Regioselective Rearrangement of 4,4-Disubstituted 2

Publication Date (Web): November 3, 2017. Copyright © 2017 American Chemical Society ... Successful application to other substrates was also demonstr...
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Regioselective Rearrangement of 4,4-Disubstituted 2‑Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions Keita Takubo,†,⊥,∥ Ahmed A.B. Mohamed,†,‡,∥ Takafumi Ide,§ Kazuyuki Saito,† Takashi Ikawa,† Takehiko Yoshimitsu,†,¥ and Shuji Akai*,† †

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt § School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan ‡

S Supporting Information *

ABSTRACT: The dienone-phenol rearrangement is a useful tool for the synthesis of highly substituted phenols. In our previous study of the rearrangement of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienone under deoxyfluorination conditions, bond migration proceeded with very poor regioselectivity. In this paper, an acid-mediated rearrangement of O-perfluoroalkylsulfonyl difluorides with regioselective migration toward the β′-carbon is reported. This method allowed the synthesis of a fluorinated analog of allocolchicinoids with improved total yield. Successful application to other substrates was also demonstrated.

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for fluorinated allocolchicinoids, treatment of 5a with the deoxyfluorination reagent XtalFluor-E in iPr2O/CHCl3 produced the desired o-fluorophenol 11a (38% yield) as a minor product along with its regioisomer 12a (45% yield). The deoxyfluorination of 5a′ with a higher diastereomeric ratio (dr = 40:1) also resulted in the formation of a mixture of 11a and 12a, in which 12a was still the major product (Scheme 2).7a It was suggested that 12a was obtained by the migration of the phenyl group of a fluorinated intermediate (9a8 or 10a) toward the β-carbon (path B); yet, the factors governing this abnormal migration under deoxyfluorination conditions were poorly understood. In this paper, we report a strategy to control the migration direction toward the β′-carbon in the rearrangement of 4,4disubstituted 2-hydroxycyclohexa-2,5-dienones under deoxyfluorination conditions to afford the desired product regioselectively. After extensive trials, we finally discovered a solution of this issue by the acid-mediated migration of the difluoro intermediates (14j and 14k), generated from 5a, in which the protection of the α-hydroxyl group by a perfluoroalkylsulfonyl group, such as trifluoromethanesulfonyl (Tf) and nonafluorobutanesulfonyl (Nf) groups, was crucial. Successful application to other substrates was also demonstrated.

INTRODUCTION The dienone-phenol rearrangement is a powerful tool for the synthesis of multisubstituted phenols that are not readily available by conventional aromatic substitution chemistry.1 Its application to spiro compounds provides easy access to polycyclic structures by ring expansion of the spirocyclic system.2 Moreover, it finds many applications in the pharmaceutical field2d,3 and natural product synthesis.2b,f,4 A typical acid-catalyzed dienone-phenol rearrangement starts with O-protonation of the carbonyl group of the dienone, followed by migration of one of the two substituents at the γ-position. According to previous studies on the influence of substituents at the α-position on the migration direction,5,6 the γ-substituent generally migrates toward the more electrondeficient β-carbon. For example, in the acid-catalyzed rearrangement of dienones 1 bearing an electron-donating R3O group at the α-position, the migration proceeds toward the more electron-deficient β′-carbon via path A to afford products 3 with exclusive regioselectivity (Scheme 1).5 Similar electronic effects of the α-substituents were observed in other cases.6 In our previous work on the synthesis of analogues of allocolchicinoid,7a we observed a similar acid-catalyzed rearrangement of dienone 5a (8:1 diastereomeric mixture) to form the phenol derivative 7a in quantitative yield by the migration of the phenyl group toward the more electron-deficient β′-carbon of 5a (path A). However, in the synthesis of the key intermediate © 2017 American Chemical Society

Received: September 1, 2017 Published: November 3, 2017 13141

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry Scheme 1. Dienone-Phenol Rearrangement of 1 under Acidic Conditions

Scheme 2. Dienone-Phenol Rearrangement of Spiro Compound 5a under Acidic or Deoxyfluorination Conditions

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RESULTS AND DISCUSSION In an attempt to explain the preferential formation of 12a, we initially hypothesized that the migration direction was affected by the conformation of the intermediate or transition state. Thus, we identified the stable conformation of the major diastereomer of 5a as A (Scheme 3) based on 1H NMR data, and we speculated that the reactive intermediate 10a adopted a similar conformation Ca (R = H). The more stable conformation Ca might be accountable for the preferential migration of the phenyl moiety toward the β-carbon to afford 12a as a major product. To obtain some insights for our hypothesis, we prepared compound 5b bearing two methoxycarbonyl groups, which under the deoxyfluorination conditions would form intermediate conformations Bb (R = CO2Me) and Cb of similar stability to produce 11b and 12b in a different ratio; however, we again obtained a mixture of 12b (38% yield) and 11b (21% yield) in a similar 1.8:1 ratio to that of 12a and 11a.

These results suggest that the conformation of the intermediates had no significant influence on the regioselectivity.9 Next, we examined the steric effects of the methyl ester moiety in 5a on the migration direction. Thus, the regioselectivity of the domino deoxyfluorination/rearrangement reaction of some congeners (5c−5g) having a different substituent was tested under the identical conditions (XtalFluor-E and Et3N· HF in a 1:1 mixture of iPr2O and CHCl3 at 50 °C for 1.5 h), and the results are shown in Table 1. The more bulky esters 5c−5e as well as the methoxymethyl compound 5f produced 12c−12f as a major product in a higher ratio (entries 2−5). On the other hand, the less bulky nitrile 5g afforded 11g as a major product along with 12g in a ratio of 2.2:1 (entry 6). Although the results showed that the steric bulkiness had some effects on the migration tendency, it did not lead us to a definitive solution of the issue. During further examination of the deoxyfluorination conditions of 5a (Table 2), difluoride 13 (69% NMR yield) was 13142

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry Scheme 3. Effect of the Intermediate Conformation on the Regioselectivity

Table 1. Substituent Effects for Deoxyfluorinative Rearrangement Reactions of 5c−5g

substrate 5

products

entry

R

dra

1 2 3 4 5 6

CO2Me (5a) CO2tBu (5c) CO2Ph (5d) CO2Naphc (5e) CH2OMe (5f) CN (5g)

8:1 8:1 13:1 13:1 10:1 10:1

11:12b 11a:12a 11c:12c 11d:12d 11e:12e 11f:12f 11g:12g

total yield (%)b 1:1.2 1:3 1:4 1:4 1:3 2.2:1

83 42 74 62 72 68

a

The relative stereochemistry of the major isomer is shown in the above scheme. bThe yield of each product was determined by 1H and 19F NMR analysis of a crude product using fluorobenzene as the internal standard. cNaph: 1-naphthyl

electron-withdrawing groups significantly improved the regioselectivity in favor of the desired compound 11. Thus, benzoate 14h underwent rearrangement along with partial deprotection to afford a mixture of desired products (11a and 11h) and undesired 12a in a 9:1 ratio (Table 4, entry 1). Tosylate 14i gave a 3:1 mixture of desired 11i and undesired 12i (entry 2). Interestingly, the triflylated derivative 14j and nonaflates 14k produced exclusively the desired 11j and 11k, respectively, in quantitative yield (entries 3 and 4). It is noteworthy that the previously reported overall yield of Tf-protected 11j (37% from 5a), which served as a key intermediate in the synthesis of a fluorinated analog of allocolchicinoids,7a increased up to 46− 55% using this new synthetic route. In addition, the TfO and NfO groups are useful functional groups for further conversion into a variety of substituents as well as hydrogen.12 We have examined a possible correlation between the electron density at the β- and β′-carbons of 13 and 14h−14k, speculated based on the chemical shifts of these carbons, and the ratio of the migration products (11 and 12). The chemical

obtained as a single diastereomer when using diethylaminosulfur trifluoride (DAST) at 0−10 °C (entry 3); moreover, at lower temperature, the NMR yield of 13 increased to 81−89% (entry 4).10 On the basis of these results, we expected 13 or its derivatives with protected enol oxygen to serve as better substrates for the regiocontrolled rearrangement leading to 11a The rearrangement of 13 was examined by using a range of acids (Table 3). We observed no reaction by methanesulfonic acid (MsOH), camphorsulfonic acid (CSA), and Et3N·3HF (entries 1−3). On the other hand, using trifluoromethanesulfonic acid (TfOH) in CHCl3 at 0 °C, 13 rearranged quantitatively to give a mixture of 11a (45% yield) and 12a (55% yield) (entry 4), in which a ratio of 11a and 12a was similar to that observed for the domino deoxyfluorination/migration reaction of 5a shown in Scheme 2. A similar migration was performed using trimethylsilyl trifluoromethanesulfonate (TMSOTf) to produce 11a in a lower yield (28%) (entry 5). Similar TfOH-mediated reactions of 14h−14k bearing a range of O-protective groups11 were examined to reveal that 13143

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry Table 2. Deoxyfluorination of 5a

NMR yield (%)a entry

deoxyfluorination reagent

temp (°C)

time

11a

12a

13b

1 2 3 4

deoxofluor deoxofluor DAST DAST

0 to 10 RT 0 to 10 −50 to 0

overnight 1.5 h overnight overnight

11 22 9 6−9c

19 42 6 5−9c

13 12 69 81−89c (60−70)c,d

a

The yield was determined by 1H and 19F NMR analysis of a crude product using trifluorotoluene as the internal standard. bObtained as a single diastereomer (dr = >20:1) in the enol form. The keto form was sometimes observed under the same conditions (see also ref 10). cYield range of several experiments. dIsolated yield by silica gel chromatography.

Table 3. Screening of Acids for Rearrangement of 13

NMR yield (%)a

a

entry

acid (equiv)

solvent

temp (°C)

time

11a

12a

1 2 3 4 5

MsOH (1.0) CSA (5.0) Et3N·3HF (5.0) TfOH (5.0) TMSOTf (5.0)

DME DME DME CHCl3 CHCl3

0 to RT to 50 0 to RT to 50 0 to RT to 50 0 0

overnight overnight overnight 1.5 h 1.5 h

no reaction no reaction no reaction 45 28

55 60

The yield was determined by 1H and 19F NMR analysis of a crude product using trifluorotoluene as the internal standard.

shifts of β- and β′-carbons of 13 and 14h−14k are summarized in Table 5. We found that the β′-carbon appears in lower field than the β-carbon in every case. In addition, the chemical shifts of the β-carbons of 13 and 14 are classified into three groups: 110 ppm, 13; 126−127 ppm, 14h and 14i; and 129 ppm, 14j and 14k. On the contrary, the chemical shifts of the β′-carbon of all these compounds are almost the same (142−144 ppm). These data indicate that the electron density at the β′-carbon of all these compounds is lower than that at the β-carbon; however, there is no good correlation between the difference in the electron densities of β- and β′-carbons and the ratio of the migration products (11 and 12). Now we are intensively studying to clarify the special effects of Tf and NF groups. Next, we examined the applicability of the method using Nf as a primary protecting group due to economical reasons.13 The deoxyfluorination reaction of nonaflates 15 using DAST in DME at 50 °C did not proceed at all (Scheme 4), indicating that, for the preparation of 14k, deoxyfluorination of the carbonyl group of 5a must be performed prior to O-nonaflylation. We further investigated the effect of the O-Nf group by subjecting 15 to the acid-mediated rearrangement; notably, the migration proceeded exclusively toward the β′-carbon giving 16 quantitatively (Scheme 4).

The generality of the dominant migration of the O-nonaflylated difluorides was then examined with compounds 19a and 19b, prepared from the corresponding dienones (17a7b and 17b7b) in 63% and 44% overall yield, respectively. The TfOH-mediated rearrangement proceeded predominantly toward the β′-carbon to give 20a (87% NMR yield) and 20b (89%NMR yield) along with 21a (10% NMR yield) and 21b (11% NMR yield), respectively (Scheme 5). Thus, these reactions proceeded with quantitative conversion into the migration products, although the regioselectivity was not perfect.

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CONCLUSION In summary, we have developed a new deoxyfluorination/migration reaction of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienones, in which difluorides bearing an O-perfluoroalkylsulfonyl group, readily available from the corresponding dienones, were quantitatively converted with highly regioselective migration toward the β′-carbon distant from the α-(perfluoroalkylsulfonyl)oxy group. Notably, perfluoroalkylsulfonyl (such as Tf and Nf) protection of the α-hydroxyl group was crucial and is advantageous for further chemical manipulations of the migration products.12 Hence, this approach provides an efficient method for the regiocontrolled preparation of highly functionalized fluorobenzenes.7,14 13144

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

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The Journal of Organic Chemistry Table 4. Rearrangement of Difluorinated Compounds 14h−14k

products entry

substrate

11

12

overall ratio of 11:12

1a 2a 3 4

14h (PG = Bz) 14i (PG = Ts) 14j (PG = Tf) 14k (PG = Nf)

11a (10%) + 11h (80%) 11i (75%) 11j (quant.) 11k (quant.)

12a (10%) 12i (25%) 12j (n.d.) 12k (n.d.)

90:10 75:25 >99:1 >99:1

a The yield was determined by 1H and 19F NMR analysis of the crude product using trifluorotoluene as the internal standard. n.d.: not detected by 1H and 19F NMR analysis.

Table 5. Comparison of the Chemical Shifts of β- and β′-Carbons of 13 and 14h−14k and the Ratio of the Migration Products 11/12 Derived from Them compound

ratio of 11/12

chemical shift β-C

13 14h 14i 14j 14k

110.4 126.1 127.4 129.3 129.4

(t, (t, (t, (t, (t,

J J J J J

= = = = =

Scheme 5. Applicability to Other Substrates (17a and 17b)

β′-C 5.0 4.0 5.5 4.0 5.0

Hz) Hz) Hz) Hz) Hz)

143.6 142.7 142.3 142.4 142.4

(t, (t, (t, (t, (t,

J J J J J

= = = = =

9.5 Hz) 10.0 Hz) 9.5 Hz) 9.5 Hz) 9.5 Hz)

45:55 90:10 75:25 >99:1 >99:1

Scheme 4. Deoxyfluorination and Acid-Mediated Migration of O-Nonaflylated Dienone 15

Further studies on the unexpected control of the migration direction by TfO and NfO groups and application of the developed method to the synthesis of fluorinated analogs of other biologically important compounds are in progress in our laboratory.

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EXPERIMENTAL SECTION

General. All reactions were carried out under an argon or nitrogen atmosphere. A round-bottomed flask, a pear-shaped flask, or a test 13145

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

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The Journal of Organic Chemistry

chromatography (hexane/EtOAc = 2:1) to provide 23 (0.50 g, 90% yield) as a colorless oil. Rf: 0.2 (hexane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3): δ 2.39−2.52 (4H, m), 3.71 (6 H, s), 3.81 (3 H, s), 3.83 (6 H, s), 5.16 (4 H, s), 6.33 (2 H, s), 6.89 (1 H, d, J = 8.5 Hz), 6.93 (1 H, dd, J = 2.0, 8.5 Hz), 7.03 (1 H, d, J = 2.0 Hz), 7.28−7.39 (6 H, m), 7.41−7.46 (4 H, dd, J = 8.0, 8.0 Hz). 13C NMR (125 MHz, CDCl3): δ 31.9, 38.2, 53.0, 56.4, 61.2, 62.3, 71.4, 71.8, 105.5, 114.3, 116.2, 121.2, 127.5, 127.7, 128.1,128.2, 128.80, 128.84, 130.1, 136.6, 137.43, 137.50, 137.55, 148.5, 149.0, 153.4, 171.4. IR (neat): 1732 cm−1. HRMS (MALDI): m/z calcd for C36H38O9Na [M + Na]+, 637.2408; found, 637.2415. Dimethyl 2-(3,4-dihydroxyphenyl)-2-(3,4,5-trimethoxyphenethyl)malonate (24). Under an argon atmosphere, MeOH (4 mL) was added to a mixture of 23 (0.46 g, 0.75 mmol) and 10% Pd/C (46 mg, 10 w/w%), and the mixture was evacuated and backfilled with hydrogen gas. The reaction mixture was stirred for 7.5 h at RT and filtrated through a Celite cake. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 1:1) to provide 24 (0.26 g, 79% yield) as colorless crystals. Mp 124−125 °C. Rf: 0.2 (hexane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3): δ 2.45−2.57 (4H, m), 3.76 (6 H, s), 3.81 (3 H, s), 3.83 (6 H, s), 5.22 (1 H, s), 5.24 (1 H, s), 6.36 (2 H, s), 6.82−6.87 (2 H, m), 7.01 (1 H, br d, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3): δ 32.0, 38.0, 53.2, 56.4, 61.2, 62.3, 105.5, 115.3, 115.6, 120.5, 129.4, 136.1, 137.8, 143.8, 143.9, 153.3, 171.8. IR (neat): 3418, 1732 cm−1. HRMS (MALDI): m/z calcd for C22H26O9Na [M + Na]+, 457.1469; found, 457.1471. Dimethyl 3-Hydroxy-6′,7′,8′-trimethoxy-4-oxo-3′,4′-dihydro-2′Hspiro[cyclohexane-1,1′-naphthalene]-2,5-diene-2′,2′-dicarboxylate (5b). Under an argon atmosphere, MsOH (38 μL, 0.59 mmol) was added to a solution of 24 (0.26 g, 0.59 mmol) and PhI(OAc)2 (0.19 g, 0.59 mmol) in DME (3 mL) at 0 °C. The reaction mixture was stirred for 12 h at 0 °C. To the reaction mixture was added 10 mL of a saturated aqueous NaHCO3 solution for quenching. The mixture was extracted three times with 15 mL of EtOAc. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/EtOAc = 3:2 to 1:1) to provide 5b (35 mg, 14% yield) as a reddish brown solid. Mp 168−172 °C. 1H NMR (500 MHz, CDCl3): δ 2.37−2.51 (2H, m), 2.70−2.78 (1 H, m), 2.82− 2.87 (1 H, m), 3.59 (6 H, s), 3.64 (3 H, s), 3.74 (3 H, s), 3.81 (3 H, s), 6.25−6.39 (2 H, m), 6.41 (1 H, s), 6.48 (1 H, d, J = 10.5 Hz), 7.62 (1 H, br s). 13C NMR (125 MHz, CDCl3): δ 27.1, 27.4, 47.2, 52.8, 53.0, 56.1, 60.8, 61.1, 63.8, 108.0, 120.1, 126.0, 130.5, 141.2, 147.3, 152.9, 153.0, 169.2, 169.8, 181.7. IR (neat): 3395, 1732, 1647 cm−1. HRMS (MALDI): m/z calcd for C22H24O9Na [M + Na]+, 455.1312; found, 455.1311. Deoxyfluorination of 5b (Scheme 3). Under an argon atmosphere, XtalFluor-E (0.11 g, 0.48 mmol) was added to a solution of Et3N·3HF (26 μL, 0.16 mmol) and Et3N (45 μL, 0.32 mmol) in iPr2O−CHCl3 (1:1, 0.8 mL, 0.1 M) at 0 °C. To the reaction mixture was added 5b (35 mg, 0.081 mmol), and the reaction mixture was stirred for 1.5 h at 50 °C before being quenched with ice water (5 mL). EtOAc (10 mL) was added, the layers were separated, and the aqueous layer was extracted three times with EtOAc (10 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (hexane/EtOAc = 1:1) afforded 11b (7.4 mg, 21% yield) and 12b (13.4 mg, 38% yield). Dimethyl 2-Fluoro-3-hydroxy-9,10,11-trimethoxy-6,7-dihydro5H-dibenzo[a,c][7]annulene-5,5-dicarboxylate (11b). A white solid. Mp 189−192 °C. Rf: 0.2 (hexane/EtOAc = 1:1).1H NMR (500 MHz, CDCl3): δ 2.35−2.47 (2 H, m), 2.78−2.82 (1 H, m), 3.09−3.16 (1 H, m), 3.30 (3 H, s), 3.81 (3 H, s), 3.85 (3 H, s), 3.86 (3 H, s), 3.87 (3 H, s), 5.17 (1 H, s), 6.48 (1 H, s), 6.73 (1 H, d, J = 8.5 Hz), 7.20 (1 H, d, J = 11.5 Hz). 13C NMR (125 MHz, CDCl3): δ 30.2, 40.3, 53.0, 53.7, 56.2, 60.7, 61.0, 62.9, 107.4, 116.0, 118.5 (d, J = 19.0 Hz), 124.7, 129.3 (d, J = 7.0 Hz), 133.1 (d, J = 2.5 Hz), 135.1, 141.1, 142.2 (d, J = 14.5 Hz), 149.0, 150.0 (d, J = 237.5 Hz), 150.5, 153.4, 171.2. 19 F NMR (470 MHz, CDCl3): δ −142.72 (1 F, br s). IR (neat): 3418,

tube, each of which contained a stir-bar, was used as a reactor. 1.6 and 2.6 M n-BuLi in hexane were purchased from Kanto Chemical Co. Anhydrous THF, MeCN, DMF, CH2Cl2, CHCl3, 1,2-dimethoxyethane (DME), diisopropyl ether, and diethyl ether (Et2O) were obtained from Wako Pure Chemical or Kanto Chemical Co. Industries and used without further purification. All other reagents were purchased from Wako Pure Chemical Industries, Tokyo Chemical Industry Co., Aldrich Chemical Co., and Kishida Chemical Co. and were used without further purification. Flash chromatography was performed with Silica gel 60N, spherical neutral (40−50 μm) purchased from Kanto Chemical Co. Analytical thin layer chromatography (TLC) was performed using Merck silica gel 60 F254, and compounds were visualized with UV light and/or stained with an anisaldehyde solution and a phosphomolybdic acid solution. Melting points were recorded on a Yanagimoto melting point apparatus and are uncorrected. IR spectra were obtained on a SHIMADZU FTIR-8400S. 1H NMR, 13C NMR, and 19F NMR spectra were recorded on an Agilent Inova 600 NMR system (13C: 150 MHz), a JEOL JMN-ECA-500 (1H: 500 MHz, 13C: 125 MHz, 19F: 470 MHz), a JEOL JMN-ECS-400 (1H: 400 MHz, 13C: 100 MHz, 19F: 376 MHz) or a JEOL AL-300 (1H: 300 MHz, 13C: 75 MHz) instrument. Chemical shifts of 1H and 13C NMR spectra are reported in ppm relative to the residual deuterated solvent and those of 19F NMR spectra reported in ppm relative to trifluorotoluene (−63.72 ppm) as an internal standard. The mass spectra were recorded on a JEOL JMS-S3000 (MALDITOF) or a JEOL JMS-700 (FAB) spectrometer. Yield refers to isolated yields of compounds greater than 95% purity as determined by 1H and 19 F NMR analysis. 1H NMR and melting points (where applicable) of all known compounds were compared with reported data. All new products were further characterized by high-resolution mass spectrum (HRMS). Preparation of 5b.

Dimethyl 2-(3,4-bis(benzyloxy)phenyl)-2-(3,4,5-trimethoxyphenethyl)malonate (23). Under an argon atmosphere, lithium bis(trimethylsilyl)amide (0.83 mL, 1.1 M in THF) was added to a solution of methyl 2-(3,4-bis(benzyloxy)phenyl)-4-(3,4,5-trimethoxyphenyl)butanoate 227a (0.50 g, 0.90 mmol) in THF-HMPA (4:1, 4.5 mL) at −78 °C. The reaction mixture was stirred for 15 min at the same temperature, and methyl chloroformate (0.14 mL, 1.8 mmol) was added to the reaction mixture at −78 °C, and the mixture was stirred for 2 h at 0 °C. To the reaction mixture was added 10 mL of a saturated aqueous solution of NH4Cl for quenching. The mixture was extracted three times with 15 mL of EtOAc. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column 13146

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry 1744 cm−1. HRMS (MALDI): m/z calcd for C22H23O8FNa [M + Na]+, 457.1269; found, 457.1271. Dimethyl 2-Fluoro-1-hydroxy-9,10,11-trimethoxy-6,7-dihydro5H-dibenzo[a,c][7]annulene-5,5-dicarboxylate (12b). A white solid. Mp 157−159 °C.Rf: 0.2 (hexane/EtOAc = 1:1).1H NMR (500 MHz, CDCl3): δ 2.30−2.37, 2.44−2.48, 2.79−2.83, 3.04−3.11 (total 4 H, each m), 3.28 (3 H, s), 3.80 (3 H, s), 3.88 (3 H, s), 3.90 (3 H, s), 3.94 (3 H, s), 6.56−6.59 (2 H, m), 6.97 (1 H, br s), 7.06 (1 H, dd, J = 9.0, 10.0 Hz).13C NMR (125 MHz, CDCl3): δ 30.2, 40.2, 53.0, 53.7, 56.4, 61.41, 61.49, 63.43, 108.9, 115.1 (d, J = 18.0 Hz), 119.3 (d, J = 8.5 Hz), 127.2, 133.1 (d, J = 3.5 Hz), 136.0, 141.0, 142.4 (d, J = 12.0 Hz), 149.4, 153.4 (d, J = 245.0 Hz), 154.0, 170.9, 171.0. 19F NMR (470 MHz, CDCl3): δ −134.61 (1 F, br s). IR (neat): 3395, 1740 cm−1. HRMS (MALDI): m/z calcd for C22H23O8FNa [M + Na]+, 457.1269; found, 457.1269. Methyl 4,4-Difluoro-3-hydroxy-6′,7′,8′-trimethoxy-3′,4′-dihydro2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-diene-2′-carboxylate (13) (Table 2). Under an argon atmosphere, DAST (0.13 mL, 0.96 mmol) was added to a solution of 5a (dr = 8:1) (60 mg, 0.16 mmol) in DME (1.6 mL) at −50 °C, and the reaction mixture was stirred at 0 °C for 15 h. Then the mixture was quenched with a saturated aqueous solution of NaHCO3 (5 mL), and the aqueous layer was extracted three times with EtOAc (10 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. 1H and 19F NMR analysis of the residue showed the formation of 11a (6% yield), 12a (5% yield), and 13 (84% yield). Purification of the residue by flash column chromatography (hexane/EtOAc = 3:1) afforded 13 (44 mg, 70% yield) as a white solid. Mp 121−123 °C. Rf: 0.3 (hexane/EtOAc = 3:1).1H NMR (400 MHz, CDCl3): δ 1.93−2.04 (2 H, m), 2.73−2.83 (3 H, m), 3.60 (3 H, s), 3.68 (3 H, s), 3.77 (3 H, s), 3.83 (3 H, s), 4.67 (1 H, br s), 5.47−5.49 (1 H, m), 5.98−6.03 (1 H, m), 6.11 (1 H, dd, J = 2.0, 9.5 Hz), 6.40 (1 H, s). 13C NMR (125 MHz, CDCl3): δ 22.4, 30.1, 44.1, 51.93, 52.01 (t, J = 6.0 Hz), 56.1, 60.9, 107.6, 110.4 (t, J = 5.0 Hz), 112.5 (dd, J = 224.5, 225.5 Hz), 119.5 (t, J = 27.0 Hz), 122.2, 132.0, 141.2, 142.4 (t, J = 24.0 Hz), 143.6 (t, J = 9.5 Hz), 153.1, 153.9, 173.2. 19F NMR (376 MHz, CDCl3): δ −93.25 (1 F, dd, J = 6.0, 297.5 Hz), −89.87 (1 F, br d, J = 297.5 Hz). IR (neat): 3428, 1732, 1654 cm−1. HRMS (MALDI): m/z calcd for C20H22O6F2Na [M + Na]+, 419.1276; found, 419.1278. Methyl 4,4-Difluoro-6′,7′,8′-trimethoxy-5-oxo-3′,4′-dihydro-2′Hspiro[cyclohexane-1,1′-naphthalene]-2-ene-2′-carboxylate (13′). This was sometimes obtained under the above-mentioned reaction conditions as a white solid. Mp: 90−92 °C. Rf: 0.2 (hexane/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ1.85−1.95 (1 H, m), 2.12 (1 H, ddd, J = 4.0, 6.5, 14.0 Hz), 2.63 (1 H, dd, J = 2.50, 12.50 Hz), 2.81 (2 H, m), 3.12 (1 H, d, J = 17.0 Hz), 3.21 (1 H, dd, J = 3.5, 17.0 Hz), 3.61 (3 H, s), 3.76 (3 H, s), 3.83 (3 H, s), 3.84 (3 H, s), 6.04−6.11 (2 H, m), 6.37 (1 H, s). 13C NMR (125 MHz, CDCl3): δ 22.6, 30.2, 44.8, 45.1, 50.5, 52.1, 56.2, 60.6, 60.9, 107.1, 107.3 (dd, J = 239.0, 241.0 Hz), 120.6 (t, J = 26.5 Hz), 124.9, 131.5, 141.0, 146.4 (t, J = 12.0 Hz), 152.6, 153.5, 173.2, 194.7 (t, J = 24.0 Hz). 19F NMR (376 MHz, CDCl3): δ −105.44 (1 F, d, J = 308.0 Hz), −94.53 (1 F, d, J = 308.0 Hz). IR (neat): 1748, 1723 cm−1. HRMS (MALDI): m/z calcd for C20H22O6F2Na [M + Na] +, 419.1276; found, 419.1275. Methyl 3-Benzoyloxy-4,4-difluoro-6′,7′,8′-trimethoxy-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-diene-2′-carboxylate (14h). Under an argon atmosphere, NaH (60% containing in mineral oil, 9.0 mg, 0.23 mmol) was added to a solution of 13 (18 mg, 0.045 mmol) in DMF (0.5 mL) at 0 °C, and the mixture was stirred for 10 min at the same temperature. To the reaction mixture was added BzCl (11 μL, 0.090 mmol) at 0 °C, and the mixture was stirred for 2 h at the same temperature. The reaction mixture was quenched with 2 mL of a saturated aqueous NH4Cl solution. The mixture was extracted three times with 10 mL of Et2O. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to provide 14h (17.7 mg, 78% yield) as a white solid. Mp: 165−168 °C. Rf: 0.3 (hexane/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ 2.00−2.12 (2 H, m), 2.79−2.88

(3 H, m), 3.69 (3 H, s), 3.78 (3 H, s), 3.79 (3 H, s), 3.83 (3 H, s), 6.05−6.10 (1 H, m), 6.18 (1 H, dd, J = 2.0, 10.5 Hz), 6.35−6.37 (1 H, m), 6.41 (1 H, s), 7.44 (2 H, dd, J = 8.0, 8.0 Hz), 7.58 (1 H, tt, J = 1.5, 8.0 Hz), 8.12 (2 H, dd, J = 1.5, 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ 22.5, 29.9, 44.7, 51.9 (t, J = 5.5 Hz), 52.1, 56.1, 60.9, 107.6, 111.5 (dd, J = 225.5, 226.0 Hz), 120.0 (t, J = 27.5 Hz), 126.1 (t, J = 6.0 Hz), 128.8, 129.5, 130.5, 130.6, 132.1, 133.9, 134.0, 138.7 (t, J = 24.0 Hz), 141.1, 142.7 (t, J = 10.0 Hz), 153.4, 154.1, 164.1, 172.3. 19F NMR (376 MHz, CDCl3): δ −91.2 (1 F, dd, J = 6.0, 303.5 Hz), −89.0 (1 F, dd, J = 6.0, 303.5 Hz). IR (neat): 1732, 1714, 1651 cm−1. HRMS (MALDI): m/z calcd for C27H26F2O7Na [M + Na]+, 523.1538; found, 523.1528. Methyl 4,4-Difluoro-6′,7′,8′-trimethoxy-3-tosyloxy-3′,4′-dihydro2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-diene-2′-carboxylate (14i). Following the conversion of 13 into 14h, TsCl (29 mg, 0.15 mmol) was added to a mixture of 13 (30 mg, 0.076 mmol) and NaH (60% containing in mineral oil, 15 mg, 0.38 mmol) in DMF (0.8 mL) at 0 °C and stirred for 3.5 h at the same temperature. The crude product was purified by flash column chromatography (hexane/ EtOAc = 3:1) to provide 14i (34 mg, 82% yield) as a white solid. Mp: 156−158 °C. Rf: 0.3 (hexane/EtOAc = 3:1).1H NMR (400 MHz, CDCl3): δ 1.96−2.11 (2 H, m), 2.77 (1 H, dd, J = 3.5, 11.5 Hz), 2.80−2.91 (2 H, m), 3.60 (3 H, s), 3.63 (3 H, s), 3.78 (3 H, s), 3.84 (3 H, s), 5.88−5.96 (1 H, m), 6.07 (1 H, dd, J = 2.5, 10.0 Hz), 6.39 (1 H, m), 6.41 (1 H, s), 7.32 (2 H, d, J = 8.5 Hz), 7.87 (2 H, d, J = 8.5 Hz). 13C NMR (100 MHz, CDCl3): δ 22.0, 22.4, 29.7, 44.8, 51.7 (t, J = 5.5 Hz), 52.1, 56.1, 60.5, 60.9, 107.6, 110.7 (dd, J = 225.0, 228.0 Hz), 120.0 (t, J = 27.5 Hz), 127.4 (t, J = 5.5 Hz), 129.0, 129.8, 132.2, 133.4, 138.4 (t, J = 25.0 Hz), 140.9, 142.3 (t, J = 9.5 Hz), 145.4, 153.5, 153.7, 172.0. 19F NMR (376 MHz, CDCl3): δ −91.3 (1 F, dd, J = 6.0, 303.5 Hz), −88.1 (1 F, dd, J = 6.0, 303.5 Hz). IR (neat): 1730, 1651 cm−1. HRMS (MALDI): m/z calcd for C27H28F2O8SNa [M + Na]+, 573.1365; found, 573.1365. Methyl 4,4-Difluoro-6′,7′,8′-trimethoxy-3-((trifluoromethylsulfonyl)oxy)-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalene]2,5-diene-2′-carboxylate (14j). Following the conversion of 13 into 14h, PhN(Tf)2 (54 mg, 0.15 mmol) was added to a mixture of 13 (30 mg, 0.075 mmol) and NaH (60% containing in mineral oil, 15 mg, 0.38 mmol) in DMF (0.8 mL) at 0 °C, and the reaction mixture was stirred for 5 h at RT. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to provide 14j (31 mg, 78% yield) as a pale yellow oil. Rf: 0.3 (hexane/EtOAc = 3:1).1H NMR (400 MHz, CDCl3): δ 1.94−2.14 (2 H, m), 2.81 (1 H, dd, J = 3.0, 12.0 Hz), 2.85−2.89 (2 H, m), 3.63 (3 H, s), 3.71 (3 H, s), 3.74 (3 H, s), 3.84 (3 H, s), 6.04−6.09 (1 H, m), 6.15 (1 H, dd, J = 2.5, 10.0 Hz), 6.38−6.40 (1 H, m), 6.42 (1 H, s). 13C NMR (100 MHz, CDCl3): δ 22.5, 29.6, 45.1, 51.6 (t, J = 5.0 Hz), 52.2, 56.1, 60.5, 60.8, 107.6, 110.1 (dd, J = 226.0, 228.0 Hz), 118.8 (m), 119.6 (t, J = 27.0 Hz), 129.3 (t, J = 4.0 Hz), 132.2, 138.7 (t, J = 26.0 Hz), 140.8, 142.4 (t, J = 9.5 Hz), 153.7, 153.8, 171.8. 19F NMR (376 MHz, CDCl3): δ −92.03 (1 F, br d, J = 303.5 Hz), −88.91 (1 F, br d, J = 303.5 Hz), −73.33 (3 F, m). IR (neat): 1738, 1647 cm−1. HRMS (MALDI): m/z calcd for C21H21F5O8SNa [M + Na]+, 551.0769; found, 551.0764. Methyl 4,4-Difluoro-6′,7′,8′-trimethoxy-3-((perfluorobutylsulfonyl)oxy)-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-diene-2′-carboxylate (14k). Following the conversion of 13 into 14h, NfF (28 μL, 0.16 mmol) was added to a mixture of 13 (40 mg, 0.11 mmol) and NaH (60% containing in mineral oil, 13 mg, 0.32 mmol) in DMF (0.6 mL) at 0 °C, and the reaction mixture was stirred for 30 min at the same temperature. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to provide 14k (56 mg, 75% yield) as a pale yellow oil. Rf: 0.3 (hexane/ EtOAc = 3:1). In order to obtain some additional evidence for the assignment of the 13C NMR data, we measured HMQC spectra of 14k in C6D6 because of better isolation of the H signals at the C2, C5, C6, and C5′ positions in C6D6 than in CDCl3. 1 H NMR (400 MHz, CDCl3): δ 1.94−2.15 (2 H, m), 2.78−2.92 (3 H, m), 3.63 (3 H, s), 3.71 (3 H, s), 3.74 (3 H, s), 3.84 (3 H, s), 6.07 (1 H, dd, J = 4.5, 10.0 Hz), 6.15 (1 H, dd, J = 2.0, 10.0 Hz), 6.39−6.44 (2 H, m). 1H NMR (500 MHz, C6D6): δ 1.72−1.85 (2 H, m), 13147

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry

8.21−8.25 (2 H, m). 13C NMR (125 MHz, CDCl3): δ 30.9, 31.0, 35.0, 36.4, 45.9, 48.2, 52.2, 52.4, 56.3, 56.4, 60.8, 61.2, 61.4, 61.5, 108.0, 108.2, 118.9 (d, J = 20.5 Hz), 119.5 (d, J = 19.0 Hz), 120.7, 123.9, 124.1, 125.1, 129.0 (d, J = 5.0 Hz), 129.1, 129.2, 130.7, 131.3, 133.0 (d, J = 3.5 Hz), 134.2 (d, J = 5.0 Hz), 134.5 (d, J = 3.5 Hz), 135.2, 135.3, 135.6, 135.8, 137.0 (d, J = 13.0 Hz), 137.3 (d, J = 13.0 Hz), 141.2, 141.4, 150.8, 151.3, 153.0 (d, J = 248.0 Hz), 153.1 (d, J = 248.0 Hz), 153.6, 153.7, 164.4, 164.6, 173.5, 174.2. 19F NMR (376 MHz, CDCl3): δ −130.85 (1 F × 10/27, dd, J = 8.5, 14.5 Hz), −130.57 (1 F × 17/27, dd, J = 8.5, 14.5 Hz). IR (CHCl3): 1734, 1701 cm−1. HRMS (MALDI): m/z calcd for C27H25O7FNa [M + Na]+, 503.1476; found, 503.1477. Acid-Mediated Rearrangement of 14i (Table 4, Entry 2). Following the conversion of 13 into 11a, TfOH (25 μL, 0.28 mmol) was added to a solution of 14i (31 mg, 0.056 mmol) in CHCl3 (0.6 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. The crude product was purified by flash column chromatography (hexane/ EtOAc = 6:1) to provide 11i (21 mg, 70% yield) and 12i (5.4 mg, 18% yield). Methyl 2-Fluoro-9,10,11-trimethoxy-3-tosyloxy-6,7-dihydro-5Hdibenzo[a,c][7]annulene-5-carboxylate (11i). A white solid. Rf: 0.1 (hexane/EtOAc = 6:1). NMR data were observed as a 3:2 mixture of two diastereomers due to the axial chirality. 1H NMR (400 MHz, CDCl3): δ 2.12−2.36 (19/5 H, m), 2.45 (3 H × 2/5, s), 2.46 (3 H × 3/5, s), 2.48−2.50 (1 H × 2/5, m), 2.91−3.00 (1 H × 2/5, m), 3.26 (3 H × 2/5, s), 3.37−3.45 (2 H × 2/5, m), 3.50−3.55 (1 H × 2/5, m), 3.64 (3 H × 3/5, s), 3.65 (3 H × 2/5, s), 3.69 (3 H × 3/5, s), 3.83 (3 H × 2/5, s), 3.883 (3 H × 2/5, s), 3.888 (3 H × 3/5, s), 3.89 (3 H × 3/5, s), 6.53 (1 H × 2/5, s), 6.56 (1 H × 3/5, s), 7.05 (1 H × 3/5, d, J = 8.0 Hz), 7.14 (1 H × 2/5, d, J = 8.0 Hz), 7.18 (1 H × 2/5, d, J = 11.0 Hz), 7.20 (1 H × 3/5, d, J = 11.0 Hz), 7.325 (2 H × 2/5, d, J = 8.5 Hz), 7.329 (2 H × 3/5, d, J = 8.5 Hz), 7.77 (2 H × 3/5, d, J = 8.5 Hz), 7.80 (2 H × 2/5, d, J = 8.5 Hz). 13C NMR (100 MHz, CDCl3): δ 22.1, 30.8, 30.9, 34.9, 36.0, 45.8, 48.0, 52.2, 52.3, 56.3, 56.4, 60.7, 61.2, 61.40, 61.44, 108.0, 108.1, 119.0 (d, J = 19.0 Hz), 119.7 (d, J = 19.0 Hz), 121.9, 123.3, 123.6, 126.1, 129.0 (d, J = 5.0 Hz), 130.0 (d, J = 3.0 Hz), 132.6, 132.7, 133.3 (d, J = 3.0 Hz), 134.6 (d, J = 4.0 Hz), 135.2 (d, J = 13.5 Hz), 135.5 (d, J = 12.5 Hz), 136.5 (d, J = 7.5 Hz), 136.7 (d, J = 7.5 Hz), 141.1, 141.3, 146.0, 150.7, 151.1, 153.2 (d, J = 251.0 Hz), 153.3 (d, J = 251.0 Hz), 153.80, 153.84, 153.9, 173.2, 173.7. 19F NMR (376 MHz, CDCl3): −130.87 (1F × 2/5, dd, J = 6.0, 11.5 Hz), −130.64 (1F × 3/5, dd, J = 8.5, 11.5 Hz). IR (CHCl3): 1732 cm−1. HRMS (MALDI): m/z calcd for C27H27O8FNaS [M + Na]+, 553.1302; found, 553.1302. Methyl 2-Fluoro-9,10,11-trimethoxy-1-tosyloxy-6,7-dihydro-5Hdibenzo[a,c][7]annulene-5-Carboxylate (12i). A white solid. Mp: 153−156 °C. Rf: 0.1 (hexane/EtOAc = 6:1). 1H NMR (400 MHz, CDCl3): δ 2.04−2.36 (total 4 H, m), 2.39 (3 H, s), 3.32 (1 H, dd, J = 5.5, 12.0 Hz), 3.68 (3 H, s), 3.70 (3 H, s), 3.75 (3 H, s), 3.90 (3 H, s), 6.42 (1 H, s), 7.04−7.14 (total 4 H, m), 7.41 (2 H, d, J = 8.0 Hz). 13C NMR (150 MHz, CDCl3): δ22.0, 30.5, 35.5, 46.0, 52.3, 56.3, 61.0, 61.2, 106.9, 119.4, 124.5 (d, J = 8.0 Hz), 129.0, 129.7, 130.0 (d, J = 5.5 Hz), 133.0, 133.90 (d, J = 3.0 Hz), 133.94, 135.1 (d, J = 13.0 Hz), 135.8, 140.6, 145.0, 151.2, 154.4, 154.9 (d, J = 253.5 Hz), 174.0. 19F NMR (376 MHz, CDCl3): −126.30 (1 F, dd, J = 6.0, 8.5 Hz). IR (CHCl3): 1732 cm−1. HRMS (MALDI): m/z calcd for C27H27O8FNaS [M + Na]+, 553.1302; found, 553.1303. Acid-Mediated Rearrangement of 14j (Table 4, entry 3). Following the conversion of 13 into 11a, TfOH (18 μL, 0.21 mmol) was added to a solution of 14j (22 mg, 0.041 mmol) in CHCl3 (0.5 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. After extraction with EtOAc, the combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 11j (21 mg, 99% yield) as a pale yellow oil, which was >95% pure based on NMR analysis. NMR data were observed as a 3:2 mixture of two diastereomers due to the axial chirality. The 1H and 13C NMR data (CDCl3) of this product are in good agreement with those of the reported compound.7a Acid-Mediated Rearrangement of 14k (Table 4, entry 4). Following the conversion of 13 into 11a, TfOH (15 μL, 0.17 mmol) was

2.36−2.44 (1 H, m), 2.48 (1 H, dt, J = 4.5, 11.5 Hz), 2.57 (1 H, dd, J = 3.0, 11.0 Hz), 3.40 (3 H, s), 3.53 (3 H, s), 3.68 (3 H, s), 3.74 (3 H, s), 5.67 (1 H, dd, J = 2.5, 10.5 Hz), 5.83−5.87 (1 H, m), 6.13 (1 H, s), 6.66 (1 H, br s). 13C NMR (100 MHz, CDCl3): δ 22.6, 29.6, 45.1, 51.6 (t, J = 5.0 Hz), 52.2, 56.1, 60.6, 60.8, 107.7, 110.1 (dd, J = 227.0, 228.0 Hz), 112.0−118.5 (4C, m), 118.9, 119.8 (t, J = 28.0 Hz), 129.4 (t, J = 5.0 Hz), 132.2, 138.8 (t, J = 26.0 Hz), 140.9, 142.4 (t, J = 9.5 Hz), 153.8, 153.9, 171.8. 13C NMR (150 MHz, C6D6): δ 22.7, 29.3, 45.2 (t, J = 3.5 Hz), 51.63, 51.69, 55.5, 60.3, 60.5, 108.1, 110.7 (dd, J = 227.0, 228.0 Hz), 119.1, 119.8 (t, J = 27.0 Hz), 130.5 (t, J = 5.0 Hz), 132.0, 139.2 (t, J = 26.0 Hz), 141.6, 142.5 (t, J = 9.5 Hz), 154.1, 154.3, 171.3. 19F NMR (470 MHz, CDCl3): δ −125.7 (2 F, m) −120.8 (2 F, m), −109.1 (2 F, m), −91.89 (1 F, dd, J = 5.5, 305.0 Hz), −88.90 (1 F, dd, J = 5.5, 305.0 Hz), −80.5 (3 F, m). IR (neat): 1736 cm−1. HRMS (MALDI): m/z calcd for C24H21O8F11NaS [M + Na]+, 701.0673; found, 701.0677. 1H NMR, 13C NMR data for selected protons and carbons based on HMQC spectra are given below.

Acid-Mediated Rearrangement of 13 (Table 3, Entry 4). Under an argon atmosphere, TfOH (12 μL, 0.14 mmol) was added to a solution of 13 (11 mg, 0.028 mmol) in CHCl3 (0.5 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. Then the mixture was quenched with a saturated aqueous solution of NaHCO3 (3 mL), and the aqueous layer was extracted three times with EtOAc (5 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. 1H and 19F NMR analysis of the residue showed the formation of 11a (45% NMR yield) and 12a (55% NMR yield). The 1H and 13C NMR data (CDCl3) of these products are in good agreement with those of the reported compound.7a Acid-Mediated Rearrangement of 14h (Table 4, entry 1). Following the conversion of 13 into 11a, TfOH (19 μL, 0.21 mmol) was added to a solution of 14h (21 mg, 0.041 mmol) in CHCl3 (0.5 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. 1 H and 19F NMR analysis of the residue showed the formation of 11a (10% yield), 11h (80% yield), and 12a (10% yield). The crude product was purified by flash column chromatography (hexane/EtOAc = 5:1) to afford 11h (14.5 mg, 72% yield). Methyl 3-Benzoyloxy-2-fluoro-9,10,11-trimethoxy-6,7-dihydro5H-dibenzo[a,c][7]annulene-5-carboxylate (11h). A white solid. Rf: 0.1 (hexane/EtOAc = 5:1). NMR data were observed as a 17:10 mixture of two diastereomers due to the axial chirality. 1H NMR (400 MHz, CDCl3): δ 2.22−2.54 (total 105/27 H, m), 2.93−3.02 (1 H × 10/27, m), 3.27 (3 H × 10/27, s), 3.48−3.50 (1 H × 10/27, m), 3.52 (1 H × 10/27, d, J = 5.5 Hz), 3.58 (1 H × 10/27, d, J = 7.5 Hz), 3.70 (3 H × 17/27, s), 3.72 (3 H × 17/27, s), 3.73 (3 H × 10/27, s), 3.86 (3 H × 10/27, s), 3.89 (3 H × 10/27, s), 3.91 (3 H × 17/27, s), 3.92 (3 H × 17/27, s), 6.56 (1 H × 10/27, s), 6.59 (1 H × 17/27, s), 7.17 (1 H × 10/27, d, J = 8.0 Hz), 7.19 (1 H × 17/27, d, J = 8.0 Hz), 7.37 (1 H, d, J = 11.0 Hz), 7.50−7.57 (2 H, m), 7.64−7.70 (1 H, m), 13148

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry added to a solution of 14k (23 mg, 34 μmol) in CHCl3 (0.5 mL) at 0 °C and the mixture was stirred at the same temperature for 1.5 h. After extraction with EtOAc, the combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 11k (22 mg, 99% yield). Methyl 2-Fluoro-9,10,11-trimethoxy-3-((perfluorobutylsulfonyl)oxy)-6,7-dihydro-5H-dibenzo-[a,c][7]annulene-5-carboxylate (11k). A pale yellow oil, which was >95% pure based on NMR analysis. NMR data were observed as a 17:10 mixture of two diastereomers due to the axial chirality. 1H NMR (500 MHz, CDCl3): δ 2.17−2.42, 2.47−2.56 (total 105/27 H, m), 2.93−3.03 (1 H × 10/27, m), 3.27 (3 H × 10/ 27, s), 3.46−3.50 (2 H × 10/27, m), 3.57−3.59 (1 H × 10/27, m), 3.71 (3 H × 17/27, s), 3.72 (3 H × 17/27, s), 3.73 (3 H × 10/27, s), 3.85 (3 H × 10/27, s), 3.89 (3 H × 10/27, s), 3.907 (3 H × 17/27, s), 3.909 (3 H × 17/27, s), 6.54 (1 H × 10/27, s), 6.58 (1 H × 17/27, s), 7.20 (1 H × 10/27, d, J = 8.0 Hz), 7.29 (1 H × 17/27, d, J = 8.0 Hz), 7.39 (1 H × 10/27, d, J = 11.5 Hz), 7.40 (1 H × 17/27, d, J = 11.0 Hz). 13C NMR (125 MHz, CDCl3): δ 30.7, 30.9, 34.9, 36.3, 45.8, 48.1, 52.35, 52.4, 56.3, 56.4, 60.9, 61.2, 61.4, 61.5, 108.10, 108.14, 119.6 (d, J = 18.0 Hz), 120.3 (d, J = 19.0 Hz), 120.6, 122.8, 124.5, 133.9 (d, J = 3.5 Hz), 135.3 (d, J = 5.0 Hz), 135.7 (d, J = 13.0 Hz), 138.2 (d, J = 8.5 Hz), 138.5 (d, J = 7.0 Hz), 141.2, 141.4, 150.8, 151.2, 152.2 (d, J = 252.0 Hz), 152.4 (d, J = 252.0 Hz), 154.1, 154.2, 172.9, 173.7. 19F NMR (376 MHz, CDCl): δ −129.9 (1 F, m), −125.7 (2 F, m), −120.7 (2 F, m), −109.1 (2 F, m), −80.5 (3 F, m). IR (neat): 1740 cm−1. HRMS (MALDI): m/z calcd for C24H20O8F10NaS [M + Na]+, 681.0611; found, 681.0611. Methyl 6′,7′,8′-Trimethoxy-4-oxo-3-[(perfluorobutylsulfonyl)oxy]-3′,4′-dihydro-2′H-spiro-[cyclohexane-1,1′-naphthalene]-2,5diene-2′-carboxylate (15) (Scheme 4). Following the conversion of 13 into 14h, NfF (29 μL, 0.17 mmol) was added to a mixture of 5a (0.15 g, 0.40 mmol) and NaH (60% containing in mineral oil, 48 mg, 1.2 mmol) in DMF (2.0 mL) at 0 °C, and the reaction mixture was stirred for 30 min at RT. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to afford 15 (0.26 g, 98% yield, d.r. = 16:1) as a white solid. Rf: 0.3 (hexane/EtOAc = 2:1). 1 H NMR (500 MHz, CDCl3): δ 2.02−2.22 (1 H, m), 2.16−2.21 (1 H, m), 2.86−2.98 (3 H, m), 3.58 (1 H × 1/17, s), 3.60 (3 H × 16/17, s), 3.64 (3 H × 1/17, s), 3.66 (3 H × 16/17, s), 3.73 (3 H, s), 3.85 (3 H, s), 6.40 (1 H × 1/17, d, J = 10.0 Hz), 6.46 (1 H, s), 6. 49 (1 H × 16/ 17, d, J = 10.0 Hz), 6.78 (1 H × 1/17, d, J = 3.0 Hz), 6.89 (1 H × 16/ 17, dd, J = 3.0, 10.0 Hz), 6.92 (1 H × 16/17, d, J = 3.0 Hz), 7.04 (1 H × 1/17, dd, J = 3.0, 10.0 Hz). 13C NMR (125 MHz, CDCl3): δ 22.8, 29.6, 47.0, 51.7, 52.5, 56.2, 60.8, 61.0, 107.5−116.2 (4 C, m), 108.2, 117.0, 127.3, 132.3, 138.3, 140.9, 144.9, 153.6, 154.1, 155.3, 171.5, 177.9. 19F NMR (470 MHz, CDCl3): δ −125.7 (2 F, m), −120.8 (2 F, m), −109.6 (2 F, m), −80.5 (3 F, m). IR (neat): 1736, 1678 cm−1. HRMS (MALDI): m/z calcd for C24H21O9F9NaS [M + Na]+, 679.0654; found, 679.0653. Acid-Mediated Rearrangement of 15 (Scheme 4). Following the conversion of 13 into 11a, TfOH (20 μL, 0.23 mmol) was added to a solution of 15 (30 mg, 0.046 mmol) in CHCl3 (0.5 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 1.5 h. After extraction with EtOAc, the combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 16 (30 mg, > 99% yield), which was >95% pure based on NMR analysis. Methyl 2-Hydroxy-9,10,11-trimethoxy-3-((perfluorobutylsulfonyl)oxy)-6,7-dihydro-5H-dibenzo[a,c][7]annulene-5-carboxylate (16). A white solid. NMR data were observed as a 17:10 mixture of two diastereomers due to the axial chirality. 1H NMR (500 MHz, CDCl3): δ 2.22−2.57 (total 105/27 H, m), 2.93−3.03 (1 H × 10/27, m), 3.31 (3 H × 10/27, s), 3.47−3.52 (1 H × 10/27, m), 3.59 (1 H × 10/27, d, J = 7.5 Hz), 3.65 (3 H × 17/27, s), 3.68 (3 H × 10/27, s), 3.76 (3 H × 17/27, s), 3.90 (3 H × 10/27, s), 3.91 (3 H × 10/27, s), 3.93 (3 H × 17/27, s), 3.96 (3 H × 17/27, s), 6.45 (1 H, br s), 6.59 (1 H × 10/27, s), 6.62 (1 H × 17/27, s), 7.14 (1 H × 10/27, s), 7.19 (1 H × 17/27, s), 7.27 (1 H × 10/27, s), 7.31 (1 H × 17/27, s). 13C NMR (125 MHz, CDCl3): δ 30.8, 31.0, 34.7, 36.1, 45.7, 48.0, 52.2, 52.3, 56.3, 56.4, 60.7, 61.4, 61.5, 61.6, 108.4, 108.5, 119.5, 119.9, 120.6,

123.6, 123.7, 123.9, 129.8, 131.1, 135.8, 135.9, 136.3, 136.9, 137.2, 137.4, 141.0, 141.1, 146.8, 146.9, 150.4, 150.9, 153.60, 153.63, 166.2, 173.7, 174.1. 19F NMR (376 MHz, CDCl3): δ −125.7 (2 F, m), −120.7 (2 F, m), −109.5 (2 F, m), −80.5, (3 F, m). IR (CHCl3): 3499, 1732 cm−1. HRMS (MALDI): m/z calcd for C24H21O9F9NaS [M + Na]+, 679.0654; found, 679.0660. 4,4-Difluoro-6′,7′,8′-trimethoxy-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalen]-2-en-5-one (18a) (Scheme 5). Following the conversion of 5a into 13, DAST (0.25 mL, 1.9 mmol) was added to a solution of 17a7b (0.10 g, 0.32 mmol) in DME (3.2 mL) at −50 °C, and the reaction mixture was allowed to stir at RT for 15.5 h. The crude product was purified by flash column chromatography (hexane/ EtOAc = 3:1) to afford 18a (81 mg, 75% yield) as a white solid. Mp: 119−121 °C. Rf: 0.3 (hexane/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ 1.57−1.73 (3 H, m), 1.81−1.88 (1 H, m), 2.64−2.75 (2 H, m), 2.80 (1 H, ddd, J = 1.5, 3.6, 13.5 Hz), 3.52 (1 H, dt, J = 1.5, 14.0 Hz), 3.79 (3 H, s), 3.83 (3 H, s), 3.89 (3 H, s), 5.92 (1 H, ddd, J = 4.0, 6.5, 10.5 Hz), 6.24 (1 H, dt, J = 1.5, 10.0 Hz), 6.38 (1 H, s). 13 C NMR (125 MHz, CDCl3): δ 19.5, 30.6, 37.2 (d, J = 2.5 Hz), 44.0, 48.2, 56.1, 60.8, 60.9, 107.4, 109.2 (dd, J = 240.0, 242.5 Hz), 118.3 (dd, J = 26.5, 29.0 Hz), 124.8, 132.9, 140.6, 150.8 (1 H, t, J = 11.0 Hz), 152.9, 153.2, 196.8 (t, J = 24.0 Hz). 19F NMR (376 MHz, CDCl3): δ −111.85 (1 F, ddd, J = 3.0, 6.0, 295.0 Hz), −91.30 (1 F, br d, J = 295.0 Hz). IR (neat): 1748, 1651 cm−1. HRMS (MALDI): m/z calcd for C18H20O4F2 [M + Na]+, 338.1324; found, 338.1325. Dimethyl 4,4-Difluoro-6′,7′,8′-trimethoxy-5-oxo-2′H-spiro[cyclohexane-1,1′-naphthalen]-2-ene-3′,3′(4′H)-dicarboxylate (18b) (Scheme 5). Following the conversion of 5a into 13, DAST (0.11 mL, 0.83 mmol) was added to 17b7b (60 mg, 0.14 mmol) in DME (1.4 mL) at −50 °C, and the reaction mixture was stirred for 13.5 h at 0 °C. The crude product was purified by column chromatography (hexane/ EtOAc = 3:1) to give 18b (36 mg, 57% yield) as a white solid. Mp: 180−182 °C. Rf: 0.2 (hexane/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ 2.26 (1 H, dd, J = 1.5, 14.5 Hz), 2.32 (1 H, d, J = 14.5 Hz), 2.43 (1 H, ddd, J = 1.5, 3.5, 14.5 Hz), 2.91 (1 H, d, J = 17.0 Hz), 3.37 (1 H, d, J = 15.5 Hz), 3.53 (1 H, d, J = 13.0 Hz), 3.74 (3 H, s), 3.77 (3 H, s), 3.81 (3 H, s), 3.84 (3 H, s), 3.86 (3 H, s), 5.96 (1 H, dt, J = 5.5, 10.5), 6.19 (1 H, td, J = 1.5, 10.5 Hz), 6.44 (1 H, s). 13C NMR (125 MHz, CDCl3): δ 35.3, 40.4, 43.2, 48.2, 51.7, 53.3, 53.4, 56.1, 60.9, 107.0, 108.4 (dd, J = 238.0, 242.5 Hz), 119.2 (t, J = 28.0 Hz), 122.3, 129.2, 141.0, 149.7 (t, J = 10.5 Hz), 152.6, 153.8, 171.3, 171.6, 195.7 (t, J = 24.0 Hz). 19F NMR (376 MHz, CDCl3): δ −109.93 (1 F, dd, J = 8.5, 300.5 Hz), −93.24 (1 F, dd, J = 8.5, 300.5 Hz). IR (neat): 1738, 1732, 1651 cm−1. HRMS (MALDI): m/z calcd for C22H24NaO8F2 [M + Na]+, 477.1331; found, 477.1328. 4,4-Difluoro-6′,7′,8′-trimethoxy-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-dien-3-yl perfluorobutyl-1-sulfonate (19a) (Scheme 5). Following the conversion of 13 into 14h, NfF (24 μL, 0.13 mmol) was added to a mixture of 18a (30 mg, 0.089 mmol) and NaH (60% containing in mineral oil, 11 mg, 0.28 mmol) in DMF (0.5 mL) at 0 °C, and the reaction mixture was stirred for 30 min at RT. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to provide 19a (46 mg, 84% yield) as a colorless oil. Rf: 0.25 (hexane/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ 1.78−1.87 (4 H, m), 2.79 (2 H, m), 3.72 (3 H, s), 3.76 (3 H, s), 3.84 (3 H, s), 5.96 (1 H, dt, J = 5.0, 10.0 Hz), 6.28 (1 H, dd, J = 2.0, 10.0 Hz), 6.37−6.39 (1 H, m), 6.43 (1 H, s). 13C NMR (125 MHz, CDCl3): δ 19.9, 30.6, 38.0 (t, J = 6.0 Hz), 43.0, 56.2, 60.7, 60.9, 107.6−117.0 (4 C, m), 107.9, 110.29 (dd, J = 226.0, 228.0 Hz), 118.1 (t, J = 27.5 Hz), 120.4, 133.2, 134.7 (t, J = 5.0 Hz), 138.0 (t, J = 26.5 Hz), 140.7, 144.0 (t, J = 9.5 Hz), 153.6, 153.7. 19F NMR (376 MHz, CDCl3): δ −125.73 (2 F, br s), −120.74 (2 F, br s), −109.15 (2 F, br s), −89.67 (1 F, br d, J = 308.0 Hz), −88.66 (1 F, br d, J = 308.0 Hz), −80.52 (3 F, br s). IR (neat): 1651 cm−1. HRMS (MALDI): m/z calcd for C22H19O6F11NaS [M + Na]+, 643.0618; found, 643.0613. Dimethyl 4,4-Difluoro-6′,7′,8′-trimethoxy-3-((perfluorobutylsulfonyl)oxy)-2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-diene3′,3′(4′H)-dicarboxylate (19b) (Scheme 5). Following the conversion of 13 into 14h, NfF (10 μL, 0.053 mmol) was added to a mixture of 18b (16 mg, 0.035 mmol) and NaH (60% containing in mineral oil, 13149

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry

(2 F, m), −80.4 (3 F, m). IR (CHCl3): 1734 cm−1. HRMS (MALDI): m/z calcd for C26H22O10F10NaS [M + Na]+, 739.0666; found, 739.0664. Dimethyl 10-Fluoro-1,2,3-trimethoxy-11-((perfluorobutylsulfonyl)oxy)-5,7-dihydro-6H-dibenzo-[a,c][7]annulene-6,6-dicarboxylate) (21b). A white solid. Mp: 95−98 °C. Rf: 0.2 (hexane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3): δ 2.64 (1 H, d, J = 13.5 Hz), 2.66 (1 H, d, J = 13.5 Hz), 3.26 (1 H, d, J = 13.5 Hz), 3.32 (1 H, d, J = 13.5 Hz), 3.71 (3 H, s), 3.73 (3 H, s), 3.75 (3 H, s), 3.87 (3 H, s), 3.90 (3 H, s), 6.71 (1 H, s), 7.15 (1 H, dd, J = 8.0, 9.5 Hz), 7.34 (1 H, dd, J = 5.0, 8.0 Hz). 13C NMR (150 MHz, CDCl3): δ 36.6, 53.30, 53.33, 56.4, 61.30, 61.35, 61.4, 64.0, 109.5, 116.0 (d, J = 19.0 Hz), 119.1 (d, J = 2.5 Hz), 125.0, 130.7 (d, J = 7.0 Hz), 132.5, 133.0, 133.5 (d, J = 4.5 Hz), 141.5, 151.1, 153.3 (d, J = 252.0 Hz), 154.6, 170.8, 170.9. 19F NMR (376 MHz, CDCl3): −127.8 (1 F, m), −125.8 (2 F, m), −120.7 (2 F, m), −109.9 (2 F, m), −80.5 (3 F, m). IR (neat): 1738 cm−1. HRMS (MALDI): m/z calcd for C26H22O10F10NaS [M + Na]+, 739.0666; found, 739.0668.

7 mg, 0.18 mmol) in DMF (0.5 mL) at 0 °C, and the reaction mixture was stirred for 30 min at the same temperature. The crude product was purified by flash column chromatography (hexane/EtOAc = 3:1) to provide 19b (19.7 mg, 76% yield) as a colorless oil. Rf: 0.2 (hexane/ EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ 2.39−2.47 (2 H, m), 3.15 (1 H, d, J = 16.5 Hz), 3.26 (1 H, d, J = 16.5 Hz), 3.70 (3 H, s), 3.75 (6 H, s), 3.76 (3 H, s), 3.85 (3 H, s), 5.97 (1 H, dt, J = 4.5, 10.0 Hz), 6.03 (1 H, dd, J = 2.0 Hz, 10.0 Hz), 6.17−6.19 (1 H, m), 6.47 (1 H, s). 13C NMR (125 MHz, CDCl3): δ 35.5, 40.5 (t, J = 6.0 Hz), 42.3, 51.9, 53.4, 53.5, 56.2, 60.7, 60.9, 107.7, 109.8 (dd, J = 228.0, 228.0 Hz), 118.0, 118.6 (t, J = 27.5 Hz), 129.6, 133.6 (t, J = 5.0 Hz), 138.3, 141.1, 143.2 (t, J = 9.5 Hz), 153.4, 154.2, 171.3, 171.5. 19 F NMR (376 MHz, CDCl3): δ −125.7 (2 F, m), −120.8, (2 F, m), −109.1 (2 F, m), −91.08 (1 F, br d, J = 303.5 Hz), −89.90 (1 F, dd, J = 6.0, 303.5 Hz), −80.5 (3 F, m). IR (neat): 1738, 1659 cm−1. HRMS (MALDI): m/z calcd for C26H23NaO10F11S [M + Na]+, 759.0728; found, 759.0725. Acid-Mediated Migration of 19a (Scheme 5). Following the conversion of 13 into 11a, TfOH (39 μL, 0.44 mmol) was added to a solution of 19a (45 mg, 0.073 mmol) in CHCl3 (0.7 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. 1H and 19F NMR analysis of the residue showed the formation of 20a (87% NMR yield) and 21a (10% NMR yield). The crude product was purified by flash column chromatography (hexane/EtOAc = 6:1) to provide a mixture of 20a (34 mg, 78% yield) and 21a (3.5 mg, 8% yield). 2-Fluoro-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulen-3-yl perfluorobutyl-1-sulfonate (20a). A colorless oil. Rf: 0.1 (hexane/EtOAc = 6:1). 1H NMR (400 MHz, CDCl3): δ 2.05−2.16 (2 H, m), 2.21−2.19 (1 H, m), 2.32−2.41 (1 H, m), 2.45−2.57 (2 H, m), 3.64 (3 H, s), 3.90 (3 H, s), 3.91 (3 H, s), 6.58 (1 H, s), 7.18 (1 H, d, J = 7.5 Hz), 7.39 (1 H, d, J = 11.5 Hz). 13C NMR (125 MHz, CDCl3): δ 31.1, 31.6, 33.2, 56.4, 61.3, 61.4, 108.2, 119.5 (d, J = 18.0 Hz), 122.7, 123.8, 135.4 (d, J = 14.5 Hz), 136.0, 137.4 (d, J = 3.5 Hz), 138.5 (d, J = 7.0 Hz), 141.2, 151.1,151.8 (d, J = 249.5 Hz), 153.7. 19 F NMR (376 MHz, CDCl3): −131.7 (1 F, br s), −125.7 (2 F, m), −120.7 (2 F, m), −109.2 (2 F, m), −80.5 (3 F, m) IR (neat): 1651 cm−1. HRMS (MALDI): m/z calcd for C22H18O6F10S [M]+, 600.0658; found, 600.0662. 2-Fluoro-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulen-1-yl perfluorobutyl-1-sulfonate (21a). A colorless oil. Rf: 0.1 (hexane/EtOAc = 6:1). 1H NMR (400 MHz, CDCl3): δ 1.97−2.08 (2 H, m), 2.26−2.36 (2 H, m), 2.45−2.58 (2 H, m), 3.59 (3 H, s), 3.67 (3 H, s), 3.84 (3 H, s), 6.59 (1 H, s), 7.12 (1 H, dd, J = 8.0, 9.5 Hz), 7.18 (1 H, dd, J = 5.0, 8.0 Hz). 13C NMR (150 MHz, CDCl3): δ 31.0, 31.1, 32.6, 56.3, 61.2, 61.3, 107.6, 115.9 (d, J = 18.5 Hz), 119.1, 128.4 (d, J = 7.5 Hz), 131.3, 133.0, 136.9, 137.8 (d, J = 3.0 Hz), 140.7, 147.4, 151.2, 152.7 (d, J = 250.0 Hz), 154.6. 19F NMR (376 MHz, CDCl3): −129.5 (1 F, m), −125.8 (2 F, m), −120.8 (2 F, m), −109.9 (2 F, m), −80.5 (3 F, m). IR (neat): 1653 cm−1. HRMS (MALDI): m/z calcd for C22H18O6F10NaS [M + Na]+, 623.0556; found, 623.0553. Acid-Mediated Migration of 19b (Scheme 5). Following the conversion of 13 into 11a, TfOH (10 μL, 0.11 mmol) was added to a solution of 19b (14 mg, 0.019 mmol) in CHCl3 (0.2 mL) at 0 °C, and the mixture was stirred at the same temperature for 1.5 h. 1H and 19F NMR analysis of the residue showed the formation of 20b (89% NMR yield) and 21b (11% NMR yield). The crude product was purified by flash column chromatography (hexane/EtOAc = 6:1) to provide a mixture of 20b (11.5 mg, 85% yield) and 21b (1.0 mg, 7% yield). Dimethyl 10-Fluoro-1,2,3-trimethoxy-9-((perfluorobutylsulfonyl)oxy)-5,7-dihydro-6H-dibenzo-[a,c][7]annulene-6,6-dicarboxylate (20b). A white solid. Mp: 80−82 °C. Rf: 0.2 (hexane/EtOAc = 3:2). 1 H NMR (400 MHz, CDCl3): δ 2.60 (1 H, d, J = 14.0 Hz), 2.73 (1 H, J = 14.0 Hz), 3.23 (1 H, d, J = 14.0 Hz), 3.26 (1 H, d, J = 14.0 Hz), 3.65 (3 H, s), 3.75 (3 H,s), 3.76 (3 H, s), 3.90 (3 H, s), 3.91 (3 H, s), 6.70 (1 H, s), 7.31 (1 H, d, J = 7.5 Hz), 7.42 (1 H, d, J = 11.0 Hz). 13C NMR (125 MHz, CDCl3): δ 36.4, 37.2, 53.29, 53.32, 56.4, 61.4, 64.6, 110.1, 119.4 (d, J = 19.0 Hz), 123.6, 124.9, 131.7, 133.2 (d, J = 2.5 Hz), 135.3 (d, J = 13.0 Hz), 138.2 (d, J = 7.0 Hz), 142.0, 151.1, 151.4, 152.4 (d, J = 252.0 Hz), 153.7, 170.8. 19F NMR (376 MHz, CDCl3): −129.9 (1 F, m), −125.7 (2 F, m), −120.7 (2 F, m), −109.1

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02208. 1 H NMR, 13C NMR, 19F NMR, and HMQC (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takashi Ikawa: 0000-0002-1642-3273 Shuji Akai: 0000-0001-9149-8745 Present Addresses ⊥

Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Chevron Science Center, Pittsburgh, PA 15260, United States. ¥ Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, Okayama 700−8530, Japan. Author Contributions ∥

K.T. and A.A.B.M. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by JSPS KAKENHI [Grant JP16H01151 (Middle Molecular Strategy)] and the Platform Project for Supporting Drug Discovery and Life Science Research funded by Japan Agency for Medical Research and Development (AMED). We are grateful to Prof. Masayoshi Arai, Dr. Ryosuke Ishida, and Dr. Gamal A. I. Moustafa of Graduate School of Pharmaceutical Sciences, Osaka University (Japan), for measuring 13C NMR (150 MHz) and HMQC.

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REFERENCES

(1) (a) Wada, Y.; Otani, K.; Endo, N.; Kita, Y.; Fujioka, H. Chem. Commun. 2010, 46, 797−799. (b) Glushkov, V. A.; Rotermel, E. V.; Odegova, T. F.; Shklyaev, Y. V. Russ. J. Org. Chem. 2011, 47, 1318− 1322. (c) Yoshida, M.; Nozaki, T.; Nemoto, T.; Hamada, Y. Tetrahedron 2013, 69, 9609−9615. (d) Xia, Z.; Hu, J.; Shen, Z.; Yao, Q.; Xie, W. RSC Adv. 2015, 5, 38499−38502. (e) Kuzuguchi, T.; Yabuuchi, Y.; Yoshimura, T.; Matsuo, J. Org. Biomol. Chem. 2017, 15, 5268−5271. 13150

DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151

Article

The Journal of Organic Chemistry (2) (a) Brunow, G.; Karhu, M. J. Chem. Soc., Chem. Commun. 1976, 753. (b) Oda, T.; Yamaguchi, Y.; Sato, Y. Chem. Pharm. Bull. 1986, 34, 858−863. (c) Prata, J. V.; Clemente, D. S.; Prabhakar, S.; Lobo, A. M.; Mourato, I.; Branco, P. S. J. Chem. Soc., Perkin Trans. 1 2002, 513−528. (d) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043−9048. (e) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem. Biol. 2012, 9, 21−29. (f) Hirose, T.; Kojima, Y.; Matsui, H.; Hanaki, H.; Iwatsuki, M.; Shiomi, K.; Omura, S.; Sunazuka, T. J. Antibiot. 2017, 70, 574−581. (3) (a) Awale, S.; Tezuka, Y.; Wang, S.; Kadota, S. Org. Lett. 2002, 4, 1707−1709. (b) Schwarz, O.; Jakupovic, S.; Ambrosi, H.; Haustedt, L.; Mang, C.; Muller-kuhrt, L. J. Comb. Chem. 2007, 9, 1104−1113. (c) Murakata, M.; Kimura, M. Tetrahedron Lett. 2010, 51, 4950−4952. (4) (a) Bhakuni, D. S.; Jain, S. Tetrahedron 1981, 37, 3175−3181. (b) Banerjee, A.; Castillo-Melendez, J. A.; Vera, W.; Azocar, J. A.; Laya, M. S. J. Chem. Res. 2000, 2000, 324−325. (c) Shen, L.; Huang, S.; Tang, Y.; Lei, F. Steroids 2012, 77, 1398−1402. (5) For reviews, see: (a) Concepción, G.; Castedo, L. The Chemistry of Phenols, Part 2, Rappoport, Z., Ed., Wiley & Sons, 2003; Chapter 6. (b) Lukyanov, S. M.; Koblik, A. V. The Chemistry of Phenols, Part 2, Rappoport, Z., Ed., Wiley & Sons, 2003; Chapter 11. (6) (a) Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831−1834. (b) Kusama, H.; Uchiyama, K.; Yamashita, Y.; Narasaka, K. Chem. Lett. 1995, 24, 715−716. (7) (a) Takubo, K.; Furutsu, K.; Ide, T.; Nemoto, H.; Ueda, Y.; Tsujikawa, K.; Ikawa, T.; Yoshimitsu, T.; Akai, S. Eur. J. Org. Chem. 2016, 2016, 1562−1576. See also: (b) Nemoto, H.; Takubo, K.; Shimizu, K.; Akai, S. Synlett 2012, 23, 1978−1984. (c) Nemoto, H.; Nishiyama, T.; Akai, S. Org. Lett. 2011, 13, 2714−2717. (8) A similar cyclic intermediate was proposed. See: Staretz, M. E.; Hastie, S. B. J. Med. Chem. 1993, 36, 758−764. (9) We had also investigated solvent effects on the deoxyfluorinative rearrangement of 5a to find no clear relation between the polarity of solvents and the ratio of 11a to 12a (ref 7a). (10) During the study of the deoxyfluorination of 5a, we found that the use of fresh DAST produced 13 in better yields and high reproducibility. We sometimes observed the formation of a keto form of 13 in various ratios. The enol and keto forms were isolated separately and did not cause interconversion under neutral conditions. (11) Both enol and keto forms of 13 were converted into 14h−14k in almost the same yields. (12) For selected reviews, see: (a) Vorbrüggen, H. Synthesis 2008, 2008, 1165. (b) Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351, 2747. For related studies, see: (c) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898−12899. (d) Boltukhina, E. V.; Sheshenev, A. E.; Lyapkalo, I. M. Tetrahedron 2011, 67, 5382−5388. (e) Ikawa, T.; Saito, K.; Akai, S. Synlett 2012, 23, 2241−2246. (f) Green, A. E.; Agouridas, V.; Deniau, E. Tetrahedron Lett. 2013, 54, 7078−7079. (g) Sumida, Y.; Sumida, T.; Hosoya, T. Synthesis 2017, 49, 3590−3601. (13) The use of PhN(Tf)2(25g: 252 USD; 3.6 USD per 1 mmol) was found to produce a better yield of 14j (77% isolated) from 13 in comparison to Tf2O (up to 60% NMR yield of 14j). The latter reagent caused the formation of some amounts of the migration products 11j and 12j. In addition, 14k was prepared from 13 using NfF (25g: 80 USD; 0.97 USD per 1 mmol) in 75% yield. Based on the difference of the price of PhN(Tf)2 and NfF, the Nf group was selected as a primary protecting group. (14) (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134−7135. (b) Watson, D. A.; Su, M. J.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661−1664. (c) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482−11484. (d) Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q Angew. Chem., Int. Ed. 2011, 50, 9081−9084. (e) Ikawa, T.; Masuda, S.; Nishiyama, T.; Takagi, A.; Akai, S. Aust. J. Chem. 2014, 67, 475−480. (f) Lou, S.-J.; Xu, D.-Q.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2014, 53, 10330−10335. (g) Sather, A. C.; Buchwald, S. L. Acc. Chem. Res. 2016, 49, 2146−2157. (h) Gutierrez, D. A.; Lee, W-C. C.; Shen, Y.; Li, J. J. Tetrahedron Lett. 2016, 57, 5372−5376.

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DOI: 10.1021/acs.joc.7b02208 J. Org. Chem. 2017, 82, 13141−13151