Synthesis of C2-Symmetric gem-Difluoromethylenated Angular

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Cite This: J. Org. Chem. 2018, 83, 388−402

Synthesis of C2‑Symmetric gem-Difluoromethylenated Angular Triquinanes Watcharaporn Thaharn,† Darunee Soorukram,‡ Chutima Kuhakarn,‡ Vichai Reutrakul,‡ and Manat Pohmakotr*,‡ †

Chemistry Program, Faculty of Education, Chiangrai Rajabhat University, Mueang Chiang Rai, Chiang Rai 57100, Thailand Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand

‡

S Supporting Information *

ABSTRACT: A synthesis of symmetrical gem-difluoromethylenated angular triquinanes is described. The synthetic strategy involved sequential fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to 2,2-diallylated or 2,2dipropargylated indane-1,3-diones 2 followed by stereoselective radical cyclization of the resulting adducts 3 to provide the cyclized gem-difluoromethylenated diquinanes 4 as a mixture of stereoisomers. Repeated addition of 1 to 4 followed by cyclization resulted in the stereoselective synthesis of the desired C2-symmetric gem-difluoromethylenated angular triquinanes 6 in good yields with high stereoselectivity.

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synthesis of fluorinated substances. The gem-difluoromethylene group (−CF2−) is a valuable structural motif5 found in fluorinated organic compounds, and some of those were shown to have broad applications in pharmaceuticals, agrochemicals, materials science, and other areas of research.6 As a part of our ongoing research interest in developing synthetic approach for the synthesis of fluorine-containing organic molecules, we sought for a general method to access gem-difluoromethylenated angular triquinanes (tricyclo[6.3.0.01,5]undecane carbon skeleton). To the best of our knowledge, no general and efficient methods to access gem-difluoromethylenated angular triquinanes were reported. Conceptually, the introduction of a gem-difluoromethylene group onto the angular triquinane skeleton would open opportunities toward the discovery of new biologically active molecules due to the unique properties of the CF2 group. Recently, we have demonstrated the synthetic utilities of PhSCF2SiMe3 (1) as a gem-difluoromethylene radical anion building block (•CF2−) for the preparation of gem-difluoromethylenated linear triquinanes,7a 1-azabicyclic compounds,7b cyclopentanol,7c polycyclic cage compounds,7d and propanoylbicyclo[3.3.0]octanes.7e We herein demonstrated a general strategy to access gem-difluoromethylenated angular triquinane scaffolds by using 1 as a “radical anion” (•CF2−) building block. Our proposed synthetic route for the synthesis of gem-difluoromethylenated angular triquinane is shown in Scheme 1. Initially, fluoride-catalyzed nucleophilic addition of 1 to 2,2-diallylated or 2,2-dipropargylated cyclopentane-1,3-dione derivatives 2 would provide the

INTRODUCTION The sesquiterpenes bearing an angular triquinane moiety are prevalent in a variety of naturally occurring terpenes1 such as silphinene,1a silphiperfol-5-en-3-ol,1b and pentalenene.1c,d Silphinene and silphiperfol-5-en-3-ol isolated from the roots of Siliphium perfoliatum were reported to exhibit chrysomelidae antifeedants as well as antimicrobial activity.2 Pentalenene is a key biogenetic precursor for the pentalenolactone family which possess antibiotic and antitumor properties3a−d (Figure 1).

Figure 1. Some representatives of angular triquinane-type compounds.

Owing to the intricate molecular structure and diverse biological properties, much attention was drawn to triquinane and its derivatives, particularly angularly fused tricyclopentanoids as synthetic targets.3e−n Fluorinated organic compounds have been described to possess unique physical, chemical, and biological properties. The presence of fluorine atoms in small biologically active compounds can enhance pharmacological properties of drug molecules including their stability, lipophilicity, and bioavailability.4 Therefore, considerable attentions were directed toward the introduction of fluorine atoms or fluorinecontaining moieties into small organic molecules for the © 2017 American Chemical Society

Received: November 2, 2017 Published: December 8, 2017 388

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry Scheme 1. Proposed Synthetic Route to gem-Difluoromethylenated Angular Triquinanes

partial separation of trans-4e, designated by the relative orientation between the hydroxyl and the methyl groups, could be achieved by column chromatography (SiO2). The relative stereochemistry of trans-4a could be established by NOESY experiments (see the Supporting Information). By comparison of the NMR spectral data, the isomeric ratios (cis and trans) of 4c and 4d can be assigned on the same basis. The stereochemical outcome of 4a−b can be rationalized as shown in Scheme 2. The gem-difluoroalkyl radical intermediates derived from 3a and 3b underwent radical cyclization via a 5exo-dig mode through the transition state TS-3A leading to vinylic radicals 4A, which proceeded hydrogen atom abstraction with Bu3SnH to give Z-4a and Z-4b as the major isomers. The formation of minor isomers E-4a and E-4b can be rationalized by an isomerization of 4A to 4B followed by hydrogen atom abstraction. The gem-difluoroalkyl radical intermediates derived from 3c−e underwent 5-exo-trig mode of cyclization through the transition states TS-4C and TS-4D. The transition state TS-4C is energetically more favorable than TS-4D,6b,10 owing to a minimized steric repulsion between a pseudo-axial hydroxyl group and a pseudo-equatorial vinylic moiety resulting in the formation of thermodynamically more stable trans-isomers of 4c−e as the major isomers (Scheme 2). Having the cyclized products 4 in hand, the stereoselective fluoride-catalyzed nucleophilic addition of 1 to 4 was next investigated. Thus, treatment of 4a (Z:E = 82:18) was treated with 1 (2 equiv) in the presence of TBAF (10 mol%) in THF at 0 οC to rt for 24 h followed by quenching with saturated NaHCO3. The addition of 1 to the carbonyl group of 4a proceeded with high stereoselectivity providing 5a (P = TMS) in 87% yield as an inseparable mixture of Z-5a and E-5a (Z:E = 88:12)11 as shown in Scheme 3. The addition of 1 to silylated compound 4a′ was performed. It was found that the reaction proceeded with high stereoselectivity providing the corresponding mixture of 5a (42% yield, Z:E = 94:6) and 5a′ (41% yield, Z:E = 94:6) together with only traces amount of other isomers. Under similar reaction conditions, 4b (Z:E = 68:32) afforded 5b in 85% yield (Z:E = 72:28).11 The relative stereochemistry of Z-5a−b, E-5a−b was assigned on the basis of NOESY experiments (see the Supporting Information). The high stereoselectivity for the addition of 1 to 4a and 4b leading to the corresponding adducts 5a and 5b as the major isomer could be rationalized by the preferential attack of “PhSCF2−” anion derived from 1 from the less sterically hindered convex face of 4a or 4b through the transition state TS-5A as depicted in

corresponding adducts 3. Subsequent reductive cleavage of a phenylsulfanyl group could afford a radical intermediate that should then undergo intramolecular radical cyclization to give gem-difluoromethylenated diquinanes 4. Repeated addition of 1 to 4 followed by reduction and cyclization of the resulting adducts 5 should afford the desired C2-symmetric gemdifluoromethylenated angular triquinanes 6.

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RESULTS AND DISCUSSION The requisite indane-1,3-diones 2a−e were readily prepared by allylation or alkynylation of indane-1,3-dione by following the known procedure (see the Experimental Section).8 First, the fluoride-catalyzed nucleophilic addition of 1 to indane-1,3diones 2a−b was investigated. It was found that treatment of 1 (2 equiv) with dipropargylated indane-1,3-dione derivative 2a (1 equiv) in the presence of tetrabutylammonium fluoride (TBAF, 10 mol%) in THF at 0 οC to rt for 24 h followed by quenching the reaction mixture with water gave the corresponding hydroxylated adduct 3a in 82% yield (Table 1, entry 1). It should be noted here that quenching the reaction mixture with aqueous TBAF led to a competing cleavage of the trimethylsilyl group at the acetylenic carbon. Under similar reaction conditions, the reaction of dipropargylated indane-1,3dione 2b with 1 provided the corresponding gem-difluoromethylenated adduct 3b in 86% yield (Table 1, entry 2). The reactions of diallylated indane-1,3-diones 2c−e with 1 followed by quenching the reaction mixture with an excess amount of TBAF gave the corresponding gem-difluoromethylenated adducts 3c, 3d, and 3e in 84%, 88%, and 86% yields, respectively (Table 1, entries 3−5). We next investigated the reductive cleavage of the phenylsulfanyl group followed by radical cyclization of adducts 3a−e to the required gem-difluoromethylenated diquinanes 4a−e. Thus, treatment of dipropargylated indane-1,3-dione 3a with Bu3SnH and a catalytic amount of AIBN in refluxing toluene generated the corresponding gem-difluoromethylene radical intermediate that underwent intramolecular cyclization stereoselectively to provide the desired diquinane 4a in 85% yield as an inseparable isomeric mixture (Z:E, 82:18) (Table 1, entry 1). Thus, under similar reaction conditions, the reactions of silylated adduct 3a′, dipropargylated adduct 3b, and diallylated adducts 3c−e readily proceeded and provided the corresponding gem-difluoromethylenated diquinanes 4a′−e in high yields (Table 1, entries 1−5). In all cases, each of the diquinanes 4 was obtained as a mixture of isomeric mixtures. Fortunately, 389

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry Table 1. Preparation of gem-Difluoromethylenated Adducts 3 and of gem-Difluoromethylenated Diquinanes 4a−e9

a

Yield after column chromatography (SiO2). bDetermined by 19F- and 1H NMR analyses. cDiastereoisomers could not be separated by chromatographic methods. dStereochemistries of 4a, 4a′, and 4b were later confirmed by NOESY data of their corresponding products 5a, 5a′, and 5b (see the Supporting Information). eDiquinane 4a′ was obtained via radical cyclization of 3a′. fThe trans and cis isomers were assigned on the basis of the relative orientation between the hydroxyl and the alkyl groups. gRelative stereochemistry was established by NOESY experiments (see the Supporting Information).

Figure 2. Additionally, a possible H-bonding between the hydroxyl group of 4 (TS-5B), the fluoride ion (TBAF), and the alkylsilyl group (R-OH···F···SiR4) to direct the addition on the same face of the OH group should also be taken into account.12 Having succeeded in the preparation of adducts 5, we next focused on their cyclization to form the desired gemdifluoromethylenated angular triquinanes 6. Thus, treatment of 5a (Z:E = 88:12) with Bu3SnH and AIBN in toluene under refluxing temperature gave a mixture of C2-symmetric gemdifluoromethylenated 6aA along with its isomer 6aB (Z,Z:E,Z =

86:14) in 91% yield. Desilylation of the mixture of 6a (TBAF, DMF) afforded the expected C2-symmetric gem-difluoromethylenated angular triquinane 7a in 83% yield. Under similar radical cyclization reaction conditions, 5b (Z:E = 72:28) provided a mixture of the C2-symmetric gem-difluoromethylenated 6bA together with its isomer 6bB (Z,Z:E,Z = 85:15) in 80% yield. According to these observed results, it implied that the radical cyclization of 5a and 5b proceeded with high stereoselectivity leading to 6A and 6B, respectively. The 390

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

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The Journal of Organic Chemistry

Scheme 2. Proposed Transition States of gem-Difluoromethyl Radical Cyclization Derived from 3a−e to Corresponding gemDifluoromethylenated Diquinanes 4a−e

Scheme 3. Preparation of C2-Symmetric gem-Difluoromethylenated Angular Triquinanes 6A, 7a, and gem-Difluoromethylenated Angular Triquinanes 6B

stereochemistries of 6A and 6B13 were assigned on the basis of NOESY experiments (see the Supporting Information). We next explored the preparation of alkyl-substituted gemdifluoromethylenated angular triquinanes, starting from 4c−d (as a mixture of trans and cis isomers) and trans-4e. Thus, the reaction of 4c (trans:cis = 78:22) with 1 in the presence of TBAF (10 mol%) in THF followed by quenching with aqueous TBAF yielded the corresponding mixture of 5cA and 5cB (72% yield, 5cA:5cB = 86:14) along with a mixture of 5cC and 5cD

(15% yield, 5cC:5cD = 67:33) (Table 2, entry 1). Under similar reaction conditions as for 4c, 4d (trans:cis = 74:26) gave a mixture of 5dA and 5dB (73% yield, 5dA:5dB = 74:26) and a mixture of 5dC and 5dD (18% yield, 5dC:5dD = 65:35) (Table 2, entry 2). Finally, trans-4e gave a mixture of the required dihydroxy derivatives 5eA and 5eC together with their corresponding silyl ether derivatives, which could not be separated from the starting material trans-4e. Gratifyingly, attempts to quench the reaction with saturated aqueous 391

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

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The Journal of Organic Chemistry

isomer 6cB (82:18) in 89% yield (Table 2, entry 1). The stereochemical outcome for the formation of 6cA and 6cB can be explained that the radical cyclization of the gemdifluoromethyl radical derived from 5cA and 5cB proceeded via a 5-exo-trig mode of cyclization through a half-chair transition state TS-6A (Figure 3), providing the corresponding Figure 2. Proposed Transition State for the Stereoselective FluorideCatalyzed Nucleophilic Addition of 1 to Diquinanes 4a−b

NaHCO3 led to the isolation of trimethylsilyl ether derivatives which could be easily purified. The required silyl ether derivatives 5eA and 5eC were readily separated and were obtained in 70% and 15% yields, respectively (Table 2, entry 3). Again, it is worth mentioning that the stereoselective fluoridecatalyzed nucleophilic addition of 1 to the carbonyl carbon of 4c, 4d, and 4e proceeded preferentially from the less sterically hindered convex face, leading to the corresponding major isomer of adducts 5c−d. Next, reductive cleavage of the phenylsulfanyl group followed by stereoselective radical cyclization of 5c−d (as a mixture of isomers) leading to the required alkyl-substituted gemdifluoromethylenated angular triquinanes 6c−d was investigated. It was found that treatment of the mixture of transdihydroxy derivatives 5cA and 5cB (86:14) with Bu3SnH/ AIBN in refluxing toluene provided the corresponding mixture of C2-symmetric gem-difluoromethylenated 6cA along with its

Figure 3. Proposed transition state for cyclization of the gemdifluoromethyl radical derived from 5c−e to 6c−e

mixture of C2-symmetric gem-difluoromethylenated 6cA13 together with its isomer 6cB (6cA:6cB = 82:18). Under similar reaction conditions, a mixture of 5dA and 5dB (74:26) afforded a mixture of C2-symmetric gem-difluoromethylenated 6dA13 and its isomer 6dB (6dA:6dB = 87:13) in 91% yield (Table 2, entry 2). Similarly, trans-5eA gave an inseparable mixture of C2symmetric gem-difluoromethylenated 6eA13 together with its isomer 6eB (6eA:6eB = 74:26) in 82% yield (Table 2, entry 3).

Table 2. Preparation of Alkyl-Substituted C2-Symmetric gem-Difluoromethylenated Angular Triquinanes 6c−eA and their Isomers (6c−eB)

entry

substrates

R1

R2

R3

R4

5; yield (%)a,b (trans/cis)c

6; yield (%)a,b (trans/cis)c

1

4c (trans:cis = 78:22)

Me

Me

Me

Me

6cA + 6cB; 89 (82:18)

Me

Me

Me

Me

Ph

H

Ph

H

Ph

H

Ph

H

H

H

H

H

H

H

H

H

5cA + 5cB; 72 (P = H, 86:14) 5cC + 5cD; 15 (P = H, 67:33) 5dA + 5dB; 73 (P = H, 74:26) 5dC + 5dD; 18 (P = H, 65:35) 5eA (P = TMS, 70%) 5eC (P = TMS, 15%)

2

3

4d (trans:cis = 74:26)

trans-4e

6dA + 6dB; 91 (87:13)

6eA + 6eB; 82 (74:26)

a

Yield after column chromatography (SiO2). bThe diastereoisomers could not be separated by means of chromatography. cDetermined by 19F NMR and 1H NMR. 392

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

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The Journal of Organic Chemistry Scheme 4. Radical Cyclization of a Mixture of 5cC and 5cD to 6cC and 6cD

dure A: To a solution of indane-1,3-dione (438 mg, 3 mmol) in dry acetone (20 mL) at 0 °C was added cesium carbonate (2.9 g, 9 mmol) and 3-bromo-1-(trimethylsilyl)-1-propyne (1.7 g, 9 mmol). The reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo. The residual was partitioned with water (50 mL) and CH2Cl2 (25 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2, 5% EtOAc in hexanes) to yield 2a (890 mg, 81% yield) as a colorless crystals. Mp 122−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 5.7, 3.1 Hz, 2H), 7.28 (dd, J = 5.7, 3.1 Hz, 2H), 2.60 (s, 4H), 0.29 (s, 18H); 13C{1H}NMR (100 MHz, CDCl3) δ 201.4 (2 × C), 143.3 (2 × C), 135.8 (2 × CH), 123.1 (2 × CH), 100.4 (2 × C), 89.1 (2 × C), 56.4 (C), 24.4 (2 × CH2), −0.5 (6 × CH3); IR (CHCl3) νmax 2181s, 1716s, 1249s, 847s cm−1; MS m/z (%) relative intensity 367 (M+, 12), 351 (36), 277 (41), 204 (30), 73 (100); HRMS (ESI-TOF) calcd for C21H26NaO2Si2 [M + Na]+ 389.1369, found 389.1362. 2,2-Di(but-2-yn-1-yl)-1H-indene-1,3(2H)-dione (2b). According to the general procedure A, the reaction of indane-1,3-dione (438 mg, 3 mmol), 1-bromo-2-butyne (1.2 g, 9 mmol), and cesium carbonate (2.9 g, 9 mmol) in dry acetone (20 mL) gave 2b (661 mg, 88% yield) as a white solid after column chromatography (SiO2, 5−10% EtOAc in hexanes). Mp 77−79 °C; 1H NMR (400 MHz, CDCl3) δ 7.93−7.85 (m, 2H), 7.80−7.71 (m, 2H), 2.46 (d, J = 2.52 Hz, 4H), 1.27 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 201.8 (2 × C), 142.6 (2 × C), 135.7 (2 × CH), 123.1 (2 × CH), 79.4 (2 × C), 73.0 (2 × C), 56.5 (C), 23.3 (2 × CH2), 3.1 (2 × CH3); IR (CHCl3) νmax 2240m, 1712s, 1600s, 1252s, 936s cm−1; MS m/z (%) relative intensity 251 (M+ + 1, 20), 250 (M+, 17), 236 (100), 180 (30), 106 (9); HRMS (ESI-TOF) calcd for C17H15O2 [M + H]+ 251.1072, found 251.1083. 2,2-Bis(3-methylbut-2-en-1-yl)-1H-indene-1,3(2H)-dione (2c). According to the general procedure A, the reaction of indane-1,3-dione (438 mg, 3 mmol), 1-bromo-3-methyl-2-butene (1.3 g, 9 mmol), and cesium carbonate (2.9 g, 9 mmol) in dry acetone (20 mL) gave 2c (644 mg, 76% yield) as a white solid after column chromatography (SiO2, 5−10% EtOAc in hexanes). Mp 106−108 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.6, 3.1 Hz, 2H), 7.74 (dd, J = 5.7, 3.1 Hz, 2H), 4.71 (dt, J = 7.1, 2.4 Hz, 2H), 2.46 (d, J = 8.0 Hz, 4H), 1.49 (s, 6H), 1.37 (s, 6H); 13C{1H}NMR (100 MHz, CDCl3) δ 204.6 (2 × C), 142.8 (2 × C), 135.9 (2 × C), 135.5 (2 × CH), 122.9 (2 × CH), 117.7 (2 × CH), 59.1 (C), 33.7 (2 × CH2), 25.8 (2 × CH3), 17.8 (2 × CH3); IR (CHCl3) νmax 1717s, 1605m, 1041m, 924m cm−1; MS m/z (%) relative intensity 283 (M+ + 1, 61), 282 (M+, 63), 240 (100), 171 (46), 77 (21); HRMS (ESI-TOF) calcd for C19H22NaO2 [M + Na]+ 305.1517, found 305.1506. 2,2-Dicinnamyl-1H-indene-1,3(2H)-dione (2d). According to the general procedure A, the reaction of indane-1,3-dione (438 mg, 3

Finally, it is of particular interest to evaluate the possibility for the intramolecular radical cyclization of the cis-dihydroxy derivatives 5cC and 5cD. Thus, under the standard reduction followed by radical cyclization, a mixture of 5cC and 5cD (67:33) readily proceeded smoothly to yield the corresponding mixture of alkyl-substituted gem-difluoromethylenated angular triquinanes 6cC and 6cD (6cC:6cD = 51:49) in 71% yield. The transition state for radical cyclization of the cis-dihydroxy derivatives 5cC and 5cD leading to 6cC and 6cD was proposed to occur via TS-6B, of which •CF2R and prenyl groups occupied the pseudo-equatorial position (Scheme 4). The structure of 6cC was confirmed by X-ray crystallography (see the Supporting Information).

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CONCLUSION In summary, we have reported the synthetic utilities of PhSCF2SiMe3 (1) as a useful gem-difluoromethylene building block for the synthesis of C2-symmetric gem-difluoromethylenated angular triquinanes. The synthesis involved the sequential fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to readily available 2,2-diallylated or -dipropargylated indane-1,3diones followed by stereoselective intramolecular radical cyclization. The method provided a general synthetic entry to C2-symmetric gem-difluoromethylenated angular triquinanes. Our developed strategy may be applied to the synthesis of highly substituted angular triquinanes containing a gemdifluoromethylene unit and their analogues, which may be useful for drug development.

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EXPERIMENTAL SECTION

General Procedures. 1H NMR spectra were recorded on 400 MHz spectrometers and are reported in ppm. Proton decoupled 13C NMR spectra were recorded on a 100 MHz spectrometer and are reported in ppm. The 19F NMR spectra were recorded on a 376 MHz spectrometer, and chemical shifts (δ) were measured with fluorotrichloromethane (δ = 0) as an internal standard. Reactions were monitored by thin-layer chromatography and visualized by UV and a solution of KMnO4. Tetrahydrofuran (THF) was distilled from sodium-benzophenone ketyl. Acetone and toluene were distilled from calcium hydride and stored over activated molecular sieves (4 Å). All glasswares and syringes were oven-dried and kept in a desiccator before use. Purification of the reaction products was carried out by preparative thin-layer chromatography plates or column chromatography on silica gel. Preparation of Indane-1,3-diones 2a−g.8 2,2-Bis(3-(trimethylsilyl)prop-2-yn-1-yl)-1H-indene-1,3(2H)-dione (2a). General Proce393

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry

relative intensity 599 (M+, 4), 439 (100), 338 (21), 277 (25), 203 (20), 73 (95); HRMS (ESI-TOF) calcd for C31H40F2NaO2SSi3 [M + Na]+ 621.1923, found 621.1933. (R*)-2,2-Di(but-2-yn-1-yl)-3-(difluoro(phenylsulfanyl)methyl)-3hydroxy-2,3-dihydro-1H-inden-1-one (3b). According to the general procedure B, the reaction of 1 (928 mg, 4 mmol) with 2b (501 mg, 2 mmol) in dry THF (4 mL) in the presence of 10 mol% TBAF (1.0 M in dry THF, 0.4 mL, 0.4 mmol) followed by quenching with saturated TBAF solution (10 mL) gave 3b (706 mg, 86% yield) as a white solid after column chromatography (SiO2, 5−10% EtOAc in hexanes). Mp 145−147 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.62 (ddd, J = 7.5, 1.1, 1.1 Hz, 1H), 7.50 (ddd, J = 7.5, 0.9, 0.8 Hz, 1H), 7.39−7.18 (m, 5H), 3.34 (s, 1H), 3.12−3.02 (m, 1H), 2.92−2.83 (m, 1H), 2.80−2.71 (m, 1H), 2.38− 2.27 (m, 1H), 1.75 (t, J = 2.4 Hz, 3H), 1.53 (t, J = 2.5 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −79.26 (d, J = 203.4 Hz, 1 × F), −81.63 (d, J = 204.2 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 200.1 (C), 148.1 (C), 136.6 (2 × CH), 135.9 (C), 134.3 (CH), 130.7 (CH), 130.1 (CH), 130.0 (t, J = 291.0 Hz, CF2), 129.1 (2 × CH), 126.6 (CH), 125.4 (C), 123.5 (CH), 85.7 (t, J = 24.0 Hz, C), 81.9 (C), 79.0 (C), 75.5 (C), 73.6 (C), 61.0 (C), 26.9 (CH2), 20.2 (CH2), 3.8 (CH3), 3.7 (CH3); IR (KBr) νmax 3390br, 1716s, 1210m, 1058s, 748s cm−1; MS m/z (%) relative intensity 411 (M+ + 1, 47), 410 (M+, 6), 252 (52), 235 (73), 209 (100), 166 (76), 77 (36); HRMS (ESI-TOF) calcd for C24H21F2O2S [M + H]+ 411.1230, found 411.1247. (R*)-3-(Difluoro(phenylsulfanyl)methyl)-3-hydroxy-2,2-bis(3methylbut-2-en-1-yl)-2,3-dihydro-1H-inden-1-one (3c). According to the general procedure B, the reaction of 1 (928 mg, 4 mmol) with 2c (565 mg, 2 mmol) in dry THF (4 mL) in the presence of 10 mol% TBAF (1.0 M in dry THF, 0.4 mL, 0.4 mmol) followed by quenching with saturated TBAF solution (10 mL) gave 3c (744 mg, 84% yield) as a white solid after column chromatography (SiO2, 5− 10% EtOAc in hexanes). Mp 122−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.82−7.65 (m, 2H), 7.61−7.52 (m, 2H), 7.50−7.40 (m, 1H), 7.35−7.15 (m, 4H), 5.38−5.28 (m, 1H), 4.83−4.71 (m, 1H), 3.28 (s, 1H), 2.81 (dd, J = 16.1, 9 1 Hz, 1H), 2.55 (dd, J = 14.7, 7.5 Hz, 2H), 1.91 (dd, J = 14.8, 6.8 Hz, 1H), 1.65 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −78.46 (d, J = 203.0 Hz, 1 × F), −81.31 (d, J = 203.0 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 203.2 (C), 148.8 (C), 136.7 (C), 136.6 (CH), 135.2 (CH), 135.1 (C), 134.2 (C), 134.1 (CH), 130.5 (CH), 130.4 (t, J = 290 Hz, CF2), 130.1 (CH), 129.1 (CH), 128.1 (CH), 126.3 (CH), 125.7 (C), 123.3 (CH), 119.7 (CH), 118.9 (CH), 86.7 (t, J = 23.4 Hz, C), 63.1 (C), 33.6 (CH2), 28.5 (CH2), 26.4 (CH3), 26.2 (CH3), 18.1 (CH3), 17.8 (CH3); IR (CHCl3) νmax 3435br, 1744s, 1709s, 1596s, 1242s, 735s; MS m/z (%) relative intensity 443 (M+ + 1, 100), 442 (M+, 8), 314 (32), 247 (19), 91 (3), 77 (5); HRMS (ESI-TOF) calcd for C26H28F2NaO2S [M + Na]+ 465.1676, found 465.1670. (R*)-2,2-Dicinnamyl-3-(difluoro(phenylsulfanyl)methyl)-3-hydroxy-2,3-dihydro-1H-inden-1-one (3d). According to the general procedure B, the reaction of 1 (928 mg, 4 mmol) with 2d (757 mg, 2 mmol) in dry THF (4 mL) in the presence of 10 mol% TBAF (1.0 M in dry THF, 0.4 mL, 0.4 mmol) followed by quenching with saturated TBAF solution (10 mL) gave 3d (949 mg, 88% yield) as a pale yellow oil after column chromatography (SiO2, 5−10% EtOAc in hexanes). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.69 (dd, J = 7.5, 1.0 Hz, 1H), 7.56 (dd, J = 7.5, 0.6 Hz, 1H), 7.46−7.11 (m, 13H), 7.08−7.01 (m, 2H), 6.59−6.43 (m, 2H), 6.19 (d, J = 15.8 Hz, 1H), 5.78 (dd, J = 8.5, 7.0 Hz, 1H), 3.24 (s, 1H), 3.13−2.96 (m, 2H), 2.73 (dd, J = 14.4, 8.4 Hz, 1H), 2.38 (dd, J = 14.3, 6.5 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −78.42 (d, J = 203.4 Hz, 1 × F), −81.77 (d, J = 203.0 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 202.6 (C), 148.7 (C), 137.8 (C), 137.3 (C), 136.8 (C), 136.7 (2 × CH), 134.6 (CH), 134.0 (CH), 133.4 (CH), 131.0 (CH), 130.5 (t, J = 284.5 Hz, CF2), 130.4 (CH), 129.3 (2 × CH), 128.7 (2 × CH), 128.6 (2 × CH), 127.4 (2 × CH), 126.4 (2 × CH), 126.3 (2 × CH), 126.2 (CH), 125.9 (CH), 125.4 (C), 125.2 (CH), 123.4 (CH), 86.3 (t, J = 23.4 Hz, C), 63.1 (C), 39.4 (CH2), 34.3 (CH2); IR (neat) νmax 3029br, 1722s, 1605m, 1190s, 969s cm−1; MS m/z (%) relative intensity 539 (M+, 3), 411 (20), 220 (44), 205 (100), 91 (42); HRMS

mmol), (E)-3-bromo-1-phenyl-1-propene (1.8 g, 9 mmol), and cesium carbonate (2.9 g, 9 mmol) in dry acetone (20 mL) gave 2d (942 mg, 83% yield) as a white solid after column chromatography (SiO2, 5− 10% EtOAc in hexanes). Mp 105−107 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 5.7, 3.1 Hz, 2H), 7.69 (dd, J = 5.7, 3.1 Hz, 2H), 7.28−7.02 (m, 10H), 6.32 (d, J = 15.7 Hz, 2H), 5.82 (dt, J = 15.7, 7.7 Hz, 2H), 2.67 (dd, J = 7.6, 0.8 Hz, 4H); 13C{1H}NMR (100 MHz, CDCl3) δ 203.6 (2 × C), 142.3 (2 × C), 137.0 (2 × C), 136.0 (2 × CH), 134.6 (2 × CH), 128.6 (4 × CH), 127.6 (2 × CH), 126.4 (4 × CH), 123.4 (2 × CH), 123.2 (2 × CH), 59.3 (C), 38.2 (2 × CH2); IR (CHCl3) νmax 1743m, 1708s, 1243m, 968s cm−1; MS m/z (%) relative intensity 379 (M+ + 1, 1), 378 (M+, 1), 220 (100), 203 (28), 91 (18), 65 (4); HRMS (ESI-TOF) calcd for C27H22NaO2 [M + Na]+ 401.1517, found 401.1512. 2,2-Diallyl-1H-indene-1,3(2H)-dione (2e). According to the general procedure A, the reaction of indane-1,3-dione (438 mg, 3 mmol), allyl bromide (1.1 g, 9 mmol), and cesium carbonate (2.9 g, 9 mmol) in dry acetone (20 mL) gave 2e (611 mg, 90% yield) as a colorless oil after column chromatography (SiO2, 5−10% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.94−7.87 (m, 2H), 7.82−7.76 (m, 2H), 5.50− 5.35 (m, 2H), 4.98 (dd, J = 16.9, 1.8 Hz, 2H), 4.84 (dd, J = 10.1, 1.7 Hz, 2H), 2.50 (d, J = 7.5 Hz, 4H); 13C{1H}NMR (100 MHz, CDCl3) δ 203.5 (2 × C), 142.4 (2 × C), 135.9 (2 × CH), 131.6 (2 × CH), 123.2 (2 × CH), 119.7 (2 × CH2), 58.5 (C), 39.0 (2 × CH2); IR (neat) νmax 1744m, 1708s, 1248m, 924m cm−1; MS m/z (%) relative intensity 227 (M+ + 1, 76), 226 (M+, 11), 183 (57), 129 (80), 128 (100), 115 (16); HRMS (ESI-TOF) calcd for C15H14NaO2 [M + Na]+ 249.0891, found 249.0889. Preparation of gem-Difluoromethylenated Adducts 3. (R*)-3(Difluoro(phenylthio)methyl)-3-hydroxy-2,2-bis(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-one (3a) and (R*)-3(Difluoro(phenylsulfanyl)methyl)-3-((trimethylsilyl)oxy)-2,2-bis(3(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-one (3a′). General Procedure B: A solution of PhSCF2TMS (1) (928 mg, 4 mmol) and 2a (733 mg, 2 mmol) in dry THF (4 mL) was treated with a solution of 10 mol % TBAF (1 M in dry THF, 0.4 mL, 0.4 mmol). The reaction mixture was stirred at 0 °C followed by slowly warming up to room temperature under an argon atmosphere for 24 h. The reaction mixture was quenched with water (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2, 5−15% EtOAc in hexanes) to give 3a (P = H) (864 mg, 82% yield) and 3a′ (P = SiMe3) (131 mg, 11% yield). 3a (a colorless crystal): Mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.5, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.30−7.09 (m, 5H), 3.24 (s, 1H), 3.00 (d, J = 17.8 Hz, 1H), 2.77 (dd, J = 17.3, 3.4 Hz, 2H), 2.51 (d, J = 17.2 Hz, 1H), 0.00 (s, 9H), −0.16 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −79.10 (d, J = 204.2 Hz, 1 × F), −81.22 (d, J = 204.5 Hz, 1 × F); 13 C{1H}NMR (100 MHz, CDCl3) δ 199.6 (C), 148.3 (C), 136.7 (2 × CH), 136.0 (C), 134.7 (CH), 131.0 (CH), 130.2 (CH), 129.9 (t, J = 290.1 Hz, CF2), 129.2 (2 × CH), 126.7 (CH), 125.5 (C), 123.5 (CH), 103.7 (C), 101.1 (C), 91.2 (C), 88.9 (C), 85.8 (t, J = 24.1 Hz, C), 60.5 (C), 27.8 (CH2), 21.9 (CH2), 0.2 (3 × CH3), 0.0 (3 × CH3); IR (KBr) νmax 3420br, 1702s, 1251s, 1035m, 841s cm−1; MS m/z (%) relative intensity 527 (M+, 1), 351 (44), 277 (63), 251 (43), 91 (21), 73 (100); HRMS(ESI-TOF) calcd for C28H32F2NaO2SSi2 [M + Na]+ 549.1527, found 549.1532. 3a′ (a colorless oil): 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.55 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 7.43 (ddd, J = 7.4, 7.3, 0.7 Hz, 1H), 7.35−7.15 (m, 5H), 3.11 (d, J = 17.9 Hz, 1H), 2.88 (d, J = 17.9 Hz, 1H), 2.71 (d, J = 16.7 Hz, 1H), 2.65 (d, J = 16.9 Hz, 1H), 0.13 (s, 9H), 0.00 (s, 9H), −0.15 (s, 9H); 19 F NMR (376 MHz, CDCl3) δ −73.50−(−79.95) (m, 2 × F); 13 C{1H}NMR (100 MHz, CDCl3) δ 200.6 (C), 149.1 (C), 136.7 (C), 136.4 (2 × CH), 134.5 (CH), 130.7 (CH), 130.0 (CH), 129.9 (t, J = 290.0 Hz, CF2), 129.8 (2 × CH), 127.1 (CH), 126.1 (C), 123.4 (CH), 103.2 (C), 102.3 (C), 89.2 (C), 87.7 (C), 87.5 (t, J = 23.9 Hz, C), 60.6 (C), 27.4 (CH2), 23.4 (CH2), 2.5 (3 × CH3), 0.3 (3 × CH3), 0.0 (3 × CH3); IR (neat) νmax 2178s, 1724s, 1251s, 846s cm−1; MS m/z (%) 394

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry (ESI-TOF) calcd for C34H28F2NaO2S [M + Na]+ 561.1676, found 561.1679. (R*)-2,2-Diallyl-3-(difluoro(phenylsulfanyl)methyl)-3-hydroxy2,3-dihydro-1H-inden-1-one (3e). According to the general procedure B, the reaction of 1 (928 mg, 4 mmol) with 2e (453 mg, 2 mmol) in dry THF (4 mL) in the presence of 10 mol% TBAF (1.0 M in dry THF, 0.4 mL, 0.4 mmol) followed by quenching with saturated TBAF solution (10 mL) gave 3e (665 mg, 86% yield) as a pale yellow oil after column chromatography (SiO2, 5−10% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.62 (ddd, J = 7.5, 1.1, 1.1 Hz, 1H), 7.50 (ddd, J = 7.5, 1.0, 1.0 Hz, 1H), 7.36−7.16 (m, 5H), 6.07−5.93 (m, 1H), 5.49−5.35 (m, 1H), 5.16−5.04 (m, 2H), 4.87−4.74 (m, 2H), 3.31 (s, 1H), 2.79 (d, J = 7.3 Hz, 2H), 2.58 (dd, J = 14.4, 7.6 Hz, 1H), 2.00 (dd, J = 14.4, 7.1 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −78.32 (d, J = 203.0 Hz, 1 × F), −81.62 (d, J = 203.0 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 202.4 (C), 148.6 (C), 136.6 (2 × CH), 136.5 (C), 134.5 (CH), 134.8 (CH), 133.0 (CH), 130.9 (CH), 130.3 (t, J = 289.8 Hz, CF2), 130.2 (CH) 129.2 (2 × CH), 126.3 (CH), 125.5 (C), 123.3 (CH), 118.9 (CH2), 118.6 (CH2), 86.4 (t, J = 23.4 Hz, C), 62.3 (C), 39.7 (CH2), 34.2 (CH2); IR (neat) νmax 3454br, 1709s, 1605s, 1059s, 918s cm−1; MS m/z (%) relative intensity 386 (M+, 0.3), 235 (21), 227 (100), 217 (79), 159 (36), 77 (14); HRMS (ESI-TOF) calcd for C22H20F2NaO2S [M + Na]+ 409.1050, found 409.1055. Preparation of gem-Difluoromethylenated Diquinanes 4a−g. (3aR*,8aR*)-3,3-Difluoro-3a-hydroxy-2-((trimethylsilyl)methylene)8a-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (4a). General Procedure C: An argon gas was bubbled through a solution of compound 3a (527 mg, 1 mmol) in dry toluene (25 mL) for 1 h. The solution was heated to reflux, and a solution of Bu3SnH (0.5 mL, 1.75 mmol) and AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) was added dropwise at reflux over a 1 h period. After the completion of the reaction (24 h), the reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel. The tin byproducts were first removed by eluting with hexanes (500 mL), and the products were then eluted with 5−10% EtOAc in hexanes to afford an inseparable 82:18 (Z:E) diastereomeric mixture of 4a (355 mg, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.84 (dd, J = 7.6, 2.2 Hz, 2H of major and minor), 7.75 (d, J = 7.3 Hz, 4H of major and minor), 7.52 (dd, J = 7.4, 7.4 Hz, 2H of major and minor), 5.87 (s, 1H*), 5.68 (s, 1H of minor), 3.75 (s, 1H*), 3.74 (s, 1H of minor), 3.15 (d, J = 15.4 Hz, 1H of minor), 2.99 (d, J = 15.4 Hz, 1H*), 2.78− 2.65 (m, 2H* and 1H of minor), 2.58−2.45 (m, 1H* and 2H of minor), 0.10 (s, 9H*), 0.00 (s, 9H*), −0.14 (s, 9H of minor), −0.15 (s, 9H of minor); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −103.91 (d, J = 237.6 Hz, 1 × F of minor), −104.28 (d, J = 232.0 Hz, 1 × F*), −117.76 (d, J = 237.6 Hz, 1 × F of minor), −123.60 (d, J = 232.0 Hz, 1 × F*); 13C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 205.5 (C of minor), 205.2 (C*), 150.4 (2 × C of major and minor), 145.3 (t, J = 21.0 Hz, 2 × C of major and minor), 136.2 (CH*), 136.1 (CH of minor), 133.5 (d, J = 4.6 Hz, CH of minor), 130.9 (CH*), 130.8 (CH of minor), 129.3 (d, J = 3.1 Hz, CH*), 127.7 (d, J = 2.8 Hz, 2 × CH of major and minor), 123.5 (CH of minor), 123.4 (CH*), 123.3 (C*), 123.1 (C of minor), 122.2 (dd, J = 259.7, 246.5 Hz, CF2 of minor), 120.8 (dd, J = 262.9, 246.8 Hz, CF2*), 102.8 (2 × C of major and minor), 90.0 (C*), 89.9 (C of minor), 84.7 (t, J = 23.1 Hz, C of minor), 84.2 (t, J = 22.3 Hz, C*), 58.0 (d, J = 6.6 Hz, C*), 57.5 (d, J = 6.1 Hz, C of minor), 39.6 (d, J = 4.7 Hz, CH2 of minor), 35.4 (d, J = 2.3 Hz, CH2*), 23.0 (CH2*), 22.8 (CH2 of minor), −0.1 (3 × CH3*), −0.5 (6 × CH3 of minor), −0.6 (3 × CH3*); IR (neat) νmax 3529br, 2174s, 1719s, 1252s, 1032s, 854s cm−1; MS m/z (%) relative intensity 419 (M+, 14), 399 (24), 309 (27), 215 (69), 190 (37), 77 (52), 73 (100); HRMS (ESI-TOF) calcd for C22H28F2NaO2Si2 [M + Na]+ 441.1494, found, 441.1499. (3aR*,8aR*)-3,3-Difluoro-2-((trimethylsilyl)methylene)-3a((trimethylsilyl)oxy)-8a-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3,3a,8atetrahydrocyclopenta[a]inden-8(1H)-one (4a′). According to the general procedure C, the reaction of 3a′ (1.2 g, 2 mmol) in dry toluene (50 mL) with a solution of Bu3SnH (1 mL, 3.5 mmol), AIBN

(32 mg, 0.2 mmol) in dry toluene (50 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 94:6 (Z/E) isomeric mixture of 4a′ (892 mg, 91% yield) as colorless oil. 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.78−7.62 (m, 6H of major and minor), 7.48 (t, J = 7.2 Hz, 2H of major and minor), 5.83 (s, 1H*), 5.63−5.45 (m, 1H of minor), 2.98−2.92 (m, 1H of minor), 2.83 (dd, J = 16.9, 2.7 Hz, 1H*), 2.68−2.53 (m, 1H of minor and 3H*), 2.46−2.36 (m, 2H of minor), 0.06 (s, 9H*), 0.05 (s, 9H of minor), 0.02 (s, 9H of minor), 0.00 (s, 9H*), −0.06 (s, 9H*), −0.10 (s, 9H of minor); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −100.07 (d, J = 236.5 Hz, 1 × F of minor), −101.31 (d, J = 230.1 Hz, 1 × F*), −115.58 (d, J = 236.5 Hz, 1 × F of minor), −119.93 (d, J = 230.5 Hz, 1 × F*); 13 C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 205.3 (C*), 204.2 (C of minor), 151.5 (C of minor), 150.5 (C*), 146.2 (t, J = 21.2 Hz, C*), 145.6 (t, J = 16.3 Hz, (C of minor), 136.8 (2 × C of major and minor), 135.4 (CH*), 135.2 (CH of minor), 132.9 (d, J = 4.8 Hz, CH of minor), 130.6 (CH of minor), 130.5 (CH*), 128.7 (d, J = 2.6 Hz, CH*), 127.9 (d, J = 6.9 Hz, CH of minor), 127.7 (d, J = 6.9 Hz, CH*), 123.9 (CH of minor), 123.7 (CH*), 121.1 (dd, J = 259.4, 251.2 Hz, 2 × CF2), 103.4 (C of minor), 103.3 (C*), 87.1 (C*), 86.9 (C of minor), 85.2 (t, J = 23.0 Hz, 2 × C of major and minor), 58.6 (d, J = 6.3 Hz, 2 × C of major and minor), 40.3 (CH2 of minor), 36.1 (d, J = 2.4 Hz, CH2*), 23.3 (CH2*), 23.1 (CH2 of minor), 2.1 (3 × CH3*), 1.2 (3 × CH3 of minor), 0.1 (6 × CH3 of major and minor), −0.7 (6 × CH3 of major and minor); IR (CHCl3) νmax 2180s, 1725s, 1591m, 1251m, 844s cm−1; MS m/z (%) relative intensity 491 (M+, 7), 475 (6), 363 (5), 342 (100), 73 (3); HRMS (ESI-TOF) calcd for C25H36F2NaO2Si3 [M + H]+ 513.1889, found 513.1890. (3aR*,8aS*)-8a-(But-2-yn-1-yl)-2-ethylidene-3,3-difluoro-3a-hydroxy-1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (4b). According to the general procedure C, the reaction of 3b (822 mg, 2 mmol) in dry toluene (50 mL) with a solution of Bu3SnH (1 mL, 3.5 mmol), AIBN (32 mg, 0.2 mmol) in dry toluene (50 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 68:32 (Z/E) isomeric mixture of 4b (544 mg, 90% yield) as colorless crystals. Mp 124−126 οC; 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.85−7.76 (m, 2H of major and minor), 7.70−7.62 (m, 4H of major and minor), 7.50− 7.42 (m, 2H of major and minor), 5.83−5.72 (m, 1H*), 5.58−5.45 (m, 1H of minor), 3.70 (d, J = 4.3 Hz, 1H of minor), 3.67 (d, J = 4.4 Hz, 1H*), 2.99−2.88 (m, 1H of minor), 2.85−2.74 (m, 1H*), 2.74− 2.52 (m, 1H* and 3H of minor), 2.48−2.32 (m, 2H*), 1.65−1.57 (m, 6H of major and minor), 1.64−1.57 (m, 3H of minor), 1.49 (t, J = 5.7 Hz, 3H*); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −101.05 (d, J = 230.5 Hz, 2 × F of major and minor), −116.38 (d, J = 242.5 Hz, 1 × F of minor), −122.76 (d, J = 233.1 Hz, 1 × F*); 13 C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 205.9 (2 × C of major and minor), 150.5 (C of minor), 150.4 (C*), 136.4 (C of minor), 136.2 (C*), 136.1 (CH*), 136.0 (CH of minor), 130.9 (t, J = 20.1 Hz, C*), 130.7 (2 × CH of major and minor), 129.6 (t, J = 19.7 Hz, C of minor), 128.7 (d, J = 5.2 Hz, CH of minor), 127.8 (d, J = 4.6 Hz, CH of minor), 127.7 (d, J = 3.8 Hz, CH*), 125.4 (dd, J = 5.6, 3.4 Hz, CH*), 123.6 (CH*), 123.5 (CH of minor), 123.4 (dd, J = 263.6, 254.8 Hz, CF2 of minor), 122.1 (dd, J = 260.7, 243.7 Hz, CF2*), 85.9 (t, J = 22.5 Hz, C of minor), 85.0 (dd, J = 24.2, 22.8 Hz, C*), 80.1 (2 × C of major and minor), 75.0 (2 × C of major and minor), 57.9 (d, J = 6.6 Hz, C*), 57.5 (d, J = 6.2 Hz, C of minor), 37.0 (d, J = 3.9 Hz, CH2 of minor), 31.9 (d, J = 3.4 Hz, CH2*), 22.0 (CH2*), 21.9 (CH2 of minor), 13.9 (d, J = 1.2 Hz, CH3*), 13.2 (d, J = 5.2 Hz, CH3 of minor), 3.6 (2 × CH3 of major and minor); IR (CHCl3) νmax 3545br, 1718s, 1606m, 1066m, 953m cm−1; MS m/z (%) relative intensity 303 (M+ + 1, 7), 302 (M+, 5), 250 (100), 231 (68), 77 (11); HRMS (ESITOF) calcd for C18H16F2NaO2 [M + H]+ 325.1016, found 325.1017. (3aR*,8aS*)-3,3-Difluoro-3a-hydroxy-2-isopropyl-8a-(3-methylbut-2-en-1-yl)-1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (4c). According to the general procedure C, the reaction of 3c (885 mg, 2 mmol) in dry toluene (50 mL) with a solution of Bu3SnH (1 mL, 3.5 mmol), AIBN (32 mg, 0.2 mmol) in dry toluene (50 mL) at reflux followed by the removal of tin byproduct and column 395

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry

A mixture of (3aR*,8aS*)-8a-allyl-3,3-difluoro-3a-hydroxy-2methyl-1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (4e) and (2R*,3aR*,8aS*)-8a-Allyl-3,3-difluoro-3a-hydroxy-2-methyl1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (trans-4e). According to the general procedure C, the reaction of 3e (773 mg 2 mmol) in dry toluene (50 mL) with a solution of Bu3SnH (1 mL, 3.5 mmol), AIBN (32 mg, 0.2 mmol) in dry toluene (50 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 73:27 (trans/cis) diastereomeric mixture of 4e (440 mg, 79% yield) and trans-4e (56 mg, 10% yield). 4e (colorless oil): 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.48−7.58 (m, 6H of major and minor), 7.55−7.45 (m, 2H of major and minor), 5.92−5.65 (m, 2H of major and minor), 5.18−4.95 (m, 4H of major and minor), 3.33 (s, 1H*), 3.27 (s, 1H of minor), 2.75− 2.59 (m, 1H*), 2.52 (t, J = 6.7 Hz, 2H*), 2.44 (d, J = 7.6 Hz, 2H of minor), 2.11−1.97 (m, 2H of major and minor), 1.74−1.43 (m, 1H* and 2H of minor), 0.97 (d, J = 6.3 Hz, 3H of minor), 0.89 (d, J = 6.9 Hz, 3H*); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −119.32 (d, J = 224.8 Hz, 1 × F of minor), −119.72 (d, J = 4.9 Hz, 1 × F*), −119.76 (d, J = 8.6 Hz, 1 × F*), −128.23 (dd, J = 225.2, 25.4 Hz, 1 × F of minor); 13C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 207.2 (C of minor), 206.3 (C*), 150.9 (C of minor), 149.5 (C*), 136.7 (C*), 136.5 (C of minor), 135.8 (CH of minor), 135.6 (CH*), 133.9 (CH*), 133.5 (CH of minor), 130.5 (CH of minor), 130.4 (CH*), 127.2 (d, J = 3.1 Hz, CH of minor), 126.7 (dd, J = 272.1, 257.8 Hz, 2 × CF2 of major and minor), 125.0 (CH*), 123.5 (CH of minor), 123.3 (CH*), 119.0 (CH2*), 118.9 (CH2 of minor), 85.4 (t, J = 24.2 Hz, C of minor), 85.2 (t, J = 21.5 Hz, C*), 59.7 (C*), 58.5 (d, J = 5.0 Hz, C of minor), 38.6 (d, J = 22.9 Hz, CH*), 38.5 (CH2*), 37.0 (CH2 of minor), 36.8 (d, J = 7.5 Hz, CH2 of minor), 35.5 (d, J = 2.4 Hz, CH2*), 35.4 (t, J = 21.0 Hz, CH of minor), 11.2 (CH3*), 9.9 (d, J = 5.5 Hz, CH3 of minor); IR (neat) νmax 3588br, 1716s, 1605s, 1136s, 927s cm−1; MS m/z (%) relative intensity 279 (M+ + 1, 100), 238 (46), 213 (37), 159 (31), 77 (12); HRMS (ESITOF) calcd for C16H16F2NaO2 [M + Na]+ 301.1016, found 301.1025. trans-4e (a white solid): Mp 124−126 οC; 1H NMR (400 MHz, CHCl3) δ 7.75−7.63 (m, 3H), 7.49 (ddd, J = 7.3, 6.9, 1.1 Hz, 1H), 5.84−5.65 (m, 1H), 5.08 (dd, J = 17.1, 1.4 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 3.65−3.32 (m, 1H), 2.77−2.59 (m, 1H), 2.58−2.43 (m, 2H), 2.02 (ddd, J = 13.6, 8.3, 1.5 Hz, 1H), 1.67 (dd, J = 13.5, 10.3 Hz, 1H), 0.88 (d, J = 7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −119.95 (d, J = 19.4 Hz, 1 × F), −120.05 (d, J = 12.1 Hz, 1 × F), 13C{1H}NMR (100 MHz, CDCl3) δ 206.5 (C), 149.5 (C), 136.4 (C), 135.6 (CH), 133.9 (CH), 130.3 (CH2), 126.7 (t, J = 258.8 Hz, CF2), 125.1 (CH), 123.5 (CH), 118.9 (CH), 85.4 (dd, J = 25.5, 22.8 Hz, C), 59.8 (C), 38.6 (t, J = 22.9 Hz, CH), 38.5 (CH2), 35.4 (d, J = 2.1 Hz, CH2), 11.1 (CH3); IR (CHCl3) νmax 3444br, 1705s, 1604s, 1126s, 918s cm−1; MS m/z (%) relative intensity 279 (M+ + 1, 78), 260 (100), 238 (67), 159 (54), 77 (27); HRMS (ESI-TOF) calcd for C16H16F2NaO2 [M + Na]+ 301.1016, found 301.1017. Preparation of gem-Difluoromethylenated Angular Triquinanes 5a−e. (((3aR*,8R*,8aR*)-8-(Difluoro(phenylthio)methyl)-3,3-difluoro-2-((trimethylsilyl)methylene)-8a-(3-(trimethylsilyl)prop-2-yn1-yl)-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diyl)bis(oxy))bis(trimethylsilane) (5a). According to the general procedure B, the reaction of 4a (419 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry THF (2 mL) in the presence of 10 mol% TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated NaHCO3 solution (10 mL) gave a 88:12 (Z/E) diastereomeric mixture of 5a (630 mg, 87% yield) as a white solid after column chromatography (SiO2, 5−10% EtOAc in hexanes). Mp 109−111 °C; 1H NMR (400 MHz, CDCl3, isomer Z marked*) δ 7.66−7.50 (m, 8H of isomers Z and E), 7.43−7.27 (m, 10H of isomers Z and E), 6.12 (s, 1H*), 5.74− 5.68 (m, 1H of isomer E), 3.12 (d, J = 6.3 Hz, 2H*), 3.02−2.93 (m, 2H of isomer E), 2.77 (d, J = 18.4 Hz, 1H of isomer E), 2.70 (d, J = 18.3 Hz, 1H*), 2.59−2.48 (m, 1H of isomer E), 2.43−2.30 (m, 1H*), 0.27 (s, 9H*), 0.13 (s, 18H of isomers E and Z), 0.09 (s, 18H of isomers E and Z), −0.04 (s, 9H of isomer E), −0.07 (s, 9H*), −0.12 (s, 9H of isomer E); 19F NMR (376 MHz, CDCl3, isomer Z marked*) δ −71.59 (d, J = 206.4 Hz, 1 × F*), −71.95 (d, J = 209.8 Hz, 1 × F of

chromatography (SiO2, 2% EtOAc in hexanes) gave a 78:22 (trans/cis) diastereomeric mixture of 4c (642 mg, 96% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.79−7.28 (m, 8H of major and minor), 5.14−5.08 (m, 1H of minor), 4.98−4.90 (m, 1H*), 3.35 (s, 1H*), 3.17 (d, J = 5.4 Hz, 1H of minor), 2.59−2.48 (m, 1H*), 2.45−2.22 (m, 4H of major and minor), 2.14−2.05 (m, 1H of minor), 1.97−1.82 (m, 1H*), 1.78−1.61 (m, 4H* and 3H of minor), 1.62−1.45 (m, 4H* and 5H of minor), 1.25−1.12 (m, 1H of minor), 0.94 (d, J = 6.5 Hz, 3H*), 0.85 (d, J = 7.0 Hz, 3H of minor), 0.83 (d, J = 6.8 Hz, 3H*), 0.75 (d, J = 6.8 Hz, 3H of minor); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −111.04 (d, J = 225.6 Hz, 1 × F of minor), −116.18−(−117.20) (m, 2 × F*), −125.55 (dd, J = 227.5, 28.2 Hz, 1 × F of minor); 13C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 208.0 (C of minor), 206.7 (C*), 151.5 (C of minor), 149.4 (C*), 136.8 (C*), 136.4 (C of minor), 136.0 (C of minor) 135.9 (CH of minor), 135.8 (C*), 135.6 (CH*), 130.6 (CH of minor), 130.2 (CH*), 128.0 (CH of minor), 127.5 (d, J = 3.7 Hz, CH of minor), 127.0 (dd, J = 261.4, 254.9 Hz, 2 × CF2 of major and minor), 124.7 (CH*), 123.4 (CH*), 119.3 (CH*), 118.7 (CH of minor), 86.3 (t, J = 23.5 Hz, C*), 85.8 (t, J = 20.3 Hz, C of minor), 59.4 (C*), 58.0 (d, J = 5.3 Hz, C of minor), 50.6 (dd, J = 21.0, 20.1 Hz, CH*), 46.9 (dd, J = 22.5, 18.1 Hz, CH of minor), 34.7 (d, J = 7.8 Hz, CH2 of minor), 33.4 (d, J = 3.8 Hz, CH2*), 33.2 (CH2*), 31.2 (CH2 of minor), 27.3 (CH3*), 27.2 (CH3 of minor), 26.1 (CH3 of minor), 26.0 (CH3*), 21.5 (CH3*), 21.3 (CH3 of minor), 21.2 (CH3*), 21.0 (d, J = 2.9 Hz, CH3 of minor), 18.1 (CH of minor), 18.0 (CH*); IR (neat) νmax 3591br, 1721s, 1605m, 1120s, 704s cm−1; MS m/z (%) relative intensity 335 (M+ + 1, 88), 334 (M+, 4), 317 (52), 302 (100), 299 (64), 161 (64), 77 (18); HRMS (ESI-TOF) calcd for C20H24F2NaO2 [M + Na]+ 357.1642, found 357.1645. (3aR*,8aS*)-2-Benzyl-8a-cinnamyl-3,3-difluoro-3a-hydroxy1,3,3a,8a-tetrahydrocyclopenta[a]inden-8(2H)-one (4d). According to the general procedure C, the reaction of 3d (1.1 g, 2 mmol) in dry toluene (50 mL) with a solution of Bu3SnH (1 mL, 3.5 mmol), AIBN (32 mg, 0.2 mmol) in dry toluene (50 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 74:26 (trans/cis) diastereomeric mixture of 4d (706 mg, 82% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.79−7.61 (m, 6H of major and minor), 7.53−7.41 (m, 2H of major and minor), 7.28−6.93 (m, 20H of major and minor), 6.42 (d, J = 15.8 Hz, 1H of minor), 6.31 (d, J = 15.8 Hz, 1H*), 6.24−6.12 (m, 1H of minor), 6.00 (ddd, J = 15.6, 7.7, 7.6 Hz, 1H*), 3.06 (s, 1H of minor), 3.05 (s, 1H*), 2.97−2.75 (m, 4H of major and minor), 2.67−2.46 (m, 4H of major and minor), 2.29 (dd, J = 14.0, 10.6 Hz, 1H*), 2.08−1.95 (m, 1H of minor), 1.93−1.66 (m, 4H of major and minor); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −117.37 (d, J = 226.4 Hz, 1 × F of minor), −117.52 (dd, J = 211.5, 21.6 Hz, 1 × F*), −119.00 (d, J = 227.1 Hz, 1 × F*), −125.67 (dd, J = 226.0, 24.8 Hz, 1 × F of minor); 13C{1H}NMR (100 MHz, CDCl3 δ major isomer marked*) δ 206.8 (C of minor), 206.1 (C*), 150.9 (C of minor), 149.2 (C*), 138.8 (C*), 138.4 (C of minor), 137.3 (C of minor), 137.2 (C*), 136.8 (2 × C of major and minor), 136.2 (CH of minor), 136.1 (CH*), 134.2 (CH of minor), 134.0 (CH*), 130.9 (CH of minor), 130.7 (CH*), 129.3 (t, J = 298.1 Hz, 2 × CF2 of major and minor), 128.9 (4 × CH of major and minor), 128.8 (4 × CH of major and minor), 128.7 (2 × CH of minor), 128.6 (2 × CH*), 127.6 (CH*), 127.5 (d, J = 3.0 Hz, CH of minor), 126.7 (CH of minor), 126.6 (CH*), 126.5 (2 × CH of minor), 126.4 (2 × CH*), 125.4 (2 × CH of major and minor), 125.1 (CH*), 125.0 (CH of minor), 123.8 (CH*), 123.7 (CH of minor), 85.9 (dd, J = 21.0 Hz, 2 × C of major and minor), 60.2 (C*), 58.7 (C of minor), 46.1 (t, J = 21.7 Hz, CH*), 42.8 (t, J = 21.1 Hz, CH of minor), 37.8 (CH2*), 36.6 (CH2 of minor), 35.5 (d, J = 7.0 Hz, CH2 of minor), 33.7 (d, J = 5.6 Hz, CH2*), 33.2 (d, J = 3.0 Hz, CH2*), 32.7 (d, J = 4.6 Hz, CH2 of minor); IR (neat) νmax 3590br, 1717s, 1604s, 1044s, 970m cm−1; MS m/z (%) relative intensity 431 (M+ + 1, 71), 430 (M+, 3), 413 (99), 283 (42), 116 (100), 91 (54), 77 (10); HRMS (ESI-TOF) calcd for C28H24F2NaO2 [M + Na]+ 453.1642, found 453.1683. 396

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry isomer E), −78.01 (d, J = 203.4 Hz, 1 × F of isomer E), −78.20 (d, J = 206.4 Hz, 1 × F*), −86.58 (d, J = 252.3 Hz, 1 × F*), −88.51 (d, J = 251.9 Hz, 1 × F of isomer E), −103.85 (d, J = 252.7 Hz, 1 × F*), −105.32 (d, J = 252.3 Hz, 1 × F of isomer E); 13C{1H}NMR (100 MHz, CDCl3, isomer Z marked*) δ 149.1 (t, J = 22.1 Hz, C*), 147.9 (t, J = 20.2 Hz, C of isomer E), 142.3 (2 × C of isomers Z and E), 140.1 (2 × C of isomers Z and E), 137.2 (2 × CH of isomer E), 136.9 (2 × CH*), 130.5 (t, J = 290.0 Hz, CF2*), 130.1 (t, J = 290.0 Hz, CF2 of isomer E), 129.8 (2 × CH of isomers Z and E), 129.6 (d, J = 6.0 Hz, CH*), 129.5 (CH of isomer E), 129.2 (2 × CH of isomers Z and E), 129.0 (4 × CH of isomers Z and E), 128.5 (d, J = 3.0 Hz, 2 × CH of isomers Z and E), 127.9 (d, J = 8.6 Hz, 4 × CH isomers Z and E), 127.6 (C of isomer E), 127.5 (C*), 122.2 (dd, J = 256.7, 252.1 Hz, 2 × CF2 of isomers Z and E), 105.9 (C of isomer E), 105.6 (C*), 91.9 (t, J = 26.1 Hz, 2 × C of isomers Z and E), 88.0 (t, J = 20.8 Hz, 2 × C of isomers Z and E), 87.0 (C*), 86.7 (C of isomer E), 59.5 (d, J = 5.4 Hz, 2 × C of isomers Z and E), 39.7 (CH2 of isomer E) 36.7 (CH2*), 22.1 (CH2 of isomer E) 21.6 (CH2*), 3.4 (3 × CH3 of isomer E), 3.1 (3 × CH3*), 1.8 (3 × CH3 of isomer E), 1.7 (3 × CH3*), 0.4 (3 × CH3*), 0.1 (3 × CH3 of isomer E), −0.6 (3 × CH3*), −0.7 (3 × CH3 of isomer E); IR (CHCl3) νmax 2174s, 1328m, 1252s, 1083s, 886s cm−1; MS m/z (%) relative intensity 723 (M+, 1) 564 (38), 563 (85), 309 (34), 149 (22), 73 (100); HRMS (ESI-TOF) calcd for C35H50F4NaO2SSi4 [M + Na]+ 745.2442, found, 745.243. (3aR*,8R*,8aR*)-8-(Difluoro(phenylthio)methyl)-3,3-difluoro-2((trimethylsilyl)methylene)-8-((trimethylsilyl)oxy)-8a-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3,8,8a-tetrahydrocyclopenta[a]inden-3a(1H)ol (5a′). According to the general procedure B, the reaction of 4c (491 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry THF (2 mL) in the presence of 10 mol % TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated TBAF solution (10 mL) gave a 96:4 diastereomeric mixture of 5a (304 mg, 42% yield) and a 96:4 diastereomeric mixture of 5a′ (267 mg, 41% yield) after column chromatography (SiO2, 5−10% EtOAc in hexanes) as a colorless oil. 1 H NMR (400 MHz, CDCl3, major isomer marked*) δ 7.59−7.38 (m, 8H of major and minor), 7.37−7.19 (m, 10H of major and minor), 6.05 (s, 1H*), 5.71−5.64 (1H of minor), 3.07−2.86 (m, 6H of major and minor), 2.68−2.59 (m, 1H of minor), 2.54 (dd, J = 18.1, 2.6 Hz, 1H*), 2.49−2.41 (m, 1H of minor), 2.41−2.29 (m, 1H*), 0.21 (s, 9H*), 0.08 (s, 9H of minor), 0.04 (s, 9H of minor), 0.00 (s, 9H*), −0.12 (s, 9H*), −0.13 (s, 9H of minor); 19F NMR (376 MHz, CDCl3, major isomer marked*) δ −72.31 (d, J = 205.3 Hz, 1 × F*), −72.46 (d, J = 205.3 Hz, 1 × F of minor), −77.71 (d, J = 204.2 Hz, 1 × F of minor), −77.78 (d, J = 205.3 Hz, 1 × F*), −87.35 (d, J = 251.5 Hz, 1 × F*), −87.85 (d, J = 253.8 Hz, 1 × F of minor), −104.35 (d, J = 232.7 Hz, 1 × F of minor), −104.99 (d, J = 247.5 Hz, 1 × F*); 13 C{1H}NMR (100 MHz, CDCl3, major isomer marked*) δ 148.7 (t, J = 22.1 Hz, C*), 147.6 (t, J = 21.3 Hz, C of minor), 142.4 (2 × C of major and minor), 139.9 (2 × C of major and minor), 137.0 (2 × CH*), 135.4 (2 × CH of minor), 133.3 (CH of minor), 130.4 (CH of minor), 130.2 (CH of minor), 129.7 (2 × CH*), 129.5 (2 × CH of major and minor), 129.3 (2 × CH of major and minor), 128.9 (4 × CH of major and minor), 128.2 (CH*), 127.9 (d, J = 8.6 Hz, 2 × CH of major and minor), 127.5 (t, J = 277.0, 2 × CF2 of major and minor), 127.1 (2 × C of major and minor), 122.2 (dd, J = 281.4, 251.5 Hz, 2 × CF2 of major and minor), 91.8 (t, J = 26.2 Hz, C*), 90.7 (t, J = 20.0 Hz, C of minor), 87.8 (t, J = 20.9 Hz, C*), 86.9 (t, J = 21.3 Hz, C of minor), 82.9 (2 × C of major and minor), 70.9 (C*), 70.7 (C of minor), 59.4 (d, J = 5.4 Hz, C*), 58.4 (d, J = 5.2 Hz, C of minor), 40.0 (CH2 of minor), 36.7 (CH2*), 20.5 (CH2 of minor), 20.4 (CH2*), 2.9 (3 × CH3*), 2.6 (3 × CH3 of minor), 1.70 (3 × CH3*), 0.4 (3 × CH3 of minor), 0.1 (3 × CH3 of minor), −0.7 (3 × CH3*); IR (CHCl3) νmax 3311s, 2121m, 1441m, 1251s, 843s cm−1; MS m/z (%) relative intensity 652 (M+ + 1, 5), 651 (M+, 9), 493 (44), 491 (100), 358 (8), 74 (13); HRMS (ESI-TOF) calcd for C32H42F4NaO2SSi3 [M + H]+ 673.2047, found 673.2046. (3aR*,8R*,8aS*)-8a-(But-2-yn-1-yl)-8-(difluoro(phenylthio)methyl)-2-ethylidene-3,3-difluoro-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5b). According to the general procedure B, the reaction of 4b (303 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry

THF (2 mL) in the presence of 10 mol % TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated TBAF solution (10 mL) gave a 72:28 (Z/E) mixture of 5b (393 mg, 85% yield) as a colorless oil after column chromatography (SiO2, 5−10% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, isomer Z marked*) δ 7.75−7.61 (m, 4H of isomers Z and E), 7.53−7.26 (m, 14H of isomers Z and E), 6.06−5.93 (m, 1H*) 5.75−5.64 (m, 1H of isomer E), 3.40 (s, 2H*), 3.30 (s, 2H of isomer E), 2.95−2.74 (m, 4H of isomers Z and E), 2.69−2.44 (m, 4H of isomers Z and E), 1.88−1.78 (m, 3H* and 6H of isomer E), 1.59−1.50 (m, 3H*); 19F NMR (376 MHz, CDCl3, isomer Z marked marked*) δ −78.52 (d, J = 56.4 Hz, 2 × F of isomer E), −78.74 (d, J = 45.1 Hz, 2 × F*), −89.34 (d, J = 248.2 Hz, 1 × F*), −91.21 (d, J = 255.7 Hz, 1× F of isomer E), −107.02 (d, J = 255.7 Hz, 1 × F of isomer E), 114.71 (d, J = 248.2 Hz, 1 × F*); 13C{1H}NMR (100 MHz, CDCl3, isomer Z marked marked*) δ 141.0 (C of isomer E), 140.8 (C*), 139.6 (C of isomer E), 139.3 (C*), 137.1 (4 × CH of isomers Z and E), 134.2 (dd, J = 255.1, 245.4 Hz, CF2*), 131.7 (t, J = 19.1 Hz, C*), 131.5 (t, J = 20.5 Hz, C of isomer E), 130.8 (CH*), 130.6 (CH of isomer E), 130.5 (d, J = 3.2 Hz, CH of isomer E), 130.2 (CH*), 130.1 (CH of isomer E), 130.0 (d, J = 4.1 Hz, CH*), 129.2 (4 × CH of isomers Z and E), 128.5 (dd, J = 282.5, 243.4 Hz, CF2 of isomer E), 127.5 (d, J = 8.7 Hz, CH of isomer E), 127.2 (CH of isomer E), 127.1 (2 × CH* and CH of isomer E), 126.7 (d, J = 4.2 Hz, CH*), 126.1 (C of isomer E), 125.9 (C*), 124.6 (dd, J = 280.5, 248.9 Hz, CF2 of isomer E), 123.6 (dd, J = 258.4, 245.4 Hz, CF2*), 89.1 (t, J = 25.0 Hz, C*), 88.9 (t, J = 25.1 Hz, C*), 87.8 (t, J = 20.9 Hz, C of isomer E), 86.9 (t, J = 20.9 Hz, C of isomer E), 79.2 (C of isomer E), 79.1 (C*), 76.8 (C*), 76.6 (C of isomer E), 57.8 (C of isomer E), 57.1 (C*), 37.5 (d, J = 4.2 Hz, CH2 of isomer E), 33.6 (CH2*), 20.7 (CH2*), 19.5 (CH2 of isomer E), 14.1 (CH3*), 13.9 (CH3 of isomer E), 3.8 (2 × CH3 of isomers Z and E); IR (neat) νmax 3340br, 2402s, 1650s, 1252s, 846s cm−1; MS m/z (%) relative intensity 462 (M+, 9), 304 (100), 304 (89), 287 (51), 221 (43), 162 (47), 77 (17); HRMS (ESI-TOF) calcd for C25H22F4NaO2S [M + Na]+ 485.1174, found 485.1175. A Mixture of (2S*,3aR*,8R*,8aS*)-8-(Difluoro(phenylthio)methyl)-3,3-difluoro-2-isopropyl-8a-(3-methylbut-2-en-1-yl)1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5cA) and (2R*,3aR*,8R*,8aS*)-8-(Difluoro(phenylthio)methyl)-3,3-difluoro-2isopropyl-8a-(3-methylbut-2-en-1-yl)-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5cB) and a Mixture of (2S*,3aR*,8S*,8aS*)-8-(Difluoro(phenylthio)methyl)-3,3-difluoro-2isopropyl-8a-(3-methylbut-2-en-1-yl)-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5cC) and (2R*,3aR*,8S*,8aS*)-8(Difluoro(phenylthio)methyl)-3,3-difluoro-2-isopropyl-8a-(3-methylbut-2-en-1-yl)-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8diol (5cD). According to the general procedure B, the reaction of 4c (333 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry THF (2 mL) in the presence of 10 mol % TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated TBAF solution (10 mL) gave a 86:14 diastereomeric mixture of 5cA and 5cB (356 mg, 72% yield) and a 67:33 diastereomeric mixture of 5cC and 5cD (75 mg, 15% yield) after column chromatography (SiO2, 5−10% EtOAc in hexanes). 5cA and 5cB (a colorless oil): 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.71−7.46 (m, 6H of isomers A and B), 7.41− 7.14 (m, 12H of isomers A and B), 5.28 (s, 1H*), 5.11−5.02 (m, 1H of isomer B), 3.06−2.79 (m, 4H of isomers A and B), 2.69−2.25 (m, 2H* and 3H of isomer B), 2.08−1.82 (m, 2H*), 1.65 (s, 3H*), 1.58 (s, 3H*), 1.55 (s, 3H of isomer B), 1.55−1.32 (m, 1H* and 4H of isomer B), 1.29−1.11 (m, 2H of isomers A and B), 0.90 (d, J = 6.2 Hz, 3H*), 0.85 (d, J = 6.4 Hz, 3H of isomer B), 0.84−71 (m, 4H of isomer B), 0.64 (d, J = 6.5 Hz, 3H*); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −77.97 (d, J = 207.6, 1 × F*), −78.74 (d, J = 205.7 Hz, 1 × F of isomer B), −79.09 (d, J = 206.8 Hz, 1 × F*), −80.03 (d, J = 205.3 Hz, 1 × F of isomer B), −87.8 (d, J = 238.4 Hz, 1 × F*), −108.3 (d, J = 237.6 Hz, 1 × F*), −111.8 (d, J = 230.1 Hz, 1 × F of isomer B), −124.1 (dd, J = 230.5, 27.1 Hz, 1 × F of isomer B); 13C{1H}NMR (100 MHz, CDCl3, isomer A marked*) δ 140.0 (J = 3.8 Hz, C of isomer B), 139.7 (C*), 135.7 (2 × CH of isomers A and B), 134.4 (C of isomer B), 134.2 (C*) 134.1 (2 × CH of isomer B), 133.9 (2 × CH*), 133.4 (C of isomer B), 133.3 (C*), 129.8 (t, J = 262.5 Hz, 397

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry CF2*), 129.7 (t, J = 261.1 Hz, CF2 of isomer B), 129.4 (t, J = 290.1 Hz, CF2*), 129.2 (2 × CH of isomers A and B), 129.0 (d, J = 2.2 Hz, CH*), 128.8 (CH of isomer B), 128.6 (CH*), 127.9 (2 × CH of isomers A and B), 126.8 (2 × CH*), 126.6 (d, J = 7.3 Hz, CH of isomer B), 126.3 (dd, J = 286.0 Hz, CF2 of isomer B), 125.0 (2 × CH of isomer B), 124.4 (C*), 124.2 (C of isomer B), 119.1 (CH*), 118.8 (CH of isomer B), 88.7 (dd, J = 24.8, 20.4 Hz, C*), 88.2 (t, J = 26.5 Hz, C of isomer B), 87.8 (t, J = 25.4 Hz, C*), 86.3 (t, J = 19.7 Hz, C of isomer B), 58.0 (d, J = 5.4 Hz, C*), 54.2 (s, C of isomer B), 49.1 (t, J = 21.9 Hz, CH*), 44.5 (t, J = 19.29 Hz, CH of isomer B), 31.5 (d, J = 8.9 Hz, CH2*), 31.2 (d, J = 8.7 Hz, CH2 of isomer B), 29.7 (CH2 of isomer B), 27.6 (d, J = 3.5 Hz, CH of isomer B), 26.4 (d, J = 5.8 Hz, CH*), 26.0 (CH2*), 25.1 (CH3*), 24.7 (CH3 of isomer B), 20.3 (CH3*), 19.9 (CH3 of isomer B), 19.8 (CH3 of isomer B), 19.6 (CH3*), 17.0 (CH3*), 16.8 (CH3 of isomer B); IR (neat) νmax 3392br, 1732s, 1616m, 1224s, 706s, cm−1; MS m/z (%) relative intensity 495 (M+, 0.4), 348 (74), 328 (53), 265 (82), 264 (100), 77 (21); HRMS (ESI-TOF) calcd for C27H30F4O2SNa [M + Na]+ 517.1800, found 517.1808. 5cC and 5cD (a colorless oil): 1H NMR (400 MHz, CDCl3, isomer C marked*) δ 8.09−8.03 (m, 1H*), 7.95−7.90 (m, 1H of isomer D), 7.66−7.50 (m, 6H of isomers C and D), 7.44−7.30 (m, 10H of isomers C and D), 5.49−5.38 (m, 2H of isomers C and D), 3.01 (s, 1H*), 2.30 (s, 1H*), 2.91−2.98 (m, 2H of isomer D), 2.75− 2.43 (m, 4H* and 1H of isomer D), 2.15−1.88 (m, 2H of isomers C and D), 1.75−1.68 (m, 3H* and 4H of isomer D), 1.66 (s, 6H of isomers C and D), 1.65−1.53 (m, 1H of isomer D), 1.52−1.18 (m, 1H* and 2H of isomer D), 0.94−0.85 (m, 6H of isomers C and D), 0.73 (d, J = 6.3 Hz, 3H of isomer D), 0.64 (d, J = 6.7 Hz, 3H*); 19F NMR (376 MHz, CDCl3, isomer C marked*) δ −70.03 (d, J = 210.2 Hz, 1 × F*), −71.65−(−73.95) (m, 1 × F* and 2 × F of isomer D), −91.89 (d, J = 281.6 Hz, 1 × F*), −110.08 (dd, J = 238.4, 20.3 Hz, 1 × F*), −114.99 (d, J = 229.0 Hz, 1 × F of isomer D), −123.73 (d, J = 228.6 Hz, 1 × F of isomer D); 13C{1H}NMR (100 MHz, CDCl3, isomer C marked*) δ 143.0 (C of isomer D), 142.3 (d, J = 4.5 Hz, C*), 141.9 (d, J = 4.4 Hz, C isomer D), 141.7 (d, J = 3.6 Hz, C*), 137.0 (2 × CH*), 136.9 (2 × CH of isomer D), 134.9 (C*), 134.4 (C of isomer D), 132.0 (t, J = 269.1 Hz, CF2*), 131.8 (t, J = 260.3 Hz, CF2 of isomer D), 130.7 (CH of isomer D), 130.5 (CH*), 130.1 (2 × CH*), 130.0 (2 × CH of isomer D), 129.1 (2 × CH of isomer D), 129.0 (2 × CH*), 127.8 (t, J = 247.6 Hz, CF2*), 127.4 (d, J = 7.5 Hz, CH*), 127.1 (t, J = 258.9 Hz, CF2 of isomer D), 126.9 (d, J = 8.3 Hz, CH of isomer D), 126.5 (C*), 126.4 (C of isomer D), 125.7 (CH*), 125.5 (CH of isomer D), 121.2 (d, J = 3.0 Hz, CH*),120.7 (CH of isomer D), 90.7 (t, J = 23.6 Hz, C of isomer D), 89.6 (t, J = 21.9 Hz, C*), 89.4 (t, J = 22.1 Hz, C of isomer D), 88.4 (t, J = 25.6 Hz, C*), 59.0 (d, J = 5.4 Hz, C*), 55.9 (C of isomer D), 51.1 (t, J = 21.8 Hz, CH*), 45.8 (t, J = 19.4 Hz, CH of isomer D), 32.2 (d, J = 4.1 Hz, CH2 of isomer D), 31.8 (CH2*), 31.5 (t, J = 4.2 Hz, CH2 of isomer D), 27.7 (CH*), 27.4 (CH of isomer D), 27.3 (CH2*), 26.2 (CH3 of isomer D), 26.1 (CH3*), 21.4 (CH3 of isomer D), 20.9 (2 × CH3 of isomers C and D), 20.6 (CH3*), 17.9 (2 × CH3 of isomers C and D); IR (neat) νmax 3591br, 1721s, 1605m, 1120s, 704s cm−1; MS m/z (%) relative intensity 495 (M+, 1), 348 (29), 265 (61), 264 (100), 77 (11); HRMS (ESI-TOF) calcd for C27H30F4O2SNa [M + Na]+ 517.1800, found 517.1806. A Mixture of (2R*,3aR*,8R*)-2-Benzyl-8a-cinnamyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5dA) and (2S*,3aR*,8R*)-2-Benzyl-8acinnamyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-1,2,3,3a,8,8ahexahydrocyclopenta[a]indene-3a,8-diol (5dB) and a Mixture of (2R*,3aR*,8S*)-2-Benzyl-8a-cinnamyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene3a,8-diol (5dC) and (2S*,3aR*,8S*)-2-Benzyl-8a-cinnamyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-3a,8-diol (5dD). According to the general procedure B, the reaction of 4d (431 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry THF (2 mL) in the presence of 10 mol % TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated TBAF solution (10 mL) gave a 74:26 diastereomeric mixture of 5dA and 5dB (431 mg, 73% yield) and a 65:35 diastereomeric mixture of 5dC and 5dD (106 mg, 18% yield) as a pale yellow oil after

column chromatography (SiO2, 5−10% EtOAc in hexanes). 5dA and 5dB: 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.88−7.52 (m, 6H of isomers A and B), 7.53−6.89 (m, 32H of isomers A and B), 6.48 (d, J = 15.9 Hz, 1H*), 6.34−6.19 (m, 1H*), 6.13 (d, J = 15.8 Hz, 1H of isomer B), 5.75−5.65 (m, 1H of isomer B), 3.20 (s, 1H of isomer B), 3.07−2.89 (m, 3H*), 2.88−2.77 (m, 1H* and 3H of isomer B), 2.76−2.64 (m, 2H of isomers A and B), 2.62−2.52 (m, 2H of isomers A and B), 2.35−2.25 (m, 1H of isomer B), 2.06−1.92 (m, 2H*), 1.92−1.75 (m, 1H of isomer B), 1.71−1.58 (m, 1H of isomer B), 1.38 (t, J = 13.0 Hz, 1H*); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −78.20 (d, J = 206.8 Hz, 1 × F*), −78.38 (d, J = 204.5 Hz, 1 × F of isomer B), −79.36 (d, J = 207.2 Hz, 1 × F*), −79.98 (d, J = 205.3 Hz, 1 × F of isomer B), −94.20 (d, J = 248.5 Hz, 1 × F*), −107.86 (dd, J = 235.0, 12.0 Hz, 1 × F*), −118.04 (d, J = 228.2 Hz, 1 × F of isomer B), −124.07 (d, J = 229.4, 26.3 Hz, 1 × F of isomer B); 13 C{1H}NMR (100 MHz, CDCl3, isomer A marked*) δ 149.3 (C of isomer B), 148.8 (C*), 141.0 (C*), 140.9 (C of isomer B), 139.0 (2 × C of isomers A and B),137.5 (C*), 137.3 (C of isomer B), 136.9 (2 × CH of isomers A and B), 136.8 (CH of isomer B), 136.7 (CH*), 134.6 (CH of isomer B), 134.2 (t, J = 281.2 Hz, CF2*), 134.1 (CH*), 133.6 (t, J = 226.4 Hz, CF2 of isomer B), 133.4 (2 × CH of isomers A and B), 131.3 (CH of isomer B),131.0 (CH*), 130.4 (CH*), 130.3 (2 × CH of isomer B), 130.2 (CH*), 129.3 (4 × CH of isomers A and B), 128.8 (2 × CH of isomer B), 128.7 (2 × CH*), 128.6 (4 × CH of isomers A and B), 128.4 (t, J = 295.8 Hz, CF2 of isomer B), 127.8 (t, J = 257.3 Hz, CF2*), 127.7 (d, J = 6.9 Hz, 2 × CH of isomer B), 127.4 (2 × CH*), 126.4 (8 × CH of isomers A and B), 125.4 (2 × C of isomers A and B), 125.2 (2 × CH of isomers A and B), 123.8 (CH of isomer B), 123.4 (CH*), 89.6 (t, J = 23.9 Hz, C*), 89.0 (t, J = 23.5 Hz, C*), 86.3 (t, J = 23.4 Hz, C of isomer B), 87.4 (t, J = 18.7 Hz, C of isomer B), 63.1 (C*), 59.3 (d, J = 5.3 Hz, C of isomer B), 44.5 (t, J = 22.7 Hz, CH*), 41.4 (t, J = 20.0 Hz, CH of isomer B) 39.5 (CH2*), 36.6 (CH2 of isomer B), 34.5 (d, J = 7.9 Hz, CH2*), 34.0 (d, J = 5.6 Hz, CH2 of isomer B), 33.7 (d, J = 7.4 Hz, CH2*), 32.7 (d, J = 7.9 Hz, CH2 of isomer B); IR (neat) νmax 3591s, 1717s, 1604s, 1187s, 1093s, 698s cm−1; MS m/z (%) relative intensity 591 (M+, 4), 446 (97), 414 (54), 257 (23), 166 (11), 115 (100), 91 (40); HRMS (ESI-TOF) calcd for C35H30F4NaO2S [M + Na]+ 613.1800, found 613.1798. 5dC and 5dD: 1H NMR (400 MHz, CDCl3, isomer C marked*) δ 7.73− 7.55 (m, 6H of isomers C and D), 7.53−7.38 (m, 4H of isomers C and D), 7.37−6.93 (m, 28H of isomers C and D), 6.43 (d, J = 15.8 Hz, 1H of isomer D), 6.35−6.28 (m, 1H*), 6.21−6.14 (m, 1H of isomer D), 6.06−5.94 (m, 1H*), 3.09−2.94 (m, 2H* and 1H of isomer D), 2.93− 2.78 (m, 2H* and 3H of isomer D), 2.63−2.49 (m, 1H* and 2H of isomer D), 2.35−2.24 (m, 1H*), 2.08−1.68 (m, 2H* and 3H of isomer D), 1.38 (t, J = 13.1 Hz, 1H*); 19F NMR (376 MHz, CDCl3, isomer C marked*) δ −76.56 (d, J = 205.3 Hz, 1 × F*), −77.05 (d, J = 212.7 Hz, 1 × F of isomer D), −78.01 (d, J = 204.9 Hz, 1 × F*), −78.20 (d, J = 188.3 Hz, 1 × F isomer D), −86.53 (dd, J = 252.3, 21.4 Hz, 1 × F*), −106.27 (dd, J = 233.3, 10.2 Hz, 1 × F*), −115.03 (d, J = 227.9 Hz, 1 × F of isomer D), −119.84 (dd, J = 227.7, 25.2 Hz, 1 × F of isomer D); 13C{1H}NMR (100 MHz, CDCl3, isomer C marked*) δ 139.8 (C of isomer D), 139.6 (C*), 137.8 (C of isomer D), 137.6 (2 × C*), 137.2 (C of isomer D), 136.2 (C*), 136.0 (C of isomer D), 135.7 (2 × CH of isomers C and D), 135.6 (t, J = 249.8 Hz, CF2 of isomer D), 135.5 (t, J = 223.4 Hz, CF2*), 134.9 (CH of isomer D), 134.6 (2 × CH*), 133.0 (CH of isomer D), 132.8 (2 × CH of isomers C and D), 132.2 (CH*), 129.7 (CH of isomer D), 129.5 (2 × CH*), 129.1 (CH of isomer D), 129.0 (CH of isomer D), 128.1 (2 × CH of isomer D), 127.7 (2 × CH*), 127.5 (4 × CH of isomers C and D), 127.4 (2 × CH*), 126.6 (d, J = 6.9 Hz, CH of isomer D), 126.4 (CH of isomer D), 126.3 (CH*), 126.2 (2 × CH of isomers C and D), 125.6 (t, J = 253.8 Hz, CF2 of isomer D), 125.5 (t, J = 259.9 Hz, CF2*), 125.4 (2 × CH of isomer D), 125.3 (2 × CH of isomer D), 125.2 (4 × CH*), 124.1 (2 × CH of isomers C and D), 123.9 (CH*), 123.7 (CH of isomer D), 122.8 (C of isomer D), 122.6 (C*), 122.4 (CH of isomer D), 88.4 (t, J = 23.3 Hz, C of isomer D), 87.7 (t, J = 24.2 Hz, C*), 84.6 (t, J = 24.2 Hz, C*), 84.3 (t, J = 21.1 Hz, C of isomer D), 58.1 (d, J = 6.5 Hz, C*), 57.5 (d, J = 4.3 Hz, C of isomer D), 43.2 (t, J = 22.7 Hz, CH*), 41.5 (t, J = 21.1 Hz, CH of 398

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry

of isomer B), −110.39 (d, J = 242.1 Hz, 1 × F of isomer B), −112.28 (d, J = 240.3 Hz, 2 × F*); 13C{1H}NMR (100 MHz, CDCl3 isomer A marked*) δ 148.4 (t, J = 20.2 Hz, C of isomer B), 148.1 (t, J = 20.6 Hz, 2 × C*), 147.6 (t, J = 20.8 Hz, C of isomer B), 141.0 (2 × C of isomer B), 140.9 (2 × C*), 132.8 (CH of isomer B),130.8 (CH of isomer B), 130.7 (2 × CH*), 128.5 (2 × CH of isomer B), 128.3 (2 × CH*), 128.0 (dd, J = 259.7, 246.0 Hz, CF2 of isomer B), 125.7 (CH of isomer B), 125.6 (2 × CH* and CH of isomer B), 123.5 (dd, J = 258.8, 248.5 Hz, CF2 of isomer B), 122.1 (dd, J = 257.2, 249.0 Hz, 2 × CF2*), 88.0. (t, J = 24.7 Hz, C of isomer B), 87.8 (t, J = 21.7 Hz, C of isomer B), 87.4 (d, J = 21.8 Hz, 2 × C*), 56.9 (C*), 56.3 (C of isomer B), 39.0 (2 × CH2 of isomer B), 35.2 (2 × CH2*), 0.0 (3 × CH3 of isomer B), −0.4 (3 × CH3 of isomer B), −0.9 (6 × CH3*); IR (neat) νmax 3594br, 1654m, 1066s, 1016s, 854s cm−1; MS m/z (%) relative intensity 471 (M+, 0.2), 377 (37), 376 (100), 215 (12), 77 (12), 73 (47); HRMS (ESI-TOF) calcd for C23H30F4NaO2Si2 [M + Na]+ 493.1618, found, 493.1619. A Mixture of (2Z,5Z,6aR*,10bR*)-2,5-Diethylidene-1,1,6,6-tetrafluoro-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6bA) and (2Z,5E,6aR*,10bR*)-2,5-Diethylidene-1,1,6,6tetrafluoro-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6bB). According to the general procedure C, the reaction of 5b (464 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 85:15 diastereomeric mixture of 6bA and 6bB (283 mg, 80% yield) as a colorless oil after column chromatography (SiO2, 5−10% in hexanes). 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.48− 7.41 (m, 4H of isomers A and B), 7.39−7.32 (m, 4H of isomers A and B), 5.95−5.83 (m, 2H*), 5.74−5.66 (m, 2H isomer B), 3.14 (d, J = 17.5 Hz, 2H*), 3.04−2.95 (m, 2H of isomer B), 2.66−2.59 (m, 2H*), 2.57−2.53 (m, 2H of isomer B), 2.48−2.37 (m, 2H of isomer B), 2.27 (d, J = 17.6 Hz, 2H*), 1.78−1.71 (m, 3H of isomer B), 1.63−1.57 (m, 3H of isomer B), 1.50 (d, J = 16.3 Hz, 6H*); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −102.70 (d, J = 253.8 Hz, 1 × F of isomer B), −104.18 (d, J = 253.4 Hz, 1 × F of isomer B), −104.40 (d, J = 242.5 Hz, 1 × F of isomer B), −105.58 (d, J = 241.4 Hz, 2 × F*), −111.05 (d, J = 241.8 Hz, 2 × F*), −112.52 (d, J = 241.4 Hz, 1 × F of isomer B); 13C{1H}NMR (100 MHz, CDCl3, isomer A marked*) δ 139.8 (2 × C*), 139.7 (C of isomer B), 132.2 (t, J = 20.0 Hz, 2 × C*), 131.6 (t, J = 21.7 Hz, C of isomer B), 129.4 (2 × CH*), 129.4 (2 × CH of isomer B), 127.5 (2 × CH of isomer B), 127.3 (C of isomer B), 124.5 (d, J = 3.5 Hz, 2 × CH*), 124.4 (d, J = 3.3 Hz, 2 × CH of isomer B), 123.9 (t, J = 4.4 Hz, 2 × CH*), 123.1 (t, J = 238.8 Hz, CF2 of isomer B), 122.8 (t, J = 236.7 Hz, CF2 of isomer B), 122.1 (dd, J = 255.9, 247.1 Hz, 2 × CF2*), 120.4 (t, J = 17.2 Hz, C of isomer B), 87.2 (t, J = 22.4 Hz, 2 × C*), 85.6 (t, J = 29.3 Hz, C of isomer B), 84.7 (t, J = 30.8 Hz, C of isomer B), 62.7 (C of isomer B), 55.8 (C*), 35.3 (CH2 of isomer B), 30.7 (2 × CH2*), 30.1 (CH2 of isomer B), 22.4 (CH3 of isomer B), 12.9 (2 × CH3*), 12.4 (CH3 of isomer B); IR (CHCl3) νmax 3591s, 1691m, 1062s, 833s cm−1; MS m/z (%) relative intensity 354 (M+, 1), 337 (16), 235 (20), 233 (100), 230 (18), 78 (4); HRMS (ESI-TOF) calcd for C19H18F4NaO2 [M + Na]+ 377.1141, found 377.1155. A Mixture of (2S*,5S*,6aR*,10bR*)-1,1,6,6-Tetrafluoro-2,5-diisopropyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6cA) and (2R*,5S*,6aR*,10bR*)-1,1,6,6-Tetrafluoro2,5-diisopropyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene-6a,10b-diol (6cB). According to the general procedure C, the reaction of a mixture of 5cA and 5cB (492 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 82:18 diastereomeric mixture of 6cA and 6cB (343 mg, 89% yield) as a colorless oil after column chromatography (SiO2, 5−10% in hexanes). 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.55−7.49 (m, 1H of isomer B), 7.45− 7.35 (m, 4H* and 2H of isomer B), 7.34−7.30 (m, 1H of isomer B), 2.88−2.79 (m, 3H of isomer B), 2.62−2.51 (m, 2H*), 2.27−2.07 (m, 2H* and 1H of isomer B), 2.00 (dd. J = 13.1, 13.1 Hz, 2H* and 1H of

isomer D), 34.3 (d, J = 7.0 Hz, CH2 of isomer D), 33.3 (d, J = 7.9 Hz, CH2 of isomer D), 32.5 (2 × CH2*), 31.9 (d, J = 3.2 Hz, CH2*), 31.8 (CH2 of isomer D); IR (neat) νmax 3499s, 1707s, 1623s, 1207s, 695s cm−1; MS m/z (%) relative intensity 591 (M+, 2), 447 (13), 441 (80), 166 (15), 115 (100), 91 (32); HRMS (ESI-TOF) calcd for C35H30F4NaO2S [M + Na]+ 613.1800, found 613.1799. A Mixture of (2R*,3aR*,8R*,8aS*)-8a-Allyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-2-methyl-8-((trimethylsilyl)oxy)1,2,3,3a,8,8a-hexahydrocyclopenta[a]inden-3a-ol (5eA) and (2S*,3aR*,8R*,8aS*)-8a-Allyl-8-(difluoro(phenylthio)methyl)-3,3-difluoro-2-methyl-8-((trimethylsilyl)oxy)-1,2,3,3a,8,8a-hexahydrocyclopenta[a]inden-3a-ol (5eC). According to the general procedure B, the reaction of trans-4e (278 mg, 1 mmol) with 1 (464 mg, 2 mmol) in dry THF (2 mL) in the presence of 10 mol % TBAF (1.0 M in dry THF, 0.2 mL, 0.2 mmol) followed by quenching with saturated NaHCO3 solution (10 mL) gave 5eA (357 mg, 70% yield) and 5eC (76 mg, 15% yield) as a colorless oil after column chromatography (SiO2, 5−10% EtOAc in hexanes). 5eA: 1H NMR (400 MHz, CDCl3) δ 7.66−7.56 (m, 2H), 7.52−7.28 (m, 7H), 6.08−5.92 (m, 1H), 5.12 (d, J = 12.3 Hz, 2H), 2.95−2.82 (m, 2H), 2.42−2.33 (m, 2H), 1.48− 1.38 (m, 2H), 0.89 (d, J = 6.1 Hz, 3H), 0.10 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −77.98 (d, J = 201.9 Hz, 1 × F), −78.70 (d, J = 201.9 Hz, 1 × F), −117.88 (d, J = 225.6 Hz, 1 × F), −123.65 (dd, J = 225.6, 26.3 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 142.0 (C), 141.5 (C), 137 (2 × CH), 135.9 (CH), 131.0 (dd, J = 296.0, 286.7 Hz, CF2), 130.1 (CH and C), 130.0 (CH), 129.5 (CH), 129.1 (2 × CH), 128.4 (dd, J = 261.0, 254.4 Hz, CF2), 126.8 (d, J = 7.8 Hz, CH), 126.3 (CH), 118.7 (CH2), 89.2 (t, J = 23.2 Hz, C), 88.0 (t, J = 19.9 Hz, C), 57.5 (C), 37.6 (CH2), 34.5 (t, J = 21.1 Hz, CH), 33.4 (d, J = 8.4 Hz, CH2), 11.6 (d, J = 6.3 Hz, CH3), 2.2 (3 × CH3); IR (neat) νmax 3481s, 1687s 1452s, 1108s, 701s cm−1; MS m/z (%) relative intensity 511 (M+, 1), 351 (44), 261 (100), 221 (62), 193 (32), 73 (20); HRMS (ESI-TOF) calcd for C26H30F4O2NaSSi [M + Na]+ 533.1570, found 533.1582; 5eC: 1H NMR (400 MHz, CDCl3) δ 7.71−7.62 (m, 2H), 7.55−7.28 (m, 7H), 6.14−5.98 (m, 1H), 5.17−5.06 (m, 2H), 2.94 (d, J = 15.6 Hz, 1H), 2.67 (s, 1H), 2.43−2.22 (m, 2H), 2.14−2.02 (m, 1H), 1.09 (t, J = 12.2 Hz, 1H), 0.76 (dd, J = 7.0, 2.5 Hz, 3H), 0.00 (s, 9H); 19 F NMR (376 MHz, CDCl3) δ −76.63 (d, J = 204.5 Hz, 1 × F), −78.09 (d, J = 204.9 Hz, 1 × F), −85.74 (dd, J = 233.1, 25.0 Hz, 1 × F), −108.58 (d, J = 233.5 Hz, 1 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 142.0 (C), 141.2 (C), 136.9 (2 × CH), 135.9 (CH), 130.6 (t, J = 289.0 Hz, CF2), 129.7 (CH), 129.3 (CH), 129.2 (CH), 128.9 (2 × CH), 128.0 (d, J = 9.1 Hz, CH), 127.3 (C), 126.8 (CH), 126.1 (t, J = 255.1 Hz, CF2), 117.6 (CH2), 90.6 (t, J = 21.6 Hz, C), 88.8 (t, J = 23.9 Hz, C), 60.5 (d, J = 7.1 Hz, C), 37.3 (t, J = 24.3 Hz, CH), 35.1 (d, J = 7.3 Hz, CH2), 32.9 (CH2), 13.7 (d, J = 10.2 Hz, CH3), 1.7 (3 × CH3); IR (neat) 3385s, 1698s, 1489s,1208s, 705s cm−1; MS m/z (%) relative intensity 511 (M+, 3), 310 (62), 261 (50), 261 (100), 221 (52), 193 (35), 73 (43); HRMS (ESI-TOF) calcd for C26H30F4O2NaSSi [M + Na]+ 533.1570, found 533.1579. Preparation of gem-Difluoromethylenated Angular Triquinanes 6a−e and 7a. A Mixture of (2Z,5Z,6aR*,10bR*)-1,1,6,6-Tetrafluoro2,5-bis((trimethylsilyl)methylene)-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene-6a,10b-diol (6aA) and (2Z,5E,6aR*,10bR*)-1,1,6,6-Tetrafluoro-2,5-bis((trimethylsilyl)methylene)-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6aB). According to the general procedure C, the reaction of 5a (725 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 86:14 diastereomeric mixture of 6aA and 6aB (428 mg, 91% yield) as a colorless oil after column chromatography (SiO2, 5−10% in hexanes). 1 H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.56−7.38 (m, 8H of isomers A and B), 5.99 (s, 2H*), 5.80 (d, J = 5.6 Hz, 2H of isomer B), 3.27 (dd, J = 17.3, 8.5 Hz, 2H*), 3.17 (d, J = 17.6 Hz, 2H of isomer B), 2.79−2.48 (m, 4H of isomer B and 2H*), 2.40 (dd, J = 17.4, 2.0 Hz, 2H*), 0.08 (s, 18H*), 0.03 (s, 18H of isomer B); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −106.51 (d, J = 246.3 Hz, 1 × F of isomer B), −108.91 (d, J = 240.6 Hz, 2 × F*), −109.22 (d, J = 242.3 Hz, 1× F of isomer B), −109.41 (d, J = 246.3 Hz, 1 × F 399

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry

(CH3*), 19.8 (2 × CH3 of isomer D), 19.5 (2 × CH3*), 19.1 (CH3 of isomer D); IR (KBr) νmax 3568br, 1467s, 1193s, 876m cm−1; MS m/z (%) relative intensity 386 (M+, 5), 292 (42), 274 (22), 148 (23), 65 (17); HRMS (ESI-TOF) calcd for C21H26F4NaO2 [M + Na]+ 409.1767, found 409.1763. A Mixture of (2R*,5R*,6aR*,10bR*)-2,5-Dibenzyl-1,1,6,6-tetrafluoro-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6dA) and (2R*,5S*,6aR*,10bR*)-2,5-Dibenzyl-1,1,6,6tetrafluoro-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6dB). According to the general procedure C, the reaction of a mixture of 5dA and 5dB (590 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 87:13 diastereomeric mixture of 6dA and 6dB (441 mg, 91% yield) as a colorless oil after column chromatography (SiO2, 5−10% in hexanes). 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.43−7.33 (m, 8H of isomers A and B), 7.24−7.04 (m, 20H of isomers A and B), 2.97 (dd, J = 13.9, 4.3 Hz, 1H of isomer B), 2.90 (dd, J = 13.9, 4.7 Hz, 2H*), 2.82 (dd, J = 13.9, 4.3 Hz, 1H of isomer B), 2.74−2.55 (m, 8H of isomers A and B), 2.46 (dd, J = 13.6, 9.7 Hz, 2H*), 2.15 (t, J = 12.5 Hz, 1H of isomer B), 2.04 (t, J = 12.9 Hz, 2H*), 1.45−1.34 (m, 2H*), 1.29−1.03 (m, 2H of isomer B), 0.89− 0.69 (m, 2H of isomer B), 0.67−0.56 (m, 1H of isomer B); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −111.59 (d, J = 230.5 Hz, 1 × F of isomer B), −115.44 (dd, J = 229.0, 22.9 Hz, 2 × F*), −116.91 (d, J = 227.9 Hz, 2 × F*), −118.07 (d, J = 235.0 Hz, 1 × F of isomer B), −119.63 (d, J = 224.5 Hz, 1 × F of isomer B), −126.76 (dd, J = 224.3, 26.9 Hz, 1 × F of isomer B); 13C{1H}NMR (100 MHz, CDCl3 isomer A marked*) δ 141.1 (C of isomer B), 140.7 (d, J = 3.0 Hz, 2 × C*), 140.5 (C of isomer B), 139.4 (C of isomer B), 139.3 (2 × C*), 139.0 (C of isomer B), 130.8 (CH of isomer B), 130.6 (2 × CH*), 130.5 (CH of isomer B), 129.1 (4 × CH*), 129.0 (2 × CH of isomer B), 128.9 (2 × CH of isomer B), 128.7 (4 × CH*), 128.6 (2 × CH of isomer B), 128.4 (2 × CH of isomer B), 127.6 (t, J = 227.5 Hz, CF2 of isomer B), 127.3 (CH of isomer B), 126.7 (t, J = 257.8 Hz, 2 × CF2*),126.6 (2 × CH*), 126.5 (CH of isomer B), 126.2 (t, J = 223.7 Hz, CF2 of isomer B), 125.1 (2 × CH*), 125.0 (CH of isomer B), 124.3 (CH of isomer B), 88.6 (J = 28.3, 20.4 Hz, 2 × C*), 88.5 (t, J = 21.1 Hz, C of isomer B), 88.2 (t, J = 17.8 Hz, C of isomer B), 58.7 (C*), 56.7 (C of isomer B), 46.2 (t, J = 21.8 Hz, 2 × CH*), 45.8 (t, J = 21.7 Hz, CH of isomer B), 43.0 (t, J = 18.6 Hz, CH of isomer B), 35.5 (d, J = 6.9 Hz, CH2 of isomer B), 34.1 (d, J = 6.8 Hz, 2 × CH2*), 33.0 (d, J = 4.0 Hz, 2 × CH2*), 32.6 (d, J = 4.6 Hz, CH2 of isomer B), 29.1 (CH2 of isomer B), 27.5 (CH2 of isomer B); IR (neat) νmax 3592s, 1604m, 1456s, 1031m, 938s cm−1; MS m/z (%) relative intensity 483 (M+, 5), 263 (100), 248 (67), 229 (17), 91 (1); HRMS (ESI-TOF) calcd for C29H26F4NaO2 [M + Na]+ 505.1767, found 505.1763. A Mixture of (2R*,5R*,6aR*,10bR*)-1,1,6,6-Tetrafluoro-2,5-dimethyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6eA) and (2R*,5S*,6aR*,10bR*)-1,1,6,6-Tetrafluoro2,5-dimethyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6eB). According to the general procedure C, the reaction of a mixture of 5eA (493 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 74:26 diastereomeric mixture of 6eA and 6eB (271 mg, 82% yield) as a colorless oil after column chromatography (SiO2, 5−10% in hexanes). 1H NMR (400 MHz, CDCl3, isomer A marked*) δ 7.54− 7.33 (m, 8H of isomers A and B), 2.62−2.29 (m, 8H of isomers A and B), 2.03−1.94 (m, 2H of isomer B), 1.89 (t, J = 13.2 Hz, 2H*), 1.61− 1.47 (m, 2H*), 1.37−1.20 (m, 2H of isomer B), 1.03 (d, J = 6.4 Hz, 6H*), 1.00 (d, J = 10.0 Hz, 3H of isomer B), 0.96 (d, J = 6.8 Hz, 3H of isomer B). 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −116.49 (dd, J = 223.7, 9.4 Hz, 1 × F of isomer B), −118.12 (dd, J = 229.4, 22.6 Hz, 2 × F*), −119.12 (dd, J = 225.6, 22.6 Hz, 1 × F of isomer B), −119.91 (d, J = 229.4 Hz, 2 × F*), −120.69 (d, J = 221.8 Hz, 1 × F of isomer B), −128.94 (dd, J = 223.7, 22.6 Hz, 1 × F of isomer B). 13C{1H}NMR (100 MHz, CDCl3 isomer A marked*) δ

isomer B), 1.89−1.74 (m, 4H of isomers A and B), 1.73−1.66 (m, 2H* and 1H of isomer B), 1.42−1.21 (m, 2H of isomer B), 1.05 (dd, J = 6.6, 2.0 Hz, 6H*), 1.02 (dd, J = 6.5, 2.0 Hz, 6H of isomer B), 0.91 (d, J = 8.0 Hz, 6H*), 0.85 (d, J = 6.8 Hz, 6H of isomer B); 19F NMR (376 MHz, CDCl3, isomer A marked*) δ −110.84 (d, J = 231.6 Hz, 2 × F*), −113.82 (d, J = 231.2, 1 × F of isomer B), −114.06 (d, J = 226.0 Hz, 1 × F of isomer B), −114.56 (dd, J = 231.2, 26.3 Hz, 2 × F*) −117.11 (dd, J = 229.9, 26.9 Hz, 1 × F of isomer B), −127.51 (dd, J = 226.7, 26.9 Hz, 1 × F of isomer B); 13C{1H}NMR (100 MHz, CDCl3, isomer A marked*) δ 142.1 (C of isomer B), 141.1 (C of isomer B), 140.9 (d, J = 4.0 Hz, 2 × C*), 130.5 (2 × CH of isomer B), 130.4 (2 × CH*), 128.6 (dd, J = 298.0, 220.0 Hz, CF2 of isomer B), 127.7 (dd, J = 245.0, 237.0 Hz, CF2 of isomer B), 127.2 (dd, J = 246.0, 236.0 Hz, 2 × CF2*), 126.9 (d, J = 4.0 Hz, CH of isomer B), 125.1 (2 × CH*), 123.5 (CH of isomer B), 89.9 (dd, J = 24.0, 17.0 Hz, C of isomer B), 89.0 (dd, J = 23.0, 16.0 Hz, 2 × C*), 88.1 (t, J = 17.0 Hz, C of isomer B), 57.7 (C*), 55.1 (C of isomer B), 50.9 (dd, J = 18.5, 15.5 Hz, 2 × CH*), 50.3 (dd, J = 18.5, 15.0 Hz, CH of isomer B), 47.3 (dd, J = 17.0, 14.0 Hz, CH of isomer B), 35.2 (d, J = 6.0 Hz, CH2 of isomer B), 34.6 (d, J = 7.0 Hz, CH2 of isomer B), 33.6 (d, J = 7.0 Hz, 2 × CH2*), 27.3 (d, J = 2.0 Hz, CH of isomer B), 27.2 (CH of isomer B), 27.0 (2 × CH*), 21.8 (2 × CH3*), 21.3 (2 × CH3*), 21.2 (2 × CH3 of isomer B), 21.1 (2 × CH3 of isomer B); IR (neat) νmax 3567br, 1466s, 1193s, 896m cm−1; MS m/z (%) relative intensity 386 (M+, 4), 292 (45), 274 (52), 148 (65), 91 (88), 65 (25); HRMS (ESI-TOF) calcd for C21H26F4NaO2 [M + Na]+ 409.1767, found 409.1760. A Mixture of (2R*,5R*,6aR*,10bS*)-1,1,6,6-Tetrafluoro-2,5-diisopropyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene6a,10b-diol (6cC) and (2S*,5S*,6aR*,10bS*)-1,1,6,6-Tetrafluoro2,5-diisopropyl-1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene-6a,10b-diol (6cD). According to the general procedure C, the reaction of a mixture of 5cC and 5cD (493 mg, 1 mmol) in dry toluene (25 mL) with a solution of Bu3SnH (0.5 mL, 1.75 mmol), AIBN (16 mg, 0.1 mmol) in dry toluene (25 mL) at reflux followed by the removal of tin byproduct and column chromatography (SiO2, 2% EtOAc in hexanes) gave a 51:49 diastereomeric mixture of 6cC and 6cD (274 mg, 71% yield) as a colorless crystal after column chromatography (SiO2, 5−10% in hexanes). Mp 185−187 οC; 1H NMR (400 MHz, CDCl3, isomer C marked*) δ 7.66−7.58 (m, 2H of isomers C and D), 7.40−7.25 (m, 6H of isomers C and D), 3.33 (d, J = 2.0 Hz, 1H of isomer D) 3.29 (s, 1H of isomer D), 3.02 (s, 1H*), 2.87 (s, 1H*), 2.56−2.23 (m, 3H* and 1H of isomer D), 2.12−1.83 (m, 1H* and 3H of isomer D), 1.72−1.58 (m, 1H* and 2H of isomer D), 1.47−1.33 (m, 1H*), 1.32−1.15 (m, 1H* and 2H of isomer D), 1.05 (d, J = 2.7 Hz, 3H of isomer D), 1.03 (d, J = 2.8 Hz, 3H*), 0.95 (dd, J = 6.6, 2.2 Hz, 1H*), 0.92 (d, J = 6.3 Hz, 6H of isomer D), 0.89 (d, J = 6.5 Hz, 6H*), 0.68 (d, J = 6.7 Hz, 3H of isomer D), 0.59 (d, J = 6.7 Hz, 3H*); 19F NMR (376 MHz, CDCl3, isomer C marked*) δ −85.07 (dd, J = 239.1, 29.7 Hz, 1 × F of isomer D), −90.18 (dd, J = 236.1, 25.9 Hz, 1 × F of isomer D), −92.02 (dd, J = 229.5, 27.4 Hz, 1 × F of isomer D), −116.40 (d, J = 238.0 Hz, 1 × F*), −116.81 (d, J = 230.1 Hz, 1 × F*), −121.5 (d, J = 236.5 Hz, 1 × F*), −122.86 (dd, J = 229.5, 24.3 Hz, 1 × F of isomer D), −123.69 (d, J = 235.0 Hz, 1 × F*); 13C{1H}NMR (100 MHz, CDCl3, isomer C marked*) δ 147.0 (d, J = 4.7 Hz, C*), 145.9 (d, J = 2.5 Hz, C of isomer D), 140.2 (C*), 139.9 (C of isomer D), 128.7 (CH*), 128.6 (2 × CH of isomers C and D), 128.2 (CH of isomer D), 128.1 (d, J = 9.0 Hz, CH*), 127.0 (dd, J = 250.9, 230.9 Hz, CF2*), 126.8 (dd, J = 242.7, 226.1 Hz, CF2*), 126.5 (d, J = 5.6 Hz, CH of isomer D), 124.7 (dd, J = 265.9, 255.9 Hz, CF2 of isomer D), 124.2 (dd, J = 237.5, 216.8 Hz, CF2 of isomer D), 122.1 (CH*), 121.6 (CH of isomer D), 90.9 (dd, J = 35.2, 30.1 Hz, C*), 90.7 (dd, J = 35.1, 30.6 Hz, C*), 84.2 (t, J = 23.8 Hz, C of isomer D), 82.6 (t, J = 22.4 Hz, C of isomer D), 57.6 (dd, J = 7.3, 5.0 Hz, C*), 56.9 (t, J = 21.9 Hz, CH of isomer D), 56.5 (t, J = 22.4 Hz, CH*), 56.2 (t, J = 4.7 Hz, C of isomer D), 49.7 (t, J = 21.1 Hz, CH of isomer D), 45.1(t, J = 19.4 Hz, CH*), 35.7 (t, J = 7.7 Hz, CH2*), 34.8 (t, J = 5.5 Hz, CH2 of isomer D), 32.2 (d, J = 3.4 Hz, CH2 of isomer D), 27.6 (d, J = 2.6 Hz, CH2*), 27.9 (s, CH of isomer D), 27.6 (d, J = 2.6 Hz, CH of isomer D), 26.7 (d, J = 4.0 Hz, CH*), 21.4 (d, J = 5.0 Hz, CH3 of isomer D), 21.3 (d, J = 4.4 Hz, CH3*), 20.6 (d, J = 3.6 Hz, CH*), 19.9 400

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

The Journal of Organic Chemistry 141.2 (C of isomer B), 140.9 (C of isomer B), 140.6 (d, J = 4.0 Hz, 2 × C*), 130.3 (2 × CH of isomer B), 130.2 (2 × CH*), 128.4 (dd, J = 215.5, 200.5 Hz, CF2 of isomer B), 127.5 (dd, J = 243.5, 235.5 Hz, CF2 of isomer B), 127.0 (dd, J = 213.5, 202.0 Hz, 2 × CF2*), 126.6 (d, J = 5.0 Hz, CH of isomer B), 124.9 (2 × CH*), 123.8 (CH of isomer B), 88.8 (dd, J = 24.0, 16.0 Hz, 2 × C*), 87.9 (t, J = 16.5 Hz, C of isomer B), 87.4 (t, J = 14.5 Hz, C of isomer B), 58.5 (C of isomer B), 56.6 (C*), 51.8 (t, J = 21.0 Hz, CH of isomer B), 50.7 (dd, J = 19.0, 15.0 Hz, 2 × CH*), 49.9 (t, J = 16.5 Hz, CH of isomer B), 34.0 (d, J = 7.0 Hz, CH2 of isomer B), 33.4 (d, J = 6.0 Hz, 2 × CH2*), 32.7 (d, J = 9.0 Hz, CH2 of isomer B), 21.2 (d, J = 3.0 Hz, CH3 of isomer B), 21.1 (d, J = 2.0 Hz, 2 × CH3*), 21.0 (d, J = 3.0 Hz, CH3 of isomer B); IR (neat) νmax 3544s, 1653m, 1435s, 1155s, 962m cm−1; MS m/z (%) relative intensity 330 (M+, 3), 264 (22), 262 (34), 248 (100), 91 (8); HRMS (ESI-TOF) calcd for C17H18F4NaO2 [M + Na]+ 353.1141, found 353.1132. (6aR*,10bR*)-1,1,6,6-Tetrafluoro-2,5-dimethylene1,2,3,4,5,6,6a,10b-octahydrodicyclopenta[a,b]indene-6a,10b-diol (7a). A mixture of 6a (472 mg, 1 mmol) was treated with TBAF (784 mg, 3 mmol) at 0 °C in DMF (5 mL) for 24 h. The reaction mixture was neutralized by adding saturated NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed successively with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc in hexanes) to afford 7a (270 mg, 83% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.50−7.32 (m, 4H), 5.34 (s, 2H), 5.14 (s, 2H), 3.14 (d, J = 16.8 Hz, 2H), 2.66 (s, 1H), 2.65 (s, 1H), 2.37 (d, J = 16.9 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −107.87 (d, J = 239.9 Hz, 2 × F), −116.83 (d, J = 240.3 Hz, 2 × F); 13C{1H}NMR (100 MHz, CDCl3) δ 140.8 (dd, J = 38.5, 17.6 Hz, 2 × C), 130.4 (2 × CH), 126.9 (2 × C), 125.6 (2 × CH), 122.4 (dd, J = 259.2, 247.7 Hz, 2 × CF2), 113.3 (2 × CH2), 87.9 (t, J = 22.5 Hz, 2 × C), 59.6 (C), 34.8 (CH2), 29.7 (CH2); IR (neat) νmax 3589br, 1654m, 1045s, 811s cm−1; MS m/z (%) relative intensity 326 (M+, 1), 305 (17), 288 (22), 163 (40), 77 (24); HRMS (ESI-TOF) calcd for C17H14F4NaO2 [M + Na]+ 349.0828, found, 349.0819.

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(to W.T.). We also would like to thank Asst. Prof. Dr. Saowanit Saithong, Department of Chemistry, Faculty of Science, Prince of Songkla University, Thailand, for valuable discussion on Xray crystallography.

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(1) (a) For reviews, see: Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671−719. (b) Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647− 3692. (c) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41−165. (d) Paquette, L. A.; Doherty, A. M. Recent Synthetic Developments in Polyquinane Chemistry; Springer: New York, 1987. (2) (a) Bohlmann, F; Jakupovic, J. Phytochemistry 1980, 19, 259−265. (b) González-Coloma, A.; Valencia, F.; Martín, N.; Hoffmann, J. J.; Hutter, L.; Marco, J. A.; Reina, M. J. Chem. Ecol. 2002, 28, 117−129. (c) Weyerstahl, P.; Marschall, H.; Seelmann, I.; Jakupovic, J. Eur. J. Org. Chem. 1998, 1998, 1205−1212. (3) (a) Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 1165− 1169. (b) Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 9, 5625−5628. (c) Cane, D. E.; Abell, C.; Tillman, A. M. Bioorg. Chem. 1984, 12, 312−328. (d) Seto, H.; Yonehara, H. J. J. Antibiot. 1980, 33, 92−93. (e) Srikrishna, A.; Nagaraju, G.; Sheth, V. M. Tetrahedron 2012, 68, 2650−2656. (f) Srikrishna, A.; Sheth, V. M.; Nagaraju, G. Synlett 2011, 2011, 2343−2346. (g) Srikrishna, A.; Gowri, V. Tetrahedron: Asymmetry 2011, 22, 1553−1559. (h) Pearson, A. J.; Kim, E. H.; Sun, H. Tetrahedron 2010, 66, 4943−4946. (i) Sethofer, S. G.; Staben, S. T.; Hung, O. Y.; Toste, F. D. Org. Lett. 2008, 10, 4315−4318. (j) De Boeck, B.; Harrington-Frost, N. M.; Pattenden, G. Org. Biomol. Chem. 2005, 3, 340−347. (k) Singh, V.; Lahiri, S. Tetrahedron Lett. 2003, 44, 4239−4242. (l) Iura, Y.; Sugahara, T.; Ogasawara, K. Org. Lett. 2001, 3, 291−293. (m) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 174− 181. (n) Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.; Shuda, P. J. Am. Chem. Soc. 1978, 100, 6536−6538. (4) (a) Enantiocontrolled Challenges and Biochemical Targets; Soloshonok, V. A., Ed.; John Wiley & Sons Ltd.: Chichester, 1999. (b) Selective Fluorination in Organic and Bioorganic Chemistry; Welch, J. T., Ed.; American Chemical Society: Washington, DC, 1990. (c) Schlosser, M. Angew. Chem., Int. Ed. 1998, 37, 1496−1513. (d) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17, 621−631. (e) Smart, B. E. J. Fluorine Chem. 2001, 109, 3−11. (f) Organofluorine Compounds, Chemistry and Applications; Hiyama, T., Ed.; Springer: New York, 2000. (g) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Blackwell: Oxford, 2009. (5) (a) Premchandran, R. H.; Ogletree, M. L.; Fried, J. J. Org. Chem. 1993, 58, 5724−5731. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (6) For selected recent references, see: (a) Xie, J.; Zhang, T.; Chen, F.; Mehrkens, N.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 2934−2938. (b) Zhang, Z.; Tang, X.-J.; Dolbier, W. R., Jr. Org. Lett. 2016, 18, 1048−1051. (c) Zhang, H.-R.; Chen, D.-Q.; Han, Y.-P.; Qiu, Y.-F.; Jin, D.-P.; Liu, X.-Y. Chem. Commun. 2016, 52, 11827−11830. (d) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem., Int. Ed. 2016, 55, 1872−1875. (e) Douglas, J. J.; Albright, H.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2015, 54, 14898−14902. (f) Lin, Q.-Y.; Xu, X.-H.; Qing, F.-L. Org. Biomol. Chem. 2015, 13, 8740−8749. (g) Zemtsov, A. A.; Kondratyev, N. S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 818−822. (h) Hashimoto, R.; Iida, T.; Aikawa, K.; Ito, S.; Mikami, K. Chem. - Eur. J. 2014, 20, 2750−2754. (7) (a) Thaharn, W.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Pakawatcha, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2015, 80, 816−827. (b) Thaharn, W.; Bootwicha, T.; Soorukram, D.; Kuhakarn, C.; Prabpai, S.; Kongsaeree, P.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2012, 77, 8465−8479. (c) Peewasan, K.; Kuhakarn, C.; Soorukram, D.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. J. Fluorine Chem. 2012, 135, 367−372. (d) Masusai, C.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Pakawatcha, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. J. Org.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02777. Copies of 1H, 13C, 19F NMR spectra for compounds 2− 7, NOESY of trans-4e, Z-5a, Z-5a′, Z-5b, 6aA, and 6bA (PDF) CIF data for single crystal X-ray analysis of 6cC (CCDC 1502302) (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (+)-66-2-2015158. Fax: (+)-66-2-6445126. ORCID

Chutima Kuhakarn: 0000-0003-4638-4356 Manat Pohmakotr: 0000-0002-6174-1211 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial supports from the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative, the Center of Excellence for Innovation in Chemistry (PERCH-CIC), and IFS-NRCT (Thailand) Collaboration on Enhancement of Scientific Capacity of Young Researchers in South East Asia 401

DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402

Article

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DOI: 10.1021/acs.joc.7b02777 J. Org. Chem. 2018, 83, 388−402