap 2-hydroxybenzaldehyde and 1,3-diketones. 2. Results and discussion

* Corresponding author. ** Corresponding author. E-mail address: [email protected] (D.-S. Yang).

For the initial feasibility studies, 2-hydroxybenzaldehyde (1a) and 2,4-pentanedione (2a) were selected as model substrates to study the cycloaddition. 1a (1 mmol) and 2a (2.0 mmol) were

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D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6 Table 1 Optimization studies for the synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivative 3a.a

Fig. 1. Biologically interesting natural products containing 2,8-dioxabicyclo [3.3.1] non-3-ene skeleton.

treated with piperidine (0.6 eq.) and acetic acid (1.1 eq.) in toluene at 75
C under argon atmosphere for 20 h. It was found that the expected 1-phenyl 2,8-dioxabicyclo [3.3.1] nonane (3a) was obtained only in 16% yield (Table 1, entry 1). The structure of 3a was unambiguously confirmed by its 1H NMR, 13C NMR, HRMS spectra and X-ray crystallographic analysis (see Fig. 2 and the corresponding datablock was in the Supporting Information).20 A brief survey on the proportion of 1a and 2a indicated that appropriately excessive 2a was favorable to the transformation (entries 1e4). 3a was obtained in relatively higher yield in dichloroethane (DCE) according to the screen of solvents (entries 5e7). The transformation was also attempted under catalysis of other bases and acids, such as DABCO, pyridine, DBU, Ac2O, TsOH and CF3CO2H, but 3a wasn't isolated in higher yields (entries 8e13). Also, no increasing yield was obtained after increasing the amount of piperidine to 1.0 eq. (entry 14). Next, by decreasing the dosage of piperidine to 0.3 eq., higher yield of 50% was achieved (entry 15). But the yield decreased obviously after continuing decreasing the dosage of piperidine (entry 16). The amount of acetic acid was also explored, but no better results were given (entries 17 and 18). Finally, to our excitement, the product was obtained in excellent yield under solvent-free condition (entry 19). Additionally, slight decreasing in the reaction temperature was favorable to increase the yield, but continuous decreasing the reaction temperature gave the opposite result (entries 21 and 22). After sifting different bases and acids, the optimal conditions were identified as the use of 1a (1 mmol), piperidine (0.3 eq.), acetic acid (1.1 eq.) under argon atmosphere and solvent-free conditions at 70
C for 20 h (entry 21 is shown in Table 1 boldly). Under the optimal conditions, the generality of the reaction was explored for the synthesis of diverse 1-aryl-substituted 2,8-dioxabicyclo [3.3.1] nonanes. Primarily, 1,3-diketone 2a was used to react with a variety of 2-hydroxybenzaldehyde derivatives (1). In all these reactions, products 3 were produced in moderate to good yields (Table 2). The substrates bearing electron-withdrawing substituent such as -F, -Cl, -Br on C-4 or C-5 position of the

Entry

1a:2a

Base

Acid

Solvent

T/
C

Yield/%b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

1: 2 1: 2.5 1: 3 1: 3.5 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3 1: 3

Piperidine Piperidine Piperidine Piperidine Piperidine Piperidine Piperidine DABCO Pyridine DBU Piperidine Piperidine Piperidine Piperidinec Piperidined Piperidinee Piperidined Piperidined Piperidined Piperidined Piperidined Piperidined DABCO Pyridine DBU Piperidine Piperidine Piperidine Piperidine

AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH Ac2O TsOH CF3CO2H AcOH AcOH AcOH AcOHf AcOHg AcOH AcOH AcOH AcOH AcOH AcOH AcOH Ac2O TsOH CF3CO2H

toluene toluene toluene toluene THF CH3CN DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE e e e e e e e e e e e

75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 65 70 80 70 70 70 70 70 70 70

16 17 27 23 22 28 45 36 NR trace NR NR NR 40 50 26 38 41 78 57 89 77 39 NR trace NR NR NR NR

a All reactions were conducted under the following conditions unless otherwise indicated: 1a (1 mmol), base (0.6 eq.) and acid (1.1 eq.) in anhydrous solvent (2 mL) under argon atmosphere for 20 h. b Isolated yield. c 1.0 eq. piperidine was used. d 0.3 eq. piperidine was used. e 0.2 eq. piperidine was used. f 1.0 eq. AcOH was used. g 1.2 eq. AcOH was used.

Fig. 2. X-ray crystallography of 3a.

phenyl ring could react smoothly with 2a to deliver the corresponding 3b, 3c, 3e, 3g in excellent yields (70e85%) (entries 2, 3, 5 and 7). However, the halogen atom on the C-3 position was found to be unfavorable for this transformation due to steric hindrance

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D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6 Table 2 Substrate scope of the synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives 3a¡o.a

Entry

Substrate

Product

Yield/%a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

R ¼ H, 1a R ¼ 5-Br, 1b R ¼ 4-Br, 1c R ¼ 3-Br, 1d R ¼ 5-Cl, 1e R ¼ 3, 5-Cl, 1f R ¼ 5-F, 1g R ¼ 5-NO2, 1h R ¼ 5-Me, 1i R ¼ 3-Me, 1j R ¼ 4-OMe,1k R ¼ 5-OMe, 1l R ¼ 3-OH, 1m R ¼ 2-NH2, 1n 2-hydroxy-1-naphthaldehyde, 1o

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o

89 80 70 45 73 23 85 30 70 87 25 50 78b 75b 20

a b

Isolated yield. Only condensation products were generated.

(entries 4 and 6). The extremely strong electron-withdrawing substituent like nitryl on the phenyl ring (3h) was also found to be unfavorable for this transformation (entry 8). The electrondonating substituents on the aromatic ring were found to be unfavorable to this reaction, because these substituents make the double bond of the reaction intermediate a bad Michael acceptor in the reaction process (see the following mechanistic study section). For examples, the substrates bearing methoxyl groups (-OMe) on the phenyl ring were found to give the corresponding products 3k and 3l in poor yields of 25% and 50%. It is worthy of note that the substrates bearing small and weak electron-donating substituent like methyl group could afford the corresponding products 3i and 3j in good yields (70% and 87%). Subsequently, the substrates bearing hydroxy group at C-3 position or amino group at C-2 position of the phenyl ring could only afford condensation products (3m and 3n). The substrate 2-hydroxy-1-naphthaldehyde (1o) can also provide the corresponding products 3o in 20% yield. Next, 2-hydroxybenzaldehyde (1a) was employed to react with a variety of diketones 2 under standard reaction conditions. As shown in Table 3, diketone derivatives 2,5-hexanedione (2p) and 3pentylpentane-2,4-dione (2q) couldn't react with 1a. When the reaction was conducted with substrates 2r and 2s, the desired products 3r and 3s could be generated smoothly in moderate yields (Table 3, 3r and 3s, 40% and 50%). The same result was also obtained when compound 2t was applied as the substrate (3t). It is pleased to find that 1,3-cyclohexanedione (2u) could also react with 1a to give more complex polycyclic 2,8-dioxabicyclo [3.3.1] nonane compounds (3u) in good yields of 70%. Overall, these results highlight the great potential and versatility of the present method, which provides a direct and practical access to highly valuable 2,8dioxabicyclo [3.3.1] nonane derivatives from readily accessible starting materials. During the following study, the experiments for mechanistic studies on this reaction were performed and the results are presented in Scheme 1. a,b-Unsaturated condensation compound C was firstly prepared, which was presumed to be an intermediate of

3

the reaction and applied to react with 1,3-diketones. It was found that compound C could react smoothly with 1,3-diketones 2a and generate 3a in 80% yield under the standard reaction conditions (Scheme 1, path a). It proved that 2,8-dioxabicyclo [3.3.1] nonanes are most likely synthesized via this unsaturated condensation intermediate. When the reaction was performed under the same conditions in the absence of acetic acid, 3a was obtained in a lower yield of 66% (path b). On contrary, when the reaction was performed in the absence of piperidine, 3a could not be obtained (path c). Therefore, the following cyclization was proved to be carried under base-acid catalyzing condition. On the basis of the previous reports and the experiment results obtained above, a tentative mechanism was proposed in Scheme 2.13d, 16a Initially, 2-hydroxybenzaldehyde 1a reacts with piperidine via known mechanism of Knoevenagel condensation to give the intermediate A, which can react with another deprotonated substrate 2a via Michael addition and generates intermediate B. In the following process, the phenolic hydroxyl group of intermediate B is deprotonated by piperidine, meanwhile, the continuous nucleophilic addition reaction happens to give intermediate E. Finally, the desired product 3a is formed through the elimination of water from intermediate E. 3. Conclusions In summary, a novel and efficient approach to synthesize 2,8dioxabicyclo [3.3.1] nonane derivatives from readily accessible 2hydroxybenzaldehydes and 1,3-diketones under mild reaction conditions have been developed. Four chemical bonds (two CC bond and two CO bonds) and two six-member cycles were formed in this one-pot operation. The use of toxic and expensive transition-metal catalysts were completely avoided in this process. This atom-economical and mild approach delivers an attractive synthetic protocol for complex 2,8-dioxabicyclo [3.3.1] nonane derivatives, which are important motifs in many natural and pharmaceutical products. 4. Experimental section 4.1. General experimental detials Product purification was realized by flash column chromatography. 1H NMR and 13C NMR spectra were recorded on an Agilent 400 MHz nuclear magnetic resonance spectrometer in CDCl3. Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard. Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet) or m (multiplet). IR spectra were recorded on a FT-IR spectrometer and only major peaks are reported in cm1. HR-MS was obtained using a Q-TOF instrument equipped with ESI source. Copies of the 1 H NMR and 13C NMR spectra are provided. Commercially available reagents were used without further purification. All solvents were dried before using. 4.2. General reaction procedures Piperidine (25.5 mg, 0.3 eq.) and acetic acid (66 mg, 1.1 eq.) were added to a mixture of 2-hydroxybenzaldehyde (120 mg, 1 mmol) and 1,3-diketones derivatives (300 mg, 3 mmol), which was then heated at 70
C under argon atmosphere for 20 h until no starting material remained (monitored by thin layer chromatography). The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (3*15 mL), the combined organic layers were washed in turn with water and saturated brine, dried over Na2SO4 and evaporated under

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D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6

Table 3 Substrate scope of the synthesis of 2,8-Dioxabicyclo [3.3.1] nonane derivatives 3ru.a

Scheme 1. Experiments for mechanistic studies.

reduced pressure. The residue was purified by chromatography on silica gel to afford the corresponding 3a. Compound 3a: yield 0.2546 g (89%); mp 159e161
C; IR (neat, cm1): 3566.8, 3400.7, 2982.3, 2946.6, 1457.8, 1377.2; 1H NMR (400 MHz, CDCl3) d ppm 7.28 (dd, J ¼ 7.5, 1.3 Hz, 1H), 7.10e7.06 (m, 1H), 6.86e6.81 (m, 2H), 4.63 (d, J ¼ 2.4 Hz, 1H), 3.07 (d, J ¼ 2.6 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz,CDCl3) d ppm 203.3, 195.3, 164.2, 150.3, 127.9, 127.5, 126.3, 121.2, 115.9, 114.9, 97.8, 49.3, 31.2, 31.0, 29.5, 24.2, 21.0; HRMS (ESI) Calcd for C17H18O4: [MþNa] ¼ 309.1103. Found: 309.1105. Compound 3b: yield 0.2908 g (80%); mp 159e160
C; IR (neat, cm1): 3256.0, 2994.8, 2257.6, 1973.4, 1709.1, 1358.5; 1H NMR (400 MHz, CDCl3) d ppm 7.45 (d, J ¼ 2.4 Hz, 1H), 7.19 (dd, J ¼ 8.6, 2.4 Hz, 1H), 6.72 (d, J ¼ 8.6 Hz, 1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.04 (d, J ¼ 2.6 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H); 13C

Scheme 2. Plausible mechanism for the synthesis of 2,8-dioxabicyclo [3.3.1] nonanes.

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D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6

NMR (100 MHz, CDCl3) d ppm 203.1, 195.3, 164.6, 149.7, 130.9, 130.3, 128.5, 117.9, 114.8, 113.6, 98.1, 49.1, 31.4, 30.9, 29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17BrO4: [MþNa] ¼ 387.0208. Found: 387.0215. Compound 3c: yield 0.2548 g (70%); mp 141e143
C; IR (neat, cm1): 3256.5, 2984.1, 2315.5, 1766.8, 1707.7, 1376.5; 1H NMR (400 MHz, CDCl3) d ppm 7.18 (d, J ¼ 8.1 Hz, 1H), 7.02e6.97 (m, 2H), 4.62 (d, J ¼ 2.4 Hz, 1H), 3.04 (d, J ¼ 2.6 Hz, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.1, 195.4, 164.5, 151.4, 128.9, 125.6, 124.5, 120.9, 119.3, 115.0, 98.1, 49.2, 31.4, 30.8, 29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17BrO4: [MþNa] ¼ 387.0208. Found: 387.0210. Compound 3d: yield 0.1637 g (45%); mp 167e169
C; IR (neat, cm1): 3241.7, 3016.5, 2883.7, 2367.8, 1712.4, 1329.8; 1H NMR (400 MHz, CDCl3) d ppm 7.34 (dd, J ¼ 8.0, 1.5 Hz, 1H), 7.27 (dd, J ¼ 7.4, 1.6 Hz, 1H), 6.24 (t, J ¼ 7.8 Hz, 1H), 4.67 (d, J ¼ 2.5 Hz, 1H), 3.06 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.91 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.0, 195.4, 164.4, 147.7, 131.8, 128.1, 126.9, 122.3, 114.9, 109.9, 98.5, 49.3, 31.4, 31.3, 29.8, 24.3, 21.2; HRMS (ESI) Calcd for C17H17BrO4: [MþNa] ¼ 387.0208. Found: 387.0222. Compound 3e: yield 0.2340 g (73%); mp 152e154
C; IR (neat, 1 cm ): 2982.1, 2355.5, 2328.9, 2048.5, 1709.4, 1369.9; 1H NMR (400 MHz, CDCl3) d ppm 7.30 (d, J ¼ 2.5 Hz, 1H), 7.05 (dd, J ¼ 8.7, 2.6 Hz, 1H), 6.76 (d, J ¼ 8.7 Hz, 1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.05 (d, J ¼ 2.6 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.1, 195.3, 164.7, 149.2, 128.0, 127.9, 127.4, 126.2, 117.4, 114.8, 98.1, 49.2, 31.4, 30.9, 29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17ClO4: [MþNa] ¼ 343.0713. Found: 343.0720. Compound 3f: yield 0.0814 g (23%); mp 171e173
C; IR (neat, cm1): 3073.1, 2952.8, 2985.2, 1709.0, 1369.2, 1222.9; 1H NMR (400 MHz, CDCl3) d ppm 7.21 (d, J ¼ 2.4 Hz, 1H), 7.13 (d, J ¼ 2.5 Hz, 1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.03 (d, J ¼ 2.6 Hz, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 202.6, 195.1, 164.6, 145.5, 128.9, 128.3, 126.0, 125.9, 121.6, 114.4, 98.5, 48.8, 31.3, 30.9, 29.7, 24.1, 21.1; HRMS (ESI) Calcd for C17H16Cl2O4: [MþNa] ¼ 377.0323. Found: 377.0340. Compound 3g: yield 0.2585 g (85%); mp 149e151
C; IR (neat, cm1): 2987.3, 2945.6, 2158.8, 2018.1, 1706.2, 1328.9; 1H NMR (400 MHz, CDCl3) d ppm 7.02 (d, J ¼ 8.3, 2.3 Hz, 1H), 6.79e6.76 (m, 2H), 4.60 (d, J ¼ 2.5 Hz, 1H), 3.06 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.3, 195.3, 164.8, 157.2 (d, 1JCF ¼ 240.2 Hz), 146.5 (d, 6JCF ¼ 2.3 Hz), 127.5 (d, 5JCF ¼ 7.7 Hz), 116.9 (d,4 JCF ¼ 8.2 Hz), 114.6 (d, 3 JCF ¼ 23.5 Hz), 114.0 (d, 2JCF ¼ 23.8 Hz), 98.0, 49.2, 31.3, 31.1, 31.0, 29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17FO4: [MþNa] ¼ 327.1009. Found: 327.1014. Compound 3h: yield 0.0993 g (30%); mp 135e137
C; IR (neat, 1 cm ): 3069.3, 2928.5, 2853.4, 2156.4, 1982.7, 1359.9; 1H NMR (400 MHz, CDCl3) d ppm 8.22 (d, J ¼ 2.7 Hz, 1H), 7.98 (dd, J ¼ 9.0, 2.7 Hz, 1H), 6.90 (d, J ¼ 9.0 Hz, 1H), 4.73 (d, J ¼ 2.4 Hz, 1H), 3.08 (d, J ¼ 2.5 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 202.5, 195.1, 164.3, 156.0, 141.1, 127.3, 124.1, 123.8, 116.7, 114.5, 98.7, 48.8, 31.4, 30.9, 29.7, 24.2, 21.0; HRMS (ESI) Calcd for C17H17NO4: [MþNa] ¼ 354.0954. Found: 354.0963. Compound 3i: yield 0.2100 g (70%); mp 127e129
C; IR (neat, cm1): 2922.9, 2340.5, 2152.4, 2072.8, 1760.8, 1328.3; 1H NMR (400 MHz, CDCl3) d ppm 7.10 (d, J ¼ 1.8 Hz, 1H), 6.90 (dd, J ¼ 8.1, 1.8 Hz, 1H), 6.73 (d, J ¼ 8.2 Hz, 1H), 4.61 (d, J ¼ 2.5 Hz, 1H), 3.07 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.6, 195.5, 164.5, 148.2, 130.7, 128.6, 127.9, 126.1, 115.8, 115.1, 97.9, 49.6, 31.4, 31.1, 29.6, 24.3, 21.2, 20.1; HRMS (ESI) Calcd for C18H20O4: [MþNa] ¼ 323.1259. Found: 323.1261. Compound 3j: yield 0.2611 g (87%); mp 178e179
C; IR (neat, cm1): 3249.3, 2980.7, 2274.8, 2160.1, 1708.6, 1377.1; 1H NMR

5

(400 MHz, CDCl3) d ppm 7.15 (d, J ¼ 7.5 Hz, 1H), 6.97 (d, J ¼ 7.4 Hz, 1H), 6.77 (t, J ¼ 7.5 Hz, 1H), 4.64 (d, J ¼ 2.5 Hz, 1H), 3.06 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H) 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.7, 195.6, 164.3, 148.6, 129.4, 126.0, 125.4, 125.2, 120.9, 115.1, 97.8, 49.9, 31.4, 31.3, 29.7, 24.5, 21.3, 15.9; HRMS (ESI) Calcd for C18H20O4: [MþNa] ¼ 323.1259. Found: 323.1263. Compound 3k: yield 0.0790 g (25%); Liquid; IR (neat, cm1): 3674.5, 2966.1, 2245.8, 1760.2, 1502.3, 1376.0; 1H NMR (400 MHz, CDCl3) d ppm 7.20 (d, J ¼ 8.3 Hz, 1H), 6.46e6.41 (m, 2H), 4.59 (d, J ¼ 2.5 Hz, 1H), 3.73 (s, 3H), 3.07 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.7, 195.7, 164.2, 159.7, 151.4, 128.2, 118.9, 115.6, 107.8, 101.4, 98.0, 55.5, 49.8, 31.4, 30.7, 29.7, 24.4, 21.2; HRMS (ESI) Calcd for C18H20O5: [MþNa] ¼ 339.1208. Found: 339.1213. Compound 3l: yield 0.1580 g (50%); mp 100e102
C; IR (neat, cm1): 2944.1, 2833.1, 2214.0, 1712.5, 1492.2, 1378.5; 1H NMR (400 MHz, CDCl3) d ppm 6.85 (d, J ¼ 3.0 Hz, 1H), 6.76 (d, J ¼ 8.8 Hz, 1H), 6.66 (dd, J ¼ 8.8, 3.0 Hz, 1H), 4.61 (d, J ¼ 2.6 Hz, 1H), 3.72 (s, 3H), 3.08 (d, J ¼ 2.7 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.6, 195.5, 164.8, 154.0, 144.3, 126.9, 116.8, 114.9, 114.3, 112.0, 97.9, 55.9, 49.5, 31.4, 31.3, 29.7, 24.3, 21.3; HRMS (ESI) Calcd for C18H20O5: [MþNa] ¼ 339.1208. Found: 339.1218. Compound 3o: yield 0.0672 g (20%); mp 160e162
C; IR (neat, cm1): 2924.6, 2204.6, 2179.1, 1713.0, 1604.8, 1352.2; 1H NMR (400 MHz, CDCl3) d ppm 8.25 (d, J ¼ 8.5 Hz, 1H), 7.74 (d, J ¼ 8.1 Hz, 1H), 7.64 (d, J ¼ 8.8 Hz, 1H), 7.55e7.51 (m, 1H), 7.37e7.33 (m, 1H), 7.09 (d, J ¼ 8.9 Hz, 1H), 5.44 (d, J ¼ 2.7 Hz, 1H), 3.18 (d, J ¼ 2.8 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.9, 196.9, 164.4, 148.7, 131.3, 129.6, 128.9, 128.4, 127.2, 124.1, 123.8, 118.9, 117.9, 115.2, 98.1, 49.8, 31.5, 29.7, 27.6, 24.0, 21.1; HRMS (ESI) Calcd for C21H20O4: [MþNa] ¼ 359.1259. Found: 359.1273. Compound 3r: yield 0.1592 g (40%); mp 115e117
C; IR (neat, cm1): 2968.0, 2873.2, 2196.8, 1725.7, 1382.8, 1233.9; 1H NMR (400 MHz, CDCl3) d ppm 7.23e7.19 (m, 1H), 7.08e7.07 (m, 1H), 7.06e7.04 (m, 1H), 7.02e7.00 (m, 1H), 4.65 (d, J ¼ 9.5 Hz, 1H), 4.27 (d, J ¼ 9.5 Hz, 1H), 3.33 (dt, J ¼ 13.8, 6.9 Hz, 1H), 3.23e3.16 (m, 1H), 2.48 (dt, J ¼ 13.7, 6.9 Hz, 1H), 2.15 (dt, J ¼ 13.8, 6.9 Hz, 1H), 1.26 (d, J ¼ 6.9 Hz, 3H), 1.13 (d, J ¼ 6.5 Hz, 3H), 1.06 (d, J ¼ 7.0 Hz, 3H), 1.00 (d, J ¼ 3.0 Hz, 3H), 0.98 (d, J ¼ 3.1 Hz, 3H), 0.93 (d, J ¼ 2.4 Hz, 3H), 0.92 (d, J ¼ 1.9 Hz, 3H), 0.46 (d, J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) d ppm 206.9, 206.7, 206.1, 163,9, 153.2, 128.8, 128.2, 124.3, 123.6, 115.9, 114.2, 69.0, 42.9, 42.3, 38.1, 37.0, 29.3, 20.1, 19.8, 19.5, 17.9, 17.7, 17.5, 17.3, 16.7; HRMS (ESI) Calcd for C25H34O4: [MþNa] ¼ 421.2355. Found: 421.2364. Compound 3s: yield 0.2670 g (50%); mp 162e164
C; IR (neat, cm1): 3058.6, 2921.0, 2157.8, 1981.2, 1374.2, 1205.2; 1H NMR (400 MHz, CDCl3) d ppm 8.03e8.01 (m, 2H), 7.76e7.74 (m, 2H), 7.45e7.41 (m, 3H), 7.36e7.24 (m, 4H), 7.20e7.15 (m, 2H), 7.13e7.08 (m, 4H), 7.01e6.99 (m, 3H), 6.98e6.92 (m, 4H), 6.37 (d, J ¼ 4.3 Hz, 1H), 4.99 (d, J ¼ 4.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) d ppm 197.8, 195.6, 195.2, 160.2, 152.6, 138.2, 137.2, 136.6, 133.4, 133.3, 132.2, 132.1, 130.2, 130.1, 129.6, 129.4, 128.9, 128.8, 128.6, 128.5, 127.9, 127.8, 124.5, 121.9, 116.2, 111.3, 61.8, 38.3, 27.0; HRMS (ESI) Calcd for C37H26O4: [MþNa] ¼ 557.1729. Found: 557.1742. Compound 3t: total yield 0.2296 g (56%); mp 152e154
C; IR (neat, cm1): 2945.3, 2920.6, 1687.0, 1594.3, 1374.3, 1152.2; 1H NMR (400 MHz, CDCl3) d ppm 7.93e7.91 (m, 2H), 7.63e7.59 (m, 1H), 7.51e7.43 (m, 3H), 7.40e7.38 (m, 2H), 7.33 (t, J ¼ 7.5 Hz, 2H), 7.16e7.12 (m, 1H), 7.03 (d, J ¼ 7.7 Hz, 1H), 6.80 (dd, J ¼ 7.5, 1.6 Hz, 1H), 6.71 (td, J ¼ 7.4, 1.1 Hz, 1H), 4.57 (d, J ¼ 2.4 Hz, 1H), 4.01 (d, J ¼ 2.7 Hz, 1H), 1.91 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) d ppm 196.4, 195.2, 158.7, 152.1, 140.6, 136.0, 133.7, 132.2, 129.1,

Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

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D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6

128.6, 128.5, 128.4, 128.3, 127.2, 122.0, 121.5, 117.5, 115.7, 98.9, 45.3, 35.2, 24.7, 20.3; HRMS (ESI) Calcd for C27H22O4: [MþNa] ¼ 433.1416. Found: 433.1414. Compound 3u: yield 0.2170 g (70%); mp 150e152
C; IR (neat, cm1): 2957.7, 2327.3, 2028.6, 1716.5, 1621.8, 1378.6; 1H NMR (400 MHz, CDCl3) d ppm 7.38e7.35 (m, 1H), 7.11e7.07 (m, 1H), 6.87 (dd, J ¼ 10.8, 4.4 Hz, 2H), 4.45 (d, J ¼ 1.9 Hz, 1H), 2.86 (d, J ¼ 2.2 Hz, 1H), 2.64 (d, J ¼ 13.8 Hz, 1H), 2.49e2.45 (m, 1H), 2.40e2.33 (m, 1H), 2.32e2.29 (m, 3H), 2.26e2.18 (m, 2H), 2.11e2.05 (m, 1H), 1.92e1.80 (m, 3H); 13C NMR (100 MHz, CDCl3) d ppm 203.5, 195.8, 166.9, 150.9, 128.6, 127.8, 126.5, 121.8, 115.7, 115.2, 100.9, 49.5, 40.4, 36.4, 35.1, 27.4, 24.3, 20.8, 20.6; HRMS (ESI) Calcd for C19H18O4: [MþNa] ¼ 333.1103. Found: 333.1106. Acknowledgments The authors gratefully acknowledge the financial support for this work from the National Natural Science Fund (51675006), the project of Science and Technology Department of Shaanxi Province (2016JZ017) and the PhD research startup foundation of Baoji University of Arts and Sciences (ZK15047). Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.07.054. References 1. (a) Ma WW, Fang J, Ren J, Wang ZW. Org Lett. 2015;17:4180; (b) Brawn RA, Guimaraes CR, McClure KF, Liras S. Org Lett. 2012;14:4802. 2. (a) Zhang H, Yerigui, Yang Y, Ma C. J Agric Food Chem. 2013;61:8814; (b) Gallina L, Dal PF, Galligioni V, Bombardelli E, Scagliarini A. Antivir Res. 2011;92:447. 3. (a) Tao Y, Chen Z, Zhang Y, Wang Y, Cheng Y. J Pharm Biomed Anal. 2013;78: 190;

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Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054