Intramolecular Benzannulation of 3-Sulfonyl-2-benzylchromen-4-ones

Publication Date (Web): December 14, 2018. Copyright © 2018 American Chemical Society. *E-mail: [email protected]. Cite this:J. Org. Chem. XXXX, XXX...
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Intramolecular Benzannulation of 3‑Sulfonyl-2-benzylchromen-4ones: Synthesis of Sulfonyl Dibenzooxabicyclo[3.3.1]nonanes Meng-Yang Chang,*,†,‡ Han-Yu Chen,† and Yu-Lin Tsai† †

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

‡

J. Org. Chem. 2019.84:443-449. Downloaded from pubs.acs.org by WESTERN SYDNEY UNIV on 01/09/19. For personal use only.

S Supporting Information *

ABSTRACT: In this work, a concise route for the synthesis of sulfonyl dibenzo-oxabicyclo[3.3.1]nonanes by a two-step route is described, including (i) NaBH4/LiCl-mediated reduction of 3-sulfonyl-2-benzylchromen-4-ones and (ii) sequential BF3·OEt2-mediated intramolecular annulation of the resulting 3-sulfonyl-2-benzylchroman-4-ols. A plausible mechanism is proposed and discussed herein. This protocol provides a highly effective stereocontrolled aryl-hydroxyl Friedel−Crafts-type cross-coupling to construct the tetra- or pentacyclic bridged framework. The use of various reaction conditions is investigated for an efficient transformation.

T

Scheme 1. Synthesis of Dibenzo-Oxabicyclo[3.3.1]nonanes

he family of dibenzodioxabicyclo[3.3.1]nonane represents a key class of naturally occurring oxygen-containing bis-flavonoids, including cyanomaclurin,1 procyanidin A1,2a diinsininol,2b and dracoflavans B and D.2c These natural components possess various biological activities including those with antibacterial and antioxidant properties. There are many reports on the preparation of a dibenzodioxabicyclo[3.3.1]nonane skeleton, as well as related derivatives.3−13 However, some efforts on the synthesis of dibenzofused [3.3.1]-bicyclic carbocycles are also welldocumented.14 Among these synthetic applications toward a dioxa[3.3.1]-bicyclic acetal/ketal-containing core structure, the facile intermolecular stereoselective annulation of oxygenated arenes and o-hydroxychalcone surrogates has seen growing interest by different routes, including transition-metalcatalyzed cyclization (e.g., AuBr3, CeCl3, Pd(PhCN)2Cl2, AgOTf), thermolytic annulation, and other special routes. These recent significant efforts were also demonstrated to provide different synthetic pathways, as shown in Scheme 1. However, among these existing preparations toward dibenzofused bicyclo[3.3.1]nonane, the major attention is still focused on the templates of 2,6- and 2,8-dioxabicyles 1−2, which is due to their spontaneous acetalization or ketalization of aldehyde-diol or ketone-diol to the corresponding acetal or ketal being easier than that of their derivatives. In fact, to the best of our knowledge, to date, no sulfonyl-conjugated substituent on the core dibenzo structure of mono-oxa bicyclo[3.3.1]nonane has been reported for the family, and a little data is available for the formation of mono-oxa-bridged dibenzo[b,f ]cyclooctane (3, Kagan’s ether).15 Regarding the installation of the sulfonyl moiety into a key core skeleton, the synthetic route has long held a respected position in a number of reports in synthetic and pharmaceutic fields due to its specific chemoselectivity and diversified bioactivity.16 On the basis of the observations, new methods to investigate their preparation of sulfonyl dibenzo-oxabicyclo[3.3.1]nonane are © 2018 American Chemical Society

needed. In an ongoing effort to emphasize the synthesis of sulfonyl skeletons,17 this study presents a two-step synthetic route toward 10-sulfonyl dibenzo-2-oxabicyclo[3.3.1]nonane 6 via reduction of 3-sulfonyl-2-benzylchromen-4-ones 4, followed by BF3·OEt2-mediated intramolecular annulation of the resulting chroman-4-ols 5. According to review articles18 and our preliminary report,17a the starting material, 3-sulfonyl-2-benzylchromen-4-ones 4, was afforded from the Cu(OAc)2-promoted one-pot (4+2) annulation of sulfonyl benzylacetylenes with salicyclic acids in the presence of BOP and DMAP in MeNO2 at reflux in moderate to good yields. In the following NaBH4/LiClmediated stereocontrolled reduction of 4, the formation of 5 with three contiguous cis−trans chiral centers had been documented in recent studies.17b On the basis of two Received: October 23, 2018 Published: December 14, 2018 443

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

Note

The Journal of Organic Chemistry reports, 17a,b herein, the main works focused on the investigation of various promoter-mediated intramolecular benzannulation conditions of 5. The initial study commenced with treatment of model substrate 4a (1.0 mmol) with an in situ formed LiBH4 (2.1 equiv, prepared from the combination of NaBH4 and LiCl) in a cosolvent of MeOH and THF (8 mL, v/v = 1/1) at 0 °C for 3 h. To achieve the facile and efficient two-step route, the resulting 5a was directly treated with the promoter without further purification. First, by the addition of BF3·OEt2 (1 equiv), 5a was self-cyclized to produce 6a in a 52% yield at 25 °C for 1 h via intramolecular benzannulation (Table 1, entry

temperature-dependent with higher yields obtained at 25 and 50 °C. With the time elongated (5 → 8 h), the yield of 6a was maintained (88%). On the basis of the above-mentioned experimental data, different Brønsted acids were checked. By changing the promoters from BF3·OEt2 to H2SO4, a lower yield (25%) of 6a was observed (entry 10).19 Subsequently, two sulfonic acidcontaining promoters, pTsOH and TfOH, were studied. However, neither of them obtained higher yields of 6a (25% and 15%) than the boron-containing promoter (entries 11 and 12). From these results, we found that sulfonic acid-containing promoters were inappropriate for the formation of 6a. In the other methods, other Lewis acids were chosen as the promoters to further screen the reaction conditions. However, 6a was provided in 43%, 63%, 50%, and 58%, respectively, for AlCl3-, InCl3-, BiCl3-, and FeCl3-mediated annulations (entries 13−16). Among the four metal chlorides, no yields of 6a performed better than BF3·OEt2. Finally, the stoichiometric equivalent of BF3·OEt2 was tested. The amount of BF3·OEt2 was decreased to 0.5 equiv, and a lower yield (47%) was provided (entry 17). The amount of BF3·OEt2 was increased to 1.2 equiv, and 6a was provided in a slightly lower yield (88%, entry 18). From these observations, we concluded that entry 9 provided the optimal conditions for the formation of 6a via intramolecular annulation of 5a. Generally, we found that BF3· OEt2 (1.0 equiv), ethylene dichloride, 5 h, and reflux temperature (85 °C) could efficiently obtain a higher yield of 6a. The stereochemical structure of 6a was determined by single-crystal X-ray crystallography.20 On the basis of our experimental results, a plausible mechanism for the formation of 6 is illustrated in Scheme 2.

Table 1. Reaction Conditionsa,b

entry

promoters

solvent

time (h)

temp (°C)

6a (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 H2SO4 pTsOH TfOH AlCl3 InCl3 BiCl3 FeCl3 BF3·OEt2e BF3·OEt2f

CH2Cl2 MeNO2 MeOH (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2 (CH2Cl)2

1 1 1 1 3 5 8 5 5 5 5 5 5 5 5 5 5 5

25 25 25 25 25 25 25 50 85 85 85 85 85 85 85 85 85 85

52 c 18d 70 74 76 71 80 90 25d 35 15d 43 63 50 58 47 88

Scheme 2. Plausible Mechanism

a

Reactions were run on a 1.0 mmol scale with 4a, NaBH4 (80 mg, 2.1 equiv), LiCl (90 mg, 2.1 equiv), and MeOH/THF (8 mL, v/v = 1/1), 3 h, 0 °C. bThe reactions were run on the resulting crude 5a, solvent (8 mL), and promoter (1.0 equiv). cIsolated yields; no reaction. dThe major complex mixture was isolated. e0.5 equiv. f1.2 equiv.

Initially, the reduction of 4a yields 5a with three contiguous cis−trans chiral centers via the formation of borohydride anion (BH4−)-chelated intermediates.17b By the involvement of BF3, the chelation of the hydroxyl group of 5a leads to A. Following the intramolecular Friedel−Crafts-type annulation, the phenyl group attacks the C-4 position of A to generate B by the removal of the hydroxyl-chelated BF3 leaving group. After dehydrogenative aromatization, 6a was formed spontaneously. To study the scope and limitations of this approach, 4a−4x were reacted with the reaction combination of NaBH4/LiCl and BF3·OEt2 to afford diversified 6, as shown in Table 2. With optimal conditions established (Table 1, entry 9) and a plausible mechanism proposed (Scheme 2), we found that this route allowed a direct one-pot reduction under mild conditions in moderate to good yields (70−90%), with the exception of 6n, 6w, and 6x. Among entries 1−10, efficient formations of 6a−6j showed that the R substituent (methyl and aryl) on the sulfonyl group did not affect the yield. In entries 11−16,

1). With the results in mind, the optimal annulation condition was examined next. Controlling BF3·OEt2 as the promoter, we surveyed the factors of solvent, time, and reaction temperature on the ring-closure process. However, no desired 6a was observed for MeNO2 (entry 2), and MeOH provided a low yield (18%) along with other major complex mixtures (entry 3). By changing the solvent system as (CH2Cl)2, a better yield of 6a was provided in a 70% (entry 4). In order to increase the yield, an elongated time (3, 5, and 8 h) was investigated. In entries 5−7, three reaction times provided yields of nearly 74%, 76%, and 71% under BF3·OEt2/(CH2Cl)2 conditions. The results showed that a longer reaction time (8 h) could not enhance the yield. Furthermore, reaction temperature screening (50 and 85 °C) was performed. With the temperature increased to 50 °C, an 80% yield of 6a was isolated (entry 8). Gratifyingly, when the reaction was treated with a reflux temperature (85 °C), the yield of 6a was enhanced to 90% (entry 9). It was obvious that the reaction was highly 444

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

Note

The Journal of Organic Chemistry Table 2. Synthesis of 6a,b

chromen-4-one 4z was tested, as shown in Scheme 3. By the two-step synthetic route, however, dibenzo-oxabicyclo[3.2.1]Scheme 3. Reaction of 4y and 4z

entry

4, Ar, Ar′, R

6, %c

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

4a, Ph, Ph, Me 4b, Ph, Ph, Ph 4c, Ph, Ph, tol 4d, Ph, Ph, 4-FC6H4 4e, Ph, Ph, 4-MeOC6H4 4f, Ph, Ph, 3-MeC6H4 4g, Ph, Ph, 4-EtC6H4 4h, Ph, Ph, 4-iPrC6H4 4i, Ph, Ph, 4-tBuC6H4 4j, Ph, Ph, 4-nBuC6H4 4k, 4-FC6H3, Ph, tol 4l, 4-BrC6H3, Ph, tol 4m, 4-ClC6H3, Ph, tol 4n, 5-MeOC6H3, Ph, tol 4o, naphthyl, Ph, tol 4p, 4-Br-naphthyl, Ph, tol 4q, Ph, 2-MeOC6H4, tol 4r, Ph, 4-MeC6H4, tol 4s, Ph, 2-cC5H9OC6H4, tol 4t, Ph, 3,4-CH2O2C6H3, tol 4u, Ph, 3,4-(MeO)2C6H3, tol 4v, Ph, 1-naphthyl, tol 4w, Ph, 4-NO2C6H4, tol 4x, 5-MeOC6H3, 2-MeOC6H4, tol

6a, 90 6b, 82 6c, 81 6d, 78 6e, 82 6f, 83 6g, 84 6h, 78 6i, 77 6j, 76 6k, 80 6l, 78 6m, 84 6nd 6o, 76 6p, 70 6q, 84 6r, 83 6s, 84 6t, 88 6u, 84 6v, 80 6we 6xf

octane 7a or dibenzo-oxabicyclo[4.3.1]decane 7b was not detected, thus only complex products were provided as the major components. In summary, we have developed one facile two-step route for the stereocontrolled synthesis of polycyclic sulfonyl dibenzooxabicyclo[3.3.1]nonanes via NaBH4/LiCl-mediated reduction of 3-sulfonyl-2-benzylchromen-4-ones, followed by BF3·OEt2mediated intramolecular Friedel−Crafts-type annulation of the resulting 3-sulfonyl-2-benzylchroman-4-ols. Related plausible mechanisms have been proposed. The structures of the key products were confirmed by X-ray crystallography. The usees of various reaction conditions were investigated for an efficient transformation. Further investigations regarding the synthetic application of sulfonyl chromen-4-ones will be conducted and published in due course.

■

a

Reactions were run on a 1.0 mmol scale with 4a−4x, NaBH4 (80 mg, 2.1 equiv), LiCl (90 mg, 2.1 equiv), and MeOH/THF (8 mL, v/v = 1/1), 3 h, 0 °C. bThe reactions were run on the resulting crude 5a− 5x, (CH2Cl)2 (8 mL) and BF3·OEt2 (1.0 equiv), 5 h, 85 °C. cIsolated yields. d58% of 6n-1 was isolated. eComplex products. f66% of 6x-1 was isolated.

EXPERIMENTAL SECTION

General Methods. All reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry air with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm), and the coupling constants (J) are given in hertz (Hz). High-resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an EnrafNonius FR-590 diffractometer (CAD4, Kappa CCD). General Synthetic Route for the Synthesis of Skeleton 6. NaBH4 (80 mg, 2.1 mmol) was added to a solution of 4 (1.0 mmol) and LiCl (90 mg, 2.1 mmol) in a cosolvent of MeOH and THF (8 mL, v/v = 1/1) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was warmed to 25 °C, and the solvent was concentrated. The residue was diluted with water (10 mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford the crude product under reduced pressure. Without further purification, BF3·OEt2 (150 mg, 1.06 mmol) was added to the resulting alcohols in (CH2Cl)2 (10 mL). The reaction mixture was stirred at 85 °C for 5 h. The reaction mixture was cooled to 25 °C. The reaction mixture was diluted with water (10 mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford crude products under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1 to 4/1) afforded skeleton 6. 13-Methylsulfonyl-7,12-dihydro-6H-6,12-methanodibenzo[b,e]oxocine (6a). Yield: 90% (270 mg). Colorless solid. Mp: 166−168 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z:

regarding the electronic nature of aryl substituent (Ar) of 4, both the electron-neutral naphthyl group and electronwithdrawing 4-fluorophenyl group were appropriate. However, only the electron-donating 5-methoxyphenyl group (for 4n) was not suitable for intramolecular annulation. Entry 14 provided a dehydrated product 6n-1 in a 58% yield. The possible reason could be that the methoxy group-promoted dehydration was easier than the phenyl-mediated ring closure. For another aryl substituent (Ar′) of 4, both electron-neutral and electron-donating groups were well-tolerated (entries 17− 23). However, for the electron-withdrawing 4-nitrophenyl group of 4w, only complex products were produced (entry 23). We envisioned that the nitro group inhibited the formation of the bridged skeleton, which induced a retro-sulfonyl-aldol-type ring opening of sulfonyl chroman-4-ols to occur. In entry 24, 4x with two electron-donating methoxyaryl groups (Ar = 5MeOC6H3, Ar′ = 2-MeOC6H4) provided the dehydrated product 6x-1 in a 66% yield. The results were similar to 6n-1. From the phenomenon, we understood that the 5-oxygenated group on the Ar ring is a key substituent for the formation of cyclic vinyl sulfones. The stereochemical structures of 6d, 6e, 6u, and 6v were determined by single-crystal X-ray crystallography.20 Encouraged by the results, intramolecular annulation of 2-phenylchromen-4-one 4y or 2-homobenzyl445

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

Note

The Journal of Organic Chemistry [M + H]+ calcd for C17H17O3S, 301.0899; found, 301.0898. 1H NMR (400 MHz, CDCl3): δ 7.30−7.28 (m, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 7.17−7.08 (m, 4H), 6.88 (dt, J = 1.2, 7.2 Hz, 1H), 6.81 (dd, J = 0.8, 8.4 Hz, 1H), 5.48−5.45 (m, 1H), 4.54 (t, J = 2.0 Hz, 1H), 3.54 (br s, 1H), 3.49 (dd, J = 5.6, 18.8 Hz, 1H), 3.38 (d, J = 18.8 Hz, 1H), 2.53 (d, J = 0.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.3, 140.2, 131.0, 129.1, 128.8, 128.1, 127.2, 126.9, 126.8, 122.1, 121.7, 116.7, 67.7, 62.4, 40.0, 39.1, 37.0. Single-crystal X-ray diagram: a crystal of compound 6a was grown by slow diffusion of EtOAc into a solution of compound 6a in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P21 21 21, a = 6.4521(4) Å, b = 10.1091(6) Å, c = 21.6537(12) Å, V = 1412.36(14) Å3, Z = 4, dcalcd = 1.413 g/cm3, F(000) = 632, 2θ range 2.223−26.391°, R indices (all data) R1 = 0.0311, wR2 = 0.0714. 13-Benzenesulfonyl-7,12-dihydro-6H-6,12-methanodibenzo[b,e]oxocine (6b). Yield: 82% (297 mg). Colorless solid. Mp: 165− 167 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H19O3S, 363.1055; found, 363.1058. 1H NMR (400 MHz, CDCl3): δ 7.69−7.66 (m, 2H), 7.46−7.42 (m, 1H), 7.31−7.23 (m, 3H), 7.14−7.07 (m, 3H), 7.05 (dd, J = 1.6, 7.6 Hz, 1H), 6.79 (dt, J = 1.6, 8.0 Hz, 1H), 6.71 (dt, J = 1.2, 8.8 Hz, 1H), 6.22 (dd, J = 1.2, 8.0 Hz, 1H), 5.48−5.45 (m, 1H), 4.49 (t, J = 2.0 Hz, 1H), 3.75 (d, J = 0.8 Hz, 1H), 3.43 (dd, J = 5.6, 18.4 Hz, 1H), 3.30 (d, J = 18.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.1, 140.4, 137.3, 133.6, 131.2, 129.21 (2×), 129.16, 128.3 (2×), 128.2, 127.5, 127.1, 126.9, 126.8, 121.7, 120.8, 116.1, 67.3, 62.8, 39.4, 37.3. 13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6c). Yield: 81% (305 mg). Colorless solid. Mp: 169−171 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H21O3S, 377.1211; found, 377.1213. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.25−7.22 (m, 1H), 7.13−7.02 (m, 6H), 6.81 (dt, J = 1.6, 8.0 Hz, 1H), 6.70 (dt, J = 1.2, 8.8 Hz, 1H), 6.23 (dd, J = 0.8, 8.0 Hz, 1H), 5.46−5.43 (m, 1H), 4.46 (t, J = 2.0 Hz, 1H), 3.71 (d, J = 0.8 Hz, 1H), 3.42 (dd, J = 5.6, 18.4 Hz, 1H), 3.29 (d, J = 18.4 Hz, 1H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.1, 144.6, 140.5, 134.1, 131.2, 129.21 (2×), 129.15, 128.9 (2×), 127.7, 127.6, 127.1, 126.9, 126.8, 121.9, 120.8, 116.1, 67.4, 62.6, 39.4, 37.3, 21.5. 3-(4-Fluorophenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6d). Yield: 78% (296 mg). Colorless solid. Mp: 203−205 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H18FO3S, 381.0961; found, 381.0960. 1H NMR (400 MHz, CDCl3): δ 7.66−7.61 (m, 2H), 7.26−7.24 (m, 1H), 7.15−7.08 (m, 3H), 7.03 (dd, J = 1.6, 7.6 Hz, 1H), 6.91−6.86 (m, 2H), 6.81 (dt, J = 1.6, 8.0 Hz, 1H), 6.71 (dd, J = 1.2, 8.0 Hz, 1H), 6.17 (dd, J = 0.8, 8.0 Hz, 1H), 5.48−5.45 (m, 1H), 4.51 (t, J = 2.0 Hz, 1H), 3.75 (br s, 1H), 3.45 (dd, J = 5.6, 18.4 Hz, 1H), 3.29 (d, J = 18.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.7 (d, J = 254.7 Hz), 150.8, 140.3, 133.1 (d, J = 3.8 Hz), 132.2 (d, J = 9.9 Hz, 2×), 131.0, 129.2, 128.2, 127.6, 127.2, 126.90, 126.88, 121.7, 121.0, 116.1, 115.3 (d, J = 22.8 Hz, 2×), 67.5, 63.1, 39.3, 37.3. Single-crystal X-ray diagram: a crystal of compound 6d was grown by slow diffusion of EtOAc into a solution of compound 6d in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P21/c, a = 8.8548(5) Å, b = 10.0501(6) Å, c = 20.0035(12) Å, V = 1744.88(18) Å3, Z = 4, dcalcd = 1.448 g/cm3, F(000) = 792, 2θ range 2.077− 26.508°, R indices (all data) R1 = 0.0355, wR2 = 0.0811. 3-(4-Methoxyphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6e). Yield: 82% (321 mg). Colorless solid. Mp: 194−196 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H21O4S, 393.1161; found, 393.1160. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.8 Hz, 2H), 7.25−7.23 (m, 1H), 7.13−7.03 (m, 4H), 6.80 (dt, J = 1.6, 8.0 Hz, 1H), 6.73−6.69 (m, 3H), 6.25 (dd, J = 1.2, 8.4 Hz, 1H), 5.46− 5.43 (m, 1H), 4.47 (t, J = 2.0 Hz, 1H), 3.79 (s, 3H), 3.70 (d, J = 0.8 Hz, 1H), 3.42 (dd, J = 5.6, 18.4 Hz, 1H), 3.28 (d, J = 18.4 Hz, 1H). 13 C{1H} NMR (100 MHz, CDCl3): δ 163.6, 151.0, 140.5, 131.4 (2×), 131.2, 129.1, 128.4, 127.9, 127.6, 127.1, 126.9, 126.8, 121.9, 120.8, 116.1, 113.5 (2×), 67.5, 62.6, 55.5, 39.4, 37.3. Single-crystal X-

ray diagram: a crystal of compound 6e was grown by slow diffusion of EtOAc into a solution of compound 6e in CH2Cl2 to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P1, a = 7.0055(13) Å, b = 10.701(2) Å, c = 13.367(3) Å, V = 916.3(3) Å3, Z = 2, dcalcd = 1.422 g/cm3, F(000) = 412, 2θ range 1.661−26.474°, R indices (all data) R1 = 0.0782, wR2 = 0.1321. 3-(3-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6f). Yield: 83% (312 mg). Colorless solid. Mp: 144−146 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H21O3S, 377.1211; found, 377.1212. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.2 Hz, 1H), 7.40 (s, 1H), 7.26−7.19 (m, 3H), 7.14−7.04 (m, 4H), 6.81 (dt, J = 1.6, 8.0 Hz, 1H), 6.71 (dt, J = 1.2, 8.0 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 5.46−5.44 (m, 1H), 4.49 (t, J = 2.0 Hz, 1H), 3.74 (d, J = 0.8 Hz, 1H), 3.42 (dd, J = 5.6, 18.4 Hz, 1H), 3.29 (d, J = 18.8 Hz, 1H), 2.26 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.2, 140.4, 138.6, 137.1, 134.4, 131.2, 129.7, 129.2, 128.2, 128.1, 127.5, 127.1, 126.9, 126.8, 126.4, 121.8, 120.7, 116.1, 67.3, 52.8, 39.4, 37.3, 21.1. 13-(4-Ethylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6g). Yield: 84% (328 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23O3S, 391.1368; found, 391.1369. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H), 7.25−7.22 (m, 1H), 7.13−7.02 (m, 6H), 6.78 (dt, J = 1.6, 8.0 Hz, 1H), 6.69 (dt, J = 1.2, 8.4 Hz, 1H), 6.20 (dd, J = 1.6, 8.0 Hz, 1H), 5.47−5.45 (m, 1H), 4.49 (t, J = 2.0 Hz, 1H), 3.72 (d, J = 0.8 Hz, 1H), 3.43 (dd, J = 5.6, 18.4 Hz, 1H), 3.29 (d, J = 18.8 Hz, 1H), 3.61 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 150.0, 150.6, 140.5, 134.3, 131.2, 129.3 (2×), 129.1, 128.0, 127.7 (2×), 127.6, 127.1, 126.9, 126.8, 121.8, 120.8, 116.1, 67.4, 52.7, 39.4, 37.3, 28.8, 15.0. 13-(4-Isopropylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6h). Yield: 78% (315 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25O3S 405.1524; found, 405.1523. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.4 Hz, 2H), 7.26−7.24 (m, 1H), 7.13−7.03 (m, 6H), 6.75 (dt, J = 1.6, 8.0 Hz, 1H), 6.69 (dt, J = 1.2, 7.6 Hz, 1H), 6.16 (dd, J = 0.8, 8.0 Hz, 1H), 5.49−5.46 (m, 1H), 4.51 (t, J = 2.0 Hz, 1H), 3.73 (d, J = 1.2 Hz, 1H), 3.43 (dd, J = 5.6, 18.8 Hz, 1H), 3.28 (d, J = 18.4 Hz, 1H), 2.90−2.83 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.0, 151.0, 140.5, 134.4, 131.2, 129.4 (2×), 129.1, 128.1, 127.5, 127.1, 126.9, 126.8, 126.3 (2×), 121.8, 120.7, 116.0, 67.4, 62.8, 39.4, 37.2, 34.1, 23.5, 23.3. 13-(4-tert-Butylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6i). Yield: 77% (322 mg). Colorless solid. Mp: 163−165 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H27O3S, 419.1681; found, 419.1683. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.8 Hz, 2H), 7.26−7.23 (m, 3H), 7.13−7.02 (m, 4H), 6.74 (dt, J = 1.6, 8.0 Hz, 1H), 6.68 (dt, J = 1.2, 8.8 Hz, 1H), 6.13 (dd, J = 0.8, 8.0 Hz, 1H), 5.49−5.46 (m, 1H), 4.52 (t, J = 2.0 Hz, 1H), 3.73 (d, J = 1.2 Hz, 1H), 3.44 (dd, J = 5.6, 18.4 Hz, 1H), 3.28 (d, J = 18.8 Hz, 1H), 1.27 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.2, 151.0, 140.5, 134.0, 131.2, 129.1, 129.1 (2×), 128.1, 127.6, 127.1, 126.9, 126.8, 125.2 (2×), 121.8, 120.7, 116.0, 67.5, 62.8, 39.4, 37.3, 35.0, 30.9 (3×). 13-(4-n-Butylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6j). Yield: 76% (318 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H27O3S, 419.1681; found, 419.1679. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.8 Hz, 2H), 7.26−7.23 (m, 1H), 7.14−7.03 (m, 6H), 6.78 (dt, J = 1.6, 8.0 Hz, 1H), 6.69 (dt, J = 1.6, 8.8 Hz, 1H), 6.20 (dd, J = 1.2, 8.0 Hz, 1H), 5.48−5.45 (m, 1H), 4.49 (t, J = 2.0 Hz, 1H), 3.73 (d, J = 0.8 Hz, 1H), 3.43 (dd, J = 5.6, 18.4 Hz, 1H), 3.29 (d, J = 18.8 Hz, 1H), 2.57 (t, J = 7.6 Hz, 2H), 1.58−1.51 (m, 2H), 1.39−1.29 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.1, 149.4, 140.5, 134.4, 131.2, 129.2 (2×), 129.1, 128.3 (2×), 128.0, 127.6, 127.1, 126.9, 126.8, 121.8, 120.8, 116.1, 67.4, 62.8, 39.4, 37.3, 35.5, 33.0, 22.2, 13.8. 2-Fluoro-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6k). Yield: 80% (315 mg). Colorless solid. Mp: 200−202 °C (recrystallized from hexanes and EtOAc). 446

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

Note

The Journal of Organic Chemistry HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20FO3S, 395.1117; found, 395.1118. 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.4 Hz, 2H), 7.22−7.20 (m, 1H), 7.15−7.08 (m, 5H), 6.74 (dd, J = 2.8, 8.4 Hz, 1H), 6.53 (dt, J = 2.8, 8.8 Hz, 1H), 6.22 (dd, J = 4.4, 8.8 Hz, 1H), 5.45−5.42 (m, 1H), 4.39 (t, J = 2.0 Hz, 1H), 3.68 (s, 1H), 3.42 (dd, J = 5.6, 18.4 Hz, 1H), 3.27 (d, J = 18.4 Hz, 1H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 156.9 (d, J = 237.2 Hz), 147.1, 144.9, 139.8, 134.1, 131.3, 129.3 (2×), 129.2, 129.0 (2×), 127.4, 126.93, 126.88, 122.8 (d, J = 7.6 Hz), 117.1 (d, J = 7.6 Hz), 114.4 (d, J = 22.7 Hz), 113.5 (d, J = 23.5 Hz), 67.4, 62.2, 39.3, 37.3, 21.5. 2-Bromo-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6l). Yield: 78% (354 mg). Colorless solid. Mp: 218−220 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20BrO3S, 455.0317; found, 455.0315. 1H NMR (400 MHz, CDCl3): δ 7.59−7.57 (m, 2H), 7.26−7.19 (m, 1H), 7.14−7.09 (m, 6H), 6.92 (dd, J = 2.8, 8.4 Hz, 1H), 6.20 (d, J = 8.8 Hz, 1H), 5.46−5.44 (m, 1H), 4.37 (t, J = 2.0 Hz, 1H), 3.68 (s, 1H), 3.41 (dd, J = 5.2, 18.4 Hz, 1H), 3.28 (d, J = 18.4 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 150.4, 145.1, 139.6, 133.9, 131.1, 130.5, 130.0, 129.3 (2×), 129.2, 129.1 (2×), 127.4, 127.03, 126.99, 124.0, 118.0, 112.5, 67.7, 62.1, 39.2, 37.0, 21.6. 2-Chloro-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6m). Yield: 74% (303 mg). Colorless solid. Mp: 188−190 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H20ClO3S, 411.0822; found, 411.0823. 1H NMR (400 MHz, CDCl3): δ 7.60−7.57 (m, 2H), 7.22−7.20 (m, 1H), 7.15−7.08 (m, 5H), 6.98 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 2.4, 8.8 Hz, 1H), 6.25 (d, J = 8.8 Hz, 1H), 5.46− 5.44 (m, 1H), 4.37 (t, J = 2.0 Hz, 1H), 3.69 (br d, J = 1.6 Hz, 1H), 3.41 (dd, J = 5.2, 18.4 Hz, 1H), 3.28 (d, J = 18.4 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 149.8, 145.1, 139.7, 134.0, 131.1, 129.3 (2×), 129.2, 129.1 (2×), 127.6, 127.4, 127.1, 127.02, 126.98, 125.3, 123.4, 117.6, 67.6, 62.2, 39.3, 37.1, 21.5. 2-Benzyl-7-methoxy-3-(toluene-4-sulfonyl)-2H-chromene (6n-1). Yield: 58% (235 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23O4S, 407.1317; found, 407.1318. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.31−7.21 (m, 3H), 7.17−7.13 (m, 3H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 5.03 (dd, J = 2.8, 10.0 Hz, 1H), 3.80 (s, 3H), 3.07 (dd, J = 10.4, 14.4 Hz, 1H), 2.93 (dd, J = 2.4, 14.8 Hz, 1H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.8, 153.8, 144.6, 137.1 (2×), 132.2, 130.7, 130.4, 130.1 (2×), 129.4 (2×), 128.3 (2×), 127.9 (2×), 126.6, 113.3, 108.4, 102.8, 74.8, 55.6, 39.5, 21.6. 15-(Toluene-4-sulfonyl)-9,14-dihydro-8H-8,14-methanobenzo[e]naphtho[1,2-b]oxocine (6o). Yield: 76% (324 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H23O3S, 427.1368; found, 427.1368. 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, J = 1.6, 8.0 Hz, 1H), 7.54 (dd, J = 1.6, 7.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.31−7.19 (m, 4H), 7.14−7.07 (m, 4H), 6.61 (d, J = 8.0 Hz, 2H), 5.71−5.70 (m, 1H), 4.60 (t, J = 2.0 Hz, 1H), 3.83 (d, J = 0.8 Hz, 1H), 3.54 (dd, J = 5.6, 18.4 Hz, 1H), 3.38 (d, J = 18.8 Hz, 1H), 1.79 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 146.3, 144.4, 140.5, 134.0, 133.5, 131.3, 129.2, 128.8 (2×), 128.4 (2×), 127.1, 126.79, 126.76, 125.9, 125.5, 124.7, 124.6, 124.1, 121.5, 120.6, 115.6, 68.2, 63.2, 39.8, 37.5, 21.0. 6-Bromo-15-(toluene-4-sulfonyl)-9,14-dihydro-8H-8,14methanobenzo[e]naphtho[1,2-b]oxocine (6p). Yield: 70% (353 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H22BrO3S, 505.0473; found, 505.0477. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 0.8, 8.4 Hz, 1H), 7.45−7.40 (m, 3H), 7.39 (s, 1H), 7.33 (dt, J = 1.2, 8.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.16−7.09 (m, 3H), 6.66 (d, J = 8.0 Hz, 2H), 5.74−5.71 (m, 1H), 4.52 (t, J = 2.4 Hz, 1H), 3.82 (d, J = 0.8 Hz, 1H), 3.54 (dd, J = 5.6, 18.4 Hz, 1H), 3.38 (d, J = 18.4 Hz, 1H), 1.83 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 146.1, 144.7, 139.8, 133.8, 131.4, 131.1, 129.3, 128.9 (2×), 128.8, 128.5 (2×), 127.4, 127.3, 127.0, 126.9, 126.5, 125.5, 125.4, 121.9, 116.7, 113.3, 68.5, 63.0, 39.7, 37.2, 21.1.

8-Methoxy-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6q). Yield: 84% (341 mg). Colorless solid. Mp: 224−226 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23O4S, 407.1317; found, 407.1318. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.03 (dt, J = 1.6, 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.80 (dt, J = 1.6, 8.4 Hz, 1H), 6.69 (dt, J = 0.8, 7.6 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 5.48−5.46 (m, 1H), 4.45 (t, J = 2.4 Hz, 1H), 3.74 (s, 3H), 3.68 (br s, 1H), 3.22 (dd, J = 5.2, 18.0 Hz, 1H), 3.15 (d, J = 17.6 Hz, 1H), 2.32 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.5, 151.1, 144.5, 141.8, 134.2, 129.2 (2×), 128.8 (2×), 127.74, 127.66, 127.6, 121.8, 120.6, 120.0, 118.7, 116.1, 108.2, 66.9, 62.5, 55.2, 37.0, 34.9, 21.5. 10-Methyl-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H-6,12methanodibenzo[b,e]oxocine (6r). Yield: 83% (324 mg). Colorless solid. Mp: 200−202 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23O3S, 391.1368; found, 391.1365. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.4 Hz, 2H), 7.08−7.04 (m, 4H), 6.97 (d, J = 7.6 Hz, 1H), 6.90 (dt, J = 1.6, 8.0 Hz, 1H), 6.82 (dt, J = 1.6, 8.0 Hz, 1H), 6.72 (dt, J = 1.2, 7.6 Hz, 1H), 6.24 (dd, J = 0.8, 8.0 Hz, 1H), 5.45−5.43 (m, 1H), 4.40 (t, J = 2.0 Hz, 1H), 3.69 (s, 1H), 3.37 (dd, J = 6.4, 18.4 Hz, 1H), 3.25 (d, J = 18.8 Hz, 1H), 2.33 (s, 3H), 2.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.2, 144.6, 140.3, 136.5, 134.2, 129.2 (2×), 129.0, 128.9 (2×), 128.0 (2×), 127.7, 127.5, 127.3, 121.9, 120.7, 116.0, 67.5, 52.7, 39.0, 37.3, 21.5, 20.9. 8-Cyclopentyl-13-(4-Methylphenyl)sulfonyl-7,12-dihydro-6H6,12-methanodibenzo[b,e]oxocine (6s). Yield: 84% (386 mg). Colorless gum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H29O4S, 461.1787; found, 461.1789. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H), 7.08−7.03 (m, 4H), 6.85− 6.80 (m, 2H), 6.70 (dt, J = 1.2, 7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.27 (dd, J = 0.4, 8.0 Hz, 1H), 5.46−5.45 (m, 1H), 4.69−4.65 (m 1H), 4.43 (t, J = 2.4 Hz, 1H), 3.67 (br s, 1H), 3.20 (dd, J = 5.2, 19.2 Hz, 1H), 3.12 (d, J = 18.8 Hz, 1H), 2.32 (s, 3H), 1.90−1.65 (m, 8H). 13 C{1H} NMR (100 MHz, CDCl3): δ 155.9, 151.1, 144.5, 141.8, 134.2, 129.1 (2×), 128.8 (2×), 127.7, 127.6, 127.4, 121.9, 120.5, 120.4, 118.0, 116.0, 110.1, 79.0, 67.0, 62.4, 37.0, 35.0, 32.9, 32.7, 23.93, 23.91, 21.4. 9,10-Methylenedioxy-13-(4-methylphenyl)sulfonyl-7,12-dihydro6H-6,12-methanodibenzo[b,e]oxocine (6t). Yield: 88% (370 mg). Colorless solid. Mp: 241−243 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H21O5S, 421.1110; found, 421.1113. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.99 (dd, J = 1.6, 7.2 Hz, 1H), 6.82 (dt, J = 1.6, 7.2 Hz, 1H), 6.71 (dt, J = 1.6, 7.6 Hz, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 6.21 (dd, J = 0.8, 8.0 Hz, 1H), 5.88 (d, J = 1.2 Hz, 1H), 5.81 (d, J = 1.6 Hz, 1H), 5.40−5.38 (m, 1H), 4.31 (t, J = 2.0 Hz, 1H), 3.69 (t, J = 1.2 Hz, 1H), 3.31 (dd, J = 5.6, 18.4 Hz, 1H), 3.17 (d, J = 18.4 Hz, 1H), 2.32 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.1, 146.8, 146.3, 144.6, 134.0, 133.7, 129.2 (2×), 128.9 (2×), 127.7, 127.3, 124.2, 122.0, 120.7, 116.0, 108.7, 106.8, 101.0, 67.3, 62.8, 39.5, 37.1, 21.5. 9,10-Dimethoxy-13-(4-methylphenyl)sulfonyl-7,12-dihydro-6H6,12-methanodibenzo[b,e]oxocine (6u). Yield: 84% (366 mg). Colorless solid. Mp: 186−188 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25O5S, 437.1423; found, 437.1425. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.02 (dd, J = 1.6, 7.6 Hz, 1H), 6.81 (dt, J = 1.6, 8.0 Hz, 1H), 6.72 (dd, J = 1.2, 7.6 Hz, 1H), 6.68 (s, 1H), 6.55 (s, 1H), 6.21 (d, J = 8.0 Hz, 1H), 5.43−5.41 (m, 1H), 4.35 (t, J = 2.0 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.71 (br s, 1H), 3.35 (dd, J = 5.2, 18.4 Hz, 1H), 3.21 (d, J = 18.0 Hz, 1H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.2, 148.1, 147.8, 144.6, 134.1, 132.7, 129.2 (2×), 128.9 (2×), 127.7, 127.3, 122.9, 122.1, 120.7, 116.1, 111.7, 109.7, 67.4, 63.0, 56.0, 55.9, 39.3, 36.9, 21.5. Single-crystal X-ray diagram: a crystal of compound 6u was grown by slow diffusion of EtOAc into a solution of compound 6u in CH2Cl2 to yield colorless prisms. The compound crystallizes in the 447

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

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The Journal of Organic Chemistry monoclinic crystal system, space group P21/c, a = 12.756(4) Å, b = 8.772(3) Å, c = 19.326(6) Å, V = 2068.7(11) Å3, Z = 4, dcalcd = 1.402 g/cm3, F(000) = 920, 2θ range 1.669−26.329°, R indices (all data) R1 = 0.0579, wR2 = 0.1156. 15-(Toluene-4-sulfonyl)-7,14-dihydro-8H-8,14-methanobenzo[b]naphtho[2,1-e]oxocine (6v). Yield: 80% (341 mg). Colorless solid. Mp: 217−219 °C (recrystallized from hexanes and EtOAc). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H23O3S, 427.1368; found, 427.1366. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.49 (dt, J = 1.2, 8.4 Hz, 1H), 7.43 (dt, J = 1.2, 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 1.6, 8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.80 (ddt, J = 1.6, 7.6, 8.4 Hz, 1H), 6.70 (dt, J = 0.8, 8.4 Hz, 1H), 6.21 (dd, J = 0.8, 8.4 Hz, 1H), 5.65−5.64 (m, 1H), 4.58 (t, J = 2.0 Hz, 1H), 3.86 (br s, 1H), 3.73 (dd, J = 5.2, 18.4 Hz, 1H), 3.65 (d, J = 17.6 Hz, 1H), 2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.2, 144.7, 138.0, 134.1, 132.4, 131.8, 129.3 (2×), 128.9 (2×), 128.7, 127.9, 127.8, 127.4, 126.7, 126.5, 125.8, 125.4, 122.9, 121.8, 120.7, 116.1, 67.4, 62.6, 37.7, 37.4, 21.5. Single-crystal X-ray diagram: a crystal of compound 6v was grown by slow diffusion of EtOAc into a solution of compound 6v in CH2Cl2 to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P1, a = 8.5240(16) Å, b = 10.785(2) Å, c = 12.112(2) Å, V = 1009.2(3) Å3, Z = 2, dcalcd = 1.404 g/cm3, F(000) = 448, 2θ range 1.833−26.567°, R indices (all data) R1 = 0.0854, wR2 = 0.1489. 7-Methoxy-2-(2-methoxybenzyl)-3-(toluene-4-sulfonyl)-2H-chromene (6x-1). Yield: 66% (288 mg). Colorless gum. HRMS (ESITOF) m/z: [M + H]+ calcd for C25H25O5S, 437.1423; found, 437.1429. 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.22 (dt, J = 2.0, 8.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 2.0, 7.6 Hz, 1H), 6.87−6.84 (m, 2H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.25 (d, J = 2.8 Hz, 1H), 5.22 (dd, J = 2.8, 10.8 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.03 (dd, J = 2.4, 14.4 Hz, 1H), 2.88 (dt, J = 2.4, 14.4 Hz, 1H), 2.42 (s, 3H). 13 C{1H} NMR (100 MHz, CDCl3): δ 163.6, 157.5, 153.5, 144.5, 137.1, 132.7, 131.7, 131.4, 131.2, 129.9, 129.8 (2×), 128.2, 128.1 (2×), 120.1, 113.4, 110.1, 108.3, 102.8, 72.8, 55.5, 55.1, 34.6, 21.6.

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(2) For examples on bioactive natural products with the dibenzo-2,8dioxabicyclo[3.3.1]nonane skeleton, for procyanidin A1, see: (a) Liu, Y. Z.; Cao, Y. G.; Ye, J. Q.; Wang, W. G.; Song, K. J.; Wang, X. L.; Wang, C. H.; Li, R. T.; Deng, X. M. Immunomodulatory Effects of Proanthocyanidin A-1 Derived in Vitro from Rhododendron Spiciferum. Fitoterapia 2010, 81, 108−114. For diinsininol, see: (b) Ogundaini, A.; Farah, M.; Perera, P.; Samuelsson, G.; Bohlin, L. Isolation of Two New Antiinflammatory Bflavanoids from Sarcophyte Piriei. J. Nat. Prod. 1996, 59, 587−590. For dracoflavans B and D, see: (c) Toh, Z. S.; Wang, H.; Yip, Y. M.; Lu, Y.; Lim, B. J.; Zhang, D.; Huang, D. Phenolic Group on A-Ring is Key for Dracoflavan B as A Selective Noncompetitive Inhibitor of α-Amylase. Bioorg. Med. Chem. 2015, 23, 7641−7649. (3) Du, J.-Y.; Ma, Y.-H.; Meng, F.-X.; Chen, B.-L.; Zhang, S.-L.; Gong, S.-W.; Wang, D.-Q.; Ma, C.-L.; Li, Q.-L. Lewis Acid Catalyzed Tandem 1,4-Conjugate Addition/Cyclization of in Situ Generated Alkynyl o-Quinone Methides and Electron-Rich Phenols: Synthesis of Dioxabicyclo[3.3.1]nonane Skeletons. Org. Lett. 2018, 20, 4371− 4374. (4) Liu, H.; Wang, Y.; Guo, X.; Huo, L.; Xu, Z.; Zhang, W.; Qiu, S.; Yang, B.; Tan, H. A Bioinspired Cascade Sequence Enables Facile Assembly of Methanodibenzo[bf ][1,5]dioxocin Flavonoid Scaffold. Org. Lett. 2018, 20, 546−549. (5) Ma, S.; Yu, A.; Zhang, L.; Meng, X. Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate: Synthesis of Benzothiophene-Fused Dioxabicyclo[3.3.1]nonane Derivatives. J. Org. Chem. 2018, 83, 5410−5419. (6) Yang, Z.; He, Y.; Toste, F. D. Biomimetic Approach to the Catalytic Enantioselective Synthesis of Flavonoids. J. Am. Chem. Soc. 2016, 138, 9775−9778. (7) Srinivas, V.; Koketsu, M. Synthesis of 2,8-Dioxabicyclo[3.3.1]nonane Derivatives via a Sequential Knoevenagel Condensation and Hetero-Diels−Alder Reaction in an Aqueous Medium. J. Org. Chem. 2013, 78, 11612−11617. (8) Ganguly, N. C.; Roy, S.; Mondal, P. Cerium(III)-Ctalyzed Regioselective Coupling of 2-Hydroxychalcones and Polyphenols: an Efficient Domino Approach towards Synthesis of Novel Dibenzo-2,8dioxabicyclo[3.3.1]nonanes. RSC Adv. 2014, 4, 42078−42086. (9) Wang, F.; Chen, F.; Qu, M.; Li, T.; Liu, Y.; Shi, M. A Pd(II)Catalyzed Asymmetric Approach toward Chiral [3.3.1]-Bicyclic Ketals Using 2-Hydroxyphenylboronic Acid as a Pro-Bis(nucleophile). Chem. Commun. 2013, 49, 3360−3362. (10) Rao, Y.; Yin, G. AgOTf-Catalyzed Reactions of Naphthols/ Substituted Phenols with 2-Hydroxychalcones: Facile Synthesis of DiAromatic Ring-Fused [3.3.1]Bicyclic Compounds. Org. Biomol. Chem. 2013, 11, 6029−6035. (11) Yin, G.; Ren, T.; Rao, Y.; Zhou, Y.; Li, Z.; Shu, W.; Wu, A. Stereoselective Synthesis of 2,8-Dioxabicyclo[3.3.1]nonane Derivatives via a Sequential Michael Addition/Bicyclization Reaction. J. Org. Chem. 2013, 78, 3132−3141. (12) Polat, M. F.; Hettmanczyk, L.; Zhang, W.; Szabo, Z.; Franzen, J. One-Pot, Two-Step Protocol for the Catalytic Asymmetric Synthesis of Optically Active N,O- and O,O-Acetals. ChemCatChem 2013, 5, 1334−1339. (13) Ganguly, N. C.; Mondal, P.; Roy, S. A Mild Efficient IodineCatalyzed Synthesis of Novel Anticoagulants with 2,8Dioxabicyclo[3.3.1]nonane Core. Tetrahedron Lett. 2013, 54, 2386− 2390. (14) For carbocyclic derivatives, see: (a) Wang, B.; Gu, Z. Highly Efficient and Practical Resolution of 2,3:6,7-Dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-dione and Stereoselective Synthesis of Its Chiral Diamine Derivatives. Org. Chem. Front. 2014, 1, 271−274. (b) Stončius, S.; Butkus, E.; Ž ilinskas, A.; Larsson, K.; Ö hrström, L.; Berg, U.; Wärnmark, K. Design and Synthesis of a C2-Symmetric Self-Complementary Hydrogen-Bonding Cleft Molecule Based on the Bicyclo[3.3.1]nonaneand 4-Oxo-5-azaindole Framework. Formation of Channels and Inclusion Complexes in the Solid State. J. Org. Chem. 2004, 69, 5196−5203. (c) Kimber, M. C.; Try, A. C.; Painter, L.; Harding, M. M.; Turner, P. Synthesis of Functionalized Chiral

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02726. Crystal data for compounds 6a, 6d, 6e, 6u, and 6v (CIF) NMR spectral data for all compounds and X-ray analysis data of 6a, 6d, 6e, 6u, and 6v (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Meng-Yang Chang: 0000-0002-1983-8570 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the Ministry of Science and Technology of the Republic of China for financial support (MOST 106-2628-M-037-001-MY3).

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REFERENCES

(1) For examples on bioactive natural products with the dibenzo-2,6dioxabicyclo[3.3.1]nonane skeleton for cyanomaclurin, see: Tan, H.; Tse, M. Y.; Li, E. T. S.; Wang, M. Inhibitory Effects of Oxyresveratrol and Cyanomaclurin on Adipogenesis of 3T3-L1 cells. J. Funct. Foods 2015, 15, 207−216. 448

DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449

Note

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DOI: 10.1021/acs.joc.8b02726 J. Org. Chem. 2019, 84, 443−449